GB2100264A

GB2100264A - Process for the preparation of D-alanine and derivatives thereof

Info

Publication number: GB2100264A
Application number: GB8118301A
Authority: GB
Original assignee: SHELL INT RESEARCH; Shell Internationale Research Maatschappij BV
Current assignee: SHELL INT RESEARCH; Shell Internationale Research Maatschappij BV
Priority date: 1981-06-15
Filing date: 1981-06-15
Publication date: 1982-12-22

Abstract

A process for the preparation of the D-isomer of a compound of the general formula <IMAGE> or a salt, amide or ester thereof, in which Q represents a hydrogen atom or an optionally-substituted benzyl group, comprises reacting the L- isomer of a compound of the general formula <IMAGE> or a salt, amide or ester thereof, in which R represents an optionally- substituted alkyl or aryl group, with a compound of the general formula NH2Q where Q has the meaning given above.

Description

SPECIFICATION Process for the preparation of D-alanine and derivatives thereof This invention relates to a process for the preparation of D-alanine and derivatives thereof.

Very many ways of synthesising the single optical D-isomer of the amino acid, alanine, and its derivatives, have been proposed. The majority of this work has been directed either to the separation of isomers from a D,L mixture (e.g.

Journal of Organic Chemistry, 1973 (38) pp.

4408-4412), which is in general a difficult and time-consuming procedure, or to catalytic processes usually starting from pyruvate or from acetamidoacrylic acid. (e.g. Journal of Organometallic Chemistry, 1978 (150) pp. Cl 4- C16). In general, such processes are quite impracticable on an industrpal scale.

'Nature' 1 950 (1 66) pp. 1 78-179, describes the preparation of D-alanine from the L-isomer of a-bromopropionic acid, by reaction with sodium azide and subsequent reduction over Adam' catalyst. However, such processes starting from an opticaily active a-halopropionic acid suffer from the following disadvantage. a-Halopropionic acids are most conveniently prepared by halogenation of the corresponding hydroxy acid, and under most reaction conditions, such substitutions of a hydroxy group by a halogen atom proceed with inversion of configuration (or, often, with racemisation) at the optically active centre (e.g, Journal of the Chemical Society 1937 pp. 1 57-1 58) Thus D-lactic acid is the precursor for L-a-halopropionic acids, and D-lactic acid is not readily obtainable. In contrast, L-lactic acid is readily obtainable being prepared commercially by the fermentation of crude sugars in the presence of certain Lactobaclllus.

These problems of synthesis mean that Dalanine is only available commercially at extremely high cost. There is thus a need for a synthesis of D-alanine and its derivatives which provides good chemical and optical yields, and which starts from readily obtainable starting materials.

The present invention therefore provides a process for the preparatipn of the D-isomer of a compound of the general formula

or a salt, amide or ester thereof, in which Q represents a hydrogen atom or an optionaliysubstituted benzyl group, which comprises reacting the L-isomer of a compound of the general formula

or a salt, amide or ester thereof, in which R represents an optionally-substituted alkyl or aryl group, with a compound of the general formula NH2Q where Q has the meaning given above.

A salt of a free acid I or II may for example be an alkali metal or alkaline earth metal salt, or an ammonium salt in which the ammonium ion may be substituted by one or more optionallysubstituted alkyl and/or aryl groups, for example the NH3Q+ salt, where Q has the meaning given above. A salt of compound I may also be an acid addition salt, for example a hydrohalide salt.

Moreover the formula I should be understood to include its tautomeric zwitterionic form.

An amide of a compound I or II may for example be the unsubstituted amide or a monoor di-alkyl amide in which the or each alkyl group preferably has up to 4 carbon atoms. An ester may for example be an optionally-substituted alkyl ester, for example an unsubstituted alkyl ester having up to 6, especially up to 4, carbon atoms in the alkyl group.

If a free acid II is used as starting material in the process according to the invention, the initial product of the process will usually be a salt in which the cation has the formula NH3Q+.

Preferably however an ester of an acid II is used as starting material, normally resulting in an ester of the acid I.

Substituents in a substituted benzyl group Q may for example be one or more of the same or different moieties selected from halogen atoms and alkyl, alkoxy, hydroxy, haloalkyl, amino, cyano and nitro groups. Preferably however 0 represents either a hydrogen atom or an unsubstituted benzyl group.

Moieties which may substitute an aryl group R include those given above for a substituted benzyl group 0. The aryl group is preferably a phenyl group. Moieties which may be present in a substituted alkyl group R include halogen atoms and alkoxy, aryl (especially phenyl), hydroxy and amino groups.

