WO1992000275A1 - PROCESS FOR PRODUCING ENANTIOMER-PURE α-HYDROXYLPROPONIOALDEHYDE DERIVATIVES - Google Patents

Abstract

The description relates to a process for producing enantiomer-pure α-hydroxypropionoaldehyde derivatives of the general formula (I) in which: R1 is the substituent Q which may be a hydrocarbon radical interrupted by oxygen atoms, carbonyloxy groups, nitrogen atoms and/or resonance-stabilised imido groups and/or thio groups and/or substituted by halogen atoms or a group produced by the hydrolysis of Q, containing hydroxy groups, carbonyl groups or carboxyl groups; and R2 is an alkane sulfonyl group with up to 6 carbon, a trifluoromethane sulphonyl group, a benzole sulphonyl group or a p-toluol sulphonyl group.

Description

 Process for the preparation of enantiomerically pure

 α-hydroxypropionaldehyde derivatives

The invention relates to a process for the preparation of enantiomerically pure α-hydroxypropionaldehyde derivatives of the general formula I.

 wherein

R _{1 is} the substituent Q

 which represents an optionally interrupted by oxygen atoms, carbonyloxy groups, nitrogen atoms, and / or resonance-stabilized imido groups and / or thio groups and / or substituted by halogen atoms, or

 means a group formed by hydrolysis of Q, hydroxyl groups, carboxyl groups or carboxyl groups and

R ₂ symbolizes an alkanesulfonyl group with up to 6 carbon atoms, a trifluoromethanesulfonyl group, a benzenesulfonyl group or a p-toluenesulfonyl group, which

 is characterized in that the oxirane rings one

 1,2,5,6-dianhydrohexite derivative, of the general formula II or III

 wherein

the two substituents R ₃ together form an alkylidene group with up to

6 carbon atoms or a benzylidene group,

with an organometallic compound of the general formula IV QME (IV), in which

Q has the meaning given above and

ME represents an alkali metal atom, a copper (I) atom or a magnesium halide residue,

 the compounds of general formula V or VI formed

worin

wherein

Q and R have the meanings given above,

 with a compound of general formula VII or VIII

R ₂ Cl (VII) R ₂ -OR ₂ (VIII) in which R has the meaning given above, to compounds of the general formula IX or X

(IX)

worin

wherein

Q. R ₂ and R _{3 have} the meaning given above, esterified them to give compounds of the general formula XI or XII

worin

wherein

R ₁ and R _{3 have} the meanings given above,

 hydrolyzed and cleaved using periodic acid or lead tetraacetate.

The invention further relates to the use of the enantiomerically pure α-hydroxypropionaldehyde derivatives of the general formula I thus prepared for the synthesis of enantiomerically pure α-hydroxypropionic acid derivatives of the general formula XIII

 wherein

R ₁ and R _{2 have} the meaning given above and their

 Esters, for the synthesis of enantiomerically pure α-azidopropionic acid derivatives of the general formula XIV

worin

wherein

R _{1 has} the meaning given in claim 1 and its esters, and for the synthesis of enantiomerically pure α-amino acid derivatives of the general formula XV

 wherein

R _{1 has} the meaning given in claim 1 and its esters.

It is known that the synthesis of enantiomerically pure amino acids is often quite complex, this is particularly the case when "unnatural amino acids", ie (R) -amino acids or (S) -amino acids, which do not occur in nature, are produced become. However, there is a need for the most diverse "unnatural amino acids" because these are used, for example, to produce modifications of pharmacologically active peptides.

The LHRH antagonists may be mentioned as an example of such modified peptides. (J.J. Nestor et al .; Annual Reports in Medicinal Chem., 23.

 1988, 211-220).

The present invention essentially relates to a relatively simple synthesis of enantiomerically pure amino acids or the enantiomerically pure α-azidoamino acids which are also very suitable for peptide synthesis. It also has the advantage that it is very universally applicable and enables the synthesis of the most diverse "unnatural amino acids".

