FI66859B - PROCEDURE FOR THE FRAMEWORK OF 4-AMINOTIOPHENE-3-CARBOXYL SYRADERS WITH A PHYSIOLOGICAL NETWORK - Google Patents

Description

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U.S. Pat. No. 3,8853, 7,16854, U.S. Pat. No. 716853, 716854, U.S. Pat. No. 716,853, 716854, 820521 (71) F. Hoffmann-La Roche & Co. Aktiengesellschaft, Grenzacherstrasse 124-184, Basel, Switzerland-Switzerland (CH) (72) Pasquale Nicholas Confalone, Bloomfield, New Jersey,

Giacomo Pizzolato, Belleville, New Jersey,

Hilan Radoje Uskokovic, Upper Montclair, New Jersey, USA (US),

Marianne Rouge, Basel, Switzerland-Switzerland (CH) (74) Oy Kolster Ab (54) Method for the preparation of physiologically active 4-aminothiophene-3-carboxylic acid derivatives - Preparation of physiologically active 4-aminothiophene-3-carboxylic acid derivatives

The invention relates to a process for the preparation of novel 4-aminothiophene-3-carboxylic acid derivatives of the formula / r3 0 d IL / N \ (I)

R2 (T -ξ H

R 1 wherein R 1 is lower alkyl or phenyl, R 2 is hydrogen or lower alkyl and R 8 is lower alkyl or hydrogen; and salts thereof.

The compounds of formula I and their salts are valuable drugs for use in the treatment of obesity and in the reduction of blood lipid levels of 66859 2. They are also valuable in the treatment of atherosclerosis and cardiovascular diseases associated with elevated blood lipids.

Preferred compounds of formula (I) are those wherein P 1 is lower alkyl and R 2 is lower alkyl.

The compound of formula (I) and its salts are obtained according to the invention in such a way that the compound of formula (II)

Jk J- ° H

wherein R'2 is lower alkyl and R1 is as defined above, is treated with an acid and in the compound of formula (I) thus obtained, wherein R3 is hydrogen, the lower carbalkoxy group is optionally converted to a carboxy group and / or the amino group is optionally lower-alkylated , and the compound of formula (I) is modified if desired. salt.

A compound of formula (I) wherein R 3 is hydrogen may be obtained by treating an oxime of formula (II) with an acid, preferably hydrogen halide, especially hydrogen chloride, in an inert organic solvent, e.g. an ether, especially a lower alkyl ether such as diethyl ether; in a cyclic ether such as tetrahydrofuran or dioxane; in lower alcohol or water. Reaction temperature and pressure are not critical.

The reaction may conveniently be carried out at a temperature of about 0 to 70 ° C, preferably at room temperature and atmospheric pressure.

The lower carbalkoxy group may be converted by base hydrolysis in a conventional inert organic solvent, preferably a lower alcohol, especially methanol or ethanol; in aqueous ether, preferably in aqueous diluent », ...... · · *

II

6685 9 in an alkyl ether, in particular diethyl ether, or in an aqueous cyclic ether, preferably in tetrahydrofuran or dioxane, as a carboxy group. Preferred bases include alkali metal hydroxides such as sodium, potassium and lithium hydroxide and alkaline earth metal hydroxides such as barium, calcium and magnesium hydroxides, especially alkali metal hydroxides. In this hydrolysis, temperature and pressure are not critical. The reaction may conveniently be carried out at a temperature of about 0 to 100 ° C, preferably at the reflux temperature of the reaction mixture, especially at 70 ° C and atmospheric pressure. If Rg is intended to denote lower alkyl, then this residue can be modified in a manner known per se, as used in the conversion of aromatic primary amines to an N-substituted derivative. The primary amine of formula (I) wherein R 3 is hydrogen can be reacted with a lower alkanecarboxylic anhydride and the resulting amide reduced to the corresponding lower alkylated amine.

