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Method for preparing template compound of ancylus fluviatilis [1,3 dihydro indene ¿C 4í»- piperidine 1 - carboxylic acid]

A technology of dihydroindene and compound is applied in the field of preparation of spiro compounds, can solve the problems of long route, low total yield, high price and the like, and achieves the effects of good biological activity, short reaction route and low cost

Inactive Publication Date: 2007-12-26
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This synthetic method has following deficiencies: route is very long, causes total recovery to be very low
9-BBN used, PhN(Tf) 2 , KHMDS and other reagents are expensive
The synthesis method reported in the literature does not have the feasibility of large-scale preparation

Method used

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  • Method for preparing template compound of ancylus fluviatilis [1,3 dihydro indene ¿C 4í»- piperidine 1 - carboxylic acid]
  • Method for preparing template compound of ancylus fluviatilis [1,3 dihydro indene ¿C 4í»- piperidine 1 - carboxylic acid]
  • Method for preparing template compound of ancylus fluviatilis [1,3 dihydro indene ¿C 4í»- piperidine 1 - carboxylic acid]

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017]

[0018] Synthesis of spiro[1,3-dihydroindene-4'-tert-butyloxycarbonylpiperidine-1-carboxylic acid]

[0019] The first step: the synthesis of spiro[1,3-dihydroindene-1,2-dibromo-4'-tert-butyloxycarbonylpiperidine]B

[0020] Dissolve spiro[indene-4'-tert-butyloxycarbonylpiperidine] (A, 100g, 0.35mol) in anhydrous Na 2 SO 4 To the dried THF (1500 mL), cool to 0°C in an ice bath, and add bromine (68.2 g, 0.43 mol) dropwise at about 5°C, and the addition is completed in about 30 minutes. After dropping, react at 0-5°C for 1.5 hours. Then the reaction solution was slowly poured into the solution containing NaHCO under stirring. 3 (20g) and NaHSO 3 (5 g) in aqueous solution (400 mL), ethyl acetate (700 mL) was added after 30 minutes. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (400 mL×2). The organic layers and extracts were combined, washed twice with saturated brine, anhydrous MgSO 4 After drying and concentrating to ...

Embodiment 2

[0028]

[0029] Synthesis of spiro[1,3-dihydroindene-4'-tert-butyloxycarbonylpiperidine-1-carboxylic acid]

[0030] The first step: the synthesis of spiro[1,3-dihydroindene-1,2-dibromo-4'-tert-butyloxycarbonylpiperidine]B

[0031] Dissolve spiro[indene-4'-tert-butyloxycarbonylpiperidine] (A, 100g, 0.35mol) in anhydrous Na 2 SO 4 To the dried THF (1500 mL), cool to 0°C in an ice bath, and add bromine (68.2 g, 0.43 mol) dropwise at about 5°C, and the addition is completed in about 30 minutes. After dropping, react at 0-5°C for 1.5 hours. Then the reaction solution was slowly poured into the solution containing NaHCO under stirring. 3 (20g) and NaHSO 3 (5 g) in aqueous solution (400 mL), ethyl acetate (700 mL) was added after 30 minutes. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (400 mL×2). The organic layers and extracts were combined, washed twice with saturated brine, anhydrous MgSO 4 After drying and concentrating to ...

Embodiment 3

[0041]

[0042] Synthesis of spiro[1,3-indane-4'-tert-butyloxycarbonylpiperidine-1-carboxylic acid]

[0043] The first step: the synthesis of spiro[1,3-dihydroindene-1,2-dibromo-4'-tert-butyloxycarbonylpiperidine]B

[0044] Dissolve spiro[indene-4'-tert-butyloxycarbonylpiperidine] (A, 100g, 0.35mol) in anhydrous Na 2 SO 4 To the dried THF (1500 mL), cool to 0°C in an ice bath, and add bromine (68.2 g, 0.43 mol) dropwise at about 5°C, and the addition is completed in about 30 minutes. After dropping, react at 0-5°C for 1.5 hours. Then the reaction solution was slowly poured into the solution containing NaHCO under stirring. 3 (20g) and NaHSO 3 (5 g) in aqueous solution (400 mL), ethyl acetate (700 mL) was added after 30 minutes. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (400 mL×2). The organic layers and extracts were combined, washed twice with saturated brine, anhydrous MgSO 4 After drying and concentrating to dryness...

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Abstract

This invention relates to a method for synthesizing spiro compound, i.e., spiro [1, 3-dihydrolindane-4'-piperidine-1-carboxylic acid] template compound. The method comprises: performing addition reaction between spiro[lindane-4'-tert-butoxycarbonyl piperidine] and bromine to obtain dibromide, eliminating HBr from the dibromide in the presence of alkali to obtain olefin bromide, treating with lithium compound, introducing CO2 to obtain alpha,beta-unsaturated acid, and hydrogenating to obtain the target compound, or performing carbonylation reaction to obtain alpha,beta-unsaturated ester from olefin bromide C, hydrogenating, and hydrolyzing to obtain the target compound. The method overcomes the problems of long synthesis route, low yield, expensive reagents and unable mass production faced by the present synthesis method. The method has such advantages as short synthesis route, no need for expensive reagents, mild reaction conditions and low cost, and is suitable for mass production.

Description

Technical field: [0001] The invention relates to a preparation method of a class of spiro compounds, in particular to a preparation method of a spiro[1,3-dihydroindene-4'-piperidine-1-carboxylic acid] template compound. Background technique: [0002] The spiro compound containing spiro[1,3-dihydroindene-4'-piperidine-1-carboxylic acid] structure has been proved to have a variety of physiological activities. The compound (derived from the above-mentioned spirocyclic template) has the physiological activity of stimulating the endogenous or secreted growth hormone in the body, and can be used to treat diseases related to the lack of growth hormone in the body, such as dwarfism, etc., and can specifically stimulate The growth of certain animals, so as to obtain animals with more flesh and fluff. [0003] It was also reported in the literature Bioorg.Med.Chem.Lett 1997, 7(17), 2319 that the compound 2 with this template compound as the core structure also has the function of pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/20
Inventor 陈华祥马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司