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Preparation method of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate and oxalate thereof

A technology for tert-butyl formate and diazaspiro, which is applied in the field of pharmaceutical intermediate synthesis, can solve problems such as toxic fumes, easy explosion, etc., and achieve the effects of controllable process and simple reaction

Active Publication Date: 2021-08-20
TIANJIN QUANHECHENG TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] For the above-mentioned related technologies, chlorosulfonyl isocyanate is sensitive to moisture. When thiosulfate-potassium hydroxide aqueous solution is processed, unreacted chlorosulfonyl isocyanate easily reacts violently with moisture to produce toxic fumes; while borane-dimethyl The thioether complex is a flammable and toxic gas at normal temperature, and it is prone to explosion at a reaction temperature of 70°C. In order to ensure production safety, 1,7-diazaspiro[3.5]nonane-7 - tert-butyl formate can only be produced in small quantities

Method used

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  • Preparation method of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate and oxalate thereof
  • Preparation method of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate and oxalate thereof
  • Preparation method of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate and oxalate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] A preparation method of 1,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, the reaction formula of each step is as follows:

[0037] Step S1:

[0038]

[0039] The specific operation of this step: at 25°C, mix N-tert-butoxycarbonyl-4-piperidone (200g, 1.00mol), ammonium acetate (77.08g, 1.00mol) and ethylmalonate (186g, 1.41 mol) was dissolved in ethanol (1L), heated to 80-85°C, and reacted under reflux for 1 hour. TLC spot plate (petroleum ether / ethyl acetate volume ratio=3 / 1) showed that the reaction of tert-butyl 4-amino-4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate was complete .

[0040] The reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in ethyl acetate, washed with 1N hydrochloric acid solution, then backwashed once with distilled water, and potassium carbonate was added to adjust the pH value of the washing solution to 11-12, and then ethyl acetate (0.5 L) extracting 3 times to obtain an...

Embodiment 2-3

[0058] A method for preparing tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate, the difference from Example 1 is that the molar weight of raw materials in step S1 is different, and the specific molar weight is shown in the following table :

[0059] Table 1. Molar amounts of raw materials in step S1

[0060]

Embodiment 4-5

[0062] A method for preparing tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate, the difference from Example 3 is that the incubation reaction time in step S1 is different, and the specific reaction time is shown in the following table:

[0063] Table 1. Insulation reaction time in step S1

[0064] Example Example 3 Example 4 Example 5 Reaction time / h 0.5 1 1.5 Yield of tert-butyl 4-amino-4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate / % 47 5 48.1 46.9

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Abstract

The invention relates to the field of synthesis of medical intermediates, and particularly discloses tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate and oxalate thereof. The preparation method of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate comprises the following steps: by taking N-tert-butyloxycarbonyl-4-piperidone, ethyl hydrogen malonate and ammonium acetate as initial raw materials, sequentially carrying out Mannich reaction, reduction reaction, halogenation, cyclization reaction and purification to obtain purified tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate. The preparation method disclosed by the invention is simple to operate and suitable for industrial mass production.

Description

technical field [0001] The application relates to the field of synthesis of pharmaceutical intermediates, more specifically, it relates to a preparation method of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate and its oxalate. Background technique [0002] tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate (CAS: 1180112-41-7) is an important pharmaceutical intermediate, often used as a raw material for the synthesis of protein inhibitors and other substances. Currently, there are few reports on the synthesis of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate. [0003] In the related art, the patent SUBSTITUTED PYRIDINES ASINHIBITORS OF DNMT1 with publication number WO2017216726A1 describes a preparation method of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate: using N-Boc-4- Methylene piperidine and chlorosulfonyl isocyanate are used as reaction raw materials, which are sequentially treated with thiosulfate-potassium hydroxide aqueous solution and extracted with ...

Claims

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Application Information

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IPC IPC(8): C07D471/10C07C55/07C07C51/41
CPCC07D471/10C07C51/412C07C55/07Y02P20/55
Inventor 詹润张超李静简宋艳民
Owner TIANJIN QUANHECHENG TECH
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