Process for the preparation of cyclopropylglycine

Details Process for the preparation of cyclopropylglycine Process for the preparation of cyclopropylglycine

1999-08-03

2001-02-20

O'Sullivan, Peter (Department: 1611)

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

Organic compounds

Carboxylic acid esters

C558S315000, C560S038000, C564S275000

Reexamination Certificate

active

06191306

ABSTRACT:

This invention pertains to a process for preparing cyclopropylglycine (CPG) including racemic and substantially enantiomerically pure (R) or (S)-CPG. More specifically, this invention pertains to a process for the preparation of CPG by a 5-step process wherein cyclopropanecarboxaldehyde (CPCA) is reacted with an a-aminoalkylaromatic compound to obtain an imine which is reacted with a cyanide to produce an aminonitrile compound; the aminonitrile compound is hydrolyzed to the corresponding aminocarboxylic acid and finally the arylalkyl residue is removed from the amino group by hydrogenolysis. The present invention also includes certain of the individual process steps and intermediate compounds.
Unnatural amino acids are an important class of organic compounds and often are found in physiologically active compounds. Similarly, the cyclopropyl fragment also is found in pharmaceutical products. See, for example, U.S. Pat. No. 3,474,101, 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.
The synthesis of racemic CPG first was reported by Lowry,
J. Am. Chem. Soc.,
1952, 1355 in a 9% yield using Strecker chemistry. Whitesides,
J. Am. Chem. Soc.,
111, 6354 (1989) describes the preparation of homochiral CPG by enzymatic resolution of racemic CPG. This resolution has been performed on a millimole scale, presumably because of the difficulty in preparing racemic CPG. U.S. Pat. No. 3,987,178 (1976) discloses D-, L- and DL-CPG and methods for the preparation and resolution thereof. One method for the preparation of DL-CPG starts with CPCA which is converted to CPG via cyclopropyl-5-hydantoin. Another method involves the reaction of bromocyclopropane with diethyl acetamido sodiomalonate. The resolution of DL-CPG also is disclosed in U.S. Pat. No. 3,987,178 by the enzymatic hydrolysis of the acetamide of CPG using Hog Kidney Acylase I.
The use of chiral a-methylbenzylamine as an auxiliary in Strecker-type synthesis of other compounds is disclosed in U.S. Pat. No. 3,914,249; Synth. Commun., 1986, 16, 337; J. Org. Chem., 1983, 48, 5369; Helc. Chim. Acta., 1979, 62, 956; Helv. Chim. Acta., 1980, 63, 824; J. Org. Chem., 1989, 54, 1055. In no case was a cyclopropylcarbonyl substrate used.
We have developed a process for the preparation of both racemic and substantially enantiomerically pure (R) or (S)-CPG beginning with CPCA. Our novel process comprises the steps of:
(1) contacting CPCA with an amine having the formula
in the presence of a solvent comprising an alkanol, water or a mixture thereof to obtain an imine having the formula:
(2) contacting the imine of formula (II) with a cyanide selected from alkali metal, alkaline earth metal and trimethylsilyl cyanides in the presence of a solvent comprising an alkanol, water or a mixture thereof to obtain an aminonitrile compound having the formula:
(3) contacting the aminonitrile compound of formula (III) with a strong acid in the presence of water to obtain an acid addition salt of an aminocarboxylic acid having the formula:
(4) contacting the acid addition salt of the aminocarboxylic acid of formula (IV) with a hydroxide, carbonate or bicarbonate of an alkali metal or alkaline earth metal in the presence of water to obtain the free aminocarboxylic acid of formula (IV); and
(5) contacting the aminocarboxylic acid of formula (IV) with hydrogen in the presence of a hydrogenation catalyst and an inert solvent to obtain CPG;
wherein R
1
is hydrogen or an alkyl radical, e.g., unsubstituted or substituted C
1
-C
3
alkyl; and R
2
is a carbocyclic aryl radical. The use of highly enantiomerically pure (>99% enantiomeric excess [ee], where enantiomeric excess is defined as the percent of one enantiomer minus the percent of the other enantiomer) (R) or (S) amine (I) wherein R
1
is alkyl and R
