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Method for synthesizing 1,7-diazaspiro[4.5]decane with protective group

A diazaspiro and synthetic method technology, applied in the field 1, can solve the problems of difficult purification of intermediates, impossibility of large-scale production, harsh reaction conditions, etc., and achieve the effects of easy industrial operation, high yield and few reaction steps

Active Publication Date: 2013-04-10
上海药明康德新药开发有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems that the existing 1,7-diazaspiro[4,5]decane compounds have a long synthetic route, low yield, difficult purification of intermediates, harsh reaction conditions, and inability to produce on a large scale

Method used

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  • Method for synthesizing 1,7-diazaspiro[4.5]decane with protective group
  • Method for synthesizing 1,7-diazaspiro[4.5]decane with protective group
  • Method for synthesizing 1,7-diazaspiro[4.5]decane with protective group

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026]

[0027] 1. Synthesis of N-benzyloxycarbonyl-3-piperidine oxime

[0028]

[0029] A mixture of N-benzyloxycarbonyl-3-piperidone (259 g, 1.11 mol), hydroxylamine hydrochloride (234 g, 3.33 mol) and sodium acetate (272 g, 3.33 mol) in ethanol (2000 ml) and water (600 ml ) Stir at room temperature (10-30°C) overnight. TLC monitors the completion of the reaction. Concentrate under reduced pressure to remove ethanol. The residue is extracted with ethyl acetate, washed with water, dried, and concentrated. The crude product is obtained by column chromatography to obtain N-benzyloxycarbonyl-3 - Piperidine oxime colorless oil 146.65 g (40%).

[0030] 1 H NMR (400MHz, CDCl 3 )d ppm: δ7.258-7.362 (m, 5H), δ5.134-5.154 (m, 2H), δ4.094-4.147 (m, 2H), δ3.533-3.580 (m, 2H), δ2. 603-2.636(m, 1H), δ2.364-2.396(m, 1H), δ1.744-1.772(m, 2H).

[0031] 2.1 Synthesis of N-benzyloxycarbonyl-3-nitropiperidine:

[0032]

[0033] Urea hydroperoxide (47.3 grams, 0.6 moles) was dissol...

Embodiment 2

[0065]

[0066] Synthesis reference of N-tert-butoxycarbonyl-4-nitropiperidine Example 1 Operation steps 1 and 2.

[0067] 1. Synthesis of methyl N-tert-butoxycarbonyl-3-(3-nitropiperidin-3-yl)propionate:

[0068]

[0069] Dissolve N-tert-butoxycarbonyl-3-nitropiperidine (46 g, 0.20 mol) in tert-butanol (350 ml) and add Trition B methanol solution (32 ml) dropwise at room temperature, then add methyl acrylate (17.5 g, 0.20 mol). The reaction solution was stirred overnight at room temperature. The reaction was monitored by TLC. After the reaction was completed, tert-butanol was removed by concentration, and the residue was adjusted to weak acidity with hydrochloric acid solution. Extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain a yellow oily substance N-tert-butoxycarbonyl-3-(3-nitropiperidin-3-yl)propionic acid methyl ester 40.17 grams (63....

Embodiment 3

[0077]

[0078] Synthetic reference of N-benzyloxycarbonyl-3-nitropiperidine Example 1 Operation steps 1 and 2.

[0079] 1. Synthesis of N-benzyloxycarbonyl-3-propionyl-3-nitropiperidine

[0080]

[0081] N-benzyloxycarbonyl-3-nitropiperidine (10.99 g, 41.6 mmol) and triethylamine (0.42 g, 4.16 mmol) were dissolved in 50 ml of acetonitrile, and acrolein (3.73 g , 133 mmol) and 10 ml of acetonitrile, stirred overnight. TLC (petroleum ether / ethyl acetate=1:1) showed that the starting material disappeared and the reaction was complete. After concentration, the crude product was purified by silica gel column to obtain 6.5 g (51.1%) of N-benzyloxycarbonyl-3-propanalyl-3-nitropiperidine as a yellow oil.

[0082] 2. Synthesis of N-benzyloxycarbonyl-1,7-diazaspiro[4,5]decane

[0083]

[0084] Mix N-benzyloxycarbonyl-3-propanalyl-3-nitropiperidine (4.67 g, 15.3 mmol) and 1.0 g of Raney Ni in 25 ml of ethanol, and stir overnight at 20-25 ° C under hydrogen pressure of 30 Ps...

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Abstract

The invention relates to a method for preparing 1,7-diazaspiro[4.5]decane and derivatives thereof, and mainly solves the technical problems that the synthetic route is long, the yield is low, an intermediate is difficult to purify, reaction conditions are rigorous, and mass production cannot be performed in the prior art. The method comprises the following steps of: performing Michael addition reaction on N-PG-3-nitropyridine serving as a raw material and acrylic ester or acrolein in alcoholic solution or acetonitrile to obtain N-PG-3-(3-nitropyridine-3-yl)propionate or N-PG-3-propanal-3-nitropyridine; adding a catalyst into the product in an organic solvent, and performing hydrogenation reduction ring-closing reaction to obtain 1,7-diaza-2-oxy-spiro[4.5]decane with a protective group or 1,7-diazaspiro[4.5]decane with a protective group; and adding a reducing agent into the 1,7-diaza-2-oxy-spiro[4.5]decane with the protective group in the organic solvent to obtain the 1,7-diazaspiro[4.5]decane with the protective group. The method has the advantages of a few reaction steps, high yield and mild conditions, and is a synthetic method with large-scale preparation value.

Description

[0001] Technical field: the present invention relates to a preparation method of 1,7-diazaspiro[4,5]decane with protective groups. Background technique: [0002] 1,7-diazaspiro[4,5]decane derivatives are useful drug intermediates, and WO2005 / 097794A1 reported that compounds containing this type of core structure have neurokinin antagonist activity, especially NK1 antagonism activity, combined NK1 / NK2 antagonistic activity, combined NK1 / NK3 antagonistic activity and combined NK1 / NK2 / NK3 antagonistic activity. Drug application primarily for the treatment and / or prophylaxis of the following conditions: schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, especially visceral and Neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (COPD) and voiding disorders urinary incontinence, etc. [0003] For the preparation of 1,7-diazaspiro[4,5]decan...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/10
CPCY02P20/55
Inventor 何雷张宗烈吴滨杨建新李少军虞爱加尹云星徐艳马汝建陈曙辉
Owner 上海药明康德新药开发有限公司
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