JPS5946933B2 - New method for producing 2-substituted propionic acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel 2-substituted propionic acid derivatives, the object of which is to produce thiazole derivatives substituted with propionic acid residues.

The 2-substituted propionic acid derivative obtained by the method of the present invention is a new compound having analgesic and antiinflammatory effects.

The gist of the method of the present invention is shown by the following equation.

(In the formula, A represents oxygen, N-allylimino or N-cyclopropylmethylimino, X represents hydrogen or lower alkyl, M represents lithium, sodium, potassium or magnesium monohalide, and R' represents an ester residue. The method of the present invention involves step 1 of reacting a compound represented by the general formula with a pyruvate ester, and subjecting the obtained compound () to a hydrolysis reaction to form a 2-monosubstituted propion represented by the general formula 1. The process consists of step 2 of obtaining an acid derivative, and step 3 of subjecting compound (1) to a hydrolysis reaction to obtain the corresponding 2-monosubstituted propionic acid (1V). Currently, various methods are used to synthesize 2-monosubstituted propionic acid compounds, but the method of the present invention is superior to those known methods in that it provides the target compound easily with a small amount of synthesis.

Next, the implementation of the method of the present invention will be described in detail.

The starting material compound in the method of the present invention is an organometallic compound as shown in the general formula, and has or does not have a substituent that is essentially unaffected by this reaction. It consists of an organic residue consisting of a group and a metal residue having the activity of producing a tertiary alcohol by performing a Grignard-type reaction with a carbonyl group. Examples of metal residues having such properties include lithium, sodium, potassium, and magnesium monohalide. This organometallic compound can be easily obtained from the corresponding halogenated compound or other active compound by a conventional method. First step 1 of the present invention
The raw material compound (JlI) is condensed with pyruvic acid ester to give a tertiary alcohol represented by the general formula.

This reaction is called Gram's asymmetric synthesis (Cranl5s
The reaction conditions are generally well known, and the reaction solvent used is aromatic hydrocarbons such as benzene and toluene, or ethers such as ether, propyl ether, and tetrahydrofuran. It is used in an anhydrous state, and the reaction is carried out at -75°C to room temperature, with further heating if necessary. The reaction is generally carried out under an inert atmosphere to suppress side reactions. The reaction product is separated by conventional methods to obtain the tertiary alcohol (). The compound () thus obtained is subjected to hydrolysis reaction 2.

The hydrolysis reaction referred to in the present invention refers to a reaction in which the tertiary hydroxyl group of the compound () is reduced to hydrogen, and 2-hydroxypropionate () is first subjected to (1) a dehydration reaction to form a sacrylic acid ester. After that, the target compound can be obtained by hydrogenation. Alternatively, (2) it is also possible to once halogenate the 2-halogen propionate and then replace the halogen with hydrogen to obtain the desired propionate. Examples of reduction methods such as hydrogenation and hydrogen substitution include catalytic reduction using various catalysts, reduction methods using a combination of metals (e.g., zinc, tin, etc.) and acids, and addition of Raney nickel and alkali borohydride in suitable solvents and Various commonly used reduction means can be used depending on the purpose, such as reduction using a combination of Lewis acids and the like. That is, an appropriate reduction means may be selected depending on the reduction of the acrylic ester or the reduction of 2-halogenopropionic acid and the compound to be reduced. In addition, when using a halogenated compound, a suitable halogenating reagent such as phosphorus halide (e.g., phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride, etc.), hydrogen halide (e.g., hydrogen chloride, hydrogen bromide, etc.) is used. ), thionyl rogens (e.g. thionyl chloride, thionyl bromide, etc.) and sulfonic acids (e.g.
The compound () can be halogenated with sulfuryl chloride, etc.). Examples of dehydrating agents include alkali hydrogen sulfates (e.g., sodium hydrogen sulfate, potassium hydrogen sulfate, etc.), phosphorus compounds (e.g., phosphorus pentachloride, phosphoric acid, metaphosphoric acid, etc.), and inorganic chlorides (e.g., thionyl chloride, etc.). , organic chlorides (such as methanesulfonyl chloride), organic acid anhydrides (such as acetic anhydride) or inorganic halides (such as trifluoroboron).
An intramolecularly dehydrated compound can be obtained from compound () by using These halides and dehydrated compounds are subjected to the above hydrogenation reaction to immediately give compound (1). The obtained compound (1) is subjected to a hydrolysis reaction to give the corresponding 2-monosubstituted propionic acid.

Hydrolysis is carried out using acids (e.g., inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, organic acids such as acetic acid) or alkalis (e.g., alkali hydroxide, alkali carbonate, alkali bicarbonate) in water or other water-containing solvents. etc.) at room temperature or under heating. Products of the process of the invention (JV)
For separation, purification or formulation, or for other purposes, it is usually added to appropriate alkali metal salts (e.g., sodium, potassium, etc.), alkaline earth metal salts (e.g., calcium, magnesium, barium, etc.), other aluminum salts, etc. It is possible to convert according to the law.

Embodiments of the present invention will be illustrated in Examples below. Example 1 2-phenoxy-4-methyl-5-bromothiazole 2
．． 40r (9.4 mmol) was dissolved in 36 ml of aqueous ether, and then 5 d (10 mmol, 1.06 mol equivalent) of a 2M butyllithium/hexane solution was added dropwise while stirring at -50°C or below in an argon stream. After 10 minutes, 6me of an ether solution of 1.09r (9.4 mmol) of pyruvate ethyl ester was added and stirred for 30 minutes.
:fl) Add 30d of ammonium chloride and extract with ether.

