Method for synthesizing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with protective group

A synthetic method and a technology of protecting groups, which are applied in the field of synthesis of 3-aza-bicyclo[4.1.0]heptane-6-carboxylic acid, can solve the problems of short synthetic route and overall yield, and achieve short reaction time and high yield. High efficiency and mild reaction conditions

Active Publication Date: 2013-12-25
上海药明康德新药开发有限公司 +2
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to provide a kind of synthetic route short, overall yield height, the synthetic method of the band protecting group 3-aza-bicyclo[4.1.0]heptane-6-carboxylic acid of gentle process condition, mainly solve existing Technical problems requiring multi-step column chromatography purification in the preparation process of 3-aza-bicyclo[4.1.0]heptane-6-carboxylic acid

Method used

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  • Method for synthesizing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with protective group
  • Method for synthesizing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with protective group

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Experimental program
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Effect test

Embodiment 1

[0018] 1. Mix 100g of ethyl isonicotinate (0.66mol) and 115g of benzyl bromide (13.2mol) in 1L of methanol, stir and heat to reflux at 65°C for 12 hours, remove the solvent and dissolve the white solid obtained in 1L of ethanol, cool Add 100mL aqueous solution of 25g sodium borohydride (6.5mol) dropwise at 0°C, stir at room temperature for 1 hour after dropping, evaporate the solvent ethanol, add 2L dichloromethane and 1L water to the residue, stir and separate, and use 1L dichloromethane Washed twice with water, washed once with 250mL saturated saline, anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain light yellow liquid ethyl N-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (compound 10, R=Bn). Yield 98%.

[0019] 28 g of sodium hydrogen (0.7 mol) was suspended in 1.3 L of DMSO, and 153 g (0.7 mol) of trimethylsulfoxide iodide was added in portions with stirring under nitrogen protection, and the resulting mixture was stirred at room temperature for...

Embodiment 2

[0022] Dissolve ethyl N-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (10g, 59mmol) in 100mL ether, add 0.2g palladium acetate, cool to 0°C, add freshly prepared About 0.5mol / L dry diazomethane ether solution (250mL), the temperature is controlled at 0-2°C. After the dropwise completion, the mixture was stirred at 25° C. for 12 hours. The excess diazomethane was quenched with acetic acid, the reaction solution was mixed with diatomaceous earth and filtered, the filtrate was concentrated to dryness, and purified by silica gel column chromatography to obtain 500 mg of the desired N-methyl-3-aza-bicyclo[4.1.0] Ethyl heptane-6-carboxylate (compound 11, R=Me), yield 4.9%

Embodiment 3

[0024] 1. 4.5g of ethyl N-benzyl-3-aza-bicyclo[4.1.0]heptane-6-carboxylate (compound 11, R=Bn, 17.4mmol) was dissolved in 100ml of ethanol, and 3.9g of Boc was added 2 O (17.8mmol) and 0.5g 10% Pd(OH) 2 / C, the mixture was hydrogenated under 45 psi hydrogen gas at room temperature for 5 hours with stirring, and TLC (n-hexane:ethyl acetate volume percentage=4:1) detected that the reaction was complete. The reaction solution was filtered and concentrated to obtain 4.3 g of ethyl N-Boc-3-aza-bicyclo[4.1.0]heptane-6-carboxylate (compound 11, R=Boc) as a white solid, with a yield of 92%.

[0025] 4.3g of ethyl N-Boc-3-aza-bicyclo[4.1.0]heptane-6-carboxylate (compound 11, R=Boc, 16mmol) was dissolved in 50mL of methanol, and 6.8g of lithium hydroxide monohydrate was added dropwise (160 mmol) in 50 mL aqueous solution, stirred and heated to reflux for 3 hours after dropping, cooled to room temperature, removed most of the methanol under reduced pressure, and washed with ether to rem...

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Abstract

The invention relates to a method for preparing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with a protective group, and mainly solves the technical problem that multi-step chromatographic purification is needed in the conventional process for preparing the 3-aza-bicyclo[4.1.0]heptane-6-formic acid. The method comprises the following steps of: performing reflux alkylation reaction on conventional and readily available ethyl isonicotinate serving as a raw material and halohydrocarbon in alcohol solution to obtain quaternary ammonium; performing cyanoborohydride reaction to obtain amino-protected 1,2,3,6-tetrahydropyridine-4-ethyl formate; not performing purification, and directly performing ring-closing reaction to obtain a three-membered ring; and performing alkaline hydrolysis reaction to obtain amino-protected 3-aza-bicyclo[4.1.0]heptane-6-formic acid. The 3-aza-bicyclo[4.1.0]heptane-6-formic acid with the protective group is an important medicinal intermediate.

Description

Technical field: [0001] The invention relates to a method for synthesizing protected 3-aza-bicyclo[4.1.0]heptane-6-carboxylic acid. Background technique: [0002] 3-Aza-bicyclo[4.1.0]heptane-6-carboxylic acid is a useful drug intermediate, and the synthetic method reported in the literature is obtained through multi-step reactions with 4-aminopropionic acid: first esterification, enzymatic Alkylation of the propyl group followed by protection of the amino group gave compound 4, the α-halogenated compound 4, followed by catalyst Pd(PPh 3 ) 4 In the presence of 1,8-bisdimethylaminonaphthalene (proton sponge) reagent treatment to obtain the six-membered ring compound 6; finally the alkali action to close the three-membered ring, hydrolysis to obtain the desired 3-aza-bicyclic ring with a protective group [4.1.0] Heptane-6-carboxylic acid. [0003] Literature synthesis route: [0004] [0005] The synthetic route provided in the literature has long steps, low overall yiel...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/04
CPCY02P20/55
Inventor 张明亮俞鸿斌马汝建
Owner 上海药明康德新药开发有限公司
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