SK50372006A3 - Process for preparing 7-hydroxy-3,4-dihydrocarbostyril - Google Patents

Abstract

The invented process for preparing 7-hydroxy-3,4-dihydrocarbostyril of the general formula IV with purity higher than 98 percent is characterized by execution of a catalytic hydrogenation in order to purify 7-hydroxy-3,4-dihydrocarbostyril from 7-hydroxy carbostyril of the general formula 1.

Description

Technical field

The invention relates to a process for the preparation of highly pure 7-hydroxy-3,4-dihydrocarbostyril. This compound is used, inter alia, as an intermediate for the production of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril and 7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one known as aripiprazole. Aripiprazole belongs to a new generation of antipsychotics, as it acts simultaneously as a postsynaptic dopamine D2 antagonist and a presynaptic dopamine D2 autoreceptor partial agonist.

BACKGROUND OF THE INVENTION

Aripiprazole III is prepared according to the procedure of EP 0 367 141, equivalent to US 5 006 528, cf. the following scheme 1.

SCHEME 1

The starting unit 7- (4-halobutoxy) -3,4-dihydro-1 H -quinolin-2-one I is prepared according to the following scheme 2. (EP 0367141, J. Med. Chem. 1998 (41) 658 - 667, Chem Pharm Bull 1988 (36) 4377-4388) HO

X = Br, Cl Y = Br, Cl

SCHEME 2

X '0 * · • • »'« '' '' '

-> · · · · · «· · '' '' '' '' '' ''

A common method of synthesizing 7-hydroxy-3,4-dihydrocarbostyril IV is by the following procedure

Chem. Ber. 1927 (60) 858-864 (Scheme 3). Accordingly, in the first step the 3-chloro-3'-hydroxypropioanilide VI prepared by reacting 3-aminophenol VII with 3-chloropropionyl chloride VIII in acetone solution and in the second step reacting 3-chloro-3'-hydroxypropioanilide with aluminum, sodium and potassium chloride formation of 7-hydroxy-3,4-dihydrocarbostyril IV.

HO '

SCHEME 3

A further procedure for the preparation of 7-hydroxy-3,4-dihydrocarbostyril IV was described in 1969 in J. Chem. Soc. It utilizes the Schmidt reaction of cyclic ketone IX with sodium azide in 93% sulfuric acid (Scheme 4). However, due to the formation of the undesired isomer X, which reduces the yield of the desired 7-hydroxy-3,4-dihydrocarbostyril IV and complicates its isolation at the desired quality, this reaction is not appropriate. Furthermore, the reaction is problematic in terms of technology. Production is complicated due to the difficulty of ensuring the safety of working with sodium azide and concentrated sulfuric acid. Last but not least, this preparation is unsuitable because of the large amount of waste that can be disposed of.

SCHEME 4

Experimentally it was found that following the procedure of Chem. Ber. 1927 (60) 858-864 (Examples 1 and 2), a highly contaminated 7-hydroxy-3,4-dihydrocarbostyril IV product is formed. According to ·> ο

HPLC analysis product IV contained 2% impurity, which was identified by LC-MS as a molecular weight lower than 2 units than the product, i.e. the impurity is 7-hydroxycarbostyril 1.

HO N ^X O

H

This was also confirmed from the NMR spectra of a sample that contained a larger amount of this impurity (6%). The impurity 1 content usually varied from 2 to 10% in individual experiments.

Furthermore, it has been shown that when so contaminated 7-hydroxy-3,4-dihydrocarbostyril IV is used for the preparation of aripiprazole, impurity 1 induces further impurities such as impurities 2, 3, 4 in subsequent synthesis steps. The resulting aripiprazole is thus obtained in low yield and purity and is therefore not suitable for use in the pharmaceutical industry.

X = Br, Cl

To remove or significantly reduce the impurity 1 content in the crude 7-hydroxy-3,4-dihydrocarbostyril, only unsuccessful crystallization experiments were performed consisting of the following solvents: water, ethyl acetate, 80% aqueous ethanol, 1-butanol, isobutylmethylketone, methanol, 2- propanol, ethanol, dichloromethane and mixtures thereof. Furthermore, derivatization of the 3,4-double bond of 7-hydroxycarbostyril by its hydroxylation, optionally by bromination or hydrogenation under normal pressure, was also attempted, unsuccessfully.