After washing the extract with 10(f) ammonium chloride and water and drying, the solvent is distilled off, and the residue 2.6r is subjected to silica gel column chromatography. Benzene/ethyl acetate (40:l) +X
From the benzene/ethyl acetate (20:1) eluate, 1.9y of 2-hydroxy-2-(2-J-G-noxy-4-methyl-5-thiazolyl)propionic acid ethyl ester was obtained. M+=307 IRv Hatake 3m-1: 3586, 3516, 1726, 1
590.

uvλEtOHnm (ε): 256 (7210) Max
゜ONMRδInCDCt3:1.28(3H,t,J
=7.2Hz), 1.78 (3H.s), 2.30 (3
H. s), 3.80 (1H.m), 4.27 (2H.m),
q, J=7.2Hz), 7.17-7.50 (5H.m
).

The above product 2357!1f (0.76 mmol) was dissolved in anhydrous methylene chloride 1d, and thionyl chloride 1.1d (1.52 mmol) was added dropwise while stirring under ice cooling in a nitrogen stream.

After standing overnight, the reaction mixture was poured with ice water and extracted with methylene chloride. The extract was washed with 5% sodium bicarbonate and water, dried, and the solvent was distilled off to obtain a residue 18677V. The above product 17877V was dissolved in 2d of 90% acetic acid, 1.7f of zinc dust was added at room temperature, and the mixture was stirred for 20 minutes, then ethanol was added and the solid matter was removed.

The filtrate is concentrated under reduced pressure, and the residue is made alkaline by adding ice water and sodium bicarbonate water, and then extracted with ether.
The extract was washed with water, dried, and concentrated under reduced pressure to leave a residue of 757! ! get f. Apply this product to paper chromatography (developing solvent:
benzene/ethyl acetate (10:1)) to give 2-(2
-Phenoxy-4-methyl-5-thiazolyl)propionic acid ethyl ester 4577V is obtained. The above product 7177V (0.24
After 50 minutes of standing at room temperature, the ethanol was distilled off under reduced pressure.

Water was added to the residue, extracted with ether, and the aqueous layer was made acidic with 10% hydrochloric acid and extracted with ether. After washing the extract with water and drying, the solvent was distilled off to obtain a residue of 70η. This product was recrystallized from ether/petroleum ether, and Mpll. 5-112.5℃
2-(2-phenoxy-4-methyl-5-thiazolyl)propionic acid 3677V is obtained. IR and N of this product
The MR spectrum matched that of a separately synthesized standard.
The following compound is obtained by similar reaction operations.

2-[4-(2-thiazolyloxy)phenyl]propionic acid MPll 9-120°C.

2-(2-N-allylanilino-4-methyl-5-thiadryl)propionic acid MPlO6-107℃02-(2
-N-cyclopropylmethylanilino-4-thiazolyl)calcium propionate trihydrate MPl8O~183
℃.

Calcium 2-(2-phenoxy-5-thiazolyl)propionate hemihydrate Mpl69.~170°C (decomposed).

Calcium 2-(2-phenoxy-4-thiazolyl)propionate hemipentahydrate Mpl 42°C (decomposed).

2-(2-phenoxy-5-methyl-4-thiazolyl)
Calcium propionate hemihydrate Mpl 42°C (decomposed).

2-(2-N-cyclopropylmethylanilino-4-methyl-5-thiazolyl)propionic acid Mpl2O~12
1℃2-(2-N-allylanilino-5-thiazolyl)
Propionate MPl34~135℃2-(2-N-cyclopropylmethylanilino-4-thiazolyl)calcium propionate trihydrate Mpl8O~183℃02-(
Calcium 2-N-allylanilino-4-thiazolyl)propionate dihydrate MPl 73-178°C (decomposed).

2-[4-(4-methyl-2-thiazolyloxy)phenyl]propionic acid Mp87-88℃02-[4-(N
-Allyl-N-thiazol-2-ylamino)phenyl]propionic acid Mpll8-119°C.

Claims (1)

[Claims] 1. Novel 2 characterized in that a compound represented by general formula I is subjected to a hydrolysis reaction to obtain a corresponding carboxylic acid.
- A method for producing a substituted propionic acid derivative. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (In the formula, A represents oxygen, N-allylimino or N-silkpropylmethylimino, X represents hydrogen or lower alkyl, and R' represents an ester residue. )2 A compound represented by general formula III is reacted with a pyruvate ester to obtain a compound represented by general formula II, and then (1) it is subjected to a dehydration reaction to form an acrylic ester and then hydrogenated, or (2) Novel 2-2, characterized in that it is halogenated to form a 2-halogenopropionic acid ester, then the halogen is replaced with hydrogen to obtain a compound represented by the general formula I, and then subjected to a hydrolysis reaction to obtain the corresponding carboxylic acid. Method for producing substituted propionic acid derivatives. ▲There are mathematical formulas, chemical formulas, tables, etc.▼III ▲There are mathematical formulas, chemical formulas, tables, etc.▼II ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (In the formula, A is oxygen, N-allylimino or N-cyclopropylmethyl represents imino, X represents hydrogen or lower alkyl, M represents lithium, sodium, potassium or magnesium monohalide, and R' represents an ester residue.)