The starting compounds used for the process according to the invention are preferably 1,2,5,6-dianhydro-3,4-O-isopropylidene-D-mannitol of the formula II or 1, 2, 5, 6-dianhydro-3, 4- O-isopropylidene-L-idite of formula III Both substances can be more easily

Manufacture manner from D-mannitol (Chem. Ber. 92, 1959, 2506 ff; Tetrahedron Letters 26, 1985, 319 ff). It is, of course, also possible to use 1,2,5,6-dianhydrohexite derivatives of the general formulas II or III as starting compounds which have other protective groups such as the isopropylidene radical in the 3rd and 4th position; such protective groups are, for example, the methylene group, the ethylidene group, the 3,3-pentylidene group or the benzylidene group. However, the synthesis of such compounds is generally more complex than that of the isopropylidene compounds and their use generally has no advantages.

The oxirane rings of the 1,2,5,6-dianhydro derivatives of the general formulas II or III are opened with an organometallic compound of the general formula IV. These organometallic compounds can, for example, from the corresponding halogen compounds of the general

Formula XVI

 QX (XVI), in which Q has the abovementioned meaning and X represents a halogen atom - preferably a chlorine atom, bromine atom or iodine atom - by reaction with lithium, butyllithium, phenyllithium, sodium or magnesium, optionally with the addition of copper (I) salts ; they are also reacted with the oxiranes in a manner known per se [Methods of Organic Chemistry (Houben-Weyl) 4th edition, Georg Thieme Verlag,

DE-Stuttgart Volume XIII / 1, 1970, page 87 ff and 255 ff and Volume XIII / 2a, 1973, page 47 ff; Tetrahedron Letters 17, 1979, 1503 ff].

It has already been mentioned that the substituent Q of the organometallic compounds is a hydrocarbon radical which is optionally interrupted by oxygen atoms, carbonyloxy groups, nitrogen atoms and / or resonance-stabilized imido groups and / or is substituted by halogen atoms. This hydrocarbon radical, which preferably contains a maximum of 20 carbon atoms and preferably a maximum of five heteroatoms, can be saturated or unsaturated, and can be alicyclic, cyclic or mixed cyclic-alicyclic. The cyclic or mixed

Cyclic-alicyclic hydrocarbons can be or contain non-aromatic, aromatic and / or heterocyclic ring systems. Hydrocarbons which are interrupted by oxygen atoms are, for example, those which contain ether groups (such as the methoxy group, tert-butyloxy group, benzyloxy group or the 2-tetrahydropyranyloxy group). Such ethers can optionally be used to synthesize substances containing hydroxyl groups. Further

Hydrocarbons which are interrupted by oxygen atoms are, for example, those which contain furan rings, tetrahydrofuran rings, pyran rings or 1,3-dioxolane rings. The latter can optionally be used to synthesize substances containing carbonyl groups.

Synthesize compounds whose hydrocarbon residue through

Carbonyloxy groups is interrupted, succeeds in a satisfactory yield only in exceptional cases (see, for example, Tetrahedron Letters 27, 1986, 4161 ff). If you want to synthesize substances whose hydrocarbon radical R is substituted by a carboxyl group, this can be achieved, for example, by starting from halogen compounds which are 4,4, -dimethyl-4,5-dihydro-1,3-oxazole-2 -yl group included (J. Am. Chem. Soc, 92, 1970, 6644 and 6646).

Hydrocarbons Q which are interrupted by nitrogen atoms are, for example, those which contain dialkylamino groups, such as the dimethylamino groups, pyrrolino groups (Houben-Weyl, 4th edition, volume XVII, 1974, page 293) or dibenzylamino groups. The latter can be used, for example, to synthesize substances that contain primary amino groups. On the other hand, hydrocarbons of this type are also those which contain N-alkyl or N-benzyl-substituted imido groups.

The residues of this type also include the aromatic N-heterocycles or hydrocarbons which contain such N-heterocycles.

Residues Q which contain resonance-stabilized imido groups or thio groups are the pyrrolyl and thienyl radicals and those hydrocarbons which contain pyrrole rings or thiophene rings. If the imido group in the compounds does not prove to be sufficiently resonance-stabilized, it can be protected against the preparation of the organometallic compounds, for example by benzylation or tosylation. Examples of suitable radicals Q are:

Straight-chain or branched alkyl groups, cycloalkyl groups or cycloalkyl-alkyl groups with up to 20 carbon atoms, such as the methyl group, the ethyl group, the 1-methylethyl group, the propyl group, the butyl group, the 1-methyl-propyl group or the 1,1-dimethylethyl group, the cyclopropyl group , the cyclopentyl group, the cyclohexyl group and the cyclopropylpropyl group.