The problem of contamination of 7-hydroxy-3,4-dihydrocarbostyril IV with 7-hydroxycarbostyril 1 solves the novel process for the preparation of the highly pure 7-hydroxy-3,4-dihydrocarbostyril IV object of the invention.

- Summary of the Invention

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of 7-hydroxy-3,4-dihydrocarbostyril IV having a purity of greater than 98%, which can be used inter alia as an intermediate of production of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl ] butoxy} -3,4-dihydrocarbostyril and 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one, respectively known as aripiprazole. The process according to the invention is based on the effective purification of 7-hydroxy-3,4-dihydrocarbostyril IV, which consists in the selective reduction of the double bond of the impurity 7-hydroxycarbostyril 1 by catalytic hydrogenation, in particular hydrogenation by hydrogen gas under catalysis of Pd on activated carbon. Thus, very pure 7-hydroxy-3,4-dihydrocarbostyril is obtained, which can be used to prepare the pharmaceutical substance aripiprazole.

After a series of unsuccessful attempts to purify 7-hydroxy-3,4-dihydrocarbostyril by crystallization from various solvents and derivatizing the 3,4-double bond of 7-hydroxycarbostyril by its hydroxylation or bromination or hydrogenation under normal pressure, it has proven to be the only effective solution for preparing pure aripiprazole. selective reduction of the double bond.

Only reduction to carbostyril, not to 7-hydroxycarbostyril, is described in the literature. Among the reductions to carbostyril, the following methods are described: electrochemical reduction on Ni cathode (Helv. Chim. Acta 32, 1949, 1278), sodium reduction in methanol to produce perhydroquinoline (Chem. Ber. 19, 1886, 3302), sodium amalgam reduction in ethanol (Chem. Ber. 20, 1887, 2012), reduction with magnesium in methanol, but yielding only a 30% yield (J. Chem. Soc. Perkin Transl, 1981, 2912). Hydrogenation methods of converting carbostyril to 3,4-dihydrocarbostyril have described hydrogen reduction with platinum oxide catalysis (Heterocycles 28 (2), 1989, 1085). However, none of the above-described methods showed a sufficient effect in the purification of 7-hydroxy-3,4-dihydrocarbostyril.

Surprisingly, by far the most preferred method of purification of 7-hydroxy-3,4-dihydrocarbostyril has been the selective hydrogenation of hydrogen gas with Pd on activated carbon (according to Example 3). Under suitably selected reaction conditions, this method gave an intermediate having a purity of 99.7% and an impurity content of 1.04%. C 1 -C 4 alcohols, especially methanol, have been found to be suitable for the hydrogenation. An effective catalyst for the reaction was a Pd catalyst on activated carbon with a palladium content of 1-10% at a catalyst concentration in the reaction mixture of 1-10 wt. %, in particular at a concentration of 4% by weight. % in the reaction mixture and having a Pd content of 1.5%. Hydrogen gas can be introduced into the reaction mixture under a pressure of 0.1-10 MPa, for 3-10 hours and at a temperature of 40-100 ° C, preferably at a pressure of 3-4 MPa, for 7 hours and at a temperature of 70-80 ° C. .

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 3-chloro-3'-hydroxypropioanilide

3-Aminophenol VII (0.4 mol) was dissolved in 40 ml of dried acetone and a solution of 3-chloropropionyl chloride VIII (0.2 mol) in 40 ml of dried acetone was added dropwise to the solution while cooling in a water bath. The suspension was heated to 50 ° C and after stirring for 1 hour, the reaction mixture was poured into 300 mL of 1M hydrochloric acid. 150 ml of water was added and the mixture was stirred at room temperature. The precipitated crystals were aspirated and dried at 90 ° C. 30 g of 3-chloro-3'-hydroxypropioanilide VI (75% of theory), m.p.

Example 2

Preparation of 7-hydroxy-3,4-dihydrocarbostyril

3-Chloro-3'-hydroxypropioanilide VI (0.15 mol), aluminum chloride (1.15 mol), sodium chloride (0.3 mol) and potassium chloride (0.26 mol) were mixed and heated in an oil bath at 155-160 ° C for one hour. The mixture was removed from the bath and 750 g of ice-water mixture were poured into the mixture with stirring. Stirring resulted in a solid which was aspirated and washed with water. After drying, 87% of the crude 7-hydroxy-3,4-dihydrocarbostyril IV product was obtained. The crude product was crystallized from 120 ml of 50% aqueous ethanol with the addition of activated carbon. After filtration and cooling, the precipitated product was filtered off with suction and dried. 70% of the theoretical yield of 7-hydroxy-3,4-dihydrocarbostyril IV with a melting point of 237-238 ° C was obtained. According to HPLC analysis, this product contained 2% impurity, which was identified by LC-MS as having a molecular weight lower than 2 units than the product, i.e. the impurity is 7-hydroxycarbostyril 1. The structure was also confirmed from the NMR spectra of the sample containing more of this impurity (6%).

Example 3

Purification of 7-hydroxy-3,4-dihydrocarbostyril

2550 g of 7-hydroxy-3,4-dihydrocarbostyril containing impurity 1 (6% by HPLC) was dissolved in 35 l of methanol. To the solution was added 100 g of catalyst which contained 2.35% Pd (on dry basis) on C and 45% water. Subsequent hydrogenation was performed with hydrogen at 3.5 MPa at 75-80 ° C in an autoclave with stirring for 7 hours. After the reaction mixture was spontaneously cooled, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure to a volume of 8 liters. After cooling to -18 ° C, a first crop of 1978 g (77.5% of theory) was obtained with a purity of 99.9% according to HPLC analysis, an impurity 1 content of 0.04%.

........

The filtrate was then concentrated to 1 liter and, after cooling to -18 ° C, a second crop of 307 g (12% of theory) was obtained with HPLC purity of 99.1%, impurity 1 content of 0.06%.

Combining both parts yielded 2285 g (89.5% of theory) of 7-hydroxy-3,4-dihydrocarbostyril with a purity of 99.8% and an impurity content of 1.04%.

Claims (6)

A process for the preparation of 7-hydroxy-3,4-dihydrocarbostyril of formula IV having a purity of more than 98%, characterized in that catalytic hydrogenation is carried out to purify the impurity of 7-hydroxycarbostyril of formula 1 The process of claim 1 for obtaining 7-hydroxy-3,4-dihydrocarbostyril IV with a purity greater than 99.5%. Process according to claim 1, characterized in that the catalytic hydrogenation is carried out with hydrogen gas in the presence of a metal catalyst. The process according to claim 3, characterized in that the purification of the 7-hydroxy-3,4-dihydrocarbostyril is carried out in a solution of the C 1 to C 1 alcohol by hydrogenation with hydrogen gas in the presence of 1-10 masses. % Pd of activated carbon catalyst with a palladium content of 1 -10% at a temperature of 40-100 ° C, a pressure of 0.1-10 MPa for 3-10 hours. A process according to claim 4, characterized in that the hydrogenation is carried out in methanol in the presence of 4 masses. % Pd of activated carbon catalyst with a Pd content of 1.5%, at a temperature of 70-80 ° C, a pressure of 3-4 MPa for 7 hours. 6. A process for the preparation of 7-hydroxy-3,4-dihydrocarbostyril IV having a purity greater than 99.5%, characterized in that: a) 3-chloro-3'-hydroxypropioanilide is prepared by reaction of 3-aminophenol with 3-chloropropionyl chloride in acetone solution b) 3-chloro-3'-hydroxypropioanilide is reacted with aluminum, sodium and potassium chloride to give crude 7-hydroxy-3,4-dihydrocarbostyril IV c) the crude 7-hydroxy-3,4-dihydrocarbostyril IV is purified by recrystallization d) the recrystallized 7-hydroxy-3,4-dihydrocarbostyril is purified by catalytic hydrogenation with hydrogen gas in a C 1 -C 4 alcohol medium.