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Preparation method for intermediate (namely 1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for bazedoxifene acetate

A technology of bazedoxifene acetate and benzyloxy is applied in the field of preparation of bazedoxifene acetate intermediate 1--2-bromopropyl-1-one, which can solve the problem of unsuitability for industrial production and poor bromine selectivity , the reaction is difficult to operate and other problems, to achieve the effect of improving selectivity, high selectivity and mild reaction conditions

Inactive Publication Date: 2014-01-01
河南海汇药物研究有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, bromine has poor selectivity as a bromination reagent and is difficult to control; acetic acid is difficult to operate when it is used as a solvent at zero temperature (acetic acid is solid at zero temperature), and is not suitable for industrial production

Method used

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  • Preparation method for intermediate (namely 1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for bazedoxifene acetate
  • Preparation method for intermediate (namely 1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for bazedoxifene acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] (1) Add 24g of 1-(4-benzyloxy-phenyl)-2-propyl-1-one and 45g of CuBr to a 1L three-necked flask 2 , 250 mL ethyl acetate, 250 mL chloroform, heated to reflux, tracked and monitored by TLC plate until the reaction of the main raw material (1-(4-benzyloxy-phenyl)-2-propyl-1-one) was complete, stopped heating and cooled to room temperature (25°C), and the reaction was completed to obtain a reaction solution.

[0019] (2) The reaction solution was suction filtered through a sand core funnel, the filtrate was evaporated to remove the solvent, and 37.6g of a crude brown oil was obtained. Add 250mL of absolute ethanol to the crude product, and the system was turbid and heated to reflux for 0.5h. Stop heating and cool to -5-0 The product was crystallized at ℃, washed with suction, and the filtrate was concentrated and then refluxed and crystallized again to obtain a total of 31.2 g of the product as a white solid (98% yield).

Embodiment 2

[0021] (1) Add 24g of 1-(4-benzyloxy-phenyl)-2-propyl-1-one, 24g of CuBr to a 1L three-necked flask 2 , 200 mL of a mixture of dichloromethane and 1,2-dichloroethane (the volume ratio of the two is 1:1), 200 mL of methyl formate, heating to reflux, TLC plate tracking monitoring to the main raw material (1-(4-benzyl Oxygen-phenyl)-2-propyl-1-one) reaction is complete, stop heating, cool to room temperature (25°C), and the reaction is completed to obtain the reaction solution.

[0022] (2) The reaction solution was suction filtered through a sand core funnel, the filtrate was evaporated to remove the solvent, and 36.7g of a crude brown oil was obtained. Add 230mL of ethyl acetate to the crude product, and the system was turbid and heated to reflux for 1h. Stop heating and cool to -15--10 The product was crystallized at ℃, washed with suction, and the filtrate was concentrated and then refluxed and crystallized again to obtain a total of 30.3 g of the product as a white solid (yi...

Embodiment 3

[0024] (1) Add 24g of 1-(4-benzyloxy-phenyl)-2-propyl-1-one, 240g of CuBr to a 1L three-necked flask 2 , 230 mL of a mixture of methyl formate, ethyl formate and methyl acetate (the volume ratio of the three is 1:2:1), 200 mL of DMF, heated to reflux, followed by TLC plate monitoring to the main raw material (1-(4-benzyl Oxygen-phenyl)-2-propyl-1-one) reaction is complete, stop heating, cool to room temperature (25°C), and the reaction is completed to obtain the reaction solution.

[0025] (2) The reaction solution was filtered through a sand core funnel, the filtrate was evaporated to remove the solvent, and 37.0g of the crude brown oil was obtained. Add 230mL of DMF to the crude product, and the system was turbid and heated to reflux for 2 hours. Stop heating and cool to -10--5°C to make the product Crystals were precipitated, filtered and washed with suction, and the filtrate was concentrated and refluxed and crystallized again to obtain a total of 30.9 g of the product as ...

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Abstract

The invention discloses a preparation method for an intermediate (namely 1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for bazedoxifene acetate. The preparation method comprises the following steps: adding 1-(4-benzyloxy-phenyl)-2-propan-1-one and a metal bromine salt into an organic solvent, heating for reflux, and after completion of reaction, cooling to obtain a reaction solution; treating the reaction solution to obtain a liquid crude product, adding the liquid crude product into an organic solvent, heating for reflux for 0.5-2 hours, and after completion of reflux, treating to obtain a product. According to the preparation method, the easily obtained metal bromine salt substitutes for elementary bromine for bromination reaction, so that the selectivity of reaction is improved; the reaction condition is gentle, the selectivity is high, the intermediate (1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for the bazedoxifene acetate is synthesized efficiently, and the yield and purity of the obtained product are high, so that the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic product preparation, and in particular relates to a preparation method of bazedoxifene acetate intermediate 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-one. Background technique [0002] 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-one is a key intermediate in the synthesis of bazedoxifene acetate and an important control point in the synthesis of bazedoxifene acetate. ASTRAZENECA UK LIMITED, the original research enterprise of bazedoxifene acetate, discloses a method for preparing the intermediate of the drug. The method uses bromine as the bromination reagent and acetic acid as the solvent for preparation. However, bromine has poor selectivity as a bromination reagent and is difficult to control; acetic acid is difficult to operate when it is used as a solvent at zero temperature (acetic acid is solid at zero temperature), and is not suitable for industrial production. Contents of the invention [0003]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/84C07C45/63
CPCC07C45/63C07C49/84
Inventor 叶乾堂王阳光韩永春叶福林
Owner 河南海汇药物研究有限公司
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