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Synthetic methods of 7-azaspiro[3,5]-nonane-2-ol and hydrochloride compound thereof

A technology of azaspirocycle and alcohol hydrochloride, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of difficult raw material drug production, heavy metal residues, expensive catalysts, etc. high rate effect

Inactive Publication Date: 2017-05-17
苏州汉德创宏生化科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] There are few reports on the synthesis of 7-azaspiranol
The catalyst used in this method is expensive, and the final product may face the problem of heavy metal (palladium) residues, which is difficult to be practically used in the production of raw materials

Method used

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  • Synthetic methods of 7-azaspiro[3,5]-nonane-2-ol and hydrochloride compound thereof
  • Synthetic methods of 7-azaspiro[3,5]-nonane-2-ol and hydrochloride compound thereof
  • Synthetic methods of 7-azaspiro[3,5]-nonane-2-ol and hydrochloride compound thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1 prepares 7-azaspirocyclyl alcohol:

[0031] (1) Synthesis of N-Boc-4-methylene piperidine: Methyl triphenylphosphine bromide is dissolved in methyl tert-butyl ether, and phosphorus ylide reagent (triphenylphosphene ), after reflux for 2 hours, drop the temperature and then drop N-Boc-4-piperidone into the prepared phosphorus ylide reagent at 0°C, methyl tert-butyl ether and the N-Boc-4- The volume-to-weight ratio of piperidone (ml / g) is 5-20:1, heated to reflux and stirred for 20 hours until the reaction is complete, then quenched by saturated ammonium chloride, extracted with ethyl acetate, washed with saturated brine, sodium sulfate Drying, concentration under reduced pressure to obtain crude N-Boc-4-methylenepiperidine, and then distillation under reduced pressure to obtain a product with a purity of about 95%;

[0032] (2) Synthesis of N-Boc-7-azaspirone: N-Boc-4-methylenepiperidine and zinc-copper couple catalyst (13~15 molar equivalents) are dissolve...

Embodiment 2

[0035] Embodiment 2: the synthesis of N-Boc-4-methylene piperidine:

[0036] Add 36.3 g of methyl triphenylphosphine bromide and 300 ml of methyl tert-butyl ether in a three-necked reaction flask with a stirrer under nitrogen protection, cool in an ice-water bath and cool down to 0°C, add 11 g of potassium tert-butoxide to reflux Stir for 2 hours to prepare Wittig reagent, cool down to 0°C again, add 15 g of N-Boc-4-piperidone (dissolved in 60 ml of methyl tert-butyl ether) slowly to the reaction solution, and heat up to reflux again , stirred for 20 hours, the reaction in the gas phase was completed, the reaction solution was slowly poured into 200 ml of saturated ammonium chloride solution to quench the reaction, added 100 ml of ethyl acetate, stirred for 10 minutes, separated to remove the water phase, and the organic phase was used in 200 ml Wash with saturated brine, dry over 100 g of anhydrous sodium sulfate, and concentrate under reduced pressure to obtain an oil. The ...

Embodiment 3

[0037] Embodiment 3: the synthesis of N-Boc-7-azaspirone:

[0038] Add 29.6 grams of N-Boc-4-methylene piperidine and 65.4 grams of zinc-copper couple reagent into a three-necked reaction flask with a stirrer, draw 600 ml of methyl tert-butyl ether under negative pressure, and control the temperature at 20°C Add trichloroacetyl chloride ethylene glycol dimethyl ether solution (136 g / 200 ml) dropwise, and stir at 20°C for 20 hours after the dropwise addition is completed. Slowly add dropwise into the reaction bottle to quench the reaction. During the dropwise addition, control the temperature below 20°C. After quenching, remove the insoluble matter by filtration, extract the filtrate with 200 ml of ethyl acetate, separate the liquids, and use 200 ml of saturated salt for the organic phase Washed with water, dried with 100 g of sodium sulfate for 40 minutes, concentrated under reduced pressure to obtain crude N-Boc-7-azaspirone, and then purified by column chromatography to obta...

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Abstract

The invention discloses 7-azaspiro-[3,5]-nonane-2-ol and a hydrochloride compound thereof. Concretely, N-Boc-4-piperidone is used as a raw material, a wittig reaction is carried out in order to prepare N-Boc-4-methylenepiperidine, zinc / copper is used for catalysis of trichloroacetyl chloride in order to carry out [2+2] cyclisation for preparing N-Boc-7-azaspiro ketone; the azaspiro ketone intermediate is reduced into N-Boc-7-azaspiro-ol by sodium borohydride at a room temperature, and finally 2mol / L hydrochloric acid-ethyl acetate is used for removing Boc in order to prepare a target product hydrochloride whose purity reaches 98%. The product has the advantages of economical and easily available reagents and raw materials which are needed, simple operation, and high product purity; and the product is suitable for batch production.

Description

technical field [0001] The invention relates to a method for synthesizing a pharmaceutical intermediate, in particular to a method for synthesizing 7-azaspiro-[3,5]-nonan-2-ol and its hydrochloride compound. Background technique [0002] Azaspirocyclic compounds are important pharmaceutical intermediates and have attracted widespread attention because they are widely used in the synthesis of small molecule inhibitors of diacylglycerol acyltransferase-1 (DGAT-1). A large number of studies have shown that DGAT-1 inhibitors can effectively inhibit the level of triglycerides in the blood, and are a very promising class of blood lipid-lowering drugs. At present, well-known pharmaceutical companies such as Pfizer and Bayer have invested a lot of scientific research resources in this category. Research on small molecule inhibitors. With the deepening of research on the biological structure of DGAT-1 at home and abroad, a large number of DGAT-1 inhibitors have been widely synthesiz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/20
CPCC07D221/20
Inventor 茅仲平马东旭葛永辉任雪景李景伟
Owner 苏州汉德创宏生化科技有限公司
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