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Preparation method for imipenem medicine intermediate 4AA

An intermediate and penem-like technology is applied in the field of preparation of a penem-like drug intermediate 4AA, which can solve the problems of unsuitability for industrial production, high cost, environmental pollution by heavy metals, etc., and achieves mild and stable reaction conditions, and a high conversion rate. High yield, cheap and easy-to-obtain raw materials

Inactive Publication Date: 2013-02-20
ASYMCHEM LAB TIANJIN +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of method uses precious metals, which is not only costly, but also seriously pollutes the environment due to the use of heavy metals. From the perspective of economic and social benefits, it is not suitable for industrial production.

Method used

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  • Preparation method for imipenem medicine intermediate 4AA
  • Preparation method for imipenem medicine intermediate 4AA
  • Preparation method for imipenem medicine intermediate 4AA

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0026] According to a typical embodiment of the present invention, the preparation method of penem drug intermediate 4AA comprises: (1) making 4-substituted aniline into intermediate A with structural formula I; (2) making L-threonine ring Oxidation makes (2R, 3R)-epoxybutyric acid, (3) coupling reaction occurs between (2R, 3R)-epoxybutyric acid and intermediate A, and obtaining structural formula is intermediate B of II; (4 ) Intermediate B undergoes a ring-closing reaction to obtain intermediate C with structural formula III; (5) carry out hydroxyl protection reaction to intermediate C to obtain intermediate D with structural formula IV; (6) pass carbonyl in intermediate D through Baeyer-Villiger reaction is oxidized to acetoxy; and (7) the oxidized product is subjected to an ozonation reaction to obtain the penem drug intermediate 4AA; wherein, the structural formula I is Structural formula II is Structural formula III is Structural formula IV is

[0027] Among them...

Embodiment 1

[0063] In Example 1 and Example 2, starting materials with different substituents were used to prepare penem drug intermediate 4AA.

[0064] Table 1

[0065]

[0066] Example 1:

[0067] (1) Substitution: Preparation of 2-(4-methoxyphenyl)amino-1-acetophenone using 4-methoxyaniline

[0068] Add main raw material 4-methoxyaniline 80kg (1.0eq) in 2000L reactor, toluene 418kg (6mL / g), triethylamine 170kg (2.6eq) and 2-bromoacetophenone 194kg (1.5eq), heat up To 100±2°C, keep warm until the reaction is complete;

[0069] After the reaction is complete, add 720 kg (9 mL / g) of water to the system at room temperature to terminate the reaction, filter, wash the filter cake with 100 kg of water and dry to obtain the product 2-(4-methoxyphenyl)amino-1-phenylethyl Ketone 148kg, yield 94.4%, HPLC purity 97.0%.

[0070] (2) Epoxidation: Preparation of (2R, 3R)-epoxybutyric acid using L-threonine

[0071] Add main raw material L-threonine 50kg (1.0eq) and concentrated hydrochloric a...

Embodiment 2

[0092](1) Substitution: Preparation of 2-(4-bromophenyl)amino-1-(3-methoxy)acetophenone

[0093] Add 10kg (1.0eq) of main raw material p-bromoaniline, 79kg (10mL / g) of acetonitrile, 13.8kg (3.0eq) of pyridine and 2-iodo-1-(3-methoxy)acetophenone successively into the 500L reactor 32kg (2.0eq), cool down to 10±2°C, keep warm until the reaction is complete;

[0094] After the reaction, add 150kg (15mL / g) of water to the system at room temperature to terminate the reaction, filter, wash the filter cake with 10kg of water and dry to obtain the product 2-(4-bromophenyl)amino-1-(3-methoxy)phenethyl Ketone 17kg, yield 91.3%, HPLC purity 96.9%.

[0095] (2) Epoxidation: Preparation of (2R, 3R)-epoxybutyric acid using L-threonine

[0096] Add 15kg (1.0eq) of L-threonine (1.0eq) and 222kg (10mL / g) of hydrobromic acid into a 500L reactor, cool down to 10±2°C, and add 58kg of sodium nitrite solution with a mass ratio concentration of 30% dropwise. (2.0eq); after dropping, keep warm at ...

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Abstract

The invention discloses a preparation method for imipenem medicine intermediate 4AA. The preparation method comprises making 4-substituted aniline into an intermediate A, perform epoxidation on L-threonine to produce (2R, 3R)-epoxy butyric acid; enabling (2R, 3R)-epoxy butyric acid and the intermediate A to undergo a coupling reaction, obtaining an intermediate B, enabling the intermediate B to undergo a cyclization reaction, obtaining an intermediate C, enabling the intermediate C to undergo a hydroxyl protection reaction, obtaining an intermediate D, enabling the intermediate D to be oxidized to form an acetoxy group, and enabling an oxidized product to undergo an ozonation reaction, wherein G is H, F, Cl, Br, a methoxy group, oxethyl or an amino group; and R is H, straight chain alkyl of C1-C6, cyclopropyl, isopropyl, tert-butyl, a phenyl group, p-chlorophenyl, o-chlorophenyl, p-bromophenyl, o-bromophenyl, p-methoxyphenyl, o-methoxyphenyl or m-methoxyphenyl. According to the preparation method, raw materials are cheap and easy to obtain, reaction conditions are mild, the conversion rate and the yield rate are high, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of penem drug intermediate 4AA. Background technique [0002] 4AA, namely (3R,4R)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone, has the following structural formula: [0003] [0004] 4AA is a key intermediate for the synthesis of penem drugs. In recent years, imipenem, meropenem and faropenem have been launched in China, and many varieties are currently undergoing clinical trials. The industry generally believes that the price trend of 4AA is the key factor that determines the development of carbapenem antibiotics in my country, so it is of great significance to study its synthesis. [0005] There are also various methods for synthesizing 4AA at present, such as using 6APA or (S)-3-hydroxybutyric acid or (R)-(-)-3-hydroxybutyric acid ethyl ester or (S)-(+ )-1,3-butanediol or ethyl acetoacetate as a starting material to prepare 4AA, the above-m...

Claims

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Application Information

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IPC IPC(8): C07F7/18
Inventor 洪浩陈朝勇周炎蒋勇刘凯
Owner ASYMCHEM LAB TIANJIN
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