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Process for preparing cephalosporins with salified intermediate

a technology of cephalosporins and intermediates, which is applied in the field of process for preparing cephalosporins with salified intermediates, can solve the problems of unsuitable industrial use methods, and achieve the effect of easy crystallization

Inactive Publication Date: 2005-06-02
ACS DOBFAR SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018] A further considerable advantage of the present invention derives from the fact that the cyclization reaction with thiourea, leading to the formation of HCl, finds in benzathine a base able to subtract it from the solution as the hydrochloride insoluble under reaction conditions. In this manner a solution is obtained containing only cephalosporin in acid form of such purity as to enable it to be very easily crystallized as the sodium salt, by adding a sodium salt such as sodium acetate or sodium 2-ethyl-hexanoate.
[0019] This succession of operations will be more apparent from the non-limiting examples which follow.
[0020] However, the same operative scheme can evidently be applied for the production of cephalosporins other than ceftiofur, cefotaxime and ceftriaxone, having nuclei different from the aforespecified three, but having the same 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic side chain in position 7.

Problems solved by technology

This reversal of the wash order and the use of cold water is therefore not random, but points to the fact that the intermediate does not possess great stability and that the water-soluble acid impurities which impregnate the solid just filtered off must be rapidly removed.
The corresponding derivative in which R3 is however H had already been described in U.S. Pat. No. 4,458,072 and obtained as an amorphous product (column 16, line 49) without any indication of the yield, by a laborious process using a precipitating agent such as petroleum ether: this method is certainly unsuitable for industrial use.

Method used

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  • Process for preparing cephalosporins with salified intermediate
  • Process for preparing cephalosporins with salified intermediate
  • Process for preparing cephalosporins with salified intermediate

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Sodium Ceftiofur

[0021] Two separate solutions are prepared.

Solution A

[0022] 40 g of FURACA (MW 340.38-0.118 moles) and 336 ml of tetrahydrofuran are fed into a dry 1 litre flask under a nitrogen flow in the absence of direct light. The mixture is agitated for 15 minutes until homogenization, while cooling in the meantime to +10° C.

[0023] While maintaining the temperature at +10° C.÷+12° C., 1.486 ml of trimethylchlorosilane (MW 108.64-d=0.859-0.1 eq) are quickly added. The mixture is agitated for 5 min at +10° C.÷+12° C., and 45.43 g of N,O-bis-trimethylsilyl-acetamide (MW 203.43-d=0.832-1.9 eq) are added over 5÷10 minutes.

[0024] The temperature is raised to +20° C. and the mixture agitated for 1 h35 min at 22° C.÷23° C. until a solution is obtained. It is cooled to −35° C.÷−40° C.

Solution B

[0025] 210 ml of ethyl acetate and 13.02 ml of N,N-dimethylformamide (MW 73.094-0.169 moles-d=0.95-12.37 g) are fed into a dry 1 litre flask under a nitrogen flow.

[0026] ...

example 2

Preparation of Ceftriaxone Disodium Salt

[0054] Two separate solutions are prepared.

Solution A

[0055] 15.57 g of 7-ACT (MW 371.39-0.042 mol) and 155 ml of methylene chloride are fed into a dry 1 litre flask under a nitrogen flow in the absence of direct light. The mixture is cooled to +10° C. and 34.11 g of N,O-bis-trimethylsilyl-acetamide are added, a slight amount of heat being produced. The mixture is agitated at +20÷22° C. and after 45 minutes a complete solution is obtained. The mixture is cooled to −40° C.

Solution B

[0056] 80 ml of ethyl acetate and 4.69 ml of N,N-dimethylformamide (MW 73.09, d=0.95) are fed into a dry 1 litre flask under a nitrogen flow at +25° C. 5.58 ml of phosphorus oxychloride (MW 153.33, d=1.675, 9.34 g) are added allowing the temperature to rise to 36° C. (if this temperature is not attained within 20÷25 minutes, heating is required). The mixture is cooled to 0° C. then 9.94 g of 4-chloro-3-oxo-2-methoxyimino-butyric acid, commonly known as COMBA (M...

example 3

Preparation of Cefotaxime Sodium Salt

[0064] Two separate solutions are firstly prepared.

Solution A

[0065] 64 g of 7-ACA (MW 272.28-0.235 mol) and 400 ml of tetrahydrofuran are fed into a dry 1 litre flask under a nitrogen flow and in the absence of direct light. The mixture is agitated for 15 minutes until homogenized while cooling to +15° C.

[0066] 191.34 g of N,O-bis-trimethylsilyl-acetamide (MW 203.43, d=0.832, 0.941 mol) are quickly added, maintaining the temperature at 20°÷25° C. The temperature is maintained at 20°÷25° C. while the mixture is agitated for 15 minutes at +20°÷+25° C. until dissolved, then cooled to −35° C.÷−40° C.

Solution B

[0067] 420 ml of ethyl acetate and 26.04 ml of N,N-dimethylformamide (MW 73.09, d=0.95, 0.338 mol, 24.74 g) are fed into a dry 1 litre flask under a nitrogen flow at +25° C. 30.98 ml of phosphorus oxychloride (MW 153.33, d=1.675, 51.9 g) are added allowing the temperature to rise to 36° C. (if this temperature is not attained in 20÷25 mi...

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Abstract

Cephalosporins may be conveniently prepared by a process in which 7-ACA is silylated, acylated, desilylated and then salified to give an intermediate which is eventually cyclized with thiourea.

Description

FIELD OF THE INVENTION [0001] Numerous cephalosporins of formula (I) characterised by the 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic chain in position 2 of the 7-ACA, and its derivatives of formula (II) are known in which R2 can have various meanings including CH2OCOCH3 in the case of 7-ACA, the cefotaxime nucleus or in the case of 7-ACT, the ceftriaxone nucleus, or in the case of Furaca, the ceftiofur nucleus. BACKGROUND OF THE INVENTION [0002] Each of these cephalosporins, including those having a different meaning of R1 and R2, has been invented and synthesized with its own synthesis method, so that initially there was no common method suitable for producing all cephalosporins having the 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic chain. DESCRIPTION OF THE RELATED ART [0003] Recently, in 1996, U.S. Pat. No. 5,583,216 was granted (the filing date of which however was many years previously), generically covering any process usable for inserting the aforesaid chain into 7...

Claims

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Application Information

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IPC IPC(8): C07D501/00
CPCC07D501/00
Inventor MONGUZZI, RICCARDOMANCA, ANTONIOMARSILI, LEONARDOZENONI, MAURIZIO
Owner ACS DOBFAR SPA
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