Patent Application
20240043449
The present disclosure generally relates to the field of preparing a midbody of latamoxef sodium, and especially relates to a refining method of a midbody of latamoxef sodium.
Latamoxef sodium, with a chemical name of (6R, 7R)-7-[2-carboxy-2-(4-hydroxyphenyl)-acetylamino]-7-methoxy-3-[(1-methyl-1H-tetrazole-5-ylthio)methyl]-8-oxo-5-oxa-1-azabicyclo [4, 2, 0] octyl-2-ene-2-formic acid disodium salt. A molecular formula is C20H18N6Na2O9S, a molecular weight is 564, 45, and a
structural formula is:
Latamoxef sodium is a semisynthetic oxycephem antibiotics developed by Yan Yeyi company of Japan in the 1980s, whose antibacterial spectrum is similar to that of cefotaxime and has a good antibacterial effect on a variety of gram-negative bacteria. In addition, there is α methoxy in a seventh position of its mother nucleus, due to steric hindrance of methoxy, it is resistant to β-lactamase that has a strong performance, and microorganisms rarely have a resistance to drugs, so it has a good market prospect. A synthesis process of latamoxef sodium is improved by He Xiaopeng et al: methoxycephem is prepared from oxycephem by methoxylation, (6R, 7R)-benzoylamino-3-(1-methyl-5-tetrazolium)-thiomethyl-7-methoxy-8-oxo-5-oxa-1-azabicyclo [4.2.0]octyl-2-ene-2-carboxylic acid diphenyl methyl ester is obtained by reacting with 1-methyl-5-mercaptotetrazolium under the catalysis of sulfonyl chloride and triethylamine, and then further optimized to finally prepare latamoxef sodium. But during the reaction, from 7β-benzamide-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl methyl ester to 7β-amino-7α-methoxy-3-(5-tetrazolyl)thiomethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl methyl ester, and then to 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid; 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl methyl ester, 7β-benzamide-7α-methoxy-3-(5-tetrazolyl)thiomethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl methyl ester, diphenyl methanol and benzoic acid are inevitably mixed into 7β-amino-7α-methoxy-3-(5-tetrazolyl)thiomethyl-1-oxa-3-cephem-4-carboxylic acid, therefore, the present disclosure is provided for refining the midbody of latamoxef sodium: 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid
Wherein a structural formula of 7β-benzamide-7α-methoxy-3-(5-tetrazolyl)thiomethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl methyl ester is:
A structural formula of 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl methyl ester is:
A structural formula of 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid is:
The technical problems to be solved: in view of the shortcomings of the related art, the present disclosure provides a refining method of a midbody (7β-amino-7α-methoxy-3-(5-tetrazolyl)thiomethyl-1-oxa-3-cephem-4-carboxylic acid) of latamoxef sodium which can solve problems of a high impurity content and high costs of removing subsequent impurity. The technical scheme of the present disclosure can be implemented by the following way:
A refining method of a midbody of latamoxef sodium, with the midbody of latamoxef sodium being 7β-amino-7α-methoxy-3-(5-tetrazolyl)thiomethyl-1-oxa-3-cephem-4-carboxylic acid, includes the following steps:
Wherein the acid solution in the step (1) is a hydrochloric acid solution.
Wherein a mass concentration of the acid solution is 10-15%.
Wherein a mass concentration of the NaHCO3 solution in the step (2) is 10-15%, and a stirring time is 0.5-1 h.
Wherein a stirring time of the organic layer in the step (3) is 1-2 h, and a temperature of performing crystal cultivation is 20-25° C.
Wherein a mass concentration of the hydrochloric acid in the step (4) is 3-5%, a crystallization time is 0.5-1 h, reducing the temperature to be 2-5° C., and then performing suction filtration.
Wherein a mass concentration of the NaCl solution in the step (5) is 25-30%.
Wherein the normal temperature in the step (5) is 20-30° C.
Wherein a stirring time in the step (5) is 1-2 h.
