PREPARATION OF .ALPHA.-AMINO CARBOXYLIC ACID AMIDES

PREPARATION D'AMIDES DE L'ACIDE .ALPHA.-AMINO-CARBOXYLIQUE

English Abstract

Method of preparing .alpha.-amino carboxylic acid amides directly from
aminonitriles in high yield and purity by acid hydrolysis. The method involves
preparing the amide salt such as amide hydrochloride directly from the
corresponding aminonitrile in the presence of water, a strong mineral acid
such as anhydrous HCl, and an organic solvent in which the resulting amide
salt is insoluble or substantially insoluble. Suitable organic solvents
include dialkyl ethers, dialkyl ethylene glycol ethers and secondary alcohols.

French Abstract

Procédé permettant de préparer des amides de l'acide .alpha.-amino-carboxylique directement à partir d'aminonitriles, avec des rendements et une pureté élevés, par hydrolyse acide. Selon le procédé, on prépare le sel d'amide, le chlorhydrate d'amide par exemple, directement à partir de l'aminonitrile correspondant en présence d'eau, d'un acide minéral fort tel que le HCl anhydre, et d'un solvant organique dans lequel le sel d'amide obtenu est insoluble ou sensiblement insoluble. Les solvants organiques appropriés sont les dialkyléthers, les dialkyl-éthylèneglycol-éthers et les alcools secondaires.

Claims

What is claimed is:
1. A process of preparing an .alpha.-amino carboxylic acid
amide, comprising reacting an .alpha.-amino nitrile with a strong
mineral acid in the presence of water and an organic solvent
in which the resulting salt of said amide precipitates.
2. The process of claim 1, wherein said organic solvent
is selected from the group consisting of dialkyl ethers,
dialkyl ethylene glycol ethers and secondary alcohols.
3. The process of claim 1, wherein said organic solvent
is dimethoxyethane.
4. The process of claim 1, wherein said reaction is
conducted in a closed system.
5. The process of claim 1 wherein said strong mineral
acid is hydrochloric acid.
6. The process of claim 1 wherein said strong mineral
acid is anhydrous hydrochloric acid.
7. The process of claim 1, further comprising contacting
said salt of said amide with an alkaline reagent.
8. The process of claim 7, wherein said alkaline reagent
is alkali metal hydroxide.
9. The process of claim 1 wherein said .alpha.-amino carboxylic
acid amide is glycinamide.
10. The process of claim 2 wherein said .alpha.-amino
carboxylic acid amide is glycinamide.
11. The process of claim 5 wherein said .alpha.-amino
carboxylic acid amide is glycinamide.
12. The process of claim 1 wherein said .alpha.-amino
carboxylic acid amide is leucine amide.
13. The process of claim 2 wherein said .alpha.-amino
carboxylic acid amide is leucine amide.
14. The process of claim 5 wherein said .alpha.-amino
carboxylic acid amide is leucine amide.
15. The process of claim 1 wherein said .alpha.-amino
carboxylic acid amide is cycloleucine amide.
16. The process of claim 2 wherein said .alpha.-amino
carboxylic acid amide is cycloleucine amide.
17. The process of claim 5 wherein said .alpha.-amino
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carboxylic acid amide is cycloleucine amide.
18. The process of claim 1, wherein 1-6 equivalents of
acid are added based upon said nitrile.
19. The process of claim 1, wherein one equivalent of
water is present based upon said nitrile.
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Description

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PREPARATION OF a-AMINO CARBOXYLIC ACID AMIDES
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing
a-amino carboxylic acid amides. Such amides are useful as
intermediates for N-substituted heterocyclic pharmaceutical
compositions useful in the treatment of cardiovascular diseases
including hypertension, as well as glaucoma, diabetic
retinopathy and renal insufficiency. In particular, the
pharmaceutical compositions demonstrate antagonistic action
against angiotensin II, a potent vasopressor.
Conventional processes for the preparation of a-amino
carboxylic acid amides suffer from various disadvantages,
including low yields, low purity, the requirement of many steps
in the synthetic route, and complex isolation schemes. One
route to the amides is disclosed in Abramov, et al., Zhurnal
Organ. Khimii, 20(7), p. 1243-1247 (1984) where the preparation
of a-aminoamides and cx-amino acids from the corresponding a-
aminonitriles using manganese (IV) in the form of manganese
oxide is taught. Reaction times are critical, as longer
reaction times lead to the amino acid. In addition, reversion
to the starting cyanohydrin and ketone can occur.
Another somewhat analogous synthetic scheme is disclosed
in Johnson, et al., J. Org. Chem. 27, p.798-802 (1962). This
method involves the reaction of an aminonitrile with anhydrous
HC1 in the presence of an alcohol. The aminonitrile is
dissolved in n-butanol and is then treated with anhydrous HC1
and stirred at room temperature for 24 hours. The reaction
mixture is then refluxed for one' hour. The imidate ester
hydrochloride is formed as an intermediate, and decomposes upon
the application of heat to the corresponding amide and an alkyl
chloride. Alkyl chloride is formed as a by-product of the
reaction.
U.S. Patent No. 5,352,788 discloses a synthesis that
involves the hydrolysis of the oxalate salt of the aminonitrile
using concentrated sulfuric acid, followed by treatment with
ammonia and then extraction with chloroform containing 5%
methanol. However, this method has many disadvantages.
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It is therefore an object of the present invention to
provide a method of producing aminoamides directly from the
corresponding aminonitrile.
It is a further object of the present invention to provide
a method of producing aminoamides from aminonitriles in high
yield and without the concomitant production of potentially
hazardous by-products.
It is a still further object of the present invention to
provide a method of producing aminoamides from aminonitriles
without requiring complex isolation steps.
SUMMARY OF THE INVENTION
The problems of the prior art have been overcome by the
present invention, which provides a method of preparing cx-amino
carboxylic acid amides directly from aminonitriles in high
yield and purity by acid hydrolysis. The method involves
preparing the amide hydrochloride directly from the
corresponding aminonitrile in the presence of water, a strong
mineral acid such as HC1, and an organic solvent in which the
resulting salt of the aminonitrile is insoluble or
substantially insoluble. For example, in the case of HC1, the
hydrochloride salt readily precipitates from the solvent, and
can be isolated by filtration in high purity. The solvent and
excess HCl can be recycled with no significant color build-up
or product quality deterioration.
DETAILED DESCRIPTION OF THE INVENTION
The present invention can be used in connection with any
a-amino carboxylic acid, provided that the corresponding salt
is insoluble in the solvent employed. Suitable a-amino
carboxylic acids include valine, glycine, alanine and leucine,
with glycine, leucine and cycloleucine being particularly
preferred.
The amino nitrile can be virtually any a-aminonitrile
corresponding to the a-amino carboxylic acid desired, and can
be prepared from the corresponding ketone by conventional means
well known to those skilled in the art. For example, the
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ketone in a suitable solvent such as methanol can be reacted
with an ammonia source (such as ammonia and ammonium chloride)
and a cyanide source (such as alkali metal cyanide), and the
resulting amino nitrile can be recovered by extraction with
methylene chloride and dried.
In accordance with the present invention, the amino
nitrile is dissolved in a solvent in which the amino carboxylic
acid amide salt readily precipitates. Suitable solvents
include dialkyl ethers such as diethyl ether, and dialkyl
ethylene glycols such as ethylene glycol dimethyl, diethyl,
dibutyl, butyl methyl and propyl ethyl ether; secondary
alcohols such as isopropanol (preferably anhydrous);
hydrocarbons such as heptane and hexane; and ketones such as
acetone. The particular solvent should be chosen such that it
is a solvent in which the amino nitrile has sufficient
solubility to by acid hydrolyzed, and in which the salt formed
by the reaction is at least substantially insoluble, ensuring
that it can be easily isolated from the reaction medium. As
the solubility of the salt in the solvent increases, the yield
will decrease. Ether solvents are preferred, with
dimethoxyethane being an especially preferred solvent.
water is added to the reaction medium, preferably in an
amount of about 0.5 to 4 equivalents based upon the amount of
amino nitrile employed, most preferably one equivalent based
upon the amount of amino nitrile employed. High excesses of
water lead to the production of the amino acid rather than the
desired amide. The reaction mixture is then cooled to a
temperature in the range of 0-50°C,. preferably below about 30°,
most preferably to about 10°C, and a suitably strong mineral
acid is added while keeping the reaction temperature within the
aforementioned range and preferably below about 30°C. Higher
temperatures tend to result in undesirable side reactions.
Suitable mineral acids include HC1, HBr, HzS04, toluene sulfonic
acid, methane sulfonic acid and trifluoro acetic acid. Since
excess water is deleterious to the reaction, leading to the
generation of alkyl chloride, for example, it is preferred that
the strong mineral acid be added in anhydrous form, especially
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once the appropriate amount of water is already in the system.
Suitable amounts of mineral acid range from about 1 to about
6 equivalents, with 3-4 equivalents being preferred in order
to reduce reaction times. Preferably the acid is added over
time, such as 60 minutes. Once the addition of the acid is
complete, the reaction mixture is sealed, warmed to a
temperature of about 4 0 ° C or higher to ef feet conversion to the
a-amino carboxylic amide salt, allowed to react to completion
(about 4-20 hours), and cooled. Preferably a closed system is
used) since at temperatures higher than 40°C, the loss of acid
gas to the atmosphere becomes problematic. At temperatures
below 40°C, the reaction is very sluggish. The resulting amide
salt readily precipitates, which allows for easy isolation and
purification. The salt can be collected by filtration and
washed with additional solvent. The thus produced amide salt
can be easily converted to the free amide acid by the addition
of a suitable alkaline reagent, such as ammonium hydroxide or
alkali metal hydroxide, preferably sodium or potassium
hydroxide.
The theoretical reaction mechanism can be illustrated as
follows for the preparation of cycloleucine amide:
G O O
HEN r,N ~ \\
H.. ~\
CM' ' ~N'.j2 base ~ NH'
~ HC!
H2 O C Lr1 ~ ~; C 1
CL:,
EXAMPLE ~ 1
The amino nitrite of cyclopentanone was prepared using
methods commonly found in the literature. The amino nitrite
of cyclopentanone (40.OOg, 0.36 mole) was added to a 500 ml
round bottom flask equipped with a mechanical stirrer, a
thermocouple, and a gas inlet tube. Following the addition of
131g of dimethoxyethane (DME) and 6.558 (0.36 mole) of water,
the reaction was cooled to <10°C. Anhydrous HC1 (53.148, 1.46
moles) was bubbled into the reaction mixture keeping the
reaction temperature below 30°C. The HC1 was added over a 60
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minute period. The reaction mixture was sealed and warmed to
40°C for eight hours and then cooled to 10°C. Cycloleucine
amide hydrochloride (49.40g, 0.30 mole, 83.3%) was collected
by filtration as a white solid and washed with an additional
26g of DME. Additional product can be isolated from the
filtrate. The hydrochloride salt can be easily converted to
the acid with an alkaline reagent.
EXAMPLE 2
2.8 g (0.05 mol) of anhydrous, liquid glycinonitrile was
dissolved in 1,2-dimethoxyethane in a 125 ml Erlenmeyer flask.
9.2 g of anhydrous HC1 was bubbled into the flask with cooling
to the desired weight. 0.9 g (0.05 mol) of water was added,
and the reaction mixture was stirred at the desired temperature
for 6 hours. The product was filtered off, washed with
additional solvent, and dried under vacuum. The yield of amide
was 92.0%.
EXAMPLE 3
Isopropanol was placed in a 5 liter flask equipped with
a stirrer, thermometer, gas inlet tube and condenser. The
flask was cooled in an ice-salt bath and HC1 was added from a
cylinder until saturated - 600 grams absorbed. Glycinonitrile
hydrochloride was added in one portion and the cooling bath was
removed. The connecting tube and flask were attached to a
condenser, and the flask was cooled in the ice bath to collect
isopropyl chloride. The reaction mixture was heated slowly to
about 60°C when the isopropyl chloride started to collect. The
temperature was raised to 78-92°C and held there for 3.5 - 4
hours. After cooling overnight, the resulting solid was
collected and air dried. 309 g of crude product were obtained,
resulting in a yield of 930. 37% of the isopropyl chloride was
recovered.
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