Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2001-03-29
2002-11-19
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S405000
Reexamination Certificate
active
06482978
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to production methods of a specific aromatic bromocarboxylic acid derivative and a specific aromatic acylthiocarboxylic acid derivative.
BACKGROUND OF THE INVENTION
Optically active aromatic acylthiocarboxylic acid derivatives are useful as pharmaceutical intermediates. For example, (S)-2-acetylthio-3-phenylpropionic acid (hereinafter sometimes to be abbreviated as (S)-ATPPA), (R)-2-bromo-3-phenylpropionic acid (hereinafter sometimes to be abbreviated as (R)-BPPA) and the like are known to be important intermediates for the compounds having an angiotensin converting enzyme inhibitory activity and a neutral endopeptidase inhibitory activity, and useful as antihypertensive agents [see particularly JP-A-7-48259 (EP-A-0629627)]. The aromatic acylthiocarboxylic acid derivatives can be produced from aromatic amino acid via aromatic bromocarboxylic acid derivatives.
For example, JP-A-8-337527 (EP-A-0747392) and JP-A-7-48259 (EP-A-0629627) disclose the following production method of (S)-ATPPA.
D-Phenylalanine is reacted with potassium bromide and sodium nitrite in a 2.5N sulfuric acid solution and amino group is substituted by bromine atom to give (R)-BPPA. The obtained (R)-BPPA is reacted with a mixture of thioacetic acid and potassium hydroxide in acetonitrile, and bromine atom is substituted by acetylthio group to give crude (S)-ATPPA. The obtained (S)-ATPPA is converted to a dicyclohexylamine (DCHA) salt, which is then recrystallized from ethyl acetate and desalted.
Further, EP-A-0524553 discloses the following production method.
D-Phenylalanine is reacted with hydrogen bromide and sodium nitrite in an aqueous solution to give (R)-BPPA. An aqueous solution of thioacetic acid and potassium carbonate is added to a sodium hydroxide solution of (R)-BPPA and the mixture is extracted with ethyl acetate. The solvent is distilled away to give (S)-ATPPA as an oil.
In addition, for example, Tetrahedron Letters, Vol. 34, p. 1457 (1993) discloses a method comprising reacting (R)- or (S)-phenylalanine with hydrogen bromide, sodium bromide and sodium nitrite to give (R)- or (S)-BPPA, and reacting the resulting compound with potassium thioacetate in methanol to give (S)- or (R)-ATPPA.
WO99/42431 discloses a method comprising reacting D-phenylalanine with hydrogen bromide and sodium nitrite in a mixed solvent of toluene and water to give (R)-BPPA.
According to the finding of the present inventors, the above-mentioned conventional methods are associated with by-production of highly hydrophobic impurities during bromination and conversion to acylthio compound. These impurities cannot be removed and have been further found to cause lower purity of crystals, markedly low yield of crystallization, an oil or oil-mixed crystals due to the inhibition of crystallization, thus exerting a profound influence on the properties of crystals, quality of crystals, crystallization yield and the like.
According to the finding of the present inventors, moreover, these impurities can be removed by once crystallizing (S)-ATPPA as a dicyclohexylamine (DCHA) salt, desalting the same and crystallizing (S)-ATPPA. However, this method requires complicated steps and is economically disadvantageous, combined with lower yields.
SUMMARY OF THE INVENTION
It is therefore and object of the present invention to provide a superior production method of an aromatic bromocarboxylic acid derivative, such as (R)-BPPA and the like, and an aromatic acylthiocarboxylic acid derivative, such as (S)-ATPPA and the like, at a high purity and in a high yield.
According to the present invention, it has been found that generation of highly hydrophobic impurities during bromination can be dramatically suppressed by reacting an aromatic amino acid in an aqueous solvent in the presence of sodium nitrite, hydrogen bromide, and at least one member selected from the group consisting of an aliphatic carboxylic acid and an alcohol to produce an aromatic bromocarboxylic acid derivative. It has been also found that generation of highly hydrophobic impurities during conversion to acylthio compound can be dramatically suppressed by reacting an aromatic bromocarboxylic acid derivative and an organic thio acid in the presence of an amine to produce an aromatic acylthiocarboxylic acid derivative.
The present inventors have completed the present invention based on the above-mentioned findings.
Accordingly, the present invention provides the following.
A method for producing an aromatic acylthiocarboxylic acid derivative of the formula (3)
wherein A is an optionally substituted aryl having 6 to 15 carbon atoms, an optionally substituted aralkyl having 7 to 20 carbon atoms or a group having a carbon skeleton of said aryl or aralkyl, which comprises a heteroatom in the skeleton, and R is an alkyl having 1 to 6 carbon atoms, an aryl having 6 to 10 carbon atoms or an aralkyl having 7 to 11 carbon atoms, which method comprises reacting an aromatic amino acid of the following formula (1)
wherein A is as defined above, in an aqueous solvent in the presence of sodium nitrite, hydrogen bromide and at least one member selected from the group consisting of an aliphatic carboxylic acid and an alcohol, to produce an aromatic bromocarboxylic acid derivative of the formula (2)
wherein A is as defined above, and reacting the aromatic bromocarboxylic acid derivative and an organic thio acid in the presence of an amine.
The present invention also provides a method for producing an aromatic bromocarboxylic acid derivative of the formula (2), which comprises reacting an aromatic amino acid of the formula (1) in an aqueous solvent in the presence of sodium nitrite, hydrogen bromide and at least one member selected from the group consisting of an aliphatic carboxylic acid and an alcohol.
The present invention further provides a method for producing an aromatic acylthiocarboxylic acid derivative of the formula (3), which comprises reacting an aromatic bromocarboxylic acid derivative of the formula (2) and an organic thio acid in the presence of an amine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is explained in detail in the following.
In the formulas in the present invention, A means optionally substituted aryl having 6 to 15 carbon atoms, optionally substituted aralkyl having 7 to 20 carbon atoms or a group having a carbon skeleton of said aryl or aralkyl and comprising a heteroatom in the skeleton. When A has one or more substituent(s), the substituent is not subject to any particular limitation as long as it does not adversely affect the reaction in the present invention. Examples thereof include alkoxy (preferably that having 1 to 7 carbon atoms), nitro, alkyl (preferably that having 1 to 6 carbon atoms), aralkyl (preferably that having 7 to 11 carbon atoms), halogen atoms, hydroxyl having protecting group, carboxyl, amino having protecting group and the like.
The group containing a heteroatom (e.g., nitrogen, oxygen, sulfur atoms and the like) in the carbon skeleton is, for example, (p-methylbenzyl)thiomethyl, (p-methoxybenzyl)thiomethyl, benzyloxymethyl, benzyloxyethyl, 4-(t-butoxy)phenylmethyl, 4-benzyloxyphenylmethyl, phenylthiomethyl and the like.
A may be a group introduced using aromatic amino acid having a protected side chain functional group, such as O-benzyltyrosine and the like, as a starting material.
A is particularly preferably benzyl.
In the formulas in the present invention, R is alkyl having 1 to 6 carbon atoms, aryl having 6 to 10 carbon atoms or aralkyl having 7 to 11 carbon atoms. Examples of alkyl having 1 to 6 carbon atoms preferably include methyl, ethyl, butyl, t-butyl, isopropyl and the like. Examples of aryl having 6 to 10 carbon atoms preferably include phenyl, naphthyl and the like. Examples of aralkyl having 7 to 11 carbon atoms preferably include benzyl and the like. Examples of R preferably include methyl and benzyl, particularly preferably methyl.
Representative compounds preferably produced by the production method of the present invention may be, for exa
Izawa Kunisuke
Nakazawa Masakazu
Takahashi Daisuke
Ajinomoto Co. Inc.
Reyes Hector M
Rotman Alan L.
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