SI21747A - SYNTHESIS OF 2-METHYL-4-(4-METHYL-1-PIPERAZINYL)-10H-THIENO(2,3 b)(1,5)BENZODIAZEPE - Google Patents

Abstract

An improved two-stage procedure is described in the invention for synthesis of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno(2,3-b)(1,5)benzodiazepine via the purified intermediate 2-methyl-4-(1-piperazinyl)-10H-thieno(2,3-b)(1,5)benzodiazepine.

Description

Synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -1 O -pyrimidine [2,3-b]] [1,5] benzodiazepine

The field of technology

The invention falls within the field of chemical synthesis and relates to a process for the synthesis of olanzapine.

In a narrower sense, the present invention addresses the synthesis of olanzapine via an intermediate in a synthesis that is converted to olanzapine by a novel synthetic process.

A technical problem

There is an ongoing need to prepare a pharmaceutical ingredient of a quality suitable for incorporation into the final drug in the most technologically and economically efficient manner possible. The purpose of the invention is to prepare 2-methyl-4- (4-methyl-1-piperazinyl) -10 / 7-thieno [2,3b] [1,5] benzodiazepine from 4-amino-2-methyl-10/7-thieno [2,3-b] [1,5] benzodiazepine hydrochloride of such quality that it is suitable for incorporation into the final drug.

The state of the art

Olanzapine is a pharmaceutical substance that belongs to the group of antipsychotics, it is used to treat various mental illnesses and conditions, such as. central nervous system disorders, schizophrenia, hallucinations, acute mania, depression and the like.

Chemical belongs to the group of benzodiazepines and is 2-methyl-4- (4-methyl-1-piperazinyl) 10/7-thieno [2,3-b] [1,5] benzodiazepine (formula 1).

Olanzapine and its analogs were first mentioned within the general formula in patent GB 1.533.235, which mentions general alkylation for the synthesis of 4-substituted derivatives; methylation is not explicitly mentioned. The reactions are carried out in ethanol using triethylamine as the base and R-Cl as the alkylating agent, with R representing different radicals.

GB 1,533,235 mentions two synthetic routes with general formulas, which are described in more detail in EP 454,436. In both, the last step is the reaction with Nmethylpiperazine. In the first synthesis route, N-methylpiperazine is reacted with 4-amino-2-methyl-10/7 thieno [2,3-h] [1,5] benzodiazepine (Scheme 1) - olanzapine is formed.

/ —Ni'H:

() nh ₂ n— ⁷

N = X ,, ----- 'j! —H HN NCil /

Scheme 1

In the second synthesis route, N-methylpiperazine is reacted with methyl 2- (2-aminoanilino) -5-methylthiophene-3-carboxylate (Scheme 2) in the presence of titanium tetrachloride.

Mih

N— ⁷ '

Ml '6OOCH3 / ~ N = <

HN NCH ₃ / '' M i'r'L

..... in \ H ------- ► N '' 's

H S '' - TiCI ₄ H

Scheme 2

The product, olanzapine, is purified by recrystallization from acetonitrile by first synthesis, and olanzapine prepared by the second synthesis route is purified by florisil column chromatography and acetonitrile recrystallization.

A major problem with both synthesis pathways is the coloration of the final product, which is due to sulfur or thiophene chemistry in the first stages of both synthesis pathways. If the intermediate is colored green or dark brown in the last step, this color shade is definitely transferred to the final olanzapine without effective cleaning. The staining problem of finished olanzapine has already been described in US Patent Nos. 5,229,382 and EP 733 635, which states that even after purification with activated charcoal, olanzapine may still contain traces of unwanted color.

The reaction between 4-amino-2-methyl-10/7-thieno [2,3-b] [1,5] benzodiazepine and piperazine was first mentioned in Bioorganic & Medicinal Chemistry Letters, Vol. 7, No. 1 1, pp. 25-30, 1997 and expired in a 1/4 ratio DMSO / toluene mixture with excess piperazine. The downside of the reaction in DMSO at high temperature is the coloration of the product.

WO 04/847 discloses a process for the reductive N-methylation of desmethylolanzapine (prepared by the same procedure as in the previous reference) with formaldehyde in the presence of a reducing agent, preferably a metal borohydride. Direct methylation with methyl iodide in methanol using potassium carbonate as a base is also mentioned, the weak point of the reaction being the low yield and poor quality of the final product (content only 90%).

Description of the new solution with implementation examples

The invention discloses a two-step synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 Hthieno [2,3-b] [1,5] benzodiazepine from 4-amino-2-methyl-10 H -b thieno [2,3-b] [1,5b-benzodiazepine hydrochloride via intermediate, 2-methyl-4- (1-piperazinyl) -10 H -thieno [2,3b] [1,5] benzodiazepine (Scheme 3).

