Synthetic method of (R)-5-substituted-3-(N-carbobenzoxy pyrrolidine-2-based carbonyl)-1H-benzpyrole

A technology of benzyloxycarbonylpyrrolidine and a synthesis method is applied in the field of synthesis of -5-substituted-3--1H-indole, and can solve the problems of being unsuitable for industrial mass preparation, poor operation controllability and high equipment cost, Achieving the effect of large practical application value, reduced preparation cost and low cost

Inactive Publication Date: 2013-02-20
ZHEJIANG ACAD OF MEDICAL SCI
View PDF6 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its disadvantage is that bromoethyl Grignard reagent and N-benzyloxycarbonyl-D-prolyl chloride will react with each other on the way, the operation controllability is poor, and the equipment cost is high
[0010] In the patents reported above, (R)-5-bromo-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-1H-indole needs to use column chromatography and cryogenic equipment, the preparation cost is high, and it is not necessary Suitable for industrial mass production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthetic method of (R)-5-substituted-3-(N-carbobenzoxy pyrrolidine-2-based carbonyl)-1H-benzpyrole
  • Synthetic method of (R)-5-substituted-3-(N-carbobenzoxy pyrrolidine-2-based carbonyl)-1H-benzpyrole
  • Synthetic method of (R)-5-substituted-3-(N-carbobenzoxy pyrrolidine-2-based carbonyl)-1H-benzpyrole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Prepare N-benzyloxycarbonyl-D-prolyl chloride according to the method in U.S. Patent No. 5,545,644, specifically as follows:

[0045] N-benzyloxycarbonyl-D-proline (0.4mol, 99.0g) was dissolved in 150mL of dichloromethane, and oxalyl chloride (0.6mol, 51.0mL) was added dropwise. Stir for 2 hours, and concentrate to dryness under reduced pressure to obtain 106.9 g of N-benzyloxycarbonyl-D-prolyl chloride as a pale yellow oil, with a yield of 100%.

Embodiment 2

[0047] 500ml three-necked bottle, add 5-bromoindole (30mmol, 5.9g), ZnCl 2 (66mmol, 9.0g) and 150mL of dichloromethane. Under ice-cooling, add 15 mL of THF solution of bromoethyl Grignard reagent (wherein, bromoethyl Grignard reagent is 2.0 mol L -1 ), and stirred for 2 hours. N-Benzyloxycarbonyl-D-prolyl chloride (33mmol, 8.8g) was added dropwise and the reaction was continued for 3 hours. Quench the reaction with saturated ammonium chloride aqueous solution, separate the layers to take the lower layer, wash with water, and saturated NaHCO 3 Washed with aqueous solution, washed with saturated NaCl aqueous solution. The upper aqueous phase was extracted with ethyl acetate, the organic layers were combined, dried and concentrated, and the crude product was recrystallized from ethyl acetate-petroleum ether (volume ratio 1:1) to obtain 10.1 g of a white solid with a yield of 79%.

[0048] white solid 1 H-NMR (DMSO-d 6 )δ:8.51(s,1H),7.63(s,1H),7.51-6.89(m,7H),5.27-5.16(m,2H)...

Embodiment 3

[0054] 500ml three-neck flask, add 5-bromoindole (5.9g, 30mmol), AlCl 3 (8.7g, 66mmol) and 150mL dichloromethane. Under ice-cooling, add 15 mL of THF solution of bromoethyl Grignard reagent (wherein, bromoethyl Grignard reagent is 2.0 mol L -1 ), and stirred for 2 hours. N-Benzyloxycarbonyl-D-prolyl chloride (33 mmol) was added dropwise and the reaction was continued for 3 hours. Quench the reaction with saturated ammonium chloride aqueous solution, separate the layers to take the lower layer, wash with water, and saturated NaHCO 3 Washed with aqueous solution, washed with saturated NaCl aqueous solution. The upper aqueous phase was extracted with ethyl acetate, the organic layers were combined, dried and concentrated, and the crude product was recrystallized from ethyl acetate-petroleum ether (volume ratio 1:1) to obtain 9.2 g of a white solid with a yield of 72%.

[0055] white solid 1 H-NMR (DMSO-d 6 )δ:8.51(s,1H),7.63(s,1H),7.51-6.89(m,7H),5.27-5.16(m,2H),5.06-4.93(m...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
melting pointaaaaaaaaaa
melting pointaaaaaaaaaa
melting pointaaaaaaaaaa
Login to view more

Abstract

The invention discloses a synthetic method of (R)-5-substituted-3-(N-carbobenzoxy pyrrolidine-2-based carbonyl)-1H-benzpyrole. The synthetic method comprises the steps of using 5-substituted benzpyrole shown in a formula (VI) to serve as an initial raw material, adding N-carbobenzoxy-D-prolyl chloride under existence of lewis acid, and reacting to obtain the (R)-5-substituted-3-(N-carbobenzoxy pyrrolidine-2-based carbonyl)-1H-benzpyrole shown in a formula (VII), wherein a substituted group replaces F, Cl, Br or a trifluoromethanesulfonic acid group, and substituted group in the formula (VI) and the formula (VII) are same in meaning. The synthetic method uses the initial raw material which is easy to obtain in the market and stable in molecule, a reaction process is simple and easy to control, cost is low, yield is high, and the synthetic method is applicable to industrial production.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a synthesis method of (R)-5-substituted-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-1H-indole. Background technique [0002] (R)-5-bromo-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-1H-indol, its English name: (R)-2-[(5-Bromo-1H-indol- 3-yl)carbonyl]-1-pyrrolidinecarboxylic acid benzylester, molecular formula: C 21 h 19 BrN 2 o 3 , Molecular weight: 427.29, Appearance: White powdery solid Chemical structural formula as shown in formula (II), this compound can be used to prepare (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl) -1H-indole, the structural formula of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole is shown in formula (I), (R)-5 -Bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole is used as a key intermediate in the preparation of eletriptan, a triptan migraine treatment drug. [0003] [0004] The migraine treatment drug Eletriptan (Eletriptan), de...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06
Inventor 杨叶伟
Owner ZHEJIANG ACAD OF MEDICAL SCI
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap