WO2006049113A1 - Intermediate for synthesizing carbapenem and method for preparation thereof - Google Patents

Abstract

A compound (I) which is obtained by the following reaction scheme: (II) (III) (IV) (V) (I) (wherein R1 and R2 represent a protecting group for a hydroxy group and a protecting group for a carboxy group, respectively, and X represents a halogen atom), and an amine salt thereof; and a method for producing a carbapenem derivative using the compound (1) and an amine salt thereof.

Description

 Rubapenem synthetic intermediate and process for producing the same

 Technical field

 [0001] The present invention relates to a synthetic intermediate of rubapenem having antibacterial activity and a method for producing the same. Specifically, the present invention relates to the intermediate, its amine salt, its crystal, and a process for producing strong rubapenem using them. Background art

 [0002] As a method for producing a synthetic intermediate of 1 alkyl strength rubapenem, Patent Document 1 (Reference Example 1 2) includes the following compound 5 6 as an intermediate for utilizing the Dieckmann condensation reaction. It is disclosed.

 [Chemical 1]

Patent Document 2 (Example 13) describes a method for producing doripenem from Compound 5 [Chemical Formula 2]

(式中、 TMS：トリメチルシリル）

(Where TMS: trimethylsilyl)

 Non-Patent Document 1 describes the following reaction as a method for producing the hydroxy-protected form of Compound 5 described above.

 [Chemical 3]

a: 1) TBS-C1, NaH, THF, 0°C, lh 2) BrCH2C02Allyl, NaH(TMS)2, THF, 50°C,

a: 1) TBS-C1, NaH, THF, 0 ° C, lh 2) BrCH2C02Allyl, NaH (TMS) 2, THF, 50 ° C,

30min 3) K2C03, H20, 25 ° C, lOmin 4) aq.HC1

 Patent Document 1: JP-A-1 79180

 Patent Document 2: JP-A-5-294970

 Non-patent literature l: Synlett, 315-316, 1995

 Disclosure of the invention

 Problems to be solved by the invention

[0003] When compound 5 is produced by a conventional method, it is not easy to sufficiently control the side reaction. As a result, it has been extremely difficult to produce the target force rubapenem industrially and efficiently. For example, when the 4-position carboxy of the j8-ratata ring was changed to a thioester and the N atom at the 1-position was alkylated, a part of the thioester group was released. Further, depending on the kind of hydroxy protecting group of the starting material, a by-product derived from the hydroxy protecting group is mixed into Compound 5 and it is difficult to completely remove it.

 Means for solving the problem

[0004] As a result of diligent investigations, the present inventors have found that the compound 5 and its derivatives can be produced industrially and efficiently through a novel intermediate compound (I) or an amine salt thereof. We found that the product can be manufactured. In addition, the reaction conditions for efficiently producing compound 5 (eg, the type of condensing agent) were also examined, and the present invention shown below was completed.

(1 set:

[Chemical 4]

で示される化合物 (I)またはそのアミン塩。

Or a amine salt thereof.

 (2) The amine salt as described in 1 above, wherein the amine is a primary amine or a secondary amine.

 (3) The amine salt as described in 1 above, wherein the amine is methylamine, ethylamine, isopropylamine, t-butylamine, (1) a methylbenzylamine, diisopropylamine, or dicyclohexylamine.

 (4) The amine salt as described in 1 above, which is a diisopropylamine salt.

 (5) The amine salt according to any one of 1 to 4 above, which is a crystal.

 (6) The diisopropylamine salt according to 4 above, which is a crystal having a main peak at 2 0 = 8.7, 9.7, 15.7, 22.4 degrees in a powder X-ray diffraction pattern.

 (7) The following reaction scheme:

[Chemical 5]

(Wherein R ¹ is a hydroxy protecting group; R ² is a carboxy protecting group; X is a halogen), Process of:

 (Step 1) A step of producing compound (III) by protecting carboxy of compound (Π),

(Step 2) A step of producing Compound (V) by reacting Compound (III) with Compound (IV), and

 (Step 3) The compound (I) or the amine salt thereof according to (1) above, which comprises a step of subjecting the compound (V) to a deprotection reaction and optionally reacting with an amine. Production method

(8) The production method according to the above 7, wherein R ¹ is alkylsilyl and / or R ² is alkoxyalkyl.

(9) The production method according to the above 7, wherein R ¹ is t-butyldimethylsilyl and / or R ² is 1-isobutoxyl.

 (10) comprising a step of subjecting the carboxy moiety of the compound (I) or the amine salt thereof as described in 1 above to an active esterification, an active acid anhydride formation, a thiol esterification, an aryl ester ester or a heteroester ester ester. Formula:

 [Chemical 6]

(In the formula, COZ represents an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected by a protective group, a substituted aryloxy group, or a heteroaryl carbon group. ) A method for producing a compound (VI) represented by:

 (11) A compound in which COZ is COSPh (Ph is phenol) by thiol-esterifying the carboxy moiety of the compound (I) or amine salt thereof described in 1 above in the presence of a condensing agent (VI 11. The production method according to 10 above, wherein

(12) Condensation agent power Ph P (0) C1, (PhO) P (0) Cl (Ph is full) or 2-black port-4,6- 12. The production method according to 11 above, which is dimethoxytriazine.

 (13) After the compound (VI) is produced by the method described in the above 10, it is subjected to a protective reaction of hydroxy to give the formula:

[Chemical 7]

(In the formula, COZ is an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group for a thiol force propyloxyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group; R ³ comprises preparing a compound (VII) represented by hydroxy protecting group), then treating it with a base, and further treating with a hydroxyl active esterifying agent.

 [Chemical 8]

(Wherein R ³ is a hydroxy protecting group; L is an esterified hydroxy group)

A production method of (VIII).

 (14) is alkylsilyl, 2 is -3 to 11, and Z or L is OP (OXOPh) (Ph

 14. The production method of the above-mentioned 13, which is 2 phenyl).

(15) After the compound (VIII) is produced by the method described in 14 above, it is represented by the formula: R ⁴ — SH (R ⁴ is a residue of a thioether-type side chain capable of binding to the 2-position of the carbapenem derivative) Compound

Reacting with (IX) or a salt thereof and deprotecting the resulting compound

(Wherein R ⁴ is as defined above), a method for producing a compound (X), a pharmaceutically acceptable salt thereof, or a solvate thereof.

 The invention's effect

 [0005] The present invention provides a novel synthetic intermediate of force rubapenem derivative, a method for producing the same, and a method for producing force rubapenem derivative using the same. By the production method of the present invention, the target strength rubapenem derivative can be synthesized in high yield with high efficiency.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0006] In the present invention, each term has the following meanings singly or in combination unless otherwise specified.

 Examples of the protecting group for hydroxy include trialkylsilyl (eg, trimethylsilyl, t-butyldimethylsilyl), acyl (eg, acetyl, bivaloyl), lower alkyl (eg, methyl, ethyl), lower alkoxy lower alkyl (eg, methoxymethyl, Methoxyethyl), lower alkyl sulfo (eg methanesulfol), lower alkoxy carbo (eg methoxy carboyl, t-butyloxy carbo), aralkyloxy carbo yl (eg benzyloxy) Noreboninole, o Nitrobenzinore, Xicanoreboninole, p Nitrobenzinore, Xicanorebonyl, p-methoxybenzyloxycarbonyl), substituted methyl (eg, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl) ), Tetrahydroviranyl and the like.

Carboxy protecting groups include lower alkyl (eg, methyl, ethyl, n-propoxy, isopropyl, t-butyl), substituted lower alkyl (example of substituent: lower alkoxy (eg, methoxy, ethoxy, n propoxy, Isopropoxy, n-butoxy, isobutoxy, t-butoxy)), substituted or unsubstituted aralkyl (eg benzyl, phenethyl, p-methoxybenzyl, 2, 4 dimethoxybenzyl, o nitrobenzyl, p nitrobenzyl, p— Benzyl)), hetero atoms (eg, 0, S, N) optionally intervening C3-C8 cycloalkyl, alkylsilyl (eg, trimethylsilyl, t-butyldimethylsilyl), lower alkoxymethyl (eg, methoxy) Methyl, ethoxymethyl, isobutoxymethyl), lower aliphatic acyloxymethyl (eg, acetoxymethyl, propio-oxymethyl, butyryloxymethyl, bivalyloxymethyl), lower alkoxycarboxoxyl (eg: 1-methoxycarboxoxyl), 1 ethoxycarboxetyl), substituted or unsubstituted 2 to 10 lower alkyl groups having 3 to 10 carbon atoms (eg, aryl, 2-methylaryl, 3-methylaryl, 3-phenolyl), substituted or unsubstituted Dialylalkyl groups (eg diphenylmethyl, di-p-sylmethyl), Or an unsubstituted aryl group (e.g., phenol, p chlorophene, 2, 4, 5 trichlorophenol, p-tropenol, o--trophenol, p-methoxyphenol) And heteroaryl (eg, 2 pyridyl, 3 pyridyl, 4-pyridyl, 2-pyrimidyl, 2- (4,6 dimethyl) pyrimidyl).

 “Lower” preferably means C1-C6, more preferably C1-C4.

 Halogen represents F, Cl, Br, or I.

 Amine salt amines of compound (I) include primary, secondary, and tertiary amines

Primary amines include methylamine, ethylamine, isopropylamine, sec-butylamine, tert-butylamine, isoamylamine, n-decylamine, 3-methoxypropylamine, benzylamine, phenethylamine, 4-methoxyphenethylamine, 2,2-dimethoxyethylamine, 3,3-dimethoxypropylamine, p-chloroarine, 2- (p-chlorophenol) ethylamine, (-)-α-methylbenzylamine, 3 , 4-Dimethoxyphenethylamine, Benzhydrylamine, 2- (4-aminophenol) ethylamine, 2-aminobenzylamine, (+)-dihydroabietylamine, 4-methoxybenzylamine, 3-methoxy Phenethylamine, 4-tert-butylbenzilamine, aniline, 4-bromo-2-fluoroaniline, 4,4, -dithioaniline, 2,2, -dithiodialin Illustrated, preferably, Mechiruamin, Echiruamin, isopropylamine, tert- Buchiruamin, (-) - a - methyl benzyl § Min.