The present disclosure provides the advantages as below, compared with the related art:
In order to more clearly understand the technical solution hereinafter in embodiments of the present disclosure, reference will now be made in detail to embodiments to further explain the present disclosure. Obviously, the implementation embodiment in the description is a part of the present disclosure implementation examples, rather than the implementation of all embodiments, examples. According to the described embodiment of the present disclosure, all other embodiments obtained by one of ordinary skill in the related art on the premise of no creative work are within the protection scope of the present disclosure.
A refining method of a midbody of latamoxef sodium is provided. The midbody is 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid, the refining method includes the following steps:
The acid solution in the step (1) is a hydrochloric acid solution, and a mass concentration of the acid solution is 10%.
A mass concentration of the NaHCO3 solution in the step (2) is 5%, and a stirring time is 0.5 h.
A stirring time of the organic layer in the step (3) is 1 h, and a temperature of performing crystal cultivation is 20° C.
A mass concentration of the hydrochloric acid in the step (4) is 3%, the pH is adjusted to be 4, a crystallization time is 0.5 h, reducing the temperature to be 2° C., and then performing suction filtration.
A mass concentration of the NaCl solution in the step (5) is 25%, the catalyst includes Ph2SiH2 and RhH(CO)(PPH3)3 by being mixed in a proportion of 1:1, and a weight ratio of the catalyst to the filtrate is 0.01:1.
A refining method of a midbody of latamoxef sodium is provided. The midbody is 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid, the refining method includes the following steps:
The acid solution in the step (1) is a hydrochloric acid solution, and a mass concentration of the acid solution is 15%.
A mass concentration of the NaHCO3 solution in the step (2) is 10%, and a stirring time is 1 h.
A stirring time of the organic layer in the step (3) is 2 h, and a temperature of performing crystal cultivation is 25° C.
A mass concentration of the hydrochloric acid in the step (4) is 5%, the pH is adjusted to be 5, a crystallization time is 1 h, reducing the temperature to be 5° C., and then performing suction filtration.
A mass concentration of the NaCl solution in the step (5) is 30%, the catalyst includes RhH(CO)(PPH3)3 and RhH(PPH3)4 by being mixed in a proportion of 1:2, and a weight ratio of the catalyst to the filtrate is 0.02:1.
A refining method of a midbody of latamoxef sodium is provided. The midbody is 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid, the refining method includes the following steps:
The acid solution in the step (1) is a hydrochloric acid solution, and a mass concentration of the acid solution is 12%.
A mass concentration of the NaHCO3 solution in the step (2) is 7%, and a stirring time is 0.8 h.
A stirring time of the organic layer in the step (3) is 1.5 h, and a temperature of performing crystal cultivation is 25° C.
A mass concentration of the hydrochloric acid in the step (4) is 4%, the pH is adjusted to be 4, a crystallization time is 0.5 h, reducing the temperature to be 3° C., and then performing suction filtration.
A mass concentration of the NaCl solution in the step (5) is 27%, the catalyst includes Ph2SiH2 and RhH(PPH3)4 by being mixed in a proportion of 3:1, and a weight ratio of the catalyst to the filtrate is 0.03:1.
Compared with the first embodiment, the first comparative example does not include the step (2), and others of the first comparative example are the same as that of the first embodiment.
That is, a refining method of a midbody of latamoxef sodium is provided. The midbody is 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid, the refining method includes the following steps:
The acid solution in the step (1) is a hydrochloric acid solution, and a mass concentration of the acid solution is 10%.
A stirring time of the dichloromethane layer in the step (2) is 1 h, and a temperature of performing crystal cultivation is 20° C.
A mass concentration of the hydrochloric acid in the step (3) is 3%, the pH is adjusted to be 4, a crystallization time is 0.5 h, reducing the temperature to be 2° C., and then performing suction filtration.
A mass concentration of the NaCl solution in the step (4) is 25%, the catalyst includes Ph2SiH2 and RhH(CO)(PPH3)3 by being mixed in a proportion of 1:1.
