CS202057B2 - Process for preparing derivative of 7-aminocephalosporanic acid - Google Patents

Abstract

Valuable antibiotics are obtained by reacting a compound of the formula <IMAGE> in which R<1> is acyl, or a salt or a readily hydrolysable ester thereof with 5-mercapto-1-tetrazoleacetic acid. The latter can be prepared by reacting sodium azide with an isocyanate of the formula ROOCCH2NCS and hydrolysing the resulting thiol ester.

Description

The present invention relates to a process for preparing a 7-aminocephalosporanic acid derivative of the formula

CH3COOH and characterized by removing the -7- acyl protecting group from the compound of formula I

(I) where r 'is an acyl radical of the general formula :hox :-( jh- (ch ₂ ) 3-coNH or even CO R ¹⁶ hooc-ch- (ch ₂ ) ₃ -coNH

I co

AND

NH 1 R ¹⁹ wherein R 16 and R 19 represent an alkyl group having 1 to 6 carbon atoms; This is accomplished by treating a compound of formula I with a silylating compound of formula IV or V

(ιν)

R ⁵

R ⁶ —SI — Z (V) iP where R ^ R® and R? hydrogen, chlorine, bromine or fluorine, alkyl having 1 to 6 carbon atoms, halogenoalkyl having 1 to 6 carbon atoms and phenyl, wherein at least one of said '.symbolů' R * \ ® ^R and ^R? has another meaning not ^{from chlorophyll-b} rom ^fluoro no ^b by hydrogen also represents ⁺ · a C ^to U ^P inu s ^{is from 1 to 6} carbon atoms, m represents the integer 1 or 2 and Z represents halogen or a group of formula

/

-N

X Q Q wherein R ^o is hydrogen or an alkyl group of · 1-6 carbon atoms and R 'represents hydrogen, alkyl having 1 to 6 carbon atoms or a group of formula

R ⁵

R ⁶ —Si—

R7 where · r \ R® and R? This results in the formation of a silylated derivative of a compound of formula (I) which is treated with phosphorus pentachloride to give the corresponding iminochloride, which further reacts with methanol to give iminoel-lheir, and the iminoether thus formed is hydrolyzed to give the expected reaction product.

Details of this process are described, for example, in U.S. Patent Nos. 3,575,970, 3,573,295 and 3,573,296.

Salts include oetoxic salts of carboxylic acids with cations, including oetoxic metal salts such as sodium, potassium, calcium or aluminum, ammonium and oetoxic amine salts such as trialkylmioyles such as triethylamine, procaio, dibenzylamine, N-benoyl- beta fnonthylamio, 1-ephenamine, Ν, Ν'-dibnozylnttylendiřmio, dehydroabietylemia, Ν, ^Ν> bis-dntydroαbintylnthylelΊdiamio, oižší piperidiou N-alkyl derivatives, for example N-ethyl-1piperidio and other amines which are commonly used for preparing salts benzylperiiiiliou ; aetoxic acid addition salts such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfic and phosphoric acids of organic acids such as mleioic acid, acetic, citric, oxalic, succinic, benzoic, tartaric, fumaric, malic, almond, ascorbic and the like.

Also disclosed is a process for producing a novel and valuable intermediate of the structure

If

Ch ₂ cooh and its condensation with 3-cephem-4-carboxylic acid-dependent subconditioning. The tetrazole derivative is prepared by preparing an alcoholic thiol derivative of the formula ## STR2 ## in an anhydrous solvent.

The resulting cast iron compound is treated with carbon dioxide to produce a product which is hydrolyzed to provide a compound of formula

HS-C N

CH 2 COOH

For the treatment of antibacterial infections in humans, the compound of the invention is administered parenterally or orally in an amount of about 5 to 200 mg / kg per day in divided doses and preferably in an amount of about 5 to about 20 mg / kg per day in divided doses. that is, three times aS four times a day. It can be administered in dosage units containing, for example, 125, 250 or 500 mg of active ingredient with a suitable physiologically acceptable carrier or diluent. The dosage units are usually in the form of liquid preparations such as solutions or suspensions.

Preparation of 1-carboxylic acid-5-methatottotrazole

CH2COOH

a) Recrystallization of 1-methyl-5-mercaptoetrazole

Method:

The first 110 g of 1-Mettu l · ^r -5-metríptttttrazolj is slurried in 350 ml of boiling chloroform .; a clear solution is formed.

2. The hot 50 ° C to 60 ° C solution is quickly filtered using a heated Buchner funnel (11 cm, paper # 604) and vacuum-packed to a height of 0.8 and 0.6 cm of auxiliary agent. ^{, 'Sujetrcl, s).} The filter pad is washed with 50 ml of chloroform heated to 50 DEG to 60 DEG C. and added to the filtrate.

3. The filtrate is cooled to about 0 ° C to about 6 ° C and held at this temperature for 2 hours.

The precipitated crystals are sucked off under cooling to 0 and 6 ° C, and washed with 60 ml of chloroform cooled to the same low temperature, and this chloroform portion is added to the filtrate. The crystals (Part A) were air dried at 37 ° C and 45 ° C for 18 hours.

4. The filtrate is bent on a vacuum rotary evaporator (60 ° C bath) to approximately half the original volume. The suspension obtained is cooled to 0 DEG to 6 DEG C. and maintained at that temperature for 2 hours. The crystals are separated by cooling to 0 and 6 ° C, transformed using 40 ml of chloroform cooled to 0 and 6 ° C, and this portion is added to the filtrate. The crystals (B) were air dried at 37 ° C to 45 ° C for 18 hours. Combining subsections A and B yields a substance in about 65% yield.

5. The filtrate after the removal of Part B from step 4 can be further treated twice as described in step 4; · An additional 15% yield is thereby obtained.

(b) Preparation of 1-carboxymethyl-5-mercaptothet, disodium salt

Method:

The first 500 ml of dry and essentially pure Ottrehydrofuranu in dvotliOrové Oříhrdlé NCE b ^p s ^m s ^c h ^p DLEM ^you-cooled in the shock, and ice acetone at ^{b of} draws. at -10 ° C, and dry nitrogen is introduced to the liquid surface.

2. 500ml of 15.06% (1.6 nJ rozOoku buuolliOhia hexane (Foote Mineral Co.) is added over 10 minutes under dry nitrogen and stirring to podch-lazeného Ottr (hydrtfltrpnu. ^The clear extended ^to a cooled to -5 to ^-10 ° C.

3. Dissolve 46.4 g of 1-methhl-5-meecptptetrpzole, recrystallized as described above, in 200 ml of substantially pure, dry, saturated solution. Filter the solution if it is alkaline, then cool to 5 PŽ ¹⁰ ° C.

· Fourth cooled solution of 3 sOupně added over 10 minutes with stirring under dry du- Sike to Zootech buVlliOMa ^, ^{and the} holding be Oe-phthalazin keep ktzш ^ t ^ ^d of about -5 ° ^{C d d} of PVs + 10 ° C. A precipitate may form.

5. Mix ball ^hook under dry cooling dusfžkem p np 0 to ⁺¹⁰ ° C for 3 to ^{b 0} minutes.

6. The reaction mixture was vigorously bubbled carbon uiličiOý caused vigorous stirring to ^B in 15 to ³⁰ minutes ^of back řibllžn OtpltO ^s premises ^{(P 0? 10} ° C) instead ^of the fences, and in ^ 'above +20 C.

7. A resulting white precipitate is to section the Lonja-pkosOokl vlhkosSi low, ^precipitate: promj pooužtí at about 75 ml Ottr (hy ^d t'tfUtrpnu.

8. Dissolve the precipitate in 250 ml of water (pH 8.5 to 9.5); may apply the second Vršov Ottrahydrtfuranu p Oýž may ^TDD etSOltvpt np roOpční evaporator cr OtpltOy bath of 30 ° C. '

The aqueous solution is adjusted to a pH of 1.6 to 2.0 by addition of concentrated hydrochloric acid. '

10. Extract the acidic aqueous solution twice with 250 ml of ethyl acetate each time, extracting each one with 250 ml of acetic acid ester using 100 ml of water. Aqueous solutions are not needed. The extracts in the acidic acid (freed from any aqueous medium) were filtered off.

11. The United tOhyltsOtrl extractions in the acid ocOové zPhuuSí sucha.np in a vacuum rotary evaporator at ^about t ^{p on} the LT-yl ^and Zn ^{of 60} ° C.

12. Heat the crystals in the flask with 300 ml of chlorine boiling for 2 minutes, the hot suspension of 50 ° C to 60 ° C is filmed from the heated Buctmer funnel (11 cm), the paper is passed through a dog's pool of 75 ml of chloroform heated. np 5 ⁰ ° C. ^p o · ^O OM crystal was dried at VZ ^d uc ^h u ^ for ploOy místnossi psi for 3 hours p is crushed to a particle size 0.15 to 0.07 mm.