Secondary amines include dimethylamine, jetylamine, diisopropylamine, dicyclohexylamine, 3,5-dichloro-4,4, -dihydroxydiphenylamine, benzyl-N-methyl. Ethanolamine is exemplified, and diisopropylamine and dicyclohexylamine are preferable.

 Examples of tertiary amines include N-methylmorpholine, triethylamine, tributylamine, triarylamine, N-ethyldiisopropylamine, and Ν, Ν-dimethylbutylamine. The amine salt of compound (I) is preferably a crystal. Of the above amines, those having good crystallinity with respect to compound (I) are primary or secondary amines, preferably methylamine, ethylamine, isopropylamine, tert-butylamine, (-)-α-methylbenzylamine, Diisopropylamine and dicyclohexylamine are preferable, and methylamine and diisopropylamine are more preferable. Of these, diisopropylamine is particularly preferred because it has advantages such as low crystallinity, low toxicity, and low reactivity to the β-ratata ring. It can also be used as a base (acid trapping agent) in the next step condensation.

 The amine salt or the crystal thereof may be a solvate. Examples of the solvent include water and alcohol.

 As a result of the study by the present inventors, the crystallinity was improved by converting the compound (I) into an ammine salt, and it was successfully isolated as a high-purity crystal. As a result, various by-products mixed in the synthesis process of compound (I) (eg, Ding 83-011, Ding 83-1, and (TBS) Ο)

 2 can be easily removed (TBS = t-butyldimethylsilyl). As a result, there are advantages such as no column treatment and increased reaction efficiency in the subsequent steps. Therefore, in the production method of the present invention, various power rubapenem derivatives can be efficiently synthesized industrially, particularly through the amine salt of compound (I), preferably through its crystal.

 The above amine salt crystals show the X-ray diffraction pattern shown in the examples below by powder X-ray analysis (X-ray diffraction measurement conditions: tube CuK o; line, tube voltage 40 Kv, tube current 15 mA, dsin Θ = η λ (η is an integer, d is the surface separation (unit: angstrom), Θ is the diffraction angle (unit: degree))). These crystals are characterized by a value of each diffraction angle or spacing.

The production method of compound (I) and its amine salt will be described.

 (V) (i)

(Wherein R ¹ is a hydroxy protecting group; R ² is a carboxy protecting group; X is a halogen)

(First step)

 Compound (III) is obtained by protecting carboxy of compound (II). The reaction may be carried out according to the usual carboxy protection reaction.

R ¹ is a force exemplified by the above hydroxy protecting group, preferably trialkylsilyl, particularly t-butyldimethylsilyl (TBS).

R ² is a force exemplified by the above-mentioned carboxy protecting group, preferably lower alkyl substituted with lower alkoxy, such as 1-methoxyethyl, 1-ethoxyethyl, 1 isopropoxycetyl, 1 n propoxychetil 1 n-butoxystil, 1-sobutoxyl, 1 t-butoxystil, particularly preferably 1-isobutoxyl. These protecting groups are less susceptible to side reactions such as rearrangement to the 1-position N atom during the reaction.

 If desired, a reaction accelerator such as an acid may be used. Examples of the acid include methanesulfonic acid, P-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like.

Reaction solvents include hydrocarbons (eg, pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), alcohols (eg, : Methanol, ethanol), formic acid, acetic acid, propionic acid, ethyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (eg, tetrahydrofuran, jetyl ether), water and mixed solvents thereof are exemplified. Preferably, it is toluene, acetonitrile, or a mixed solvent thereof.

 The reaction temperature is generally 0-100 ° C, preferably 0-50 ° C, more preferably 10-30 ° C.

 The reaction time is several hours to several tens of hours.

 The resulting compound (III) may be subjected to the next step without isolation.

(Second process)

 Compound (V) is produced by reacting compound (III) with compound (IV).

 The halogen represented by X is preferably C or Br.

 If desired, a reaction accelerator such as a base may be used. Examples of bases include NaH, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, and sodium bis (trimethylsilyl) amide. . If desired, an interlayer transfer catalyst may be used in combination. As the interlayer transfer catalyst, quaternary ammonium salt (eg, tetra n-butyl ammonium chloride, tetra n-butyl ammonium chloride) can be used.

 Reaction solvents include hydrocarbons (eg, pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), alcohols (eg, : Methanol, ethanol), formic acid, acetic acid, propionic acid, ethyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (eg, tetrahydrofuran, jetyl ether), water and mixed solvents thereof are preferable, , Toluene, acetonitrile, tetrahydrofuran or a mixed solvent thereof. The reaction temperature is usually 70 to 0 ° C, preferably 50 to 30 ° C.

 The reaction time is several hours to several tens of hours.

 The resulting compound (V) may be subjected to the next step without isolation.

(3rd process)

 Compound (V) is subjected to a deprotection reaction and then optionally reacted with amine to give compound (I) or an amine salt thereof.

The deprotection reaction may be carried out in accordance with the conditions for a normal carboxy deprotection reaction. Preferably, compound (V) may be treated with an acid. Acids include hydrochloric acid, sulfuric acid, potassium hydrogen sulfate Examples are sodium hydrogen sulfate, nitric acid, phosphoric acid, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. The reaction time is usually several minutes to several tens of hours.

