JPS59155355A - Novel process for preparation of 4-thiazolyloxy-and 4-thiazolylthio-phenylacetic acid derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an anti-inflammatory agent, etc. under mild condition, by reacting a specific phenyl-acetic acid derivative with halogenoacetaldehyde or its reactive derivative in the presence of an acid, and hydrolyzing the reaction product. CONSTITUTION:The objective compound of formula II can be prepared by (1) reacting the compound of formula I (A is O or S; R<1> and R<2> are H, lower alkyl or halogen; R<3> is H or lower alkyl; R<4> is lower alkyl; Y is H, cyano or lower alkoxycarbonyl) with a halogenoacetaldehyde or its reactive derivative in the presence of a catalytic amount of an anhydrous acid such as p-toluenesulfonic acid, etc., and (2) hydrolyzing the reaction product. The starting compound of formula I is obtained by reacting the hydroxy- or mercaptophenylacetic acid derivative of formula III with a halogenocyan, and reacting the resultant (thio) cyanato-phenylacetic acid derivative of formula IV with hydrogen sulfide in an ether solvent in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing thiazolyloxy and goudeazolylthiophenyl acetic acid derivatives. More specifically, it is a method for producing thiazolyloxy and thiazolylthiophenyl acetic acid derivatives, which is characterized by forming a deazole ring under mild conditions.

It is already known that deazolyloxy and thiazolylthio-phenylacetic acid derivatives have anti-inflammatory or analgesic effects (Patent Publication No. 7 No. 37-37).
. Methods for producing the compound include a method of condensing halogenothiazole and a phenylacetic acid derivative described in the above-mentioned patent publication, and a method of alkylating and hydrolyzing thiazolyloxyphenylacetonitrile (Patent Publication No. 3
3-37!3; Otsu), a method using l-alkoxysuhalogenoethyl isothiocyanate as a starting material and via a thiazoline derivative (Patent Publication No. 1993/θ99 Otsu 9
No. 1) etc. have been established, but the present invention is based on this No. 1. This is an excellent method that allows the reaction to be carried out under milder conditions than the previous method.

The outline of the method of the present invention is illustrated below.

(In the formula, A represents oxygen or sulfur; R/ and R2 each represent hydrogen, lower alkyl, or halogen; R represents hydrogen or lower alkyl; R″ represents lower alkyl; Y represents hydrogen, cyan, or lower alkoxycarbonyl.) The invention method consists of the following four steps.

Step (2) Hydroxy or mercaptophenylacetic acid derivative (v) is reacted with halogenocyan to obtain cetecyanato or thiocyanato-phenylacetic acid derivative (IV).

Step (2) Compound (Vl) is reacted with hydrogen sulfide to obtain a thiocarbamoyloxy- or thiocarbamoylthio-phenylacetic acid derivative (m).

Step (2) Compound (ITI) is reacted with halogenoacetaldehyde or a reactive derivative thereof in the presence of an acid to obtain a thiazolyloxy or thiazolylthio-phenylacetic acid derivative (Ir).

Step (2) Compound (I[) is subjected to a hydrolysis reaction to obtain the target free carboxylic acid (I) of the gouthiazolyloxy or gouthiazolylthio-phenylacetic acid derivative.

The raw material compound (V) of the present invention is a dienylacetic acid alkyl ester having a hydroxy or mercapto group at the ψ position, and the methylene at the acetic acid position 6 of the phenylacetic acid may be substituted with a cyano or lower alkoxycarbonyl group,
The benzene ring may be substituted with /-2 lower alkyl or halogen.

The lower alkyl as used in the present invention is 9, for example, methyl, ethyl, propyl, isopropyl, butyl.

It means a straight chain or branched hydrocarbon group having a carbon number of 1 to 2, such as isobutyl, butyl, etc., and 10gen means fluorine, chlorine, bromine, and iodine. Lower alkoxycarbonyl means a group in which oxycarbonyl is attached to the above alkyl, and includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, 1. -Butoxycarbonyl and the like are exemplified.

The method of the present invention consists of one step as described above. Each step will be described in detail below.

Step ■ Compound [■] in an ether-based solvent (for example.

ethers, dioxane, tetrahydrofuran, etc.), trialkylamines (e.g. triethylamine) and N-alkylpiperidines (e.g.

