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Preparation method of odanacatib, and preparation method of odanacatib intermediate

A technology for odancati and intermediates, which is applied in the field of preparation of odancati and its intermediates, can solve the problems of dangerous operation, long preparation route steps, low reaction yield and the like

Active Publication Date: 2018-11-30
上海新礼泰药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to overcome the preparation method of trifluoroacetone biphenyl methyl sulfone intermediate I in the prior art, the preparation route step is long, needs to use highly flammable lithium reagent twice, dangerous operation, needs A method for preparing odancati and its intermediates is provided due to defects such as the use of foul-smelling sulfide intermediates, serious environmental pollution, low reaction yield, and unsuitability for industrial production.

Method used

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  • Preparation method of odanacatib, and preparation method of odanacatib intermediate
  • Preparation method of odanacatib, and preparation method of odanacatib intermediate
  • Preparation method of odanacatib, and preparation method of odanacatib intermediate

Examples

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Effect test

Embodiment 1

[0075] Example 1: Preparation of 2,2,2-trifluoroacetophenone-4-boronic acid pinacol ester

[0076]

[0077]Under nitrogen protection, 20.0 g (0.079 mol) of 4'-bromo-2,2,2-trifluoroacetophenone and 25.1 g of pinacol diborate were added to 150 mL of N,N-dimethylformamide ( 0.099mol), potassium acetate 15.5g (0.158mol), bistriphenylphosphine palladium dichloride 0.28g (0.00040mol). After vacuum degassing and nitrogen replacement, it was heated to 90°C and reacted for 12 hours. After cooling, filter, add mass concentration and be 10% ammonium chloride aqueous solution (the described mass concentration refers to the quality of ammonium chloride accounts for the percentage of ammonium chloride aqueous solution gross mass) 100mL and water 300mL, extract with ethyl acetate 150mL Twice, merging organic phase with mass concentration is that 10% sodium bicarbonate aqueous solution (described mass concentration refers to the percentage that the quality of sodium bicarbonate accounts f...

Embodiment 2

[0078] Example 2: Preparation of 2,2,2-trifluoroacetophenone-4-boronic acid pinacol ester

[0079] Under nitrogen protection, 25.0 g (0.099 mol) of 4'-bromo-2,2,2-trifluoroacetophenone, 27.6 g (0.109 mol) of pinacol diborate, 31.5 g (0.148 mol) of potassium phosphate, and 0.18 g (0.00025 mol) of dichlorobis(tricyclohexylsulfone)palladium. After vacuum degassing and nitrogen replacement, it was heated to 100° C. and reacted for 8 hours. After cooling, filter, add mass concentration and be 10% ammonium chloride aqueous solution (the described mass concentration refers to the quality of ammonium chloride accounts for the percentage of ammonium chloride aqueous solution gross mass) 100mL and water 300mL, extract with ethyl acetate 150mL Twice, merging organic phase with mass concentration is that 10% sodium bicarbonate aqueous solution (described mass concentration refers to the percentage that the quality of sodium bicarbonate accounts for the total mass of sodium bicarbonate aq...

Embodiment 3

[0080] Example 3: Preparation of 2,2,2-trifluoroacetophenone-4-boronic acid pinacol ester

[0081] Under nitrogen protection, 20.0 g (0.079 mol) of 4'-bromo-2,2,2-trifluoroacetophenone and 30.1 g of pinacol diborate were added to 200 mL of N,N-dimethylacetamide ( 0.119 mol), 19.5 g (0.238 mol) of sodium acetate, and 0.58 g (0.00079 mol) of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. After vacuum degassing and nitrogen replacement, it was heated to 80° C. and reacted for 16 hours. After cooling, filter, add mass concentration and be 10% ammonium chloride aqueous solution (the described mass concentration refers to the quality of ammonium chloride accounts for the percentage of ammonium chloride aqueous solution gross mass) 100mL and water 300mL, extract with ethyl acetate 150mL Twice, merging organic phase with mass concentration is that 10% sodium bicarbonate aqueous solution (described mass concentration refers to the percentage that the quality of sodium bic...

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Abstract

The invention discloses a preparation method of odanacatib, and a preparation method of an odanacatib intermediate. The preparation method of the trifluoroethylketone biphenyl methylsulfone intermediate I comprises the following step: 2,2,2-trifluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone and 4-bromophenyl methyl sulfone undergo a coupling reaction in a solvent in the presence of a metal catalyst and an inorganic alkali to obtain the trifluoroethylketone biphenyl methylsulfone intermediate I. The preparation methods have the advantages of simplicity and safety in operation, short route steps, environmental friendliness, high reaction yield, and high purity of the obtained products, and the odanacatib II obtained by using the trifluoroethylketone biphenyl methylsulfone intermediate I as the intermediate has the advantages of high purity, meeting of bulk drug standards, and suitableness for industrial production.

Description

technical field [0001] The invention relates to a preparation method of odancati and its intermediate. Background technique [0002] Odanacatib (II) is an oral cathepsin K inhibitor for the treatment of postmenopausal osteoporosis and tumor bone metastasis. Preclinical tests have shown that Odangcate can reduce bone destruction in animal models of breast cancer bone metastasis and inhibit tumor growth. It can reduce cancer bone resorption by 50% but has no significant effect on bone formation, thereby significantly reducing osteoporosis. fracture. In a randomized double-blind clinical trial, 4-week treatment with odancate can significantly inhibit osteolysis in patients with bone metastases from breast cancer, revealing that odancate can be used as a new method for the treatment of bone metastases from breast cancer. [0003] [0004] Trifluoroacetone biphenylmethyl sulfone intermediate I is an important intermediate for the preparation of odancati. [0005] [0006...

Claims

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Application Information

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IPC IPC(8): C07C317/24C07C317/32C07C315/04
CPCC07C315/04C07F5/025C07C2601/02C07C317/24C07C317/32
Inventor 陈健刘胜辉应述欢
Owner 上海新礼泰药业有限公司
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