The crystals of this size are treated from boiling chloroform exactly Opk, as described in step 12 (the largest fraction of unreacted 1-ethyl-5-mercaptopotot is precipitated with hot chloroform). The yield is about 45 to 50 g of rat 1-kylbutyl-5-methylprototropol. These crystals may contain 0.02 to 0.05 moles of 1-methyl-5-mercapotetrpole.

14. The crystals of step 13 are stirred into 250 ml of ethyl ether at room temperature, which takes about 3 to 5 minutes, is filtered, the insoluble fraction (0.5 to 5%) may form as an impurity with; , perhaps of the following structure:

Attention:

This compound explodes at a temperature of about 205 to 210 ° C.

15. Evaporate the ether filtrate of step 14 to dryness on a vacuum rotary evaporator (50 ° C bath) to isolate 42 to 48 g of crystalline 1-carboxymethyl-5-mercaptotetrazole, having a pH of about 0.01 to 0.05 moles of 1- meelцrS-5-merkkattSterazslu.

16. Dissolve the crystals in 420 mL of absolute ethanol (approximately 100 mm / mL) and heat the solution to 50-60 ° C.

17. To the hot solution of step 16, 310 ml of a 41% solution of sodium 2-ethylhexanoic acid in itotropsanol is added with vigorous stirring over 10 minutes. A crystalline precipitate is formed; the mixture is then stirred in suspension at 50-60 ° C for 20 minutes.

18. Filter the mixture while still hot (50-60 ° C) with a heated Buchner funnel (11 cm, paper # 604); crystals trom ^ ^S: S for d .pouHl 75 ml of ethanol - 50 ° C.

19. Stir the crystals from the ethanol suspension of step 18 into 200-300 ml of ethanol, and sieve the suspension through a 0.076 mm sieve. The suspension is then heated for 5 minutes at 50-60 ° C with vigorous stirring (unreacted 1-methyl-5-mercapto-ester sodium is very soluble in hot ethanol).

20. The crystals are filtered at 50-60 ° C on a heated 11 cm diameter Buclmer funnel using SS 604 paper. Then the crystals are rubbed with 75-100 ml of ethanol, dried under vacuum for 24 to 30 minutes. 48 hours at 50 - 60 ° C. The yield was 40-48 g of 1-carboxymethyl-55-mercapto-stearazole disodium salt (free of 1-methyl-5-mercapto-tetrazole, as seen from the N-spectral).

Preparation of N -Amino-4- (1-carboxyxymethyl-trrazol-5-yl) -hisulfonyl-3-carboxylic acid N-carboxylic acid

COOH CH3COOH

COOH

EXAMPLE 1 (A) Preparation of 7- (D-amino-5-carboxyvaleraimido) -5-N-itsbuthoxycarbonyl-1- (1-carbsex;

3.46 g (0.0218 mol) of 5-mercato-1-carboxylmethylterterazole- and 9.7 g (0.018 mol) of 7- (D-5-amino-5-carboxyvaleramido) -5-N-itsbutylcarbonyl-13- are mixed under nitrogen. of cefem-4-carboxylic acid in the foam of sodium salt in an environment of 30 ml of a 3% sodium hydroxide solution at a temperature of 100 ° C.

The pH of the reaction mixture was adjusted. by adding 6N hydrochloric acid to 6.0 and the reaction mixture is stirred at 60-65 ° C for 5.5 hours under nitrogen. After cooling, the reaction mixture is diluted by adding 50 ml of acetone, overlaid with 150 ml of ethyl acetate, and adjusted to pH 2.0 by addition of 6N hydrochloric acid. The layers were separated and the aqueous portion was re-extracted into 70 mL of ethyl acetate. The combined organic layers were dried under reduced pressure to a volume of about 50 mL, and an oily residue precipitated by addition of 6.0 mL (0.03 mol) of dicyclohexylamine. The oil was separated into 300 ml of methyl isobutyl ketone, filtered, washed and dried at 50 ° C for 15 hours to give 14.6 g (95%) of the title compound. . The NMR and IR spectra are consistent with the structure, but the product is contaminated with about 5% cefploseorin C as the starting compound.

