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Preparation method of ertabeinan sodium salt

A technology of penem sodium and sodium bicarbonate, applied in the field of medicine, can solve the problems of inconvenient experimental operation, troublesome raw material synthesis, high production cost, and achieve the effects of convenient raw material source, low price and simplified operation.

Active Publication Date: 2006-03-29
SHANGHAI JIAO TONG UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

But this technology has the following disadvantages: 1. The synthesis of required raw materials is cumbersome, and the stability is relatively poor, the reaction steps are long, multi-step crystallization is required in the preparation process, the operation is troublesome, the cost is high, and the experimental operation is inconvenient; 2. The reaction process Reagents used in the process such as solvents, alkalis, etc. are all expensive, making the production cost higher; 3. The reagents required for the post-treatment of the deprotection process are also relatively expensive, which limits their use in large-scale industrial production

Method used

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  • Preparation method of ertabeinan sodium salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] [4R, 5S, 6S]-3-[[(3S, 5S)-5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R) Preparation of -1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt

[0028] [4R, 5S, 6S, 8R)-3-[(diphenylphosphonyloxy)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2 0.0 Hept-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester (2, 0.595g, 1mmol) was dissolved in NMP+DMF (10mL, v / v=3:1), stirred in Add (2S, 4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol (0.445g, 1equiv .) NMP+DMF (10mL, v / v=3:1) solution, transferred to -40°C cold bath, quickly added DIPEA (0.38mL, 2.2equiv.) after 10min, stirred vigorously, and reacted in 4h Finish.

[0029] Add 20 mL of deionized water treated with ultrasound and nitrogen bubbling to the hydrogenation bottle, add anhydrous sodium bicarbonate (84 mg, 1 equiv.), 10% palladium / carbon (0.29 g, 0.2 equiv.) in a nitrogen atmosphere at 0 ° C The above ...

Embodiment 2

[0035] [4R, 5S, 6S]-3-[[(3S, 5S)-5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R) Preparation of -1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt

[0036] [4R, 5S, 6S, 8R)-3-[(diphenylphosphonyloxy)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2 0.0 Hept-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester (2, 0.595g, 1mmol) was dissolved in NMP+DMF (10mL, v / v=3:1), stirred in Add (2S, 4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol (0.445g, 1equiv .) NMP+DMF (10mL, v / v=3:1) solution, transferred to -20°C cold bath, quickly added DIPEA (0.38mL, 2.2equiv.) after 10min, stirred vigorously, and reacted in 4h Finish.

[0037] Add 20 mL of deionized water treated with ultrasound and nitrogen bubbling to the hydrogenation bottle, add anhydrous sodium bicarbonate (84 mg, 1 equiv.), 10% palladium / carbon (0.29 g, 0.2 equiv.) in a nitrogen atmosphere at 0 ° C The above ...

Embodiment 3

[0040] [4R, 5S, 6S, 8R)-3-[(diphenylphosphonyloxy)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2 0.0 Hept-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester (2, 0.595g, 1mmol) was dissolved in NMP+DMF (10mL, v / v=3:1), stirred in Add (2S, 4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol (0.445g, 1equiv .) NMP+DMF (10mL, v / v=3:1) solution, transferred to -60°C cold bath, quickly added DIPEA (0.38mL, 2.2equiv.) after 10min, stirred vigorously, and reacted in 8h Finish.

[0041] Add 20 mL of deionized water treated with ultrasound and nitrogen bubbling into the hydrogenation bottle, add anhydrous sodium bicarbonate (0.25 g, 3 equiv.), 10% palladium / carbon (0.15 g, 0.1 equiv.) The above reaction solution was poured under the atmosphere, and kept at 20atm for 11h.

[0042] The palladium / carbon was filtered off, the filtrate was treated with activated carbon in an ice-water bath and a nitrogen atmosphere, and then extracted twic...

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Abstract

A process for preparing Ertapeinan sodium includes such steps as reaction between [4R, 5S, 6S, 8R]-3-[(diphenyl phosphorosoacyl) oxy]-6-(1-hydroxyethyl)-4-methyl-7- oxy-1-azadicyclo [3, 2, 0 hepto-2-ene-2-carboxylate (4-nitrophenyl) methylester and (2S, 4S)-1-(4-nitrobenzyloxycarbonyl)-2-(3-hydroxycarbonylphenylamino formyl) pyrrolidine-4-yl thiol to obtain deprotecting precursor, adding Pd-C catalyst and sodium dicarbonate, and hydrodeprotecting reaction. Its advantages are high output rate and low cost.

Description

technical field [0001] The invention relates to a preparation method in the technical field of medicine, in particular to a preparation method of ertapenem sodium salt. technical background [0002] Ertapenem (ertapenem, MK-0826, L-749, 345, trade name INVANZTM) is a new type of broad-spectrum carbapenem antibiotic newly developed by Merck Pharmaceutical Company of the United States. This product was launched in the United States and Europe in November 2001 and April 2002 respectively. It is the only I-β-methylcarbapenem antibiotic for parenteral administration and has a wide range of antibacterial activities, including Gram-positive With negative aerobes and anaerobes. [0003] After searching the literature of the prior art, it is found that the preparation of ertapenem in the prior art is a two-step reaction, such as the preparation method disclosed in USS 0,235,817: (1) by [4R, 5S, 6S, 8R)-3- [(Diphenoxyphosphono)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2....

Claims

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Application Information

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IPC IPC(8): C07D519/00
Inventor 张万斌刘德龙罗丽谢芳
Owner SHANGHAI JIAO TONG UNIV
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