 The reaction with amine is usually carried out under ice cooling to room temperature. When crystallizing as an amine salt, a seed crystal may be added if desired. Solvents used for crystallization include hydrocarbons (eg, pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride). , Alcohol (eg methanol, ethanol), formic acid, acetic acid, propionic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (eg tetrahydrofuran, jetyl ether), Examples thereof include water and mixed solvents thereof. In crystallization, if necessary, heat treatment, ultrasonic treatment, stirring, etc. may be performed. Further, compound (I) or an amine salt thereof is in the 4-position according to the method described in JP-A-6-316559. By converting the carboxy moiety into an active ester, an activated acid anhydride, a thiol ester, an aryl ester or a heteroaryl ester, it can be converted into the following known compound (VI).

[Chemical 11]

(In the formula, COZ represents an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected by a protective group, a substituted aryloxy group, or a heteroaryl carbon group. )

When COZ is an active ester of a carboxyl group or an active acid anhydride, the Z group may be a halogen atom such as chlorine, bromine or iodine; for example, ethoxycarboxoxy, isopropyloxycarboxoxy, sec- Lower alkyloxycarboxoxy groups having 1 to 5 carbon atoms such as butyroxycarbonyloxy; A lower alkanesulfo-loxy group having 1 to 4 carbon atoms such as ruoxy; for example, an arylsulfo-loxy group such as p-toluenesulfo-loxy; for example, di (carbon number 1) such as dimethylphosphoryloxy and jetylphosphoryloxy -4 lower alkyl) phosphoryloxy groups; diarylphosphoryloxy groups such as di (phenol) phosphoryloxy; cyclic imidooxy groups such as N-succinimidoxy, N-phthalimidoxy Groups; heteroaryl groups such as imidazole and triazole; heterocycloalkyl groups such as 3- (2-thioxo) -thiazolidinyl, and the like.

 Suitable examples of the protective group for the carboxyl group and the protective group for the thiol carboxyl group used when COZ is a protected carboxyl group or a thiol carboxyl group are the same as those described above. Furthermore, preferred examples of the substituted aryloxy group include P--trophenyloxy, o--trophenyloxy, 2,4,5-trichlorophenyloxy, etc., and the heteroaryloxy group includes o —Pyridyloxy, p-pyridyloxy and the like can be mentioned.

 The conversion from the above compound (I) to (VI) is preferably carried out in the presence of a condensing agent. More preferably, compound (VI) in which COZ is COSPh (Ph is a phenol) can be produced by subjecting the carboxy moiety of compound (I) or its amine salt to a thioester in the presence of a condensing agent.

 As a condensing agent, various forces can be used. Preferably, ClCOOiBu, tBuC OCl, CDI (carboxydiimidazole), Ph P (0) C1, (PhO) P (0) C1, (PhO) P (

 twenty two

 0) C1, 2—Black mouth—4, 6-Dimethoxytriazine, more preferably Ph P (0) C1

 twenty two

(PhO) P (0) C is 2-black mouth-4, 6-dimethoxytriazine. Selection of condensing agent

 2

Depending on the choice, the above reaction is preferably performed in a high yield of 70% or more, more preferably 80% or more, and even more preferably 90% or more.

 Further, the above reaction may be used in combination with an acid scavenger if desired. The above-mentioned amine can be used as the acid scavenger.

 Further, by subjecting compound (VI) to a hydroxy protection reaction, the formula:

[Chemical 12]

(Wherein, coz is an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group for a thiol force lpoxyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group; R ⁽³ ) is a hydroxy protecting group), after the production of compound (VII), it is treated with a base according to the method described in JP-A-6-316559, and further treated with an active esterifying agent for a hydroxyl group. ,formula:

[Chemical 13]

(Wherein R ³ is a hydroxy protecting group; L is an esterified hydroxy group), (VIII).

R ³ is a force exemplified by the above hydroxy protecting group, preferably trialkylsilyl, especially trimethylsilyl (TMS). In particular, when producing doripenem using compound (VIII), TMS is preferably used in terms of deprotection.

Specifically, after treating compound (VII) with an inert solvent with a base, the intermediate is not isolated and the residue of the active ester or acid anhydride or the thiol residue of the protected thiolcarboxyl group in the reaction solution is isolated. (Z-) is captured by alkylating agents such as iodomethane, odopropane, allylic bromide, benzyl bromide, p-toluenesulfonic acid methyl ester, and acylating agents such as p-toluenesulfuric chloride and methanesulfuruyl chloride. After activation of the hydroxyl group If treated with a natural esterifying agent.