NH _with —NCH-, \

nh ₂

N ~ \ \ H s

NH quality (which is

MI s

Scheme 3

Surprisingly, olanzapine was obtained with a pharmaceutical rate of at least 98%) and with a corresponding, i.e., a yellow, yellow color also from a darker, brown or green colored starting compound, 4-amino-2-methyl-10 / - / - thiene [ 2,3-b] [1,5] benzodiazepine hydrochloride when prepared by two-step synthesis via isolated desmethylolanzapine instead of the usual one-step process with Nmethylpiperazine as a reagent.

The first step, the reaction between 4-amino-2-methyl-10 H -thieno [2,3-b] [1,5] benzodiazepine hydrochloride and piperazine, has already been described in the 1/4 DMSO / toluene mixture , with excess piperazine. We have found that it is preferable to use at least one branched or unbranched aliphatic alcohol at high boiling point, preferably above 100 ° C, more preferably above 115 ° C, for the reaction rate alone as well as for the reaction yield, e.g. nbutanol, either at least one such alcohol alone or as a solvent mixture containing such alcohol and at least one other high boiling solvent, preferably an aromatic hydrocarbon such as e.g. xylene, toluene, ethylbenzene, anisole or the like, e.g. mixture of / i-butanol and xylene or n-butanol and toluene in n-butanol / aromatic hydrocarbon ratios = 30/70 to 100/0, preferably in ratios of 40/60 to 70 / 30. Instead of excess piperazine, the bases may be used as bases also other inorganic or organic bases, preferably tertiary amines, such as e.g. triethylamine, ethyldiisopropylamine and diazabicyclooctane. If the reaction is conducted in a medium containing n-butanol, then the hot water is obtained by precipitation of the resulting 2-methyl-4- (1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (desmethylolanzapine). we get a product that has already lost its darker brown or green hues, which are further removed by washing with ethyl acetate. Hot water has a temperature of between about 40 and about 70 ° C, preferably between about 45 and about 55 ° C. Using warm water, the sticky, lumpy precipitate dissolves into fine smaller particles. This achieves two: better filterability and better product color.

The second stage of synthesis is the methylation of piperazine nitrogen. Different methylating agents, such as e.g. dimethyl sulfate or methyl sulfonates, e.g. methyl toluenesulfonate, methyl methanesulfonate, methyl trifluoromethanesulfonate, or methyl halides, preferably methyl iodide. The reaction proceeds in various organic solvents selected from ethers, ketones, amides, nitriles or alcohols, for example: tetrahydrofuran, acetone, dimethylformamide, acetonitrile and the like. Basic conditions are required for the reaction itself. A wide variety of amines can be used, including, but not limited to, triethylamine, ethyldiisopropylamine and diazabicyclooctane, or strong alkaline or alkaline earth metal bases such as e.g. hydroxides, hydrides or alcoholates, including, for example, sodium hydride, calcium hydride, potassium t-butoxide, sodium potassium hydroxide, as well as other inorganic bases such as potassium or sodium carbonate. Following the reaction of desmethylolanzapine with olanzapine under such conditions, a product of a bright yellow color is obtained without a brown or green tint that does not need to be further removed by further purification.

Olanzapine obtained by the process of the invention is suitable for pharmaceutical use in any pharmaceutical form.

The following embodiments are explained, but not limited in any way, by the invention:

Example 1

2-methyl-4- (1-piperazinyl) -10 / 7-thienor2,3-iber t, 51benzodiazepine

10.7 g of commercial grade 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride (0.040 mol) were suspended in 70 ml / 7-butanol and 30 ml. of xylene, piperazine (31.5 g; 0.36 mol) was added, heated to reflux and stirred at this temperature for a further 4 hours, the end of the reaction was determined by HPLC. After the reaction was complete, the solvents were evaporated and 200 ml of warm water was added, the precipitate was filtered off and washed with 20 ml of ethyl acetate. 11.0 g of product (92%) were obtained.

Example 2

2-methyl-4- (1-piperazinyl) -10 / 7-thienor2,3-bile 1,51benzodiazepine

10.7 g of commercial grade 4-amino-2-methyl-10/7-thieno [2,3-b] [1,5] benzodiazepine hydrochloride (0.040 mol) was suspended in 100 ml of n-butanol, added. piperazine (31.5 g; 0.36 mol), heated to reflux and stirred at this temperature for a further 8 hours, the end of the reaction was determined by HPLC. After the reaction was complete, the solvent was evaporated and 200 ml of warm water was added, the precipitate was filtered off and washed with 20 ml of ethyl acetate. 11.7 g of product (97%) were obtained.

