HU184386B - Process for producing 2-amino-2-methyl 1-3-phenyl 1-propionic-amide derivatives - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a novel 2-amino-2-methyl-3-phenylpropionic acid amide derivative of formula (I), wherein R 1 and R 2 are methoxy or together to form a methylenedioxy or hydrochloride. According to the invention, an optically active 2-amino-2-methyl-3-phenylpropionitrile derivative of the formula (I) wherein R 1 and R 2 are as defined above or inorganic or organic acid is used. the acid addition salt is reacted with hydrochloric acid in the presence of formic acid and, if desired, the base is liberated from the hydrochloride obtained. The process of the present invention provides compounds of formula (I) with a yield of about 97%, which are useful as intermediates in the synthesis of antihypertensive L-alpha-methyl-DOPA. -1-

Description

The present invention relates to a novel optically active 2-amino-2-methyl-3-phenylpropionic acid amide or its hydrochloride, wherein R 1 and R ₂ are methoxy or together are methylenedioxy. The compounds of formula I are useful as intermediates in the synthesis of L-alpha-methyl-DOPA with antihypertensive activity.

No. 152,854. Example 7 of U.S. Patent No. 5,123,121 discloses the preparation of alpha-amino-alpanyanyl-propionamide hydrochloride by hydrolysis of the corresponding nitrile with hydrochloric acid. According to this, the hydrolysis is carried out for 18 hours at -15 ° C in aqueous concentrated hydrochloric acid solution saturated with hydrogen chloride gas at this temperature. Example 15 of the above description also refers to the hydrolysis of DL-alpha-acetamino-alpha-veratryl-propionitrile without describing the physical characteristics of the product formed.

No. 1,451,402. In Example 2 of French Patent No. 5,198, the preparation of DL-alpha-amino-alpha-veratrylpropionic acid amide by hydrolysis of the corresponding nitrile with hydrochloric acid is mentioned, but no physical identification data have been disclosed for the product obtained. Thus, the acid amides of formula (I) are considered novel compounds.

Industrial Application of the procedure described for preparing the known compounds of formula R represents a methoxy group and R ₂ is OH (I) wherein uneconomical. For a very long time, at least 20 hours, it is necessary to maintain a temperature of -15 ° C, which requires significant energy consumption. Attempts have been made to use the known process for the preparation of the novel compounds of formula (I), but have achieved only 55-65% yield.

It has now been found that the optically active 2-amino-2-methyl-3-phenylpropionic acid amide or hydrochloride of formula (I) may be prepared by an economically feasible process by employing an optionally optically active compound of formula (II). -amino-2-methyl-3-phenylpropionitrile, wherein R ₁ and R ₂ are the acid addition salts of the compounds of formula (I) or inorganic or organic acids in the presence of formic acid, and if desired, of the hydrochloride of formula (I); base is liberated in a manner known per se.

The starting material is a compound of the formula (I) or an acid addition salt thereof, for example an acid addition salt of an inorganic or organic acid, preferably its hydrochloride, optionally in the form of a solution or suspension in an organic solvent. It is possible to start from the compound of the formula (Π) or one of its active isomers or their acid addition salts.

The formic acid is generally 85-100% formic acid, preferably in an amount of 2 to 3.5 molar equivalents relative to the compound of formula II.

The hydrochloric acid required for the hydrolysis of the compound of formula (II) is preferably provided by introducing hydrogen chloride gas into the reaction mixture. However, it is also possible to prepare the hydrochloric acid in the reaction mixture by reaction of phosphorus trichloride with water or aqueous hydrochloric acid.

In a preferred embodiment of the process according to the invention, the compound of formula (Π) is dissolved in formic acid, the solution is saturated with hydrogen chloride gas, and after the hydrolysis is complete, the hydrochloride of the compound of formula I formed is isolated. If desired, the hydrochloride is used to liberate the compound of formula (I) with a base.

In another embodiment of the process of the invention, a solution of the compound of formula (Π) in an organic solvent such as dichloroethane, obtained during its preparation, is added to formic acid, saturated with hydrogen chloride gas, and hydrolyzed. hydrochloride.

The starting compound of formula (ből) can be prepared from the corresponding oxo compound by Strecker reaction.

The process of the present invention provides compounds of formula (I) in a yield of about 97% which is non-degradable and, if necessary, well stored and very well purified. Because the compounds are poorly soluble in conventional solvents, impurities can be easily removed by solvent washing.

The invention is illustrated in detail by the following examples:

Example 7

A 2-amino-2-methyl-3- (3,4-dimethoxyphenyl) propionitrile hydrobromide (20 g, 0.066 mol) and 36.6 g (0.796 mol) were placed in a round-bottomed flask fitted with a gas inlet and calcium chloride, a stirrer, a thermometer and a reflux condenser. ) 98-100% formic acid. After cooling with ice water, the solution was saturated with hydrogen chloride gas for about 4 hours and then allowed to stand overnight. After completion of the reaction, the mixture was evaporated to dryness in vacuo and the residue dissolved in hot ethanol (20-25 ml). Upon cooling and scraping, the acid amide hydrochloride salt crystallizes. The crystals were filtered off and washed with acetone. 16.9 g of racem 2-amino-2-methyl-3- (3,4-dimethoxyphenyl) -propionic acid amide hydrochloride are obtained, m.p. 106-108 ° C. The ethanol mother liquor is evaporated and 10-15 ml of acetone are added to the residue, whereupon another 1 g of crystalline hydrochloric acid salt is precipitated. Taking this into account, the yield was 17.9 g (97.8%).

Dissolve racem 2-amino-2-methyl-3- (3,4-dimethoxyphenyl) -propionic acid hydrochloride in 50 ml of water and add 40% aqueous sodium hydroxide solution until the pH is 11. . The liberated acid amide was extracted with chloroform (3 x 100 ml), the chloroform solutions were combined, washed with water (5 ml), dried over anhydrous magnesium sulfate and evaporated. The residue crystallizes slowly.

19.6 g of racem 2-amino-2-methyl-3- (3,4-dimethoxyphenyl) propionic acid amide are obtained.

Example 2 Into the apparatus described in Example 1 was added a solution of 220 g (1 mole) of L-2-amino-2-methyl-3- (3,4-dimethoxyphenylpropionitrile in 30% dichloroethane) and 108 g. (2 mol) 85% formic acid The resulting mixture was saturated with hydrogen chloride gas at 0-5 ° C for 3-4 hours and allowed to stand overnight, during which time the acid amide formation occurred and a 2-phase system was formed. To the lower dense oily phase is added 500 ml of acetone and heated to reflux, the hydrochloride salt of the acid amide crystallizes at the reflux temperature, and after cooling, the crystals are filtered off and washed with acetone.

269 g (97%) of L-2-amino-2-methyl-3- (3,4-dimethoxyphenyl) propionamide hydrochloride are obtained.

Content: 98-99%.

Example 3

To a solution of 220 g (1 mol) of L-2-amino-2-methyl-3- (3,4-dimethoxyphenyl) propionitrile base in 30% dichloroethane at 10-15 ° C was added 108 g (2 mol) of 85% han-2184 386 fatty acid and 95 g of 37% hydrochloric acid solution were cooled to below 10 ° C and 138 g (1 mol) of phosphorus trifluoride were added over 2-3 hours. The upper dichloroethane phase is discarded, 700 ml of acetone are added to the oily portion and the resulting crystal slurry is stirred for 4 hours at 0-5 ° C. The mixture is filtered and washed with acetone.

285-290 g of 2-amino-2-methyl-3- (3,4-dimethoxyphenyl) propionamide hydrochloride, m.p. 98-100 ° C.

[a] D = 12.6 ⁰ (5, MeOH)

Content: 89-91%. 10

The acetone mother liquor is evaporated to dryness. The residue was stirred with 50 ml of acetone.

Another 10-15 g of the hydrochloride salt of the acid amide is obtained.

Content: 88-90%.

Total yield: 300 g (97.1%) (based on 100% material).

Example 4

To a solution of 2-amino-2-methyl-3- (3,4-methylenedioxyphenyl) propiomtnl (180 g, 1 mol) in 30% dichloroethane was added 108 g (2 mol) in the same manner as in Example 3. 85% formic acid, 95 g 37% hydrochloric acid and 138 g phosphorus trichloride. Work up as in Example 3 to give 252 g of racem 2-amino-2-methyl-3- (3,4-methylenedioxyphenyl) -propionic acid hydrochloride, m.p. 88-90 ° C.

Content: 91%.

Yield: 97.8% (calculated on 100% content)

Claims (4)

PATENT CLAIMS A process for preparing an optically active 2-amino-2-methyl-3-phenylpropionic acid amide derivative of formula (I). wherein R 1 and R ₂ represent a methoxy group or a methylene dioxide group or a hydrochloride thereof, characterized in that an optionally optically active 2-amino-2-methyl-3-phenylpropionitrile derivative of formula II wherein R and R ₂ is the acid addition salt of the foregoing or with an inorganic or organic acid, in the presence of formic acid, reacted with hydrochloric acid and liberated, if desired, from the resulting hydrochloride. 2. A process according to claim 1, wherein the starting material is an organic solvent solution or suspension of the base or acid addition salt thereof. 3. A process according to claim 1, wherein the hydrochloric acid for the reaction is provided by introducing hydrogen chloride gas into the reaction mixture. 4. A process according to claim 1, wherein the hydrochloric acid required for the reaction is prepared by reaction of phosphorus trichloride with water or aqueous hydrochloric acid.