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Synthesis method of crizotinib serving as antitumor molecular targeting medicament

A technology for crizotinib and anti-tumor molecules, which is applied in the field of new splitting process and the synthesis of intermediates, and can solve the problems of unsatisfactory yield and purity, complicated steps and the like

Active Publication Date: 2012-07-04
JINAN TRIO PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to improve the synthesis and isomer resolution of the crizotinib chiral intermediate compound (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (TM2) in the existing literature. Separation and purification methods, especially to overcome the disadvantages of complex steps in the isomer resolution process, unsatisfactory yield and purity, etc., which are not suitable for industrialization, and provide a new isomer resolution method suitable for industrial production. At the same time, it provides a new synthetic method that can implement industrial production of crizotinib

Method used

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  • Synthesis method of crizotinib serving as antitumor molecular targeting medicament
  • Synthesis method of crizotinib serving as antitumor molecular targeting medicament
  • Synthesis method of crizotinib serving as antitumor molecular targeting medicament

Examples

Experimental program
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example 1

[0065] Example 1: Synthesis of racemic 1-(2,6-dichloro-3-fluorophenyl)ethanol (TM1)

[0066] In a 5 L three-necked flask, 832 grams of SM1 was added to a mixed solvent of 1.5 L of ethanol and 1.5 L of THF, the solution was heated to 35°C, and 182 grams of sodium borohydride was added, the reaction was exothermic, and bubbles were generated, and the reaction was carried out for 2 hours Then add 50 g of sodium borohydride, and TLC detects that the reaction is complete in 2 hours (PE / EA=10:1). Add 200 g of water to the system, stir for half an hour, a large amount of solids appear, remove the solvent under reduced pressure, add water and ethyl acetate for extraction, wash the ethyl acetate layer with salt, dry and spin dry to obtain 800 g of product TM1, the yield is 97%. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 7.42 (m, 1H), 7.32 (m, 1H), 5.42 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H).

example 2

[0067] Example 2: Preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (TM2)

[0068] 500 g of TM1, 322 g of Boc-L-proline were dissolved in 1.5 L of anhydrous dichloromethane, and 2.5 L of a dichloromethane solution of 375 g of EDCI and 118 g of p-toluenesulfonic acid was added dropwise at 0°C. After the completion of the reaction at room temperature for 2 hours, the completion of the reaction was monitored by TLC (PE / EA=5:1). The reaction solution was washed with water, dried, and evaporated to dryness, and the fraction was collected at 100-110°C under a vacuum of 10 mm Hg with an oil pump to obtain a crude oily product, which was dissolved in 250 mL of n-hexane at room temperature, and the temperature was lowered to -20°C. Precipitated, and filtered at low temperature to obtain 150 g of white solid with a yield of 60% (ee%>98%).

[0069] HPLC detection conditions (n-hexane / isopropanol=99.3:0.7, flow rate 1.5 mL / s, peak elution time 8-9 min). HPLC instrument: Shimadzu...

example 3

[0073] Example 3: Synthesis of (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-nitropyridine (TM3)

[0074] 300 grams of TM2, 205 grams of SM2 and 540 grams of triphenylphosphine were dissolved in 2L THF, and 361 grams of DEAD was added dropwise at 0°C. After the addition was completed, the mixture was stirred at room temperature for two hours, and the reaction was detected by TLC. (PE / EA=3:1). Remove THF by rotary evaporation, add water, extract with ethyl acetate 1 Lx3, wash the ethyl acetate layer with saturated aqueous sodium bicarbonate solution, dry the ethyl acetate layer, concentrate to 2 L and cool down to 0°C to precipitate a large amount of solid, remove it by filtration, and re- Concentrate to 1 L, and after cooling down, solids are precipitated again, filtered, and the solids obtained by two filtrations are combined, washed with a solution of PE / EA=5:1, filtered, and the solids (about 500 g) are removed, and the combined filtrates are decompressed to remove the s...

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Abstract

The invention discloses a synthesis method of crizotinib serving as an antitumor molecular targeting medicament, which belongs to the field of pharmacy and relates to a novel splitting process of a chiral isomer of a crizotinib precursor and a synthesis method of an intermediate. (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol is prepared by splitting a 1-(2,6- dichloro-3-fluorophenyl)ethanol racemic body into S-alcohol and R-alcohol with a catalytic splitting method for combining Boc-L-proline(N-tert-butoxycarbonyl-L-proline), paratoluenesulfonic acid serving as a catalyst and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, separating and purifying; the yield is 60 percent; and the excessive fraction ee) of the chiral enantiomer is 99 percent. According to the method, time is shortened, cost is reduced, the generation of waste acids is avoided, environmental pollution is lowered, column chromatography isolation is not required, and industrial production is easier to implement.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to a synthesis method of an anti-tumor molecular targeting drug crizotinib, and relates to a new splitting process of a chiral isomer of a crizotinib precursor and a synthesis method of an intermediate . Background technique [0002] Anti-tumor molecular targeted drug crizotinib, chemical name: 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-( 4-piperidine)-1H-pyrazol-4-yl]-2-pyridinamine, the molecular formula is: [0003] [0004] Crizotinib was approved by the US Food and Drug Administration (FDA) for the treatment of advanced non-small cell lung cancer (NSCLC) on August 26, 2011. [0005] The synthetic route of existing reported crizotinib is: [0006] With 2,6-dichloro-3-fluoroacetophenone (SM1) as the starting material, racemized 1-(2,6-dichloro-3-fluorophenyl)ethanol (TM1 ); split racemic phenylethyl alcohol (TM1) into S-type alcohol and R-type alcohol; use S-type alcohol a...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P35/00
Inventor 路国梁孙学英齐放张维军金建申培刚
Owner JINAN TRIO PHARMATECH
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