Preparation of 3-amino-3-cyclopropylpropanoate esters

Details Preparation of 3-amino-3-cyclopropylpropanoate esters Preparation of 3-amino-3-cyclopropylpropanoate esters

1999-12-15

2001-03-27

Lee, Howard C. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S155000, C562S401000, C562S402000, C562S506000, C562S553000

Reexamination Certificate

active

06207854

ABSTRACT:

INTRODUCTION
This invention pertains to a process for preparing enantiomerically enriched 3-amino-3-cyclopropylpropanoate esters, i.e., esters of 3-amino-3-cyclopropylpropanoic acid (3-cyclopropylalanine esters or 3-CPA esters) including substantially enantiomerically pure (R) or (S)-3-CPA esters. More specifically, this invention pertains to a process for the preparation of substantially enantiomerically pure 3-CPA esters by a 5-step process wherein cyclopropanecarboxaldehyde (CPCA) is reacted with malonic acid and a source of ammonia to obtain &bgr;-cyclopropylalanine (3-CPA); esterifying the 3-CPA; contacting the 3-CPA ester with a substantially enantiomerically pure acid selected from tartaric acid, dibenzoyltartaric acid and mandelic acid to obtain a diastereomeric salt of the 3-CPA ester and the acid; recrystallizing the salt to afford a substantially diastereomerically pure salt; and neutralizing the salt to afford the substantially enantiomerically pure 3-CPA ester.
3-Amino acids are an important class of organic compounds and often are found in physiologically active compounds. See, for example, Suffness, Ed., Taxol®
Science and Applications
(CRC, Boca Raton, Fla., 1995) and Plattner, in
Annual reports in Medicinal Chemistry,
J. A. Bristol, Ed (Academic Press, San Diego, 1994), vol 29, pp. 113-22. Similarly, the cyclopropyl fragment also is found in pharmaceutical products. See, for example, British Patent Publication GB 1,136,214, U.S. Pat. No. 3,433,791, Published PCT Patent Application WO 9304047, Spanish Patent ES 539110, U.S. Pat. No. 4,863,918, Czech Patent CZ 279821 and European Patent Publication EP 0380312 A1.
Only one reference to an ester of a ∃-amino acid substrate of this type can be found in the literature and concerns the use of ethyl 3-amino-3-cyclopropylpropanoate in the synthesis of a platelet aggregation inhibitor, Published PCT Patent Application WO 9307867 A1 930429 (Application: WO 92-US8512). The racemic form of ethyl 3-amino-3-cyclopropylpropanoate was prepared by the action of diazomethane and palladium acetate on the corresponding vinyl compound, the preparation of which is not trivial.
BRIEF SUMMARY OF THE INVENTION
We have developed a process for the preparation of substantially enantiomerically pure (R) or (S) 3-CPA esters beginning with CPCA. Our novel process comprises the steps of:
(1) reacting CPCA with malonic acid and a source of ammonia in the presence of an inert solvent to obtain 3-cyclopropylalanine (3-CPA);
(2) contacting the 3-CPA with an alkanol in the presence of an acidic esterification catalyst to obtain a 3-CPA ester;
(3) contacting the 3-CPA ester with a substantially enantiomerically pure acid selected from tartaric acid, dibenzoyltartaric acid and mandelic acid to obtain a diastereomeric amine addition salt of the 3-CPA ester and the acid;
(4) recrystallizing the salt to afford a substantially diastereomerically pure amine addition salt of the 3-CPA ester and the acid; and
(5) neutralizing the salt with a base to afford a substantially enantiomerically pure 3-CPA ester.
As used herein, “substantially diastereomerically pure” refers to a compound possessing greater than 95% diastereomeric excess [de] wherein diastereomeric excess is defined as the percent of one diastereomer minus the percent of the other diastereomer. Similarly, “substantially enantiomerically pure” refers to a compound possessing greater than 95% enantiomeric excess [ee] wherein enantiomeric excess is defined as the percent of one enantiomer minus the percent of the other enantiomer
