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Quetiapine synthesizing method

A synthetic method, the technology of quetiapine, applied in the field of drug synthesis, can solve the problems of a large amount of iron-containing waste liquid, increase the production cost, and be difficult to handle, and achieve the effect of simple reaction conditions, high purity, and easy operation

Active Publication Date: 2016-08-17
JIAXING UNIV
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

There are some defects in this process: one is that the acylation process uses phenyl chloroformate as the acylating reagent, and the utilization rate of atoms is low; It is prepared by condensation and reduction two-step reaction with thiophenol as the starting material, and the cost is relatively high
This route has two obvious disadvantages: one is that the price of starting materials thiosalicylic acid and o-fluoronitrobenzene is higher, which increases the production cost; the other is that there will be a large amount of iron-containing waste liquid after reducing nitro with iron , difficult to handle
[0011] As can be seen from the above process route, it is mainly the synthesis of the seven-membered ring key intermediate dibenzo[b,f][1,4]thiazepin-11-(10H)ketone, and the existing techniques mostly use multiple Closing the ring with polyphosphoric acid, or reducing nitro groups with iron, does not meet the national requirements for environmental protection

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The preparation of embodiment 1 2-carboxy diphenyl sulfide (compound II)

[0062] Add 150mL tetrahydronaphthalene, o-chlorobenzoic acid (15.6g, 0.1mol) and copper powder (0.32g, 0.005mol) into the reaction flask, and when the system drops to about 0°C, add sodium hydroxide ( 6.0g, 0.15mol), thiophenol (11.1g, 0.1mol), heated up to 130 ° C for 6 hours after the addition (monitored by TLC during the reaction), cooled after the reaction, added 100mL of water, suction filtered to remove the copper powder, and the filtrate The layers were separated, and the pH of the aqueous phase was adjusted to 2-3 with hydrochloric acid. A large amount of white solid was precipitated, and 20.5 g of the crude product was obtained by suction filtration. The yield was 89%, and the purity (HPLC): 97.8%.

[0063] Molecular formula: C 13 h 10 o 2 S; molecular weight: 230.0; MS (m / z): 231.0 (M + +H).

Embodiment 2

[0064] Embodiment 2 Preparation of thioxanthone (III)

[0065] Add 2-carboxydiphenylsulfide (23g, 0.1mol, compound II) into the reaction flask, add 100mL of toluene to dissolve, cool down to about 0°C in an ice bath, add 20mL of concentrated sulfuric acid dropwise, and heat up to 80°C after the addition Continue to stir the reaction for 1h, and TLC monitors the degree of the reaction. After the reaction is completed, the reactant is poured into water, separated, the organic phase is washed to neutrality, dried, and toluene is removed, and recrystallized with ethanol to obtain 16g of a light yellow crude product. Rate: 75.5%. Purity (GC): 98.2%.

[0066] Molecular formula: C 13 h 8 OS; molecular weight: 212.0; MS (m / z): 213.0 (M + ).

[0067] 1 H NMR (400MHz, CDCl 3 )δ8.52(d, J=8.0Hz, 2H), 7.52-7.43(m, 4H), 7.37(t, J=7.6Hz, 2H); 13 C NMR (100MHz, CDCl 3 )δ 179.2, 137.1, 132.1, 129.6, 129.0, 126.1, 125.7; melting point: 207.5°C-209.1°C.

Embodiment 3

[0068] Embodiment 3 Preparation of thioxanthone oxime (compound VI)

[0069] Add thioxanthone (21.2g, 0.1mol, compound III) into the reaction flask, add 100mL of ethanol to dissolve, then add hydroxylamine hydrochloride (7.65g, 0.11mol, CAS: 5470-11-1), and heat up after the addition Stir the reaction under reflux for 3 hours, and monitor the progress of the reaction by TLC. After the reaction is completed, most of the solvent is removed by spinning, and crystals are precipitated by cooling, and 21.1 g of a white solid are obtained by suction filtration, yield: 93%. Purity (HPLC): 99.1%.

[0070] Molecular formula: C 13 h 9 NOS; molecular weight: 227.0; MS (m / z): 228.0 (M + ).

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Abstract

The invention discloses a quetiapine synthesizing method. O-chlorobenzoic acid with the low price is adopted as a starting material to react with thiophenol, and then ring closure is performed to obtain thioxanthone. Hydroxyl amination and Beckmann rearrangement are performed to obtain a key intermediate dibenzo[b,f][1,4]thiazepines-11-(10H)one, chlorination is performed, then, a reaction is performed on 1-(2-hydroxyethoxy)ethylpiperazine with the existence of acid-binding agent to obtain quetiapine, and the quetiapine and fumaric acid form a salt in an absolute ethyl alcohol system to obtain a product. According to the quetiapine synthesizing method, raw materials are low in price and easy to obtain, the steps are simple, operation is easy, and the cost can be effectively lowered. According to the method, the high-purity quetiapine can be obtained, the liquid phase purity of the obtained semi-fumaric acid quetiapine obtained through salt forming is 99% or above, and the quetiapine synthesizing method can be applied to the field of medicine.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing quetiapine. Background technique [0002] 11-{4-[2-(2-(Hydroxyethoxy)ethyl-1-piperazine]}dibenzo[b,f][1,4]thiazepine (structure shown in formula (I)), also known as quetiapine, is generally sold in the form of hemifumarate. It is an antipsychotic drug developed by AstraZeneca UK limited (AstraZeneca Pharmaceutical Company) in the United Kingdom. It was first launched in the UK in November 1997. It is used to treat schizophrenia. It has strong antipsychotic effect and less triggers. extrapyramidal syndrome. In 2000, domestic quetiapine was approved for marketing after completing phase I and II clinical trials. Imported quetiapine also completed registration in the same year and was launched in the domestic market in 2001. [0003] [0004] There are many literature reports about the synthetic method of quetiapine hemifumarate, and the main synthetic r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D281/16
CPCC07D281/16
Inventor 姚金忠周宏伟陈佃鹏
Owner JIAXING UNIV
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