Preparation method of crizotinib intermediate (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol

A crizotinib and intermediate technology, which is applied in the field of preparation of crizotinib intermediate-1-ethanol, can solve the problems of expensive catalyst, time-consuming separation and purification, and high product cost, and saves the cost of process raw materials, Reduced handling and material loss, high optical content effect

Inactive Publication Date: 2016-02-03
WUHAN SINO SANTA CHEM TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In order to solve the problems in the above-mentioned prior art, such as expensive catalyst, time-consuming separation and purification, difficult industrialization of separation, and high product cost, the purpose of the present invention is to provide an asymmetric Catalyst-catalyzed asymmetric hydrogenation and further preparation of crizotinib intermediate (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol

Method used

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  • Preparation method of crizotinib intermediate (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol
  • Preparation method of crizotinib intermediate (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol
  • Preparation method of crizotinib intermediate (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol

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Experimental program
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Effect test

Embodiment 1

[0029] Weigh 1.9 mg, 0.002 mmol of chiral catalyst [RuCl 2 ((S)-P-Phos)((R,R)-DPEN)]; 224 mg, 2.0 mmol of potassium tert-butoxide; 30 mL of isopropanol; 14.8 mL, 0.1 mol of 1-(2,6-dichloro- 3-fluorophenyl)ethanone. The chiral catalyst consists of RuCl 2 (p-cymene), (R,R)-DPEN and (S)-P-Phos coordination combination, the RuCl 2 (p-cymene) and (R,R)-DPEN are from Reagent Company, (S)-P-Phos is from Wuhan Shenxinda Chemical Technology Co., Ltd. Potassium tert-butoxide, isopropanol, 1-(2,6 -Dichloro-3-fluorophenyl)ethanone is chemically pure purchased from a reagent company. Put the above-mentioned chiral catalyst, potassium tert-butoxide, isopropanol and 1-(2,6-dichloro-3-fluorophenyl)ethanone in the reaction tube and mix thoroughly, then put the reaction tube into the autoclave , the upper end of the reaction tube is open, and the gas in the kettle body is replaced with nitrogen and hydrogen respectively, so that the hydrogen pressure reaches 2MPa, the temperature is raised ...

Embodiment 2

[0031]Weigh 1.9 mg, 0.002 mmol of chiral catalyst [RuCl 2 ((S)-P-Phos)((R,R)-DPEN)]; 98 mg, 2.0 mmol sodium amide; 30 mL of propanol; 14.8 mL, 0.1 mol 1-(2,6-dichloro-3-fluorobenzene base) ethyl ketone. The chiral catalyst consists of RuCl 2 (p-cymene), (R,R)-DPEN and (S)-P-Phos coordination combination, the RuCl 2 (p-cymene) and (R,R)-DPEN are from reagent companies, (S)-P-Phos is from Wuhan Shenxinda Chemical Technology Co., Ltd., sodium amide, propanol, 1-(2,6-dichloro -3-fluorophenyl)ethanone is chemically pure purchased from a reagent company. The above-mentioned chiral catalyst, sodium amide, propanol and 1-(2,6-dichloro-3-fluorophenyl)ethanone are placed in a reaction tube and fully mixed, and the reaction tube is placed in a high-pressure reactor. Open the upper end of the reaction tube, replace the gas in the kettle with nitrogen and hydrogen respectively, make the hydrogen pressure reach 4MPa, raise the temperature to 80°C and keep it warm for more than 5 hours u...

Embodiment 3

[0033] Weigh 2.3 mg, about 0.002 mmol of chiral catalyst [RuCl 2 ((S)-P-Phos)((R,R)-DPEN)]; 136 mg, 2.0 mmol sodium ethoxide; 50 mL of THF; 14.8 mL, 0.1 mol 1-(2,6-dichloro-3-fluorophenyl ) ethyl ketone. The chiral catalyst consists of RuCl 2 (p-cymene), (R,R)-DPEN and (S)-P-Phos coordination combination, the RuCl 2 (p-cymene) and (R,R)-DPEN are from reagent companies, (S)-P-Phos is from Wuhan Shenxinda Chemical Technology Co., Ltd., sodium ethoxide, tetrahydrofuran, 1-(2,6-dichloro- All 3-fluorophenyl)ethanone was chemically pure purchased from a reagent company. The above-mentioned chiral catalyst, potassium tert-butoxide, tetrahydrofuran and 1-(2,6-dichloro-3-fluorophenyl)ethanone are placed in a reaction tube and fully mixed, and the reaction tube is placed in a high-pressure reactor. The upper end of the reaction tube is open, replace the gas in the kettle body with nitrogen and hydrogen respectively, make the hydrogen pressure reach 5MPa, raise the temperature to 50°...

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Abstract

The invention belongs to the technical field of organic chemistry, also belongs to the technical field of medicinal chemistry, and in particular to a preparation method of a crizotinib intermediate (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol. The method uses 1-(2,6-dichloro-3-fluorophenyl) acetophenone as the raw material to obtain a crizotinib chiral intermediate S-1-(2,6- dichloro-3-fluoro) phenethyl alcohol under the effect of a chiral catalyst, alkali and hydrogen. The chiral catalyst is [MX2((S)-a)((R,R)-b)], which is composed of chiral diphosphine ligand compound a, a chiral nitrogen ligand compound b and a metal salt catalyst MX2(P-cymene) in coordination combination. The synthetic method provided by the invention can prepare crizotinib intermediate with high enantioselectivity; the intermediate has ee% reaching 98%; and the mole dosage of the catalyst is only 1 / 150000-1 / 50000 of a reaction substrate 1-(2,6-dichloro-3-fluorophenyl) acetophenone, and the substrate can be completely transformed.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry and also belongs to the technical field of medicinal chemistry, and specifically relates to a preparation method of crizotinib intermediate (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol. Background technique [0002] Crizotinib is an oral amino acid kinase receptor inhibitor developed by Pfizer. The drug is effective in the treatment of advanced non-small cell lung cancer (NSCL) that expresses an abnormal anaplastic lymphoma kinase (ALK) gene. Its structure is as follows: [0003] In the synthesis of crizotinib, the key is the synthesis of the chiral intermediate (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol. At present, patents have reported its synthesis method. Patent US7858643B2, WO2006021881 etc. report that its synthetic method is to synthesize (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol by esterase catalyzed hydrolysis, and the synthetic route is shown in the following formula: [...

Claims

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Application Information

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IPC IPC(8): C07C33/46C07C29/145
CPCC07C29/145C07C33/46
Inventor 申永存黄毅勇夏定申宁博
Owner WUHAN SINO SANTA CHEM TECH CO LTD
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