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Synthesis method of tert butyl-1-(hydroxymethyl)-3-oxa-9-azaspiro-[5.5] undecane-9-formyl ester

A kind of technology of methylol, tert-butyl, applied in the field of preparation method of tert-butyl 1-(hydroxymethyl)-3-oxa-9-azaspiro[5.5]undecane-9-carboxylate , to achieve the effect of reasonable reaction process design and saving synthesis cost

Active Publication Date: 2017-09-29
上海药明康德新药开发有限公司 +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there is currently no complete synthetic route report

Method used

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  • Synthesis method of tert butyl-1-(hydroxymethyl)-3-oxa-9-azaspiro-[5.5] undecane-9-formyl ester
  • Synthesis method of tert butyl-1-(hydroxymethyl)-3-oxa-9-azaspiro-[5.5] undecane-9-formyl ester

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Experimental program
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Embodiment 1

[0011] Step 1: Add 1.3 mol of titanium tetrachloride to a mixed solvent of anhydrous tetrahydrofuran / chloroform (1.0 L / 0.5 L) at 0°C, followed by dropwise addition of 0.65 mol of compound 1 and 0.65 mol of diethyl ketomalonate . Afterwards, 2.6 mol of pyridine was added into the reaction system, and reacted overnight at 25°C. After the reaction was completed, the reaction was quenched with 1 L aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (1 L*2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified on a silica gel column to obtain 438 g of compound 2 , Yield: 64%.

[0012] Step 2: 0.505 mol of lithium hexamethylsilyl ammonium was added into a mixed solvent of 0.505 mol of ethyl acetate and 1.2 L of anhydrous tetrahydrofuran at -70°C. Stir at -70°C for 30 minutes. Subsequently, 0.417 mol of compound 2 was added into the system, and it was kept overnight at 25°C. Aft...

Embodiment 2

[0018] Step 1: Add 1.1 mol of titanium tetrachloride to a mixed solvent of anhydrous tetrahydrofuran / chloroform (1.0 L / 1 L) at 0°C, followed by dropwise addition of 0.5 mol of compound 1 and 0.5 mol of diethyl ketomalonate . Afterwards, 2.5 mol of pyridine was added into the reaction system, and reacted overnight at 25°C. After the reaction was completed, the reaction was quenched with 1 L aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (1 L*2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified on a silica gel column to obtain 400 g of compound 2 , Yield: 58%.

[0019] Step 2: 0.5 mol of lithium hexamethylsilyl ammonium was added into a mixed solvent of 0.50 mol of ethyl acetate and 1.0 L of anhydrous tetrahydrofuran at -70°C. Stir at -70°C for 2 hours. Subsequently, 0.4 mol of compound 2 was added into the system, and it was kept overnight at 25°C. After the react...

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Abstract

The present invention relates to a synthesis method of tert butyl-1-(hydroxymethyl)-3-oxa-9-azaspiro-[5.5] undecane-9-formyl ester, and mainly solves the technical problems of low imperfect rate, no easiness in control of reaction, experimental operation inconvenience and the like of the synthesis process in the prior art. The tert butyl-1-(hydroxymethyl)-3-oxa-9-azaspiro-[5.5] undecane-9-formyl ester is prepared from 1-phenylmethyl piperidine-4-one as a starting raw material by a three-step reaction. The reaction formula is as shown in the specification, and the product obtained by the method is a useful intermediate or product for synthesis of many pharmaceuticals.

Description

technical field [0001] The invention relates to a synthetic method of tert-butyl 1-(hydroxymethyl)-3-oxa-9-azaspiro[5.5]undecane-9-carboxylate. Background technique [0002] tert-butyl 1-(hydroxymethyl)-3-oxa-9-azaspiro[5.5]undecane-9-carboxylate (CAS: 1357352-71-6) and related derivatives in medicinal chemistry It has important applications in organic synthesis and organic synthesis, and has excellent prospects. However, there is no complete synthetic route report so far. Therefore, it is of great significance to develop a synthetic method that is easy to obtain cheap raw materials, easy to operate, easy to control the reaction in batch production, and suitable for the overall yield. Contents of the invention [0003] The purpose of this invention is to develop a kind of raw material that has cheap, easy to operate, can enlarge, five steps higher yield tert-butyl 1-(hydroxymethyl)-3-oxa-9-azaspiro[5.5]11 Process for the preparation of alkane-9-carboxylates. The method...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107
CPCC07D491/107
Inventor 徐学芹周强王瑞琪刘倩何燕平安自强吴艳刘月领焦家盛于凌波马汝建
Owner 上海药明康德新药开发有限公司
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