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Preparation method of 11-chlorodibenzo[b,f][1,4]thiazepine in presence of Vilsmeier reagent

A technology for thiazepine and chlorodiphenyl, which is applied in the field of preparing 11-chlorodibenzo[b,f][1,4]thiazepine and can solve the problem of reducing the safety of quetiapine hemi-fumarate , thionyl chloride and oxalyl chloride are highly toxic, harsh reaction conditions, etc., to achieve the effects of good promotion and application prospects, short reaction time, and simple post-treatment

Active Publication Date: 2014-05-21
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are following shortcoming in the method of above report: 1. reaction conditions are harsh, need down to-25 ℃ as temperature of reaction; 2. chlorination agent phosphorus oxychloride, phosphorus pentachloride etc. can cause phosphorus pollution to environment; Sulfone and oxalyl chloride have disadvantages such as high toxicity and instability; ④ Some amine compounds are used as acid-binding agents in the synthesis process, which increases the production cost; ⑤ The reaction time is longer
These shortcomings not only greatly reduce the safety of quetiapine hemifumarate in industrialized production, but also increase the production cost

Method used

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  • Preparation method of 11-chlorodibenzo[b,f][1,4]thiazepine in presence of Vilsmeier reagent
  • Preparation method of 11-chlorodibenzo[b,f][1,4]thiazepine in presence of Vilsmeier reagent
  • Preparation method of 11-chlorodibenzo[b,f][1,4]thiazepine in presence of Vilsmeier reagent

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Experimental program
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Effect test

Embodiment 1

[0019] To a 100mL three-neck flask equipped with a thermometer, a constant pressure dropping funnel and mechanical stirring, add 6.81g (30mmol) of 10H-dibenzo[b,f][1,4]thiazepin-11-one, 7.43 g (25 mmol) BTC, 0.18 g (2.4 mmol) DMF and 50 mL toluene. Heating to toluene reflux (112°C) for 3.0 hours stopped the reaction, spin-dried the system under reduced pressure to obtain a brown viscous liquid, recrystallized with toluene, precipitated a solid, and washed with petroleum ether after suction filtration to obtain a white solid product which was 11-chloro Dibenzo[b,f][1,4]thiazepine, dried to obtain 6.76g. Melting point: 104~105°C, yield is 92%.

[0020] white solid; 1 H NMR (400MHz, CDCl 3 ):=7.15(t,J=8.0Hz,1H),7.25~7.45(m,6H),7.72(d,J=7.5Hz,1H); 13 C NMR (100MHz, CDCl 3 ):125.7,127.2,127.5,128.4,129.3,129.7,131.8,132.4,132.5,137.7,138.8,146.0,154.6.MS(ESI):m / z(%)=245(100),247(37)[ M+2] +

Embodiment 2

[0022] To a 100mL three-neck flask equipped with a thermometer, a constant pressure dropping funnel and mechanical stirring, add 6.81g (30mmol) of 10H-dibenzo[b,f][1,4]thiazepin-11-one, 5.94 g (20 mmol) BTC, 0.22 g (3.0 mmol) DMF and 50 mL toluene. Heated to 90°C, stopped the reaction after 4.0 hours, spin-dried the system under reduced pressure to obtain a brown viscous liquid, recrystallized with toluene, precipitated a solid, and washed with petroleum ether after suction filtration to obtain a white solid product which was 11-chlorodibenzo [b,f][1,4]thiazepine, dried to obtain 6.69g. Melting point: 103~105°C, yield is 91%. Physical property data is with embodiment 1.

Embodiment 3

[0024] Add 6.81g (30mmol) of 10H-dibenzo[b,f][1,4]thiazepin-11-one, 4.46 (15 mmol) BTC, 0.26 g (3.6 mmol) DMF and 50 mL toluene. Heating to 70°C, the reaction was stopped after 5.0 hours, and the system was spin-dried under reduced pressure to obtain a brown viscous liquid, which was recrystallized with toluene, and a solid was precipitated. After suction filtration, it was washed with petroleum ether to obtain a white solid product which was 11-chlorodibenzo [b,f][1,4]thiazepine, dried to obtain 6.62g. Melting point: 104~106°C, yield is 90%. Physical property data is with embodiment 1.

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Abstract

The invention discloses a preparation method of 11-chlorodibenzo[b,f][1,4]thiazepine in presence of a Vilsmeier reagent. The preparation method comprises the following steps: by using 10H-dibenzo[b,f][1,4]thiazepine-11-one as shown in a structural formula (I) and the Vilsmeier reagent as shown in a structural formula (III) as raw materials, preparing the 11-chlorodibenzo[b,f][1,4]thiazepine as shown in the structural formula (II) through a heating reaction in an organic solvent, wherein the Vilsmeier reagent is prepared from di-(trichloromethyl)carbonic ester as shown in a structural formula (a) and DMF (Di-Methyl Formamide) as shown in a structural formula (b). The preparation method provided by the invention has the advantages of short reaction time, simplicity and convenience in operation, simple post-treatment, less pollution and low cost and the like and is a chemical synthesis method with a better popularization and application prospect.

Description

(1) Technical field [0001] The invention relates to a method for preparing 11-chlorodibenzo[b,f by heating reaction of novel Vilsmeier reagent and 10H-dibenzo[b,f][1,4]thiazepine-11-one in a solvent. ][1,4] Thiazepine method. (2) Technical background [0002] Quetiapine hemifumarate is a novel thienazine antipsychotic that interacts with multiple neurotransmitter receptors. The drug was developed by British AstraZeneca, and has strong antipsychotic effect. The drug has the advantages of good oral absorption and complete metabolism. It is a basic drug for clinical treatment of schizophrenia. Among them, 11-chlorodibenzo[b,f][1,4]thiazepine with the structure of formula (II) is the key intermediate of the drug. [0003] [0004] Prior to the present invention, the chlorinating agents with synthetic structures such as formula (II) reported in recent years include phosphorus pentachloride, phosphorus oxychloride, thionyl chloride and the like. For example, document (1) Boz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D281/16
CPCC07D281/16
Inventor 翁意意苏为科童小兵王玮陈琴春陶伟锋
Owner ZHEJIANG UNIV OF TECH
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