 The active ester of a hydroxyl group represented by L is, for example, a substituted or unsubstituted aryl sulfonic acid ester group (substituted or unsubstituted aryl sulfonic sulfo-oxy group), a lower alkane sulfonic acid ester group (lower alkane sulfo-oxy group), a halogeno lower alkanthol. It represents a phosphonic acid ester group (norogeno-lower alkanesulfo-oxyloxy group) or a dialyl phosphoric acid ester group (diarylphosphoryloxy group) or a halogenated metal atom that is an ester with a hydrogen halide. Therefore, the active esterifying agent for a hydroxyl group is a reagent that produces an active ester as described above. Furthermore, examples of the substituted or unsubstituted aryl sulfonic acid ester include benzene sulfonic acid ester, p toluene sulfonic acid ester, p-trobenzene sulfonic acid ester, and p bromobenzene sulfonic acid ester. Examples of the acid ester include methanesulfonic acid ester and ethanesulfonic acid ester. Examples of the halogeno lower alkanesulfonic acid ester include trifluoromethanesulfonic acid ester. Examples of the dialyl phosphoric acid ester include Examples of the diphenyl phosphoric acid ester and the halogenated compounds include chlorine, bromine, and iodide. Among these active esters of alcohol, p-toluenesulfonic acid ester, methanesulfonic acid ester and diphenylphosphoric acid ester can be mentioned, and diphenylphosphoric acid ester is preferable. . Accordingly, diphenyl phosphoric acid chloride (eg, diphenyl phosphoric acid chloride) is preferable as the active esterifying agent.

 Bases for treating compound (VII) in an inert solvent include metal salts of amines such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, and sodium amide, metal salts of alcohols such as potassium tert-butoxide, Examples thereof include alkali metal hydrides such as sodium hydride and lithium hydride, and sodium methylsulfinylmethide. The amount of base used is usually 1.5 to 3 equivalents. The preferred reaction temperature is -75 ° C to 50 ° C.

In the above reaction, preferably R ³ is alkylsilyl, Z is SPh, and Z or L is OP (OXOPh) (Ph is full). The compound (ring) has the formula: R ⁴ — SH (R ⁴ is the same as the method described in JP-A-1-79180, JP-A-6-316559, JP-A-5-294970, USP 5,317,016, etc. By reacting with the compound (IX) or a salt thereof represented by the thioether-type side chain residue capable of binding to the 2-position of the rubabapenem derivative and optionally deprotecting the resulting compound. ,formula

 [Chemical 14]

(Wherein R ⁴ is as defined above), a pharmaceutically acceptable salt thereof or a solvate thereof can be produced.

Examples of pharmaceutically acceptable salts include basic salts such as alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; trimethylamine salts. , Triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, medalamine salt, diethanolamine salt or aliphatic amine amine salt such as ethylenediamine salt; Ν, Ν-dibenzyl ethylenediamine, Aralkylamine salts; Heterocyclic aromatic amine amines such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltrie Tiluamum salt, benzyltri Examples include quaternary ammonium salts such as butyl ammonium salt, methyl trioctyl ammonium salt and tetrabutyl ammonium salt; and basic amino acid salts such as arginine salt and lysine salt. Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate, and ascorbate; sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate, and ト ル エ ン -toluenesulfonate Salt: aspartate, glutamate And acidic amino acids such as Examples of solvates include hydrates and alcohol solvates.

Compound (X) includes: (1) cenamycin, (2) imipenem, (3) meropenem, (4) beer penem, (5) panipenem, (6) BQ-2727, (7 ) S-4661 (Doripenem) is an example (each "SR ⁴ " is shown below).

[Chemical 15]

以下に実施例を示す。

Examples are shown below.

(Abbreviation)

 TBS: t butyldimethylsilyl TMS: trimethylsilyl tBu: t butyl

iPr: Isopropyl Ph: Phenyl Ally CH CH = CH Alloc: CO CH CH = CH

 2 2 2 2:

 DMF: Dimethylformamide THF: Tetrahydrofuran

[Chemical 16]

TMSCI, iPr ₂ NH

AcOEt -DMF

 8 9 Example 1 (1 → 4)

 (1) Sodium hydride (purity: 60%) 12.21 g (1.15 eq), 120 ml of toluene, 40 ml of acetonitrile, heated at 40 ° C, 34.9 ml (1.2 eq) of tert-amyl alcohol Toluene 40 ml solution was added dropwise and stirred as it was for 20 minutes, and then cooled to room temperature (hereinafter referred to as a toluene-acetonitrile solution of sodium tert-pentoxide).

To compound 1 (80.00 g, 0.2654 mol), add 91 mg (0.002 eq) of paratoluenesulfonic acid and 400 ml of anhydrous toluene, add 44.99 g (1.3 eq) of isobutyl vinyl ether while stirring at room temperature, and continue for 2.5 hours. Stir.

 (2) The reaction solvent was changed from toluene to d -THF, and the same reaction as in the above (1) was performed. Anti

 8

A part of the reaction solution was taken out over time and subjected to NMR measurement to confirm the disappearance of the peak of the raw material 1 compound. The NMR value in that case is shown below. NMR value and compound 2 formed ) ^S

^ nffi ^. ΠΠ 纖 ^ 翻 S'I¾ (bs S'Dlui SZ

 , Μιι οοτ 邈邈 (氺.:

oiベエ Ai¾ (氺 οοΐ氺¾»べェ 。：ふ

0r ^a 00 ^

oi Bei Ai¾ (氺 οοΐ 氺 ¾ »Be

0

9ΐ 氺; (bs 9 · ΐ) § 9-SS best army. Tsu 翻 9ΐ ^^ Ο) ¾, ( ^b3 S'0) F "Z'W

 Νε, Stop If ^ ^ ^ oof 6 Τ «ffiW« (s) giT (

 uidd

(ω Ήΐ) 06 ''S' (ZH re = f 'b Ήΐ) 68'S' (ω 'HZ) OS'S' (ω 'ΗΖ) Z9'f' (ZH 0 / 8ΐ 'S'I = f' PP)) 6Z'f '(ω' Ηΐ) 9Vf '(ω' Ηΐ) SI '' (0 ・ 8ΐ = ί "'P' Ηΐ) S8T '(ω' I) ο · ε '(^' ΗΪ) ιζτ '( ω 'ΗΪ) 66' (^ 'HI) LS'Z' (^ Ήε) ε8 · ΐ '(ω Ήε) 8 ε · ΐ' (ω Ή9) Ζ'Ϊ '(ω Ϊ9) 06' ( ^s ' H6 ) 68 '( ^s ' H9) Ο-(OQD) Η Ν-Η _Τ

° ^-§ 6 Τ

ozベエ β¾¾氺、つ 回 S 1 00S氺 ¾簠ベエ ί

00S氺: Z'0)S 9 z-f

-ベ エ ίθ)、 ^ ベ - マ っ灞鱸^ 、 つ。 s—〜(^一、 (^b3 ε·ΐ) ^s 9 -Ϊ94— ^ f

(I) 3IT (ε) uidd ( ZH VQ=i 'i>.a> £

oz beer β¾¾ 氺, times S 1 00S 氺 ¾ 簠 ベ エ ί

00S 氺: Z'0) S 9 zf

-Bee ίθ), ^ Bee-ma ^^, tsu. s— ~ (^ 1, ( ^b3 ε · ΐ) ^s 9 -Ϊ94— ^ f

(I) 3IT (ε) uidd (ZH VQ = i 'i>

'HI) Z8 "S' (ω 'Ηΐ) Vf' (ω 'Ηΐ) 9ZT' (ω 'Ηΐ) ΖΥΖ' (^ 'Ηΐ) ΖΖ' (^ 'Ηΐ) WZ' (ω 'Ηΐ) 9' ( ω 'Ηΐ) 8Γΐ' (ω Ήε) Γΐ '( ^Ζ Η 2- = Γ' Ρ Ήε) 6ΐ ・ ΐ '( ^Ζ Η Ζ • Ζ = ί "' Ρ ίε) 8ΐ · ΐ '(ω Ή9) 06' (s Ή6) 68 '(s' H9) 80: (Η 丄) Ρ) Η 顺-Η _τ

. SR

81

0.66T0 / S00Zdf / X3d εΐΐ6ΐ7θ / 900Ζ OAV Yield: 65%).

 Anal. Calcd for C H N O -0.2H O: C, 58.50; H, 8.89; N, 7.18; H O, 0.92. Found:

 19 34 2 6 2 2

C, 58.74; H, 8.72; N, 7.25, HO, 0.97. ^J H-NMR (CDC1): 1.23 (3H, d, J = 7.2 Hz)

 twenty three

 , 1.29 (6H, d, J = 6.3 Hz), 1.32 (3H, d, J = 6.3 Hz), 2.51 (1H, m), 2.89 (1H, dd, J = 2.1, 9.3 Hz), 3.34 (1H, m), 3.82 (1H, dd, J = 1.8, 8.7 Hz), 3.87 (1H, d, 18.6 Hz), 4.11 (1H, m), 4.31 (1H, d, 18 Hz), 4.63 (2H, d, J = 5.7 Hz), 5.31 (2H, m), 5.90 (1H, m), 7.0 (4H, br) ppm

 The powder X-ray diffraction pattern of diisopropylamine salt 4 is shown in FIG. In particular, the main peaks were shown at 2 Θ = 8.7, 9. 7, 15.7, and 22.4 degrees.

Example 2 (4 → 6)

To 80.00 g of compound 4 (purity: 97.2%, 0.201 mol), 311 ml of ethyl acetate was added, and 64.80 g (1.2 eq) of diphenyl phosphate chloride was added dropwise with stirring under ice cooling, followed by stirring at room temperature for 1 hour. The mixture was ice-cooled again, and 78 ml of DMF and 22.7 ml (l.l eq) of thiophenol were collected, and then 37.1 ml (1.3 eq) of diisopropylamine was added dropwise and stirred for 1.5 hours. At this point, it was confirmed by HPLC (high performance liquid chromatography) that Compound 5 was formed. Further, at the same temperature, 33.2 ml (1.3 eq) of trimethylsilyl chloride and 42.8 ml (1.5 eq) of diisopropylamine were successively added dropwise and stirred for 1.5 hours. After adding 367 ml (1.3 eq) of 6% sodium bicarbonate water and stirring at room temperature for 10 minutes, 1.2 L of water was added to separate the layers. The ethyl acetate layer was washed twice with 389 ml of water, the aqueous layer was extracted with 311 ml of ethyl acetate, the ethyl acetate layers were combined, concentrated under reduced pressure, 200 ml of toluene was added, and the solution was concentrated under reduced pressure to give a 6-like residue 108.16 g (quantitative value: 85.0 g, yield: 94%) was obtained.

1H-NMR (CDC1): 0.15 (9H, s), 1.29 (6H, d, J = 6.9Hz), 3.08 (1H, dd, J = 2.7, 8.1

 Three

 Hz), 3.15 (1H, qd, J = 6.9, 3.0 Hz), 2.85 (1H, dd, J = 0.6, 18.0 Hz), 4.12 (1H, dd, J = 2.4, 3.0 Hz), 4.32 (1H, d , 18.0 Hz), 4.60 (2H, m), 5.27 (2H, m), 6.87 (1H, m), 7.40 (5H, m) ppm

Example 3 (6 → 7)

Sodium hydride (purity: 60%) 9.86 g (2.3 eq), toluene-acetonitrile (85-15) 160 ml suspension in 35 ° C under heating, 28.2 ml (1.2 eq) tert-amyl alcohol A 37 ml solution of toluene-acetononitrile (85-15) was added dropwise, and the mixture was stirred as it was for 15 minutes. — Conducted under 45 ° C cooling and stirring A solution of 6 (purity: 78.6%, 0.107 mol) obtained in Example 2 in 95 ml of toluene-acetonitrile (85-15) was added dropwise at −40 ° C. or lower and stirred for 1.5 hours. Further, 8.67 ml (1.2 eq) of methyl iodide was added dropwise at the same temperature, and the mixture was stirred for 1.5 hours, and then a solution of 30.22 g (1.05 eq) of diphenylphosphate chloride in 27 ml of toluene-acetonitrile (85-15) was added dropwise to ice. It was cooled and stirred for 2 hours and 40 minutes. To this was added a solution of 13.5 g (1.5 eq) of sodium bicarbonate in 270 ml of water, followed by liquid separation. The toluene layer was washed sequentially with 270 ml of water and 270 ml of saturated saline, the aqueous layer was extracted with 160 ml of toluene, the toluene layers were combined, concentrated under reduced pressure, and 92.70 g (quantitative value: 53.36 g, yield) of 7 Rate: 87%).

JH-NMR (CDC1): 0.12 (9H, s), 1.19 (3H, d, J = 7.2 Hz), 1.25 (3H, d, J = 6.0 Hz),

 Three

 3.25 (1H, dd, J = 3.0, 6.9 Hz), 3.46 (1H, m), 4.11 (1H, dd, J = 3.0, 9.9 Hz), 4.19 (1H, qu, J = 6.6 Hz), 4.66 (1H , m), 5.29 (2H, m), 5.87 (1H, m), 7.31 (15H, m) ppm

Example 4 (7 → 9)

 According to the method described in Example 13 of JP-A-5-294970, compound 7 obtained in Example 3 was subjected to a condensation reaction for forming a 2-position side chain to synthesize compound 8, and further deprotection By subjecting to reaction, compound 9 (doripenem) is obtained.

Example 5

 In accordance with the method of Example 1, the corresponding amine salt was obtained by reacting the above-mentioned various amines other than diisopropylamine with the free form of Compound 4. Dicyclohexylamine salt, methylamine salt, ethylamine salt, isopropylamine salt, t-butylamine salt, and (1) -a-methylbenzylamine salt were obtained as crystals. In particular, dicyclohexylamine, methylamine, t-butylamine, and (1) a methylbenzylamine showed good crystallinity. The powder X-ray diffraction patterns are shown in Figures 2 to 5, and the diffraction angles of the main peaks are shown below.

Dicyclohexenoleamine salt

 2 Θ = 8.5, 15.0, 18.1, 19.3, 21.7, 22.6, 24.5 degrees

Methylamine salt

 2 Θ = 9.5, 11.3, 17.6, 18.0, 21.6, 22.3, 23.8, 26.0, 30.5, 33.6 degrees

t Butylamine salt 2 θ = 6.7, 8.1, 9.7, 13.3, 16.2, 17.7, 19.3, 20.0, 22.7 degrees

(-)-α-Methylbenzylamine salt

 2 Θ = 7.2, 17.1, 17.4, 18.0, 18.3, 20.6, 22.5, 25.1, 26.6, 27.3 degrees

Example 6

 Using the various amine salts obtained in Example 5 as raw materials, Compound 9 is obtained according to the methods of Examples 2-4.

Reference example

 4-Nitrobenzyl (2S, 4S) -4-acetylylthio-2- (Ν-sulfamoyl-tert-butoxycarboxamidomethyl) pyrrolidine-1-carboxylate (ATS, 51.0 g) was dissolved in methanol (169 ml). To this was added a 17% salt / hydrogen / methanol solution (82.8 g), and the mixture was heated and stirred at 35 ° C for 2 hours and at 40 ° C for 3 hours. Benzyl (2S, 4S) -4-mercapto-2-sulfamoyl-aminomethylpyrrolidine-1-carboxylate (hereinafter referred to as SPL) was derived. The obtained SPL / methanol solution was cooled to 18 ° C., and 10% aqueous sodium hydroxide solution (130.5 g) was added to adjust the pH to 2.4. Next, ethyl acetate (357 ml) and brine (113 ml) were added, liquid separation was performed, and SPL was extracted into the organic layer. Subsequently, the organic layer was washed successively with water (357 ml) and 2% brine (119 mix x 2). The resulting four aqueous layers were back extracted with ethyl acetate (102 ml) to recover SPL lost to the aqueous layer. Water (368 mg, lwt%) was added to the concentrated solution (36.9 g) obtained by combining the organic layers, dehydrating and concentrating, and allowed to cool overnight at 5 ° C. The precipitated crystals were collected by filtration and dried to obtain SPL hemihydrate crystals (13.1 g). The crystals were converted to anhydrous crystals by heating at 40 ° C. and drying under reduced pressure.

 [Chemical 17]

Data of 0.5 hydrate crystal: Elemental analysis H (%) 4.66 C (%) 39.06 N (%) 13.96

In addition, the powder X-ray diffraction patterns of each of the 0.5 hydrate crystals and anhydrous crystals

The (X-ray diffraction measurement conditions: tube Cn, tube voltage 40Kv, tube current 40mA)

Brief Description of Drawings

FIG. 1 is a powder X-ray diffraction pattern and peak value of diisopropylamine salt crystals obtained in Example 1. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2 Θ, unit: degree).

FIG. 2 is a powder X-ray diffraction pattern and peak value of dicyclohexylamine salt crystals obtained in Example 5.

 FIG. 3 shows a powder X-ray diffraction pattern and peak value of methylamine salt crystals in Example 5.

FIG. 4 shows a powder X-ray diffraction pattern and peak value of t-ptylamine salt crystal in Example 5.

 FIG. 5 shows the powder X-ray diffraction pattern and peak value of (1) -a-methylbenzylamine salt crystals in Example 5.

 FIG. 6 is a powder X-ray diffraction pattern of SPL hemihydrate crystals obtained in Reference Example 1. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2 Θ, unit: degree).

FIG. 7 is a powder X-ray diffraction pattern of anhydrous SPL crystals obtained in Reference Example 1. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2 Θ, unit: degree).

Claims

The scope of the claims  [1 set:  [Chemical 1]

Or a amine salt thereof.  The amine salt according to claim 1, wherein the amine is a primary amine or a secondary amine.  The amine salt according to claim 1, wherein the amine is methylamine, ethylamine, isopropylamine, t-butylamine, (1) a methylbenzylamine, diisopropylamine, or dicyclohexylamine.  [4] The amine salt according to claim 1, which is a diisopropylamine salt. [5] The amine salt according to any one of claims 1 to 4, which is a crystal. 6. The diisopropylamine salt according to claim 4, which is a crystal having a main peak at 20 = 8.7, 9.7, 15.7, 22.4 degrees in a powder X-ray diffraction pattern.  [7] The following reaction scheme:  [Chemical 2]

(Wherein R ¹ is a hydroxy protecting group; R ² is a carboxy protecting group; X is a halogen), Process of:  (Step 1) A step of producing compound (III) by protecting carboxy of compound (Π), (Step 2) A step of producing Compound (V) by reacting Compound (III) with Compound (IV), and  (Step 3) Compound (I) or an amine salt thereof according to claim 1, which comprises a step of subjecting compound (V) to a deprotection reaction and optionally reacting with amine. Manufacturing method. 8. The production method according to claim 7, wherein R ¹ is alkylsilyl and Z or R ² is alkoxyalkyl. [9] The production method according to claim 7, wherein R ¹ is t-butyldimethylsilyl and Z or R ² is 1-isobutoxyl. [10] The carboxy moiety of the compound (I) or the amine salt thereof according to claim 1, is converted into an active ester salt. Comprising the steps of: activating, anhydride anhydride, thiol esterification, aryl esterification or heteroaryl esterification,  [Chemical 3]

(In the formula, COZ represents an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected by a protective group, a substituted aryloxy group, or a heteroaryl carbon group. ) A method for producing a compound (VI) represented by: The compound (VI) in which COZ is COSPh (Ph is phenol) is produced by thiol-esterifying the carboxy moiety of the compound (I) or the amine salt thereof according to claim 1 in the presence of a condensing agent. The production method according to claim 10. [12] The condensing agent is Ph P (0) C1, (PhO) P (0) Cl (Ph is a phenol) or 2-chloro-4,6-dimethoxy. twenty two  12. The production method according to claim 11, which is citriazine. [13] After the compound (VI) is produced by the method according to claim 10, it is subjected to a hydroxy protection reaction to obtain a compound of the formula:  [Chemical 4]

(In the formula, COZ is an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group for a thiol force propyloxyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group; R ³ comprises preparing a compound (VII) represented by hydroxy protecting group), then treating it with a base, and further treating with a hydroxyl active esterifying agent.  [Chemical 5]

(Wherein R ³ is a hydroxy-protecting group; L is an esterified hydroxy group). [14] R ³ is alkylsilyl, Z is SPh, and Z or L is OP (OXOPh) (Ph is 2  14. The production method according to claim 13, wherein [15] After the production of compound (VIII) by the method according to claim 14, R ⁴ — SH (R ⁴ is carba A compound comprising a compound (IX) or a salt thereof represented by (a residue of a thioether-type side chain capable of binding to the 2-position of a nem derivative), and a step of deprotecting the resulting compound [Chemical 6]

(Wherein R ⁴ is as defined above), a method for producing a compound (X), a pharmaceutically acceptable salt thereof, or a solvate thereof.