HK1047114B

HK1047114B - Streptogramin derivatives, production thereof and compositions containing the smae

Info

Publication number: HK1047114B
Application number: HK02108626.3A
Authority: HK
Inventors: E‧拜克奎; J-C‧巴里尔; G‧多夫林格; G‧杜图克-罗塞特; G‧潘特尔
Original assignee: 诺维赛尔公司
Priority date: 1999-07-27
Filing date: 2000-07-26
Publication date: 2010-10-08

Description

Streptogramin derivatives, preparation method and compositions containing them

The invention relates to streptogramin B derivatives of general formula:

they have particularly interesting antibacterial activity alone or in combination with streptogramin class a derivatives.

Among the known streptogramins, pristinamycin (RP 7293), a naturally derived antibacterial agent produced by Streptomyces pristinaespiralis, was first isolated in 1 month of 1955. To be provided withPristinamycin, which is sold under the trade name pristinamycin IA consists mainly of pristinamycin IA in combination with pristinamycin IIA.

The virginiamycin, another antibacterial agent of the streptogramin class, was isolated from Streptomyces virginiae, ATCC 13161 [ Antibiotics and chemotherapeutics ], 5, 632(1955)]. VirginiamycinMainly by the sum factor M₁Bound factor S.

Semisynthetic derivatives of streptogramins, represented by the following structures, have been described in patents or patent applications EP133097, EP248703, EP770132 and EP 772630:

in the formula:

ra is-CH wherein R' a is a heterocyclylthio-type group which may be substituted₂R ' a, or represents a group of the structure CHR ' a wherein R ' a is substituted alkylamino, alkoxy or alkylthio, or a substituted heterocyclylamino, heterocyclyloxy, heterocyclylthio group, Rb and Rc are hydrogen atoms and Rd is hydrogen atom or dimethylamino group, or Ra is hydrogen atom and Rb is hydrogen or methyl, and Rc and Rd are hydrogen or various substituents.

In combination with the streptogramin class A semi-synthetic composition, the above compounds exhibit a synergistic effect and can be used as antibacterial agents, either by injection only or by oral route only.

Group B synergystin derivatives with aminomethylene chains in position 5 delta are also described as synthetic intermediates in European patent EP 133098.

Compounds of general formula (I) have now been found and form the subject of the present invention, wherein:

r represents a group-NR₁R₂or-SR₃Wherein:

R₁and R₂Identical or different, represents a hydrogen atom, an alkyl (1 to 8 carbon atoms), optionally substituted by a hydroxyl group, an alkenyl (3 to 8 carbon atoms), a cycloalkyl (3 to 8 carbon atoms), an alkoxy (1 to 8 carbon atoms), a dialkylamino group, optionally substituted by [ one or more halogen atoms or alkyl, hydroxyalkyl, alkoxy or dialkylamino groups]Substituted phenylalkyl, saturated or unsaturated heterocyclylalkyl (3 to 8 mer) containing one or more heteroatoms selected from nitrogen, sulfur or oxygen, or dialkylaminoalkyl, or

R₁And R₂Together with the nitrogen atom to which they are bound, form a saturated, partially saturated or unsaturated monocyclic or polycyclic heterocycle having from 3 to 12 membered chains, optionally containing further heteroatoms selected from oxygen, sulphur or nitrogen, and optionally substituted by [ one or more hydroxyl groups, alkyl groups, phenyl groups optionally substituted by halogen atoms, phenylalkyl groups, phenylalkenyl groups (alkenyl groups containing from 2 to 4 carbon atoms), hydroxyalkyl groups, acyl groups, alkoxycarbonyl groups, or a heterocyclyl group or a heterocyclylcarbonyl group thereof whose heterocyclyl moiety is saturated or unsaturated (4 to 6 membered chains) and contains one or more heteroatoms selected from oxygen, sulphur or nitrogen]The substitution is carried out by the following steps,

R₃is alkyl (containing 1 to 8 carbon atoms) or cycloalkyl (containing 3 to 8 carbon atoms) substituted by-NR₁R₂Is substituted by radicals in which R₁And R₂Identical or different, they represent a hydrogen atom or an alkyl group, or form, together with the nitrogen atom to which they are bound, a heterocyclic ring as defined above, or R₃Represents a monocyclic or polycyclic heterocyclic group, or a saturated or unsaturated heterocyclylmethyl group, which contains 3 to 7 links and optionally further heteroatoms selected from oxygen, sulphur or nitrogen and optionally substituted by alkyl groups,residue representing an unsaturated ring unsubstituted in position 5 γ:or a residue of a saturated ring substituted by fluorine at position 5 γ:ra is methyl or ethyl, and

rb, Rc and Rd are defined as follows:

1) rb and Rc are hydrogen atoms and Rd is a hydrogen atom or a methylamino or dimethylamino group,

2) rb is a hydrogen atom, Rc is a hydrogen atom, a chlorine or bromine atom, or represents an alkenyl group (3-5C), and Rd is a group-NMeR 'in which R' represents an alkyl group, a hydroxy (2-4C) alkyl group, or a (2-8C) alkenyl group optionally substituted with a phenyl group, (3-6C) cycloalkylmethyl, benzyl, substituted with [ one or more halogen atoms or a hydroxy, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino or dialkylamino group]Substituted benzyl, heterocyclylmethyl or heterocyclylethyl wherein the heterocyclyl moiety is saturated or unsaturated and contains 5-6 links and 1 or 2 substituents selected from the group consisting of optionally substituted [ alkyl, (2-8C) alkenyl, (3-6 carbon) cycloalkyl, saturated or unsaturated (4-6 link) heterocycle, phenyl, as previously described for R₁Substituted phenyl, or benzyl, as defined]A substituted sulfur, oxygen or nitrogen heteroatom, or R' represents cyanomethyl or carboxymethyl, or represents-CORe or-CH₂CORe, wherein Re is-OR 'e, R' e is (1-6 carbon) alkyl, (2-6 carbon)) Alkenyl, benzyl, phenyl, tolyl or a heterocyclylmethyl group whose heterocyclyl part contains 5-6 chains and 1 or 2 heteroatoms selected from sulfur, oxygen or nitrogen, or Re is alkylamino, alkylmethylamino, heterocyclylamino or heterocyclylmethylamino, whose heterocyclyl part is saturated and contains 5-6 chains and 1 or 2 heteroatoms selected from sulfur, oxygen or nitrogen optionally substituted by alkyl, benzyl or alkoxycarbonyl,

3) rb is a hydrogen atom, Rd is-NHCH₃or-N (CH)₃)₂A group, and Rc is a chlorine or bromine atom, or represents (3-5C) alkenyl, [ if Rd is-N (CH)₃)₂]，

4) Rb and Rd are hydrogen atoms and Rc is a halogen atom, or alkylamino or dialkylamino, alkoxy, trifluoromethoxy, thioalkyl, (1-6C) alkyl or trihalomethyl,

5) rb and Rc are hydrogen atoms, Rd is a halogen atom, or ethylamino, diethylamino or methylethylamino, alkoxy or trifluoromethoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, (1-6C) alkyl, phenyl or trihalomethyl,

6) rb is a hydrogen atom, Rc is a halogen atom or an alkylamino or dialkylamino group, an alkoxy or trifluoromethoxy group, a thioalkyl group, (1-3C) alkyl group, and Rd is a halogen atom or an amino, alkylamino or dialkylamino group, an alkoxy or trifluoromethoxy group, a thioalkyl group, (1-6C) alkyl group or trihalomethyl group,

7) rc is a hydrogen atom, and Rb and Rd represent a methyl group,

the activity of particular interest is exhibited by both oral and parenteral administration.

Streptogramin derivatives of general formula (I) are in fact of particular interest because of their strong activity both in oral and parenteral administration, which brings to them undeniable advantages, in particular in the case of serious infections, in hospitalized environments by means of injection and then in ambulatory treatments by means of oral administration, which are easier to administer to the patient. Thus, the doctor does not have to change the patient's drug type between the end of the hospitalization and the end of the total treatment.

In the above general formula (I), the halogen atom may be selected from fluorine, chlorine, bromine or iodine; alkyl or acyl groups are straight or branched chain and, unless otherwise specified, contain 1 to 4 carbon atoms. The alkenyl radicals can also be straight-chain or branched and have 2 to 4 carbon atoms.

It is also understood that in the above definitions, when R is₁And R₂When they represent heterocyclylalkyl groups, they contain a heterocyclyl group or, together with the nitrogen atom, form a heterocycle, or when R is₃When represents a heterocyclic group or a heterocyclylmethyl group, the heterocyclic group may be saturated or unsaturated, and is optionally polycyclic (particularly bicyclic or tricyclic).

Without limitation, among the above heterocyclic groups, there may be specifically mentioned pyrrolyl, pyrrolidinyl, piperidinyl, pyrazinyl, imidazolyl, piperazinyl, pyridyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl, imidazolidinyl, imidazolyl, benzimidazolyl, furyl, thienyl, dioxolanyl.

According to the invention, a fluorinating agent is used to react with a type B synergistic rhzomycin derivative represented by the following general formula:

wherein R, Ra, Rb, Rc and Rd are as defined above, followed by isolation of the fluorinated derivative or the derivative unsaturated in the 5. gamma. -5. delta. position, a compound of the general formula (I) can be prepared.

Typically by a fluorinating agent such as a sulfur fluoride [ e.g. aminosulfur trifluoride: morpholino sulfur trifluoride, diethylamino sulfur trifluoride [ Tetrahedron (Tetrahedron), 44, 2875(1988)]Bis (2-methoxyethyl) aminosulfur trifluorideOr for example sulfur tetrafluoride [ journal of organic chemistry (j. org. chem.),40，3808(1975)]or a reagent such as hexafluoropropyldiethylamine (JP2039546) or N- (2-chloro-1, 1, 2-trifluoroethyl) diethylamine. The reaction is carried out in an organic solvent, such as, for example, a chlorinated solvent (in particular dichloromethane, dichloroethane, chloroform) at a temperature of-70 ℃ to 50 ℃, preferably in an inert medium (for example argon or nitrogen).

According to the usual methods of not altering the rest of the molecule, the fluorinated derivatives are isolated andrepresentsThe unsaturated derivative of (1). For example, by chromatography or crystallization.

According to an alternative of the invention, whereinRepresentsThe synergestin derivatives of the general formula (I) can be prepared by reacting a thionyl halide with a synergestin derivative of the class B of the general formula (II) in the presence of a nitrogen-containing base.

The reaction is carried out by treatment with thionyl chloride or thionyl bromide in the presence of a nitrogen-containing base such as, for example, triethylamine or pyridine, in a chlorine-containing solvent, in particular dichloromethane, 1, 2-dichloroethane, chloroform, or an ether such as, for example, tetrahydrofuran [ THF ], at a temperature of-50 ℃ to +80 ℃.

Group B synergestin derivatives of the general formula (II) can be prepared by reducing the ketone function at the 5. gamma. position in streptogramin derivatives of the general formula:

wherein R, Ra, Rb, Rc and Rd are as defined above.

The operation is carried out by treatment with a reducing agent such as a hydride, like an alkali metal borohydride (in particular sodium borohydride, potassium borohydride, triacetoxy-sodium borohydride, sodium cyanoborohydride) in an organic solvent such as an ether (for example THF) or an alcohol (for example methanol, ethanol) or a chlorinated solvent (for example dichloromethane) at a temperature of-70 ℃ to 60 ℃.

Streptogramin derivatives of general formula (III) can be prepared according to the methods described in European patents EP133097, EP133098, EP248703, EP432029, EP770132 or EP772630 or analogously thereto.

According to the invention, by HNR₁R₂Amines or HS-R₃The thiol can also be prepared by reacting it with a halogenated derivative of streptogramin of the formulaRepresentsA streptogramin derivative represented by the general formula (I):

wherein Ra, Rb, Rc and Rd are as defined above and Hal represents a halogen atom. Preferably, the symbol Hal represents a chlorine or bromine atom.

In organic solvents such as amides (e.g. dimethylformamide), or nitriles (e.g. acetonitrile) or chlorinated solvents (e.g. methanol)E.g. chloroform) at a temperature of 0-80 deg.C₁R₂NH amine reaction. Optionally, the operation is carried out in the presence of triethylamine. Make HS-R₃The thiol reaction is carried out, for example, in the presence of an alkali metal hydride (e.g. sodium hydride) in an organic solvent such as an amide (e.g. dimethylformamide) or a nitrile (e.g. acetonitrile), optionally in the presence of triethylamine, at a temperature of 0 to 80 ℃ in a basic medium.

Streptogramin derivatives of general formula (IV) can be prepared by treating 5 delta-methylenestreptogramins of general formula (IV) with a halogenating agent:

wherein Ra, Rb, Rc and Rd are as defined above.

Advantageously, the operation is carried out using conventional halogenating agents which do not alter the rest of the molecule. In particular, thionyl chloride or thionyl bromide is reacted in an organic solvent such as a chlorine-containing solvent (e.g. dichloromethane, dichloroethane, chloroform) or such as an ether (e.g. tetrahydrofuran), or operated at a temperature of-60 ℃ to 80 ℃ in a mixture of these solvents.

Streptogramin derivatives of general formula (V) can be prepared by reduction of the ketone function in position 5 gamma of the synechocin

Wherein Ra, Rb, Rc and Rd are as defined above.

The reaction is carried out using a derivative of the general formula (III) under similar conditions as those described for obtaining streptogramin derivatives of the general formula (II). Advantageously, it is operated at a temperature of-60 ℃ to 60 ℃ in an organic solvent such as an alcohol (e.g. methanol) or a chlorinated solvent (e.g. dichloromethane, dichloroethane, chloroform) or in an alcoholic solvent/chlorinated solvent mixture (e.g. methanol/dichloromethane) in the presence of anhydrous cerium chloride.

Streptogramin derivatives of general formula (VI) can be prepared according to the methods described in European patents EP133098 and EP432029 or analogously thereto or in the methods described in EP248703, EP770132, EP772630, EP 8216997 or WO99/43699 or in the examples below.

If necessary, the streptogramin derivative represented by general formula (I) or (IV) can be purified by physical means such as crystallization or chromatography.

Streptogramin derivatives of general formula (II) in which R, Ra, Rb, Rc and Rd are as defined above, are novel compounds. It is to be understood that these product compounds also fall within the scope of the present invention.

Certain streptogramin derivatives of general formula (I) can be converted into addition salt forms with acids by known methods. It is understood that these possible salts are also within the scope of the present invention.

Examples of pharmaceutically acceptable addition salts with acids include salts with inorganic acids (hydrochloride, hydrobromide, sulphate, nitrate, phosphate) or with organic acids (succinate, fumarate, tartrate, acetate, propionate, maleate, citrate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, isethionate, naphthalenesulphonate or camphorsulphonate, or salts with substituted derivatives of these compounds).

If necessary, the derivatives bearing a carboxyl substituent can be converted into metal salts or addition salts with a nitrogen-containing base according to methods known per se. These salts may be obtained by the interaction of a metal (e.g. alkali or alkaline earth metal) base, ammonia or amine with the compounds of the invention or by salt exchange reaction with an organic acid in a suitable solvent such as an alcohol, ether or water. After optional concentration of this solution, a salt precipitate is formed, which is then isolated by filtration, decantation or lyophilization. As examples of pharmaceutically acceptable salts, salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (magnesium, calcium), ammonium salts, salts with nitrogen-containing bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl- β -phenylethylamine, N' -diphenylmethylethylenediamine, diphenylenediamine, diphenylmethylamine, quinine, choline, arginine, lysine, leucine, diphenylmethylamine) can be cited.

The streptogramin derivative disclosed by the invention has antibacterial property and generates synergistic property with the antibacterial activity of the A-type streptogramin derivative. They are of particular interest because they are active alone or in combination with streptogramin group a components, in particular because they are active both by oral and parenteral administration and thus open up a mobile rotation treatment method without altering the properties of the drug product.

When they are combined with a component of streptogramins class a or with a derivative, their component or derivative is chosen in particular from the natural components: pristinamycin IIA, pristinamycin IIB, pristinamycin IIC, pristinamycin IH, pristinamycin IIE, pristinamycin IIF, pristinamycin IIG, or selected from semisynthetic derivatives as described in patents or patent applications US4590004 and EP191662, or selected from semisynthetic derivatives of the following general formula as described in international application WO 99/051265:

in the formula R₁Is a-NR 'R' group wherein R 'is a hydrogen atom or a methyl group, and R' is a hydrogen atom, an alkyl group, a cycloalkyl group, an allyl group, a propargyl group, a benzyl group, or a-O R 'group, and R' is a hydrogen atom, an alkyl group, a cycloalkyl group, an allyl group, a propargyl group orBenzyl, or-NR₃R₄Group, wherein R₃And R₄May represent methyl or together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-or 5-membered heterocyclic ring which may also contain other heteroatoms selected from nitrogen, oxygen or sulfur, R2 is a hydrogen atom or a methyl or ethyl group and bond … represents a single or double bond, and salts thereof. The class A derivatives which may be combined with them may also be selected from semi-synthetic derivatives of the following general formula:

in the formula R₁Represents a halogen atom or an azido or thiocyanato group, R₂Represents a hydrogen atom or a methyl or ethyl group, R₃Represents a hydrogen atom, or an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocycloaliphatic ester group which may be substituted, and the bond … represents a single bond (stereochemistry 27R) or a double bond, and salts thereof which may be present. In particular, compounds of the formula (. beta.), in which R₃The ester group may be selected from R₃' -CO-group, and R₃' is unsubstituted phenyl or phenylalkyl or phenyl or phenylalkyl in which the phenyl group is substituted [ substituted with one or more groups selected from the following classes: alkyl optionally bearing a NR 'R' group, where the radicals R 'and R' are identical or different and can be hydrogen or alkyl, which together with the nitrogen atom to which they are attached constitutes a saturated or unsaturated heterocyclyl group having 3 to 8 membered chains, optionally containing a further heteroatom selected from oxygen, sulphur or nitrogen, the heterocycle itself being possibly substituted by one or more groups (alkyl, hydroxyalkyl, alkoxyalkyl, alkoxy-carbonylalkyl, aryl, saturated or unsaturated heterocyclyl or heterocyclylalkyl having 3 to 8 membered chains or-CH)₂-CO-NR "R '") or R "and/or R '" can be hydroxyalkyl, phenyl, saturated or unsaturated heterocyclylalkyl having 3-8 membered chains, a-CO-NR "R '" group wherein NR "R '" is as previously defined, or alkyl or acyl substituted with NR "R '" as previously defined]Or is orR₃' may be chosen from phenyl or phenylalkyl, the phenyl of which may be substituted by one or more groups [ chosen from alkyl, which may be substituted by alkoxy or alkylthio, which alkoxy or alkylthio itself optionally bears carboxyl groups or groups NR "R '" as defined previously, or from acid groups which may be substituted by NR "R '" as defined previously]Substituted, or R₃' may be selected from alkyl or cycloalkyl optionally substituted by [ carboxy, carboxyalkyldisulfanyl or a group NR ' R ', -CH₂-NR "R '", -CO-NR "R '", or alkoxycarbonyl, alkoxy or alkyldisulfanyl optionally substituted by NR "R '" or-CO-NR "R '", wherein NR "R '" is as previously defined]Substituted, or R₃'may be selected from alkyl or acyl optionally substituted by [ itself optionally substituted by NR "R' ]]Substituted saturated or unsaturated heterocyclic groups having 3-8 membered chains.

It is to be understood that in the above formula (. beta.) R₁When halogen, it may be selected from chlorine, bromine, fluorine or iodine and combinations of the derivatives of the invention with class A streptogramins are also within the scope of the invention.

In vitro, streptogramin derivatives of the invention, in combination with streptogramin class a derivatives such as pristinamycin IIB, exhibit activity at concentrations ranging from 0.25 to 32 micrograms/ml with respect to staphylococcus aureus 209P; the streptogramin derivatives of the invention exhibit activity in combination with pristinamycin IIB at concentrations ranging from 0.5 to 32 micrograms/ml, with respect to Staphylococcus aureus Schiclia (methicillin resistant); in vivo, subcutaneously in a dose of 10-150 mg/kg (DC)₅₀) Orally administered in a dose of 24-150 mg/kg (DC)₅₀) [30/70 Combined form]The streptogramine derivative and the pristinamycin HB have synergistic action on the antibacterial activity of a mouse infected by adopting a staphylococcus aureus IP8203 test.

Finally, the compounds of the invention are of particular interest because of their low toxicity, neither being produced by oral doses of 150 mg/kg (2 doses).

Of these compounds, of particular interest are compounds of the general formula (I) wherein:

r represents a group-NR₁R₂or-SR₃Wherein:

R₁and R₂Identical or different, they represent a hydrogen atom, an alkyl (1-8 carbons) optionally substituted by a hydroxyl group, an alkenyl (3-8 carbons), a cycloalkyl (3-8 carbons), an alkoxy (1-8 carbons), a dialkylamino, optionally substituted by [ one or more halogen atoms or alkyl, hydroxyalkyl, alkoxy or dialkylamino groups]Substituted phenylalkyl, saturated or unsaturated heterocyclylalkyl (3-to 8-membered chain) or dialkylaminoalkyl containing 1 or more heteroatoms selected from nitrogen, sulfur or oxygen, or

R₁And R₂Together with the nitrogen atom to which they are attached, form a mono-or poly-heterocyclic ring which is a saturated, partially saturated or unsaturated 3-12 membered chain, optionally containing further heteroatoms selected from nitrogen, sulphur or oxygen, and which is optionally substituted by [ one or more hydroxyl, alkyl, phenyl optionally substituted by halogen atoms, phenylalkyl, hydroxyalkyl, acyl, alkoxycarbonyl, or a heterocyclic group or a heterocyclic carbonyl group in which the heterocyclic moiety is a saturated or unsaturated 4-6 membered chain and contains 1 or more heteroatoms selected from oxygen, sulphur or nitrogen]The substitution is carried out by the following steps,

R₃is made of-NR₁R₂Alkyl (containing 1-8 carbon atoms) substituted by a group, wherein R₁And R₂Identical or different, they represent alkyl or, together with the nitrogen atom to which they are attached, form a heterocycle as defined above, or R₃Represents a mono-or polycyclic heterocyclic radical or a saturated or unsaturated heterocyclylmethyl radical having 3 to 7 chain members and optionally further heteroatoms selected from oxygen, sulfur or nitrogen and optionally substituted by alkyl,

residue representing an unsaturated ring unsubstituted in position 5 γ:or a residue of a saturated ring substituted by fluorine at position 5 γ:

ra is ethyl, and

rb, Rc and Rd have the following meanings:

1) rb and Rc are hydrogen atoms and Rd is methylamino or dimethylamino,

2) rb is a hydrogen atom, Rc is a hydrogen atom or a chlorine atom, and Rd is a group-NMeR',

wherein R 'represents alkenyl (2-8C), heterocyclylmethyl, or represents-COOR' e, wherein

R' e is alkyl (1-6C), alkenyl (2-6C), phenyl or tolyl,

3) rb is a hydrogen atom and Rd is a group-NHCH₃or-N (CH)₃)₂And Rc is a chlorine atom.