Example 3

2-Methyl-4- (1-piperazinyl) -10H-thieno [2,3-b1,51 benzodiazepine

10.7 g of 4-amino-2-methyl-10 H -thieno [2,3-b] [1,5] benzodiazepine hydrochloride (0.040 mol) of commercial quality and dark brown color were suspended in 50 ml of n-butanol and 50 ml of toluene, piperazine (31.5 g; 0.36 mol) was added, heated to reflux and stirred at this temperature for a further 7 hours, the end of the reaction was determined by HPLC. After the reaction was complete, the solvents were evaporated and 200 ml of warm water was added, the precipitate was filtered off and washed with 20 ml of ethyl acetate. 9.7 g of product (81%) were obtained.

Example 4

2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] 1,51benzodiazepine 2-methyl-4- (1-piperazinyl) -10B-thieno [2,3-b] [ 1,5] benzodiazepine (0.034 mol) was dissolved in 240 ml of tetrahydrofuran and cooled to -10 ° C with stirring. We added

9.4 ml of triethylamine and 5 ml (0.080 mol) of methyl iodide. The reaction mixture was stirred for 4 hours at -10 ° C, and the end of the reaction was determined by HPLC. After completion of the reaction, 500 ml of demineralized water were added and the tetrahydrofuran was evaporated, and the yellow crystals of the title compound were crystallized. The precipitate was filtered off and washed with water, yielding 8.6 g of olanzapine (yield: 82%).

Example 5

2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] -1,51-benzodiazepine 2-methyl-4- (1-piperazinyl) -10 H -thieno [2. 3-b] [1,5] benzodiazepine (0.034 mol) was dissolved in 240 ml of tetrahydrofuran and cooled to -15 ° C with stirring. 3 g of sodium hydroxide and 5 ml (0.080 mol) of methyl iodide were added. The reaction mixture was stirred for 4 hours at -15 [deg.] C, and the end of the reaction was determined by HPLC. After completion of the reaction, 500 ml of demineralized water were added and the tetrahydrofuran was evaporated, and the yellow crystals of the title compound were crystallized. The precipitate was filtered off and washed with water, yielding 10.3 g of olanzapine (yield: 98%).

Example 6

2-methyl-4- (4methyl-1-piperazinyl) -10H-thienor2,3-b1 [1,5benzodiazepine 2-methyl-4- (1-piperazinyl) -10 H -thieno [2,3-b] ] [1,5] benzodiazepine (0.034 mol) was dissolved in 120 ml of tetrahydrofuran and cooled to -10 ° C with stirring. 1.6 g of sodium hydride and 5 ml (0.080 mmol) of methyl iodide were added. The reaction mixture was stirred for 3 hours at -10 ° C, and the reaction was determined by HPLC. After completion of the reaction, 60 ml of demineralized water were added and tetrahydrofuran was evaporated, 200 ml of methanol were added, and the yellow crystals of the title compound were crystallized. The precipitate was filtered off and washed with water, yielding 10.3 g of olanzapine (yield: 98%).

Example 7

2-methyl-4- (4methyl-1-piperazinyl) -10H-thienof2,3-bir, 51benzodiazepine 2-methyl-4- (1-piperazinyl) -10H-thieno [2,3-b] [ 1,5] benzodiazepine (0.034 mol) was dissolved in 240 ml of tetrahydrofuran and cooled to 0 ° C with stirring. 4.48 g of potassium ί-butoxide and 5 ml (0.080 mmol) of methyl iodide were added. The reaction mixture was stirred for 2 hours at 0 ° C, and the reaction was determined by HPLC. After completion of the reaction, 200 ml of demineralized water was added and the tetrahydrofuran was evaporated, and the yellow crystals of the title compound were crystallized. The precipitate was filtered off and washed with water to give 10.4 g of olanzapine (yield: 99%).

Example 8

2-methyl-4- (4methyl-1-piperazinyl) -10 H -thieno [2,3-b] 1,51benzodiazepine 2-methyl-4- (1-piperazinyl) -10 H -thieno [2,3 -b] [1,5] benzodiazepine (0.034 mol) was dissolved in 200 ml of methanol. 20 g of potassium carbonate and 4.4 ml (0.046 mmol) of dimethyl sulfate were added. The reaction mixture was stirred for 2 hours at 25 ° C, and the end of the reaction was determined by HPLC. After completion of the reaction, 350 ml of demineralized water were added and the methanol was evaporated, and the yellow crystals of the title compound were crystallized. The precipitate was filtered off and washed with water to give 6.3 g of olanzapine (yield: 60%).

Example 9

2-methyl-4- (4methyl-1-piperazinyl) -10 H -thieno [2,3-bF 1,51benzodiazepine 2-methyl-4- (1-piperazinyl) -10H-thieno [2,3- b] [1,5] benzodiazepine (0.034 mol) was dissolved in 200 ml of acetone and cooled to -10 ° C with stirring. 20 g of potassium carbonate and 4.4 ml (0.046 mmol) of dimethyl sulfate were added. The reaction mixture was stirred for 4 hours at -10 ° C, and the end of the reaction was determined by HPLC. After completion of the reaction, 350 ml of demineralized water were added and acetone was evaporated, and the yellow crystals of the title compound were crystallized. The precipitate was filtered off and washed with water to give 4.8 g of olanzapine (yield: 46%).

