Process for the preparation of a quetiapine intermediate

Abstract

The application discloses a preparation method of a quetiapine intermediate, which comprises the following steps: taking o-aminothiophenol potassium salt as a starting material, condensing with o-chlorobenzoic acid, then performing intramolecular cyclization, and refining to obtain a target compound, i.e. dibenzo[b,f][1,4]thiazepine-11-[10H] ketone. The application optimizes process operation steps, is more convenient to operate, is safer under milder reaction conditions, has fewer side reactions, improves yield, and has a total yield of more than 85%. The obtained product is high in purity, good in quality, friendly to environment, low in pollution, and low in production cost, and is more suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to a method for preparing quetiapine intermediate. Background Technology

[0002] Quetiapine intermediate: dibenzo[b,f][1,4]thiazepine-11-[10H]one, CAS number [3159-07-7], molecular structure as follows:

[0003]

[0004] Dibenzo[b,f][1,4]thiazolide-11-[10H]one is a key intermediate in the synthesis of quetiapine. Quetiapine, chemically named 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzothiazolide hemifumarate, was developed by AstraZeneca in the UK and approved by the US FDA in 1997 as a first-line atypical antipsychotic. Domestically produced quetiapine was approved for marketing in 2000 and is effective in treating schizophrenia.

[0005] The preparation of dibenzo[b,f][1,4]thiazazo-11-[10H]one mainly involves the following methods:

[0006] 1. Chinese patent CN1367782A discloses a method for preparing dibenzothiazazolide derivatives. This patent uses o-chloronitrobenzene as a starting material, which is condensed with thiosalicylic acid to obtain a 2-nitro-2'-carboxyphenyl sulfide derivative. After hydrogenation reduction, a 2-amino-2'-carboxyphenyl sulfide derivative is obtained, which is then dehydrated and condensed to obtain a dibenzothiazazolide derivative. This method uses catalytic hydrogenation, which requires high-end equipment and uses precious metal catalysts, resulting in high production costs.

[0007] 2. Chinese patent CN103788014A discloses a method for preparing a quetiapine intermediate. This patent uses 2-nitro-2'-carboxy-diphenyl sulfide as the starting material, and obtains the target compound dibenzo[b,f][1,4]thiazazo-11-[10H]one through carboxyl esterification, nitro hydrogenation reduction, and ester ammonolysis cyclization. This method also involves catalytic hydrogenation, which requires high-end equipment and involves many steps, resulting in high cost. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention provides a method for preparing a quetiapine intermediate, comprising the following steps:

[0009] Potassium anaminobenzyl thiophenol was dissolved in the first solvent, and an anaminobenzoic acid was added to carry out a condensation reaction. The mixture was cooled, crystallized, filtered, and dried to obtain a grayish-white crystalline product, 2-amino-2'-carboxylic diphenyl sulfide.

[0010] 2-Amino-2'-carboxylated diphenyl sulfide was added to a second solvent to carry out an intramolecular cyclization reaction. After cooling, crystallization, filtration and drying, crude dibenzo[b,f][1,4]thiazazepine-11-[10H]one was obtained.

[0011] The crude dibenzo[b,f][1,4]thiazolactone-11-[10H]one was purified by adding a third solvent, cooled, crystallized, filtered, and dried to obtain the target compound, quetiapine intermediate dibenzo[b,f][1,4]thiazolactone-11-[10H]one.

[0012] Preferably, the first solvent is selected from one or more of sulfolane, DMF, DMSO, toluene, and xylene (preferably DMF).

[0013] Preferably, the mass-to-volume ratio of the potassium anthiophene to the first solvent is 1:5 to 15 (preferably 1:8).

[0014] Preferably, the molar ratio of the potassium anthiophene to the anthiocyanate is 1:1 to 2 (preferably 1:1.1 to 1.5).

[0015] Preferably, the condensation reaction is carried out at a temperature of 60–150°C (preferably 100–120°C) and for a reaction time of 2–10 hours (preferably 5 hours).

[0016] Preferably, the second solvent is selected from one or more of toluene, xylene, and glacial acetic acid (preferably glacial acetic acid).

[0017] Preferably, the mass ratio of the 2-amino-2'-carboxydiphenyl sulfide to the second solvent is 1:5 to 15 (preferably 1:10).

[0018] Preferably, the cyclization reaction is carried out at a temperature of 80–150°C (preferably 100–120°C) and for a time of 5–10 hours (preferably 8 hours).

[0019] Preferably, the third solvent is selected from one or more of methanol, ethanol, acetone, and isopropanol (preferably ethanol).

[0020] Preferably, the weight ratio of the crude product to the third solvent is 1:5 to 10 (preferably 1:5); the refining temperature is 70 to 80°C.

[0021] The chemical reaction formula of this invention is as follows:

[0022]

[0023] This invention uses potassium anthiophene as the starting material, which is condensed with anthiochlorobenzoic acid, then cyclized intramolecularly and purified to obtain the target compound dibenzo[b,f][1,4]thiazazepine-11-[10H]one.

[0024] The advantages and beneficial effects of this invention are as follows: It provides a method for preparing the quetiapine intermediate dibenzo[b,f][1,4]thiazazepine-11-[10H]one, which optimizes the process operation steps, makes the operation simpler, the reaction conditions are milder and safer, has fewer side reactions, improves the yield, and the total yield reaches more than 85%. The obtained product has high purity and good quality, is environmentally friendly with less pollution, and reduces production costs, making it more suitable for industrial production. Detailed Implementation

[0025] The specific embodiments of the present invention will be further described below with reference to examples. These examples are only used to more clearly illustrate the technical solutions of the present invention and should not be construed as limiting the scope of protection of the present invention.

[0026] This invention provides a method for preparing the quetiapine intermediate dibenzo[b,f][1,4]thiazazepine-11-[10H]one, comprising the following steps:

[0027] Potassium anaminothiophene was dissolved in a first solvent, and o-chlorobenzoic acid was added to carry out a condensation reaction. The mixture was cooled, crystallized, filtered, and dried to obtain a grayish-white crystalline product, 2-amino-2'-carboxylic diphenyl sulfide. The first solvent was selected from one or more of sulfolane, DMF, DMSO, toluene, and xylene (preferably DMF). The mass-to-volume ratio of potassium anaminothiophene to the first solvent was 1:5 to 15 (preferably 1:8). The molar ratio of potassium anaminothiophene to o-chlorobenzoic acid was 1:1 to 2 (preferably 1:1.1 to 1.5). The reaction temperature of the condensation reaction was 60 to 150°C (preferably 100 to 120°C), and the reaction time was 2 to 10 hours (preferably 5 hours).

[0028] 2-Amino-2'-carboxylated diphenyl sulfide was added to a second solvent to carry out an intramolecular cyclization reaction. The mixture was cooled, crystallized, filtered, and dried to obtain crude dibenzo[b,f][1,4]thiazazepine-11-[10H]one. The second solvent was selected from one or more of toluene, xylene, and glacial acetic acid (preferably glacial acetic acid). The mass ratio of 2-amino-2'-carboxylated diphenyl sulfide to the second solvent was 1:5 to 15 (preferably 1:10). The cyclization reaction was carried out at a temperature of 80 to 150°C (preferably 100 to 120°C) and a reaction time of 5 to 10 hours (preferably 8 hours).

[0029] The crude dibenzo[b,f][1,4]thiazo-11-[10H]one was purified by adding it to a third solvent, followed by cooling, crystallization, filtration, and drying to obtain the target compound quetiapine intermediate dibenzo[b,f][1,4]thiazo-11-[10H]one. The third solvent was selected from one or more of methanol, ethanol, acetone, and isopropanol (preferably ethanol). The weight ratio of the crude product to the third solvent was 1:5 to 10 (preferably 1:5). The purification temperature was 70 to 80°C.

[0030] Specific embodiments of the present invention are as follows:

[0031] 1. Obtain 2-amino-2'-carboxydiphenyl sulfide:

[0032] Example 1

[0033] 32.84 g (0.2 mol) of potassium o-aminobenzyl thiophene and 263 mL of DMF were added to a 500 mL four-necked flask and stirred and heated to dissolve. 34.5 g (0.22 mol) of o-chlorobenzoic acid was added and stirred and heated to 100 °C. The reaction was carried out for 5 hours, cooled slightly, and water was added at about 80 °C to crystallize. The crystals were filtered at 20 °C and dried to obtain 45.57 g of 2-amino-2'-carboxylic diphenyl sulfide, with a yield of 93% and a purity of 99.2% as determined by HPLC.

[0034] Example 2

[0035] 32.84 g (0.2 mol) of potassium o-aminobenzyl thiophene and 263 mL of toluene were added to a 500 mL four-necked flask and stirred and heated to dissolve. 34.5 g (0.22 mol) of o-chlorobenzoic acid was added and stirred and heated to 100 °C. The reaction was carried out for 5 hours, cooled slightly, and water was added at about 80 °C to crystallize. The crystals were filtered at 20 °C and dried to obtain 35 g of 2-amino-2'-carboxylic diphenyl sulfide, with a yield of 71.4% and a purity of 98.5% as determined by HPLC.