Among these compounds, more directionally active are, inter alia:

-5 delta- (1-morpholino) methyl-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- [ N-methyl-N-2- (1, 3-dioxolanyl) methyl]Aminomethyl-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta-morpholinomethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta-morpholinomethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin I_E

-5 delta- [ bis- (2-methoxyethyl) aminomethyl]-5 delta, 5 gamma-dehydropristinamycin I_E。

The products listed in the examples are particularly preferred: the following streptogramin derivatives are also interesting products:

-4 epsilon-chloro-5 delta- (diethylaminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (diethylaminoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (diethylaminoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (3-diethylaminopropylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (3-diethylaminopropylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (3-diethylaminopropylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (3-diethylaminopropylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (dimethylaminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (dimethylaminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (dimethylaminoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (dimethylaminoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (1-methyl-2-imidazolylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (1-methyl-2-imidazolylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (1-methyl-2-imidazolylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (morpholinoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (morpholinoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (morpholinoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (morpholinoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (2-piperidinoethyl) thiomethyl-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (2-piperidinoethyl) thiomethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (2-piperidinoethyl) thiomethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (3-piperidinopropyl) thiomethyl-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (3-piperidinopropyl) thiomethyl-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (3-piperidinopropyl) thiomethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (3-piperidinopropyl) thiomethyl-4 zeta-methylAmino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (4-pyridylmethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (4-pyridylmethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (4-pyridylmethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (3-pyridylmethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (3-pyridylmethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (3-pyridylmethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (2-pyridylmethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (2-pyridylmethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (2-pyridylmethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (2-pyridylmethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 δ - { [2- (4-methylpiperazin-1-yl) ethyl]Thiomethyl } -5 delta, 5 gamma-dehydropristinamycin I_E

-4 ε -chloro-5 δ - { [2- (4-methylpiperazin-1-yl) ethyl]Thiomethyl } -5 delta, 5 gamma-dehydropristinamycin I_E

-5δ-{[2- (4-methylpiperazin-1-yl) ethyl]Thiomethyl } -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 ε -chloro-5 δ - { [2- (4-methylpiperazin-1-yl) ethyl]Thiomethyl } -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (butoxycarbonylaminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (butoxycarbonylaminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (butoxycarbonylaminomethyl thioethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (butoxycarbonylaminoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (aminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (aminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (aminomethyl thioethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (aminoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (pyrrolidinoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (pyrrolidinoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (pyrrolidinoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (pyrrolidinoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (diisopropylaminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (diisopropylaminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (diisopropylaminoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (diisopropylaminoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (N-ethyl-N-methylaminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (N-ethyl-N-methylaminoethylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- (N-ethyl-N-methylaminoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- (N-ethyl-N-methylaminoethylthiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- ((2R) -3-diethylaminopropyl-2-thiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- ((2R) -3-diethylaminopropyl-2-thiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- ((2R) -3-diethylaminopropyl-2-thiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- ((2R) -3-diethylaminopropyl-2-thiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- ((2S) -3-diethylaminopropyl-2-thiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- ((2S) -3-diethylaminopropyl-2-thiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_E

-5 delta- ((2S) -3-diethylaminopropyl-2-thiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

-4 epsilon-chloro-5 delta- ((2S) -3-diethylaminopropyl-2-thiomethyl) -4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E

Streptogramin derivatives of general formula (. alpha.) and their preparation are described in international application WO 99/05165, which is incorporated herein by reference.

Streptogramin derivatives of general formula (. beta.) described in International application WO 01/02427 are prepared by halogenating streptogramin derivatives of general formula:

in the formula R₂As defined above, a key…Represents a single bond (27R stereochemistry) or a double bond, wherein the hydroxyl group at position 14 is previously protected, followed by removal of the protecting group, if necessary, in order to obtain a compound wherein R is₃Derivatives (. beta.) of radicals other than hydrogen, by adding aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclylaliphatic ester groups (R) which may be substituted, according to the usual methods without altering the rest of the molecule₃) The above reaction was completed.

Halogenation, conversion to azides or conversion to thiocyanates can be carried out in the presence of aminosulfur trifluoride (diethylaminosulfur trifluoride, bis (2-methoxyethyl) aminosulfur trifluorideMorpholino sulphur trifluoride) or alternatively in the presence of sulphur tetrafluoride using reactants such as tetraalkylammonium (tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium), trialkylphenylmethylammonium or trialkylphenylammonium halides, azides or thiocyanates or using alkali metal halides, azides or thiocyanates optionally with addition of crown ethers. The reaction is carried out in a chlorinated organic solvent (dichloromethane, dichloroethane, chloroform) or in an ether (tetrahydrofuran) at-78 ℃ to 40 ℃, preferably under argon or nitrogen. The use of the configurational (16S) hydroxy derivative gives the configurational (16R) derivative. Protection and deprotection of the hydroxyl group at position 14 according to the usual methods without altering the rest of the molecule [ T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis (second edition), A.Wiley-Interscience Publication (1991)]。

To prepare a compound in which R is₃The product (. beta.) is an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocycloaliphatic ester which may be substituted, the esterification reaction being carried out using an acid or a reactive derivative of an acid (acid chloride, reactive ester, anhydride) in an organic solvent such as an amide (e.g.dimethylformamide or N-methyl-2-pyrrolidone), pyridine, a halogen-containing solvent (e.g.dichloromethane, dichloroethane or chloroform) or an ether (tetrahydrofuran, dioxane, dimethoxyethane) at a temperature of-40 ℃ to +80 ℃ in the presence or absence of a coupling agent (carbodiimide: dicyclohexylcarbodiimide) and a tertiary amine (trialkylamine: triethylamine, diisopropylethylamine, pyridine or a derivative) and optionally a catalyst such as 4-N-dimethylaminopyridine. The functions which may interfere with the reaction should be protected beforehand.

The following non-limiting examples illustrate the invention.

In the examples below, NMR spectra were studied in deuterochloroform using the nomenclature j.o. anteunis and co-workers in eur. biochem., 58, 259(1975), in particular:

unless otherwise stated, column chromatography was carried out using 0.063-0.02 mm silica gel at atmospheric pressure. Where explicitly indicated, flash chromatography using 0.04-0.063 mm silica gel or using C₈Or C₁₈The grafted silica gel was purified by High Performance Liquid Chromatography (HPLC). During the chromatographic determination, these fractions are analyzed by thin layer chromatography (CCM) on Merck 60F254 silica gel plates or by analytical HPLC. Fractions corresponding to the same Rf or the same retention time were pooled and concentrated to dryness under reduced pressure (30-45 ℃ C.; 2.7 kPa). The product thus obtained is analyzed by means of customary spectroscopic techniques (NMR, IR, MS) in order to be able to identify the expected product.

Example 1

Into a three-necked flask containing 500 ml of acetonitrile was charged 60 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I prepared under the following conditions and containing 33 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EThe crude mixture was then charged with 18 ml of morpholine. The mixture was heated under reflux for 5 hours and then concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa) to give 68.8 g of a solid which was dissolved in 200 ml of a saturated aqueous sodium bicarbonate solution and 200 ml of dichloromethane. The organic phase is decanted, dried over sodium sulfate, filtered and concentrated to dryness at 45 ℃ (2.7 kpa) to give 56.4 g of a yellow solid to which 300 ml of water and 140 ml of 1N hydrochloric acid are added. The aqueous phase obtained is extracted four times successively with 100 ml of ethyl acetate and 100 ml of dichloromethane, then 12 g of sodium bicarbonate are added, the pH is adjusted to 7-8 and extracted with 400 ml of dichloromethane. Organic compoundsAfter decantation, the phases are dried over sodium sulfate, filtered and then concentrated to dryness, giving 41.3 g of a yellow solid which is purified by chromatography on 200 g of silica gel (eluent: dichloromethane/methanol, 98/2 by volume). The solid thus obtained was crystallized from a methanol/water mixture (90/10 by volume). 5.05 g of the solid thus crystallized are crystallized a second time in 20 ml of methanol and after filtration and drying at 45 ℃ C (90 Pa) 4.5 g of 5 delta- (1-morpholino) methyl-5 delta, 5 gamma-dehydropristinamycin I are obtained_EIt is in the form of white powder and is melted at 180 deg.C.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.08 (very broad d, J ═ 16.5Hz, 1H: CH at the 5. beta. position₂1H) of (1); 1.27(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.57(mt, 1H: CH at position 3. gamma.)₂The other H); 1.66 and 1.72(2mts, 1H each: CH at position 2. beta₂) (ii) a 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.36(mf, 4H: NCH of morpholine)₂) (ii) a 2.47 (Widdd, J ═ 16.5 and 5Hz, 1H: CH in the 5. beta. position₂The other H); 2.85(s, 2H: CH)₂N)；2.94(s，6H：ArN(CH₃)₂) (ii) a 2.99(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.17(mt, 1H: CH at position 4. beta. -₂The other H); 3.17(s, 3H: NCH)₃) (ii) a 3.27(mt, 1H: CH at position 3. delta₂1H) of (1); 3.34 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂The other H); 3.70(mt, 4H: CH for morpholine)₂O); 4.57(dd, J ═ 8 and 5Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.82 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.89(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.11(d, J ═ 5Hz, 1H: CH at position 5 α); 5.27(dd, J ═ 9 and 6.5Hz, 1H: CH at position 4 α); 5.50-5.55(mt, 1H: CH at position 5 γ); 5.52(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.58(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.65(d, J ═ 9.5)Hz, 1H: CONH at 2 position); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.45 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.76(dd, J ═ 4 and 1Hz, 1H: H₆) (ii) a 8.47(d, J ═ 10Hz, 1H: CONH at position 1); 8.51(d, J ═ 8Hz, 1H: CONH at position 6); 11.69(s, 1H: OH).

5 delta-chloromethyl-5 delta, 5 gamma-dehydropristinamycin I was obtained in the following manner_E：

In a three-necked flask containing 100 ml of tetrahydrofuran, 5.9 g of (5. gamma.R, 5. gamma.S) -5. gamma. -hydroxy-5. gamma. -deoxy-5. delta. -methylenepristinamycin I was added_A(mixture of two isomers 50/50) and then 1 ml of thionyl chloride was added. The mixture was stirred overnight at 20 ℃ and then filtered. The filtrate was concentrated to dryness under reduced pressure at 45 ℃ and the resulting solid was dissolved with 100 ml of saturated aqueous sodium bicarbonate solution and 100 ml of dichloromethane. The organic phase was decanted, dried over sodium sulfate, filtered and concentrated to dryness. This gives 1.45 g of crude product, which is purified twice successively by chromatography on silica gel (eluent: dichloromethane/methanol, 98/2% by volume) to give 1.24 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 50 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I_EThe crude mixture was in the form of a yellow solid.

(5. gamma. R) and (5. gamma. S) -5. gamma. -hydroxy-5. gamma. -deoxy-5. delta. -methylenepristinamycin I are obtained in the following manner_A：

In a three-necked flask containing 100 ml of methanol and 50 ml of dichloromethane, 10 g of 5 delta-methylenepristinamycin I was added_AAnd 2.8 grams of anhydrous cerium chloride. The mixture was cooled to 0 ℃ and 0.47 g of sodium borohydride was added in small portions. The reaction mixture was stirred for 3 hours and then diluted with 100 ml of water. The pH of the aqueous phase was adjusted to 5 by adding acetic acid. The resulting mixture was then concentrated under reduced pressure. The pH was adjusted to 7 by adding saturated aqueous sodium bicarbonate solution to the residual aqueous phase and then extracting 2 times with 50 ml of dichloromethane each time. The organic phases are combined, dried over sodium sulfate, filtered and concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa) to give 7.6 g of a solid, 2g of which are successively charged with 450 g of C₈10 micron silica gel was purified 3 times by preparative High Performance Liquid Chromatography (HPLC) (eluent: water/acetonitrile 70/30 by volume, containing 0.1% trifluoroacetic acid). The fractions containing the desired 5. gamma.S isomer were combined, acetonitrile was removed at 40 ℃ under reduced pressure (2.7 kPa), and the pH of the aqueous phase was adjusted to 7 by addition of saturated aqueous sodium bicarbonate solution. The precipitate which appeared was filtered off and stirred in 20 ml of diethyl ether. The solid obtained is filtered and dried at 40 ℃ under reduced pressure (90 Pa) to yield 0.19 g of (5. gamma.S) -5. gamma. -hydroxy-5. gamma. -deoxy-5. delta. -methylenepristinamycin I_AIn the form of a white solid, melted at 166 ℃ and, in the same manner as for the fraction containing the (5. gamma.R) isomer, 0.18 g of (5. gamma.R) -5. gamma. -hydroxy-5. gamma. -deoxy-5. delta. -methylenepristinamycin I are obtained_AIn the form of a white solid, melted at 246 ℃.

(5 gamma S) -5 gamma-hydroxy-5 gamma-deoxy-5 delta-methylenepristinamycin I_A：

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.47(dt, J-15 and 5.5Hz, 1H: CH in the 5. beta. position₂1H) of (1); 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.10(mt, 1H: CH at position 3. beta₂1H) of (1); 1.25-1.40(mt, 1H: CH at position 3. gamma.)₂1H) of (1); 1.35(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.55-1.80 (mt: 3H corresponds to CH at the 3. gamma. position₂And corresponds to CH in the 2 beta position₂) (ii) a 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.13 (width d, J ═ 15Hz, 1H: in the 5. beta. position CH₂The other H); 2.90(dd, J ═ 13 and 5Hz, 1H in the 4. beta. position CH₂1H) of (1); 2.98(s, 6H: ArN (CH)₃)₂) (ii) a 3.15-3.35(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.20(s, 3H: NCH)₃) (ii) a 3.38(d, J ═ 14.5Hz, 1H in the 5 epsilon position CH₂1H) of (1); 3.52(mt, 1H: CH at position 3. delta₂The other H); 3.90(mt, 1H: CH at position 5 γ); 4.53(t, J ═ 7.5Hz, 1H: CH at position 3 α); 4.81(mt, 1H: CH at position 2 α); 4.88(d, J ═ 14.5Hz, 1H in the 5 epsilon position CH₂The other H); 4.91 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.03 (width d, J ═ 5.5Hz,1H: CH at position 5 α); 4.95 and 5.00(2 wide s, 1H: ═ CH each₂) (ii) a 5.17(dd, J ═ 11 and 5Hz, 1H: CH at position 4 α); 5.70(d, J ═ 8Hz, 1H: OH at the 5 γ position); 5.77(d, J ═ 8.5Hz, 1H: CH at position 6 α); 5.92 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.54(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.35 (mt: 5H corresponding to aromatic H at position 6 α); 7.38(AB limit, 2H: H)₄And H₅)；7.78(mt，1H：H₆) (ii) a 8.44(d, J ═ 10Hz, 1H: CONH at position 1); 9.10(d, J ═ 8.5 Hz: CONH at position 6); 11.66(s, 1H: OH).

(5 gamma R) -5 gamma-hydroxy-5 gamma-deoxy-5 delta-methyleneprimycin I_A：

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.17 (deduplicated t, J ═ 12 and 5.5Hz, 1H: CH in the 5. beta. position₂1H) of (1); 0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.18(mt, 1H: CH at position 3. beta₂1H) of (1); 1.28(mt, 1H: CH at position 3. gamma.)₂) 1H) of (1); 1.34(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.57(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.80 (mt: corresponding to CH at position 2. beta.)₂2H) of (1); 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.39(dd, J. 12 and 6Hz, 1H in the 5. beta. CH position₂The other H); 2.90-3.00(mt, 1H: CH at position 4. beta₂1H) of (1); 2.96(s, 6H: ArN (CH)₃)₂) (ii) a 3.06(d, J ═ 14Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.17(s, 3H: NCH)₃) (ii) a 3.20(dd, J ═ 13.5 and 10Hz, 1H: CH in the 4. beta. position₂The other H); 3.28 and 3.49(2mts, 1H each: CH at position 3. delta₂) (ii) a 4.55(dd, J ═ 8 and 7Hz, 1H: CH at position 3 α); 4.70(mt, 1H: CH at position 5 γ); 4.79(mt, 1H: CH at position 2 α); 4.87 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.00-5.15(mt, 3H: CH at position 5. alpha. to CH at position 5. epsilon.)₂Another H and ═ CH₂1H) of (1); 5.17 (Width s, 1H: ═ CH)₂The other H); 5.21(dd, J ═ 10 and 6.5Hz, 1H: CH at position 4 α); 5.65(d, J ═ 8.5Hz, 1H: CH at position 6 α); 590(mt, 1H: CH at position 1 β); 6.56(d, J ═ 10Hz, 1H: CONH at position 2); 6.59(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 6.91(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.45 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.76 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.41(d, J ═ 10Hz, 1H: CONH at position 1); 8.61(d, J ═ 8.5 Hz: CONH at position 6); 11.66(s, 1H: OH).

Example 2

In a three-necked flask with 350 ml of dichloromethane, 21.2 g of 5 δ - (1-morpholino) methyl-5 γ -deoxy-5 γ -hydroxy-pristinamycin IA (5 δ and 5 γ isomer mixture) were added. To the mixture cooled to 0 ℃ was added 14.3 ml of diethylaminosulfur trifluoride. After the addition was complete, the reaction mixture was stirred at 20 ℃ for 18 hours and then poured into 400 ml of water. The aqueous phase was adjusted to pH7 by the addition of saturated aqueous sodium bicarbonate. The organic phase is decanted, washed with 200 ml of water, dried over sodium sulfate, filtered, then concentrated to dryness and then dissolved in 200 ml of ethyl acetate. Insoluble material was filtered off and the filtrate was concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). 10.6 g of crude product are obtained, which is purified by chromatography on 250 g of silica gel (eluent: dichloromethane/methanol, 97.5/2.5 by volume) to give 4.5 g of solid, which is used successively in two portions (1.5 g and 3.0 g) with 450 g of C₈10 μm silica gel was purified 2 times by preparative HPLC (eluent: water-acetonitrile, 70/30 by volume, containing 0.1% trifluoroacetic acid). Fractions 4-8 and 3-5 were combined, acetonitrile was removed at 40 ℃ under reduced pressure (2.7 kPa), and the pH of the residual aqueous phase was adjusted to 7 by adding saturated aqueous sodium bicarbonate solution. The precipitate which appeared was filtered off, washed with 20 ml of water and 20 ml of isopropyl ether and then dried at 40 ℃ under reduced pressure (90 Pa) to give 0.35 g (1.7%) of 5 delta- (1-morpholino) methyl-5 delta, 5 gamma-dehydropristinamycin I_E。

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.08: (very broad d, J ═ 16.5Hz, 1H: CH in the 5. beta. position₂1H) of (1); 1.27(mt,2H: at the 3 beta position CH₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.57(mt, 1H: CH at position 3. gamma.)₂The other H); 1.66 and 1.72(2mts, 1H each: CH at position 2. beta₂) (ii) a 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.36(mf, 4H: NCH of morpholine)₂) (ii) a 2.47 (Widdd, J ═ 16.5 and 5Hz, 1H: CH in the 5. beta. position₂The other H); 2.85(s, 2H: CH)₂N)；2.94(s，6H：ArN(CH₃)₂) (ii) a 2.99(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.17(mt, 1H: CH at position 4. beta. -₂The other H); 3.17(s, 3H: NCH)₃) (ii) a 3.27(mt, 1H: CH at position 3. delta₂1H) of (1); 3.34 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂The other H); 3.70(mt, 4H: CH for morpholine)₂O); 4.57(dd, J ═ 8 and 5Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.82 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.89(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.11(d, J ═ 5Hz, 1H: CH at position 5 α); 5.27(dd, J ═ 9 and 6.5Hz, 1H: CH at position 4 α); 5.50-5.55(mt, 1H: CH at position 5 γ); 5.52(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.58(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.65(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.45 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.76(dd, J ═ 4 and 1Hz, 1H: H₆) (ii) a 8.47(d, J ═ 10Hz, 1H: CONH at position 1); 8.51(d, J ═ 8Hz, 1H: CONH at position 6); 11.69(s, 1H: OH).

5 delta- (1-morpholino) methyl-5 gamma-deoxy-5 gamma-hydroxy-pristinamycin I is obtained in the following manner_A(5 δ and 5 γ isomer mixture):

11 g of 5 delta- (1-morpholino) methyl pristinamycin I are placed in a flask_A(mixture of 5. delta. S and 5. delta. R isomers 90/10) in 120 ml of 1, 2-dimethoxyethane, followed by the addition of 0.42 g of sodium borohydride. At 20 deg.CAfter stirring overnight, 60 ml of isopropanol and 0.42 g of supplemental sodium borohydride were added, followed by stirring for an additional 5 hours. The reaction mixture was concentrated to dryness under reduced pressure, and diluted with 40 ml of methylene chloride and 400 ml of distilled water to which 1N hydrochloric acid was added so as to adjust the pH to 3. The aqueous phase is decanted and washed 3 times with 30 ml of dichloromethane each time. The combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure to give 10.84 g of a solid which is purified by flash chromatography (gradient elution: CH by volume)₂Cl₂: MeOH 98/2 to 96/4) to give 1.6 g of product, which was stirred in 50 ml of diethyl ether. After filtration and drying at 50 ℃ under reduced pressure (90 Pa), 1.14 g of 5 delta- (1-morpholino) methyl-5 gamma-deoxy-5 gamma-hydroxy-pristinamycin IA (5 delta 90/10 isomer mixture, 5 gamma 50/50 isomer mixture) are obtained as a white solid which melts (less pure) at 180 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃D, in ppm) 0.42(dt, J ═ 15 and 5Hz, 1H: at position 5b CH₂1H) of (1); 0.89(t, J ═ 7.5Hz, 3H: CH at position 2g₃) (ii) a 1.02(mt, 1H: CH at position 3b₂1H) of (1); 1.15-1.35(mt, 1H: CH at position 3 g)₂1H) of (1); 1.33(d, J ═ 7Hz, 3H: in the 1g position CH₃) (ii) a 1.45-1.80 (mt: corresponding to CH at position 5 d-CH at position 3g₂And CH at the 2b position₂4H) of (1); 1.97(mt, 1H: CH at position 3b₂The other H); 2.13 (width d, J ═ 15Hz, 1H: CH at position 5b₂The other H); 2.27(dd, J ═ 12 and 6Hz, 1H: CH)₂1H for N); 2.30-2.50(mt, 4H: CH)₂Another H-2 morpholine NCH of N₂And CH at position 5e₂1H) of (1); 2.45-2.60(mt, 2H: 2 morpholine NCH)₂The other H); 2.80-3.00(mt, 1H: CH at position 4 b)₂1H) of (1); 2.96(s, 6H: ArN (CH)₃)₂) (ii) a 3.10-3.30(mt, 2H: CH at position 3 d)₂1H and CH at position 4b₂The other H); 3.21(s, 3H: NCH)₃) (ii) a 3.40-3.60(mt, 2H: CH at position 3 d)₂And CH at the 5g position); 3.76(mt, 4H: 2OCH of morpholine₂) (ii) a 4.46 (width d, J ═ 13Hz, 1H: CH at position 5e₂To another one ofH); 4.50(t, J ═ 8Hz, 1H: CH at position 3 a); 4.81(mt, 1H: CH at position 2 a); 4.90(dd, J ═ 10 and 1Hz, 1H: CH at position 1 a); 5.04 (width d, J ═ 5Hz, 1H: CH at position 5 a); 5.25-5.35(mt, 2H: OH at position 5g and CH at position 4 a); 5.80(d, J ═ 9Hz, 1H: CH at position 6 a); 5.98(dq, J ═ 7 and 1Hz, 1H: CH at position 1 b); 6.56(d, J ═ 10Hz, 1H: CONH at position 2); 6.59(d, J ═ 8.5Hz, 2H: aromatic H at the 4e position); 6.99(d, J ═ 8.5Hz, 2H: aromatic H at the 4d position); 7.15-7.35 (mt: aromatic 5H at position 6); 7.40(AB limit, 2H: H)₄And H₅) (ii) a 7.86(dd, J ═ 4 and 2Hz, 1H: H₆) (ii) a 8.48(d, J ═ 10Hz, 1H: CONH at position 1); 9.15(d, J ═ 9Hz, 1H: CONH at position 6); 11.66(s, 1H: OH).

5 delta- (1-morpholino) methyl pristinamycin I can be obtained in the following manner_A(mixture of 5 δ R and 5 δ S isomers (90/10)): in a round bottom flask kept under nitrogen atmosphere, a solution of 4 g of 5 δ -methylene pristinamycin IA in a mixture of 10 ml of dichloromethane and 50 ml of methanol was added, followed by 1.8 ml of morpholine. The mixture was stirred for a further 4 days, concentrated to dryness at 30 ℃ under reduced pressure and then stirred in 40 ml of diethyl ether. The supernatant was decanted off and the resulting solid was stirred in 40 ml of diethyl ether, filtered and then dried under reduced pressure (2.7 kPa) to give 3.54 g of 5 delta- (1-morpholino) methyl pristinamycin I_A(mixture of 5 δ R and 5 δ S isomers (90/10)) as a slightly white solid containing one mole of morpholine per mole of product. This solid can be used as such.