The corresponding cyanato or thiocyanate compound is obtained by reacting a halogenocyanine (e.g. cyanogen bromide, cyanogen chloride, etc.) in the presence of a tertiary amine such as N-methylpiperidine).
■Make it. The reaction was performed by E, Vowinkcl et al. (chcn
tBcr, , 107. /2/3(/97'l-)
) under cooling, preferably about -2θ
~θ℃.

Most preferably it is carried out at about -70°C.

Step (2) The compound y obtained in Step (2) is reacted with hydrogen sulfide in an ethereal solvent in the presence of a base to obtain a thiocarbamoyloxy or thiocarbamoylthio-phenylacetic acid derivative [ml]. Specifically, the reaction is carried out by dissolving Compound 1-Iv] in an ether solvent and passing hydrogen sulfide gas through the solution.

The ether solvent and base used are exemplified in step ①]
, is something. The reaction proceeds easily at room temperature.

This step is described by Griga C et al. (Cbent Ber, 97
, 3θ22(/Waotori)). Incidentally, this step may be carried out following step (2) without isolating the product of step (2).

Step (1) The product 1-(1) of Step (2) is reacted with halochenoacetaldehyde or a reactive derivative thereof in the presence of an acid in an anhydrous state to use a deazolyloxy- or deazolylthio-phenylacetic acid derivative IJTI in a medium amount. For example, p-1-luenesulfonic acid, sodium hydrogen sulfate, pyridine hydrochloride, sulfuric acid, phosphoric acid, and polyphosphoric acid are used. Examples of halogenoacetaldehyde include chloroacetaldehyde and bromoacetaldehyde, and examples of the reactive derivatives include dialkyl acetals (e.g., bromoacetaldehyde dimethyl acetal, chloroacetaldehyde diethyl acetal, etc.), 12-dihalogenoethyl Alkyl ethers (e.g., 12-dichloroethyl methyl ether, etc.), /-acetoxysuhalochenoethyl alkyl ethers (e.g., /-acetoxysubromoethyl ethyl ether, etc.), l-acetoxy-
2x-dihalogenoethane (e.g. /-acetoxy-1
2,-dichloroethane, etc.). as a solvent.

Alcohol'fA (e.g. methanol, ethanol.

propatool, etc.), carboxylic acids (e.g. acetic acid, propionic acid, etc.), ethers (e.g.

ether, dioxane, tetrahydrofuran, etc.).

Acetone, acetonitrile, etc. are used alone or in combination. Preferred reaction conditions use chloroacetaldehyde diethyl acecure in the presence of P-toluenesulfonic acid, and acetic acid-ether (more preferably /'l/, (/v
) is used as a solvent. The reaction is carried out under heat, preferably about 3
Perform at 0-100°C.

Step (2) The compound obtained in Step (2) [TO is subjected to a hydrolysis reaction in the presence of an acid or an alkali. The hydrolysis reaction in this step does not only mean the removal of the ester residue in the acetate ester moiety, but also the hydrolysis reaction necessary to remove the cyano group and alkoxycarbonyl group that substitute the methylene of the acetate residue. Also includes carbonic acid reactions. These reactions are carried out using alkalis (e.g. sulfur/lium hydroxide, potassium hydroxide,
in the presence of aqueous alcohols (e.g. methanol-water, ethanol-water,
(propanol-water, etc.) at room temperature or under heating.

Generally, the deesterification and decarboxylation reactions occur simultaneously, but if necessary, after the deesterification reaction, the decarboxylation reaction may be further performed by heating.

Next, embodiments of the present invention will be shown in Examples.

These examples do not limit the present invention in any way. In the diagrams of Examples, Me represents methyl, and El represents methyl.

means ethyl.

(Left below) Examples/ (a) (b) (C) (d) (1) Diethyl °2-(g-hydroxyphenyl)
-2-methyl-malonate (a,)zθy, triethylamine 3. θtty, a mixture of anhydrous etherg θml.