[0036] Example 3

[0037] 49.26 g (0.3 mol) of potassium o-aminobenzyl thiophene and 394 mL of DMF were added to a 1000 mL four-necked flask and stirred and heated to dissolve. 51.65 g (0.33 mol) of o-chlorobenzoic acid was added and stirred and heated to 100 °C. The reaction was carried out for 5 hours, cooled slightly, and water was added at about 80 °C to crystallize. The crystals were filtered at 20 °C and dried to obtain 68.7 g of 2-amino-2'-carboxylic diphenyl sulfide, with a yield of 93.5% and a purity of 99.% as determined by HPLC.

[0038] Example 4

[0039] 32.84 g (0.2 mol) of potassium o-aminobenzyl thiophene and 263 mL of DMF were added to a 500 mL four-necked flask and stirred and heated to dissolve. 46.95 g (0.3 mol) of o-chlorobenzoic acid was added and stirred and heated to 100 °C. The reaction was carried out for 5 hours, cooled slightly, and water was added at about 80 °C to crystallize. The crystals were filtered at 20 °C and dried to obtain 46 g of 2-amino-2'-carboxylic diphenyl sulfide, with a yield of 93.87% and a purity of 99.1% as determined by HPLC.

[0040] 2. Crude dibenzo[b,f][1,4]thiazo-11-[10H]one was obtained:

[0041] Example 5

[0042] 45.57 g (0.186 mol) of 2-amino-2'-carboxylated diphenyl sulfide and 456 g of glacial acetic acid were added to a 1000 ml four-necked flask. The mixture was stirred and heated to reflux for 8 hours for cyclization. After cooling to 25 °C, the mixture was filtered and dried to obtain 41 g of crude dibenzo[b,f][1,4]thiazepine-11-[10H]one, with a yield of 97% and a purity of 99% as determined by HPLC.

[0043] Example 6

[0044] 45.57 g (0.186 mol) of 2-amino-2'-carboxylated diphenyl sulfide and 456 g of xylene were added to a 1000 ml four-necked flask. The mixture was stirred and heated to reflux for 8 hours for cyclization. After cooling to 25 °C, the mixture was filtered and dried to obtain 36 g of crude dibenzo[b,f][1,4]thiazepine-11-[10H]one, with a yield of 79.1% and a purity of 99% as determined by HPLC.

[0045] 3. The intermediate dibenzo[b,f][1,4]thiazo-11-[10H]one, the target compound quetiapine, was obtained:

[0046] Example 7

[0047] 41 g of crude dibenzo[b,f][1,4]thiazolactone-11-[10H]one and 205 g of ethanol were added to a 500 ml four-necked flask. The mixture was stirred and heated to reflux, and kept at reflux for 2 hours. After cooling, the mixture was filtered at 25 °C and dried to obtain 40 g of the target compound, quetiapine intermediate dibenzo[b,f][1,4]thiazolactone-11-[10H]one. The purified yield was 97.6%, and the purity was 99.9% according to HPLC analysis.

[0048] Example 8

[0049] 41 g of crude dibenzo[b,f][1,4]thiazolactone-11-[10H]one and 205 g of methanol were added to a 500 ml four-necked flask. The mixture was stirred and heated to reflux, and kept at reflux for 2 hours. After cooling, the mixture was filtered at 25 °C and dried to obtain 38.5 g of the target compound, quetiapine intermediate dibenzo[b,f][1,4]thiazolactone-11-[10H]one. The purified yield was 93.9%, and the purity was 99.9% according to HPLC analysis.

[0050] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A process for the preparation of an intermediate of quetiapine characterized in that, The method comprises the following steps: Potassium o-aminothiophenol is dissolved in a first solvent, and o-chlorobenzoic acid is added for condensation reaction, cooling, crystallization, suction filtration and drying to obtain off-white crystalline 2-amino-2'-carboxy diphenyl sulfide; the first solvent is selected from DMF; the mass and volume ratio of the potassium o-aminothiophenol and the first solvent is 1:8; the molar ratio of the potassium o-aminothiophenol and the o-chlorobenzoic acid is 1:1.1-1.5; the condensation reaction is carried out at a temperature of 100-120 ℃ for 5 hours; 2-amino-2'-carboxy diphenyl sulfide is added into a second solvent for intramolecular cyclization reaction, cooling, crystallization, suction filtration and drying to obtain crude dibenzo[b,f][1,4]thiazepine-11-[10H] ketone; the second solvent is selected from glacial acetic acid; the mass ratio of the 2-amino-2'-carboxy diphenyl sulfide and the second solvent is 1:10; the cyclization reaction is carried out at a temperature of 100-120 ℃ for 8 hours; The crude dibenzo[b,f][1,4]thiazepine-11-[10H] ketone is added into a third solvent for purification, cooling, crystallization, suction filtration and drying to obtain the target compound quetiapine intermediate dibenzo[b,f][1,4]thiazepine-11-[10H] ketone; the third solvent is selected from ethanol; the weight ratio of the crude product and the third solvent is 1:5; the purification is carried out at a temperature of 70-80 ℃.

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