Compounds of formula (II) may be obtained by administering a compound of formula (III) 0 R ^ O ^ ^ / ^ SH (III) 66859 ____: r

react with a compound of formula IV

Wherein R 1 is and R 1 is as defined above, R 1 is lower alkyl and R 8 is halogen, mesyloxy or tosyloxy. This reaction may be carried out in the presence of a lower alcohol and an alkali metal alkoxide, preferably in the presence of methanol and sodium methoxide. Although temperature and pressure are not critical, the reaction is generally carried out at atmospheric pressure and at a temperature between about 15 ° C and about 60 ° C, preferably at 25 ° C.

The compound of formula V is then treated with an alkali metal alkoxide, preferably sodium methoxide, in the presence of an aromatic hydrocarbon, preferably benzene, to form a compound of formula VI R, 2 ° '' '> Sf (VI) S 1 R 1 where R and R' 2 are as defined above.

Although temperature and pressure are not critical, this reaction is generally carried out at atmospheric pressure and at a temperature between about 15 ° C and about 60 ° C, preferably at 25 ° C,

The compound of formula VI is then converted to the oxime of formula II according to methods known per se, such as those used for the conversion of ketones to oximes. Preferably, ketone VI is treated with a hydroxylamine hydrohalide, preferably hydroxylamine hydrochloride, in a nitrogenous base. Any conventional nitrogen-containing base, preferably an amine, can be used. Suitable amines include primary amines such as lower alkylamines, especially methylamine, ethylamine or aniline; secondary amines such as dialkylalkylamines, especially dimethylamine or diethylamine; or pyrrole; and tertiary amines such as trialkylalkylamines, especially trimethylamine and triethylamine or pyridine or picoline. Temperature and pressure are not critical. The reaction is conveniently carried out at a temperature between room temperature and reflux temperature, preferably at about 22 ° C and atmospheric pressure in an inert organic solvent such as an aliphatic or aromatic hydrocarbon, e.g. n-hexane or benzene. Preferably, the reaction is carried out in an excess of a nitrogen-containing base which acts as a solvent.

As already mentioned, the thiophene derivatives of the formula I and their pharmaceutically acceptable salts are hypolipemic agents, i.e. they lower the blood lipids of mammals. This property was demonstrated in normal female Charles-River rats weighing 150-180 g. .

The animals were first fed a mixture of corn oil and glucose for a few days, after which they were given the new compounds in dimethyl sulfoxide orally or parenterally.

A comparison of blood triglycerides, fatty acids, and cholesterol levels in rats that had received the new compounds showed a significant reduction in the corresponding values compared to the corresponding values in the untreated animals. Similar results were obtained with rat hepatocytes,

Fatty Acid and Cholesterol Synthesis in Isolated Hepatocytes Female Charles-River rats were fasted for 48 h, followed by a diet of 70% glucose and 1% corn oil for 7-14 days at 8-11 a.m. Isolated rat hepatocytes were obtained by in situ perfusion of the liver. Hepatocytes were germinated for 60 min at 37 ° C. Each sample contained a total volume of 2.1 ml consisting of 1 ml of isolated rat hepatocytes (10 ^ 20 mg dry cells). ), 1 ml of Krebs-Henseleit b.carbonate buffer pH 7.4, 16.5 moles of glucose, 1 μM L-alanine (1 μl Ci), 1 mCi H 2 O and 2 mM inhibitor in water, or in dimethyl sulfoxide at pH 7.4. All experiments were repeated 2 times and performed on three samples each. To the cell-containing medium was added 0.4 ml of 62.5% citric acid and germinated for 45 min. I drive. The evolved CCl 2 was collected in 0.3 ml of a mixture of ethanolamine / 2-methoxyethanol (1: 2). At the end of the experiment, 14 was determined in this solution. . . ......