Claims (26)

Patent claims A process for the synthesis of 2-methyl-4- (1-piperazinyl) -10H-thieno [2,3-h] [1,5] benzodiazepine from 4-amino-2-methyl-10H-thieno [2,3- b] [1,5] benzodiazepine or its salts and bases, characterized in that it is carried out in a solvent containing at least one high boiling point aliphatic alcohol. Process for the synthesis of 2-methyl-4- (1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine according to claim 1, characterized in that the solvent contains n-butanol. Process for the synthesis of 2-methyl-4- (1-piperazinyl) -10H-thieno [2,3-phe] [1,5] benzodiazepine according to claims 1-2, characterized in that the solvent contains n-butanol and at least one high boiling point aromatic hydrocarbon. Process for the synthesis of 2-methyl-4- (1-piperazinyl) -1 OH-thieno [2,3-bj [1,5] benzodiazepine according to claim 3, characterized in that the high boiling point aromatic hydrocarbon is xylene or toluene. 5. Process for the synthesis of 2-methyl-4- (1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine from 4-amino-2-methyl-10H-thieno [2 , 3-b] [1,5] benzodiazepine and bases according to claims 1-4, characterized in that the base is excess piperazine or another inorganic or organic base. 6. Process for the synthesis of 2-methyl-4- (1-piperazinyl) -10H-thieno [2,3-h] [1,5] benzodiazepine from 4-amino-2-methyl-10H-thieno [2,3 -b] [1,5] benzodiazepines and bases according to claim 5, characterized in that the base is selected from the group of tertiary amines. Process for the synthesis of 2-methyl-4- (1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine according to claims 1-6, characterized in that it is continued by warm precipitation water and washing with ethyl acetate. 8. A process for the synthesis of 2-methyl-4- (1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine from 4-amino-2-methyl-10H-thieno [2, 3-b] [1,5] benzodiazepine or its salts and bases, characterized by continued precipitation with warm water and washing with ethyl acetate. 9. A process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine, characterized in that it is synthesized from 2-Methyl-4- (1-piperazinyl) -10H10 thieno [2,3-b] [1,5] benzodiazepine in light color with no darker brown or green hues. Process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine, characterized in that, as a raw material, 2 -methyl-4- (1-piperazinyl) -1 OH-thieno [2,3-b] [1,5] benzodiazepine, the product prepared according to the procedure of claims 1-8 is used. Process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine according to claims 9-10, characterized in that the agent is for methylation in this process methyl iodide. 12. A process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine according to claims 9-10, characterized in that the methylating agent in this process is dimethyl sulfate. Process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine according to claims 9-10, characterized in that in this process the methylating agent is selected from the group of methyl sulfonates. Process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine according to claims 9-13, characterized in to use ethyldiisopropylamine or diazabicyclooctane as a base in this process. 15. A process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine according to claims 9-13, characterized in to use as strong bases alkali or alkaline earth metals in the process. A process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine according to claim 15, characterized in that Alkali metal alcoholates are used as a base in this process. Process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 / 7-thieno [2,3-b] [1,5] benzodiazepine according to claim 16, characterized in that alkali metal alcoholate uses potassium f-butoxide in this process. 18. A process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine according to claim 15, characterized in that as a base in use alkali metal or alkaline earth metal hydride in this process. A method for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine according to claim 18, characterized in that Sodium hydride is used as a base in this process. 20. A process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine according to claim 15, characterized in that uses alkali metal hydroxide in this process. 21. A process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine according to claim 20, characterized in that Sodium hydroxide is used as a base in this process. Process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine according to claim 20, characterized in that Potassium hydroxide is used as a base in this process. 23. A process for the synthesis of 2-methyl-4- (4-methyl-1-piperazinyl) -10 H -thieno [2,3-b] [1,5] benzodiazepine according to claims 9-22, characterized in that the solvents used in this process are aprotic organic solvents selected from the group acetonitrile, acetone, tetrahydrofuran, diethyl ether or diisopropylether. A pharmaceutical formulation with olanzapine and other pharmaceutically acceptable excipients, comprising olanzapine prepared according to the methods of claims 9-23. 25. The use of olanzapine, characterized in that it is prepared according to the methods of claims 9-23, for the preparation of the pharmaceutical form together with other pharmaceutically acceptable excipients. Use of olanzapine, characterized in that it is prepared according to the methods of claims 9-23, for the preparation of a medicament for the treatment of various mental illnesses and conditions.