Synthesis method of crizotinib

A synthetic method and the technology of crizotinib, which are applied in the field of preparation of small molecule chemical drugs, can solve the problems of large amount of precious metal palladium catalyst, unfavorable large-scale industrial production, low reaction yield, etc., and achieve low cost, short route and high product yield. The effect of high purity

Inactive Publication Date: 2015-06-10
ARROMAX PHARMATECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] At present, most of the synthetic routes of crizotinib use these two routes, the route is longer, the reaction yield is low, the consumption of noble metal palladium catalyst is larger, the cost is higher, the operation is cumbersome, and there are many impurities, which is not conducive to large-scale industrial production.

Method used

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  • Synthesis method of crizotinib
  • Synthesis method of crizotinib
  • Synthesis method of crizotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035]

[0036] Compound 1 (10 g, 48 mmol) was dissolved in 1,4-dioxane (100 ml), and (-) DIPCl (22.8 g, 72 mmol) was added dropwise at -20 °C, and the reaction was kept at -20 °C for 2 h, and water (50 ml) was added. , with saturated NaHCO 3 The aqueous solution was adjusted to pH 7, extracted with ethyl acetate (30 ml x 3), dried and concentrated to give a pale yellow oil, compound 2 (8.1 g, 80% yield).

[0037] 1 H NMR (400MHz, CDCl 3 , δppm): 1.65 (d, J=6.8Hz, 3H) 5.58 (q, J=6.9Hz, 1H) 6.96-7.10 (m, 1H) 7.22-7.36 (m, 1H).

Embodiment 2

[0039]

[0040] To a solution of compound 2 (460 mg, 2.2 mmol) in THF (20 ml) were added 3-hydroxy-2-nitropyridine (350 mg, 2.42 mmol) and triphenylphosphine (880 mg, 3.2 mmol) successively under nitrogen protection. Stir at room temperature for 1 hour, then drop to 0°C, add DIAD (0.68 mL, 3.2 mmol), continue to stir and react for 12 hours, the reaction solution is spin-dried to obtain oil, which is purified by column to obtain a white solid (677 mg, 2.04 mmol, yield 93%).

[0041] 1 H NMR (400MHz, CDC l3, δppm): 1.85 (d, J=6.6Hz, 3H), 6.10 (q, J=6.6Hz, 1H), 7.04-7.13 (m, 1H), 7.21 (dd, J=8.5, 1.14Hz, 1H) , 7.30 (dd, J=9.0, 4.9Hz, 1H), 7.35-7.38 (m, 1H), 8.04 (dd, J=4.6, 1.3Hz, 1H).

Embodiment 3

[0043]

[0044] Reduced iron powder (25.5g, 0.455mol) was added to the solution of compound 3 (30g, 0.091mol) in acetic acid (200ml), and after stirring at room temperature for 5 hours, most of the acetic acid was removed, water (200ml) was added, ethyl acetate Ester extraction (3X 250ml), organic phase with saturated NaHCO 3 Wash (2×250ml), organic phase anhydrous Na 2 SO 4 After drying, it was filtered and spin-dried to obtain compound 4 (24 g, yield: 88%).

[0045] 1 H NMR (400MHz, DMSO-d6, δppm): 1.75 (d, J=6.6Hz, 3H), 5.67 (brs, 2H), 5.97-5.92 (q, J=6.6Hz, 1H), 6.38-6.35 (dd , J=5.0Hz, 7.7Hz, 1H), 6.61 (d, J=7.1Hz, 1H), 7.47-7.42 (m, 2H), 7.56-7.52 (dd, J=5.0Hz, 7.7Hz, 1H).

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Abstract

The invention provides a synthesis method of crizotinib. The method comprises the following steps: performing chemical exchange reaction for a compound (10) to obtain an intermediate compound (11); adding a compound (6) to react to obtain a compound (12); performing deprotection reaction for the compound (12) to obtain crizotinib. The method is simple in steps, short in line, simple in after-processing, low in cost, and particularly suitable for industrial production; the reaction line is shown in the specification, wherein X is Br or I; Nu is MgX or ZnX; R1 and R2 are independently selected from Boc or H.

Description

technical field [0001] The invention relates to the field of small molecule chemical drug preparation, and more particularly to a method for synthesizing crizotinib. Background technique [0002] Crizotinib (1), chemical name is 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4- Piperidinyl)-1H-pyrazol-4-yl]-2-aminopyridine, is a dual inhibitor of Alk and c-Met developed by Pfizer. It was approved by the US FDA on August 26, 2011 to be listed in the United States. Named Xalkori, it was subsequently listed in South Korea, Japan and the European Union. In 2013, it was approved by the CFDA to be listed in China, and the Chinese brand name is Cyric. [0003] [0004] Crizotinib is the first drug to target anaplastic lymphoma kinase (ALK) for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) confirmed to be ALK-positive by an FDA-approved test . ALK gene variants are considered to be key drivers of cancer development such as NSCLC. ALK is more...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 洪健许忻刘国斌徐艳超
Owner ARROMAX PHARMATECH
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