The CO 2 content by means of a scintillation counter, the cell medium was saponified, acidified (only to determine lipogenesis values) and extracted with hexane. At this stage, the lipids were either counted (to determine lipogenesis values) or precipitated. tonin, washed and counted (to determine cholesterolenesis values i). The conversion of H 2 O and / C / alanine to fatty acids or sterols was determined using a liquid calculator. The results are reported in Table I as n moles of H 2 O and alanine converted to fatty acids or cholesterol and n moles of alanine oxidized to CCl 2 per mg dry cells and per 60 min.

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The rats were fasted for 48 hours and then fed a diet of 1% corn oil and 70% glucose for 5-15 days. On the day of the experiment, the test compound was administered for 30-60 min. before a 3-hour feeding period using oral intubation, or 60 min. After a 3-hour feeding period by intraperitoneal injection. 30 min.

. 3 animals were then injected with 1 mCi of H 2 O, 12.3 mg of alanine (5 μCi) and 30.6 mg of o (keto-glutaric acid in 0.25 ml of saline) into the tail vein. the animals were decapitated, the liver was rapidly excised, saponified and acidified (for lipogenesis only) and extracted with hexane, and the lipids were either counted (for lipogenesis) or precipitated with digitonin, washed and counted (for cholesterogenesis) and alanine. conversion to fatty acids or sterols was performed using a liquid scintillation counter.

The results are reported in Tables II-V.

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The following Table VI shows the activity of the compounds of formula I,

Table VI

Compound of formula I Inhibition of fatty acid synthesis (Rg = H)% R1_R2 1 -CH2CH2CH3 ch3100 2 -CH3 CH3 100 3 -CH2CH3 CH3 100 4 -CH (CH3) 2 CH3 100 5 -CH3 H 100 6 -CH2CH3 H 100 7 -CH (CH3) 2 H 100 8 -ch2ch2ch3 H 100 9 -CcHc H 19 10 - (CH2) 3CH3 CH3 11 11 -CgH5 CH3 16

The compounds of formula I and their pharmaceutically acceptable salts can be administered parenterally and orally. For parenteral administration, solutions and suspensions of the compounds in dimethyl sulfoxide, water or acacia may be employed. Sterile aqueous solutions of the corresponding water-soluble salts are especially suitable.

The dose needed to lower blood lipids depends on the quality and number of symptoms. Higher amounts of active ingredient are required for oral administration than for parenteral administration. Dosages of about 0.1 to 1.2 mg of active ingredient per kg of body weight are generally contemplated in order to achieve a significant reduction in blood lipid levels. comparison Tests

Comparative experiments were performed according to Sullivan, A.C., Triscari, J & Hamilton, J, G, Lipids, Vol. 12, p 1-a (1977) by determining the effect of test compounds on fatty acid synthesis in isolated rat liver cells.

14 6 6 8 5 9

Reduction in fatty acid synthesis was determined using tritium water and carbon 14 (C_7 alanine). A compound that, at low concentrations, reduces statistically significantly compared to a control compound is useful as a triglyceride lowering agent. Triglyceride is a specific blood lipid.

The compounds tested were A, B, C and D, wherein A and B were prepared according to the invention A = 4-amino-5-ethyl-3-3-thiophenecarboxylic acid methyl ester hydrochloride; B = 4-amino-5-methyl-3-thiophenecarboxylic methyl ester hydrochloride; and compounds C and D are the positional isomers of the compounds of the invention known from GB Patent 1,278,034. C = 3-amino-5-ethyl-2-thiophenecarboxylic acid methyl ester hydrochloride; D = 3-amino-5-methyl-2-thiophenecarboxylic acid methyl ester hydrochloride,

The results are shown in Table VII below.

Table VII

^ H ^ O-conversion Z ^ c / aiani.ini-convert- reduction-% reduction-%

Compound Dose umol compared to control f * ΊΤ ·· ° __r__Compared to control A 0.5 4-2 9-1 1.0 24 ± 18 34 ± 23 2.0 59 ± 3XXK 70 ± 4 *** 5, 0 60 i 5 *** 69 ± 5 *** 10.0 67 ± 4X * K 79 - 4xxx B 10.0 43 ± 7 ** 66 - 4 *** C 10.0 6 ± 4 31 ± 14 D 10.0 -8 ± 4 29 - 10

Reduction percentage values are always the averages of at least three assays, Rat isolated dry liver cells were 8-10 mg in each flask. Doses of test compounds were dissolved in 25 μl of dimethyl sulfoxide in each case.

Il 15 66859 xx p O »01» statistically significant reduction compared to control xxx p ^ 0.001; statistically significant reduction compared to control,

The above results show that the novel compounds A and B of the formula I already have a significant inhibitory effect on fatty acid synthesis at a dose of 10 [mu] mol, while the compounds C and D of the formula IV known from GB patent 1,278,084 are practically ineffective at this dose.

The following examples illustrate the invention. All temperature values are expressed in degrees Celsius,

Example 1

To a solution of 100 g of 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene-1-oxime in one liter of anhydrous ether was introduced at 0 ° C for 1 hour gaseous hydrogen chloride. The reaction vessel was sealed with a drying tube and stirred overnight at room temperature. The solvent was evaporated until the product crystallized. The white solid was filtered and washed with ether. 60 g of 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride, m.p. 178-180 ° C, were obtained. Recrystallization from methanol / ether gave the product, m.p. was 180-181 ° C. The starting material can be prepared as follows: a) To a solution of 116.55 g of 3-mercaptopropionic acid methyl ester in 220 ml of dry methanol was added 52.46 g of sodium methoxide at -20 °. After 20 min, a solution of 3 g of 2-bromo-valeric acid ethyl ester in 150 g of dry methanol was added dropwise. The reaction mixture was allowed to warm with stirring overnight at room temperature. The methanol was evaporated and the residue partitioned between ether and water. The organic phase was washed with 10% bicarbonate solution and water, dried over magnesium sulfate and evaporated. 130 g of 4-thia-5-carbomethoxyoctanoic acid methyl ester were obtained as a colorless oil. si-oktaanihappometyyliesteriä. The mixture was stirred overnight and poured into ice water. The aqueous phase was extracted with benzene / ether (1: 1) and then acidified by the addition of 6 N HCl to pH 1. The product, which was partially separated from the aqueous solution, was dissolved in methylene chloride. The aqueous phase was extracted with methylene chloride. The combined organic phases were dried and evaporated to give 94 g of pure 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene as a colorless oil.

c) To a solution of 94.0 g of 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene in 250 ml of dry pyridine was added at 25 ° C 40.0 g of hydroxylamine hydrochloride. The reaction mixture was stirred overnight at room temperature, the solvent was evaporated and the residue partitioned between 1N hydrochloric acid and methylene chloride. The organic phase was dried over sodium sulfate and evaporated to give 100 g of pure 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene oxime as a colorless oil.

Example 2

A solution of 41.1 g of 4-carbomethoxy-3-keto-2-methyl-tetrahydrothiophene oxime in 600 ml of anhydrous ether was saturated at 0 ° with hydrogen chloride and then stirred at 25 ° C overnight. The separated solid was collected, washed with ether and dried. After recrystallization and further work-up of the mother liquors, a total of 37.4 g of 3-amino-4-carbomethoxy-2-methylthiophene hydrochloride was obtained, m.p. was 191-192 ° C.

Similarly, 49.12 g of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene oxime was converted to 18.49 g of 3-amino-4-carbomethoxy-2-isopropylthiophene hydrochloride, m.p. was 185 ° C (dec.).

The starting material can be prepared as follows: a) To a solution of 66.29 g of 3-mercaptopropionic acid methyl ester in 50 ml of anhydrous methanol was added at 0 ° 120 ml of a 25% sodium methoxide solution in methanol. A solution of 100 g of 2-bromo-propionic acid ethyl ester in 100 ml of anhydrous methanol was added dropwise to the solution. The reaction mixture was allowed to warm to 25 ° C overnight. The solvent was evaporated and the residue partitioned between ether and 10% sodium bicarbonate solution. The aqueous phase was extracted with ether. The combined organic extracts were dried over magnesium sulphate and evaporated to give 121.40 g of 2-methyl-3-thia-adipic acid 1-ethyl-6-methyl ester as a pale yellow oil.

I! 17 66859

Similarly, 61.4 g of 3-mercaptopropionic acid methyl ester was reacted with 106.8 g of 2-bromo-valeric acid ethyl ester to give 120.91 g of 2-isopropyl-3-thia-adipic acid-1-ethyl-6 -methylester.

b) A solution of 121.4 g of 2-methyl-3-thia-adipic acid 1-ethyl-6-methyl ester in 90 ml of dry benzene was added dropwise to a suspension of 30 g of anhydrous sodium methoxide in 200 ml of dry benzene. The reaction mixture was allowed to warm overnight, then partitioned between water and ether. The aqueous phase was extracted with benzene. The aqueous phase was then acidified to pH 1 by the addition of 6 N HCl and extracted three times with methylene chloride. The methylene chloride extracts were dried over sodium sulfate and evaporated to give 79.17 g of pure 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene as a colorless oil.

In a similar manner, 120.91 g of 2-isopropyl-3-thia-adipic acid 1-ethyl-6-methyl ester was converted to 91 g of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene.

c) To a solution of 37.26 g of 4-carbomethoxy-3-keto-2-methyl-tetrahydrothiophene in 100 ml of anhydrous pyridine was added 18.0 g of hydroxylamine hydrochloride. The mixture was stirred for 24 hours at 25 ° C, then evaporated and partitioned between 1N hydrochloric acid and methylene chloride. The aqueous phase was extracted twice with methylene chloride, the combined organic extracts dried and evaporated to give 40.1 g of pure 4-carbomethoxy-3-keto-2-methyltetrahydro-thiophene oxime as a colorless oil.

In a similar manner, 52.8 g of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene was converted to 49.0 g of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene oxime.

.Example 3

A solution of 2.07 g of 3-amino-4-carbomethoxy-2-methyl-

thiophene hydrochloride in 35 mL of methanol was treated with 23 mL of 1N

caustic-soda solution. The mixture was heated at reflux for 1/2 hour, cooled and poured into brine. The pH of the solution was adjusted to 5. The solution was extracted 7 times with methylene chloride / methanol (4: 1). The organic extracts were dried and evaporated to give 1.23 g of pure 3-amino-3-carboxy-2-methylthiophene, m.p. 18,6859, m.p. was 162-164 ° C. The analytical preparation was recrystallized from ethyl acetate / pentane, m.p. was 163-164 ° C.

In a similar manner, 5 g of 3-amino-4-carbomethoxy-2-isopropylthiophene hydrochloride was converted to 3.3 g of 3-amino-4-carboxy-2-isopropylthiophene, m.p. was 117-118 ° C and 1.41 g of 3-amino-4-carbomethoxy-2-propylthiophene hydrochloride was converted to 0.625 g of 3-amino-4-carboxy-2-propylthiophene, m.p. was 144-145 ° C.

Example 4

To a solution of 80.0 g of 4-carbomethoxy-3-keto-2-phenyl-tetrahydrothiophene oxime in 600 ml of anhydrous ether was introduced gaseous hydrogen chloride at 0 ° C for 1 hour. To the suspension was added 300 ml of methanol and stirred overnight at 25 ° C. The reaction product was filtered and washed with ether. 70.0 g of 4-amino-5-phenylthiophene-3-carboxylic acid methyl ester hydrochloride were obtained as a pale yellow solid, m.p. was 181-182 ° C. This compound can be recrystallized from methanol.

The starting material can be prepared as follows: a) To a solution of 104.95 g of 3-mercaptopropionic acid methyl ester in 200 ml of methanol was added at 0 ° 207.5 g of a 25% solution of sodium methoxide in methanol. To the resulting homogeneous solution was added dropwise, under an argon atmosphere, a solution of 200 g of bromo-phenylacetic acid methyl ester in 200 ml of methanol. The reaction mixture was stirred overnight at 25 ° C, the solvent was evaporated and the residue partitioned between water and methylene chloride. 234 g of 2-phenyl-3-thia-adipic acid dimethyl ester were obtained as a colorless oil.

b) A solution of 234 g of 2-phenyl-3-thia-adipic acid dimethyl ester in 300 ml of dry benzene was added dropwise at 25 ° C to 54.05 g of sodium methoxide. The reaction mixture was stirred overnight and poured into water. The solid was filtered and the filtrate was extracted twice with diethyl ether. The solid was added to the aqueous phase, which was then adjusted to pH 1 by the addition of 6 N HCl. The mixture was extracted 3 times with methylene chloride, the organic extracts were dried over sodium sulfate and evaporated to give 145.24 g of 4-carbomethoxy-3-keto-2-phenyl-tetrahydro-

II

19 66859 thiophene as a yellow oil.

c) To a solution of 82.24 g of 4-carbomethoxy-3-keto-2-phenyltetrahydrothiophene in 120 ml of anhydrous pyridine was added 28.85 g of hydroxylamine hydrochloride. The solution was stirred for 2 days at 25 ° C, the solvent was evaporated under reduced pressure and the residue partitioned between 1N hydrochloric acid and methylene chloride. The aqueous phase was extracted with methylene chloride. The organic extracts were dried over sodium sulfate and evaporated to give 90.0 g of 4-carbomethoxy-3-keto-2-phenyltetrahydrothiophene oxime as a colorless oil.

Example 5

To a solution of 10.0 g of 4-amino-5-phenylthiophene-3-carboxylic acid methyl ester hydrochloride in 80 ml of methanol was added 82 ml of 1N sodium hydroxide solution. The mixture was heated for 30 min. under reflux, cooled to room temperature and adjusted to pH 5. The separated product was filtered off and dried, yielding 8.2 g of pure 4-amino-5-phenyl-thiophene-3-carboxylic acid, m.p. 201-202 ° C (ethyl acetate / pentane).

Example 6 Preparation of 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride

To a solution of 125 g of methyl 3-mercaptopropionate in 75 ml of dry methanol is added dropwise at 0 ° C 249 ml of methanol containing 25% sodium methoxide. 200 g of ethyl 2-bromobutyrate in 75 ml of dry methanol are added dropwise to the mixture at 0 ° C. The mixture is stirred overnight at 25 ° C, then concentrated and run between water and methylene chloride. The organic phase is dried and concentrated to give 229 g of 2-ethyl-3-thia-1,6-hexanedione-1-ethyl-6-methyl ester as a colorless oil.

To a suspension of 63.5 g of sodium methoxide in 300 ml of dry benzene is added dropwise at 25 ° 229 g of 2-ethyl-3-thia-1,6-hexanedione-1-ethyl-6-methyl ester in 200 ml of dry benzene. . The mixture is stirred at room temperature overnight, then poured into 800 ml of water and the benzene layer is extracted with 200 ml Γ.

66859 20 water. The aqueous phases are combined, carefully acidified with 6N HCl and extracted three times with methylene chloride / methanol. 5/1. The organic extracts are dried and evaporated to give 149.7 g of pure 4-carbomethoxy-3-keto-2-ethyltetrahydrothiophene as a colorless oil.

To a solution of 276.1 g of 4-carbomethoxy-3-keto-2-ethyltetrahydrothiophene in 500 ml of anhydrous pyridine is added portionwise 121.6 g of hydroxylamine hydrochloride. The mixture is allowed to stand for 20 hours at 25 °, then concentrated and partitioned between methylene chloride and 3 N HCl. The aqueous phase is washed twice with methylene chloride / methanol 5/1. The organic phases are dried and evaporated to give 253 g of pure 4-carbomethoxy-3-keto-2-ethyltetrahydro-thiophene oxime as a yellow oil.

To a solution of 253 g of 4-carbomethoxy-3-keto-2-ethyl-tetrahydrothiophene oxime in 2 liters of anhydrous ether is introduced at 25 ° for 1 hour gaseous hydrogen chloride. 0.5 g of authentic product is inoculated into the mixture and stirred overnight at 25 °. The crude product is filtered, washed with anhydrous ether and recrystallized from methanol-ether to give 173 g of pure 4-amino-5-ethyl-3-thiophenecarboxylic hydrochloride, m.p. is 161 °.

In a similar manner the following compounds were prepared: 4-amino-5-propyl-3-thiophenecarboxyethyl ester hydrochloride, m.p. 144 ° C (decomposes, ethyl acetate), 4-amino-5-ethyl-3-thiophenecarboxyethyl ester hydrochloride, m.p. 159 ° C (decomposes, isopropanol / diethyl ether).

Example 7 Preparation of 5-ethyl-4-ethylaminothiophene-3-carboxylic acid methyl ester hydrochloride

To a solution of 7.4 g (0.0326 mol) of 4-acetamido-5-ethyl-3-thiophenecarboxylic acid methyl ester in 70 ml of anhydrous tetrahydrofuran was added dropwise 52 ml of a 1 N diborane / tetrahydrofuran solution at 25 ° C. The reaction mixture was stirred overnight at room temperature, cooled (dropwise) with water and partitioned between concentrated ammonium hydroxide and methylene chloride. The aqueous phase was extracted 2,6659 times with a mixture of methylene chloride and methanol (4: 1). The organic extracts were combined, dried over ammonium sulphate and evaporated to dryness to give 7.3 g of residue. The residue was chromatographed on a 1 kg silica gel column and eluted with a mixture of chloroform and methanol (9: 1). 5-Ethyl-4-ethylaminothiophene-3-carboxylic acid methyl ester was first eluted and obtained as a colorless oil by evaporation of the appropriate fractions. Said compound was taken up in 50 ml of methanol previously saturated with gaseous hydrogen chloride. After evaporation to dryness, 1.37 g (17%) of pure 5-ethyl-4-ethylaminothiophene-3-carboxylic acid methyl ester hydrochloride, m.p. 135 ° C (decomposes, methanol / diethyl ester).

The starting material can be prepared as follows: To a solution of 11.085 g (0.05 mol) of 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride in 50 ml of anhydrous pyridine was added 5.0 ml of acetic anhydride in one portion at 25 ° C. The reaction mixture was stirred at room temperature for 3 h, the reaction mixture was concentrated and partitioned between 1N hydrochloric acid and methylene chloride. The aqueous phase was extracted twice with methylene chloride. The organic phases were combined, dried over sodium sulfate and evaporated to dryness to give 11.17 g (98%) of pure 4-acetamido-5-ethyl-3-thiophenecarboxylic acid methyl ester, m.p. 85-86 ° C (benzene / hexane).

Claims (2)

22 Claims 6 68 5 9 A process for the preparation of physiologically active β-aminothiophene-3-carboxylic acid derivatives of the formula: wherein R 1 is lower alkyl or phenyl, R 1 is hydrogen or lower alkyl and R 1 is lower alkyl or hydrogen; and for the preparation of their salts, characterized in that the compound of formula O 1 v V-OH r'2 i-r wherein R'2 is lower alkyl and R1 is as defined above is treated with an acid and the compound of formula I thus obtained, wherein Rg is hydrogen, the lower carbalkoxy group is optionally converted to a carboxy group and / or the amino group is optionally lower alkylated, and the compound of formula I is optionally converted to a salt. Process according to Claim 1, characterized in that N-amino-S-ethyl-S-thiophenecarboxylic acid methyl ester hydrochloride is prepared.