Anhydrous ethereal θNt containing 3.21 cyanogen bromide cooled to -70°C is added dropwise to the solution over 3θ minutes, and further reacted at the same temperature for 2θ minutes. After removing the insoluble matter with P, the ether was distilled off, and the residue was crude diethylni(cousitoanaphenyl)-no-methylmalonate (1)) &7&
△ Get 1/y. IR (CC~), 7. ．． 27θ, 2,2
．． In the evening, 223θ(J(2)) Diethyl, 2-(ll--cyanatophenyl)-nomethylmalonate (b) & 711-1 obtained above was dissolved in 100 rttl of anhydrous ether with a catalytic amount of triethylamine. Hydrogen gas was introduced for 0 minutes at room temperature with stirring. The ether was distilled off, the residue was dissolved in ether/θ0ml to remove insoluble matter, the nitrogen was concentrated to 1/2 ml, and the precipitated yellow crystals were taken off.
p7~Lf2° diethyl 2-(4-thiocarbamoyloxyphenyl)-eumethylmalone+-(C)9
Get 2 y. IR (No, 1on) 3330.327
0,3/7θ,/Otsu23ctn' Elemental analysis C,,J
(,,O,,,calculated value as NS (section) 20, 337th
:H,3ノ9;N,g3/;S,9. Experimental value (related): C, 333/, H, 3,92,: N,'
A/3; S, 9 Tough (3) Diethyls-(ketiocarnocumoyloxyphenyl)-no-methylmalonate (a) 92 obtained above
3. Add chloroacetaldehyde diethyl acetal to g.
22f, p-) luenesulfonic acid 9 gmg.

Add glacial acetic acid and react with stirring in an oil bath at 9θ°C for 3 hours. Acetic acid was distilled off under reduced pressure and benzene/θθml was added to the residue.
3 with 30ml of 7-width sodium bicarbonate aqueous solution.
Wash twice and dry over magnesium sulfate. Silica gel benzene column chromatography
2-Thiazolyloxy)-phenylcose-methylmalonate (d) K9'l-f is obtained. NMRδCI)(J
! , Otsu, r 5 ((J, ) old/(J=3.7H7,
)(4)” Diethyl 2-[4-(2-thiazolyloxy)phenyl]-2-methylmalonate (d
), 15>9g, potassium carbonate 3. Za99. Add methanol and water to the mixture, stir and reflux for an hour. Methanol is distilled off under reduced pressure, and the residue is dissolved in water and washed three times with methylene chloride. After treating the aqueous layer with activated carbon, the pH was adjusted to a high value with hydrochloric acid to obtain 2-[4/--(2-thiazolyloxy)phenyl]propionic acid (e).

Recrystallized in dichloroethane L”p/2//
, 53 guda of purified product of 12″C was obtained.

IR (No, ioJ') 2. ! ;20, /
7/ TaCno〃-' Elemental analysis C,,H,,,03NS
Calculated value (regret): C,,3-7za/;Hβ44
'J-iN, J-su; S, /, 2I15' Experimental value (related): C, 57 Otsu θ; H9≠Gugu iN, left jθ
2S, IQ9g (f) (g) (1+
) (blank below) (e') (1) Methyl 2-(g-hydroxyphenyl)propionate (f)! f and triethylamine λ, gy were dissolved in 30 ml of anhydrous ether, and added to 3θml of an anhydrous ether solution containing 32y of cyanogen bromide at −/θ°C for 2 hours with stirring.
It takes 0 minutes to drip. Further, the reaction was carried out for 3θ minutes at the same temperature, and the precipitated triethylamine hydrobromide was removed from the furnace, and then the ether was distilled off under reduced pressure to obtain crude, methyl, 1-(4t
-cyanatophenyl)propione-) (g)j: Otsug is obtained. IR (CC/,)22. ! ;0°223θ, /7
≠θα−′ This product is used in the next step without purification.

(2) Methyl 2-(ll--cyanatophenyl)propionate (g) obtained above,! Dissolve 1g in 20ml of anhydrous ether, add 3 drops of triethylamine, and pass through the hydrogen sulfide residue while stirring at ~23°C.

One of the precipitated crystals was taken, washed with ether, and t'p/31
～/ri/"0 methylni(cutiocal)<moyloxyphenyl)propione-1-(1+)J: Obtain 3 g. Recrystallize the ice crystals from chloroform"], bob/ψ3
~/Gugu indicates °C.

Elemental analysis Calculated value as C77H, 3NS (phantom: C, 3!;, 2/:H, J Guza Bodhisattva N, j
Zaj;S, /3t/Xθ Experimental value (phantom: C, 311-,97;T(', google:
N, 37s; S, /3.39 IR (No, 1ol) 3333.329. ! ;,3/za0. /Otsu33゜/7/,! ;ono,-/ (3) Methyl 2-(≠-thiocarbamoyloxyphenyl)propionate (h) 3y obtained in the previous step was mixed with glacial acetic acid 'i'Oml, chloroacetic acid altehyde ethyl acetic acid tar 311 ．． Anhydrous ■)-Toluenesulfonic acid 0. /f
/ and heat and stir at 3-9θ°C for 2 hours. After distilling off the acetic acid under reduced pressure, the residue was dissolved in ether, washed sequentially with dilute aqueous sodium hydrogen carbonate solution, dilute aqueous sodium hydroxide solution, dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give methyl, 2- [g-(2-thiazolyloxy)feninotetrapropionate ('+'> θ1 is obtained.

The ice crystals are used in the first step without being purified.

(4) Methyl 2-[g-(2-thiazolyloxy)phenyl]propionate obtained in the above step (i) jθy is θ
9y sodium hydroxide and j0 methanol aqueous solution 23
Stir with ml for 2 hours at room temperature.

After 11 hydration with hydrochloric acid, the mixture was again made alkaline with sodium bicarbonate, and methanol was distilled off under reduced pressure. The residue was dissolved in water, washed with methylene chloride, treated with activated carbon, and then adjusted to pH 3 with dilute hydrochloric acid. Knee [g-1,2-
thiazocontaruoxy)phenyl]propionic acid (e)'A
2f! get. Recrystallized from dichloroethane/
2/~/, 22°C crystals are obtained.

TR(NujoI)2320, /7/Oan
'Elemental analysis Calculated values as C,, H,, O, NS (
Person in charge): CJ7za/;H1≠Gushio;N, Yuoyu;S,/,
2. ,5>B Experimental value (bite): C, S77.2. H,IIIO2N,
9;S, /2.7θ Example 3-// The following compound is obtained by carrying out the reaction treatment in the same manner as in Example 3-//.

■ (margin below c) r1~ The upper row shows calculated values, and the lower row shows experimental values.

*4 Indicates the 5th position of the thiazole ring or the δ value of absorption at the 5th position.

...V. The approximate arc of the recrystallization solvent is as follows.

A-ethyl acetate, B-bennan.

D-dichloroethane, E-ether.

H Nihe Katasan patent applicant Shionogi & Co., Ltd. procedure? Mukatsu 1. Indication of the case 1982 Patent Application No. 28108 2. Name of the invention 4. New method for producing 4-thiazolyloxy- and 4-thiazolylthio-phenylacetic acid derivatives 3. Case with the person making the amendment Related: Patent Applicant 4, Agent Address: 5-12-4 Sagisu, Fukushima-ku, Osaka 553 Shionogi & Co., Ltd. Patent Department (Telephone: 06-458-5861) Detailed explanation of the invention in the specification subject to amendment Column.

Contents of Amendment B (1) [-Hydrogen gas] on page 13, line 9 of the specification is corrected to "Hydrogen sulfide scum J.

(2) "Silica gel benzene" in line 9 of page Meg of the same book is corrected to "silica gel/benzene".

(3) In the same book, page 23, between line 7 and line g, it says,
The yield of compound H from is shown in the table for each step only, but
The yield of compound (1) is the total yield throughout the entire process. ”
Insert.

2.

Claims (3)

[Claims] (1) General formula (wherein A is oxygen or sulfur, R/ and R2 are each hydrogen, lower alkyl or halogen, R3 is hydrogen or lower alkyl, R'' is lower alkyl, Y is hydrogen, cyano or lower alkoxycarbonyl ) is reacted with halochenoacetaltehyde or a reactive derivative thereof in the presence of an acid, and then subjected to a hydrolysis reaction to form A, R', & and R3 in the general formula C. represents the same meaning as above. ) A novel method for producing g-thiazolyloxy- or gouthiazolylthio-phenylacetic acid derivatives, which is characterized by obtaining a compound represented by: (2) A phenylacetic acid derivative represented by the following general formula. 3 R' (wherein A is oxygen or sulfur, R' and R, 2 are respectively)], hydrogen, lower alkyl or halogen, R3 is hydrogen or lower alkyl, R'' is lower alkyl, Y is hydrogen, cyanide or lower alkoxycarbonyl) (3) In the general formula c, A is oxygen or sulfur, B/ and R' are each hydrogen, lower alkyl, or halogen, R3 is hydrogen or lower alkyl, R'' is lower alkyl, Y is hydrogen, cyano, or lower alkoxycarbonyl. A compound represented by the formula (formula r41.A, R', R' and d have the same meanings as defined above.) A novel method for producing gouthiazolyloxy or t-thiazolylthio-phenylacetic acid derivatives, which is characterized by obtaining a compound represented by: