SU759053A3 - Method of preparing derivatives of l-isomeric cephalosporine - Google Patents

Description

Union of Soviet Socialist Republics

USSR State Committee for Inventions and Discoveries

DESCRIPTION

Inventions

TO THE PATENT (61) Additional to the patent (22) Declared 05.03.77 (21)

2459055 / 23-04 "" 759053 (51) M. Cl. ³ (23) Priority _{? 3ί} . 664 795 ^k '664796 (32) 08.03.76 (33) NIT

Published on 23.0 880. Bulletin No. 31

Date of publication of the description 08.25.80

S 07 o 501/60 //

A 61 K 31/5 ^ 5 (53) UDC547.869.1.

.07 (088.8) (72) The inventors

Foreigners

German Breyer and Uwe D. Trainer (Germany) (71) Applicant

Foreign firm E.R. Squibb & Sons Inc. (OPL) (54) METHOD FOR PRODUCING L-ISOMERIC CEPHALOSPORIN DERIVATIVES. A method is proposed for producing new cephalosporin derivatives with an improved spectrum of antimicrobial activity, which can be used in medicine.

A known method of producing c5-ureidocephalosporins by the interaction of 7-aminocephalosporanic acid in the presence of dicyclohexylcarbodiimide with | θ Λ-ureido acid £ 1}.

The aim of the invention is to obtain new L-isomeric cephalosporins, expanding the arsenal of means of exposure to the body.

This goal is achieved by the method ’E obtaining derivatives of L-isomeric cephalosporin of the General formula k s

Kj-CHCONH-J-g`` ''. s — jf 20

KH S-ky'K in С -ЫН ₂ ^С00К 2 where Rj is phenyl, thienyl or furyl, 25

R j is a hydrogen atom or an alkali metal atom,

R <~ a hydrogen atom or alkyl with the number of carbon atoms 1-4,30 consisting in the fact that the acid addition salt of the compound of the general formula

R + -CHC0NH-1 - <> KN kng ^{sn g} ~ ^s

UNHI

C3 where R4 and Rj have the indicated meanings, are subjected to interaction with an alkali metal cyanate in an aqueous solution at room temperature, followed by isolation of the target product, in which R _g is a hydrogen atom or an alkali metal atom.

Suitable C ₄ alkyl are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.

The salt-forming ions represented by the symbol are alkali metal ions such as sodium or potassium.

Example!. 7β - (L-L-Aminocarbonylamino-2-thienylacetamido) -3- (1-methyl-1H-tetrazolyl-5-thiomethyl) -Z-cefem-4-carboxylic acid (1).

g trifluoroacetate salt 7g- (L-L-amino-2-thienylacetamido) -3- (1-methyl-1H-tetrazolyl-5-thiomethyl) -3-cefem3

Β-M-carboxylic acid is added to the solution, 3.4 g of potassium cyanate in 85 ml of water and stirred for 3 hours at room temperature. This mixture is filtered off and the filtrate is acidified to pH 1.5 with a 2N hydrochloric acid solution under cooling. Precipitate 5 was isolated and 6.8 g of compound 1 were obtained, mp. 149-153 ° C (with decomposition).

An aqueous equimolar solution of this acid (compound 1) and sodium bicarbonate was lyophilized to obtain the sodium 0 salt of compound 1, mp. 187188®C (with decomposition). Similarly, you can get a potassium salt.

PRI me R 2. 7β- (L-Y-Aminocarbonylamino-3-thienidacetamido) -3- (1-methyl-1Н - teraz about Lil-5 - thiomethyl). - 3-zem fem-4-carboxylic acid (2).

7.9 g of the trifluoroacetate salt of 7ft-r (L-ys-amimo-3-thienylacetamido) -3- (1-methyl-1H-tetrazolyl-5-thiomethyl ^ -3-cefem-4-carboxylic acid is dissolved in 50 ml of water pH adjusted to

7.2 2N sodium hydroxide solution. After adding 1.5 g of potassium cyanate, the mixture was stirred for 25 3 hours at constant pH. The reaction mixture is cooled, the pH value is adjusted to 1.5 with 2N hydrochloric acid solution, the precipitate is filtered off and dissolved in methanol, then charcoal is treated jq. When the methanol solution is concentrated, 4.2 g of acid crystallizes (compound 2), t .pl. 157 ^ C (with decomposition)., An equimolar solution of this acid 35 and potassium bicarbonate is lyophilized to obtain the potassium salt of compound 2 as a yellow powder, mp. 174 ° C (with decomposition). In a similar way, using sodium bicarbonate, get the sodium salt. , ^ 0

Example 3. 7d- (L-tf-Aminocarbonylaminophenylacetamido) -3- (1-methyl-1H-tetrazolyl ~ 5-thiomethyl) -3-cefem-. -4-carboxylic acid (3).