¹H N.M.R. Spectrum (400MHz, CDCl)₃D, in ppm) 0.68(dd, J15 and 5.5Hz, 1H: at position 5b CH₂1H) of (1); 0.91(t, J ═ 7.5Hz, 3H: CH at position 2g₃) (ii) a 1.12(mt, 1H: CH at position 3b₂1H) of (1); 1.15-1.35(mt, 1H: CH at position 3 g)₂1H) of (1); 1.32(d, J ═ 7Hz, 3H: in the 1g position CH₃) (ii) a 1.45-1.70(mt, 2H: CH at position 3 g)₂And CH at the 2b position₂1H) of (1); 1.75(mt, 1H: CH at position 2b₂The other H); 2.01(mt, 1H: CH at position 3b₂The other H); 2.20-2.45(mt, 5H: CH at position 5 d-at position 5bCH₂Another H-NCH of₂1H and morpholine 2NCH₂1H) of (1); 2.40-2.60(mt, 3H: CH at position 5 e)₂2NCH of (1H) and morpholine₂The other H); 2.79(dd, J ═ 12.5 and 4Hz, 1H: NCH₂The other H); 2.80-2.95(mt, 1H: CH at position 4b₂1H) of (1); 2.92(s, 6H: ArN (CH)₃)₂) (ii) a 3.15-3.25(mt, 1H: CH at position 3 d)₂1H) of (1); 3.25(s, 3H: NCH)₃) (ii) a 3.32(t, J-12 Hz, 1H: CH at position 4b₂The other H); 3.53(mt, 1H: in 3d position CH₂The other H); 3.72 (mt: 2CH corresponding to morpholine₂4H for O); 4.54(t, J ═ 8Hz, 1H: CH at position 3 a); 4.82(mt, 1H: CH at position 2 a); 4.87(dd, J ═ 10 and 1Hz, 1H: CH at position 1 a); 4.95 (Widdd, J ═ 13 and 6Hz, 1H: CH at position 5e₂The other H); 5.25(dd, J ═ 12 and 4Hz, 1H: CH at position 4 a); 5.29 (width d, J ═ 5.5Hz, 1H: CH at position 5 a); 5.85(d, J ═ 9.5Hz, 1H: CH at position 6 a); 5.89(mt, 1H: CH at position 1 b); 6.49(d, J ═ 10Hz, 1H: CONH at position 2); 6.61(d, J ═ 8Hz, 2H: aromatic H at the 4e position); 7.04(d, J ═ 8Hz, 2H: aromatic H at the 4d position); 7.10-7.35 (mt: 5H is aromatic at the 6 position); 7.44(AB bound, 2H: H)₄And H₅) (ii) a 7.83(dd, J ═ 4 and 1.5Hz, 1H: H₆) (ii) a 8.40(d, J ═ 10Hz, 1H: CONH at position 1); 8.75(d, J ═ 9.5Hz, 1H: CONH at position 6).

Example 3

The fractions 10 to 14 and 7 to 13 obtained by chromatography in example 2 were treated under the same conditions as in example 2 to obtain 0.37 g (1.8%) (5. delta. R, 5. gamma. S) -5. gamma. -deoxy-5. gamma. -fluoro-5. delta. - (1-morpholino) methyl pristinamycin I_AIn a white solid state, melts at 162-164 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.29(mt, 1H: CH at position 5. beta₂1H) of (1); 0.90(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.10(mt, 1H: CH at position 3. beta₂1H) of (1); 1.26(mt, 1H: CH at position 3. gamma.)₂1H) of (1); 1.33(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃)；1.55(mt, 1H: at the 3 gamma position CH₂The other H); 1.65(mt, 1H: CH at position 2. beta₂1H) of (1); 1.75(mt, 2H: CH at position 5. delta. and CH at position 2. beta.)₂The other H); 1.98(mt, 1H: CH at position 3. beta₂The other H); 2.05(t, J ═ 13.5Hz, 1H in the 5 epsilon position CH₂1H) of (1); 2.22 (Width t, J ═ 11.5Hz, 1H: CH)₂1H for N); 2.30-2.45(mt, 3H: CH at position 5. beta₂And morpholine 2CH₂2H for N); 2.55-2.65(mt, 3H: CH)₂Another H of N and morpholine 2CH₂The other two H's of N); 2.90-3.00(mt, 1H: CH at position 4. beta₂1H) of (1); 2.95(s, 6H: ArN (CH)₃)₂) (ii) a 3.15-3.30(mt, 2H: CH at position 3. delta₂1H and CH at the 4 beta position₂The other H); 3.18(s, 3H: NCH)₃) (ii) a 3.49(mt, 1H: CH at position 3. delta₂The other H); 3.77(mt, 4H: 2CH for morpholine)₂O); 4.53(t, J ═ 7.5Hz, 1H: CH at position 3 α); 4.65-4.90(mt, 2H: CH at position 5. gamma. and CH at position 5. epsilon.)₂The other H); 4.79(mt, 1H: CH at position 2 α); 4.88 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.09(mt, 1H: CH at position 5 α); 5.27(dd, J ═ 10 and 6Hz, 1H: CH at position 4 α); 5.65(d, J ═ 8Hz, 1H: CH at position 6 α); 5.89 (width q, 1H: CH at position 1. beta.); 6.55(d, J ═ 10Hz, 1H: CONH at position 2); 6.64(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.97(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.15-7.45 (mt: 5H corresponding to aromatic H at 6 α); 7.36(AB limit, 2H: H)₄And H₅) (ii) a 7.84(dd, J ═ 4 and 2Hz, 1H: H₆) (ii) a 8.42(d, J ═ 10Hz, 1H: CONH at position 1); 8.70(d, J ═ 8Hz, 1H: CONH at position 6); 11.66(s, 1H: OH).

Example 4

The procedure is as in example 1, but using 100 ml of acetonitrile, 5g of 5. delta. chloromethyl-5. delta. 5. gamma. -dehydropristinamycin I containing 50 mol% of 5. delta. -chloromethyl-5. delta_EThe crude mixture of (1.2 ml) of di-n-propylamine was used as the starting material. The reaction mixture was heated under reflux for 2 hours and then concentrated under reduced pressure to give 5.2 g of a solid which was purified by chromatography on silica gel (eluent: dichloromethane/methanol, 98/2 by volume). Thus obtaining1.35 g of solid, which was successively charged with 450 g of C₈10 micron silica gel was purified twice (0.5 g and 0.75 g) by preparative HPLC (eluent: water-acetonitrile, 60/40 by volume, containing 0.1% trifluoroacetic acid). For each batch, the fractions containing the desired product were combined and acetonitrile was removed under reduced pressure (2.7 kPa) at 40 ℃. The pH of the residual aqueous phase was adjusted to 7-8 by addition of saturated aqueous sodium bicarbonate solution and then extracted with 400 ml dichloromethane. After decantation of the organic phase, it is dried over sodium sulfate, filtered and then concentrated to dryness under reduced pressure. The 2 solids thus obtained were each crystallized from 100 ml of cyclohexane to give 0.3 g and 0.28 g of solid, respectively. The two batches were combined, dissolved in 10 ml dichloromethane and 3 ml ethanol, concentrated to dryness and then stirred in 20 ml isopropyl ether. The precipitate was filtered off and dried at 40 ℃ under reduced pressure (90 Pa) to give 0.35 g of 5. delta. -dipropylaminomethyl-5. delta., 5. gamma. -dehydropristinamycin I_EIs white crystal and melts at 200-202 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.85-0.95(mt, 9H: CH at 2. gamma. position₃And 2CH of dipropylamine₃) (ii) a 1.10 (very broad d, J ═ 16Hz, 1H: CH in the 5. beta. position₂1H) of (1); 1.25(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.32(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.45(mt, 4H: 2 dipropylamine centres CH₂) (ii) a 1.50-1.65 (mt: corresponding to CH at the 3. gamma. position₂1H of another H); 1.66 and 1.74(2mts, 1H each: CH at position 2. beta₂) (ii) a 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.30(mt, 4H: 2NCH of dipropylamine₂) (ii) a 2.47 (Widdd, J-16 and 4.5Hz, 1H: CH in position 5. beta₂The other H); 2.80-3.05(mt, 3H: CH at position 4. beta₂1H and CH₂N)；2.94(s，6H：ArN(CH₃)₂) (ii) a 3.15-3.30(mt, 2H: CH at position 3. delta₂1H and CH at the 4 beta position₂The other H); 3.17(s, 3H: NCH)₃) (ii) a 3.33 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.46(mt, 1H: CH at position 3. delta₂The other H); 4.57(dd, J ═ 8 and 6Hz, 1H: CH at position 3 α); 4.78(mt,1H: CH at the 2 α position); 4.84 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.89 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.13 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.24(dd, J ═ 10 and 8Hz, 1H: CH at position 4 α); 5.47(mt, 1H: CH at position 5 γ); 5.56(d, J ═ 8Hz, 1H: CH at position 6 α); 5.88 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.57(d, J ═ 10Hz, 1H: CONH at position 2); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.70 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.42(d, J ═ 8Hz, 1H: CONH at position 6); 11.66(s, 1H: OH).

Example 5

The procedure is as in example 1, but using 70 ml of acetonitrile, 5g of 5. delta. chloromethyl-5. delta. 5. gamma. -dehydropristinamycin I containing 50 mol% of 5. delta. -chloromethyl-5. delta_EAnd 0.7 ml of piperidine as starting materials. The reaction mixture is heated at reflux for 45 minutes and then concentrated under reduced pressure to give 5.7 g of a solid which is purified by chromatography on silica gel (eluent: dichloromethane/methanol gradient 99/1 to 95/5 by volume). The fractions containing the desired product were combined and then concentrated to dryness. The solid was stirred in 100 ml of cyclohexane, filtered and dried under reduced pressure to give 0.58 g of a solid which crystallized in 50 ml of cyclohexane and then 40 ml of the same solvent. The solid thus obtained was filtered and dried at 40 ℃ under reduced pressure (90 Pa) to give 0.37 g of 5. delta. -piperidinomethyl-5. delta., 5. gamma. -dehydropristinamycin I_EIs in a white cotton-wool solid state and is melted at the temperature of 200-202 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.08 (width d, J ═ 16.5Hz, 1H: CH in position 5. beta.)₂1H) of (1); 1.15-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.35-1.75(mt, corresponding to CH at the 3. gamma. position₂Of another H-piperidine CH₂CH₂CH₂And CH in the 2 beta position₂8H of 1H of (1); 1.75(mt, 1H: CH at position 2. beta₂The other H); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.29(mf, 4H: NCH of piperidine)₂) (ii) a 2.48 (Widdd, J ═ 16.5 and 5Hz, 1H: CH in the 5. beta. position₂The other H); 2.81(s, 2H: CH)₂N)；2.94(s，6H：ArN(CH₃)₂) (ii) a 2.98(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.10-3.30(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.18(s, 3H: NCH)₃) (ii) a 3.36 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.46(mt, 1H: CH at position 3. delta₂The other H); 4.59(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.83 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.88 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.12(d, J ═ 5Hz, 1H: CH at position 5 α); 5.23(dd, J ═ 9 and 6.5Hz, 1H: CH at the 4 α position); 5.47(mt, 1H: CH at position 5 γ); 5.53(d, J ═ 8Hz, 1H: CH at position 6 α); 5.89 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.58(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.93(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.72 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.35-8.45(mt, 2H: CONH at 1 position and CONH at 6 position); 11.68(s, 1H: OH).

Example 6

The procedure is as in example 1, but using 50 ml of acetonitrile, 5.3 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 25 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin, prepared under the same conditions as described in example 1_EAnd 0.4 ml pyrrolidine as starting materials. The reaction mixture was heated under reflux for 45 minutes and then concentrated at 45 ℃ under reduced pressure (2.7 kPa) to obtain a solid which was stirred in 100 ml of cyclohexane and 100 ml of diethyl ether. The resulting precipitate was filtered, washed with 25 ml of diethyl ether and then with 450 g of C₈Purification of 10 μm silica gel by preparative HPLC(eluent: water-acetonitrile containing 0.1% trifluoroacetic acid, 65/35 by volume). The fractions containing the desired product were combined and acetonitrile was removed at 40 ℃ under reduced pressure (2.7 kPa). The residual aqueous solution was adjusted to pH7-8 by addition of saturated aqueous sodium bicarbonate solution and then extracted with 100 ml dichloromethane. The organic phase is dried over sodium sulfate, filtered and then concentrated to dryness under reduced pressure, and the solid obtained is stirred in 20 ml of isopropyl ether, filtered and then dried at 45 ℃ under reduced pressure (90 Pa). 0.49 g of 5 delta- (1-pyrrolidinylmethyl) -5 delta, 5 gamma-dehydropristinamycin I are obtained_EIs white crystal and melts at 164-166 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.11 (width d, J ═ 17Hz, 1H: in the 5. beta. position CH₂1H) of (1); 1.24(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.54(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.85 (mt: corresponding to CH at position 2. beta.)₂And pyrrolidine CH₂6H) of (1); 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.42(mt, 4H: NCH of pyrrolidine₂) (ii) a 2.48 (Widdd, J ═ 17 and 5.5Hz, 1H in the 5. beta. position CH₂The other H); 2.90-3.05(mt, 1H: CH at position 4. beta₂1H) of (1); 2.93(s, 6H: ArN (CH)₃)₂)；2.98(s，2H：CH₂N); 3.15-3.30(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.16(s, 3H: NCH)₃) (ii) a 3.38 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.45(mt, 1H: CH at position 3. delta₂The other H); 4.58(dd, J ═ 8.5 and 5.5Hz, 1H: CH at position 3 α); 4.77(mt, 1H: CH at position 2 α); 4.80-4.95(mt, 2H: CH at position 5. epsilon.)₂And CH at the 1 alpha position); 5.10(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.24(dd, J ═ 10 and 7Hz, 1H: CH at position 4 α); 5.50(mt, 1H: CH at position 5 γ); 5.54(d, J ═ 8Hz, 1H: CH at position 6 α); 5.86 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.57(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.59(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position);6.91(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.71 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.43(d, J ═ 8Hz, 1H: CONH at position 6); 11.66 (width s, 1H: OH).

Example 7

The procedure is as in example 1, but using 100 ml of acetonitrile, 10 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 50 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EAnd 3.7 ml of 2, 6-dimethylmorpholine (mixture of cis and trans isomers) as starting materials. The reaction mixture was heated under reflux for 1 hour and then concentrated under reduced pressure (2.7 kPa) at 45 ℃ to give 13.4 g of a solid, which was dissolved with 100 ml of a saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted 2 times with 100 ml of dichloromethane each time. The organic phases are combined, dried over sodium sulfate, filtered and then concentrated to dryness, giving 12.1 g of a yellow solid which is successively purified 2 times by chromatography on silica gel (eluent: dichloromethane/methanol, 98/2 by volume), the solid obtained being stirred in 30 ml of diethyl ether, filtered and then dried at 40 ℃ under reduced pressure (90). This gives 0.5 g of 5 delta- (2, 6-dimethyl-codinylmethyl) -5 delta, 5 gamma-dehydropristinamycin I_E(mixture of isomers) as a cream solid, melted to 165 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): we observed a mixture of two diastereomers, morpholine cis and trans: 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.02 (width d, J ═ 17Hz, 1H: in the 5. beta. CH position₂1H) of (1); 1.15 and 1.20(2d, J ═ 7Hz, CH for each 3H: 2, 6-dimethylmorpholine₃) (ii) a 1.20-1.45(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.55(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.75 (mt: corresponding to CH at position 2. beta. -₂3H of 1H and-NCH corresponding to 2, 6-dimethylmorpholine₂2H) of (1); 1.74(mt, 1H: CH at position 2. beta₂In addition toOne H); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.45 (Widdd, J ═ 17 and 5.5Hz, 1H: CH in the 5. beta. position₂The other H); 2.68 (NCH of mt, 2H: 2, 6-dimethylmorpholine)₂2 additional H) of (a); 2.77 and 2.86(2d, J ═ 13Hz, 1H: CH each₂N); 2.90-3.00(mt, 1H: CH at position 4. beta₂1H) of (1); 2.95(s, 6H: ArN (CH)₃)₂) (ii) a 3.15-3.30(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.17(s, 3H: NCH)₃) (ii) a 3.32 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂The other H); 3.60 and 3.70(2mts, CHO per 1H: morpholine); 4.58(dd, J ═ 8.5 and 5.5Hz, 1H: CH at position 3 α); 4.77(mt, 1H: CH at position 2 α); 4.84 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.88(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.10(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.21(dd, J ═ 9 and 6.5Hz, 1H: CH at position 4 α); 5.48(mt, 1H: CH at position 5. gamma.); 5.52(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.56(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.58(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.90(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.72(dd, J ═ 4 and 1Hz, 1H: H₆) (ii) a 8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.48(d, J ═ 8Hz, 1H: CONH at position 6); 11.66(s, 1H: OH).

Example 8

The procedure is as in example 1, but using 100 ml of acetonitrile, 10 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 40 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EAnd 3.8 g of 4- (4-fluorophenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride and 2.75 ml of triethylamine as starting materials. The reaction mixture is heated under reflux for 1 hour and then concentrated at 45 ℃ under reduced pressure (2.7 kPa) to give 14.3 g of a chestnut-colored solid which is obtained with 450 g of C₈10 micron silica gel was purified 2 times by preparative HPLC chromatography (eluent: water-acetonitrile, 65/35% by volume, containing 0.1%Trifluoroacetic acid). The fractions containing the desired product were combined and acetonitrile was removed at 40 ℃ under reduced pressure (2.7 kPa). The pH of the residual aqueous phase was adjusted to 7-8 by adding saturated aqueous sodium bicarbonate solution. The precipitate obtained is filtered, washed with 50 ml of isopropyl ether and dried at 40 ℃ C (90 Pa) to give 0.63 g of 5 delta- [4- (4-fluorophenyl) -1, 2, 3, 6-tetrahydropyridoylmethyl]-5 delta, 5 gamma-dehydropristinamycin I_EIn the form of a yellow solid, melted at 172 ℃.

¹H N.M.R. Spectrum (600MHz, CDCl)₃): 0.90(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.13 (width d, J ═ 16Hz, 1H: in the 5. beta. position CH₂1H) of (1); 1.21(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.53(mt, 1H: CH at position 3. gamma.)₂The other H); 1.65 and 1.73(2 mts: corresponding to the 2. beta. CH position)₂2H) of (1); 1.98(mt, 1H: CH at position 3. beta₂The other H); 2.40-2.65 (NCH of mt, 5H: 1, 2, 3, 6-tetrahydropyridine)₂CH₂And CH at the 5 beta position₂The other H); 2.90-3.05(mt, 3H: CH)₂N and CH in the 4 beta position₂1H) of (1); 2.93(s, 6H: ArN (CH)₃)₂) (ii) a 3.06 (NCH for mt, 2H: 1, 2, 3, 6-tetrahydropyridine)₂) (ii) a 3.10-3.30(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.15(s, 3H: NCH)₃) (ii) a 3.40 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.45(mt, 1H: CH at position 3. delta₂The other H); 4.56(dd, J ═ 8 and 6Hz, 1H: CH at position 3 α); 4.76(mt, 1H: CH at position 2 α); 4.83(d, J-18 Hz, 1H: CH at the 5 epsilon position₂The other H); 4.86 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.12(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.22(dd, J ═ 9 and 7Hz, 1H: CH at position 4 α); 5.54(d, J ═ 8Hz, 1H: CH at position 6 α); 5.56(mt, 1H: CH at position 5. gamma.); 5.87 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.00(mt, CH ═ for 1H: 1, 2, 3, 6-tetrahydropyridine); 6.56(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.59(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 6.97(t,j-8.5 Hz, 2H: h) aromatic in the F ortho position); 7.20-7.30 (mt: 5H corresponding to aromatic H at 6 α); 7.30-7.40(mt, 4H: aromatic H at F meta position₄And H₅H) of (e); 7.71(d, J ═ 4Hz, 1H: H)₆) (ii) a 8.48(d, J ═ 10Hz, 1H: CONH at position 1); 8.45(d, J ═ 8Hz, 1H: CONH at position 6); 11.65(s, 1H: OH).

Example 9

The procedure is as in example 1, but using 50 ml of acetonitrile, 5g of 5. delta. chloromethyl-5. delta. 5. gamma. -dehydropristinamycin I containing 50 mol% of 5. delta. -chloromethyl-5. delta_EAnd 0.6 g of thiomorpholine as starting material. The reaction mixture was heated for 2 hours and then concentrated at 45 ℃ under reduced pressure (2.7 kPa) and the solid was dissolved in 100 ml of water. The insoluble material is filtered off and washed with 20 ml of water to give 5.4 g of a chestnut solid which is purified by chromatography on silica gel (eluent: dichloromethane/methanol gradient: 99/1 to 98/2 by volume) and then with 450 g of C₈10 μm silica gel was purified by preparative HPLC (eluent: water-acetonitrile, 65/35 by volume, containing 0.1% trifluoroacetic acid). The fractions containing the desired product were combined and acetonitrile was removed at 40 ℃ under reduced pressure (2.7 kPa). The residual aqueous phase was adjusted to pH7-8 by addition of saturated aqueous sodium bicarbonate solution. The precipitate obtained is filtered, washed with 20 ml of water and then dried at 45 ℃ C (90 Pa) to give 0.31 g of 5. delta. -thiomorpholinylmethyl-5. delta., 5. gamma. -dehydropristinamycin I_EIn the form of a white solid, melting at 160 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.04 (width d, J ═ 16Hz, 1H: in the 5. beta. CH position₂1H) of (1); 1.15-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.55(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.85 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.46 (width d, J ═ 16Hz, 1H: in the 5. beta. position CH₂The other H); 2.65(mf, 8H: thiomorpholine NCH)₂CH₂S); 2.90 (Width s, 2H: CH)₂N)；2.95(s，6H：ArN(CH₃)₂) (ii) a 2.95-3.05(mt, 1H: CH at position 4. beta₂1H) of (1); 3.10-3.25(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.19(s, 3H: NCH)₃) (ii) a 3.29 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂The other H); 4.59(dd, J ═ 8 and 6.5Hz, 1H: CH at position 3 α); 4.75-4.85(mt, 1H: CH at position 2 α); 4.82 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.89 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.11 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.24(mt, 1H: CH at position 4 α); 5.50(mt, 1H: CH at position 5 γ); 5.53(d, J ═ 8.5Hz, 1H: CH at position 6 α); 5.89 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.55-6.65(mt, 1H: CONH at 2-position); 6.59(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.45 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.74(mt, 1H: H)₆) (ii) a 8.41(d, J ═ 10Hz, 1H: CONH at position 1); 8.51(d, J ═ 8.5Hz, 1H: CONH at position 6); 11.68(s, 1H: OH).

Example 10

The procedure is as in example 1, but using 200 ml of acetonitrile, 6 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 50 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EAnd 4.8 g of 4-acetyl-4-phenylpiperidine as starting materials. The reaction mixture was heated for 3 hours and then concentrated at 45 ℃ under reduced pressure (2.7 kPa) and the solid was dissolved with 100 ml of water and 100 ml of dichloromethane. The organic phase is decanted, dried over sodium sulfate, filtered and then concentrated to dryness, giving 10.6 g of a chestnut solid which is purified successively 2 times by chromatography on silica gel (eluent: dichloromethane/methanol: 97/3 by volume). The solid thus obtained was stirred in 30 ml of diethyl ether, filtered and then dried at 45 ℃ C (90 Pa) to give 0.46 g of 5. delta. - (4-acetyl-4-phenylpiperidinomethyl) -5. delta.,. 5. gamma. -dehydropristinamycin I_EIn the form of a yellow solid, melted at 171 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.93(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.06 (very broad d, J ═ 16Hz, 1H: CH at the 5. beta. position₂1H) of (1); 1.15-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.53(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.85 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 1.90-2.25-2.45 and 2.62 (group 3 mt, total 8H: NCH of piperidine)₂CH₂)；1.91(s，3H：COCH₃) (ii) a 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.40-2.45(mt, 1H: CH at position 5. beta₂The other H); 2.82 (Width s, 2H: CH)₂N); 2.85-3.05(mt, 1H: CH at position 4. beta₂1H) of (1); 2.94(s, 6H: ArN (CH)₃)₂) (ii) a 3.10-3.30(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.16(s, 3H: NCH)₃) (ii) a 3.31 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.48(mt, 1H: CH at position 3. delta₂The other H); 4.58(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.70-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.89 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.10 (width d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.23(dd, J ═ 9 and 7Hz, 1H: CH at position 4 α); 5.47(mt, 1H: CH at position 5 γ); 5.56(d, J ═ 8Hz, 1H: CH at position 6 α); 5.89 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.55-6.65(mt, 1H: CONH at 2-position); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.91(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.15-7.40 (mt: corresponding to aromatic H-phenylaromatic H-H in the 6 alpha position₄And H₅12H) of (1); 7.74 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.42(d, J ═ 10Hz, 1H: CONH at position 1); 8.49(d, J ═ 8Hz, 1H: CONH at position 6); 11.67(s, 1H: OH).

Example 11

The procedure is as in example 1, but using 100 ml of acetonitrile, 6 g of raw 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydrogen containing 40 mol% of 5. delta. -chloromethylMycin I_EAnd 2.4 ml of N-methylbutylamine as starting materials. The reaction mixture was heated for 3 hours, then concentrated at 45 ℃ under reduced pressure (2.7 kPa) and the solid was dissolved in 100 ml of water. The resulting mixture was extracted 2 times with 70 ml of dichloromethane each time. The organic phase is decanted, dried over sodium sulfate, filtered and then concentrated to dryness, yielding 6.5 g of crude product, which is purified successively 2 times by chromatography on silica gel (eluent: dichloromethane/methanol: 97/3 by volume). The solid thus obtained is stirred in 30 ml of diethyl ether, filtered and then dried at 40 ℃ C (90 Pa) to yield 0.50 g of 5. delta. -N-methyl-N-butylaminomethyl-5. delta., 5. gamma. -dehydropristinamycin I_EIn the form of a yellow solid, melting at 168 ℃.

¹H N.M.R. Spectrum (500MHz, CDCl)₃): 0.85-0.95(mt, 6H: CH at 2. gamma. position₃And butyl CH₃) (ii) a 1.10 (width d, J ═ 16Hz, 1H: in the 5. beta. position CH₂1H) of (1); 1.15-1.30(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.34 and 1.44(2mts, butyl center CH)₂CH₂2H) of (1); 1.54(mt, 1H: CH at position 3. gamma.)₂The other H); 1.66(mt, 1H: CH at position 2. beta₂1H) of (1); 1.74 (mt: 1H corresponds to CH at position 2. beta₂The other H); 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.11(s, 3H: NCH)₃) (ii) a 2.27(mt, 2H: butyl NCH)₂) (ii) a 2.47 (Widdd, J-16 and 5Hz, 1H: CH in position 5. beta₂The other H); 2.83(AB, J ═ 13Hz, 2H: CH)₂N)；2.93(s，6H：ArN(CH₃)₂) (ii) a 2.98(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.15-3.30(mt, 2H: CH at position 3. delta₂1H and CH at the 4 beta position₂The other H); 3.17(s, 3H: NCH)₃) (ii) a 3.34 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.46(mt, 1H: CH at position 3. delta₂The other H); 4.57(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.75-4.85(mt, 1H: CH at position 2 α); 4.80 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.87(dd, J ═ 10 and 1Hz, 1H: at 1 αBit CH); 5.11 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.24(dd, J ═ 9 and 6.5Hz, 1H: CH at the 4 α position); 5.48(mt, 1H: CH at position 5. gamma.); 5.56(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.52(d, J ═ 10Hz, 1H: CONH at position 2); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.35 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.72 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.43(d, J ═ 8Hz, 1H: CONH at position 6); 11.68 (width s, 1H: OH).

Example 12

The procedure is as in example 1, but using 100 ml of acetonitrile, 6 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 40 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EAnd 2 ml of (S) -prolinol (prolinol) as starting materials. The reaction mixture was heated for 3 hours and then concentrated at 45 ℃ under reduced pressure (2.7 kPa) and the solid was dissolved with 200 ml of water and 100 ml of dichloromethane. The organic phase is decanted, dried over sodium sulfate, filtered and concentrated to dryness to give 6.2 g of crude product, which is purified by chromatography on silica gel (eluent: dichloromethane/methanol: 95/5 by volume). The solid thus obtained was stirred in 30 ml of diethyl ether and 30 ml of petroleum ether, filtered, and then dried at 40 deg.C (90 Pa) to obtain 0.67 g of 5. delta. [ (S) -2-hydroxymethylpyrrolidino]-methyl-5 delta, 5 gamma-dehydropristinamycin I_EIn the form of a yellow solid, melted at 147 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.01 (width d, J ═ 17Hz, 1H: in the 5. beta. CH position₂1H) of (1); 1.15-1.30(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.57(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-2.00 (mt: corresponding to CH at position 2. beta. -₂And pyrrolidine CH₂6H) of (1); 2.02(mt, 1H: CH at position 3. beta. -₂The other H); 2.30(mt, 1H:pyrrolidine NCH₂1H) of (1); 2.44 (Widdd, J ═ 17 and 5Hz, 1H in the 5. beta. position CH₂The other H); 2.62(mt, 1H: pyrrolidine NCH); 2.77 (Width d, J ═ 12Hz, 1H: CH)₂1H for N); 2.85-3.05(mt, 1H: CH at position 4. beta₂1H) of (1); 2.94(s, 6H: ArN (CH)₃)₂) (ii) a 3.05-3.35(mt, 5H: pyrrolidine NCH)₂Another H-is in the 4. beta. position CH₂Another H-CH of₂Another H-of N in the 3 delta position CH₂And CH at the 5 epsilon position₂1H) of (1); 3.19(s, 3H: NCH)₃)；3.40(mt，1H：CH₂1H for O); 3.46(mt, 1H: CH at position 3. delta₂The other H); 3.64(dd, J ═ 11.5 and 3Hz, 1H: CH)₂Another H of O); 4.56(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.88(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 4.94 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 5.12(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.24(dd, J ═ 9 and 6.5Hz, 1H: CH at the 4 α position); 5.51(mt, 1H: CH at position 5 γ); 5.59(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.55-6.70(mt, 1H: CONH at 2-position); 6.59(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 6.94(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.74(dd, J ═ 4 and 1.5Hz, 1H: H₆) (ii) a 8.41(d, J ═ 10Hz, 1H: CONH at position 1); 8.49(d, J ═ 8Hz, 1H: CONH at position 6); 11.68 (width s, 1H: OH).

Example 13

The procedure is as in example 1, but using 50 ml of acetonitrile, 2g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 40 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EAnd 0.75 ml of 2- (N-methyl-N-aminomethyl) -1, 3-dioxolane as starting material. The reaction mixture was heated for 3 hours and then concentrated at 45 ℃ under reduced pressure (2.7 kPa) and the solid was dissolved with 100 ml of water and 100 ml of dichloromethane. The organic phase is decanted, dried over sodium sulfate, filtered and concentrated to dryness to give 2.0 g of a yellow solid which is purified by chromatography on silica gel (eluent): dichloromethane/methanol: 97/3 by volume). After concentrating the fractions, the solid obtained is dried at 40 ℃ C (90 Pa) to yield 0.24 g of 5 delta- [ N-methyl-N-2- (1, 3-dioxolanyl) methyl]Aminomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIn the form of a yellow solid, melted at 149 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.01 (width d, J ═ 16Hz, 1H: in the 5. beta. CH position₂1H) of (1); 1.15-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.53(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.80 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 1.98(mt, 1H: CH at position 3. beta₂The other H); 2.28(s, 3H: NCH)₃) (ii) a 2.44 (Widdd, J-16 and 5Hz, 1H: CH in position 5. beta₂Another 1H) of (a); 2.50 and 2.58(2dd, J ═ 13 and 4.5Hz, 1H: NCH each₂) (ii) a 2.85-3.05(mt, 3H: CH at position 4. beta₂1H and CH at the 5 delta position₂N)；2.94(s，6H：ArN(CH₃)₂) (ii) a 3.10-3.30(mt, 2H: CH at position 4. beta₂And CH at position 3₂1H) of (1); 3.17(s, 3H: NCH)₃) (ii) a 3.36 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.44(mt, CH at position 3. delta₂The other H); 3.75-4.00(mt, 4H: OCH)₂CH₂O); 4.56(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.76(mt, 1H: CH at position 2 α); 4.83 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.88(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 4.97(t, J ═ 4.5Hz, 1H: OCHO); 5.11(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.21(dd, J ═ 9 and 6Hz, 1H: CH at position 4 α); 5.48(mt, 1H: CH at position 5. gamma.); 5.57(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.57(d, J ═ 9Hz, 1H: CONH at position 2); 6.62(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.93(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.72(dd, J ═ 4 and 1Hz, 1H: H₆) (ii) a 8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.44(d, J ═ 8Hz, 1H: CONH at position 6); 11.67 (width s, 1H: OH).

Example 14

The procedure is as in example 1, but using 100 ml of acetonitrile, 10 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EAnd 3.5 g of 4-piperidineethanol as starting materials. The reaction mixture was heated for 2 hours and then concentrated at 45 ℃ under reduced pressure (2.7 kPa). The resulting solid was dissolved in 50 ml of water and 50 ml of dichloromethane. After the organic phase has been decanted, dried over sodium sulfate, filtered and concentrated to dryness, 6.2 g of a chestnut solid are obtained which is purified by chromatography on silica gel (eluent: dichloromethane/methanol: 95/5 by volume) and then with 450 g of C₈10 μm silica gel was purified by HPLC (eluent: water-acetonitrile, 70/30 by volume, containing 0.1% trifluoroacetic acid). The fractions containing the desired product were combined and acetonitrile was removed at 40 ℃ under reduced pressure (2.7 kPa). The residual aqueous phase β H was adjusted to 7-8 by addition of saturated aqueous sodium bicarbonate solution. The aqueous phase is extracted twice with 50 ml of dichloromethane each time. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to dryness. The resulting solid was stirred in 25 ml of diethyl ether, filtered, washed with 10 ml of isopropyl ether and then dried at 40 deg.C (90 Pa) to give 0.70 g of 5. delta. - [4- (2-hydroxyethyl) piperidino]Methyl-5 delta, 5 gamma-dehydropristinamycin I_EIn the form of a white solid, melting at 240 ℃.

¹H N.M.R. Spectrum (500MHz, CDCl)₃): 0.93(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.10 (width d, J ═ 16.5Hz, 1H: CH in position 5. beta.)₂1H) of (1); 1.15-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.15-1.80(mt, 5H: piperidine CH)₂And piperidine CH); 1.32(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.45-1.60(mt, 1H: CH at position 3. gamma.)₂The other H); 1.51(q, J ═ 7Hz, 2H: CH for hydroxyethyl₂) (ii) a 1.60-1.80(mt, 2H: CH at position 2. beta₂) (ii) a 1.84 (width t, J ═ 11Hz, 2H:piperidine NCH₂Shaft H) of (a); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.49 (Widdd, J ═ 16.5 and 5.5Hz, 1H: CH in the 5. beta. position₂The other H); 2.75-2.90(mt, 4H: CH)₂N and piperidine NCH₂Flat H); 2.95(s, 6H: ArN (CH)₃)₂) (ii) a 2.99(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.15-3.35(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.18(s, 3H: NCH)₃) (ii) a 3.35 (width d, J ═ 17.5Hz, 1H: CH at the 5 epsilon position₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂Another 1H) of (a); 3.70(t, J ═ 7Hz, 2H: CH)₂O); 4.59(dd, J ═ 8.5 and 6Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.83 (width d, J ═ 17.5Hz, 1H: CH at position 5. epsilon₂The other H); 4.87 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.12(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.24(dd, J ═ 8 and 6.5Hz, 1H: CH at the 4 α position); 5.48(mt, 1H: CH at position 5. gamma.); 5.54(d, J ═ 7.5Hz, 1H: CH at position 6 α); 5.89(q, J ═ 7Hz, 1H: CH at position 1 β); 6.55-6.65(mt, 1H: CONH at 2-position); 6.59(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.25-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.73 (width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.43(d, J ═ 7.5Hz, 1H: CONH at position 6); 11.67 (width s, 1H: OH).

Example 15

The procedure is as in example 1, but using 100 ml of acetonitrile, 7 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl_EAnd 1.25 ml of 1- (2-pyridyl) piperazine as starting materials. The reaction mixture was heated at 60 ℃ for 2 hours and then concentrated at 45 ℃ under reduced pressure (2.7 kPa). The resulting solid was dissolved in 50 ml of water and 100 ml of dichloromethane. The aqueous phase was re-extracted with 30 ml dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness, giving 7.6 g of a pale beige solid which is successively purified by flash chromatography on silica gel (washings)Removing the agent: dichloromethane/methanol: 95/5 by volume, then 98/2). The solid thus obtained is stirred in 60 ml of diethyl ether, filtered and dried at 40 ℃ C (90 Pa) to yield 1.5 g of 5. delta. [4- (2-pyridyl) piperazin-1-yl]Methyl-5 delta, 5 gamma-dehydropristinamycin I_EIt is in the form of light grayish brown powder and is melted at 148 deg.C.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.06 (width d, J ═ 16Hz, 1H: in the 5. beta. position CH₂1H) of (1); 1.22(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.32(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.55(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.80 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 1.98(mt, 1H: CH at position 3. beta₂The other H); 2.40-2.55(mt, 5H: CH at position 5. beta₂And the other H of piperazine and CH₂N)；2.90(s，2H：CH₂N)；2.95(s，6H：ArN(CH₃)₂) (ii) a 2.98(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.10-3.30(mt, 2H: CH at position 3. delta₂And the other CH at the 4 beta position₂H) of (e); 3.18(s, 3H: NCH)₃) (ii) a 3.36 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.40-3.65(mt, 5H: CH at position 3. delta₂And the other H of piperazine and CH₂NAr); 4.60(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.88 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.88(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.12 (width d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.24(dd, J ═ 9 and 6.5Hz, 1H: CH at the 4 α position); 5.51(mt, 1H: CH at position 5 γ); 5.54(d, J ═ 8.5Hz, 1H: CH at position 6 α); 5.88 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.50-6.70(mt, 3H: CONH at the 2-position-H at the 3-position and H at the 5-position of pyridine); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.46 (deduplicated t, J ═ 8 and 2Hz, 1H: H at pyridine position 4); 7.73(dd, J ═ 4 and 1.5Hz，1H：H₆) (ii) a 8.18(dd, J ═ 5 and 2Hz, 1H: H at pyridine position 6); 8.40(d, J ═ 10Hz, 1H: CONH at position 1); 8.48(d, J ═ 8.5Hz, 1H: CONH at position 6); 11.67(s, 1H: OH).

Example 16

The procedure is as in example 1, but using 30 ml of acetonitrile, 3g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl_EAnd 1.4 ml of N-benzylethanolamine as starting materials. The reaction mixture was heated under reflux for 8 hours and then concentrated at 45 ℃ under reduced pressure (2.7 kPa). The solid obtained was dissolved in 50 ml of water and 10 ml of 2N hydrochloric acid. The aqueous phase is extracted twice with 100 ml of ethyl acetate and twice with 100 ml of diethyl ether each time, and then 2g of sodium bicarbonate are added. The resulting white precipitate was filtered and dissolved in 50 ml of dichloromethane. The resulting solution was washed successively 3 times with 50 ml of water each time and 3 times with 50 ml of saturated aqueous sodium chloride solution each time, then dried over magnesium sulfate, filtered and concentrated to dryness to give 2g of a white product which was purified by chromatography on silica gel (eluent: dichloromethane/methanol gradient: 99/1 to 96/4 by volume). The solid thus obtained is stirred in 60 ml of diethyl ether, filtered and dried at 40 ℃ C (90 Pa) to yield 0.68 g of 5. delta. - [ N-benzyl-N- (2-hydroxyethyl)]Aminomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIn solid form, melted at 148 ℃.

To this solid, dissolved in 10 ml of ethyl acetate, 0.063 g of methanesulfonic acid was added. The resulting mixture was stirred for 1 hour and then diluted with 10 ml of diethyl ether. After stirring overnight, the precipitate was filtered, washed 2 times with 5 ml of diethyl ether each time and then dried over phosphorus pentoxide at 20 ℃ under reduced pressure (90 Pa). Thus, 0.5 g of 5. delta. - [ N-benzyl-N- (2-hydroxyethyl) ethyl ] was obtained]Aminomethyl-5 delta, 5 gamma-dehydropristinamycin I_EMesylate salt, in the form of white crystals, melted at 165 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.85-1.05(mt, 1H: CH at position 5. beta₂1H) of (1); 0.91(t, J ═ 7.5Hz,3H: at the 2 gamma position CH₃) (ii) a 1.10-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.56(mt, 1H: CH at position 3. gamma.)₂The other H); 1.65 and 1.72(2mts, 1H each: CH at position 2. beta₂) (ii) a 2.02(mt, 1H: CH at position 3. beta. -₂The other H); 2.44 (width d, J ═ 16Hz, 1H: in the 5. beta. position CH₂The other H); 2.84(s, 3H: SO)₂CH₃)；2.90-3.30(mt，2H：NCH₂) (ii) a 2.95-3.05(mt, 1H: CH at position 4. beta₂1H) of (1); 2.98 (Width s, 6H: ArN (CH)₃)₂) (ii) a 3.10-3.25(mt, 2H: CH at position 3. delta₂1H and CH at the 4 beta position₂The other H); 3.18(s, 3H: NCH)₃) (ii) a 3.35-4.00(2 broadened mfs, total 2H: CH)₂N); 3.40-3.55(mt, 2H: CH at position 5. epsilon.)₂1H and CH at the 3 delta position₂The other H); 3.90 (very broad s, 2H: CH)₂O); 4.40 and 4.54(2mts, 1H each ArCH)₂N); 4.54(mt, 1H: CH at position 3 α); 4.76(mt, 1H: CH at position 2 α); 4.85-4.95(mt, 1H: CH at position 5. epsilon.)₂The other H); 4.87 (width d, J ═ 10Hz, 1H: CH at position 1 α)5.13 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.18(dd, J ═ 9.5 and 5.5Hz, 1H: CH at position 4 α); 5.66(mt, 1H: CH at position 6 α); 5.80-5.95(mf, 1H: CH at the 5. gamma. -position); 5.86 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.53(d, J ═ 9Hz, 1H: CONH at position 2); 6.55-6.95 (broadened mf, 2H: aromatic H at the 4 ε position); 6.98(mf, 2H: aromatic H at the 4. delta. position); 7.20-7.55 (mt: corresponding to aromatic H-benzylaromatic H-H in 6. alpha. position₄And H₅12H) of (1); 7.73(mf, 1H: H)₆) (ii) a 8.34(d, J ═ 10Hz, 1H: CONH at position 1); 8.72 (broadened mf, 1H: CONH at 6 bits); 9.60-10.50 (very broad mf, 1H: OH for mesylate); 11.64(s, 1H: OH).

Example 17

The procedure is as in example 1, but 80 ml of acetonitrile are used, 8 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EAnd 1.48 g of N-ethoxycarbonylThe base piperazine is used as a raw material. The reaction mixture was heated under reflux for 3 hours and then concentrated at 45 ℃ under reduced pressure (2.7 kPa). The solid was dissolved in 200 ml of dichloromethane. The resulting solution was washed twice with 100 ml of water each time, decanted, dried over magnesium sulfate, filtered and concentrated to dryness to give 7.4 g of a green solid which was purified twice by flash chromatography on silica gel (eluent: dichloromethane/methanol: 95/5 by volume, then 98/2), then twice by preparative HPLC chromatography on 500 g of 20-45 μm silica gel (eluent: dichloromethane/methanol 98/2 by volume, and 99/1), and finally 450 g of C₈10 μm silica gel was purified by preparative HPLC (eluent: water-acetonitrile, 60/40 by volume, containing 0.1% trifluoroacetic acid). The fractions containing the desired product were combined, acetonitrile was removed at 40 ℃ under reduced pressure (2.7 kPa), and the pH of the aqueous phase was adjusted to 7 by addition of saturated aqueous sodium bicarbonate. The resulting precipitate was filtered, washed with 30 ml of water and then twice with 30 ml of isopropyl ether each time, and dried at 40 deg.C (90 Pa) to give 0.36 g of 5. delta. - [ 4-ethoxycarbonylpiperazin-1-yl]Methyl-5 delta, 5 gamma-dehydropristinamycin I_EIt is white powder and melts at 165 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.06 (very broad d, J ═ 16Hz, 1H: CH in the 5. beta. position₂1H) of (1); 1.15-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.25(t, J ═ 7.5Hz, 3H: CH for ethyl)₃) (ii) a 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.55(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.80 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 1.98(mt, 1H: CH at position 3. beta₂The other H); 2.15-2.60 (stretched mf, 4H: CH for piperazine)₂N); 2.46(dd, J-16 and 5.5Hz, 1H: CH in the 5. beta. position₂The other H); 2.85-3.05(mt, 3H: CH)₂N and CH in the 4 beta position₂1H) of (1); 2.93(s, 6H: ArN (CH)₃)₂) (ii) a 3.15-3.30(mt, 2H: CH at position 3. delta₂1H and CH at the 4 beta position₂The other H); 3.17(s, 3H: NCH)₃) (ii) a 3.30-3.75 (broadened mf,4H: piperazine CH₂NCO); 3.34 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.46(mt, 1H: CH at position 3. delta₂The other H); 4.13(q, J ═ 7.5Hz, 2H: COOCH)₂) (ii) a 4.57(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.77(mt, 1H: CH at position 2 α); 4.83 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.87(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.11 (width d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.21(dd, J ═ 9 and 6.5Hz, 1H: CH at position 4 α); 5.50-5.60(mt, 1H: CH at position 5 γ); 5.53(d, J ═ 7.5Hz, 1H: CH at position 6 α); 5.88 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.50-6.60(mt, 1H: CONH at 2 position); 6.58(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.90(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.72(dd, J ═ 4 and 1.5Hz, 1H: H₆) (ii) a 8.38(d, J ═ 10Hz, 1H: CONH at position 1); 8.51(d, J ═ 7.5Hz, 1H: CONH at position 6); 11.66(s, 1H: OH).

Example 18

The procedure is as in example 1, but using 30 ml of acetonitrile, 3g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl_EAnd 1.8 g of 1- (2-furoyl) piperazine as starting materials. The reaction mixture was heated at reflux for 24 hours and then concentrated at 45 ℃ under reduced pressure (2.7 kPa). The solid obtained was dissolved in 50 ml of water and 10 ml of 2N hydrochloric acid. The resulting solution is extracted three times with 100 ml of ethyl acetate each time, twice with 100 ml of diethyl ether and then with 2g of sodium bicarbonate. The white precipitate formed is filtered, washed 6 times with 20 ml of water each time and then dissolved in 80 ml of dichloromethane. The resulting solution is washed three times with 50 ml of water each time, twice with 50 ml of saturated aqueous sodium chloride solution and then concentrated to dryness, and the 2.15 g of solid obtained are purified by chromatography on silica gel (eluent: dichloromethane/methanol gradient, 100/0 to 97/3 by volume). The solid obtained is dissolved in 80 ml of diethyl ether, filtered, washed 3 times with 10 ml of diethyl ether each time and then dried at 40 ℃ C (90 Pa) to give 0.73 g of 5. delta. -4- (2-furan)Formyl) piperazin-1-yl]Methyl-5 delta, 5 gamma-dehydropristinamycin I_EIt is in the form of variegated white crystal, and can be melted at 148 deg.C.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.08 (width d, J ═ 16Hz, 1H: in the 5. beta. position CH₂1H) of (1); 1.25(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.56(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.80 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.25-2.55 (stretched mf, 4H: 2CH for piperazine)₂N); 2.46(dd, J-16 and 5Hz, 1H in the 5. beta. position CH₂The other H); 2.88(s, 2H: CH)₂N)；2.93(s，6H：ArN(CH₃)₂) (ii) a 2.98(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.15-3.30(mt, 2H: CH at position 3. delta₂1H and CH at the 4 beta position₂The other H); 3.19(s, 3H: NCH)₃) (ii) a 3.34 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.46(mt, 1H: CH at position 3. delta₂The other H); 3.50-4.10 (very broad extension mf, 4H: 2CH of piperazine)₂NCO); 4.58(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.77(mt, 1H: CH at position 2 α); 4.84 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.87(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.12 (width d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.24(dd, J ═ 9.5 and 6.5Hz, 1H: CH at the 4 α position); 5.50(mt, 1H: CH at position 5 γ); 5.53(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.46(dd, J ═ 3 and 2Hz, 1H: H at furan 4 position); 6.55-6.65(mt, 1H: CONH at 2-position); 6.58(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 6.98(dd, J ═ 3Hz, 1H: H at furan position 3); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.48(dd, J ═ 2Hz, 1H: H at furan position 5); 7.73(dd, J ═ 4 and 1.5Hz, 1H: H₆) (ii) a 8.41(d, J ═ 10Hz, 1H: at position 1CONH); 8.53(d, J ═ 8Hz, 1H: CONH at position 6); 11.67 (width s, 1H: OH).

