Welcome to chemicalbook!
Chinese English Japanese Germany Korea
400-158-6606
Try our best to find the right business for you.
Do not miss inquiry messages Please log in to view all inquiry messages.

Welcome back!

ChemicalBook CAS DataBase List Cefoxitin
35607-66-0

Cefoxitin synthesis

6synthesis methods
Cefoxitin, 3-(hydroxymethyl)-8-oxo-7-methoxy-7-[(2-thienylacetyl)amino]- 5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid carbamate (32.1.2.30), is synthesized in various ways starting from cefamicin C-7β-(D-5-amino-5-carboxyvaleramido)- 3-aminocarbonylhydroxymethyl-7-methoxy-3-cefem-4-carboxylic acid, in which a methoxy group is initially present at C7, and the task of making the desired drug essentially consists of a transamidation reaction.
The other way is to start synthesis from 7-aminocephalosporanic acid, to which it is necessary to insert a methoxy group at C7. In one of the examples of the synthesis of cefoxitin starting from cefamicin C, the free amino group is initially protected via tosylation, and the product in the form of a well-crystallizing dicyclohexylamine salt is isolated (32.1.2.28). Next, the carbonyl group at position 2 of the cephalosporanic system is esterified using methylchloromethyl ether. The resulting compound (32.1.2.29) is reacted with 2-(2-thienyl)acetylchloride, then the ester protection is removed from the carboxylic group with hydrogen chloride in methanol, producing the desired cefoxitin (32.1.2.30).
CB9490581-1.jpg
Another way for the synthesis of cefoxitin is started from 7-aminocephalosporanic acid, more correct, from its benzhydryl ester (32.1.2.31), which is synthesized by previous tosylation of the amino group of the initial 7-aminocephalosporanic acid, esterification of the carboxyl group by diphenyldiazomethane, and subsequent removal of the tosyl protection.
When reacted with nitrous acid, the product is diazotized, giving the diphenyl methyl ester of 7-diazocephalosporanic acid (32.1.2.32). A subsequent reaction of the resulting compound with triethylammonium azide in dichloromethane and then with bromine azide gives the diphenyl methyl ester of 7-bromo-7-azidocephalosporanic acid (32.1.2.33). Treating this with methanol in the presence of silver borofluoride results in the replacement of the bromine atom, giving the diphenylmethyl ester of 7-methoxy-7-azidocephalosporanic acid (32.1.2.34). The resulting azide is reduced by hydrogen in the presence of a platinum oxide catalyst, forming the diphenyl methyl ester of 7-methoxy-7-aminocephalosporanic acid (32.1.2.35). Acylation of this compound with 2-(2-thienyl)acetylchloride gives the benzhydryl ester of 7-methoxy-7-[2-(2-thienyl)-acetamido]cephalosporanic acid (32.1.2.36), the ester protecting group of which is hydrolyzed using trifluoroacetic acid and then upon reacting the resulting acid with sodium bicarbonate, it is transformed to the potassium salt (32.1.2.37). The resulting product is then hydrolyzed by the enzyme Citrusi acetylesterase to the potassium salt of 3-hydroxymethyl-7-methoxy-7-[2-(2-thienyl)acetamido]-3-cefem- 4-carboxylic acid (32.1.2.38). Using the method described above, i.e. the initial reaction with chlorosulfonyl isocyanate followed by hydrolysis with water, the resulting compound, (32.1.2.38), is transformed to the desired cefoxitin (32.1.2.20).
CB9490581-2.jpg
-

Yield:35607-66-0 96%

Reaction Conditions:

Stage #1:desacetyl cephalosporin C with N,N'-dibenzylethylenediamine diacetate in dichloromethane;water at 25;
Stage #2: with isocyanate de chlorosulfonyle in dichloromethane at -40;Further stages;Temperature;

Steps:

1-5; 1-5 Example 1
200 ml of dichloromethane was added to 1000 ml of an aqueous solution of 110 g of deacetylcephalosporin,At a temperature of 25°C, 108g of N,N’-dibenzylethylenediamine diacetate and 800ml of aqueous solution were added,After the reaction, there is solid precipitation, and the temperature is reduced to 0 ,Filtration gave 153g of intermediate with a yield of 96%.
Add the intermediate compound to 500ml of dichloromethane,Reduce the temperature to -40 , dropwise add 42g of chlorosulfonic acid isocyanate,After the TLC detection reaction is completed, add 200ml of dilute hydrochloric acid to ph=6,Raise the temperature to 10 to carry out the hydrolysis reaction, and then filter out after solid precipitation.The filtrate was added with sodium bicarbonate to adjust the pH to 8, and the temperature was lowered to -30,Drop 50ml of sodium methoxide (17.8g) in methanol, and control the temperature for 3h.After the reaction is completed, the temperature is raised to 10°C, sodium bicarbonate is added to adjust the pH to 8,After decolorization of the aqueous phase activated carbon, dilute hydrochloric acid was added to adjust the pH to 4, 0 crystallization,After filtering and drying, cefoxitin 132g was obtained with a yield of 98%.

References:

Hou Ermei CN111217836, 2020, A Location in patent:Paragraph 0017-0036

FullText

Cefoxitin Related Search: