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Preparation method of quetiapine intermediate

A technology of intermediates and thiazepines, applied in the field of medicinal chemistry, can solve problems such as loss of removal and transfer, difficulty in taking out phenyl groups, etc.

Inactive Publication Date: 2015-03-25
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In industrialized production, it is difficult to take out phenyl (2-phenylthio) phenyl carbamate solid from the reactor, and there will be losses in the process of taking out and transferring
Therefore, the method reported in the prior art is defective for industrialized production

Method used

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  • Preparation method of quetiapine intermediate
  • Preparation method of quetiapine intermediate
  • Preparation method of quetiapine intermediate

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specific Embodiment approach

[0030] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0031] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0032] In the present invention, min means minute, h means hour, g means gram, ml means milliliter.

Embodiment 1

[0033] Example 1 10H-dibenzo[b,f][1,4]thiazepine Preparation of -11 Ketone

[0034] Add 3.00kg of water and 0.26kg of sodium hydroxide to the round bottom flask to control the temperature at 20°C, add 5.25kg of toluene and 1.22kg of 2-aminodiphenyl sulfide, and after the reaction solution is clarified, dissolve 1.04kg of phenyl chloroformate Add 1.00kg of toluene solution dropwise to it for 1.5h, keep warm for 3h after the dropwise addition, remove toluene by distillation under reduced pressure, add 10.06kg of polyphosphoric acid and 2.51kg of phosphorus pentoxide, raise the temperature to 90°C, react for 9h, then add 18.0kg of ice water and continue to cool down to 20°C and stir for 8h, filter to obtain a filter cake, beat with methanol and stir for 2h at room temperature, heat and crystallize at 0°C for 2h, filter, and vacuum dry at 60°C to obtain 1.21kg10H-dibenzo[b,f][ 1,4] Thiazepine -11 ketone, yield 95%, purity 99.391%.

Embodiment 2

[0035] Example 2 10H-dibenzo[b,f][1,4]thiazepine Preparation of -11 Ketone

[0036] Add 3.00kg of water and 0.26kg of sodium hydroxide to the round bottom flask to control the temperature at 30°C, add 5.25kg of toluene and 1.22kg of 2-aminodiphenyl sulfide, and after the reaction solution is clarified, dissolve 1.04kg of phenyl chloroformate Add 1.00kg of toluene solution dropwise to it for 1.5h, keep warm for 3h after the dropwise addition, add 8kg of water to wash once, remove toluene by distillation under reduced pressure, add 10.06kg of polyphosphoric acid and 2.51kg of phosphorus pentoxide, and heat up to 105 ℃, after reacting for 9 hours, add 18.0kg of ice water and continue to cool down to 25℃ and stir for 8h, filter to obtain a filter cake, beat with methanol and stir at room temperature for 2h, keep warm and crystallize at 0℃ for 2h, filter, and vacuum dry the filter cake at 60℃ to obtain 1.21kg 10H-dibenzo[b,f][1,4]thiazepine -11 ketone, yield 90.8%, purity 99.56...

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Abstract

The invention relates to a method for preparing a compound as shown in a formula (II), namely 10H-dibenzo[b,f][1,4]thiazepine-11one, through 'one-pot process'. The formula is as shown in the specification and the 10H-dibenzo[b,f][1,4]thiazepine-11one comprises a compound as shown in a formula (III) as shown in the specification. The method comprises the following steps: carrying out an acylation reaction on 2-amino diphenyl sulfide and phenyl chloroformate; and after the reaction, without post-treatment or separation of a target intermediate product in the period, adding polyphosphoric acid (PPA) for a cyclization reaction, wherein the formula III is as shown in the specification. In a process of preparing the 10H-dibenzo[b,f][1,4]thiazepine-11one, the 'one-pot process' disclosed by the invention can be used for preventing a phenyl(2-thiophenyl)phenyl carbamate solid from being moved out of a reaction kettle, simplifying the operation course of the process and reducing the consumption of the reaction intermediate product on one aspect, and on the other aspect, the 'one-pot process' can be used for achieving the yield above 90%, preferably above 95%, and achieving the high performance liquid chromatography (HPLC) purity above 99.0%.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a diphenylthiazepine Preparation method of drug-like intermediates. Background technique [0002] Quetiapine is a new generation of atypical psychiatric drugs, mainly for the treatment of schizophrenia, bipolar I mania, bipolar II depression, bipolar I depression, its chemical name is 11-[4-[2 -(2-Hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine , its chemical structure is shown in formula (Ia): [0003] [0004] In the preparation, the active ingredient of the medicine is quetiapine fumarate, which is prepared by forming a salt of quetiapine and fumaric acid, and its chemical structure is as shown in formula (I): [0005] [0006] European patents EP 240228, EP 282236 and PCT application WO 2005014590 reported that the compound represented by formula (II), 10H-dibenzo[b,f][1,4]thiazepine After -11 ketone is chlorinated with phosphorus oxychloride, it...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D281/14
CPCC07D281/16
Inventor 刘浏高峰李宇熙刘继阳
Owner SUNSHINE LAKE PHARM CO LTD
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