Example 19

The procedure is as in example 1, but 60 ml of acetonitrile and 6 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl-5. delta., are used_EAnd 4.1 ml of N' -benzyl-N, N-dimethylethylenediamine as starting materials. The reaction mixture was heated at reflux for 15 hours and then concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). The solid obtained was dissolved with 100 ml of water and with 2N hydrochloric acid solution so that the pH reached 1. The aqueous phase is extracted twice with 100 ml of diethyl ether each time, twice with 100 ml of ethyl acetate, and then the pH is adjusted to 7 by addition of saturated aqueous sodium bicarbonate solution and then twice with 100 ml of dichloromethane each time. The organic phase is dried over sodium sulfate, filtered and then concentrated to dryness under reduced pressure, giving 7.4 g of a solid which is purified by chromatography on silica gel (eluent: dichloromethane/methanol, 98/2 by volume). The resulting solid was stirred in 50 ml of diethyl ether, filtered and dried to give 0.64 g of a white solid, which was dissolved in 20 ml of water and a hydrochloric acid solution was added to reach pH 1. Extracted twice with 20 ml of ether each time. Adding saturated aqueous sodium bicarbonate solution to the aqueous phase, filtering the precipitate, and adding P at 20 deg.C (90 Pa)₂O₅Drying to give 0.14 g of 5 delta-N-benzyl-N- (2-dimethylaminoethyl) aminomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIt is white powder and melts at 182 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.06 (width d, J ═ 16Hz, 1H: in the 5. beta. position CH₂1H) of (1); 1.20-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.29(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.50-1.85 (mt: corresponding to CH at the 3. gamma. position₂Another H and CH in the 2 beta position₂3H) of (1); 2.02(mt, 1H: CH at position 3. beta. -₂The other H); 2.33(mf, 6H: 2NCH of dimethylamine₃) (ii) a 2.43 (Widdd, J. ltoreq.16 and 5Hz, 1H: CH in position 5. beta.)₂The other H); 2.59(mf, 4H: NCH)₂CH₂N); 2.85-3.05(mt, 1H: CH at position 4. beta₂1H) of (1); 2.91(s, 6H: ArN (CH)₃)₂)；3.00(s，2H：CH₂N); 3.15-3.30(mt, 2H: CH at position 3. delta₂1H and CH at the 4 beta position₂The other H); 3.17(s, 3H: NCH)₃) (ii) a 3.33 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.46(mt, 1H: CH at position 3. delta₂The other H); 3.55(s, 2H: ArCH)₂N); 4.57(dd, J ═ 8 and 6Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.87 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.87(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.13 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.24(dd, J ═ 10 and 6Hz, 1H: CH at position 4 α); 5.46(d, J ═ 8Hz, 1H: CH at position 6 α); 5.55(mt, 1H: CH at position 5. gamma.); 5.85 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.54(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.57(d, J ═ 10Hz, 1H: CONH at position 2); 6.88(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.15-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.71(dd, J ═ 4 and 1.5Hz, 1H: H₆) (ii) a 8.38(d, J ═ 10Hz, 1H: CONH at position 1); 8.53(d, J ═ 8Hz, 1H: CONH at position 6); 11.66(mf, 1H: OH).

Example 20

The procedure is as in example 1, but using 100 ml of acetonitrile, 20 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EAnd 4.5 g of 4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride and 3.25 ml of triethylamine as starting materials. The reaction mixture was heated under reflux for 1.5h and then concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). The resulting solid was dissolved in 100 ml of water, then filtered, washed with 20 ml of water, and dried under reduced pressure to give 26 g of a solid. This solid was purified by chromatography on silica gel (eluent: dichloromethane/methanol, 97/3% by volume) and then washed with 450 g of C₈Purification by preparative HPLC on 10 μm silica gel (eluent: water-acetonitrile, 65/35 by volume, containing 0.1% trifluoroAcetic acid). The fractions containing the desired product were combined, acetonitrile was removed at 40 ℃ under reduced pressure (2.7 kPa), and then the pH of the aqueous phase was adjusted to 7-8 by adding saturated aqueous sodium bicarbonate. The resulting precipitate was filtered, washed with 20 ml of water and dried at 40 ℃ under reduced pressure (90 Pa) to give 0.47 g of 5. delta. [1- (4-phenyl) -1, 2, 3, 6-tetrahydropyridinyl]Methyl-5 delta, 5 gamma-dehydropristinamycin I_EIn the form of a white solid, melting at 154 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.00-1.15 (broadened mf, 1H: CH at position 5. beta.)₂1H) of (1); 1.22(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.32(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.54(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.85 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.40-2.80 (NCH of mt, 5H: 1, 2, 3, 6-tetrahydropyridine)₂CH₂And CH at the 5 beta position₂The other H); 2.90-3.30(mt, 7H: CH at position 4. beta₂N-CH₂NCH of (E) -1, 2, 3, 6-tetrahydropyridine₂And CH at the 3 delta position₂1H) of (1); 2.95(s, 6H: ArN (CH)₃)₂)；3.17(s，3H：NCH₃) (ii) a 3.35-3.55(mt, 2H: CH at position 5. epsilon.)₂1H and CH at the 3 delta position₂The other H); 4.57(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.77(mt, 1H: CH at position 2 α); 4.80-4.95(mt, 1H: CH at position 5. epsilon.)₂The other H); 4.87(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.14(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.22(mt, 1H: CH at position 4 α); 5.50-5.65(mf, 1H: CH at the 5. gamma. -position); 5.57(d, J ═ 8Hz, 1H: CH at position 6 α); 5.88 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.06(mt, 1H: 1, 2, 3, 6-tetrahydropyridine CH ═ g); 6.56(d, J ═ 9Hz, 1H: CONH at position 2); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.93(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.45 (mt: corresponding to aromatic H-phenylaromatic H-H in the 6 alpha position₄And H₅12H) of (1); 7.73(dd, J ═ 4 and 1Hz, 1H: H₆)；8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.49(mf, 1H: CONH at 6 position); 11.66(s, 1H: OH).

Example 21

The procedure is as in example 1, but using 30 ml of acetonitrile, 3g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl_EAnd 1.9 g of 4-benzyl-4-hydroxy-piperidine as starting materials. The reaction mixture was heated at reflux for 20 hours and then concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). The solid obtained was dissolved in 50 ml of water and 10 ml of 2N hydrochloric acid. The resulting solution is extracted successively four times with 50 ml of ethyl acetate and twice with 50 ml of diethyl ether each time, adjusted to pH7-8 by addition of 2g of sodium bicarbonate and then extracted three times with 100 ml of dichloromethane each time. The organic phase is decanted, dried over sodium sulfate, filtered and then concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa) to give 2.6 g of a solid which is purified by chromatography on silica gel (eluent: dichloromethane/methanol gradient, 99.5/0.5 by volume, then 90/10). The solid obtained is stirred in 50 ml of isopropyl ether, then filtered and dried at 40 ℃ under reduced pressure (90 Pa) to yield 0.2 g of 5 delta- (4-benzyl-4-hydroxy-piperazinomethyl) -5 delta, 5 gamma-dehydropristinamycin I_EIt is in the form of variegated white crystal, and can be melted at 172 deg.C.

¹Hn.m.r. spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.03 (width d, J ═ 16Hz, 1H: in the 5. beta. CH position₂1H) of (1); 1.15-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.50-1.90 (mt: corresponding to CH at the 3. gamma. position₂And CH in the 2 beta position₂3H) of (1); 1.50 to 1.90-2.10 to 2.35 and 2.50-2.65 (group 3 mt: NCH corresponding to piperidine₂CH₂And CH₂10H for Ar); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.45(mt, 1H: CH at position 5. beta. -₂The other H); 2.75-3.05(mt, 3H: CH)₂N and CH in the 4 beta position₂1H) of (1); 2.93(s, 6H: Ar)N(CH₃)₂) (ii) a 3.15-3.30(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.18(s, 3H: NCH)₃) (ii) a 3.30 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂The other H); 4.58(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.80-4.90(mt, 1H: CH at position 5. epsilon.)₂The other H); 4.87 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.11 (width d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.22(dd, J ═ 9 and 7Hz, 1H: CH at position 4 α); 5.47(mt, 1H: CH at position 5 γ); 5.54(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.55-6.65(mt, 1H: CONH at 2-position); 6.58(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.91(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.10-7.40 (mt: corresponding to aromatic H-phenylaromatic H-H in the 6. alpha. position₄And H₅12H) of (1); 7.72 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.46(d, J ═ 8Hz, 1H: CONH at position 6); 11.67(s, 1H: OH).

Example 22

The procedure is as in example 1, but using 30 ml of acetonitrile, 3g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl_EAnd (5 delta R) -5 delta-methylene-5 gamma-chloropristinamycin I_EThe crude mixture (ratio 33/67) and 1.25 g of N-allyl-cyclopentylamine were used as starting materials. The reaction mixture was heated at reflux for 28 hours and then concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). The solid obtained was dissolved in 50 ml of water and 10 ml of 2N hydrochloric acid. The resulting solution is extracted four times successively with 50 ml of ethyl acetate and twice with 50 ml of diethyl ether each time, the pH being adjusted to 8 by addition of 2g of sodium bicarbonate. The resulting precipitate was filtered, washed with water, optionally to remove the remaining inorganic salts, and then dissolved in 50 ml of dichloromethane. The resulting solution is washed four times with 50 ml of water each time and twice with 50 ml of saturated aqueous sodium chloride solution each time, then dried over sodium sulfate, filtered and concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). Thus 2.3 g of solids are obtainedThe solid was purified by chromatography on silica gel (eluent: dichloromethane/methanol gradient 100/0 by volume, then 98/2). The solid obtained is stirred in 50 ml of isopropyl ether and then filtered, washed three times with 10 ml of isopropyl ether each time and dried at 20 ℃ under reduced pressure (90 Pa) to give 0.59 g of 5 delta- (N-allyl-N-cyclopentyl) aminomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIt is in the form of white crystals and melts at 140 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.93(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.07 (very Wide d, J ═ 16Hz, 1H: CH in the 5. beta. position₂1H) of (1); 1.15-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.35-1.85 (mt: corresponding to CH at the 3. gamma. position₂Of another H-cyclopentane₂And CH in the 2 beta position₂11H) of (1); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.47(mt, 1H: CH at position 5. beta₂The other H); 2.85-3.05(mt, 3H: CH at position 4. beta₂1H-CH of₂N)；2.93(s，6H：ArN(CH₃)₂) (ii) a 3.05-3.20(mt, 3H: NCH and allylic NCH₂) (ii) a 3.15-3.45(mt, 3H: CH at position 3. delta₂1H-in the 4 beta position CH₂And in the 5 epsilon position CH₂1H) of (1); 3.17(s, 3H: NCH)₃) (ii) a 3.47(mt, 1H: CH at position 3. delta₂The other H); 4.58(dd, J ═ 8.5 and 6Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.80-4.95(mt, 1H: CH at position 5. epsilon.)₂The other H); 4.86 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.00-5.30(mt, 4H: ═ CH)₂-CH at position 5 α and CH at position 4 α); 5.47(mt, 1H: CH at position 5 γ); 5.55(d, J ═ 8Hz, 1H: CH at position 6 α); 5.80-5.95(mt, 21H: allyl CH ═ and CH at the 1 β position); 6.56(d, J ═ 10Hz, 1H: CONH at position 2); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.91(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.73(dd, J ═ 4 and 1Hz, 1H: H₆) (ii) a 8.35-8.45(mt, 2H: CONH at 1 position and at6-position CONH); 11.66(s, 1H: OH).

Example 23

The procedure is as in example 1, but using a mixture containing 5 delta-chloromethyl-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin I_EStarting from the crude mixture of (a) to (b) to produce 0.5 g of 5 delta-morpholinomethyl-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin I_EIn the form of a white solid, melting at 150 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.10-1.35(mt, 3H: CH at position 5. beta₂1H-in the 3. beta. position CH₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.57(mt, 1H: CH at position 3. gamma.)₂The other H); 1.67 and 1.75(2mts, 1H each: CH at position 2. beta₂) (ii) a 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.35(mf, 4H: NCH of morpholine)₂) (ii) a 2.57 (Widdd, J ═ 16 and 5Hz, 1H in the 5. beta. position CH₂The other H); 2.80(s, 6H: ArN (CH)₃)₂) (ii) a 2.88(AB Limit, J ═ 14Hz, 2H: CH)₂N); 3.02(dd, J ═ 14 and 7.5Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.10-3.25(mt, 1H: CH at position 4. beta₂The other H); 3.14(s, 3H: NCH)₃) (ii) a 3.28(mt, 1H: CH at position 3. delta₂1H) of (1); 3.36 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.48(mt, 1H: CH at position 3. delta₂The other H); 3.70(mt, 4H: CH for morpholine)₂O); 4.56(dd, J ═ 8 and 6Hz, 1H: CH at position 3 α); 4.75-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.87(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.13(d, J ═ 5Hz, 1H: CH at position 5 α); 5.26(dd, J ═ 8 and 7.5Hz, 1H: CH at the 4 α position); 5.50(d, J ═ 8Hz, 1H: CH at position 6 α); 5.55(mt, 1H: CH at position 5. gamma.); 5.88 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.56(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.87(AB limit, 2H: aromatic H at the 4. epsilon. position and aromatic H at the 4. delta. Cl para position); 7.09(d, J ═ 2Hz, 1H: aromatic in the 4. delta. position and in the Cl-ortho positionGroup H); 7.25-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.69(dd, J ═ 4 and 2Hz, 1H: H₆) (ii) a 8.33(d, J ═ 10Hz, 1H: CONH at position 1); 8.46(d, J ═ 8Hz, 1H: CONH at position 6); 11.68(s, 1H: OH).

5 delta-chloromethyl-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin was prepared in a similar manner to that described in example 1 using 4 epsilon-chloro-5 delta-methylenepristinamycin IA.

4 epsilon-chloro-5 delta-methylenepristinamycin IA can be prepared as follows:

to a solution of 11.4 g of 5 delta-methylenepristinamycin IA in 120 ml of acetonitrile, 1.9 g of N-chlorosuccinimide are added under argon. The mixture was stirred at reflux for 2 hours, then 346 mg of N-chlorosuccinimide was added. After additional 1.5h of reflux and 18h of stirring at 20 ℃ the reaction mixture was concentrated to dryness at 30 ℃ under reduced pressure (2.7 kPa). The solid obtained is stirred in 250 ml of diethyl ether for 4 hours, filtered, washed and dried at 20 ℃ in a fume hood to give 11.7 g of 4. epsilon. -chloro-5. delta. -methylenepristinamycin IA as a rose powder which can be used as such.

Example 24

The procedure is as in example 1, but using a mixture containing 5 delta-chloromethyl-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin I_E0.25 g of 5 delta-piperidinomethyl-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin I was obtained_EIn the form of white solid, decomposed at 160 ℃.

¹H N.M.R. Spectrum (500MHz, CDCl)₃): 0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.10-1.35(mt, 3H: CH at position 5. beta₂1H-in the 3. beta. position CH₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.35-1.75 (mt: corresponding to CH at the 3. gamma. position₂Is another H-piperidine CH₂CH₂CH₂And CH in the 2 beta position₂8H of 1H of (1); 1.74(mt, 1H:in the 2 beta position CH₂The other H); 1.98(mt, 1H: CH at position 3. beta₂The other H); 2.27(mf, 4H: NCH of piperidine)₂) (ii) a 2.50-2.65(mt, 1H: CH at position 5. beta₂The other H); 2.78(s, 6H: ArN (CH)₃)₂)；2.80(s，2H：CH₂N); 3.01(mt, 1H: CH at position 4. beta₂1H) of (1); 3.10-3.25(mt, 1H: CH at position 4. beta₂The other H); 3.14(s, 3H: NCH)₃) (ii) a 3.26(mt, 1H: CH at position 3. delta₂1H) of (1); 3.36(mt, 1H: CH at the 5 epsilon position₂1H) of (1); 3.46(mt, 1H: CH at position 3. delta₂The other H); 4.56(dd, J ═ 7 and 6Hz, 1H: CH at position 3 α); 4.70-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.86 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.12(d, J ═ 5Hz, 1H: CH at position 5 α); 5.25(mt, 1H: CH at position 4 α); 5.45-5.55(mt, 2H: CH at position 5. gamma. and CH at position 6. alpha.); 5.87 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.55(d, J ═ 9Hz, 1H: CONH at position 2); 6.86(mt, 2H: aromatic H at the 4. epsilon. position and aromatic H at the 4. delta. position in the Cl para-position); 7.09 (width s, 1H: aromatic H in the Cl ortho position at the 4. delta. position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.69(mt, 1H: H)₆) (ii) a 8.30-8.45(mt, 2H: CONH at 1 position and CONH at 6 position); 11.68(s, 1H: OH).

Example 25

The procedure is as in example 1, but using a mixture containing 5 delta-chloromethyl-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin I_E0.35 g of 5 delta- (2, 6-dimethylmorpholino) methyl-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin I was obtained_EIn the form of a white solid, melting at 179 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): we observed a mixture of two diastereomers of morpholine cis and trans, as well as the presence of minimal amounts of other unidentified pristinamycins and configurations.

0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃)；1.05-1.40(mt，3H：At position 5 beta CH₂1H-in the 3. beta. position CH₂And CH at the 3. gamma. position₂1H) of (1); 1.15 and 1.19(2d, J ═ 7Hz, CH for each 3H: 2, 6 dimethylmorpholine₃) (ii) a 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.50-1.75 (mt: corresponding to CH at the 3. gamma. position₂Is in the 2 beta position CH₂1H and 2, 6-dimethylmorpholine NCH₃4H of 2H of (1); 1.75(mt, 1H: CH at position 2. beta₂The other H); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.57 (Widdd, J-16 and 5.5Hz, 1H: CH in position 5. beta₂The other H); 2.66(mt, 2H: 2, 6-dimethylmorpholine NCH)₂2 further H) of (a); 2.80(s, 6H: ArN (CH)₃)₂) (ii) a 2.85 (width s, 2H: CH)₂N); 3.03(dd, J ═ 14 and 7Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.10-3.25(mt, 1H: CH at position 4. beta₂The other H); 3.16(s, 3H: NCH)₃) (ii) a 3.30(mt, 1H: CH at position 3. delta₂1H) of (1); 3.35 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.48(mt, 1H: CH at position 3. delta₂The other H); 3.59 and 3.69(2mts, 1H: morpholine CHO each); 4.58(dd, J ═ 7 and 5Hz, 1H: CH at position 3 α); 4.70-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.87 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.13(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.27(mt, 1H: CH at position 4 α); 5.51(d, J ═ 7.5Hz, 1H: CH at position 6 α); 5.53(mt, 1H: CH at position 5. gamma.); 5.88 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.57(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.87(mt, 2H: aromatic H at the 4. epsilon. position and aromatic H at the 4. delta. position in the C para-position); 7.11 (width s, 1H: aromatic H in the Cl ortho position at the 4. delta. position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.70(mt, 1H: H)₆) (ii) a 8.35(d, J ═ 10Hz, 1H: CONH at position 1); 8.46(d, J ═ 8Hz, 1H: CONH at position 6); 11.68(s, 1H: OH).

Example 26

The procedure is as in example 1, but using a mixture containing 5 delta-chloromethyl-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin I_EOf the crude mixtureIs used as a raw material. Thus, 0.46 g of 5. delta. -N, N-dipropylaminomethyl-5. delta.5. gamma. -dehydro-4. epsilon. -chloropristinamycin I was obtained_EIn the form of a yellow solid, melting at 139 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.85-0.95(mt, 9H: CH at 2. gamma. position₃And dipropylamine CH₃) (ii) a 1.14 (width d, J ═ 16Hz, 1H: in the 5. beta. position CH₂1H) of (1); 1.20-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.44(mt, 4H: dipropylamine centre CH₂) (ii) a 1.57 (mt: corresponding to CH at the 3. gamma. position₂1H of another H); 1.60-1.80(2 mts: corresponding to CH at position 2. beta. -₂2H) of (1); 1.98(mt, 1H: CH at position 3. beta₂The other H); 2.15-2.40(mt, 4H: NCH of dipropylamine)₂) (ii) a 2.56 (Widdd, J. ltoreq.16 and 5.5Hz, 1H: CH in position 5. beta.)₂The other H); 2.78(s, 6H: ArN (CH)₃)₂) (ii) a 2.84 and 2.98(2d, J-13 Hz, 1H: CH each₂N); 3.02(dd, J ═ 14 and 7Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.15-3.30(mt, 2H: CH at position 3. delta₂1H and CH at the 4 beta position₂The other H); 3.15(s, 3H: NCH)₃) (ii) a 3.38 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂The other H); 4.55(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.70-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.88(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.14 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.27(dd, J ═ 7.5 and 7Hz, 1H: CH at the 4 α position); 5.49(mt, 1H: CH at position 5 γ); 5.54(d, J ═ 8Hz, 1H: CH at position 6 α); 5.88 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.57(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.86(d, J ═ 8Hz, 1H: aromatic H at the 4 ε position); 6.89(dd, J ═ 8 and 1.5Hz, 1H: aromatic H para to Cl in the 4 δ position); 7.11(d, J ═ 1.5Hz, 1H: aromatic H in the Cl ortho position at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.67(mt, 1H: H)₆) (ii) a 8.34(d, J ═ 10Hz, 1H: CONH at position 1); 8.40(d is,j-8 Hz, 1H: CONH at 6 position); 11.68(mf, 1H: OH).

Example 27

The procedure is as in example 1, but using a mixture containing 5 delta-chloromethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_EThe crude mixture of (3) is the starting material. 0.5 g of 5 delta-morpholinomethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I are obtained_EIn the form of a yellow solid, melting at 173 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.15-1.40(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.16 (width d, J ═ 16.5Hz, 1H: CH in position 5. beta.)₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.56(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.80 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.35(mf, 4H: NCH of morpholine)₂) (ii) a 2.49 (Widdd, J ═ 16.5 and 5Hz, 1H: CH in the 5. beta. position₂The other H); 2.84 and 2.86(2s, total 5H: ArNCH)₃And CH₂N); 2.97(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.10-3.20(mt, 1H: CH at position 4. beta₂The other H); 3.17(s, 3H: NCH)₃) (ii) a 3.26(mt, 1H: CH at position 3. delta₂1H) of (1); 3.33 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂The other H); 3.70(mt, 4H: CH for morpholine)₂O); 4.56(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.77(mt, 1H: CH at position 2 α); 4.82 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.87(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.12(d, J ═ 5Hz, 1H: CH at position 5 α); 5.25(dd, J ═ 9 and 6.5Hz, 1H: CH at the 4 α position); 5.52(d, J ═ 8Hz, 1H: CH at position 6 α); 5.53(mt, 1H: CH at position 5. gamma.); 5.87 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.45(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position);6.60(d, J ═ 10Hz, 1H: CONH at position 2); 6.86(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.72(dd, J ═ 4 and 1Hz, 1H: H₆) (ii) a 8.42(d, J ═ 10Hz, 1H: CONH at position 1); 8.50(d, J ═ 8Hz, 1H: CONH at position 6); 11.68(s, 1H: OH).

