SE446982B - BETA, BETA, BETA-TRIHALOGENO-ALFA-HYDROXYETHYL-SUBSTITUTED-2-AROYLPYR ROLLER DERIVATIVES FOR USE AS INTERMEDIATE IN THE PREPARATION OF ETHIC ACID COMPOUNDS - Google Patents

Description

Hitherto, the following aroylation methods of pyrrole-2-acetic acid or a pyrrole-2-acetonitrile derivative have been generally known for the preparation of these 1-methyl-5-aroyl-pyrroleacetic acids. 1) Method comprising reaction with an aroyl chloride in the presence of a Lewis acid, such as aluminum chloride, etc. [reference to Japanese Patent Publication 34153/1976]. 2. A method using a mixed acid anhydride obtained from an aryl carboxylic acid and anhydrous fluoroacetic acid [reference to Japanese Patent Publication 418/1971]. 3) Method using a reaction product of dimethylaroylamide and phosphorus oxychloride [reference to Japanese Patent Publication 418/1971]. 4) Method using a mixed acid anhydride obtained from an aryl carboxylic anhydride and an acid such as methanesulfonic acid [reference to Japanese Patent Publication No. 126660/1975]. 5] A process comprising reaction with phosgene to produce a 5-chlorocarbonyl derivative, which is then reacted with an aryl metal compound [reference to Japanese Patent Publication 55659 / 197Q].

However, these conventional methods have various disadvantages in that the yield of the product would be low and in that isomers in which the aroyl group is condensed at the β-position of the pyrrole ring are formed as by-products, which must be separated afterwards.

There has now been found a process for the preparation of B, β, β-trihalo-hydroxyethyl-substituted-2-aroyl-1-alkylpyrrole derivatives in high yield using as starting material 2-aroyl-1-alkylpyrrole derivatives, which can be easily obtained from commercially available pyrrole derivatives, and formyl-substituted-2-aroyl-1-alkylpyrrole derivatives, which can be obtained from the above 2-aroyl-1-alkylpyrrole derivatives, and have completed the present invention. The process for the preparation of β, β, β-trihalo-hydroxyethylethyl substituted-2-aroylpyrrole derivatives corresponding to the above formula (I) of the present invention can be illustrated by the following reaction scheme: 3 446 982 I 1 I I I | H0 "EY 3 * o R o ll, (II) (III) Method (A) Method (B) HOR 'H' _ ßcïwg fl cxs (I LJ I 1 \ '/ R! | CHZCOOH Q- UY 0 R Method (A The 2-aroylpyrrole derivatives corresponding to formula (II) and used as starting materials in this method can be easily prepared by reacting phosphorus oxychloride with an arylamide derivative to produce an adduct and then reacting the resulting adduct with a pyrrole derivatives.

Examples of 2-aroylpyrrole derivatives corresponding to the above formula (II) are 2-benzoyl-1-methylpyrrole, 2-p-chlorobenzoyl-1-methylpyrrole, 2-p-bromobenzoyl-1-methylpyrrole, 2-p- methylbenzoyl-1-methylpyrrole, 2-p-methoxybenzoyl-1-methylpyrrole, 2-m-methylbenzoyl-1-methylpyrrole, 2-m-chlorobenzoyl-1-methylpyrrole, 2-m-bromobenzoyl-1-methylpyrrole, 2-m -methoxybenzoyl-1-methylpyrrole and the like.

The reaction may be carried out in the presence of an acid catalyst in an inert organic solvent, e.g. ether solvents such as diethyl ether, tetrahydrofuran and the like, halogenated hydrocarbons such as 1,2-dichloroethane, carbon tetrachloride, dichloromethane and the like.

Examples of acid catalysts are protic acids such as sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and the like, and Lewis acids such as boron fluoride, aluminum chloride, zinc chloride, titanium tetrachloride and the like, but in the practice of the present invention a Lewis acid and in particular a boron trifluoride-ether complex is effective.

Catalyst in an amount of 50 to 5% with respect to the reaction reagent is sufficient and the reaction temperature is suitably room temperature.

In this reaction, R the position. The mixture can be separated into each pure isomer by column chromatography.

Method (B): which corresponds to formula (III) above and which is used as the starting material. The formyl-substituted-2-aroylpyrrole derivatives, starting materials in this method, can be easily prepared by, for example, reacting a 2-aroylpyrrole derivative corresponding to formula (II) above, with a formylating agent such as dimethylformamide phosphorus oxychloride (see reference examples described below).

Examples of formyl-substituted-2-aroylpyrrole derivatives corresponding to formula (III) above are 4-formyl-2-benzoyl-1-methylpyrrole, 4-formyl-2-p-chlorobenzoyl-1-methylpyrrole, 4 -formyl-2-p-bromo-benzoyl-1-methylpyrrole, 4-formyl-2-p-methylbenzoyl-1-methylpyrrole, 4-formyl-2-p-methoxybenzoyl-1-methylpyrrole, 4-formyl-Zm-bromobenzene oyl-1-methylpyrrole, 4-formyl-2-m-methylbenzoyl-1-methylpyrrole, 4-formyl-2-m-methoxybenzoyl-1-methylpyrrole, 5-formyl-2-benzoyl-1-methylpyrrole, 5-formyl -2-p-chlorobenzoyl-1-methylpyrrole, 5-formyl--2-pebromobenzoyl-1-methylpyrrole, 5-formyl-2-p-methylbenzoyl-1-methylpyrrole, 5-formyl-2-p-methoxybenzoyl-1- methylpyrrole, S-formyl-2-bromo-benzoyl-1-methyl-pyrrole, 5-formyl-2-m-methyl-benzoyl-1-methyl-pyrrole, 5-formyl-2-m-methoxy-benzoyl-1-methyl-pyrrole and the like.

In this method, a trihalomethane was used as another starting material. Examples of trihalomethanes that can be used are bromoform, chloroform and the like.

The reaction is carried out in the presence of a base as an essential requirement, and t-butoxy-potassium, sodium hydride, potassium hydride, sodium amide, potassium amide, n-butyllithium and the like can be suitably used as a base.

The reaction is conveniently carried out using a solvent, e.g. THF, dimethoxyethane, diethyl ether, t-butanol and the like. The reaction is conveniently carried out at room temperature, but heating and cooling can be used if necessary. 10 15 20 25 30 35 40 5 446 982 Reference Example ~ 1. A 1,2-dichloroethane solution (25 ml) of 11.43 g (0.07 mol) of N, N-dimethyl-p-tolylamide was added dropwise to 10.7 g (0.07 mol) of phosphorus oxychloride at room temperature and after completion of the additive, the mixture was heated under reflux for 2 hours. After cooling to room temperature, a solution of 5.7 g (0.07 mol) of N-methylpyrrole in 15 ml of dichloroethane was added dropwise and the mixture was heated to 50-60 ° C and stirred for one day. After cooling again to room temperature, a solution of 48 g of sodium acetate in 150 ml of water was added dropwise under ice-cooling, and the mixture was then heated under reflux for 30 minutes. The reaction mixture was poured into ice water, extracted with chloroform and the extract was dried. The solvent was removed and the residue was distilled (b.p. 170-180 ° C / 133 Pa).

The distillate was purified by column chromatography (silica gel, 20% ethyl acetate-n-hexane solution) to give 8.98 g of 2-p-toluoyl-N-methylpyrrole. Yield 64%.

Reference Example 2. To 0.365 g (5 mmol) of dimethylformamide while cooling with ice- Phosphorus oxychloride (1 ml) was added dropwise water. After complete addition, the mixture was stirred for 15 minutes at room temperature and 25 ml of a 1,2-dichloroethane solution of 0.995 g (5 mmol) of 2-p-toluoyl-1-methylpyrrole was added dropwise under cooling again with ice water. After completion of the addition, the mixture was allowed to stand overnight at room temperature. The reaction solution was poured into a 10% aqueous solution of sodium carbonate and the mixture was allowed to stand at room temperature for 15 minutes, then heated to 60 ° C for 10 minutes, cooled to room temperature and extracted with chloroform. The extract was dried and concentrated. . The residue thus obtained (1.2Z g) was purified by silica gel column chromatography to give 0.78 g of 5-p-toluoyl-2-formyl-1-methyl-pyrrole. Yield se%. melting point 81-sz ° c. NMR (cDc13): δ 2.50 (3n, s), 4.33 (3H, s), 6.77 (1H, d, J = s, 6Hz3, 7.03 (1H, d, J = 3 , 6Hz), 7.42 (2H, d, J = 7.3Hz), 7.90 (2H, d, J = 7.3Hz), 9.98 (1H, s).

IR (KBr): 3025, 2950, 2830, 1640, 1610, 1360, 1270, 1095, 895, 745 cm -1. Reference Example 3. 0.995 g (5 mmol) of 2-p-toluoyl-1-methylpyrrole was added dropwise to a solution of 1.0 g of phosphorus oxychloride in 9 ml of dimethylformamide under an ethereal solution (3 ml) of cooling with ice water. After completion of this process, the mixture was stirred for 5 minutes under-cooling with ice-water and the bath water was removed. The reaction mixture was allowed to stand at room temperature for 19 hours and after cooling with ice-water was added. 15 ml of water followed by stirring for 15 minutes A saturated aqueous sodium carbonate solution was added to the mixture and the mixture was extracted with chloroform, the extract was dried, concentrated and the resulting residue was purified by column chromatography (silica gel, ethyl acetate: n-hexane = 1: 9 v / v) for to give 0.80 g of 5-p-toluyl-3-formyl-1-methylpyrrole Yield 70%.

NMR (cDc13) = δ 2.50 (3H, s), 4.15 (3H, §), 7.32 (1H, d, J = 1.7Hz), 7.45 (zH, d, J = 6 , 7Hz), 7.07 (1H, d, J = 1.7Hz), 7.92 (1H, d, J = 6.7Hz), 10.0 (1H, S).

Example Gel 1. 1-Methyl-2-formyl-5-p-toluoylpyrrole (114 mg, 0.5 mmol) and chloroform (418 mg, 3.5 mmol) were dissolved in tetrahydrofuran (7 mL) and potassium t-butoxide ( 112 mg, 1 mmol) dissolved in t-butanol (15 ml) was added to the solution in an argon atmosphere with stirring at 0 ° C.

After stirring for 30 minutes, an aqueous solution of ammonium chloride was added thereto, and the mixture was extracted with ethyl acetate.

The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. Crystals obtained by concentrating the filtrate were purified by silica gel column chromatography, eluting with n-hexane-ethyl acetate to give 1-methyl-2- (2,2,2-trichloro-1-hydroxyethyl) -5-p-toluoylpyrrole ( 165 mg, 95%) as colorless crystals. melting point 131-132 ° C. IR (KBr1: 3250, 1605, 1565, 1520, 1380, 1270 cm-1.

NHR (CDCl 3); Δ 2.43 (S, 3H), 4.08 (s, 3H), 4.27 (d, J = 7Hz, 1H), 5.45 (d, J = 7Hz, 1H), 6.75 ( QAB, J = 5Hz, 2H), 7.58 CQAB, J = 8Hz, 4H).

Elemental analysis: Found: C 52.2 H 4.1 N 3.9% Calculated: 52.0 4.1 4.0% Example gel Z. In the same manner as described in Example 1 but using 454 mg (2 mmol) 1-methyl-fl3-formyl-5-p-toluoylpyrrole - 1-methyl-3- (2,2,2-trichloro-1-hydroxyethyl) -5-p-toluoylpyrrole (640 mg) was obtained as light yellow crystals . Yield 92%. melting point 1ss-190 ° c.

IR (more flat, cnfß: 3350, 1620, 1005, 1405, 920, szo, 760 ram (000133: 6 2.41 (; _, -_, _ s¿1) _, _____ 3, s (ba, m), 4.00 (s, z_0n, 4.11 (s, mlhelsstni, Trszïaaz, m), 7.00 (a, J = z, o Hz; un, ii "r ^ 7, _.1 = s, 0 m), zu), vïftcasgeaäañz, xzx-n. "_ \\ _» ç m. 10 15 20 25 30 35 40 Example 3. 7 446 982 A boron trifluoride4ether compound (1.42 g) was added. to a solution of 1.99 g of Zp-toluyl-1-methylpyrrole dissolved in 10 ml of anhydrous diethyl ether, then a solution of 2.95 g of chloral dissolved in 20 ml of diethyl ether was added dropwise to the mixture at room temperature, and the resulting mixture was stirred overnight. Then the reaction mixture was diluted with diethyl ether, the mixture was washed with a saturated aqueous solution of sodium bicarbonate, dried and concentrated to give 6 g of a crude product, the crude product thus obtained was purified by silica gel column chromatography (eluted with 20% ethyl acetate) to give hexane. give 0.48 g (14% yield) of 1-methyl-2- (2,2,2-trichloro-1-hydroxy) -5-toluoylpyrrole and 2.47 g (71% yield) of 1- methyl 3- (Z, 2,2-trichloro-1-hydroxyethyl) -S-p-toluoylpyrrole.

Reference Example 4. 4. 1-Methyl-2- (2,2,2-trichloro-1-hydroxyethyl) -5-p-toluoylpyrrole (150 mg, 0.43 mmol) was dissolved in dimethyl sulfoxide (DMSO) (3 mL). ) and water (3 mL) and ethyl mercaptan (187 mg, 3 mmol) were added to the solution. To the mixture was added potassium hydroxide (142 mg, 2.2 mmol) dissolved in 50% DMSO aqueous solution (2 ml) while cooling with ice water and stirring. The temperature of the mixture was slowly increased to room temperature followed by stirring overnight. The mixture was stirred for an additional Z hours at 70 ° C and cooled to room temperature. Water (50 ml) and ethyl acetate (SO ml) were added thereto, and the organic layer was separated.

The aqueous layer was acidified with dilute hydrochloric acid to give white crystals which were extracted with ethyl acetate (100 ml).

The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give 1-methyl-5-p-toluoylpyrrole-2-acetic acid (tolmethine) (77 mg, 70%) as pale yellow crystals.

IR (KBr): 3425, 2940, 2900, 1700, 1600 cm -1 NMR (CDCl 3): δ 2.37 (s, 3H), 3.69 (s, 2H), 3.89 (s, 3H), δ .06 (d, J = 4Hz, 1H), 6.62 (d, J = 4Hz, 1H), 7.18 (d, J = 8Hz, HU, 7.66 (d, _J = 8Hz, ZH) Reference Example Gel 5. 1-Methyl-3- (2,2,2-trichloro-1-hydroxy-ethyl) -5-p-toluoylpyrrole (1.52 g, 44 mmol) was dissolved in 30 ml of DMSO, and 2.16 ml of ethyl mercaptan and 30 ml of water were added To the resulting reaction mixture was added dropwise a solution of 1.26 g (22, 5 mmol) of potassium hydroxide dissolved in 20 ml of an SO 2 DMSO aqueous solution while cooling in an ice-water bath. The ice-water bath and the mixture were stirred at room temperature for 12 hours and at 80 DEG C. for 3 hours.The reaction solution was cooled to room temperature, diluted with SO4 ml of water and washed with ethyl acetate.The aqueous layer was separated, acidified with concentrated hydrochloric acid and the liberated acid was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, was concentrated and purified by column chromatography on silica gel, ethyl acetate-hexane = 1: 1 v / v] to give 0.87 g of 1-methyl-5-p-toluoylpyrrole-3-acetic acid as light yellow crystals.

Yield 77 2,. melting point 139-140 ° C-IR (KBr-p1atta): 1730, 1605, 1415, 1280, 1210, 1165, 925, 75 SO4 NMR (CDCl 2H), 3.86 (s, 3H), 6.62 (d, J = fl, HD, 6.83 (d, fi QHz; Hü, 7.17 (d, J = 8Hz, ZH), 7.65 (d, J = 8Hz, 2H)

Claims (4)

446,982 Patent claims B, ß, B-trihalo-u-hydroxyethyl-substituted-2-aroyl-pyrrole derivative for use as an intermediate in the preparation of acetic acid compounds, such as 1-ethyl-5-aroylpyrrol-2-acetic acid compounds (e.g. methyl 1-4-alkyl-5-aroylpyrrole-2-acetic acid compounds (such as Zomepírac), represented by the formula _ÉT¶} -c-cx HS m YO 1 OR wherein R represents a lower alkyl group, R 'represents hydrogen or methyl, Y represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom and X represents a chlorine or bromine atom. A compound according to claim 1, characterized in that: wherein R, R ', Y and X are defined as in claim 1. A compound according to claim 1 or 2, characterized by the formula 'W c-cx3 on * O wherein R, R', Y and X are defined as in claim 1. O = O 1 | R A compound according to claim 1 or 2, characterized by the formula I T rkB "§'CX3 å on Yo wherein R, R ', Y and X are defined as in claim 1. OZEÛ