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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
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  • Abstract
  • Description
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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 removes tert-butoxycarbonyl and acetyl to obtain (2S, 4S)-1-p-nitrobenzyloxycarbonyl-2-(N-sulfamoylamino)methyl 4-mercaptopyrrolidine, and then use and (1R, 5R, 6S) 6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphoryloxy-1-methyl-1-carbo-2-penem-3-carboxylic acid p-nitrogen benzyl ester reaction to generate protected pyrrolidinylthiocarbapenem, and then use palladium / carbon as a catalyst to carry out hydrogen deprotection to prepare doripenem (Organic Process Research & Development 2003, 7, 846-850; CN1032257) (as shown -4), the route uses sulfuric acid to remove tert-butoxycarbonyl and acetyl to prepare (2S, 4S)-1-p-nitrobenzyloxycarbonyl-2-(N-sulfamoylamino)methyl-4- The carbocations produced in the process of mercaptopyrrolidine bring more side reactions, and the impurities produced are difficult to remove. If a carbocation capture agent is added, the production cost will be increased, and the intermediate obtained by sulfuric acid deprotection is oily at room temperature material, which brings difficulties to the metering and feeding of industrial production

Method used

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

Examples

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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...

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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

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Application Information

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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
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