Example 28

The procedure is as in example 1, but using a mixture containing 5 delta-chloromethyl-4 zeta-methylamino-4 zeta-dedimethylamino-4 epsilon-chloro-5 delta, 5 gamma-dehydropristinamycin I_EThe crude mixture of (3) is the starting material. 0.88 g of 5 delta-morpholinomethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin I are obtained_EIn the form of a yellow solid, melted at 170 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.93(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.15-1.40(mt, 3H: CH at position 3. beta₂1H-in the 3. gamma. CH₂1H and CH at the 5 beta position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.57(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.85 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 1.98(mt, 1H: CH at position 3. beta₂The other H); 2.35(mf, 4H: NCH of morpholine)₂) (ii) a 2.59 (Widdd, J ═ 16.5 and 5.5Hz, 1H in the 5. beta. CH position₂The other H); 2.85-3.05(mt, 3H: CH)₂N and CH in the 4 beta position₂1H) of (1); 2.88(d, J-5 Hz, 3H: ArNCH)₃) (ii) a 3.05-3.25(mt, 1H: CH at position 4. beta₂The other H); 3.14(s, 3H: NCH)₃) (ii) a 3.28(mt, 1H: CH at position 3. delta₂1H) of (1); 3.36 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂The other H); 3.68(mt, 4H: CH for morpholine)₂O); 4.30(q, J ═ 5Hz, 1H: ArNH); 4.56(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.70-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.87(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.18(d, J ═ J ═5Hz, 1H: CH at position 5 α); 5.20-5.35(mt, 1H: CH at position 4 α); 5.52(d, J ═ 8Hz, 1H: CH at position 6 α); 5.57(mt, 1H: CH at position 5 γ); 5.88 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.43(d, J ═ 8Hz, 1H: aromatic H at the 4 epsilon position); 6.57(d, J ═ 10Hz, 1H: CONH at position 2); 6.83(dd, J ═ 8 and 1.5Hz, 1H: aromatic H at the 4 δ position in the C para position); 6.95(d, J ═ 1.5Hz, 1H: aromatic H in the Cl ortho position at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.64(dd, J ═ 4 and 1Hz, 1H: H₆) (ii) a 8.35(d, J ═ 10Hz, 1H: CONH at position 1); 8.51(d, J ═ 8Hz, 1H: CONH at position 6); 11.68(s, 1H: OH).

Example 29

The procedure is as in example 1, but using a mixture containing 5 delta-chloromethyl-4 zeta- (N-methyl-N-allyloxycarbonyl) amino-4 zeta-dedimethylamino-4 epsilon-chloro-5 delta, 5 gamma-dehydropristinamycin I_EThe crude mixture of (3) is the starting material. 0.85 g of 5 delta-morpholinomethyl-4 zeta- (N-methyl-N-allyloxycarbonyl) amino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I are obtained_EIn the form of cream solid, melted at 154 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.13 (width d, J ═ 16Hz, 1H: in the 5. beta. position CH₂1H) of (1); 1.15-1.40(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.55(mt, 1H: CH at position 3. gamma.)₂The other H); 1.55-1.80 (mt: corresponding to CH at position 2. beta₂2H) of (1); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.35(mf, 4H: NCH of morpholine)₂) (ii) a 2.55 (Widdd, J-16 and 5.5Hz, 1H: CH in position 5. beta₂The other H); 2.85(s, 2H: CH)₂N); 3.08(dd, J ═ 14.5 and 7Hz, 1H: CH in the 4. beta. position₂1H) of (1); 3.15(s, 3H: NCH)₃) (ii) a 3.20-3.35(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.29(s, 3H: ArNCH)₃) (ii) a 3.35 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.48(mt, 1H: CH at position 3. delta₂The other H); 3.68(mt, 4H: CH for morpholine)₂O); 4.56(dd, J ═ 8.5 and 6Hz, 1H: CH at position 3 α); 4.64(d, J ═ 5.5Hz, 2H: ArNCOOCH)₂) (ii) a 4.78(mt, 1H: CH at position 2 α); 4.82 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.85(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.12(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.19 and 5.27(2 wide d, J11 Hz and J18 Hz, respectively, each 1H; ═ CH;)₂) (ii) a 5.31(dd, J ═ 9 and 7Hz, 1H: CH at position 4 α); 5.50-5.60(mt, 1H: CH at position 5 γ); 5.53(d, J ═ 8Hz, 1H: CH at position 6 α); 5.80-6.00(mt, 1H: CH) ═ g; 5.87 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.56(d, J ═ 9.5Hz, 1H: CONH at position 2); 7.03(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 7.12(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.68(dd, J ═ 4 and 1Hz, 1H: H₆) (ii) a 8.37(d, J ═ 10Hz, 1H: CONH at position 1); 8.44(d, J ═ 8Hz, 1H: CONH at position 6); 11.67(s, 1H: OH).

Preparation of 5 delta-chloromethyl-4 zeta- (N-methyl-N-allyloxycarbonyl) amino-4 zeta-dedimethylamino-4 epsilon-chloro-5 delta, 5 gamma-dehydropristinamycin I by the same procedure as in example 1_E。

Example 30

The procedure is as in example 1, but using 150 ml of acetonitrile, 15 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EThe crude mixture and 2.5 ml of tetrahydroisoquinoline as starting materials. The reaction mixture was heated to reflux for 1 hour and then concentrated to dryness. The resulting solid was dissolved with a dichloromethane/saturated aqueous sodium bicarbonate mixture. The organic phase was decanted and then concentrated to dryness (45 ℃, 2.7 kpa) yielding 15.4 g of a solid. The solid is purified by chromatography on silica gel (eluent: dichloromethane/methanol gradient, 99.5/0.5 to 98.5/1.5 by volume) followed by 450 g Kromasil C810 μmSilica gel was purified by preparative HPLC using a water-acetonitrile mixture (60/40 by volume, containing 0.1% trifluoroacetic acid) as eluent. After concentrating the fractions to remove acetonitrile, the pH of the aqueous phase was adjusted to 7-8 by adding saturated aqueous sodium bicarbonate. The resulting precipitate was filtered, washed with 25 ml of water, and stirred overnight in a saturated aqueous sodium bicarbonate solution. The solid thus obtained was filtered, washed with 20 ml of water, and then dried at 40 ℃ under reduced pressure (90 Pa) to give 0.73 g of 5. delta. - (tetrahydroisoquinolinyl) methyl-5. delta., 5. gamma. -dehydropristinamycin I_EIt is white crystal and melts at 212-214 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.12 (width d, J ═ 16.5Hz, 1H: CH in position 5. beta.)₂1H) of (1); 1.23(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.33(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.54(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.85 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 1.96(mt, 1H: CH at position 3. beta₂The other H); 2.51 (Width d, J ═ 16.5 and 5.5Hz, 1H: CH in the 5. beta. position₂The other H); 2.66(mt, 2H: ArCH)₂) (ii) a 2.80-3.05(mt, 3H: CH at position 4. beta₂1H and NCH₂)；2.94(s，6H：ArN(CH₃)₂)；3.03(AB，J＝13Hz，2H：CH₂N); 3.10-3.35(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.16(s, 3H: NCH)₃) (ii) a 3.39 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.46(mt, 1H: CH at position 3. delta₂The other H); 3.57(s, 2H: ArCH)₂N); 4.57(dd, J ═ 8 and 6Hz, 1H: CH at position 3 α); 4.77(mt, 1H: CH at position 2 α); 4.84 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.87(dd, J ═ 10 and 1Hz, 1H: CH at position 1 α); 5.13 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.23(dd, J ═ 9 and 7Hz, 1H: CH at position 4 α); 5.51(d, J ═ 8Hz, 1H: CH at position 6 α) (ii) a 5.58(mt, 1H: CH at position 5 γ); 5.88 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.58(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.62(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.93(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.00-7.40 (mt: aromatic H-H corresponding to aromatic 4H-3, 4-dihydro-1H-isoquinoline in the 6. alpha. position₄And H₅11H) of (1); 7.73(dd, J ═ 4 and 1Hz, 1H: H₆) (ii) a 8.35-8.45(mt, 2H: CONH at 1 position and CONH at 6 position); 11.68(s, 1H: OH).

Example 31

The procedure is as in example 1, but using 150 ml of acetonitrile, 15 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EStarting from 3.6 g of 4-fluorophenylpiperazine. The reaction mixture was heated to reflux for 4 hours and then concentrated to dryness. The resulting solid was dissolved in 250 ml of ethyl acetate. The resulting solution was washed three times with 150 ml of water each time and three times with 150 ml of hydrochloric acid each time. The aqueous phases were combined and the pH was adjusted to 7-8 by addition of saturated aqueous sodium bicarbonate. The resulting precipitate was filtered, washed with 50 ml of water, and then dried to give 11.2 g of a solid. The solid obtained is purified by chromatography on silica gel (eluent: dichloromethane/methanol, 99/1% by volume) and then purified using 450 g Kromasil C810 μmSilica gel was purified twice by preparative HPLC using a water-acetonitrile mixture (60/40 by volume, containing 0.1% trifluoroacetic acid) as eluent. After concentrating the fractions to remove acetonitrile, the pH was adjusted to 7-8 by adding saturated aqueous sodium bicarbonate solution to the residual aqueous phase. The precipitate formed is filtered off to give 0.7 g of a solid which is stirred in 20 ml of ether, filtered and then dried at 40 ℃ under reduced pressure (90 Pa). This gave 285 mg of 5 delta- [4- (4-fluorophenyl) piperazin-1-yl]Methyl-5 delta, 5 gamma-dehydropristinamycin I_EIt is in the form of white crystal with variegated color, and is melted at 165-167 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃): 0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.03 (width d, J ═ 16Hz, 1H: in the 5. beta. CH position₂1H) of (1); 1.21(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.32(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.53(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.80 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 1.98(mt, 1H: CH at position 3. beta₂The other H); 2.46(mt, 1H: CH at position 5. beta. -₂The other H); 2.55-3.35(mt, 10H: CH for piperazine)₂N and CH₂N)；2.95(s，6H：ArN(CH₃)₂) (ii) a 2.98(mt, 1H: CH at position 4. beta₂1H) of (1); 3.10-3.35(mt, 2H: CH at position 3. delta₂1H and CH at the 4 beta position₂The other H); 3.18(s, 3H: NCH)₃) (ii) a 3.35-3.50(mt, 2H: CH at position 5. epsilon.)₂1H and CH at the 3 delta position₂The other H); 4.56(dd, J ═ 8 and 6Hz, 1H: CH at position 3 α); 4.77(mt, 1H: CH at position 2 α); 4.83(mt, 1H: CH at the 5. epsilon. position₂The other H); 4.88 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.14 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.20(dd, J ═ 9 and 6Hz, 1H: CH at position 4 α); 5.54(d, J ═ 8Hz, 1H: CH at position 6 α); 5.65(mf, 1H: CH at the 5. gamma. -position); 5.88 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.56(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.80-7.05(mt, 6H: aromatic H at the 4 delta position and fluorophenyl aromatic H); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.73 (width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.38(d, J ═ 10Hz, 1H: CONH at position 1); 8.57(mf, 1H: CONH at 6-position); 11.66(s, 1H: OH).

Example 32

The procedure is as in example 1, but using a mixture containing 5 delta-chloromethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E0.61 g of 5 delta-piperidinomethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_EIn the form of white crystals, melting at 234 ℃And (4) transforming.

¹H N.M.R. Spectrum (600MHz, CDCl)₃δ, in ppm): we observed the presence of very small amounts of other, unidentified pristinamycins and configurations.

0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.16 (width d, J ═ 17.5Hz, 1H: CH in position 5. beta.)₂1H) of (1); 1.23(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.35-1.65(mt, 7H: CH at position 3. gamma.)₂And another H of piperidine and CH of piperidine₂) (ii) a 1.60-1.80 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 1.97(mt, 1H: CH at position 3. beta₂The other H); 2.20-2.40(mf, 4H: NCH of piperidine)₂) (ii) a 2.49 (Widdd, J ═ 17.5 and 5.5Hz, 1H: CH in the 5. beta. position₂The other H); 2.78(s, 2H: CH)₂N)；2.82(s，3H：ArNCH₃) (ii) a 2.95(dd, J ═ 14 and 7Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.10-3.30(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.15(s, 3H: NCH)₃) (ii) a 3.35 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.45(mt, 1H: CH at position 3. delta₂The other H); 3.60-3.80 (broadened mf, 1H: ArNH); 4.55(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.70-4.90(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.86 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.10(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.22(dd, J ═ 10 and 7Hz, 1H: CH at position 4 α); 5.48(mt, 1H: CH at position 5. gamma.); 5.52(d, J ═ 8Hz, 1H: CH at position 6 α); 5.85 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.45(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.58(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.85(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.71 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.41(mt, 2H: CONH at 1 position and CONH at 6 position); 11.67(s, 1H: OH).

Example 33

The procedure is as in example 1, but using 100 ml of acetonitrile, 30 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EThe crude mixture of (a) and 2.9 ml of 2-methoxyethylamine are used as starting materials. The reaction mixture was heated at reflux for 2 hours and then concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). The solid obtained is dissolved in 50 ml of dichloromethane and in 50 ml of 0.1N hydrochloric acid three times. The pH was adjusted to 7-8 by adding saturated aqueous sodium bicarbonate to the aqueous solution and extracting twice with 50 ml of dichloromethane each time. The organic phase was decanted, dried over sodium sulfate, filtered and concentrated to dryness at 45 ℃ under reduced pressure (2.7 kpa). This gives 8.5 g of a solid which is purified by chromatography on silica gel (eluent: dichloromethane/methanol gradient 98/2 by volume and then 97/3). The solid obtained is stirred in 25 ml of diethyl ether, filtered and washed with 10 ml of diethyl ether and dried at 45 ℃ under reduced pressure (90 Pa) to give 0.77 g of 5 delta- (2-methoxyethylaminomethyl) -5 delta, 5 gamma-dehydropristinamycin I_EIn the form of cream solid, melted at 200 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ in ppm): we observed the presence of very small amounts of other, unidentified pristinamycins and configurations.

0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.20 (width d, J ═ 17Hz, 1H: in the 5. beta. position CH₂1H) of (1); 1.25(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.55(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.80 (mt: 2H corresponds to CH at position 2. beta₂) (ii) a 1.98(mt, 1H: CH at position 3. beta₂The other H); 2.51 (Widdd, J ═ 17 and 5.5Hz, 1H: CH in the 5. beta. position₂The other H); 2.71(mt, 2H: NCH)₂)；2.85-2.95(mt，1H：NH)；2.93(s，6H：ArN(CH₃)₂) (ii) a 2.99(dd, J ═ 14 and 7Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.10-3.30(mt, 4H: CH at position 4. beta₂Another H-is in the 3. delta. position CH₂1H and CH₂N)；3.13(s，3H：NCH₃) (ii) a 3.30-3.40(mt, 1H: CH at position 5. epsilon.)₂1H) of (1); 3.33(s, 3H: OCH)₃) (ii) a 3.40-3.55(mt, 1H: CH at position 3. delta₂The other H); 3.48(t, J ═ 5.5Hz, 2H: OCH)₂) (ii) a 4.57(dd, J ═ 8.5 and 5Hz, 1H: CH at position 3 α); 4.70-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.87 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.12(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.25(dd, J ═ 8 and 7Hz, 1H: CH at position 4 α); 5.53(mt, 1H: CH at position 5. gamma.); 5.56(d, J ═ 8Hz, 1H: CH at position 6 α); 5.86 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.50-6.65(mt, 1H: CONH at 2 position); 6.57(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 6.89(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.69 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.54(d, J ═ 8Hz, 1H: CONH at position 6); 11.65 (broadened mf, 1H: OH).

Example 34

The procedure is as in example 1, but using 100 ml of acetonitrile, 10 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin_EAnd 2.27 g of bis- (2-methoxyethyl) amine. The reaction mixture was heated at reflux for 18h and then concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). The solid obtained was dissolved with 200 ml of dichloromethane and 100 ml of aqueous solution. The pH was adjusted to 7-8 by adding sodium bicarbonate to the aqueous phase. The organic phase is decanted, dried over sodium sulfate, filtered and then concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa) to give 9.4 g of yellow egg icing which is purified by chromatography on silica gel (eluent: dichloromethane/methanol, 97/3 by volume). The fractions containing the desired product were concentrated to dryness. The solid thus obtained was dissolved in 200 ml of dichloromethane. The resulting solution was extracted three times with 150 ml of 0.1N hydrochloric acid solution each time. The aqueous phase is dissolved in saturated aqueous sodium bicarbonate solution and extracted three more times with 150 ml of dichloromethane each time. The organic phases are combined and then concentrated to dryness to give 2g of product, which is recrystallized from 30 ml of methanol. Thus obtainedThe solid was filtered, washed 2 times with 5 ml of methanol each time and then dried at 45 ℃ under reduced pressure (90 Pa) to give 1.38 g of 5. delta. [ bis- (2-methoxyethyl) aminomethyl-]-5 delta, 5 gamma-dehydropristinamycin I_EIs in the form of white crystal and is melted at 180-182 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm) we observed the presence of very small amounts of other unidentified pristinamycins and configurations.

0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.05 (very broad d, J ═ 17Hz, 1H: CH in position 5. beta.)₂1H) of (1); 1.24(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.45-1.65 (mt: corresponding to CH at the 3. gamma. position₂1H of another H); 1.66 and 1.73(2mts, 1H each: CH at position 2. beta₂) (ii) a 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.46 (width d, J ═ 17Hz, 1H: in the 5. beta. position CH₂The other H); 2.68(mt, 4H: NCH)₂) (ii) a 2.90-3.05(mt, 1H: CH at position 4. beta₂1H) of (1); 2.94(s, 6H: ArN (CH)₃)₂) (ii) a 3.05 (Width s, 2H: CH)₂N); 3.10-3.30(mt, 2H: CH at position 4. beta₂Another H and CH at the 3 delta position₂1H) of (1); 3.18(s, 3H: NCH)₃) (ii) a 3.25-3.40(mt, 1H: CH at position 5. epsilon.)₂1H) of (1); 3.33(s, 6H: OCH)₃) (ii) a 3.40-3.55(mt, 1H: CH at position 3. delta₂The other H); 3.48(t, J ═ 6Hz, 4H: OCH)₂) (ii) a 4.58(mt, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.80-4.95(mt, 1H: CH at position 5. epsilon.)₂The other H); 4.87 (width d, J ═ 10Hz, 1H: at position CH 1 α); 5.12(d, J ═ 5Hz, 1H: CH at position 5 α); 5.22(mt, 1H: CH at position 4 α); 5.48(mt, 1H: CH at position 5. gamma.); 5.57(d, J ═ 8Hz, 1H: CH at position 6 α); 5.86 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.55(d, J ═ 9.5Hz, 1H: CONH at position 2); 6.62(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.92(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.70 (Width d, J ═4Hz，1H：H₆) (ii) a 8.37(d, J ═ 10Hz, 1H: CONH at position 1); 8.45(d, J ═ 8Hz, 1H: CONH at position 6); 11.66(s, 1H: OH).

Example 35

In a three-necked flask containing 50 ml of acetonitrile, 0.14 g of 2-mercapto-1-methylimidazole and then 62 mg of sodium hydride, 0.33 ml of triethylamine and 2.5 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 33 mol% of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydroprimycin I were added_EThe crude mixture of (1). The reaction mixture was heated at 40 ℃ for 48 hours. After addition of 2 ml of water, the reaction mixture is concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). The residue was dissolved in 25 ml of dichloromethane and the resulting mixture was washed twice with 20 ml of water each time. The organic phase is decanted and extracted three times with 20 ml of 0.1N hydrochloric acid each time. After decantation, the pH was adjusted to 7 by adding saturated aqueous sodium bicarbonate solution to the aqueous phase. The organic phase is extracted twice with 25 ml of dichloromethane each time, dried over sodium sulfate, filtered and then reduced to dryness. The residue is dissolved in 20 ml of isopropyl ether, filtered and dried at 40 ℃ and 90 Pa to give 0.6 g of 5 delta- (1-methyl-2-imidazolylthiomethyl) -5 delta, 5 gamma-dehydropristinamycin I_EIn the form of cream solid, melted at 147 ℃.

0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.15-1.35(mt, 3H: CH at position 5. beta₂1H-in the 3. beta. position CH₂And CH at the 3. gamma. position₂1H) of (1); 1.29(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.56(mt, 1H: CH at position 3. gamma.)₂The other H); 1.64 and 1.72(2mts, 1H each: CH at position 2. beta₂) (ii) a 1.98 (mt: 1H corresponds to CH at position 3. beta₂The other H); 2.38 (Widdd, J ═ 17 and 5Hz, 1H in the 5. beta. position CH₂The other H); 2.90-3.00(mt, 1H: CH at position 4. beta₂1H) of (1); 2.92(s, 6H: ArN (CH)₃)₂) (ii) a 3.10-3.30(mt, 2H: CH at position 4. beta₂Is at the 3 delta position CH₂1H) of (1); 3.18(s, 3H: NCH)₃) (ii) a 3.30 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂The other H); 3.55(d, J ═ 14Hz, SCH 1H: 1H)₂)；3.65(s，3H：NCH₃)；3.81(d，J＝14Hz，1H：SCH₂The other H); 4.56(dd, J ═ 8 and 7Hz, 1H: CH at position 3 α); 4.76(mt, 1H: CH at position 2 α); 4.87 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.00 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 5.05(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.17(dd, J ═ 10 and 6Hz, 1H: CH at position 4 α); 5.50(mt, 1H: CH at position 5 γ); 5.58(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.53(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.57(d, J ═ 9Hz, 1H: CONH at position 2); 6.87(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 6.93 and 7.10(2 widths s, each 1H: imidazolyl CH ═ CH); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.68 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.45(d, J ═ 8Hz, 1H: CONH at position 6); 11.65 (broadened mf, 1H: OH).

Example 36

In a three-necked flask containing 25 ml of acetonitrile, 0.57 ml of 2- (diethylamino) ethanethiol, 18 mg of sodium hydride and 0.54 ml of triethylamine were successively added. To the resulting solution, 50 ml of acetonitrile and 7.5 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 40 mol% were added_EThe crude mixture of (e.g. as obtained in example 1) was pre-adjusted to pH7 by addition of triethylamine. The reaction mixture was heated at 45 ℃ for 48 hours. At this point 2 ml of water were added and the resulting mixture was concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). The residue was dissolved in 50 ml of dichloromethane and the resulting solution was washed twice with 25 ml of water each time. The organic phase is decanted, dried over sodium sulfate, filtered and concentrated to dryness to give 6 g of crude product, which is purified by chromatography on silica gel (eluent: dichloromethane/methanol gradient 98/2 to 95/5 by volume). Containing the desired productThe fractions were concentrated to dryness and the residue was taken up in 20 ml of dichloromethane. The resulting solution was filtered and concentrated to dryness at 45 ℃ under reduced pressure (2.7 kPa). The residue is dissolved in 25 ml of isopropyl ether, filtered and dried at 40 ℃ under 90 Pa to give 1g of 5 delta-diethylaminoethylthiomethyl-5 delta, 5 gamma-dehydropristinamycin I_ELight yellow, in the form of the hemi-hydrochloride salt, melts at 135 ℃.

¹H N.M.R. Spectrum (600MHz, CDCl)₃δ, in ppm):

0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.10(mt, 1H: CH at position 5. beta. -₂1H) of (1); 1.17(mf, 6H: ethyl CH)₃) (ii) a 1.15-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.57(mt, 1H: CH at position 3. gamma.)₂The other H); 1.66 and 1.73(2mts, 1H each: CH at position 2. beta₂) (ii) a 2.01(mt, 1H: CH at position 3. beta. -₂The other H); 2.47 (Widdd, J ═ 17 and 5.5Hz, 1H: CH in the 5. beta. position₂The other H); 2.55-2.95(mt, 6H: NCH)₂)；2.94(s，6H：ArN(CH₃)₂) (ii) a 3.00(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. CH position₂1H) of (1); 3.09(d, J ═ 15Hz, 1H: CH)₂1H of S); 3.10-3.30(mt, 3H: CH at position 4. beta₂Another H-is in the 3. delta. position CH₂1H and CH₂The other H of S); 3.18(s, 3H: NCH)₃) (ii) a 3.46(mt, 1H: CH at position 3. delta₂1H) of (1); 3.53 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.58(dd, J ═ 8 and 6Hz, 1H: CH at position 3 α); 4.70-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.87 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.11(d, J ═ 5Hz, 1H: CH at position 5 α); 5.22(dd, J ═ 10 and 6.5Hz, 1H: CH at the 4 α position); 5.47(d, J ═ 8Hz, 1H: CH at position 6 α); 5.56(mt, 1H: CH at position 5. gamma.); 5.86 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.55-6.65(mt, 1H: CONH at 2-position); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.93(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to in6 alpha-aromatic H-H₄And H₅7H) of (1); 7.72 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.40(d, J ═ 10Hz, 1H: CONH at position 1); 8.54(d, J ═ 8Hz, 1H: CONH at position 6); 11.67(mf, 1H: OH).

Example 37

The procedure is as in example 36, but using, on the one hand, 25 ml of acetonitrile, 0.32 ml of (4-pyridyl) methanethiol, 120 mg of sodium hydride and, on the other hand, 5g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 40 mol% of_EStarting from a crude mixture of (a) and triethylamine in 40 ml of acetonitrile. The reaction mixture is heated at 45 ℃ for 1.5 hours and worked up as in example 36 to give 5g of crude product which is purified by flash chromatography on 0.04-0.063 mm silica gel (eluent: dichloromethane/methanol gradient: 99/1 to 98/2 by volume). The fractions containing the desired product were concentrated to dryness to give 1.2 g of yellow egg icing which was comminuted in 25 ml of isopropyl ether for 1 hour with stirring. The solid obtained is filtered, washed with 10 ml of isopropyl ether and then dried at 45 ℃ and 90 Pa. This gave 0.85 g of 5 delta- (4-pyridylmethyl) thiomethyl-5 delta, 5 gamma-dehydropristinamycin I_EAs a pale yellow solid, melting at 138 ℃.

According to J.BARNES and coworkers, "Eur.J.Med.chem.",23211-16(1988) 4-pyridylmethanethiol can be prepared.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm). 0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.08 (width d, J ═ 17Hz, 1H: CH in position 5. beta.)₂1H) of (1); 1.20-1.35(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.33(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.58(mt, 1H: CH at position 3. gamma.)₂The other H); 1.67 and 1.74(2mts, 1H each: CH at position 2. beta.)₂) (ii) a 2.01(mt, 1H: CH at position 3. beta. -₂The other H); 2.53 (Widdd, J ═ 17 and 5Hz, 1H in the 5. beta. position CH₂The other H); 2.85-3.00(mt, 2H: CH)₂S)；2.95(s，6H：ArN(CH₃)₂) (ii) a 3.00(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. CH position₂1H) of (1); 3.10-3.25(mt, 1H: CH at position 4. beta₂The other H); 3.19(s, 3H: NCH)₃) (ii) a 3.32(mt, 1H: CH at position 3. delta₂1H) of (1); 3.45-3.60(mt, 1H: CH at position 5. epsilon.)₂1H) of (1); 3.50(mt, 1H: CH at position 3. delta₂The other H); 3.54 and 3.62(2d, J ═ 14Hz, 1H each: SCH₂Ar); 4.60(dd, J ═ 8 and 6Hz, 1H: CH at position 3 α); 4.70-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.90 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.13 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.26(dd, J ═ 9.5 and 6.5Hz, 1H: CH at the 4 α position); 5.39 (width d, J ═ 4Hz, 1H: CH at the 5 γ position); 5.60(d, J ═ 8Hz, 1H: CH at position 6 α); 5.89 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.50-6.65(mt, 1H: CONH at 2 position); 6.60(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.93(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄-H₅And 9H with pyridine aromatic H in the beta position); 7.74 (Width d, J ═ 4Hz, 1H: H)₆) (ii) a 8.40(d, J ═ 10Hz, 1H: CONH at position 1); 8.45-8.60(mt, 3H: CONH at 6 position and pyridine aromatic H at alpha position); 11.68(s, 1H: OH).

Example 38

The procedure is as in example 36, but using, on the one hand, 25 ml of acetonitrile, 0.84 g of (3-pyridyl) methanethiol, 0.24 g of sodium hydride and, on the other hand, 10 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 40 mol% of_EStarting from a crude mixture of (a) and triethylamine in 75 ml of acetonitrile. The reaction mixture was heated at 60 ℃ for 2 hours and then worked up as in example 36 to give 8 g of crude product which was purified by chromatography on silica gel (eluent: dichloromethane/methanol gradient: 99/1 to 98/2 by volume). Thus 2.1 g of product are obtained which is purified again by flash chromatography on 0.040-0.063 mm silica gel (eluent: dichloromethane/methanol gradient: 99/1 to 97/3 by volume). The fractions containing the desired product were concentrated and the residue obtained was dried at 45 ℃ C (90 Pa) to give 0.19 g of 5Delta-3-pyridylmethylthiomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIn the form of a yellow solid, melting at 128 ℃.

3-pyridylmethanethiol can be prepared according to T.BROWN and co-workers J.Med.chem., 35, 3613-24 (1992).

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm):

0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.08 (width d, J ═ 17Hz, 1H: CH in position 5. beta.)₂1H) of (1); 1.27(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.33(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.58(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.80 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 2.01(mt, 1H: CH at position 3. beta. -₂The other H); 2.55(dd, J ═ 17 and 5.5Hz, 1H in the 5. beta. position CH₂The other H); 2.93(s, 6H: ArN (CH)₃)₂) (ii) a 2.85-3.05(mt, 3H: CH at position 4. beta₂1H and SCH₂) (ii) a 3.15-3.25(mt, 1H: CH at position 4. beta₂The other H); 3.18(s, 3H: NCH)₃) (ii) a 3.31(mt, 1H: CH at position 3. delta₂1H) of (1); 3.45-3.60(mt, 2H: CH at position 5. epsilon.)₂1H and CH at the 3 delta position₂The other H); 3.57 and 3.66(2d, J ═ 14Hz, 1H each: SCH₂Ar); 4.60(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.75-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.88(dd, J ═ 10 and 1.5Hz, 1H: CH at position 1 α); 5.12(d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.24(dd, J ═ 9 and 6.5Hz, 1H: CH at the 4 α position); 5.54 (width d, J ═ 5Hz, 1H: 5 γ); 5.60(d, J ═ 8Hz, 1H: CH at position 6 α); 5.88 (deduplicated q, J ═ 7 and 1Hz, 1H: CH at position 1 β); 6.57(d, J ═ 9Hz, 1H: CONH at position 2); 6.59(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 6.93(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.25-7.45 (mt: corresponding to aromatic H at 6. alpha. -position H- -H at pyridine 5-position₄And H₅8H) of (1); 7.70-7.80(mt, 2H: H)₆And H at pyridine 4-position); 8.41(d, J ═ 10Hz, 1H: CONH at position 1);8.48(dd, J ═ 5 and 1Hz, 1H: H at pyridine position 6); 8.51(d, J ═ 8Hz, 1H: CONH at position 6); 8.58d, J ═ 1Hz, 1H: h at pyridine 2-position); 11.68(s, 1H: OH).

Example 39

The procedure is as in example 36, but using, on the one hand, 2 l of acetonitrile, 12.2 g of 2-piperidinoethanethiol, 4.7 g of sodium hydride and, on the other hand, 190 g of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 40 mol% of 5. delta. -chloromethyl_EAnd a solution of triethylamine in 1 liter of acetonitrile as starting materials. The reaction mixture was heated at 55 ℃ for 4 hours and then worked up as in example 36 to give 215 g of crude product which was purified by flash chromatography on 0.040-0.063 mm silica gel (eluent: dichloromethane/methanol gradient: 100/0 to 95/5 by volume). The fractions containing the desired product were concentrated and then processed through 500 g Kromasil C810 micronSilica gel was purified by preparative High Performance Liquid Chromatography (HPLC) using a water-acetonitrile mixture (70/30 by volume, containing 0.1% trifluoroacetic acid) as eluent. After concentration of the fractions containing the desired product, the pH was adjusted to 7-8 by adding saturated aqueous sodium bicarbonate to the remaining aqueous phase, followed by extraction with 100 ml of dichloromethane. The organic phase is decanted, dried over magnesium sulfate, filtered and concentrated to thousand. The residue was dried at 45 deg.C (90 Pa) to give 5.2 g of 5 delta-pyridinoethylthiomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIt is yellow egg frosted and melted at 128 deg.C.

2-Piperidinylmethanethiol can be prepared according to CLINTON and co-workers journal of the American society for chemistry, 70, 950-51 (1948).

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm):

0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 1.10 (width d, J ═ 16.5Hz, 1H: CH in position 5. beta.)₂1H) of (1); 1.26(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃)；1.43(mt，2H：CH₂)；1.59(mt，5H：2CH₂And CH at the 3. gamma. position₂The other H); 1.60-1.80(mt, 2H: CH at position 2. beta₂) (ii) a 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.35-2.60(mt, 5H: SCH)₂CH₂N and CH in the 5 beta position₂The other H); 2.58(mf, 4H: NCH)₂)；2.95(s，6H：ArN(CH₃)₂) (ii) a 2.99(dd, J ═ 14 and 7Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.09 (Width s, 2H: SCH)₂) (ii) a 3.10-3.20(mt, 1H: CH at position 4. beta₂The other H); 3.17(s, 3H: NCH)₃) (ii) a 3.28(mt, 1H: CH at position 3. delta₂1H) of (1); 3.40-3.55(mt, 2H: CH at position 5. epsilon.)₂1H and CH at the 3 delta position₂The other H); 4.57(dd, J ═ 8 and 5Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.84 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.87(dd, J ═ 10 and 1.5Hz, 1H: CH at position 1 α); 5.09 (width d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.22(dd, J ═ 9 and 7Hz, 1H: CH at position 4 α); 5.50 (width d, J ═ 4.5Hz, 1H: CH at the 5 γ position); 5.52(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (deduplicated q, J ═ 7 and 1.5Hz, 1H: CH at position 1 β); 6.58(d, J ═ 9Hz, 1H: CONH at position 2); 6.61(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.91(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.70(dd, J ═ 4 and 1Hz, 1H: H₆) (ii) a 8.38(d, J ═ 10Hz, 1H: CONH at position 1); 8.45(d, J ═ 8Hz, 1H: CONH at position 6); 11.67(mf, 1H: OH).

Example 40

The procedure is as in example 36, but using, on the one hand, 4 ml of acetonitrile, 67.3 mg of 2-mercaptobenzimidazole, 21.5 mg of sodium hydride and, on the other hand, 750 mg of 5. delta. -chloromethyl-5. delta., 5. gamma. -dehydropristinamycin I containing 40 mol% of_EStarting from a crude mixture of (a) and triethylamine in 2 ml of acetonitrile. The reaction mixture is added at 45 DEG CThe mixture was heated for 4 hours and then worked up as in example 36, and the crude product obtained was purified by flash chromatography on 32-63 μm silica gel (eluent: dichloromethane/methanol gradient: 99/1 to 95/5 by volume). The fractions containing the desired product were concentrated and the residue obtained was dried at 45 ℃ C (90 Pa) to give 115 mg of 5 delta-2-benzimidazolylthiomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIn the form of a white solid.

Examples 41 to 49

The following products were prepared, operating analogously to the process described in example 29 or in international application WO 99/43699:

EXAMPLE 41

4 zeta-dedimethylamino-4 zeta- (N-methyl-N-4-pyridylmethyl) amino-5 delta-morpholinomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIn an orange-red solid.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm):

0.91(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.03(mf, 1H: CH at position 5. beta.)₂1H) of (1); 1.25(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.33(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.40-1.80 (mt: corresponding to CH at the 3. gamma. position₂And CH in the 2 beta position₂3H) of (1); 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.39(mf, 4H: NCH)₂) (ii) a 2.48 (width d, J ═ 17Hz, 1H: in the 5. beta. position CH₂The other H); 2.85-3.05(mt, 3H: CH at position 4. beta₂1H and NCH₂)；3.09(s，3H：ArNCH₃) (ii) a 3.10-3.45(mt, 3H: CH at position 4. beta₂Is at the 3 delta position CH₂And CH at the 5 epsilon position₂1H) of (1); 3.16(s, 3H: NCH)₃) (ii) a 3.46(mt, 1H: CH at position 3. delta₂The other H); 3.73(mf, 4H: CH)₂O)；4.53(AB，J＝17Hz，2H：ArNCH₂Ar); 4.57(dd, J ═ 8.5 and 5.5Hz, 1H: CH at position 3 α); 4.70-4.85 (m)t, 2H: at the 2 alpha position CH and at the 5 epsilon position CH₂The other H); 4.87(dd, J ═ 10 and 1.5Hz, 1H: CH at position 1 α); 5.10 (width d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.20(dd, J ═ 10 and 7Hz, 1H: CH at position 4 α); 5.50-5.65(mf, 1H: CH at the 5. gamma. -position); 5.53(d, J ═ 8Hz, 1H: CH at position 6 α); 5.86 (deduplicated q, J ═ 7 and 1.5Hz, 1H: CH at position 1 β); 6.52(d, J ═ 8Hz, 2H: aromatic H at the 4 ε position); 6.90(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.00(mf, 1H: CONH at 2 position); 7.20-7.40 (mt: corresponding to aromatic H at 6. alpha. -aromatic H-H at pyridine. beta. -position₄And H₅9H) of (1); 7.62 (Width d, J ═ 4 and 1Hz, 1H: H)₆) (ii) a 8.37(d, J ═ 10Hz, 1H: CONH at position 1); 8.48 (width d, J ═ 8Hz, 1H: CONH at position 6); 8.60(d, J ═ 6Hz, 2H: aromatic H in the pyridine alpha position); 11.65(s, 1H: OH).

Example 42

4 zeta-dedimethylamino-4 zeta- (N-methyl-N-phenoxycarbonyl) amino-5 delta-morpholinomethyl-5 delta, 5 gamma-dehydropristinamycin I_EAnd is white amorphous powder.

Mass spectrometry-DCI chemical ionization (Desorption chemical ionization-Ammonia)

M/z1056 corresponds to M + H⁺

Purity 85% (HPLC eluent: water-CH)₃CN (50/50 by volume) + 0.1% trifluoroacetic acid)

Example 43

4 ζ -dedimethylamino-4 ζ - (N-methyl-N-propoxycarbonyl) amino-5 δ -morpholinomethyl 5 δ, 5 γ -dehydropristinamycin I_EAnd is white amorphous powder.

M/z1022 corresponds to M +^H+

Purity 86% (HPLC eluent: water-CH)₃CN (50/50 by volume) + 0.1% trifluoroacetic acid)

Example 44

4 zeta-dedimethylamino-4 zeta- (N-methyl-N-isobutoxycarbonyl) amino-5 delta-morpholinomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIn the form of white amorphous powder, melted (decomposed) to 148 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ in ppm):

0.80-1.00(mt, 9H: CH at 2. gamma. position₃And isobutyl CH₃) (ii) a 1.15-1.35(mt, 3H: CH at position 5. beta₂1H-in the 3. beta. position CH₂And CH at the 3. gamma. position₂1H) of (1); 1.32(d, J ═ 7Hz, 3H: CH)₃At the 1 γ position); 1.55-1.80 (mt: corresponding to CH at the 3. gamma. position₂And CH in the 2 beta position₂3H) of (1); 1.85-2.05(mt, 2H: CH at position 3. beta₂The other H and isobutyl CH); 2.36(mf, 4H: NCH)₂) (ii) a 2.59 (Widdd, J ═ 18 and 5Hz, 1H in the 5. beta. position CH₂The other H); 2.86(s, 2H: NCH)₂) (ii) a 3.09(dd, J ═ 14 and 6.5Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.14(s, 3H: NCH)₃) (ii) a 3.20-3.35(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.30(s, 3H: ArNCH)₃) (ii) a 3.36 (width d, J ═ 17Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.49(mt, 1H: CH at position 3. delta₂The other H); 3.70(mt, 4H: CH)₂O)；3.93(d，J＝7Hz，2H：ArNCOOCH₂) (ii) a 4.56(dd, J ═ 7 and 5.5Hz, 1H: CH at position 3 α); 4.75-4.90(mt, 3H: CH at position 2. alpha. to CH at position 5. epsilon.)₂And CH at the 1 alpha position); 5.15 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.35(mt, 1H: CH at position 4 α); 5.54(d, J ═ 8Hz, 1H: CH at position 6 α); 5.56(mt, 1H: CH at position 5. gamma.); 5.88 (deduplicated q, J ═ 7 and 1.5Hz, 1H: CH at position 1 β); 6.57(d, J ═ 9Hz, 1H: CONH at position 2); 7.03(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 7.13(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.15-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.70 (Width d, J ═ 4.5Hz, 1)H：H₆) (ii) a 8.37(d, J ═ 10Hz, 1H: CONH at position 1); 8.46(d, J ═ 8Hz, 1H: CONH at position 6); 11.68(s, 1H: OH).

Example 45

4 zeta-dedimethylamino-4 zeta- (N-methyl-N-ethoxycarbonyl) amino-5 delta-morpholinomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIn the form of white amorphous powder, melted (decomposed) to 158 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm):

0.93(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.05-1.20(mt, 1H: CH at position 5. beta₂1H) of (1); 1.20-1.40(mt, 2H: CH at position 3. beta₂And CH at the 3. gamma. position₂1H) of (1); 1.26(t, J ═ 7Hz, 3H: CH)₃) (ii) a 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.50-1.80 (mt: corresponding to CH at the 3. gamma. position₂And CH in the 2 beta position₂3H) of (1); 2.01(mt, 1H: CH at position 3. beta. -₂The other H); 2.37(mf, 4H: NCH)₂) (ii) a 2.54(mt, 1H: CH at position 5. beta. -₂The other H); 2.86(s, 2H: NCH)₂) (ii) a 3.08(dd, J ═ 13 and 7Hz, 1H: CH in the 4. beta. position₂1H) of (1); 3.17(s, 3H: NCH)₃) (ii) a 3.20-3.40(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.28(s, 3H: ArNCH)₃) (ii) a 3.35 (width d, J ═ 17Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.50(mt, 1H: CH at position 3. delta₂The other H); 3.70(mt, 4H: CH)₂O)；4.21(q，J＝7Hz，2H：ArNCOOCH₂) (ii) a 4.58(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.70-4.90(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.88 (width d, J ═ 10Hz, 1H: CH at position 1 α); 5.13 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.31(dd, J ═ 10 and 7Hz, 1H: CH at position 4 α); 5.50-5.60(mt, 2H: CH at position 5. gamma. and CH at position 6. alpha.); 5.88 (width q, J ═ 7Hz, 1H: CH at position 1 β); 6.56(d, J ═ 9Hz, 1H: CONH at position 2); 7.05(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 7.13(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.68 (Width d, J ═ 4.5Hz, 1H: H)₆) (ii) a 8.37(d, J ═ 10Hz, 1H: CONH at position 1); 8.45(d, J ═ 8Hz, 1H: CONH at position 6); 11.67(s, 1H: OH).

Example 46

4 ζ -dedimethylamino-4 ζ - (N-methyl-N-p-tolyloxycarbonyl) amino-5 δ -morpholinomethyl-5 δ, 5 γ -dehydropristinamycin I_EIn the form of white amorphous powder, melted (decomposed) at 147 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm):

0.93(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.15-1.35(mt, 3H: CH at position 5. beta₂1H-in the 3. beta. position CH₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.50-1.65 (mt: corresponding to CH at the 3. gamma. position₂The other H); 1.67 and 1.77(2mts, 1H each: CH at position 2. beta₂) (ii) a 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.30-2.40(mf, 4H: NCH)₂)；2.35(s，3H：ArCH₃) (ii) a 2.52(mt, 1H: CH at position 5. beta₂The other H); 2.82(s, 2H: NCH)₂) (ii) a 3.11(dd, J ═ 14 and 7Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.16(s, 3H: NCH)₃) (ii) a 3.20-3.50(mt, 3H: CH at position 4. beta₂Is at the 3 delta position CH₂And CH at the 5 epsilon position₂1H) of (1); 3.40 (Width s, 3H: ArNCH)₃) (ii) a 3.50(mt, 1H: CH at position 3. delta₂The other H); 3.70(mt, 4H: CH)₂O); 4.58(dd, J ═ 8 and 6.5Hz, 1H: CH at position 3 α); 4.75-4.90(mt, 3H: CH at position 2. alpha. to CH at position 5. epsilon.)₂And CH at the 1 alpha position); 5.13 (width d, J ═ 5.5Hz, 1H: CH at position 5 α); 5.34(dd, J ═ 7.5 and 7Hz, 1H: CH at position 4 α); 5.45(mf, 1H: CH at the 5. gamma. -position); 5.53(d, J ═ 8Hz, 1H: CH at position 6 α); 5.87 (deduplicated q, J ═ 7 and 1.5Hz, 1H: CH at position 1 β); 6.56(d, J ═ 9Hz, 1H: CONH at position 2); 6.95-7.40 (mt: corresponding to aromatic H at the 4. epsilon. -aromatic H-tolylaromatic H at the 4. delta. -aromatic H at the 6. alpha. -aromatic H-H₄And H₅15H) of (1); 7.64 (Width d, J ═ 4.5Hz, 1H: H)₆) (ii) a 8.35(d, J ═ 10Hz, 1H: CONH at position 1); 8.44(d, J ═ 8Hz, 1H: CONH at position 6); 11.67(s, 1H: OH).

Example 47

4 Zeta-dedimethylamino-4 Zeta- (N-methyl-N-3-butenyloxycarbonyl) amino-5 delta-morpholinomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIn a white solid state, melts at 138-140 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm):

0.93(t, J ═ 7.5Hz, 3H: CH at the 2. gamma. position₃) (ii) a 1.15-1.35(mt, 3H: CH at position 5. beta₂1H-in the 3. beta. position CH₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.50-1.65 (mt: 1H corresponds to CH at the 3. gamma. position₂The other H); 1.65-1.80(mt, 2H: CH at position 2. beta₂) (ii) a 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.30-2.45(mt, 2H: CH)₂)；2.37(mf，4H：NCH₂) (ii) a 2.57 (Widdd, J ═ 17 and 5.5Hz, 1H: CH in the 5. beta. position₂The other H); 2.86(s, 2H: NCH)₂) (ii) a 3.09(dd, J ═ 14 and 7Hz, 1H in the 4. beta. position CH₂1H) of (1); 3.14(s, 3H: NCH)₃) (ii) a 3.15-3.35(mt, 2H: CH at position 4. beta₂And CH at the 3 delta position₂1H) of (1); 3.27(s, 3H: ArNCH)₃) (ii) a 3.36 (width d, J ═ 17Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.50(mt, 1H: CH at position 3. delta₂The other H); 3.69(mt, 4H: CH)₂O)；4.19(t，J＝7Hz，2H：ArNCOOCH₂) (ii) a 4.57(dd, J ═ 8 and 6.5Hz, 1H: CH at position 3 α); 4.70-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.87(dd, J ═ 10 and 1.5Hz, 1H: CH at position 1 α); 5.05-5.15(mt, 2H: ═ CH)₂) (ii) a 5.14 (width d, J ═ 5.5Hz,1H: CH at position 5 α); 5.34(dd, J ═ 7.5 and 7Hz, 1H: CH at position 4 α); 5.54(d, J ═ 8Hz, 1H: CH at position 6 α); 5.56(mt, 1H: CH at position 5. gamma.); 5.65-5.85(mt, 1H: CH) ═ c; 5.88 (deduplicated q, J ═ 7 and 1.5Hz, 1H: CH at position 1 β); 6.57(d, J ═ 9Hz, 1H: CONH at position 2); 7.04(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 7.12(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.69(dd, J ═ 4.5 and 1Hz, 1H: H₆) (ii) a 8.37(d, J ═ 10Hz, 1H: CONH at position 1); 8.46(d, J ═ 8Hz, 1H: CONH at position 6); 11.68(s, 1H: OH).

