Process for preparing 1-aminocyclopropane-1-carboxylic acid

An improved process for preparing 1-aminocyclopropane-1-carboxylic acid, which acid is a plant growth regulator.

This invention relates to an improved process for the preparation of 
1-aminocyclopropane-1-carboxylic acid. 
1-Aminocyclopropane-1-carboxylic acid (ACPCA) is a naturally occurring 
plant hormone which regulates many aspects of plant growth and 
development. Derivatives of 1-aminocyclopropane-1-carboxylic acid have 
been claimed as plant growth regulators (West German DT No. 28 24 517). 
Unfortunately, preparative methods of ACPCA up to this time have required 
several reaction steps, have produced a low yield of the product, and have 
been uneconomical. Such multi-step processes are described by I. Bregovec 
and T. Jakovic, Manatsh. Chem. 103, 288 (1972); by D. H. Rich and J. P. 
Tam, Synthesis, 46 (1978); and by U. Schollkopf et al., Liebigs Ann. 
Chem., 611 (1973). In contrast, the process of the present invention is 
simple, requiring only two steps, with a corresponding high yield of 
ACPCA. 
The process of the present invention can be illustrated as follows: 
##STR1## 
In the above formulas, R is lower alkyl, aryl or substituted aryl; and X is 
bromo, chloro or iodo. 
In the practice of the above-outlined synthesis, the ester of formula (1) 
is reacted with at least one molar equivalent of X(CH.sub.2).sub.2 X in 
the presence of at least two molar equivalents of a base, such as lithium 
diisopropylamide or triethylbenzyl ammonium hydroxide, and a solvent 
suitable for the base used, at room temperature or below, to give the 
cyclopropyl ester of formula (2). Compound (2) is hydrolyzed with a strong 
acid, such as hydrochloric or sulfuric acid, to yield the acid salt of 
1-aminocyclopropane-1-carboxylic acid, which is then converted to the free 
compound by such means as passing through an ion exchange resin. 
The following terms, wherever used in the description herein and in the 
appended claims, have the meaning defined below, unless otherwise 
specified hereinafter. 
The term "lower alkyl" refers to an alkyl group, straight or branched, 
having a chain length of one to six carbon atoms. 
The term "aryl" refers to the aryl group phenyl or naphthyl. The term 
"substituted aryl" refers to an aryl group substituted at one, two or 
three of the ring carbon atoms with a group selected from lower alkyl, 
lower haloalkyl, halogen, nitro, cyano, hydroxy, and the like.

The following examples are provided to illustrate the practice of the 
present invention. RT means room temperature. Temperature is given in 
degrees Centigrade. 
EXAMPLE 1 
To a solution of 21.9 ml of diisopropylamine in 300 ml of tetrahydrofuran, 
under nitrogen at 0.degree., is added dropwise 180 ml of 1.6 M 
n-butyllithium is hexane. The solution is stirred at 0.degree. for 20 
minutes, then cooled to -78.degree.. Anhydrous hexamethylphosphoramide (55 
ml) is added dropwise, followed by 20 g of benzylidene glycine ethylester 
in 10 ml tetrahydrofuran. The reaction mixture is stirred at -78.degree. 
for 10 minutes, after which 45 ml of 1,2-dibromoethane is added. The 
mixture is stirred at -78.degree. for 8 hours, then at RT for 24 hours. 
This is then concentrated at 40.degree.. The oily residue is neutralized 
with saturated aqueous ammonium chloride and extracted with ether. The 
ether extracts are washed, dried and evaporated to dryness. The 
hexamethylphosphoramide is removed under vacuum at 120.degree. to yield 
benzylidene cyclopropyl ethyl ester. 
Benzylidene cyclopropyl ethyl ester (18.9 g) in 250 ml of 6 N hydrochloric 
acid is refluxed for 24 hours. Water is then removed under reduced 
pressure, and the amino salt is passed through ion-exchange resin 
(Amberlite IR-4B). The aqueous solution is freeze-dried to give 
1-aminocyclopropane-1-carboxylic acid. 
EXAMPLE 2 
Following the procedure of Example 1, benzylidene glycine phenyl ester is 
reacted with 1,2-dichloroethane to give benzylidene cyclopropyl phenyl 
ester, which is then hydrolyzed to yield 1-aminocyclopropane-1-carboxylic 
acid. 
Benzylidene glycine phenyl ester can be made by reaction of glycine phenyl 
ester hydrochloride (107 mmol) with benzaldehyde (72 mmol) in the presence 
of triethylamine (30 ml), magnesium sulfate (8 g) and dichloromethane, 
under nitrogen and with stirring at RT for about 24 hours. The mixture is 
filtrated and the filtrate is concentrated. The residue is taken up in 
ether, washed with brine and evaporated to dryness to give benzylidene 
glycine phenyl ester.