In step (1) of the process, CPCA is contacted with malonic acid and a source of ammonia in the presence of an inert solvent. The ammonia source may be ammonia or an ammonium salt such as an ammonium halide, e.g., ammonium chloride, or an ammonium carboxylate, i.e., an ammonium salt of a mono- or di-carboxylic acid containing up to about 8 carbon atoms, e.g., ammonium acetate, ammonium citrate and ammonium oxalate. The inert solvent may be selected from various non-reactive materials which are liquid under the reaction conditions. Examples of such inert solvents include alkanols, hydrocarbons, ketones, water or mixture thereof. The solvent preferably is a C
1
-C
4
alkanol, most preferably, ethanol.
Step (1) may be carried out at a temperature between room temperature and the boiling point of the solvent, preferably at about 20 to 120° C., most preferably at the boiling point of the solvent. Step (1) of the process described herein may be carried out at ambient pressures. However, pressures moderately below or above ambient pressure may be used. For example, increased pressure may be employed to limit the loss of ammonia from the reaction mixture and thus enhance the yield of the process. In particular, step (1) can be carried out using pressures in the range of about 1 to 100 atmospheres, preferably 1 to 30 atmospheres. The mole ratio of the CPCA and malonic acid may be in the range of about 0.10:1 to about 10:1, preferably in the range of about 0.5:1 to about 2:1. The mole ratio of the ammonia or ammonia source to CPCA may be in the range of about 1:1 to about 10:1, preferably in the range of about 2:1 to about 10:1. The 3-CPA product from step (1) may be isolated by standard isolation techniques such as filtration of the reaction mixture.
Step (2) of the process involves contacting the racemic 3-CPA from step (1) with a branched or unbranched alkanol, preferably a C
1
-C
4
alkanol, most preferably isopropanol, in the presence of an acidic esterification agent or catalyst to produce an alkyl ester of 3-CPA. The acidic catalyst may be selected from various acidic materials such as thionyl chloride, hydrohalic acids, e.g., hydrogen chloride, sulphonic acids, e.g., methanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid, and the polymer-bound sulphonic acids derived from vinylbenzenesulphonic acid and divinylbenzene; or a phosphoric acid. Thionyl chloride is the preferred acidic catalyst for step (2). Step (2) of the process may be carried out at a temperature in the range of from room temperature to the boiling point of the solvent, preferably at about 50 to 120° C., most preferably at the boiling point of the solvent.
In step (3) of our novel process the racemic amino ester from step (2) is contacted with an enantiomerically-enriched acid selected from comprising tartaric acid, dibenzoyltartaric acid or mandelic acid, preferably enantiomerically-enriched tartaric acid, in the presence of an inert solvent to obtain a diastereomeric salt of the ester. The mole ratio of the 3-CPA ester to the enantiomerically-enriched acid used in step (3) may be in the range of about 1.5:1 to about 3:1, most preferably about 2:1. The inert solvent may be selected from various non-reactive materials such as, for example, branched or unbranched alkanols, ethers, ketones, water or a mixture thereof. Preferred solvents comprise C
1
-C
4
alkanols and mixtures thereof with water, especially isopropanol/water mixtures, e.g., a 9:1 by volume ratio isopropanol:water mixture. Step (3) may be carried out at a temperature of from room temperature to the boiling point of the solvent, preferably at about 50 to 120° C., most preferably at the boiling point of the solvent. Upon cooling the reaction mixture to room temperature, the enantiomerically-enriched salt of the 3-CPA ester may be recovered by filtration.
Step (4) of the process involves recrystallization from the same solvent mixture to afford a substantially diastereomerically pure amine addition salt of the 3-CPA ester with the substantially enantiomerically pure acid. The substantially diastereomerically pure salt produced by the 4-step process is an amine addition salt of the 3-CPA ester and the enantiomerically-enriched tartaric acid, dibenzoyltartaric acid or mandelic acid. These substantially diastereomerically pure amine addition salts of the 3-CPA esters are novel compositions of matter.
The substantially diastereomerically pure salt produced in step (4) is contacted in step (5) with an aqueous bas

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