Process for producing propionic acid derivatives

Details Process for producing propionic acid derivatives Process for producing propionic acid derivatives

1998-09-18

2001-06-05

Richter, Johann (Department: 1621)

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

Organic compounds

Carboxylic acid esters

C560S056000, C560S060000, C562S465000, C562S466000, C562S470000

Reexamination Certificate

active

06242635

ABSTRACT:

BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a novel process for producing a propionic acid derivative. More specifically, the present invention relates to a novel process for producing a 2-aralkyl-3-hydroxypropionic acid or its ester. The 2-aralkyl-3-hydroxypropionic acid can produce the optically active substance thereof through optical resolution with a resolving agent or an enzyme. This is convertible into an intermediate which is extremely important as a constituent of a lenin inhibitor (refer to J. Med. Chem. 1988, vol. 31, 1839 and WO 9116031), an enkephalinase inhibitor (refer to Japanese Patent Kokai Publication Nos. JP-A-2-161 and JP-A-8-59,606) or a protease inhibitor (refer to Japanese Patent Kohyou Publication No. JP-A-9-505,284).
DESCRIPTION OF THE RELATED ART
As a method of producing a 2-aralkyl-3-hydroxypropionic acid, a method has been so far known which comprises treating Meldrum's acid as a starting material with benzaldehyde and a borane.triethylamine complex to form benzyl-Meldrum's acid, then reacting the same with benzyl alcohol to form &agr;-benzylmalonic acid monobenzyl ester, and reducing the same with lithium aluminum hydride to produce 2-benzyl-3-hydroxypropionic acid (refer to WO 9209297). This method is however problematic in that the reducing agent (borane.triethylamine complex and lithium aluminum hydride) of Meldrum's acid is expensive, the borane.triethylamine complex is toxic, and the lithium aluminum hydride reduction reaction requires a low-temperature reaction and is also industrially dangerous. Accordingly, this method is not said to be an industrial method. Further, a method has been known which comprises treating hydrocinnamic acid with lithium diisopropylamide and then reacting the resulting substance with a formaldehyde gas to form 2-benzyl-3-hydroxypropionic acid (refer to J. Med. Chem., 1992, vol. 35, 1472). However, this method is also industrially problematic in that expensive lithium diisopropylamide is used, the formaldehyde gas is highly toxic, a low-temperature reaction is required and the yield is low. Still further, a method has been known which comprises subjecting &bgr;-propiolactone to a ring-opening reaction with methanol in the presence of triethylamine to form 3-hydroxypropionic acid methyl ester, and then &agr;-benzylating the same with lithium diisopropylamide and with benzyl bromide to obtain 2-benzyl-3-hydroxypropionic acid methyl ester (refer to J. Med. Chem., 1993, vol. 36, 4015). However, this method is also problematic in that starting &bgr;-propiolactone and lithium diisopropylamide are expensive, a low-temperature reaction is required and the yield is low. Furthermore, a method has been known which comprises reacting &agr;-hydroxymethylacrylic acid ethyl ester with diphenyl copper magnesium bromide for a conjugate addition of a phenyl group to obtain 2-benzyl-3-hydroxypropionic acid ethyl ester (refer to J. Organometallic Chem., 308, 1986, C27). However, this reaction is also industrially problematic in that the copper (I) reagent is expensive and a low-temperature reaction is required.
1. Problems to be Solved by the Invention
The many problems to be solved for the related arts are as mentioned above, and in the course of the completion to the present invention, the above-mentioned problems have been also found by the present inventors.
The present invention is to provide a process for producing a 2-aralkyl-3-hydroxypropionic acid, particularly 2-arylmethyl-3-hydroxypropionic acid (including its ester) industrially safely and easily.
SUMMARY OF THE INVENTION
The present inventors have assiduously conducted investigations to solve the above-mentioned problems, and have consequently found that a 2-aralkyl-3-hydroxypropionic acid or its ester can be produced quite easily using an arylaldehyde and an acrylic acid ester which can be obtained industrially easily as starting materials through a short synthesis route including four simple reaction steps, namely, a step of a reaction of both starting materials, a step of an acid anhydride treatment, a step of hydrolysis (or alcoholysis) and a step of reduction. In more detail, they have found that a 2-aralkyl-3-hydroxypropionic acid (including its ester) can be produced by reacting both of the above-mentioned starting materials to easily form a 3-hydroxy-2-methylene-3-arylpropionic acid ester, then reacting this ester with an acid anhydride in the presence of an acid to form a 2-aralkylidene-3-acyloxypropionic acid ester, subjecting this ester to hydrolysis or alcoholysis, and reducing the resulting 2-aralkylidene-3-hydroxypropionic acid or its ester. This finding has led to the completion of the present invention (first invention).
Further, they have assiduously conducted investigations on a method of reducing the above-mentioned 2-aralkylidene-3-hydroxypropionic acid in a high yield as another problem, and have consequently found that this problem can be solved by the presence of a base in the reducing reaction thereof. This finding has led to the completion of the present invention (second invention).
That is, the first invention is characterized by the synthesis route including the following four simple steps.
The first step is a step of reacting an arylaldehyde represented by formula (I)
R
1
CHO  (I)
wherein R
1
represents an aryl group with an acrylic acid ester represented by formula (II)
wherein R
2
represents a hydrocarbon group to form a 3-hydroxy-2-methylene-3-arylpropionic acid ester represented by formula (III)
wherein R
1
and R
2
are as defined above.
The second step is a step of reacting a 3-hydroxy-2-methylene-3-arylpropionic acid ester of formula (III) with an acid anhydride to produce a 2-aralkylidene-3-acyloxypropionic acid ester represented by formula (IV)
wherein R
1
and R
2
are as defined above, and R
3
represents an acyl group.
The third step is a step of subjecting the 2-aralkylidene-3-acyloxypropionic acid ester of formula (IV) to hydrolysis or alcoholysis to produce a 2-arylmethylene-3-hydroxypropionic acid derivative represented by formula (V)
wherein R
1
is as defined above, and R
4
represents a hydrogen atom or a hydrocarbon group.
The fourth step is a step of reducing the 2-arylmethylene-3-hydroxypropionic acid derivative of formula (V) to produce a 2-arylmethyl-3-hydroxypropionic acid derivative represented by formula (VI)
wherein R
1
and R
4
are as defined above.
The first invention includes the above-mentioned four steps in the production. If the four steps are included therein, the other steps, for example, a step of alkyl substitution, a step of rearrangement, a step of purification and the like can be added before, after, or in the middle of, these steps. When the resulting compound (VI) is an ester, a 2-arylmethyl-3-hydroxypropionic acid in the free form can easily be obtained by subjecting the ester to a usual hydrolysis step.
In the first invention, the each steps, namely any one step in the first to fourth steps and the above-mentioned hydrolysis step, which are intended for the production of the 2-arylmethyl-3-hydroxypropionic acid derivative of formula (VI) under the above mentioned first invention are also included in the present invention.
Next, the second invention is a process for producing the 2-arylmethyl-3-hydroxypropionic acid derivative (R
4
=H) of formula (VI) in which the compound of formula (V), namely the 2-arylmethylene-3-hydroxypropionic acid derivative (R
4
=H) is reduced in the presence of a base.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The mode of carrying out the present invention is described on the basis of, for example, the following reaction scheme showing a production route in which the first through fourth steps are conducted continuously. In this reaction scheme, R
1
to R
4
are as defined above.
Reaction Scheme
The arylaldehyde used as a starting material in the present invention (first invention) has a structure represented by formula (I).
The substituent R
1
bound to the formyl group in formu

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