Alkyl groups with up to 8 carbon atoms which are substituted by benzyloxy groups and / or dibenzylamino groups, such as the benzyloxymethyl group, the dibenzylamino-methyl group, the 2-benzyloxy-ethyl group, the 2-dibenzylaminoethyl group, the 3-dibenzylamino-propyl group and the 2-benzyloxy 3-dibenzylamino-propyl group.

Alkyl groups with up to 8 carbon atoms which are substituted by a 4,4-dimethyl-4,5-didehydro-1,3-oxazol-2-yl group, such as, for example, the (4,4-dimethyl-4,5 dihydro-1,3-oxazol-2-yl) methyl group or the 3- (4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl) -3-dibenzylamino-propyl group .

Phenyl groups, 1-naphthyl groups or 2-naphthyl groups, which are substituted by lower alkyl groups with up to 4 carbon atoms (for example methyl, ethyl, 1-methylethyl or 1,1-dimethylethyl), trifluoromethyl groups, lower alkoxy groups with up to 4 carbon atoms (for example methoxy or tert-butyloxy), halogen atoms (preferably fluorine or chlorine atoms) 4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl groups, oxathiazole groups, lower dialkylamino groups with up to 4 carbon atoms in each alkyl group how the dimethylamino group and / or dibenzylamino groups can be substituted. Such groups are, for example, the phenyl radical, the p-chlorophenyl radical, the 4-benzyloxyphenyl radical, the 4-trifluoromethylphenyl radical, the 4-dimethylaminophenyl radical or the 2-naphthyl radical. Heterocyclic groups such as the 2-pyridyl group, the 3-pyridyl group, the 2-thienyl group, the N-benzyl-3-nidolyl group, the N-benzyl-2-imidazolyl group, the ß-carbolin-6-yl group, the pyrrolinomethyl group , the 2- (N-pyrrolino) ethyl radical, the tetrazolyl radical, the 2-oxa-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzoduazepin-3-yl radical, the oxathiazolyl radical or the pteridinyl residue.

The implementation of the organometallic compounds QME with the

Compounds of formula V or VI formed by 1,2,5,6-dianhydrohexite derivatives are converted into the substances of formula IX or X by reaction with a compound of formula VII or VIII. For this reaction, preference is given to using methanesulfonic acid chloride as the compound of the formula VII, but in principle it is also possible to use other alkanesulfonic acid chlorides or anhydrides, trifluoromethanesulfonic acid anhydride, benzosulfonic acid chloride or p-toluenesulfonic acid chloride. This reaction is carried out under the conditions known per se, preferably in the presence of tertiary amines such as triethylamine or pyridine.

The 1,3-dioxolane rings of the compounds of the formulas IX or X are then cleaved in a manner known per se by acid hydrolysis. Strong acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoroacetic acid are suitable for this reaction. The solvents used for this reaction are, for example, water, lower alcohols (such as methanol, ethanol or isopropanol) or aqueous lower alcohols and the like. In this hydrolysis, easily saponifiable groups of the substituent Q (such as tetrahydropyranyl residues, 1,3-dioxolane groups or ester groups) can also be split off and the corresponding residues substituted by hydroxyl groups, oxo groups and / or carbonyl groups are obtained

R ₁ .

The compounds of general formula XI or XII obtained in this way are cleaved in a manner known per se using periodic acid or lead tetraacetate (see Luis F. Fieser and Mary Fieser: Reagents for Organic Synthesis; John Wiley S. Sons Inc. New York et. Al. Vol 1 to 14 among the Keywords: Lead tetraacetate, Periodates and Periodic acid). For example, the oxidation can be carried out using periodic acid in a lower ether (such as diethyl ether, diisopropyl ether, dioxane or tetrahydrofuran) as the solvent. The oxidation using lead tetraacetate can be used, for example, using acetic acid or benzene

 Cause solvents.

Since the enantiomerically pure α-hydroxypropionaldehyde derivatives of the general formula I formed have only a low stability, it is expedient to process them immediately. For example, the aldehydes can be reduced to the corresponding alcohols or converted into the corresponding amino compounds by reductive amination. On the other hand, the aldehydes can also be oxidized by oxidation, for example using chromic acid or potassium permanganate, to give the enantiomerically pure o-hydroxypropionic acid derivatives of the general formula XIII. These can be converted into their esters in a manner known per se (preferably alkyl esters with a maximum of 6 carbon atoms in the alkyl radical, such as, for example, methyl ester, ethyl ester or tert-butyl ester or also benzyl ester). The esters thus obtained can be converted by reaction with sodium azide into the corresponding esters of the enantiomerically pure α-azidopropionic acid derivatives of the general formula XIV, which in turn can be reduced, for example, to the α-amino acid derivatives of the general formula XV.

To avoid racemate formation, the individual reaction steps are carried out at the lowest possible temperature, in a neutral medium and with the shortest possible reaction time. As usual, the suitable reaction conditions are determined by preliminary tests.

The following exemplary embodiment serves to explain the process according to the invention in more detail and to use the process products obtained according to the invention. Example 1 a) 244 mg of magnesium (10 mmol) in 3 ml of absolute tetrahydrofuran are placed in a three-necked flask flushed with argon. 1/20 of a solution of 2 g (10 mmol) of 2-naphthyl bromide in 16 ml of absolute tetrahydrofuran is added with stirring. The Grignard solution starts quickly with green-yellow discoloration; the remaining 2-naphthyl bromide solution is added so that the reaction remains at the boil. After the addition, almost all of the magnesium has dissolved and the solution is refluxed with stirring for a further 2 hours. After that, the solution is in one

 Dropping funnel (under argon) decanted.

The 2-naphthylmagnesium bromide solution is slowly added dropwise at -30 ° C. with stirring and under argon to 0.15 g (1 mmol) of anhydrous copper (I) bromide in 4 ml of tetrahydrofuran. After 5 minutes at -30 ° C., 0.4 g (2.2 mmol) of 1,2,5,6-dianhydro-3,4-O-isopropylidene-L-idite in absolute tetrahydrofuran is added dropwise. The mixture is allowed to thaw to 0 ° C. and stirred at this temperature for 2 hours. Then it is a white, hard-to-stir mass with green streaks. It is worked up as usual, the copper salts remaining in the aqueous phase with a deep blue color. After the preparation, the 1,6-dideoxy-1,6-di- (2-naphthyl-3,4-isopropylidene-L-idite) is obtained as a crude product in a yield of approx. 90 ϊ.

[α] _D22 = + 34.6 (c = 0.8 in dichloromethane) b) 2.11 g (4.77 mmol) of the crude product are dissolved in 40 ml of pyridine with stirring. At 0 ° C, 0.78 ml (1.1 eq) of mesyl chloride in dry pyridine and a micro spatula tip 4-dimethylamino-pyridine are slowly added. Allow the yellowish discolouring solution to thaw and stir for 16 hours. Then a little water is carefully added and the pyridine is removed at not more than 60 ° C. in vacuo. The residue is mixed with water and extracted with ether. The ether phases are washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and a little water, after which the solvent is removed. pulled and the residue dried under high vacuum for several hours. The 1,6-dideoxy-1,6-di- (2-naphthyl-3,4-O-isopropylidene-2,5-O-dimesyl-L-idite is obtained as a foamy solidified caramel-colored mass. The yield of the crude product is 2.7 g (952), the melting point of the raw mixture is 75 ° C.

[α] _D22 = -22.3 ° (c = 1 in dichloromethane) c) 4.65 g (7.8 mmol) of the dimesylate obtained are in 35 ml

 Trifluoroacetic acid and 1 ml of water (7eq) dissolved at 0 ° C and stirred for 4 hours at this temperature. After the solvents have been stripped off in vacuo, 4.3 g (993! Of theory) of crude mass are obtained, which is chromatographed on a silica gel column with hexane / ethyl acetate, the starting material first migrating through the column as a yellowish fraction. This gives 3.7 g (84% of theory) 1,6-dideoxy-1,6-di-naphthyl-2,5-di-O-mesyl-L-idite with a melting point of 75 ° C. (from chloroform) .

[α] _D22 = + 4.7 ° (c = 0.7 in dichloromethane) d) 0.9 g (1.6 mmol) of the product obtained are absolute in 8 ml

 Tetrahydrofuran dissolved with stirring. Freedom from water is not absolutely necessary since water is produced. 0.4 g (1.1 eq) periodic acid are added with water cooling, which initially dissolve completely. Crystalline iodic acid precipitates after a few minutes. The heterogeneous mixture is stirred for 3 hours at room temperature, then it is filtered and rinsed with a little ether. This creates a white precipitate in the filtrate, which is removed by shaking with water. The water phase is then acidic and the ether / tetrahydrofuran phase is neutral. The

 Solvents are briefly dried over magnesium sulfate and removed in vacuo at a maximum of 30 ° C.

The (S) -2-methylsulfonyloxy-3- (2-naphthylpropionaldehyde) obtained as a crude product is immediately processed further:

The yellow oily residue (1.6 mmol aldehyde) is dissolved in 10 to 11 ml of t-butanol heated to 30 ° C. with stirring. For this purpose, 7 ml of a 1.25 molar aqueous sodium dihydrogen phosphate solution are added and the resulting solution is added with a few drops of phosphoric acid adjusted a pH of 6 to 6.5. For this purpose, 11 ml of saturated (1 molar) potassium permanganate solution are added at room temperature and with vigorous stirring. After 10 minutes the reaction is complete and is stopped by adding so much saturated aqueous sodium sulfite solution that the solution loses the violet potassium permanganate color and turns brown (brown stone). Conditions that are too basic must be avoided. With ice-cold dilute (2n) hydrochloric acid, a pH value of 3 to 4 is set and the colloidal manganese dioxide is dissolved. The aqueous phase is extracted three times with ether. The combined organic phases are washed with water, dried over magnesium sulfate and removed in vacuo. The backlog can be avoided

 Recrystallize methanol and gives 0.72 g (76 l of theory)

 (S) -2-Methylsulfonyloxy-3- (2-naphthyl) propionic acid as white crystals with a melting point of 88 ° C. e) To a solution of the carboxylic acid (4 g, 13.6 mmol) in 50 ml methanol / water 10: 1, while stirring ethereal solution of diazomethane, until the solution no longer discolors and the yellow color persists even after 5 minutes. Stir until N2 evolution is complete. The solvent is not drawn off completely to dryness (water) in vacuo and the residue is dissolved in 70 ml of dichloromethane. At this level, too, work should not exceed 30 ° C. The organic phase is washed twice with sodium chloride solution and once with water and dried over magnesium sulfate. The

 The crude substance is recrystallized from dichloromethane / ether and the white fibrous crystals (melting point 103 ° C.) are washed with pentane and dried in a high vacuum. The yield of S- (2-methylsulfonyloxy-3- (2-naphthyl) propionic acid methyl ester is 3.9 g of magnesium sulfate (94% of theory)

[α] _D22 = 15.1 ° (c = 1.1 in dichloromethane) f) 1.74 g (5.6 mmol) of the methyl ester and 1 g (3 eq) sodium azide are added to 30 ml dimethylformamide and the suspension 5 Stirred for hours at room temperature. The work-up is carried out as standard, although work at this level generally does not exceed 30 ° C. The organic phase is removed in vacuo and the (R) -2-azido-3- (2- Naphthyl) propionic acid methyl ester as a yellow, viscous 01 dried for several hours with stirring in a high vacuum. The result is 1.39 g (97% of theory) of azide.

[α] _D22 = + 52.3 ° (c = 1.1 in dichloromethane)

g) 0.2 g of the azido ester in 5 ml of methanol and 10 mg (5% by weight) of palladium-barium sulfate catalyst are stirred under hydrogen for 5 hours at normal pressure and room temperature. The azide then reacted quantitatively and the α-amino ester was formed. The contents of the shaking duck are filtered off with Celite (or simply), with a lot

 Rinsed methanol and evaporated in vacuo. The residue is taken up in absolute ether and a good result from this solution

 dried hydrogen chloride stream passed. The 3- {2-naphthyl) -D-alanine methyl ester hydrochloride immediately turns out far. The solid is recrystallized from ethyl acetate, washed with hexane and gives 1.4 g (65 7th of theory) of white crystals of the hydrochloride

 Melting point 184 ° C.

