Process for the efficient preparation of N-substituted dehydroamino acid esters

A process for the preparation of N-substituted dehydroamino acid esters by contacting a .beta.-hydroxy-.alpha.-amino acid ester or N- or O-substituted .beta.-hydroxy-.alpha.-amino acid ester with an excess of acetic anhydride and a base is disclosed.

FIELD OF THE INVENTION 
This invention relates to the preparation of N-substituted dehydroamino 
acid esters by dehydration of .beta.-hydroxy-.alpha.-amino acid esters or 
N- or O-substituted .beta.-hydroxy-.alpha.-amino acid esters. 
BACKGROUND OF THE INVENTION 
Dehydro .alpha.-amino acids are key intermediates for the manufacture of 
unnatural D-.alpha.-amino acids and non-proteinaceous .alpha.-amino acids 
using asymmetric hydrogenation technology. Such amino acids are 
increasingly important intermediates in the pharmaceutical, agrichemical, 
and flavor/fragrance industries. For example, the amino acid D-alanine is 
a component of an artificial sweetener alitame while non-proteinaceous 
2-aminobutyric acid is a component of a tuberculostatic drug ethambutol. 
State-of-the-art asymmetric hydrogenation catalysts allow the manufacture 
of these .alpha.-amino acids with very high selectivity for a single 
enantiomer. For example, using rhodium catalysts bearing chiral 
phospholane ligands, the L- or D-isomer of alanine or 2-aminobutyric acid 
can be prepared from the corresponding dehydro amino acids in greater than 
99% enantiomeric excess. 
While aromatic dehydroamino acid derivatives such as dehydro phenylalanine 
are inexpensively available by the "Erlenmeyer synthesis", aliphatic 
analogous are more difficult to prepare. Of several methods devised to 
date, the most practical is the dehydration of the corresponding 
.beta.-hydroxy-.alpha.-amino acid esters. Such routes avoid the use of 
expensive and hazardous reagents such as azides, t-butyl hypochlorite, 
pyruvic acid, or cysteine derivatives which are required in alternative 
routes. The approach is especially attractive in cases where the necessary 
.beta.-hydroxy-.alpha.-amino acid is inexpensively available. Moreover, 
the hydroxyamino acid starting material need not be enantiomerically pure. 
For example, readily available DL-serine can be converted to 
dehydroalanine while threonine gives the precursor for 2-amino butyric 
acid. 
Existing procedures for the dehydration of .beta.-hydroxy-.alpha.-amino 
acids fall into two categories, namely stepwise processes and direct 
dehydration procedures. In the stepwise routes, the hydroxyl group is 
often first converted to a better leaving group, typically the 
p-toluenesulfonate. Alternatively, the hydroxyl group has been 
O-diphenylphosphorylated for this purpose. Both procedures utilize 
moisture-sensitive derivatizing agents. Another stepwise process involves 
activation of the amine functionality by converting it to a cyclic 
diamide, followed by dehydration using the acidic catalyst potassium 
bisulfate. A. G. Brown and T. C. Smale, J. Chem. Soc., Perkin Trans. 1, 65 
(1972). All of these stepwise procedures are inherently inefficient since 
they involve the isolation and purification of a reactive intermediate. 
Most of the direct dehydration processes utilize expensive reagents such as 
diisopropylcarbodiimide/copper(I) chloride, N,N'-carbonyldiimidazole, or 
DAST (diethylaminosulfur trifluoride). An alternative procedure uses 
moderately expensive diethyl chlorophosphate but additionally requires the 
hazardous (pyrophoric) base sodium hydride to effect elimination. 
Thus there is a need for an improved single step dehydration process which 
uses reagents which are readily available, inexpensive and non-hazardous. 
The present invention provides such a process. 
SUMMARY OF THE INVENTION 
This invention provides a process for the preparation of N-substituted 
dehydroamino acid esters comprising contacting a 
.beta.-hydroxy-.alpha.-amino acid ester or N- or O-substituted 
.beta.-hydroxy-.alpha.-amino acid ester of formula I 
##STR1## 
wherein R.sup.1 is hydrogen, C.sub.1 -C.sub.20 alkyl, a C.sub.3 to 
C.sub.20 cycloalkyl, a C.sub.6 -C.sub.12 aryl, C.sub.7 to C.sub.20 aralkyl 
or C.sub.7 to C.sub.20 alkylaryl optionally substituted with NR.sup.5 
R.sup.6, OR.sup.5,(CO)OR.sup.5, (CO)NR.sup.5 R.sup.6 or CN wherein R.sup.5 
and R.sup.6 are each independently C.sub.1 -C.sub.6 alkyl or C.sub.6 aryl; 
R.sup.2 is C.sub.1 -C.sub.20 alkyl, a C.sub.3 to C.sub.20 cycloalkyl, 
C.sub.6 -C.sub.12 aryl, C.sub.7 to C.sub.20 aralkyl or C.sub.7 to C.sub.20 
alkylaryl optionally substituted with NR.sup.5 R.sup.6, OR.sup.5, 
(CO)OR.sup.5, (CO)NR.sup.5 R.sup.6 or CN wherein R.sup.5 and R.sup.6 are 
each independently C.sub.1 -C.sub.6 alkyl or C.sub.6 aryl; 
R.sup.3 is hydrogen, C.sub.1 -C.sub.20 acyl, C.sub.1 -C.sub.20 alkyl, a 
C.sub.3 to C.sub.20 cycloalkyl, a C.sub.6 -C.sub.12 aryl, a C.sub.7 to 
C.sub.20 aralkyl or a C.sub.7 to C.sub.20 alkylaryl optionally substituted 
with NR.sup.5 R.sup.6, OR.sup.5, (CO)OR.sup.5, (CO)NR.sup.5 R.sup.6 or CN 
wherein R.sup.5 and R.sup.6 are each independently C.sub.1 -C.sub.6 alkyl 
or a C.sub.6 aryl; 
R.sup.4 is H or C.sub.1 -C.sub.20 acyl; with an excess of acetic anhydride 
and a base to yield an N-substituted dehydroamino acid ester of formula II 
##STR2## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above in formula I 
DETAILED DESCRIPTION OF THE INVENTION 
This invention provides a process for the preparation of N-substituted 
dehydroamino aged esters. 
The term "acyl" as used herein denotes 
##STR3## 
wherein R is hydrogen C.sub.1 -C.sub.20 alkyl, C.sub.6 -C.sub.14 aryl, 
C.sub.7 -C.sub.20 aralkyl, C.sub.7 -C.sub.20 alkylaryl and their various 
isomers. 
The term "alkyl" as used herein denotes a straight-chain or branched-chain 
alkyl such as methyl, ethyl, n-propyl, i-propyl, or the different butyl, 
pentyl, hexyl, and other isomers up to 20 carbon atoms. 
The term "cycloalkyl" denotes a cyclic alkyl such as cyclopropyl, 
cyclobutyl, cyclopentyl, cyclohexyl, and others up to 20 carbon atoms. 
The term "aryl" denotes aromatic groups such as phenyl, 1-naphthyl, 
2-naphthyl, or biphenylyl. 
The term "aralkyl" denotes aromatic groups having at least one alkyl 
substituent linked via a carbon atom of the aromatic group. Examples 
include benzyl, .alpha.-phenethyl and .beta.-phenethyl. 
The term "alkylaryl" denotes aromatic groups having at least one alkyl 
substituent linked via a carbon atom of the alkyl substituent. Examples 
include o-tolyl, m-tolyl, p-tolyl, and p-t-butylphenyl. 
The process of the present invention for preparation of esters of 
N-substituted dehydroamino acid esters by contacting an 
.beta.-hydroxy-.alpha.-amino acid ester or an N- or O-substituted 
.beta.-hydroxy-.alpha.-amino acid ester with acetic anhydride and a base 
is shown in equation 1) below: 
##STR4## 
wherein 
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined above in formula I. 