2
is phenyl, substituted phenyl, or naphthyl gives the corresponding substantially enantiomerically pure CPG (for the purposes of this invention, substantially enantiomerically pure indicates a compound possessing >95% ee) whereas the use of racemic or achiral amine (I) in which R
1
is alkyl, aryl, or hydrogen and R
2
is phenyl, substituted phenyl, or naphthyl gives racemic CPG. CPG is useful in the preparation of pennicillins as is disclosed in U.S. Pat. No. 3,987,178 (1976).
Our novel process also includes the novel intermediate compounds produced and utilized in the above-described process, i.e., imine (II), aminonitrile (III) and aminocarboxylic acid (IV).
In the first step of the process, amine (I) is reacted with CPCA in the presence of an inert solvent to produce imine (II). The inert solvent preferably is an alkanol, e.g., an alkanol containing about 1 to 4 carbon atoms, water or an alkanol/water mixture. The first step may be carried out at a temperature in the range of about room temperature up to the boiling point of the solvent, preferably at a temperature of about 50 to 70° C. The mole ratio of CPCA:amine (I) normally will be about 0.75:1 to 1.25:1. Imine (II) produced in step (1) may be isolated, e.g., by standard extraction techniques known in the art, but preferably is used in step (2) in the form of the reaction product mixture obtained from step (1).
The alkyl radicals which R
1
may represent may be unsubstituted C
1
-C
3
alkyl such as methyl, ethyl and propyl or C
1
-C
3
alkyl substituted with groups such as hydroxy; halogen, e.g., chloro and bromo; nitro; or mercapto. The carbocyclic aryl radical represented by R
2
may be unsubstituted or substituted phenyl or naphthyl. Examples of the substituents which may be present on the phenyl and naphthyl radicals which R
2
represent include alkyl, e.g., C
1
-C
4
alkyl; alkoxy, e.g., C
1
-C
4
alkoxy; halogen, e.g., chloro and bromo; nitro; hydroxy; and the like. Normally, the phenyl and naphthyl radicals will not be substituted by more than 2 of any such substituents. The amine having formula (I) preferably is &agr;-methylbenzylamine or benzylamine, the latter useful only for racemate preparation.
The second step of the process comprises contacting imine (II) obtained from the first step with a cyanide reactant in the presence of an inert solvent, typically the same solvent as that which is used in the first step. The cyanide reactant may be selected from one or more alkali metal, alkaline earth metal or trimethylsilyl cyanides, preferably an alkali metal cyanide such as potassium or sodium cyanide. The second step may be carried out at a temperature in the range of below room temperature up to the boiling point of the solvent, preferably at a temperature of about 15 to 45° C. The mole ratio of cyanide reactant:imine (II) normally will be about 1:1 to 10:1.
When amine (I) is a substantially enantiomerically pure compound, i.e., (R) or (S) amine (I) wherein R
1
is alkyl, the process of step 2 is unexpectedly observed to proceed with >2:1 diastereoselectivity. For example, when R
1
is methyl and R
2
is phenyl, the addition of cyanide to imine (II) is observed to provide aminonitrile (III) in a 3.2:1 ratio of diastereomers. The major diastereomer possesses either the (R,R) configuration [starting with the (R)-amine] as shown in IIIa or the (S,S) configuration [starting with the (S)-amine] as shown in IIIb. The minor diastereomer in each case possesses the (S,R) configuration as shown in IIIc and IIId. This diastereoselectivity is unexpected and could not be predicted, but is advantageous for the preparation of substantially enantiomerically pure CPG.
Thus, a second embodiment of the process of the present invention involves a process for the preparation of an aminonitrile having the formula
which comprises the steps of:
(1) contacting CPCA with a substantially enantiomerically pure amine having the formula
in the presence of a solvent comprising an alkanol, water or a mixture thereof to obtain an imine having the formula:
(2) contacting the imine of formula (II) with a cyanide selected from alkali metal, alka

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