[α] _D22 = -10.6 ° (c = 1.16 in methanol)

Example 2

3- (1-Naphthyl) -D-alanine methyl ester hydrochloride is prepared under the conditions of Example 1 a-g, but using 1-naphthyl bromide. White crystals with a melting point of 184 ° C. (from ethyl acetate / methanol).

[α] _D22 = -35.5 ° (methanol; c = 1)

Example 3

D-α-aminooenanthic acid methyl ester hydrochloride is prepared under the conditions of Example 1a-g, but using n-butyl bromide. White crystals with a melting point of 130 ° C (from methanol). [α] _D22 = 24.1 ° (methanol; c = 1) Example 4

Under the conditions of Example 1a-g, but using 9-phenanthrenyl bromide, the 3- (9-phenanthrenyl) -D-alanine methyl ester hydrochloride is prepared. White powder with a melting point of 210 ° C (from dichloromethane / diethyl ether / HCL). [α] _D22 = 24.9 ° (dimethyl sulfoxide; c = 0.9)

Example 5

The 3- (4-chlorophenyl) -D-alanine methyl ester hydrochloride is prepared under the conditions of Example 1a-g, but using 4-chlorophenyl bromide. White powder with a melting point of 217 ° C (from diethyl ether / HCL). [α] _D22 = -16.7 ° (methanol; c = 1)

Claims

Claims 1. Process for the preparation of enantiomerically pure α-hydroxypropionaldehyde derivatives of the general formula I

 wherein R _{1 is} the substituent Q  which one is optionally by oxygen atoms, carbonyloxy groups, Nitrogen atoms, and / or resonance-stabilized imido groups and / or Thio groups interrupted and / or substituted by halogen atoms Represents hydrocarbon residue or  means a group containing hydroxyl groups, carbonyl groups or carboxyl groups formed by hydrolysis of Q and R _{2 is} an alkanesulfonyl group with up to 6 carbon atoms, one  Symbolizes trifluoromethanesulfonyl group, a benzenesulfonyl group or a p-toluenesulfonyl group,  characterized in that the oxirane rings of a 1, 2, 5, 6-dianhydrohexite derivative, of the general formula II or III

 wherein the two substituents R ₃ together form an alkylidene group with up to 6 represents carbon atoms or a benzylidene group, with an organometallic compound of the general formula IV QME (IV), in which Q has the meaning given above and ME represents an alkali metal atom, a copper (I) atom or a magnesium halide residue,  the compounds of general formula V or VI formed

wherein Q and R _{3 have} the meanings given above,  with a compound of general formula VII or VIII R ₂ Cl (VII) R ₂ -OR ₂ (VIII) in which R _{1 has} the meaning given above, to compounds of the general formula IX or X

wori n Q, R ₂ and R _{3 have} the meaning given above,  esterified this to compounds of general formula XI or XII

 wherein R ₁ and R _{2 have} the meanings given above,  hydrolyzed and cleaved using periodic acid or lead tetraacetate. 2. Use of the enantiomerically pure α-hydroxypropionaldehyde derivatives of the general formula I prepared according to claim 1 for the synthesis of enantiomerically pure α-hydroxypropionic acid derivatives of the general formula XIII

 wherein R ₁ and R _{2 have} the meaning given in claim 1 and their meaning Esters. 3. Use of the enantiomerically pure α-hydroxypropionaldehyde derivatives of the general formula I prepared according to claim 1 for the synthesis of enantiomerically pure α-azidopropionic acid derivatives of the general formula XIV

 wherein R _{1 has} the meaning given in claim 1 and its esters. 4. Use of the enantiomerically pure α-hydroxypropionaldehyde derivatives of the general formula I prepared according to claim 1 for the synthesis of enantiomerically pure α-amino acid derivatives of the general formula XV

 wherein R _{1 has} the meaning given in claim 1 and its esters.