The trifluoroacetic salt of 7β- (Г-Н-amino-45 -, с (> - phenylacetamido) -3- (1-methyl-1Н-tetrazolyl-5-thiomethyl) -3-cefem-4-carboxylic acid is reacted with cyanate . Potassium analogously to example 1, and receive connection 3, 5Q.

so pl. 156 ° C (with decomposition).

An aqueous equimolar solution of acid 3 and potassium bicarbonate is dried by freezing to obtain the potassium salt of compound 3, so pl. 174 ° С (with decomposition).

Similarly, replacing sodium bicarbonate with potassium bicarbonate, get the corresponding sodium salt.!

Y rimer 4. 7p- (1-o (-Aminocarbonylamino-2-furylacetamide o) -3 - (- 1-me-60 tyl-1H-tetrazolyl-5-thiomethyl) -3-cephem-'4 -carboxylic acid (4).

28.2 g of trifluoroacetic salt

7β- (1-0 (-amino-2-furylacetamido) -3- (1-methyl-1Н-tetrazolyl-5-hyomethyl) - 65

-3-Cephem-4-carboxylic acid is suspended in 290 ml of water at room temperature. 8.15 g of potassium cyanate are added and the mixture is stirred for 3 hours at room temperature. The almost clear solution is cooled to 0-5 ° C and acidified to pH 3.5. The flocculent precipitate is filtered off. The clear filtrate is acidified to pH 1.5 and left to stand in the refrigerator at about 0-5 ° C, 19.8 g of acid 4 are obtained, mp. 142-145 ° C (with decomposition).

An aqueous equimolar solution of acid 4 and sodium bicarbonate is lyophilized to obtain the sodium salt of acid 4, so pl. 170-174 ° C (with decomposition). In a similar way, using potassium bicarbonate, get a potassium salt,

EXAMPLE 5. 7p- (1_-cA-Aminocarbonylamino-3-furylacetamido) -3- (1-methyl-1H-tetrazolyl-5-thiomethyl) -3-cefem-4-carboxylic acid (5).

Analogously to example 4, but replacing L- (2-furylglycine) with L- (3-furylglycine), 7p- (1 .- (A-aminocarbonylamino-3-furylacetamido) -3- (1-methyl-1H-tetraazolyl) is obtained -5-thiomethyl) -3-cefem-4-carboxylic acid and its sodium and potassium salts.

Claims (1)