Examples include the preparation of methyl .alpha.-(N,N-diacetyl)amido 
acrylate (obtained as a mixture with the monoacetamide) from serine methyl 
ester shown in equation 2) below and the preparation of methyl 
.alpha.-(N,N-diacetyl)amido-Z-crotonate from threonine methyl ester, as 
shown in equation 3) below: 
##STR5## 
Bases suitable for use in the process of the present invention are 
inorganic or organic. The conjugate acid of said base has a pK.sub.a in 
the range of about 4.75 to about 14, preferably 4.75 to about 10, most 
preferably 4.75 to 8. Examples of suitable inorganic bases include various 
ester salts such as sodium acetate, potassium acetate, sodium carbonate, 
potassium carbonate, sodium bicarbonate, potassium bicarbonate. Examples 
of suitable organic bases for the process of the present invention include 
tertiary amine bases. Examples include pyridine, picoline, 
diisopropylethylamine, triethylamine, tributylamine, N-methyl morpholine, 
DABCO (1,4-diazabicyclo [2.2.2]-octane), and DBU (1,8-diazabicyclo [5.4.0] 
undec-7-ene). The molar ratio of base to reactant is from about 1:1 to 
about 30:1. Preferably the molar ratio of base to reactant is from about 
1:1 to about 15:1. A range of 3:1 to 7:1 is most preferred. 
The .beta.-hydroxy-.alpha.-amino acid ester or N- or O-substituted 
.beta.-hydroxy-.alpha.-amino acid ester starting materials of the process 
may be utilized as a free base or may be introduced as a salt such as a 
hydrochloride, sulfate, or oxalate salt. Many such compounds are available 
commercially or may be prepared by methods known in the art, as further 
demonstrated by Example 7 herein. 
The process of the invention can be carried out at atmospheric pressure or 
at pressures between 100 and 1000 kP.sub.a. Reaction at atmospheric 
pressure is preferred. The process is preferably carried out under air, 
but an inert atmosphere such as nitrogen or argon may be utilized. 
The preferred solvent is excess acetic anhydride. However, organic 
co-solvents may optionally be used; examples of suitable organic 
co-solvents include toluene, xylene, chlorobenzene, pyridine, di-n-butyl 
ether, and dimethyl acetamide. 
The reaction is carried out over a temperature range of from about 
80.degree. C. to about 200.degree. C. Preferably, the reaction is 
conducted at a temperature of from about 100.degree. C. to 180.degree. C. 
A range of 120.degree. C. to 150.degree. C. is most preferred. Reaction 
times can vary from about 0.5 hour to about 48 hours. A time of 1 to 4 
hours is preferred. 
Agitation during the reaction is preferable since it is conducted under 
reflux conditions. The product is isolated using conventional techniques 
such as distillation, extraction, or chromatography. The product is 
obtained as a mono- or di-N-acetyl derivative, or a mixture thereof. 
The current invention provides advantages over prior art processes in 
several respects. The reagents used for dehydration, preferably acetic 
anhydride and a base such as sodium acetate or pyridine, are cheap and 
relatively innocuous. No separate step is required either to protect the 
amine functionality or to activate the hydroxyl group toward elimination. 
The product dehydro-.alpha.-amino acid is obtained as a mono- or 
di-N-acetyl derivative; the acetyl group is a suitable directing group for 
subsequent asymmetric hydrogenation. 
The process of the present invention is useful for the preparation of 
dehydroamino esters. Such esters are useful starting materials in 
asymmetric hydrogenation reactions to prepare particular isomers of 
.alpha.-amino acids of importance in the pharmaceutical, agrichemical, and 
flavor/fragrance industries. 
The following Examples demonstrate the process of the invention. The amino 
acid starting materials used in these examples are commercially available 
from Sigma Chemical Company, St. Louis, Mo.