A kind of preparation method of crizotinib chiral intermediate

A technology of crizotinib and intermediates, applied in the field of non-small cell lung cancer drugs, can solve the problems of difficult industrialization, complicated operation, expensive reagent yield, etc., and achieve solvent recyclability, simple operation, and stable process Effect

Inactive Publication Date: 2018-04-20
爱技特科技(北京)有限公司
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AI Technical Summary

Problems solved by technology

[0006] The key step is the synthesis of the chiral intermediate (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol. The synthesis method includes: chemical asymmetric reduction of 1-(2,6-dichloro -3-fluorophenyl) ethyl ketone to give chiral alcohol, asymmetric reducing agent has CBS reducing agent (references: Mathre, D.J.; Thompson, A.S.; Douglas, A.W.; Hoogsteen, K.; Carroll, J.D.; Corley , E.G.; Grabowski, E.J.J.J.Org.Chem.1993,58,2880); organoboron reagent (-)-DIPCl reduction, (References: Brown, H.C.; Chandrasekharan, J.; Ramachandran, P.V.J.Am.Chem.Soc.1988 ,110,1539.); proline induces the reduction of NaBH 4 / TMSCl / (S)-a,a-diphenylpyrrolidinemethane (References: Jiang, B.; Feng, Y.; Zheng, J. Tetrahedron Lett. 2000, 41, 10281.) The experimental conditions of the above chemical methods are harsh, and the chiral purity is partial Low, difficult to produce; and in the second step of the synthetic reaction, the reagents are expensive and the yield is low
[0007] Pfizer uses enzymatic resolution to obtain chiral alcohols, i.e. pig liver esterase hydrolysis method, (references: WO2006021886; WO 2006021881; Tetrahedron: Asymmetry 21 (2010) 2408-2412), the enzyme-catalyzed reaction required for this method The time is long, the conditions are harsh, the operation is complicated and the yield is low, and it is difficult to realize industrialization

Method used

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  • A kind of preparation method of crizotinib chiral intermediate
  • A kind of preparation method of crizotinib chiral intermediate
  • A kind of preparation method of crizotinib chiral intermediate

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Experimental program
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Effect test

Embodiment 1

[0033] Embodiment 1: the preparation of compound (2)

[0034] Add 500 g (2.42 mol) of 1-(2,6-dichloro-3-fluorophenyl) ethyl ketone into 1500 ml of methanol, add 101 g (2.65 mol) of sodium borohydride under stirring in an ice bath, and control the temperature at 0-5 ℃, the addition was completed, stirred at room temperature for 3 hours, concentrated methanol under reduced pressure, added water and dilute hydrochloric acid to adjust the pH to 6, extracted with ethyl acetate, dried the organic phase, and concentrated under reduced pressure to obtain 500 g of a colorless liquid. Add 500 grams of this colorless liquid into 2500 ml of dichloromethane, add 351 ml (2.53 mol) of triethylamine and 196 ml (2.53 mol) of methanesulfonyl chloride under ice-bath cooling, stir at room temperature for 3 hours, add water to extract, and depressurize the organic phase after drying Concentration gave 650 g of light yellow liquid. 650 grams of this yellow liquid was dissolved in 3500ml DMF, added...

Embodiment 2

[0036] Embodiment 2: the preparation of compound (1) resolution salt

[0037]At 70°C, dissolve 20 grams (66 mmol) of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine in 200ml of 80% ethanol, add L-diphenylmethane 23.8 grams (66mmol) of acyl tartaric acid, heated to reflux and stirred for 2 hours and then slowly lowered to room temperature, stirred for 2 hours, filtered, added 200ml of 80% ethanol to the filter cake, heated and refluxed and stirred for two hours and allowed to stand down to room temperature for 2 hours. After filtration, 17.3 g (26.2 mmol) of L-dibenzoyl tartrate salt of compound (1) was obtained as a solid. Yield: 40%. Melting point: 160.7-168.7℃(dec),[α] 20 D =-138.3° (c=1, DMSO) 1 HNMR (300MHz, DMSO) δ: 8.02(d, J=9.0Hz, 4H), 7.73(t, J=6.0Hz, 2H), 7.58(m, 5H), 7.45(m, 2H), 6.63(d, J=6.0Hz, 1H), 6.42(dd, J=6.0Hz, 1H), 6.15(br, 2H), 5.97(q, J=2.0Hz, 1H), 5.85(s, 2H), 1.75(s, 3H)

Embodiment 3

[0038] Embodiment 3: the preparation of compound (1)

[0039] With 17.3 grams (26.2 mmol) of L-dibenzoyl tartrate of compound (1) obtained in Example 2, add ethyl acetate 100 ml, water 100 ml, add dropwise 10% sodium hydroxide solution at room temperature, adjust pH =10, after the layers were separated, the organic phase was washed once with 50 ml of saturated brine, and the layers were separated. Ethyl acetate was dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 7.5 g of white solid compound (1), yield: 95%. Sampling and detection showed that the HPLC purity was 99.9%, and the optical purity ee: 99.4%. 1 HNMR (300MHz, CDCl 3 )δ: 7.60(d, J=4.8Hz, 1H), 7.29(m, 1H), 7.05(t, J=8.4Hz, 1H), 6.70(d, J=7.7Hz, 1H), 6.46(dd, J=5.3,2.28Hz,1H),6.01(q,J=6.6Hz,1H),5.2(brs,2H),1.82(d,J=6.7Hz,3H).Mp:118.1-119.2℃[α] 20 D =-184.2° (c=2, CHCl 3 ). [Chiral HPLC method: chromatographic column CHIRALCEL OD ...

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Abstract

The application relates to a preparation method of a chiral intermediate of crizotinib, which belongs to the field of drug synthesis. The preparation method of intermediate (1) is to adopt chiral organic acid as resolving agent to 3-(1-(2,6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine obtained by splitting. The method can stably obtain the high-purity, high-chiral intermediate (1), and is simple to operate, avoiding difficult-to-synthesize chiral alcohols, easy to obtain raw materials, low in price, and easy to realize industrialization.

Description

technical field [0001] The present invention mainly relates to the treatment of anaplastic lymphoma kinase (ALK)-positive locally advanced and metastatic non-small cell lung cancer (NSCLC) drug crizotinib intermediate 3-[(1R)-1-(2,6-dichloro -3-fluorophenyl)ethoxy]pyridin-2-amine chiral resolution method. Background technique [0002] Crizotinib is a small molecule inhibitor of ALK / c-MET for the treatment of anaplastic lymphoma kinase (ALK)-positive locally advanced and metastatic non-small cell lung cancer (NSCLC). Its structural formula is as follows: [0003] [0004] The currently reported synthetic route of crizotinib is: (Reference: Org.Process Res.Dev.2011,15,1018–1026) [0005] [0006] The key step is the synthesis of the chiral intermediate (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol. The synthesis method includes: chemical asymmetric reduction of 1-(2,6-dichloro -3-fluorophenyl) ethyl ketone, to obtain chiral alcohol, asymmetric reducing agent has CBS reduc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/73C07D401/14
Inventor 石立建苗强王宏志
Owner 爱技特科技(北京)有限公司
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