Example 48

4 zeta-dedimethylamino-4 zeta- (N-methyl-N-neopentyloxycarbonyl) amino-5 delta-morpholinomethyl-5 delta, 5 gamma-dehydropristinamycin I_EIs in a white solid state and melts at 140-146 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ in ppm):

0.75-1.00(mt, 12H: CH at 2. gamma. position₃And C (CH)₃)₃) (ii) a 1.15-1.35(mt, 3H: CH at position 5. beta₂1H-in the 3. beta. position CH₂And CH at the 3. gamma. position₂1H) of (1); 1.30(d, J-7 Hz, 3H: CH at position 1. gamma₃) (ii) a 1.50-1.80 (mt: corresponding to CH at the 3. gamma. position₂And CH in the 2 beta position₂3H) of (1); 1.99(mt, 1H: CH at position 3. beta. -₂The other H); 2.35(mf, 4H: NCH)₂) (ii) a 2.59 (Widdd, J ═ 17 and 5Hz, 1H in the 5. beta. position CH₂The other H); 2.85(s, 2H: NCH)₂) (ii) a 3.10-3.40(mt, 4H: CH at position 4. beta₂At the 3. delta. position CH₂And CH at the 5 epsilon position₂1H) of (1); 3.12(s, 3H: NCH)₃)；3.30(s，3H：ArNCH₃) (ii) a 3.49(mt, 1H: CH at position 3. delta₂The other H); 3.68(mt, 4H: CH)₂O)；3.84(s，2H：ArNCOOCH₂) (ii) a 4.55(dd, J ═ 7 and 5Hz, 1H: CH at position 3 α); 4.70-4.85(mt, 2H: CH at position 2. alpha. and CH at position 5. epsilon.)₂The other H); 4.86 (d)d, J ═ 10 and 1.5Hz, 1H: CH at position 1 α); 5.15 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.35(t, J ═ 8Hz, 1H: CH at position 4 α); 5.50-5.60(mt, 2H: CH at position 6 α and CH at position 5 γ); 5.87 (deduplicated q, J ═ 7 and 1.5Hz, 1H: CH at position 1 β); 6.57(d, J ═ 9Hz, 1H: CONH at position 2); 7.03(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 7.12(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.69(dd, J ═ 4.5 and 1Hz, 1H: H₆) (ii) a 8.37(d, J ═ 10Hz, 1H: CONH at position 1); 8.46(d, J ═ 8Hz, 1H: CONH at position 6); 11.67(s, 1H: OH).

Example 49

In a three-necked flask with 30 ml of dioxane, 1.3 g of 4 ζ -dedimethylamino-4 ζ - (N-methyl-N-allyloxycarbonyl) amino-5 δ -morpholinomethyl-5 δ, 5 γ -dehydropristinamycin I, as prepared in example 29, were added_EThen 10 mg of triphenylphosphine and 20 mg of palladium tribenzylacetonate were added. The reaction mixture was heated to reflux for 39 hours, while 20 mg of palladium tribenzylacetonate was added three times each during the last 21 hours. The reaction mixture was concentrated under reduced pressure to give 1.1 g of green egg icing which was purified by chromatography on silica gel (eluent: dichloromethane/methanol, 95/5 by volume). 0.45 g of product is obtained, which is obtained from 450 g of Kromasil C810. mu.mSilica gel was purified by preparative HPLC (eluent: water-acetonitrile, 65/35 by volume, containing 0.1% trifluoroacetic acid). After concentration of the fractions containing the desired product, the pH was adjusted to 7-8 by adding saturated sodium bicarbonate solution to the residual aqueous phase. The resulting mixture was extracted twice with 20 ml of dichloromethane each time. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to dryness. The residue was dried at 45 ℃ C. (90 Pa) to give 130 mg of 4 ζ -dedimethylamino-4 ζ - (N-methyl-N-allyl) amino-5 δ -morpholinomethyl-5 δ, 5 γ -dehydropristinamycin I_EAs a pale yellow solid, melting at 156 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm):

0.92(t, J ═ 7.5Hz, 3H in the 2. gamma. CH position₃) (ii) a 0.90-1.00(mt, 1H: CH at position 5. beta. -₂1H) of (1); 1.23(mt, 2H: CH at position 3. beta. -₂And CH at the 3. gamma. position₂1H) of (1); 1.31(d, J ═ 7Hz, 3H: CH at the 1. gamma. position₃) (ii) a 1.55(mt, 1H: CH at position 3. gamma.)₂The other H); 1.60-1.80 (mt: corresponding to CH at position 2. beta. -₂2H) of (1); 2.00(mt, 1H: CH at position 3. beta. -₂The other H); 2.37(mf, 4H: NCH)₂) (ii) a 2.43(dd wide, J.17 and 5Hz, 1H in the 5. beta. position CH₂The other H); 2.85(mf, 2H: NCH)₂) (ii) a 2.90-3.00(mt, 1H: CH at position 4. beta₂1H) of (1); 2.96(s, 3H: ArNCH)₃) (ii) a 3.15-3.25(mt, 1H: CH at position 4. beta₂The other H); 3.20(s, 3H: NCH)₃) (ii) a 3.33 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂1H) of (1); 3.47(mt, 1H: CH at position 3. delta₂1H) of (1); 3.65-3.80(mt, 5H: CH at position 3. delta₂And the other of H and CH₂O); 3.91 and 3.99(2dd, J ═ 16 and 5Hz, 1H each ArNCH₂) (ii) a 4.60(dd, J ═ 8 and 5.5Hz, 1H: CH at position 3 α); 4.78(mt, 1H: CH at position 2 α); 4.85 (width d, J ═ 18Hz, 1H: in the 5 epsilon position CH₂The other H); 4.88(dd, J ═ 10 and 1.5Hz, 1H: CH at position 1 α); 5.10 (width d, J ═ 5Hz, 1H: CH at position 5 α); 5.10-5.25(mt, 3H: ═ CH)₂And CH at the 4 α position); 5.49 (very wide d, J ═ 5Hz, 1H: CH at the 5 γ position); 5.52(d, J ═ 8Hz, 1H: CH at position 6 α); 5.80-5.95(mt, 1H: CH) ═ c; 5.86 (deduplicated q, J ═ 7 and 1.5Hz, 1H: CH at position 1 β); 6.56(d, J ═ 9Hz, 1H: CONH at position 2); 6.57(d, J ═ 8Hz, 2H: aromatic H at the 4 epsilon position); 6.93(d, J ═ 8Hz, 2H: aromatic H at the 4 δ position); 7.20-7.40 (mt: corresponding to aromatic H-H in the 6. alpha. position₄And H₅7H) of (1); 7.75(dd, J ═ 4.5 and 1Hz, 1H: H₆) (ii) a 8.39(d, J ═ 10Hz, 1H: CONH at position 1); 8.47(d, J ═ 8Hz, 1H: CONH at position 6); 11.66(s, 1H: OH).

As an example, streptogramin derivatives represented by general formula (. beta.) can be prepared according to or by analogy with the following methods:

reference examples

(16R) -16-deoxy-16-Fluoropristinamycin II_B

To 1.12 g of (16R) -16-deoxy-16-fluoro-14-O- (tert-butyldiphenylsilyl) pristinamycin II_BIn a solution of 10 ml in tetrahydrofuran, 0.2 ml of acetic acid and 0.6 g of tetra-n-butylammonium fluoride trihydrate were added under an argon atmosphere at 20 ℃. After stirring for 168 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kpa) to give 1g of chestnut oil which was purified by flash chromatography [ eluent: dichloromethane/methanol/acetonitrile (90/5/5 volume basis)]. 0.3 g of (16R) -16-deoxy-16-fluoropristinamycin II are obtained_BIt is a pale beige solid and melts (decomposes) at 125 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm): 0.96(d, J ═ 6.5 Hz: 3H); 1.00(d, J ═ 6.5 Hz: 3H); 1.10(d, J ═ 6.5 Hz: 3H); 1.55-2.05 (mt: 5H); 1.83 (s: 3H); 2.10-2.30 (mt: 2H); 2.76 (mt: 1H); 2.98 (mt: 1H); 3.21 (mt: 1H); 3.48 (mt: 1H); 3.87 (mt: 1H); 4.07 (mt: 1H); 4.55 (mt: 1H); 4.75-4.90 (mt: 3H); 5.14 (J)_HF48 Hz: 1H) (ii) a 5.39(d, J ═ 9Hz 1H); 5.71 (mt: 1H); 5.82(dd, J ═ 17 and 2 Hz: 1H); 6.00 (mt: 1H); 6.21(d, J ═ 16 Hz: 1H); 6.52(dd, J ═ 17 and 5 Hz: 1H); 8.12 (s: 1H).

(16R) -16-deoxy-16-fluoro-14-O- (tert-butyldiphenylsilyl) pristinamycin II may be prepared in the following manner_B：

To 2g of (16S) -16-hydroxy-14-O- (tert-butyldiphenylsilyl) pristinamycin II_BIn a solution of 50 ml of dichloromethane, 0.464 ml of diethylaminosulfur trifluoride are slowly added under an argon atmosphere at 20 ℃. After stirring for 2 hours, the reaction mixture was poured into 100 ml of saturated aqueous sodium bicarbonate solution. Decanting the organic phase, each timeWashed twice with 100 ml of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kpa) to give 2.1 g of an ochre solid which is purified by flash chromatography [ eluent: dichloromethane/acetonitrile/methanol gradient (100/0/0; 99/0.5/0.5, then 98/1/1 by volume)]. 1.35 g of (16R) -16-deoxy-16-fluoro-14-O- (tert-butyldiphenylsilyl) pristinamycin IIB are obtained as a white solid which melts (decomposes) at 116 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm): 0.96(d, J ═ 6.5 Hz: 3H); 0.99(d, J ═ 6.5 Hz: 3H); 1.00-1.15 (mt: 12H); 1.29 (s: 3H); 1.55-1.95 (mt: 4H); 1.96 (mt: 1H); 2.13 (mt: 1H); 2.24 (mt: 1H); 2.76 (mt: 1H); 2.85 (mt: 1H); 3.03 (mt: 1H); 3.39 (mt: 1H); 3.80 (mt: 1H); 4.01 (mt: 1H); 4.57 (mt: 1H); 4.72 (mt: 1H); 4.75-4.85 (mt: 2H); 5.01(JHF ═ 48 Hz: 1H); 5.38(d, J ═ 9 Hz: 1H); 5.50 (mt: 1H); 5.81(dd, J ═ 17 and 1.5 Hz: 1H); 5.97 (mt: 1H); 6.10(d, J ═ 15.5 Hz: 1H); 6.49(dd, J ═ 17 and 5 Hz: 1H); 7.30-7.50 (mt: 6H); 7.63 (width d, J ═ 7 Hz: 2H); 7.68 (width d, J ═ 7 Hz: 2H); 8.08 (s: 1H).

(16S) -16-hydroxy-14-O- (tert-butyldiphenylsilyl) pristinamycin II can be prepared in the following manner_B：

To 22 g of (16S) -16-hydroxypristinamycin II_BA solution in 200 ml of dichloromethane is added under argon at 20 ℃ to 29 ml of diisopropylethylamine and 43.2 ml of tert-butyldiphenylchlorosilane and 1.01 g of 4-dimethylaminopyridine are added dropwise. After stirring for 22 hours, the reaction mixture was poured into 600 ml of saturated aqueous sodium bicarbonate solution. The aqueous phase is decanted and extracted twice with 100 ml of dichloromethane each time. The organic phases are combined, washed with 400 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 70.6 g of an orange viscous oil which is stirred in 600 ml of isopropyl ether for 16 hours. After filtration and drying at 20 ℃ under reduced pressure (2.7 kPa), 28 g of (16S) -16-hydroxy-14-O- (tert-butyldiphenylsilyl) pristinamycin II are obtained_BIn the form of a rose solid, melted (decomposed) at 133 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm): 0.95(d, J ═ 6.5 Hz: 3H); 1.00-1.05 (mt: 9H); 1.08 (s: 9H); 1.40-1.80 (mt: 3H); 1.90-2.15 (mt: 3H); 2.23 (width d, J ═ 14 Hz: 1H); 2.75 (mt: 1H); 2.83(dd, J ═ 17 and 11 Hz: 1H); 3.10(dd, J ═ 17 and 2.5 Hz: 1H); 3.25 (mt: 1H); 3.60-3.75 (mt: 2H); 4.49 (mt: 1H); 4.56 (mt: 1H); 4.60-4.70 (mt: 2H); 4.87 (mt: 1H); 5.49 (mt: 1H); 5.74(dd, J ═ 17 and 2 Hz: 1H); 5.78(d, J ═ 9 Hz: 1H); 5.95 (mt: 1H); 6.04(d, J ═ 16 Hz: 1H); 6.41(dd, J ═ 17 and 4 Hz: 1H); 7.30-7.50 (mt: 6H); 7.64(dd, J ═ 7 and 1.5 Hz: 2H); 7.69(dd, J ═ 7 and 1.5 Hz: 2H); 8.11 (s: 1H).

(16S) -16-Hydroxyprogesterone II can be prepared in the following manner_B：

A suspension of 11.35 g of sodium borohydride in 550 ml of dichloromethane is heated at reflux for 20 minutes. At this point 68.6 ml of acetic acid are added dropwise over about 30 minutes, followed by a solution of 52.75 g of pristinamycin IIB (previously dried over sodium sulphate) in 230 ml of dichloromethane over about 45 minutes. The reaction mixture was stirred at reflux for 4.5 hours and then at 20 ℃ for 16 hours. At this point 500 ml of dichloromethane and 1500 ml of water were added to the reaction mixture. After decantation of the organic phase, the aqueous phase is extracted with 500 ml of dichloromethane. The organic phases are combined and the pH is adjusted to 8 by slow addition of 1000 ml of saturated aqueous sodium bicarbonate solution. The organic phase obtained is washed successively with 1000 ml of water and 1000 ml of saturated aqueous sodium chloride solution and then treated with 3S vegetable carbon black, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kpa) to give 50 g of a pale yellow solid. To a solution of the solid in 900 ml of dichloromethane was added 378 ml of 0.5M aqueous ammonium hydroxide solution at 20 ℃. After stirring for 16 hours at 20 ℃, the organic phase is decanted, washed with 1000 ml of water and then with 1000 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kpa) to give 46 g of a pale yellow solid,it is purified by flash chromatography [ (eluent: dichloromethane/methanol gradient 98/2 and 97/3 by volume)]31.68 g of (16S) -16-hydroxypristinamycin II are obtained_BIt is in the form of a variegated white solid, and melts (decomposes) at 131 ℃.

¹H N.M.R. Spectrum (400MHz, CDCl)₃δ, in ppm): 0.96(d, J ═ 6.5 Hz: 3H); 1.02(d, J ═ 6.5 Hz: 3H); 1.07(d, J ═ 6.5 Hz: 3H); 1.70-1.90 (mt: 3H); 1.76 (s: 3H); 1.97 (mt: 2H); 2.12 (mt: 1H); 2.26 (width d: 14.5 Hz: 1H); 2.56(d, J ═ 3 Hz: 1H); 2.76 (mt: 1H); 2.90(dd, J ═ 16 and 10 Hz: 1H); 3.08(dd, J ═ 16 and 3 Hz: 1H); 3.35 (mt: 1H); 3.82 (mt: 2H); 3.99(d, J ═ 2.5 Hz: 1H); 4.40-4.55 (mt: 2H); 4.65-4.75 (mt: 2H); 5.03 (mt: 1H); 5.65-5.85 (mt: 3H); 6.01 (mt: 1H); 6.21(d, J ═ 16 Hz: 1H); 6.46(dd, J ═ 17 and 5 Hz: 1H); 8.13 (s: 1H).

The invention also relates to pharmaceutical compositions containing at least one streptogramin derivative according to the invention, optionally in the form of a salt or in combination with one or more compatible and pharmaceutically acceptable diluents or additives. The invention also relates to the pharmaceutical composition when it further comprises at least one derivative of a streptogramin of group A, optionally in combination with one or more streptogramins of general formula (I), or optionally one of the salts thereof.

The compositions of the present invention may be administered orally, parenterally, topically, rectally, or by aerosol means.

As solid compositions for oral administration, tablets, pills, capsules, powders or granules can be used. In these compositions, the active products of the invention are generally in the form of a combination which is mixed with one or more inert diluents or additives, such as sucrose, lactose or starch. These compositions may contain other substances than diluents, for example lubricants like magnesium stearate or coatings for controlled release.

As oral liquid compositions, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions may also contain substances other than diluents, such as wetting agents, sweeteners or flavoring agents.

The parenteral pharmaceutical composition may be a sterile solution or emulsion. As solvents or carriers, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters such as ethyl oleate may be used. These compositions may also contain additives, in particular wetting agents, isotonizing agents, emulsifying agents, dispersing agents and stabilizing agents.

The sterilization process may be accomplished in a number of ways, for example, by bacteriological infiltration, irradiation, or heating. They may also be prepared in the form of sterile solid compositions which may be dissolved in sterile water or any other injectable sterile medium at the time of use.

Topical compositions may be, for example, creams, ointments, lotions or aerosols.

Rectal compositions are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

These compositions may also be aerosols. When used in the form of a liquid aerosol, these compositions may be stable sterile solutions or solid compositions which are dissolved in non-pyrogenic sterile water, serum or any other pharmaceutically acceptable carrier at the time of use. In the form of a dry aerosol for direct inhalation, the active ingredient is finely divided and combined with a water-soluble solid diluent or carrier having a particle size of 30-80 microns, for example glucopyranose-containing dextran, mannitol or lactose.

The novel streptogramin derivatives of the invention are particularly effective in the treatment of infections of bacterial origin when administered in human therapy. The dosage depends on the desired effect and the treatment time. The physician will most suitably estimate the dosage depending on the condition of treatment, the age, weight, extent of infection and other intrinsic factors of the patient to be treated. In general, oral administration to an adult human is carried out at a dose of 1 to 3 grams of active ingredient 2 or 3 times per day.

The following examples illustrate the compositions of the invention:

examples

Tablets having the following composition were prepared according to conventional techniques at a dose of 250 mg of active compound:

-5 delta- (1-morpholino) methyl-5 delta, 5 gamma-dehydropristinamycin I_E75 mg of

Pristinamycin II_B175 mg of

-excipients: starch, hydrated silica gel, dextrin,

gelatin, magnesium stearate: an appropriate amount is 500 mg.

Claims

1. Streptogramin class B derivatives having the general formula:

r represents a group-NR₁R₂or-SR₃Wherein:

R₁and R₂Identical or different, they represent a hydrogen atom, C optionally substituted by a hydroxyl group_1-8Alkyl radical, C_3-8Alkenyl radical, C_3-5Cycloalkyl radical, C_1-8Alkoxy, di-C_1-8Alkylamino, phenyl C_1-8Alkyl, 1, 3-dioxolanyl or di-C_1-8Alkylamino radical C_1-8Alkyl, or

R₁And R₂Together with the nitrogen atom to which they are attached, form a mono-or bicyclic heterocycle, which is a saturated, partially saturated or unsaturated ring having a 3-10 membered chain, optionally containing other heteroatoms selected from nitrogen, sulphur or oxygen, and optionally substituted by one or two hydroxyl groups, C_1-4Alkyl, phenyl optionally substituted by halogen atoms, phenyl C_1-4Alkyl, hydroxy C_1-4Alkyl radical, C_1-4Acyl radical, C_1-4Alkoxycarbonyl, or saturated or unsaturated heterocyclyl having 5 to 6 member chains and containing 1 heteroatom selected from oxygen or nitrogen, or heterocyclyl parts thereof, are substituted with saturated or unsaturated heterocyclylcarbonyl having 5 to 6 member chains and containing 1 heteroatom selected from oxygen or nitrogen,

r3 is a quilt group-NR₁′R₂' substituted C_1-8Alkyl radical, wherein R₁' and R₂' same or different, they represent C_1-4Alkyl or together with the nitrogen atom to which they are attached form piperidinyl, or R3 represents a chain having 5-9 members and one or two nitrogen atoms and optionally substituted by C_1-4An alkyl-substituted saturated or unsaturated monocyclic or bicyclic heterocyclic group or a heterocyclylmethyl group,

represents an unsaturated cyclic residue unsubstituted in position 5 γ:or a saturated cyclic residue substituted with fluorine at the 5 γ position:

ra is ethyl, and

rb, Rc and Rd have the following meanings:

1) rb and Rc are hydrogen atoms and Rd is methylamino or dimethylamino, or

2) Rb is a hydrogen atom, Rc is a hydrogen atom or a chlorine atom, and Rd is a group-NMeR ', wherein R' represents C_2-8Alkenyl, pyridylmethyl or represents-COOR 'e, where R' e is C_1-6Alkyl radical, C_2-6Alkenyl, phenyl or tolyl, or

2. Streptogramin class B derivatives according to claim 1, characterised in that they are 5 delta- (1-morpholino) methyl-5 delta, 5 gamma-dehydropristinamycin I_E。

3. Streptogramin class B derivatives according to claim 1, characterised in that they are 5 δ - [ N-methyl-N-2- (1, 3-dioxolanyl) methyl]Aminomethyl-5 delta, 5 gamma-dehydropristinamycin I_E。

4. Streptogramin class B derivatives according to claim 1, characterised in that they are 5 delta-morpholinomethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydropristinamycin I_E。

5. Streptogramin class B derivatives according to claim 1, characterised in that they are 5 delta-morpholinomethyl-4 zeta-methylamino-4 zeta-dedimethylamino-5 delta, 5 gamma-dehydro-4 epsilon-chloropristinamycin I_E。

6. Streptogramin B derivative according to claim 1, characterised in that it is 5 δ - [ bis- (2-methoxyethyl) aminomethyl]-5 delta, 5 gamma-dehydropristinamycin I_E。

7. A process for the preparation of streptavidin derivatives according to claim 1 characterized in that a fluorinating agent is reacted with a group B synergestin derivative of the following general formula:

in which R, Ra, Rb, Rc and Rd are as defined in claim 1, and then isolating the fluorinated derivative or the derivative unsaturated in the 5. gamma., 5. delta. position, if necessary, converting the streptogramin derivative formed into a salt.

8. A process according to claim 7, characterized in that the fluorinated derivative is separated from the unsaturated derivative in the 5 γ, 5 δ position by chromatography or crystallization.

9. The process for the preparation of streptogramin derivatives as claimed in claim 1, wherein the symbolsRepresentsCharacterized in that a sulfuryl halide is reacted with a group B colicin derivative represented by the following general formula in the presence of a nitrogen-containing base:

wherein R, Ra, Rb, Rc and Rd are as defined in claim 1, and the obtained streptogramin derivative is converted into a salt, if necessary.

10. The process for the preparation of streptogramin derivatives as claimed in claim 1, wherein the symbolsRepresentsCharacterized in that amine HNR is allowed to react₁R₂Or thiols HS-R₃Reacting with a halogenated derivative of streptogramins of the general formula:

in which Ra, Rb, Rc and Rd are as defined in claim 1 and Hal represents a halogen atom, and then, if necessary, converting the resulting streptogramin derivative into a salt.

11. Streptogramin derivatives of general formula:

wherein R, Ra, Rb, Rc and Rd are as defined in claim 1.

12. A pharmaceutical composition comprising at least one streptogramin B derivative according to claim 1, in pure form, if necessary in the form of a salt, or in combination with one or more compatible and pharmaceutically acceptable diluents or additives.