Process for preparing 3-cephem compound

The technology of a compound, cephem, is applied in the field of 3-cephem compound, which can solve the problems of loss, failure to obtain the target object, and the preparation method has not been established, so as to achieve the effect of cost saving

Inactive Publication Date: 2003-11-05
OTSUKA CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The method of using acid, such as the method using trifluoroacetic acid, has the following disadvantages: usually a large amount of expensive trifluoroacetic acid must be used; During recovery, the yield of carboxylic acid compounds is reduced due to the decomposition of acid-labile β-lactam derivatives
In addition, in the method of using formic acid, it is necessary to use a large amount of expensive 98-99% formic acid as a reaction solvent in excess, which is the same as the above-mentioned reaction using trifluoroacetic acid. Decomposition of amide derivatives reduces the yield of carboxylic acid compounds
[0010] In addition, the method of using aluminum trichloride in the presence of anisole is currently unable to obtain the desired product due to the decomposition of acid-labile β-lactam compounds.
As mentioned above, the current situation is that most of the commonly used methods are not suitable for the compound of general formula (4), which is mostly an unstable compound, and it is difficult to obtain the target object with good yield by the above-mentioned conventional preparation methods after separation, and no practical preparation method has been established yet.

Method used

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  • Process for preparing 3-cephem compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Weigh PCl in a 1L four-neck flask 5 / pyridine complex 43.9g (1.5eq.), add 250ml of dichloromethane, and cool to 5°C. Add compound (1a) (R 1 = benzyl, R 2 = H, R 3 = benzyl) 50 g, stirred for 1 hour. The reaction solution was cooled to below -10°C, 200 g of m-cresol was added, and stirred at 7-12°C for 5 hours. 150 ml of cold water was added thereto for extraction, and the organic layer was extracted with 150 ml of cold water. The obtained water layer was first treated with 2 g of activated carbon, and then 25% ammonia water was used to adjust the hydrogen ion concentration to pH=4 to precipitate crystals. The precipitated crystals were filtered off and washed with acetone to obtain 18.5 g of the target compound (3a) (90% yield). 1 H NMR (300MHz, DMSO-d 6 / DCl) δ3.60 (dd, J = 18.9, 5.4Hz, 1H), 3.66 (dd, J = 18.9, 3.6Hz, 1H), 5.11 (d, J = 5.4Hz, 1H), 5.16 (d, J =5.4Hz, 1H), 6.53(m, 1H).

Embodiment 2

[0039] Except the PCl in embodiment 1 5 / pyridine complex 43.9g (1.5eq.) into PCl 5 / pyridine complex 32.23g (1.5eq.) and pyridine 12.5ml (1.5eq.), the same reaction as in Example 1 was carried out to obtain the target compound (3a) (R 2 =H) 18.7 g (91% yield). The resulting compound (3a) 1 H NMR is completely consistent with the compound obtained in Example 1.

Embodiment 3

[0041] Except that the temperature after adding 200g m-cresol and time 7~12 ℃, 5 hours become 20~25 ℃, 3 hours, carry out the same reaction of embodiment 1, obtain target compound (3a) as a result (R 2 =H) 18.2 g (yield 88%). The resulting compound (3a) 1 H NMR is completely consistent with the compound obtained in Example 1.

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Abstract

The preparation method of 3-cephem compound is characterized in that make the beta-lactam compound shown in general formula (1) and halogenated phosphorus compound react under the presence of organic base, generate the imino- After the β-lactam compound, add phenols in the same reaction system, carry out alcohol (phenol) hydrolysis, carry out the deprotection of carboxylate simultaneously, generate the 3-cephem compound or its salt represented by general formula (3), [ In the formula, R1, R2, R3, and X are as described in the specification]. ∴(1)∴(2)∴(3)

Description

technical field [0001] The 3-cephem compound of the present invention is an important intermediate for synthesizing various antibiotics by introducing a side chain at the 7-position. For example in R 2 = Vinyl group The 7-position side chain is introduced into the compound of the general formula (3) described later to prepare cefixime and cefdinir. The aforementioned compounds are currently commercially available oral antibiotics. See, for example, the 9th edition of "An Overview of the Latest Antibiotics", written by Katsuji Sakai, pages 83 and 86. Background technique [0002] In the past, as a general method for preparing 3-cephem derivatives represented by the general formula (3), they were generally synthesized by substitution reaction of the 3-position side chain of 7-aminocephalosporanic acid (7-ACA). The method is limited to the preparation of compounds with natural cephalosporin skeletons with 3-position side chains, and is not suitable for antibiotics with non-n...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/545A61K31/546A61P31/04C07D501/00C07D501/04C07D501/18
CPCA61P31/04C07D501/00C07D501/04
Inventor 龟山丰山田贤惠徐达秀
Owner OTSUKA CHEM CO LTD
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