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Preparation method for 2-(t-butyloxycarbonyl) octahydrocyclopenta [c] pyrrole-5-carboxylic acid

A technology of tert-butoxycarbonyl and octahydrocyclopenta, which is applied in the field of synthesis of 2-octahydrocyclopenta[c]pyrrole-5-carboxylic acid, can solve problems such as dangerous raw materials, highly toxic use, and inconvenient operation, and achieve Effects of cost reduction, ease of scale-up, and shortened synthesis routes

Active Publication Date: 2013-05-01
武汉药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the current technical problems such as long synthetic route, use of highly toxic and dangerous raw materials, inconvenient operation and high cost

Method used

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  • Preparation method for 2-(t-butyloxycarbonyl) octahydrocyclopenta [c] pyrrole-5-carboxylic acid
  • Preparation method for 2-(t-butyloxycarbonyl) octahydrocyclopenta [c] pyrrole-5-carboxylic acid
  • Preparation method for 2-(t-butyloxycarbonyl) octahydrocyclopenta [c] pyrrole-5-carboxylic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011]

[0012] Dissolve 50 g (0.22 mol) of 4-oxahexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester and 316 g (3.51 mol) of sodium hydride in anhydrous tetrahydrofuran solution, add 316 g (3.51 mol) of dimethyl carbonate, stirred at room temperature for 2 hours, and the disappearance of raw materials was detected by thin layer chromatography. The reaction system was quenched with water, and the reaction solution was extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography to obtain 2-tert-butyl 5-methyl-4-oxahexahydrocyclopenta[c]pyrrole-2,5(1H) -Dicarboxylate 48.4 grams, yield: 77%, white solid.

[0013] 1 HNMR: CDCl3 400MHz, δ1.34 - 1.44 (m, 9 H), 2.02 - 2.32 (m, 1 H), 2.36 - 2.68 (m, 1 H), 2.70 - 3.15 (m, 2 H), 3.26 - 3.66 (m, 4H), 3.67 - 3.76 (m, 3H).

[0014] Embodiment 1: b,

[0015]

[0016] Dissol...

Embodiment 2

[0021]

[0022] Dissolve 50 g (0.18 mol) of 2-tert-butyl 5-methyl-4-oxahexahydrocyclopenta[c]pyrrole-2,5(1H)-dicarboxylate in 400 mL of methanol and add Sodium borohydride 3.35 g (88.3 mmol), react at room temperature for 1 hour. Thin-layer chromatography detects the disappearance of raw materials, the reaction solution is quenched with 200 ml of saturated ammonium chloride solution, and the reaction solution is extracted with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 47.34 grams of 2-tert-butyl 5-methyl-4-hydroxyhexahydrocyclopenta[c]pyrrole-2,5(1H)-dicarboxylate , Yield: 94%.

[0023] 1 HNMR: CDCl3 400MHz

[0024] δ1.35 - 1.44 (m, 9H), 1.66 - 1.91 (m, 1H), 1.97 - 2.36 (m, 1H), 2.54 - 2.93 (m, 3H), 3.00 - 3.35 (m, 2H) ), 3.41 - 3.63 (m, 2H), 3.66 (2H), 4.23 - 4.35 (m, 1H).

[0025] Embodiment 2: b,

[0026]

[0027] Dissolve 50 g (0.18 mol) of 2-tert-butyl 5-m...

Embodiment 3

[0032]

[0033] 43.12 g (0.15 mol) of 2-tert-butyl 5-methyl-4-hydroxyhexahydrocyclopenta[c]pyrrole-2,5(1H)-dicarboxylate and 30.6 g (0.3 mol) of tris Ethylamine was dissolved in 500 ml of dichloromethane, protected with nitrogen, and 20.79 g (0.18 mol) of methanesulfonyl chloride was added dropwise. The system warmed up slowly and reacted overnight at room temperature. Thin-layer chromatography detects that the starting material disappears, the reaction solution is quenched with 300 ml of 1 N dilute hydrochloric acid, and the reaction solution is extracted with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product 2-tert-butyl 5-methyl-4-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2,5(1H )-dicarboxylate 50 grams, yield: 91%, white solid.

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Abstract

The invention relates to a preparation method for a 2-(t-butyloxycarbonyl) octahydrocyclopenta [c] pyrrole-5-carboxylic acid and mainly aims to solve the technical problems that a traditional synthesis process is long in route, high in cost, difficult in reaction control and inconvenient in experimental operation. The 2-(t-butyloxycarbonyl) octahydrocyclopenta [c] pyrrole-5-carboxylic acid is prepared by taking 4-oxohexahydro [c] pyrrole-2 (1H)- formic acid tert-butyl ester as a raw material through a six-step reaction. The reaction formula is shown as follows: , the 2-(t-butyloxycarbonyl) octahydrocyclopenta [c] pyrrole-5-carboxylic acid obtained by the preparation method is a key intermediate for synthetizing a compound with a treatment potential of an active nicotinic acetylcholine receptor of combining and adjusting neurons.

Description

technical field [0001] The invention relates to a synthesis method of 2-(tert-butoxycarbonyl) octahydrocyclopenta[c]pyrrole-5-carboxylic acid. Background technique [0002] 2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-5-carboxylic acid is an important intermediate in organic synthesis, and a series of compounds derived from this compound have the activity of nicotine in binding and regulating neurons The therapeutic potential of acetylcholine receptors, and their synthesis have received much attention. The synthetic method of 2-(tert-butoxycarbonyl) octahydrocyclopenta[c]pyrrole-5-carboxylic acid in the literature【 J. Org. Chem. 1990,55,3673-3674]【WO2008121686】Mainly obtain 2-(tert-butyl Oxycarbonyl) octahydrocyclopenta[c]pyrrole-5-carboxylic acid. This synthetic method requires a total of more than nine steps to obtain the product, which mainly has the following problems: (1) The highly toxic allylamine and the dangerous product hexa-n-butyltin are used in the re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
Inventor 于凌波胡红雨付新雨王潇雨张涛陈冬枝张双双庞洲冯建龙王琏
Owner 武汉药明康德新药开发有限公司
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