Synthesis method of (3aS, 9bR)-tert-butyl-3,3 a, 4,5-tetrahydro-pyrrolo [3,4-c] quinolin-2 (9bH) ester

A technology of tetrahydropyrrole and synthesis method, applied in directions such as organic chemistry, can solve problems such as no suitable industrial synthesis method, and achieve the effects of convenient operation, easy reaction and short route

Inactive Publication Date: 2013-05-01
上海药明康德新药开发有限公司 +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Mainly solve the technical problem that there is

Method used

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  • Synthesis method of (3aS, 9bR)-tert-butyl-3,3 a, 4,5-tetrahydro-pyrrolo [3,4-c] quinolin-2 (9bH) ester
  • Synthesis method of (3aS, 9bR)-tert-butyl-3,3 a, 4,5-tetrahydro-pyrrolo [3,4-c] quinolin-2 (9bH) ester

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Experimental program
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Effect test

Embodiment 1

[0010] Example 1 : Dissolve compound 1 (8 g, 0.0396 mol) in triethylamine (14.5 g, 0.143 mol), add palladium acetate (0.09 g, 0.4 mmol) and tri(o-tolyl) phosphine (0.48 g, 1.584 mmol) , and then methyl acrylate (4.1 g, 0.047 mol) was added dropwise under nitrogen protection. After the addition was complete, the reaction temperature was raised to 60 degrees Celsius overnight. TLC (petroleum ether: ethyl acetate volume ratio=5 / 1, R f = 0.5 ) shows that the reaction is complete, the reaction mixture is diluted with dichloromethane (0.1 L) after cooling, washed three times with saturated ammonium chloride solution (30mL), the organic phase is concentrated after drying with anhydrous sodium sulfate, and the residue is purified by column chromatography Purified by the method, the eluent ratio is (petroleum ether: ethyl acetate volume ratio = 20 / 1), after removing the solvent, compound 2 (6.9 g) was obtained as a brown solid, with a yield of 84.6%.

[0011] Compound 2 (13.3 g, 0.0...

Embodiment 2

[0017] Example 2 : Dissolve compound 1 (80 g, 0.396 mol) in triethylamine (145 g, 1.43 mol), add palladium acetate (0.9 g, 0.00396 mol) and tri(o-tolyl)phosphine (4.8 g, 0.01584 mol), Then methyl acrylate (41 g, 0.476 mol) was added dropwise under the protection of nitrogen. After the addition, the temperature of the reaction was raised to 70°C overnight. TLC (petroleum ether: ethyl acetate volume ratio=5 / 1, R f = 0.5 ) to show that the reaction was complete, the reaction mixture was diluted with dichloromethane (1.0 L) after cooling, washed three times with saturated ammonium chloride solution (300 mL), the organic phase was dried with anhydrous sodium sulfate and concentrated, and the residue was used for column Purification by analytical method, the ratio of eluent is (petroleum ether: ethyl acetate volume ratio = 20 / 1), after removing the solvent, compound 2 (70.5 g) was obtained as a brown solid, with a yield of 86%.

[0018] Compound 2 (133 g, 0.643 mol) was dissolve...

Embodiment 3

[0024] Example 3 : Compound 1 (240 g, 1.2 mol) was dissolved in triethylamine (435 g, 4.29 mol), palladium acetate (2.7 g, 0.12 mol) and tri(o-tolyl)phosphine (14.4 g, 0.0475 mol) were added, Then methyl acrylate (123 g, 1.43 mol) was added dropwise under the protection of nitrogen. After the addition, the temperature of the reaction was raised to 90°C overnight. TLC (petroleum ether: ethyl acetate volume ratio=5 / 1, R f = 0.5 ) showed that the reaction was complete. After the reaction mixture was cooled, it was diluted with dichloromethane (3.0 L), washed three times with saturated ammonium chloride solution (900 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was used for column Purification by analytical method, the eluent ratio is (petroleum ether: ethyl acetate = 20 / 1), after removing the solvent, compound 2 (220 g) was obtained as a brown solid, with a yield of 90.3%.

[0025] Compound 2 (400 g, 1.93 mol) was dissolved ...

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Abstract

The invention relates to a synthesis method of a (3aS, 9bR)-tert-butyl-3,3 a, 4,5-tetrahydro-pyrrolo [3,4-c] quinolin-2 (9bH) ester, and mainly solves the technical problem that an appropriate industrial synthesis method does not exist at present. The method comprises six steps that: a compound 1 and methyl acrylate are subjected to a Michael addition reaction to obtain a compound 2, and then a compound 3 is obtained by a 3 +2 reaction; the nitro group of the compound 3 is subjected to hydrogenation reduction, and intramolecular ammonia is subjected to transesterification to obtain a compound 4; and the amide of the compound 4 is reduced with lithium aluminum hydride to obtain a compound 5, and the compound 5 is hydrogenated to remove a benzyl group, and is reacted with Boc anhydride to obtain a final compound. The reaction formula is as follows.

Description

technical field [0001] A method for synthesizing the compound (3aS,9bR)-tert-butyl-3,3a,4,5-tetrahydropyrrole[3,4-c]quinoline-2(9bH) ester involved in the present invention. Background technique [0002] Compound (3aS,9bR)-tert-butyl-3,3a,4,5-tetrahydropyrrole[3,4-c]quinoline-2(9bH) ester and related derivatives have important roles in medicinal chemistry and organic synthesis. widely used. Currently, the synthesis of (3aS,9bR)-tert-butyl-3,3a,4,5-tetrahydropyrrolo[3,4-c]quinoline-2(9bH) ester is difficult. Therefore, it is necessary to develop a synthetic method with readily available raw materials, convenient operation, easy control of the reaction, and suitable overall yield. Contents of the invention [0003] The purpose of the invention is to develop a kind of (3aS,9bR)-tert-butyl-3,3a,4,5-tetrahydropyrrole [3,4 -c] Synthetic method of quinoline-2(9bH) ester. It mainly solves the technical problem that there is no suitable industrial synthesis method at present. ...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 陈雅婷任文武孟庆洪宁振翠芮甜甜孙宝龙王庆伟袁晓斌于凌波
Owner 上海药明康德新药开发有限公司
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