Pentazane derivative intermediate, its preparation and use

A derivative, pyrrolidine technology, applied in the field of chemical synthesis, can solve the problems of difficult removal of impurities, high cost, and difficulty in product purification, and achieve the effects of avoiding side reactions and simple preparation methods.

Active Publication Date: 2007-01-17
CHENGDU DIAO JIUHONG PHARMA FACTORY
View PDF1 Cites 17 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] There are currently two production routes for doripenem. Route 1 uses (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphoryloxy-1- Methyl-1-carbo-2-penem-3-carboxylic acid benzhydryl ester and (2S,4S)-1-tert-butoxycarbonyl-2-(N-tert-butoxycarbonyl-N-ammonia Sulfonylamino) methyl 4-mercaptopyrrolidine reacts to generate protected pyrrolidinylthiocarbapenem, and then deprotects doripenem with Lewis acid aluminum chloride (Organic Process Research & Development 2003, 7, 846- 850; CN1032257) (as shown in Figure-3), the carboxylic acid benzhydryl ester intermediate used in this route has no raw material supply in China, and the cost is very high. Vinylbenzene-type macroporous resin column is used for purification, which brings inconvenience to industrial production. At the same time, it is difficult to remove the residual aluminum ions in the product, and the product purification is very difficult.
[0005] Another route 2, using (2S, 4S)-1-p-nitrobenzyloxycarbonyl-2-(N-tert-butoxycarbonyl-N-sulfamoylamino)methyl-4-acetylthiopyrrolidine Sulfuric acid

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
  • Pentazane derivative intermediate, its preparation and use
  • Pentazane derivative intermediate, its preparation and use
  • Pentazane derivative intermediate, its preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation of embodiment 1 pyrrolidine derivatives

[0032] Step 1N-Preparation of p-nitrobenzyloxycarbonylsulfonamide

[0033] Cool 38.285g (250mmol) of p-nitrobenzyl alcohol tetrahydrofuran solution to -40°C, add dropwise 21.75ml (250mmol) chlorosulfonyl isocyanate therein, continue stirring for 30 minutes after the dropwise addition, and then pass ammonia gas for 30 minutes Minutes later, the reaction mixture was acidified with 1 N hydrochloric acid, and the resulting precipitate was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and recrystallized in ethyl acetate-hexane to obtain a white 55 g of flaky crystals (80% yield), melting point: 160-162°C.

[0034] ESI-MS: 298[M+Na] + , 314[M+K] +

[0035] 1 HNMR (600MHz, DMSO-d 6 )δ5.29(s, 2H, -O-CH 2 -Ar), 7.54 (br, 2H, -SO 2 NH 2 ), 7.64 (A2 B 2 , 2H, J=8.7Hz, -ArNO 2 meta), 8.26 (A 2 B 2 , 2H, J=8.7Hz, -ArNO 2 ortho), ...

Embodiment 2

[0049] The synthesis of embodiment 2 (3S, 5S)-pyrrolidinylthio carbapenem derivatives

[0050] The preparation of step 1 mercaptopyrrolidine derivative

[0051] (2S, 4S)-1-p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)methyl-4-acetylthiopyrrolidine 50 g (81.8 mg mol) was dissolved in 200 milliliters of tetrahydrofuran, and 20 milliliters of aqueous solution of 6 grams of lithium hydroxide was added dropwise under an ice bath. After the addition was completed, stirring was continued for 120 minutes, acidified with 6 equivalents of hydrochloric acid, and a solid viscous substance was precipitated, which was washed with ethyl acetate Add ethanol after dissolving, freeze and precipitate 32 grams of light yellow amorphous solid powder, yield 68.8%.

[0052] ESI-MS: 592.1[M+Na], 608.1[M+K] +

[0053] 13 C NMR (600MHz, CD 3 COCD 3 ) δ34.3 (pyrrole ring C-3), 39.0 (pyrrole ring C-4),

[0054] 50.2(-CH 2 NSO 2 -), 55.3 (pyrrole ring C-5), 57.1 (pyrrol...

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

No PUM Login to view more

Abstract

A pentazane derivative intermediate, its production and use are disclosed. PNZ expresses p-nitrocarbobenzoxy, R represents Ac(acetyl) or-H. It is simple and has no side reaction. It can be used for donippenan.

Description

technical field [0001] The invention relates to a novel pyrrolidine derivative intermediate and a preparation method thereof, belonging to the field of chemical synthesis. Background technique [0002] Carbapenem antibiotics have been valued due to their broad antibacterial activity. Such drugs already on the market include imipenem, meropenem, etc. Formula (II) shows that doripenem is a new 1β-methyl carbapenem antibiotic, and the 2-position side chain is a sulfamic acid amide Substituted tetrahydropyrrole rings. The structure-activity relationship research shows that the acylation or sulfonylation of the side chain amino group of doripenem is conducive to the increase of antibacterial activity, and the inhibitory activity against Gram-positive bacteria is higher than that of Meropenem. The inhibitory activity is higher than that of imipenem, and it is also effective against imipenem-resistant bacteria, stable to serine β-lactamase and renal dehydropeptidase, and can be u...

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
IPC IPC(8): C07D207/12C07D477/20
CPCC07D477/06C07D207/12A61K31/40A61P13/00Y02P20/55
Inventor 徐大勇唐云周武春于源刘忠荣李伯刚
Owner CHENGDU DIAO JIUHONG PHARMA FACTORY
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