A method is proposed for obtaining cephalosporin derivative derivatives with an improved spectrum of antimicrobial action, which can be used in medicine. A known method for the production of cephalosporins El-ur by the interaction of 7-amycephalosporanic acid in the presence of dicyclohexylcarbodiimide with L-Ureidoacid Sh. The aim of the invention is to obtain new L-isomeric cephalospores, expanding the arsenal of means of action on the body. This objective is achieved by the method of producing the L-isomeric cephalosporin by completing the form. L S RI-CHCOHH-I-N CH 2 -s-CHC about s with -N "2 phenyl, thienyl or furyl, hydrogen atom or alkali metal atom, atom hydrogen or alkyl with 1-4 carbon atoms, concluded that the acid addition salt of the compound of the general formula i and-y is cnsoin-t-f cHz-sk /. where R y (and R. have the indicated values), is reacted with an alkali metal cyanate in an aqueous solution at room temperature, followed by isolation of the desired product, in which R1 is a hydrogen atom or an alkali metal atom. Methyl, ethyl , propyl, isopropyl, butyl, tert-butyl. The salt-forming ions represented by the symbol are alkali metal ions, such as sodium or potassium. Example. 7p - (LA-aminocarbonylmino-2-thienylacetamido) -3- (1-methyl- 1H-tetrazolyl-5-thiomethyl) -3-cephem-4-carboxylic acid: C l) 12 g of trifluoroacetic salt of 7p- (L- "K-amino-2-thienylacetamido) -3- (1-methyl-1H-tetrazolyl-5-thiomethyl) -3-cephem-4-carboxylic acid is added to the solution; 3.4 g of potassium cyanate in 85 ml of water and stirred for 3 hours at room temperature. This mixture is filtered and the filtrate is acidified to a pH of 1.5 with 2 and the hydrochloric acid solution with cooling. The precipitate was isolated and yielded 6.8 g of compound 1, m.p. 149-153 with (with decomposition). An aqueous equimolar solution of this acid (compound 1) and sodium bicarbonate is lyophilized to obtain the sodium salt of compound 1, so pl. 187188®С (with decomposition). Similarly, you can get the potassium salt. EXAMPLE 2. 7f- (L-L-Aminocarbone nilamino-3-thienRpracetamido) -3- (l-methyl-1H-tetrazolyl-5-thyrmethyl) .- 3-cepheme-4-carboxylic acid (2 ). 7.9 g of trifluoroacetic salt 7ft- :( L- | g of gamino-3-thienylacetamido) -3- (1-methyl 1H-tetrazolyl-5-thiomethyl) -3-cep-4-carboxylic acid is dissolved in 50 ml of water The pH is adjusted to 7.2 with 2N sodium hydroxide solution. After adding 1.5 g of potassium cyanate, the mixture is stirred for 3 hours at constant pH. The reaction mixture is cooled, the pH is adjusted to 1.5 with 2N hydrochloric acid, the filter is filtered off and dissolved in methanol, then treated with charcoal. With KOHneHT, 4.2 g of acid is crystallized in the methanol solution (Compound 2) m.p. (with razni rainy). An equimolar solution of this acid and potassium bicarbonate is lyophilized to give the potassium salt of compound 2 as a yellow powder, m.p. (with decomposition). In a similar manner using sodium bicarbonate, a sodium salt is obtained. EXAMPLE 3 7p- (1 -) (- Aminocarbonylaminophenylacetate amido) -3- (1-methyl -1H-tetrazolyl-5-thiomethyl) -3-cephem-. -4-carboxylic acid (G). The trifluoroacetic salt of 7p- (and-0 {-amin-, cA-phenylacetate-amido) -3- (1-methyl-1H-tetrazolyl-5-thiomethyl) -3-cephem-4-carboxylic acid is reacted with cyanate. 1, and receive connection 3, so pl. 15b ° C (with decomposition). An aqueous equimolar solution of acid 3 and potassium bicarbonate is freeze dried to obtain the potassium salt of compound 3, m.p. 174s (with decomposition). Similarly, replacing sodium bicarbonate with potassium bicarbonate, pfluch the corresponding sodium salt. -3-cephem-4-carboxylic acid (4). 28.2 g of the trifluoroacetic salt {Lo gamino-2-pyryl-acetamido) -3- (1-methyl-1H-tetrazolyl-5-thiomethyl) -3-cephem-4- carboxylic acid suspended in 290 ml of water at room temperature. 8.15 g of potassium cyanate is added and the mixture is stirred for 3 hours at room temperature. The nearly clear solution is cooled to 0-5 ° C and acidified to a pH value of 3.5. The flocculent precipitate is filtered off. The clear filtrate is acidified to a pH of 1.5 and left to stand in a refrigerator at about 0-5 ° C to obtain 19.8 g of acid 4, m.p. 142-145 with (with decomposition). An aqueous equimolar solution of acid 4 and sodium bicarbonate is lyophilized to give the sodium salt of acid 4, m.p. 170-174®С (with decomposition). In a similar way, using potassium bicarbonate, the potassium salt is obtained. PRI mme R 5. 7p- (L-iA-Aminocarbonylamino-3-furylacetamido) -3- (1-methyl-1H-tetrazolyl-5-thiomethyl) - 3-cephem-4-carboxylic acid (5). Analogously to example 4, but 3L1 (2-furylglycine) on L- (3-furylglycine) is prepared with 7p- (Ld-uVIIHococarbonyl-amino-3-forylac- ettamido) -3- (1-methyl-1H-tetrazolyl-5-thiomethyl) - 3-cephem-4-carboxylic acid and its sodium and potassium salts. Claims 1. Method for producing L-isomeric cephalosporin derivatives of general formula b;. - S JJy RI-CHCOHH-TY 11 H BH-X “H 2-8-xI o o - Sc ° ° sokg where RJ is phenyl, thienyl or furyl, hydrogen atom or alkali atom, hydrogen atom or eshkyl with 1 carbon atoms -four; characterized in that the acid addition salt of a compound of the general formula BI-CHCOBH I 1 VVz Re has the indicated values to be reacted with an alkali metal citate in an aqueous solution at room temperature, followed by RoGil: a og ochnog o-meGshG ° -n .. and „form., Ai, . 2. way nS t ltch; y -. "" ° introduction at examination .kl, 260-243 C. onvftntti / lm 759053fi 260-243 s, published. 1974.