Compared with the first embodiment, the second comparative example does not include the step (3), and others of the second comparative example are the same as that of the first embodiment.
That is, a refining method of a midbody of latamoxef sodium is provided. The midbody is 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid, the refining method includes the following steps:
The acid solution in the step (1) is a hydrochloric acid solution, and a mass concentration of the acid solution is 10%.
A mass concentration of the NaHCO3 solution in the step (2) is 5%, and a stirring time is 0.5 h.
A mass concentration of the hydrochloric acid in the step (3) is 3%, the pH is adjusted to be 4, a crystallization time is 0.5 h, reducing the temperature to be 2° C., and then performing suction filtration.
A mass concentration of the NaCl solution in the step (4) is 25%, and the catalyst includes Ph2SiH2 and RhH(CO)(PPH3)3 by being mixed in a proportion of 1:1.
Compared with the first embodiment, the third comparative example does not include the step (4), and others of the third comparative example are the same as that of the first embodiment.
That is, a refining method of a midbody of latamoxef sodium is provided. The midbody is 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid, the refining method includes the following steps:
The acid solution in the step (1) is a hydrochloric acid solution, and a mass concentration of the acid solution is 10%.
A mass concentration of the NaHCO3 solution in the step (2) is 5%, and a stirring time is 0.5 h.
A stirring time of the organic layer in the step (3) is 1 h, and a temperature of performing crystal cultivation is 20° C.
A mass concentration of the NaCl solution in the step (4) is 25%, and the catalyst includes Ph2SiH2 and RhH(CO)(PPH3)3 by being mixed in a proportion of 1:1.
A calculation formula: a yield=(m1/m0)*100%, wherein m1 is a mass of the midbody of latamoxef sodium that has been refined by the refining method of the present disclosure, m0 is a theory quality of the midbody that has been obtained from the improved synthetic process of latamoxef sodium by He Xiaopeng et al. {from 7β-benzamide-7α-methoxy-3-(5-tetrazolyl)thiomethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl methyl ester to 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl methyl ester, and then to 7β-amino-7α-methoxy-3-(5-tetrazolyl)thiomethyl-1-oxa-3-cephem-4-carboxylic acid, a theory quality of 7β-amino-7α-methoxy-3-(5-tetrazolyl)thiomethyl-1-oxa-3-cephem-4-carboxylic acid}; an HPLC method is used to determine the purity of the midbody of latamoxef sodium and the contents of diphenylmethanol and benzoic acid.
It can be seen from table 1 that the yield of the midbody of latamoxef sodium in each of the first to third embodiments is 95.66-96.82%, while the yield of the midbody of latamoxef sodium in each of the first to third comparative examples is 83.46-90.21%, however, the yield of the midbody of latamoxef sodium that has been obtained from the improved synthetic process of latamoxef sodium by He Xiaopeng et al, is only 80%, which is beneficial to the step of washing with the acid solution in the step (1), the hydrolysis of residual 7β-amino-7α-methoxy-3-(5-tetrazolyl) thiomethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl methyl ester, and the step (4), and also beneficial to the catalyst reduction in the step (5).
In addition, the purity of the midbody of latamoxef sodium in each of the first to third embodiments is much higher than that of each of the first and second comparative examples, which indicates that the removal of benzoic acid and diphenyl methanol in the steps (2) and (3) can greatly improve the purity of the midbody of latamoxef sodium. It can be seen from the first embodiment and the first comparative example that the benzoic acid content of the first comparative example is higher than that of the first embodiment without performing impurity removal on benzoic acid; it can be seen from the first embodiment and the first comparative example that the content of diphenyl methanol in the second comparative example is higher than that of the first embodiment without performing impurity removal on diphenyl methanol.
Although the features and elements of the present disclosure are described as embodiments in particular combinations, each feature or element can be used alone or in other various combinations within the principles of the present disclosure to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202110792892.3 | Jul 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/138335 | 12/15/2021 | WO |
