A kind of preparation method of (s)-1-(2,6-dichloro-3-fluorophenyl)ethanol

A technology of fluorophenyl and ethanol, which is applied in the field of drug synthesis, can solve the problems of long steps, high ee% value, high yield, and low yield, and achieve the effects of improved purity, safe use, and easy availability of raw materials

Active Publication Date: 2015-09-02
ZHEJIANG ZHONGXIN FLUORIDE MATERIALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The chemical resolution method by Boc-L-proline also has similar problems, the steps are long, the yield is low, and it is necessary to remove the Boc protecting group and purify with chromatography
Although the method used in the subsequent patent can be purified without deprotection and column chromatography, the product can be precipitated directly at a low temperature <-20°C in n-hexane solution, but the ee% value and yield of the product are not as good as the previous ones. method high

Method used

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  • A kind of preparation method of (s)-1-(2,6-dichloro-3-fluorophenyl)ethanol
  • A kind of preparation method of (s)-1-(2,6-dichloro-3-fluorophenyl)ethanol
  • A kind of preparation method of (s)-1-(2,6-dichloro-3-fluorophenyl)ethanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Dissolve 174g of compound 1 in 500mL of ethanol, add 45g of sodium borohydride in batches at room temperature, stir at room temperature for about 2 hours after the addition is complete, spot the sample to determine the end point of the reaction, after the completion of the reaction, quench the reaction with 2N hydrochloric acid, and Adjust the pH to about 2, then extract four times with 2L ethyl acetate, wash the organic phase with saturated sodium carbonate solution and saturated sodium chloride solution respectively, dry, and remove the solvent to obtain a light yellow viscous liquid (compound 2). The rate is 96%, and the content is 98%.

Embodiment 2

[0046] Dissolve 182g of compound 2 and 135g of phthalic anhydride in 124mL of triethylamine, add 2g of 4-dimethylaminopyridine (DMAP), reflux for 1.5 hours, stop heating, cool to about 50°C and add 40mL of acetic acid Ethyl ester, and then adjust the pH to about 2 with 2N hydrochloric acid, and then stir for half an hour, a large amount of white solid appeared, filtered and washed with water three times to obtain compound 3 with a yield of 93% and a content of 98.5%.

[0047] Alternatives 1-8:

[0048] The preparation method is the same as in Example 2, the difference is that the addition amount of compound 2 and phthalic anhydride is adjusted, and the organic base and the amount thereof are adjusted at the same time to obtain the yield and purity of compound 3 under different reaction conditions as shown in Table 1.

[0049] Table 1,

[0050]

[0051] As shown in table 1: in the preparation process of compound 3, the addition of compound 2 and phthalic anhydride has a gre...

Embodiment 3

[0054] Take 90g (98% content) of compound 3 and heat it to about 40°C and dissolve it in 650mL of absolute ethanol, then add 15g (99% content) of (S)-1-phenylethylamine dropwise, stir for 10 minutes and a large amount of Solid, heated to reflux until all solids disappeared, heated to reflux at 85°C, then slowly cooled to 5°C, kept for 2 hours, filtered, washed with a small amount of ice-water-cooled absolute ethanol to obtain product 4, the yield was 80% , ee% is greater than 99%.

[0055] Replacement Example 9-22:

[0056] The preparation method is the same as in Example 3, the difference is that the solvent, reaction temperature, and reaction time of Example 3 are adjusted, and the synergistic effect between the above-mentioned reaction parameters is tested at the same time. The yield and purity of compound 4 are shown in Table 2.

[0057] Table 2,

[0058]

[0059] As shown in table 2:

[0060] The influence of the choice of solvent on the yield and purity of compound...

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Abstract

The invention discloses a preparation method of (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol. The preparation method comprises the following steps: by taking 2,6-dichloro-3-fluoroacetophenone as a starting raw material, reducing the 2,6-dichloro-3-fluoroacetophenone by use of sodium borohydride and then reacting the 2,6-dichloro-3-fluoroacetophenone with phthalic anhydride to obtain a half-ester, next, carrying out resolution by use of s-methylbenzylamine and then carrying out deprotection by hydrolyzing to remove phthalic acid, thereby obtaining the high-optical purity target product. The preparation method is simpler and more reasonable in synthesis process and convenient and feasible in after-treatment; the intermediate can be directly applied to next step of reaction without being purified, so that the after-treatment process can be reduced; meanwhile, the adopted resolution agent and the phthalic acid both can be recovered; as a result, the whole process is suitable for large-scale industrial production.

Description

Technical field: [0001] The invention belongs to the technical field of medicine synthesis, and specifically refers to a method for preparing a crizotinib intermediate, (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol. Background technique: [0002] Crizotinib is a new type of small molecule multi-target tyrosine kinase inhibitor (TKI) developed by Pfizer Corporation of the United States. It was approved by the US Food and Drug Administration (FDA) on August 26, 2011 as a molecularly targeted drug for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced NSCLC. Crizotinib, the first small molecule tyrosine kinase inhibitor developed for ALK-positive NSCLC, inhibits c-Met / hepatocyte growth factor receptor (HGFR) and anaplastic lymphoma kinase (ALK) and its oncogenic variants . At present, crizotinib targets the fusion gene of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK), and has become a dazzling target drug in non-sma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C33/46C07C29/143C07C29/92
CPCC07C29/143C07C29/92C07C33/46
Inventor 沈永淼袁其亮黄炜尚小东王超陈寅镐
Owner ZHEJIANG ZHONGXIN FLUORIDE MATERIALS CO LTD
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