(B) ^{y or} rava acid 7-amino-3- (S ^(PR 1 ^{to b e} tt sxymeth гpzsl ^{yl-5- yl) y} h and ^{y s} ometh]-cephem-4-carboxylic acid

To a mixture of 32 ml eettyl ncSУoridu ^e, 4.17 g (0.0049 mol) of the compound obtained in step (A) and 2.3 g · ěimeehylanilinu under nitrogen was added 1.5 g íimethylllíchУorsilpnu. The reaction mixture was stirred at about 25 ° C for 50 minutes, then cooled to -40 ° C, and 1.2 g of phosphorus pentachloride was added. Next, the reaction mixture is stirred for 80 minutes with cooling to -40 ° C, the temperature is lowered to -60 ° C, 12.6 ml of the preceding methanol is added, and the temperature of the reaction mixture is allowed to rise to 0 ° C. An almost clear solution is obtained, and its pH is adjusted to 4.2 by the addition of a few ml of water. A product is precipitated which is left to crystallize for an hour to two hours with cooling to 0 to 5. Deň: 32 ° C. Filtration, washing and drying yielded 1.39 g (72%) of a slightly greenish substance, and high pressure liquid chromatography showed 67.8% of the title compound and 6.1%. of 7-amino-sulfonic acid. On a purity basis, the overall yield with respect to the sodium salt of 7- (D-5-amine) (5- (5-carbo); R, R, R, R, R, R, R, R, R, etc. N ^{issbutoxykprbon-yl-3-cephem-4-karbsxylsvé} acid 46.4%.

In a similar larger scale experiment, the title compound was obtained in 65% yield, with the product. it contained 81.6% pure 7-amino-4- (s- (1-carboxymethyltetrazol-5-yl) thiomethyl-3-eftem-4-carboxylic acid) and 4.2% 7-aeinosefalsseoranic acid viburnum. The overall yield after conversion to purity was 53.0%.

Example 2 (A) Preparation of the 7- (D-5-amino-5-carbsxyvaltramido) -5-N- (n-butoxycarbonyl) -3- (1-carbonyl-hexylethyl-azole-15-yl) -thietylethyl-3-ethoxy- 4-carboxl

When the sodium salt used in process (A) is replaced by an equimolar amount of the sodium salt of N- (n-butylcarbamosyl-cephaloppsin C), the title compound of part (A) is obtained.

^(B) Kttprava Kšely!. ^ 7-amino-3- [5-0-kaгboJ flight ^{t χ} У letra ⁰ to ⁰ · 5-yl) -TH ^with oett ^yy: У OTFE -3-4-kαrbsxllové

If, in process (B) of Example 1, the compound of step (A) of example 1 is replaced by the equimolar amount of the compound of step (A) of example 2, the acid 7-chloro-3- [1-] is obtained. karbsx; YNET yltterazsl ^yl-5-l) -0 ^{y yy} Semet iJ ^ -d ^ -carboxylic fťem.

Claims (5)

SUBJECT OF THE INVENTION Process for preparing a 7-aminocephalosporanic acid derivative of the formula COOH CH 3 COOH, characterized in that a compound of formula I is treated wherein r 1 is a radical of formula HOOC-1 H-CCH 3 -CO or WHAT R ' ^č HOOOcCH- (CH ₂ ) ₃ -CONH AND NH ^R19 wherein ^R1 and ^R19 ® alkyl with u ^{p to} 1 yne of formula IV or V to 6 carbon atoms, or a compound silylující R ⁵ R ⁶ —Si — Z 5 6 7 where R ·, R · and R · are known! hydrogen, chlorine, bromine or fluorine, (C1-C6) -alkyl, (C1-C6) -haloalkyl and phenyl, at least 5 6 7 of which R @ 1, R @ 1 and R @ 2 are other than chloro, bromo, fluoro or hydrogen; furthermore, R ^ represents an alkyl group having 1 to 6 carbon atoms, m represents an integer of 1 or 2, and Z represents a halogen or a group of the formula R ⁸ R ⁹ Wherein R is hydrogen or a (C1-C6) alkyl group and R6 is hydrogen, a (C1-C6) alkyl group or formula -Si6 Wherein R ', R ° and R' have the meanings given above to form a silylovir derivative of the compound of formula (I), the silylated and thus obtained derivative is treated with phosphorus pentachloride to give the corresponding iminochloride further treated with methanol, and the resulting iminoe.ther hydrolyzes to form the expected reaction product ·