A preparation method for enzalutamide

A technology of enzalutamide and dimethylacetamide, which is applied in the field of drug synthesis, can solve problems such as unsatisfactory demulsification effect, waste water and waste liquid, and a large amount of organic solvents, so as to avoid serious situations of extraction operation and emulsification, The effect of increasing the reaction temperature and simplifying the post-treatment process

Pending Publication Date: 2019-11-01
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patented synthetic methods involve replacing expensive chemicals with less harmful ones that have higher solubility than water. By doing this they improve their effectiveness without requiring much more costly materials compared to existing techniques. Additionally, these new processes simplify the manufacturing process and increase efficiency when producing products through concentration/recovery procedures instead of extractive operations.

Problems solved by technology

This patents discuss different methods for making certain chemical substances called entazepanserin analogs like enzonedoxybenzoquinones. These techniques involve reacting specific types of alkaloids together through various steps such as hydroformulation, cyclization, dimers formation, etc., resulting in desired products containing these intermediates.

Method used

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  • A preparation method for enzalutamide
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  • A preparation method for enzalutamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034]

[0035] Take compound A 30.0g, K 2 CO 3 19.6g and 162mL of N,N-dimethylformamide were placed in a reaction flask, stirred, added 25.3g of 2-bromoethyl ethyl ether, heated to 60°C, and reacted for 2h. Pour the reaction solution into 270mL of water, stir for 0.5h, precipitate out solid, filter, and beat the obtained filter cake with 540mL of water for 1h, filter, beat the filter cake with 240mL of n-heptane for 1h, filter, and dry at 60°C to obtain the product B1 43.5 g, yield 93%, HPLC purity: 99.0%.

[0036] MS m / z 327[M+H]+; 1H NMR (400MHz, DMSO-d6) δ7.64(t, J=5.0Hz, 1H), 7.47(t, J=8.7Hz, 1H), 6.82(s ,1H),6.32(dd,J=8.7,2.3Hz,1H),6.15(dd,J=14.6,2.2Hz,1H),4.32–4.03(m,2H),3.56–3.43(m,2H), 3.34(q, J=7.0Hz, 2H), 2.74(d, J=4.5Hz, 3H), 1.48(s, 6H), 1.02(t, J=7.0Hz, 3H).

[0037] Take 32.6g of compound B1 and 47.9g of compound C, add 40mL of isopropyl acetate and 20mL of dimethyl sulfoxide, and react at 80-85°C for 20h. Concentrate under reduced pressure to remove is...

Embodiment 2

[0040]

[0041]Mix 30g of compound A with 22.2g of p-methoxybenzyl chloride, 19.56g of potassium carbonate, 162mL of N,N-dimethylformamide, and 0.3mL of water, and stir at 50°C for 4h. After the reaction is complete, the reaction solution is Added into 270mL of purified water, stirred for 0.5h, precipitated solid, filtered, slurried with 540mL of water for 1h, filtered, and the filter cake was slurried with 240mL of n-heptane for 1h, filtered, and dried at 60°C to obtain 42.6g of product B2, yield 97% , 98.5% purity.

[0042] MS m / z 375.5[M+H]+; 1H NMR (400MHz, CDCl3) δ7.82(ddd, J=11.1,5.6,2.1Hz,1H), 7.24–7.02(m,2H),6.88–6.73( m, 2H), 6.59(dd, J=14.0, 5.0Hz, 1H), 6.31(dq, J=8.7, 2.1Hz, 1H), 6.06(dt, J=15.2, 1.9Hz, 1H), 5.06(d , J=1.3Hz, 2H), 4.78(s, 1H), 3.92–3.61(m, 3H), 2.98(s, 3H), 1.77–1.41(m, 6H).

[0043] 10 g of compound B2 was mixed with 13.6 g of compound C, dimethyl sulfoxide and isopropyl acetate, and stirred overnight at a temperature of 80-85° C. After the TL...

Embodiment 3

[0047] Mix 30g of compound A with 22.2g of p-methoxybenzyl chloride, 11.20g of pyridine, 162mL of N,N-dimethylformamide, and 0.3mL of water, stir at 50°C for 4h, and add the reaction solution to into 270mL of purified water, stirred for 0.5h, precipitated solid, filtered, slurried with 540mL of water for 1h, filtered, and the filter cake was slurried with 240mL of n-heptane for 1h, filtered, and dried at 60°C to obtain 38.7g of product B2, with a yield of 88%. HPLC purity: 98.5%.

[0048] The mass spectrum and NMR data of product B2 are basically the same as in Example 2.

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Abstract

The invention belongs to the technical field of pharmaceutical synthesis methods, and provides a preparation method of enzalutamide. The method includes: (1) a step of preparing a compound B, namely astep of reacting 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoicacid as an initial raw material in an organic solvent with the presence of an inorganic alkali or an organic alkali ata proper temperature to obtain the compound B; (2) a step of reacting the compound B prepared by the step (1) with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile to obtain the target product enzalutamide. The method avoids use of high-toxicity reagents such as iodomethane, shortens the preparation time for the compound B, avoids complex operation in aftertreatment of the enzalutamide, greatly simplifies an aftertreatment process, facilitates resource saving and is more suitable for industrial scale-up production.

Description

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Claims

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Application Information

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Owner SICHUAN KELUN PHARMA RES INST CO LTD
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