Preferably R represents an unsubstituted alkyl group, preferably having up to 6, especially up to 4, carbon atoms, a phenyl group, or an alkylphenyl group preferably having 1 or 2 alkyl groups each having up to 4 carbon atoms.

Most preferably R represents a methyl group, a phenyl group or a 4-methylphenyl group.

If the compound NH2Q is a liquid at the desired reaction temperature, excess of this compound may be used as solvent for the reaction.

Alternatively or in addition, an inert solvent may be used. Suitable inert solvents include alcohols, for example ethanol or isopropanol, ethers, for example diethyl ether, tetrahydrofuran or dioxane, hydrocarbons, for example benzene or toluene, and halogenated hydrocarbons, for example methylene chloride or chloroform. The reaction is suitably carried out at elevated temperature, for example at a temperature in the range of from 40 to 1 500 C, especially 60 to 1 200C. When using ammonia as reactant, a closed reaction vessel is suitably used to prevent loss of ammonia. In such circumstances, ammonia under pressure, for example up to 20 bars, may be used. The ammonia may be dosed into the reaction vessel as a solution, as a gas or as a liquid.

In the process according to the invention, a sulphonic acid anion RAS030 is produced. If the compound NH2Q is the only base present in the reaction mixture, said compound will act as an acid binding agent. Thus stoichiometrically, three moles of NH2Q per mole of free acid II are required, since one mole reacts with the free -CO2H group and a second mole reacts with the released sulphonic acid anion RSO3. Only two moles of NH2Q are required stoichiometrically when using an ester, salt or amide of the free acid II. However, rather than using NH2Q as acid binding agent, the reaction may if desired be conducted iri the presence of an additional base, for example a tertiary amine such as pyridine or triethylamine, or an alkali metal carbonate or bicarbonate.In this case the stoichiometric ratio of NH2Q to starting sulphonate is reduced accordingly.

The molar ratio of NH2Q to the starting sulphonate actually used in the process according to the invention is not crucial, and may vary over a wide range. Preferably an excess over the stoichiometric requirements as discussed above in the range of from 0.1 to 10, especially 0.2 to 5, moles NH2Q per mole of starting sulphonate, is used.

The process according to the invention proceeds with inversion of optical configuration.

The optical purity of the final product depends of course on the precise reaction conditions, but the optical purity of the starting material is usually the main factor in determining the optical purity of the final product. Suitably a starting material containing at least 95% L-isomer is used, but if desired for economic reasons, a starting material containing, for example, 70% L-isomer may be used, resulting of course in a product which contains at least 30% of the undesired L-isomer.

Such a result may be adequate for some purposes.

The L-isomer of an ester of an acid of the general formula II may for example be prepared by esterifying the alpha-hydroxy group in an L lactate ester with a sulphonic acid RSO3H or active derivative thereof, for example the acid anhydride (RSO2)20 or, especially, the acid chloride RSO2CI. This esterification reaction proceeds with retention of optical configuration. It is preferably carried out in the presence of a base, for example an organic base such as pyridine or triethylamine. The reaction temperature is suitably in the range of from -50C to 800C, with room temperature usually being most convenient.

If it is desired that the ultimate product of the process according to the invention be the free acid of the formula I or a salt or amide thereof, the carboxylate ester of the acid II prepared as described above may be converted into a corresponding free acid, salt or amide by known methods before reaction with the compound NH2Q. Preferably, however, the carboxylate ester function is retained during the reaction with the compound NH2Q and conversion into the desired acid, salt or amide is effected after completion of this reaction.

Thus the present invention also provides a process for the preparation of the D-isomer of an acid of the general formula I or a salt, amide or ester thereof which comprises esterifying the alpha-hydroxy group in an L-lactate ester with a sulphonic acid RSO3H or an active derivative thereof, to produce the L-isomer of an ester of an acid II; optionally converting said carboxylate ester into a corresponding free acid or salt or amide thereof; reacting the resulting compound with a compound of the general formula NH2Q; and optionally converting the acid, salt, amide or ester function in the resulting compound into another acid, salt, amide or ester function.

If Q represents an optionally-substituted benzyl group, a compound I or salt, amide or ester thereof resulting from the process according to the invention may if desired be converted into the corresponding compound in which Q represents a hydrogen atom by hydrogenation under mild conditions. Gaseous hydrogen over a suitable catalyst, for example nickel, palladium or platinum, is a suitable reagent. Elevated pressures, for example up to 20 bars, may be used if desired, but atmospheric pressure is normally quite adequate. Reaction temperatures in the range of from 0 to 1 000C, especially 10 to 500 C, are suitable.

D-alanine and its derivatives have many uses.

For example, UK Patent Specification No.

1,122,043 describes inter alia the herbicidal properties of compounds of the general formula

wherein R1 and R2, which may be the same or different each represents a hydrogen atom, a substituted or unsubstituted alkyl, aryl or alkenyl group, or a group NR3R4 wherein R3 and R4 each individually represents a hydrogen atom or an alkyl group of 1-4 carbon atoms, provided that both R1 and R2 are not hydrogen atoms or NR3R4 groups, or R1 and R2 together with the nitrogen atom to which they are attached form an heterocyclic ring system optionally containing a further hetero atom; and X, Y and Z, which may be the same or different, each represents a hydrogen or halogen atom, a cyano or nitro group, a substituted or unsubstituted alkyl or aryl group, an alkyl-sulphonyl group or an amino or carbamoyl group or mono- or di-N-alkyl derivatives thereof, provided that not all of X, Y and Z represent hydrogen atoms. In general, the D-isomers of such compounds are more active as herbicides than the L-isomers or the racemic mixtures. Thus D-isomers of compounds of the general formula

or salts, ester and amides thereof, are either herbicidally active themselves (when the amide function contains the group -NR1R2) or are useful intermediates in the preparation of herbicidally active compounds.They may be prepared by reaction of D-alanine or a salt, ester or amide thereof, with a compound of the general formula

where Hal is a halogen, especially chlorine, atom.

This reaction is preferably carried out in the presence of a suitable base to bind the acid formed during the redaction. Suitable bases are, for example, the bicarbonates, carbonates and hydroxides of alkali metals, such as sodium and potassium, and of alkaline earth metals, and nitrogenous bases such as, for example pyridine.

The reaction is preferably carried out at a temperature between 50 and 1 500C, most preferably between 70 and 1 200C, in a suitable solvent or mixture of solvents, for example ethanol or aqueous ethanol.

The following Examples illustrate the invention.

NMR results are T values in ppm relative to tetramethylsilane.

Example 1.

Preparation of the L-isomer of isopropyl lactate mesylate.

2.2 Mol pyridine were added over 2.5 hours to a stirred solution of 2.5 mol mesyl chloride and 2.0 mol L-isopropyl lactate at 50C. The mixture was then warmed to 250C for a further 2.5 hours.

It was then treated with'toluene (500 mls), and washed successively with water, dilute HCI, and water. The solvent was then removed on a rotary evaporator and the residue distilled at a temperature of 1000C under a pressure of 0.1 5 mm Hg. The resulting L-isopropyl lactate mesylate was obtained in 85% yield, and had an optical rotation aS25 Of --63 0.

Example 2.

Preparation of the D-isomer of the isopropyl ester of N-benzylalanine.

A mixture of isopropyl mesylate prepared as in Example 1 (21g, 0.1 mol) and benzylamine (329, 0.3 mol) was heated overnight at 900C. The mixture was then cooled, washed with water, and extracted three times with diethyl ether. The combined ether extracts were dried over magnesium sulphate and evaporated down. The residue was distilled under reduced pressure (1 mm Hg pressure, heating bath temperature 800 C) to give 1 6.3g of the desired product, corresponding to a yield of 75%.

NMR T values: 2.7 (singlet 5H) 5.0 (septet 1 H) 6.3 (double doublet, 2H) 6.7. (quadruplet, 1 H) 8.15 (broad singlet, 1 H) 8.7 (doublet, 9H) Example 3.

Preparation of the D-isomer of the isopropyl ester of alanine.

The N-benzyl compound prepared as in Example 2 (1 0g) was dissolved in isopropanol (20 ml) and 100 mg of 10%w palladium on charcoal catalyst was added. Hydrogen was then bubbled through the stirred mixture at 300C for 20 hours.

After filtering off the catalyst, the solvent and the toluene produced in the reaction were evaporated off at a pressure of 1 mm Hg and a temperature of 300C. 5.5 g of the desired product were obtained, corresponding to a yield of 93%. The optical rotation a2D was +0.35.

NMRz values: 5.0 (septet, 1 H) 6.4 (quartet, 1 H) 6.9 (singlet, 2H) 8.65 (doublet, 3H) 8.75 (doublet, 6H) Example 4 Preparation of the D-isomer of the isopropyl ester of alanine.

The isopropyl mesylate prepared as in Example 1 (15g)was dissolved in isopropanol (20 ml) and ammonia was bubbled through the solution until it was saturated. The solution was then heated at 800C for 3 hours in an autoclave. The solvent was then evaporated, and the residue distilled under reduced pressure. The desired product was obtained in 55% yield.

Example 5 The optical rotations of alanine esters are very small even when the compound is pure, and it is thus rather difficult to determine accurately the optical purity of a sample. For this reason the Disopropyl alanine prepared in Examples 3 and 4 was converted into the D-isomer of the compound Nmethyl-2-(4-methyl-2,6-dinitroanilino)propionamide, which has known rotation, al=--1300, which is large and therefore much easier to measure. In this conversion, no bond is broken at the optical centre, and thus the optical configuration of the starting material is retained.

A mixture of the isopropyl alanine prepared in either Example 3 or Example 4 (2.59, 19.1 mmol), 3,5-dinitro-4-chlorotoluene (4.1 g, 1 9.1 mmol) and triethylamine (4g 42 mmol) was heated for 1 6 hours at 400C. The mixture was then dissolved in chloroform and washed with water.

The chloroform layer was dried over magnesium sulphate and evaporated to give 4.59 of Disopropyl 2-(4-methyl-2,6-dinitroanilino)propionate. This product was hydrolysed to give the free acid by heating at 500C with 4.5 ml 96% sulphuric acid and 2.25 ml water. The resulting reaction mixture was poured into water, extracted with methylene chloride, and evaporated to dryness.

2.59 of the resulting product were added to 5ml thionyl chloride and one drop dimethyl formamide, and the mixture was heated under reflux for 1 hour. It was then evaporated to dryness, and the residue taken up in a mixture of chloroform and dimethyl ether. The solution was saturated with methylamine and stirred for 5 minutes, then washed with water, dried and evaporated, to give the D-isomer of N-methyl-2 (4-methyl-2,6-dinitroanilino) propionamide.

When using the product of Example 4 as starting material, the crude product obtained as above had an optical rotation a2D1 of 1070, and after 2 recrystalizations from ethyl acetate it had (g2D Of --1300. When using the product of Example 3 as starting material, the crude product obtained as above had D1 of-1 160.

Claims

1. A process for the preparation of the Disomer of a compound of the general formula

or a salt, amide or ester thereof, in which Q represents a hydrogen atom or an optionallysubstituted benzyl group, which comprises reacting the L-isomer of a compound of the general formula

2. A process as claimed in claim 1, in which an ester of the acid II is used as starting material.

3. A process as claimed in either claim 1 or claim 2, in which the reaction temperature is in the range of from 40 to 1 500C.

4. A process as claimed in any one of claims 1 to 3, in which an excess of the compound NH2Q to the starting sulphonate in the range of from 0.2 to 5 moles per mole is used.

5. A process as claimed in any one of claims 1 to 4, in which the starting sulphonate has been prepared by esterifying the alpha-hydroxy group in an L-lactate ester with a sulphonic acid RSO3H or active derivative thereof, and optionally converting the resulting carboxylate ester into a corresponding free acid II or salt or amide thereof.

6. A process as claimed in claim 5, in which a sulphonic acid chloride RSO2CI is used to esterify the alpha-hydroxy group of an L-lactate ester.

7. A process as claimed in any one of claims 1 to 6, in which R represents an unsubstituted alkyl group having up to 4 carbon atoms, a phenyl group, or an alkylphenyl group having 1 or 2 alkyl groups each having up to 4 carbon atoms.

8. A process as claimed in claim 7, in which R represents a methyl, phenyl, or 4-methylphenyl group.

9. A process as claimed in any one of claims 1 to 8, in which 0 represents an unsubstituted benzyl group.

10. A process as claimed in any one of claims 1 to 8, in which Q represent a hydrogen atom.

11. A process as claimed in any one of claims 1 to 9, in which a compound of the general formula I or a salt, ester or amide thereof, in which 0 represents an optionally substituted benzyl group, is prepared, and said compound is subsequently converted into a corresponding compound in which Q represents a hydrogen atom, by hydrogenation.

12. A process as claimed in claim 1, carried out substantially as described in either Example 2 or Example 4 herein.

13. A compound of the general formula I or a salt, ester or amide thereof, whenever prepared by a process as claimed in any one of claims 1 to 12.