Preparing method of crizotinib

A kind of crizotinib and the technology of the previous step, applied in the field of preparation of crizotinib, can solve the problems such as low yield of chemical splitting method, unfavorable large-scale production, many steps, etc., and achieve a wide source of raw materials, The reaction process is easy to control and the reaction period is short.

Active Publication Date: 2012-07-18
扬州市三药制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The purpose of the present invention is to overcome the shortcomings of using biological enzyme catalysis in the prior art, with many steps, long cycle and low yield of chemical resolution method, which is not conducive to large-scale produc...

Method used

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  • Preparing method of crizotinib
  • Preparing method of crizotinib
  • Preparing method of crizotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 Preparation of Crizotinib

[0044] The method for preparing crizotinib of the present embodiment comprises the following steps:

[0045] 1) Preparation of phenylethyl alcohol in (S)-configuration

[0046] Freshly distilled trimethylchlorosilane (130 g, 1.2 mol) was added to sodium borohydride (45 g, 1.2 mol) in dry THF (5 L). The reaction mixture was heated at 70° C. for 1 hour, cooled to room temperature, and (S)-diphenylprolinol in THF (0.1 mol, 2 L) was added. When no gas was generated, a solution of acetophenone in THF (1 mol, 2 L) was added slowly. After the reaction was complete, 2N aqueous hydrochloric acid (5 L) was added. Extract three times with ether (10 L). The combined organic phases were washed three times with saturated brine. Dry and concentrate. A white solid was obtained with a yield of 98% and an ee value of 96%.

[0047] 2) Preparation of nitro compounds

[0048]Dissolve 94g of triphenylphosphine, 52g of phenethyl alcohol and 38g of...

Embodiment 2

[0057] Example 2 Preparation of Crizotinib

[0058] The preparation method of the present embodiment comprises the following steps:

[0059] 1) Preparation of phenylethyl alcohol in (S)-configuration

[0060] Freshly distilled trimethylchlorosilane (130 g, 1.2 mol) was added to potassium borohydride (65 g, 1.2 mol) in dry THF (5 L). The reaction mixture was heated at 70° C. for 1 hour, cooled to room temperature, and (S)-diphenylprolinol in THF (0.1 mol, 2 L) was added. When no gas was generated, a solution of acetophenone in THF (1 mol, 2 L) was added slowly. After the reaction was complete, 2N aqueous hydrochloric acid (5 L) was added. Extract three times with ether (10 L). The combined organic phases were washed three times with saturated brine. Dry and concentrate. A white solid was obtained with a yield of 96%, ee value: 96%.

[0061] 2) Preparation of nitro compounds

[0062] Dissolve 94g of triphenylphosphine, 52g of phenethyl alcohol and 38g of 3-hydroxy-nitrop...

Embodiment 3

[0071] Example 3 Preparation of Crizotinib

[0072] The preparation method of the present embodiment comprises the following steps:

[0073] 1) Preparation of phenylethyl alcohol in (S)-configuration

[0074] Freshly distilled tert-butyldimethylsilyl chloride (180 g, 1.2 mol) was added to potassium borohydride (65 g, 1.2 mol) in dry THF (5 L). The reaction mixture was heated at 70oC for 1 hour, cooled to room temperature, and (S)-diphenylprolinol in THF (0.1mol, 2L) was added. When no gas was generated, a solution of acetophenone in THF (1 mol, 2 L) was added slowly. After the reaction was complete, 2N aqueous hydrochloric acid (5 L) was added. Extract three times with ether (10 L). The combined organic phases were washed three times with saturated brine. Dry and concentrate. A white solid was obtained with a yield of 97% and an ee value of 96%.

[0075] 2) Preparation of nitro compounds

[0076] Dissolve 94g of triphenylphosphine, 52g of phenethyl alcohol and 38g of 3...

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Abstract

The invention provides a preparing method of crizotinib. The preparing comprises the following steps of: 1) preparing (S)-construction phenethyl alcohol by taking acetophenone the structural formula of which is shown in a formula (1) as a raw material; 2) preparing a nitrocompound; 3) preparing an aromatic amine compound; 4) preparing a bromo-compound; 5) preparing an N-Boc compound; and 6) preparing the crizotinib. Compared with the prior art, the preparing method of the crizotinib has the advantages that 1, the conventional biological enzymatic method and chemical resolution method are replaced by an organic micromolecule catalysis method, thus the whole line is short in reaction cycle, high in yield, simple in operation, wide in raw material source and low in price; and 2) the preparing method of the crizotinib is high in total yield, the obtained product has high optical purity, the required reaction condition and reaction process are easy to control, and a new choice is provided for preparation and production of the medicament crizotinib.

Description

technical field [0001] The invention relates to a preparation method of crizotinib, which belongs to the technical field of pharmaceutical synthesis. Background technique [0002] Crizotinib is an ATP-competitive small molecule inhibitor with c-Met kinase catalytic activity and high oral bioavailability. It can effectively inhibit the phosphorylation of c-Met and effectively inhibit c-Met in vitro. Met-dependent cell proliferation, migration and invasion (IC50 value 5 ~ 20nmolPL), in addition, it can effectively inhibit endothelial cell proliferation and invasion induced by HGF stimulation and angiogenesis induced by serum stimulation. Crizotinib is well tolerated, and its antitumor activity is dose-dependent [Cancer Res., 2007, 67(9): 44082-44171]. [0003] The English name of Crizotinib: [0004] (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; Molecular formula: C 21 h 22 Cl 2 FN 5 O; molecular weight: 449.12; app...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07B53/00
Inventor 唐虹
Owner 扬州市三药制药有限公司
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