DK143502B - ANALOGY PROCEDURE FOR PREPARING 7-AMINO-CEPHALOSPORANIC ACID DERIVATIVES - Google Patents

Description

(19) DENMARK (®

É | (12) PUBLICATION WRITE OR 11 + 3502 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 606/71 (51) Int.CI.3 C 07 D 601 / 2A

(22) Filing day Feb 10 1971 (24) Race day 10 Feb 1 971 (41) Aim. available Aug. 12 1971 (44) Presented 31 Aug. 1981 (86) International Application No. - (86) International Filing Day - (85) Continuation Day - (62) Master Application No. -

(30) Priority Feb 11 1970, 11620/70, JP

(71) Applicant TAKEDA CHEMICAL INDUSTRIES LTD., Osaka, JP.

(72) Inventor Toshihiro Ishiguro, JP: Takeshi Fugono, JP: Hiroaki

Noraura, JP.

(74) The engineering firm Budde, Schou & Co.

(54) Analogous procedure for the preparation of 7-amino-cephaloeporanoic acid derivatives.

The present invention relates to an analogous process for the preparation of novel 7-amino-cephalosporanoic acid derivatives which are active against Gram-positive and Gram-negative pathogenic bacteria. More particularly, the invention relates to the preparation of 7- (α-sulfoacylamido) -cephalosporanoic acids.

There are many cephalosporanoic acid derivatives which can be used against Gram-positive and / or Gram-negative microorganisms.

US Patent No. 3,278,531 discloses cephalosporine derivatives of the general formula 2 143502

H \ S

n-ch — ce nch0 1 / I I I 2

R / -N \ c ^ C-CH 2 Z

0 I

in which the substituents may have a variety of meanings, but where in R e.g. may mean aralkenoyl or an acyl group * Z may mean

-LAKE

and Y may mean COOH.

Further, from the specification to Danish patent application No. 3770/71, cephalosporin compounds of the formula are known.

Sv X

R-NH-f Y

1-N J-CH 2 S-f | [

- </ Y

COOH J

wherein R may represent an acyl group, and X may represent a hydrogen atom or a halogen atom.

However, the compounds prepared by the present process have MIC values of 50 Mg / ml or less against Ps. aeruginosa while the compounds known from the aforementioned United States Patent are not effective thereto and the compounds known from the specification for Danish Patent Application No. 3770/71 have MIC values of over 100 µg / ml against this microorganism. Thus, the present compounds have a better effect on Pseudomonas in particular than the known compounds.

The compounds of this invention have the general formula

S

R CHC0NH - Y.

I I

Wherein R means hydrogen, alkyl of 1-6 carbon atoms or phenyl, M and M 'may be the same or different and each means hydrogen, alkali metal, alkaline earth metal or organic amine and X means ✓S, -OCOCH-j or -S- ^ J | l o

The compounds of this invention are novel as they contain the α-sulfoacylamino group at the 7-position. Typical compounds are represented by the following: (1) R = phenyl, M = M '= Na, X = -OCOCH ^ (2) R = Η, M = M' = Na, X = -OCOCH ^ (3) R = CH2 -, M = M '= Na, X = -OCOCH ^ (4) R = CH5 (CH2) 5-, M = M1 = Na, X = -OCOCHy and Λ *

(5) R = phenyl, M = M1 = Na, X - -S-L YY

O R may mean ethyl, n-propyl, isopropyl, isobutyl, n-hexyl, and cyclohexyl. M and M 'may mean potassium, calcium, magnesium or other non-toxic alkaline or alkaline earth metals. In addition, M and M1 may represent non-toxic organic amines such as triethylamine, procaine, dibenzylamine, N-benzyl-phenethylamine, 1-ephenamine, and N, N1-bisdehydroabiethylethylenediamine. Other amines which have been used for salt formation with benzylpenicillin may also be used.

The compounds of the present invention have both sulfo and carboxyl groups and may be either acidic or neutral salts depending on the acidity of the above acidic groups. There are one or two asymmetric carbon atoms in the molecule. The compounds of this invention may exist in two optically active forms (D and L diastereoisomers) when α-sulfocarboxylic acids, wherein the α-carbon atom is asymmetric, are used as starting materials.

The compounds are effective against Pseudomonas aeruginosa, Escherichia coli, Proteus vulgaris, Proteus morganii, Proteus mira-billis, Klebsiella pneumoniae, Staphylococcus aureus, Bacillus subtilis, Sarcina lutea and the like. The compounds can be administered orally, by subcutaneous injection or by intravenous injection ':' Cos'ié size 'λ.' 4 143502 is from approx. 5 to 500 mg / kg / day, preferably approx. 10-200 mg / kg / day, with 2-k daily doses against e.g. pseudomonas infections.

The process of the invention is characterized in that 7-aminocephalosporanoic acid as such, in the form of a salt or in the form of a slightly decomposable ester of the formula

S

YNH - s' η J— 1 2

C00Z'-R

'R4 in which X is defined as above, Z means silicon or tin, 23 in R, R and R are the same or different hydrocarbon groups and one of them may be halogen and in addition in this case they may be combined with an active hydrogen atom to form a polymer and Y is a hydrogen atom or -ZR 1 R 2 R 4, reacted with an alpha-sulfocarboxylic acid of the formula

H

R OCOOH

r

SO ^ H

wherein R is as defined above, or a functional derivative thereof, wherein, if desired a) when a slightly decomposable ester, an ester group present in the condensation product is cleaved by treatment with water or a lower alcohol, and / or b) a compound; where X is -OCOCH 2, is reacted with 2-mercaptopyridine oxide of the formula G-sh 1 · 0 5 143502 or a salt thereof to form a compound wherein X is

ISLAND

in 0 and / or c) a compound wherein M and / or M1 is hydrogen is converted in a manner known per se to a compound wherein M and / or M1 is alkali metal, alkaline earth metal or an organic amine.

α-Sulfophenylacetic acid, α-sulfopropionic acid, α-sulfonic acetic acid and others are commercially available and are prepared by sulfonating the corresponding carboxylic acids with sulfuric anhydride. The sulfogroup may optionally be protected in the form of sulfonamide or sulfonate during the condensation with 7-aminocephalosporanoic acid.

Functional derivatives of the α-sulfocarboxylic acids are carboxylic acid halides such as chlorides or bromides, mixed anhydrides such as lower alkyloxy or aralkyloxycarboxylic anhydrides, α-toluene sulfonic anhydrides, azides or activated esters, e.g. with p-nj-trophenol, 2,4-dinitrophenol or pentachlorophenol or carboazide. These derivatives can be obtained from the α-sulfocarboxylic acid in any conventional manner. The acid halides are prepared e.g. by treating the α-sulfocarboxylic acid with a halogenating agent such as thionyl chloride, phosphorus oxychloride or phosphorus oxybromide.

Salts of 7-aminocephalosporanoic acid are those formed with the amino group such as hydrochlorides, sulfates or acetates, or those formed with the carboxylic acid group such as sodium potassium or triethylamine salts.

The readily cleavable esters of 7-aminocephalosporanoic acid can be obtained in any conventional manner from 7-aminocephalosporanoic acid, The compound in which Y represents a hydrogen atom, Z represents a tina-2 3 4 empty, and R, R and R , manufacture? stom ?. by boiling a mixture of 7-aminocephalosporanoic acid and 0.5 mole equivalents of bis (tributyltin) oxide in dry benzene for a short time.

6 143502

In the present process, the amino group of the 7-amino epephalosporanoic acid is condensed with the carboxyl group of the α-sulfocarboxylic acid. Such methods are similar to those known in the art.

The following are some preferred methods.

1. 7-Aminocephalosporanoic acid or its salts are condensed with α-sulfocarboxylic acid in the presence of a dehydrating agent. The dehydrating agent is e.g. Ν, Ν'-dicyclhexylcarbodiimide, Ν, Ν'-diisopropylcarbodiimide or Ν, Ν'-carbonyl triazole.

2. The functional derivatives of the alpha-sulfocarboxylic acid are condensed with 7-aminocephalosporanoic acid or salts thereof, and the easily cleavable esters of 7-aminocephalosporanoic acid are condensed with the functional alpha-sulfooarboxylic acid derivatives.

The above-mentioned condensation can be carried out in the presence of solvents. The solvents are water, dioxane, acetone, dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, ethylene dichloride, toluene, benzene or any mixture of two or more of them: In the above methods 1 and 3, water is not desirable. In methods 2 and 3 above, presence of bases is preferred. The bases are organic bases such as triethylamine, tributylamine, dimethylaniline, pyridine, picoline or quinoline. Optionally, the bases are inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide or calcium hydroxide.

The condensation is carried out at a temperature in the range -5 - 40 ° C. preferably -2-10 ° C. The upper limit is 50 ° C, as the eephalosporanoic acid derivatives are otherwise easily cleaved.

In the above method 3, the product obtained in the preparation is treated with water or a lower aliphatic alcohol to decompose and decompose the ester group.

When the condensation is complete, the product can be purified in any known manner. Such purification methods are solvent extraction, concentration, chromatography, crystallization or recrystallization. The product can thus be obtained in the form of free bases or salts. The salts can, if desired, be converted to other non-toxic salts in any known manner.

The process according to the invention is explained in more detail in the following examples.

7 143502

Example 1

Preparation of 7- (α-sulfophenylacetamido) -cephalosporanoic acid

To a flask equipped with a stirrer is added 2.5 ml of 1 N sodium hydroxide solution and 5 ml of water. The mixture is cooled to 0 ~ 5 ° C in an ice-water bath and, with mechanical stirring, 680 mg of 7-aminoeephalo-sporanoic acid is added. Then, a solution prepared by dissolving 5 to 5 mg of α-sulfophenylacetyl chloride in 7 ml of diethyl ether is added dropwise to the mixture over 15 minutes. The mixture is stirred for 15 minutes, then the water layer is isolated from the reaction mixture and said layer is adjusted to pH 1.5 with 1N hydrochloric acid. Then the layer is extracted twice with 15 ml per ml. g of n-butanol, the extracts are washed twice with 5 ml of water per ml. and then extracted with a saturated aqueous sodium hydrogen carbonate solution. The extract is adjusted to a pH of 6.5 · After purification by chromatography on a column packed with polystyrene powder, the eluate fractions containing the substance are lyophilized to give a white powder in the form of sodium salt. The product is dried and the following results are obtained by analysis:

Yield = 585 mg IR s) max t0111 "1) 1 1755 (lactam, acetate), 162 (-C00-), 1680 (-CONB), 1225 (-SO2-), 1046 (-SO2 Na) NMR (D20 ) ppm: 2.09 (3H, singlet), 3.42 (2H quartet ^ = 18.0 c / s, J = = 8.0 c / s), Ca 4.75 (2H), 5.09 ( 1H, singlet), 5.10 (1H, doublet, J = 4.5 c / s), 5.70 (1H, a, J = 4.5 c / s), 7.52 (5H, multiplet) UV ^ H2 °: 259 mu (7, lx 105) max

Example 2

Preparation of 7- (q-sulfophenylacetamido) -cephalosporanoic acid 3.78 g of 7-aminocephalosporanoic acid are suspended in J> 0 ml of chloroform and 2.3 g of hexamethyldisilazane are added. The mixture is heated to 65 ° C for 1.5 hours in a hot water bath. The resulting clear solution is subjected to distillation at reduced pressure at 40 ° C. The residue is redissolved in 50 ml of chloroform and 1.9 µS of triethylamine is added. This solution is then cooled and a 30 ml chloroform solution containing 4.3 g of alpha-sulfophenylacetic acetic acid chloride is added dropwise. The mixture is stirred at 15 ° C for 15 minutes. After completion of the reaction, the reaction mixture is concentrated at room temperature under reduced pressure. The product is then dissolved in 50 ml of water. The aqueous solution is adjusted to pH 1.5 and extracted twice with 35 nil of n-butanol per ml. walk. The butanol layer is washed with a small amount of water and then extracted again with an aqueous sodium bicarbonate solution. After setting the pH of the solution to 6, the substance in question crystallizes from the solution and is dried. 4.3 g of sodium salt of the compound are obtained. The IR analysis gave the same result as the one in Example 1.

Example 3

Preparation of 7- (α-sulfoacetamido) -cephalosporanoic acid

After suspending 0.212 g of 7-aminocephalosporanoic acid in 700 ml of water, 0.78 ml of 1 F sodium hydroxide solution and 0.153 g of sodium hydrogen arbonate are added thereto. The mixture is stirred carefully and cooled on an ice-water bath. Then, 3 ml of chloroform containing 0.142 g of α-sulfoacetic acid chloride is added dropwise. After the addition is complete, the reaction is continued with stirring for 20 minutes under cooling. After adjusting the pH of the reaction mixture to 2, the reaction mixture is extracted with 15 ml of butanol. The reaction is repeated twice. The butanol extracts are combined and then washed with a small amount of water. To the butanol solution thus treated is gently added a dilute aqueous sodium hydroxide solution, maintaining the pH of 6, thereby extracting the desired compound to the aqueous layer. The aqueous layer is washed with ether and then lyophilized. Yield: 0.15 g · The IR spectra give the following results: IR analysis (cm -1): 3420 (0H), 2950 - 3100 (CH), * max 1760 (wide C = 0), 1670 (sharp) -C0NH-), 1610 (wide -C00-), 1408-1393 (wide), 1230.1050 (-S0 ^ -)

Example 4

Preparation of 7- (α-sulfopropionamido) -cephalosporanoic acid 0.272 g of 7-araocephalosporanoic acid (1.0 x 10-) are dissolved in an aqueous sodium hydroxide solution containing 1.0 x 10 The mixture is cooled to 0-2 ° C and 2 ml of ether solution containing 0.2 g of α-sulfopropionyl chloride (1.16 x ΙΟ- · 5 M) is added. The reaction is continued at 0-2 ° C. After stirring, the pH is adjusted to 1.5 and the solution is first washed with ether (9 143502) and then extracted twice with 10 ml of n-butanol. The extract is extracted again with an aqueous sodium hydrogen carbonate solution. setting the water layer to pH 6.0 is subjected to freeze drying 0.2 g of colorless crystalline powder of the desired compound is obtained. IR spectra of the compound prepared by the KBr method have maximum peaks at the following frequencies: 3400 (OH) , 2950 (CH), 1760 (lactam), 1860 (CONH), 1620 (-C00Na), 1410, 12 45 (-S0yJa).

Example 5

Preparation of 7- (α-sulfocapronamido) -cephalosporanoic acid 0.2 g of 7-aminocephalosporanoic acid (7.35 x 10 '^ M) is dissolved in a mixed solvent containing 0.75 ral IN sodium hydrophide solution and 7> 5 ral water, 0.17 g of sodium hydrogen carbonate is added. The mixture is cooled to 0-3 ° C and 2 ml of ethereal solution containing 0.15 g (7> 65 x 10 µM) of α-sulfo-n-eaproyl chloride is added.

After the reaction is continued at 0-3 ° C for 15 minutes, the reaction mixture is subjected to the same treatment as described in Example 4. The compound is obtained in a yield of 0.25 g. The crude crystals are purified by column chromatography using granular polystyrene (100 g). 400 mesh) as a filler and water as a developer to give 0.1 g of pure crystals. IR analysis yields the following results: IR + (cm , 1380, 1225 (-SO 2 -), 1180 (sharp), 1043 (-SO 2 Na), 952, 815, 791j 755, 725.

Example 6

Preparation of 7- (α-sulfophenylacetamido) -3- [β- (1-oxido-2 * pyridyl) thiomethyl7-A-cephem-4-earboxylic acid disodium salt.

^ N-CH-CONH- ^ ^ \ SO3NaOJ-NN ^ -CH2s-kNJ * «J,

COONa J

Dissolve 0.217 g of 7- (ct-sulfophenylacetamido) -cephalosporanoic acid and 0.164 g of 2-mercaptopyridine oxide in 15 ml of water and adjust the pH of the liquid to 6.4. The mixture is heated at 40 ° C for 18 hours. Upon completion of the reaction, the reaction product is subjected to freeze-drying to give 0.35ο g of powder. The product in question is isolated therefrom by column ehromatography and graphite using cellulose powder as filler and a mixed solvent of n-propanol, water and triehloroacetic acid (75: 24: 1) as the developer. The fraction is then subjected to distillation under reduced pressure and washing with hexane. Insoluble product is combined and dissolved in water. When the pH of the aqueous solution is set to 6.4, the purified product is lyophilized. The yield of the resultant compound is Ο, ΟδΟ g. IR spectra give the following results: iRÆ C ™ 1) 1 5 ^ 50 (OH), 1765 (lactam), l680 (-CONH-), 1615 (-000-) , i48o, 1360, 1215, 1050 (-so ^ -), 840, 750, 705.

Claims (1)

11 143502 Patent Claims. Analogous Process for Preparation of 7-Aminocephalosporanic Acid Derivatives of the General Formula S. RCHCONH- / SO4- M · »r ΛΠ Y 3 gJ- ^ COOM 'wherein R means hydrogen, alkyl of 1-6 carbon atoms or phenyl M and M 'may be the same or different and each means hydrogen, alkali metal, alkaline earth metal or an organic amine, and X means -COCOCH, or -SL H 0 characterized in that 7-aminocephalosporanoic acid as such, in the form of a salt or in the form of a slightly decomposable ester of the formula rs J-cjyc ^ R2 COOZ - R-5 Ni4 in which X is defined as above, Z means silicon or tin, R and R are the same or different hydrocarbon groups and one of be halogen and, in addition, in this case they can be combined with an active hydrogen atom to form a polymer, and Y is a hydrogen atom or -ZR 2 R 2, reacted with an alpha-sulfocarboxylic acid of the formula