Carbapenem penicillin ertapenem intermediate, and preparation and use thereof

A technology of carbapenems and ertapenem, which is applied in the field of organic compound synthesis, can solve problems such as difficult industrial production, high equipment requirements, and harsh conditions, and achieve the effects of simple operation, low cost, and mild reaction conditions

Inactive Publication Date: 2009-03-04
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to overcome that the synthesis method of ertapenem in the prior art is not easy to be applied to industrial production, and the industrial method needs to be carrie

Method used

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  • Carbapenem penicillin ertapenem intermediate, and preparation and use thereof
  • Carbapenem penicillin ertapenem intermediate, and preparation and use thereof
  • Carbapenem penicillin ertapenem intermediate, and preparation and use thereof

Examples

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preparation example Construction

[0051] Reference Examples Preparation of Formula V Compounds

[0052] Formula I compound (26.5g, 157.9mmol) in CH 2 Cl 2 350ml, add NEt 3 (32g, 316.1mmol), 4-methoxybenzyl chloride (PMBCl) (44.4g, 283.6mmol) was added dropwise at room temperature, the temperature was raised to 45°C, and the reaction was carried out for 3 hours. use CH 2 Cl 2 and water extraction, combined CH 2 Cl 2 layer with anhydrous NaSO 4 Dry, filter, and concentrate the filtrate to obtain a light yellow solid (Formula II) (41.5 g, yield 91.5%, purity >99%).

[0053] Compound shown in formula II (40.93g, 142.47mmol) in SnCl 2· 2H 2 O (161.0 g, 712.37 mmol) in 300 ml of ethanol was heated up to 50° C. and reacted until all solids were dissolved. Adjust the pH to 11 with 15% NaOH alcohol solution, extract with ether and water, combine the ether layers, anhydrous NaSO 4 Dry, filter, and concentrate the filtrate to obtain a light yellow solid (Formula III) (33.84 g, 92.3%).

[0054] PNZ L-Hydroxyp...

Embodiment 1

[0057] Compound of formula V (5.00g, 7.97mmol) was dissolved in DMF20ml, toluene 20ml, potassium thioacetate (AcSK) (4.09g, 35.86mmol) was added, heated to 55°C, and reacted for 8h. Extract with EA and water, combine the ethyl acetate layers, concentrate, and recrystallize the brown semi-solid from ethyl acetate and n-hexane to obtain the product (formula VI) (3.6 g, yield 74%). Melting point: 140-142°C. The identification results are as follows:

[0058] NMR (CDCl 3 )δ: 2.25(s, 3H); 2.50(m, 2H); 2.87(m, 1H); 3.78(s, 3H); 4.10(m, 1H); 4.30(m, 2H); ); 5.45(s, 2H); 6.68(m, 2H); 7.10(m, 2H), 7.30(m, 1H); 7.40(m, 2H); 7.67(m, 1H); 7.80(m, 1H) ;8.05(s,1H);8.18(m,2H);8.30(s,1H)

[0059] MS(CI):629.9(M+Na)

Embodiment 2

[0061] The compound of formula V (34.00g, 54.59mmol) was dissolved in 120ml of DMF and 100ml of ethyl acetate, and AcSK (22g, 192.78mmol) was added, heated to 58°C, and reacted for 5h. Extract with ethyl acetate and water, combine the ethyl acetate layers, concentrate, and wash the brown semi-solid with methanol to obtain the product (formula VI) (29 g, yield 88%). Melting point: 144-145°C. Identification result is the same as embodiment 1.

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Abstract

The invention discloses a preparation method of an intermediate for synthesizing carbapenems penicillin etapenem having the formula of VI, and a preparation method and application in the preparation of the carbapenems penicillin etapenem thereof. The preparation method comprises the following steps: heating a shown compound and potassium thioacetate for reacting, wherein PMB is shown in figure (1), PNZ is shown in figure (2), Ms is mesyl, and Ac is acetyl. The intermediate can be used for preparing etapenem side chain, and further etapenem. The preparation method can be carried out at the room temperature, with the advantages of mild reaction condition, low cost, simple operation, simple experiment condition, no requirement of expensive reagent, high yield, and easily realized industrial production.

Description

technical field [0001] The invention belongs to the field of organic compound synthesis, and in particular relates to an intermediate of the carbapenem penicillin ertapenem, a preparation method and application thereof. Background technique [0002] Ertapenem (ertapenem, MK-0826, L-749, 345, trade name Invanz) is a new type of broad-spectrum carbapenem antibiotic developed by Merck Pharmaceutical Company of the United States. Stability, excellent pharmacokinetic parameters, good clinical therapeutic effect, good tolerance, few adverse reactions and long half-life can be administered once a day. It is clinically used to treat infections caused by moderately to severely sensitive bacteria in adults. Satisfactory curative effect can be obtained for acquired mixed infection. This product was first launched in the United States in November 2001, and then successively launched in the United Kingdom, Ireland, Israel and the Philippines. [0003] US5478820 reports a synthetic meth...

Claims

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Application Information

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IPC IPC(8): C07D207/16
Inventor 陆洋单晓燕时惠麟
Owner SHANGHAI INST OF PHARMA IND
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