JPS6348870B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing novel tetrazole compounds. More specifically, the present invention is based on the formula 1-carboxyalkyl-5-mercaptotetrazole [1-carboxyalkyltetrazole-
5-thiol]. The tetrazole compound represented by the above formula is a novel antibacterial agent, 7-(acylamino)-3-
It is useful as a reaction reagent for producing (1-carboxyalkyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. The manufacturing method of this new antibacterial agent is the subject of the invention of the original patent application (Patent Application No. 106106 of 1975), but the manufacturing method is based on the formula (wherein R ¹ is acyl, R ³ is H or methoxy, and n is an integer from 1 to 9), or its ester or non-toxic pharmaceutically usable salt. ,
formula (However, in the formula, R ¹ is H or acyl, and R ³
is as defined above), or a salt or easily hydrolyzable ester thereof, with the formula (wherein n is 1 to 9) and when R ¹ is H, the obtained compound is reacted with a compound of the formula R ¹ -X (wherein X is a halide or a functional equivalent thereof). and R ¹ is acyl, which means that when the acyl group contains a free amino or hydroxyl, the group is occluded by a conventional protecting group and then removed to yield a compound of formula) and, if desired, in the free acid, salt or easily hydrolysable ester of the compound of the formula obtained, in the form of the corresponding ester or toxic and, if desired, converting the resulting compound of the formula into a salt or easily hydrolyzable ester into the free acid of the corresponding formula. It can be summarized as a method consisting of: According to the first aspect of the present invention, the formula (a) Treating 1-methyl-5-mercaptotetrazole with an organolithium compound to obtain the corresponding lithio derivative; (b) Treating the lithio derivative with carbon dioxide, which is then hydrolyzed. A method of manufacturing a desired product is provided. Furthermore, according to the second aspect of the present invention, the formula (wherein n is 1 to 9) In the method for producing a compound of formula (a) (wherein n is as defined above and R ¹⁰⁰ is alkyl, phenyl, phenylalkyl or substituted phenyl or phenylalkyl of 1 to 6 carbon atoms) with sodium azide. process and expression (b) hydrolyzing the thiol ^ester to produce the desired thiol acid. Ru. Example 1 1-carboxymethyl-5-mercaptotetrazole 1-Methyl-5- in 150 ml of ether at -7°C
To a solution of 5 g (0.043 mol) of mercaptotetrazole was added 60 ml (0.096 mol) of 1.6 M/l n-butyllithium in hexane under nitrogen and with vigorous stirring over a period of 5 minutes. The mixture was stirred at -5°C for 1/2 hour and warmed to room temperature (20°C) over 2 hours. To this mixture was added 25 g of dry carbon dioxide. Add 2 more of this mixture
Stir for hours. The white precipitate was removed by filtration, washed with ether and dissolved in 50ml of water.
The solution was acidified to PH2 with 6N hydrochloric acid and extracted with ethyl acetate. Wash ethyl acetate with water and heat at 60°C.
Evaporation at (15 mmHg) gave a white solid. This solid was heated to reflux with 50 ml of chloroform at 5°C.
Cool to 24°C and collect the white crystalline precipitate at 56°C.
After vacuum drying for an hour, 3.7 g of the title compound was obtained. Melting point 167-170℃ Analysis C ₃ H ₄ N ₄ O ₂ S Calculated value C, 22.50; H, 2.52; N, 34.98 Actual value C, 22.69; H, 2.69; N, 36.66 NMR: DMSO, PPMδ; 5.1, 5.2 (N-C H ₂ ) IR (KBr) cm ^-1 ; 2400, 3200 (OH, SH); 1730
(C=0) Example 2 a Recrystallization operation of 1-methyl-5-mercaptotetrazole: 1 110 g of 1-methyl-5-mercaptotetrazole is slurried in 350 ml of boiling water.
You will get something close to a solution. 2 Add 1/4 to 1/3 of this hot solution (50 to 60°)
Inch-packed super-aid (“Supercol”)
Buchner To (11cmSS604 paper) containing
Immediately vacuum through. Filter pad in chloroform at 50-60℃ 50
ml and add this to the solution. 3 Cool the liquid to about 0-6℃ and keep it at 0-6℃ for 2 hours.
Keep at ℃. The formed crystals were collected by filtration at 0 to 6°C, and then added to chloroform at 0 to 6°C.
Wash with 60ml and add this to the solution. The crystals (cut A) are air-dried at 37-45°C for 18 hours. 4 Concentrate the liquid to about half the volume on a rotary vacuum evaporator (bath 60°C). Cool the slurry to 0-6°C and keep at 0-6°C for 2 hours.
The crystals were collected by filtration at 0-6°C and
Wash with 40 ml of chloroform at ~6°C and add this to the solution. Crystals (cut B) at 37-45℃
Air dry for 18 hours. Crystal cuts A and B are mixed to give a yield of about 65% by weight. 5 Step 4 Cut B liquor can be reprocessed twice as described in Step 4 to obtain an additional 15% recovery. b. Preparation of the di-sodium salt of 1-carboxymethyl-5-mercaptotetrazole Procedure 1: 100 ml of substantially dry pure tetrahydrofuran in a 2 liter 3-necked flask with a stirrer was dissolved in a salt-acetone-ice bath for about -10 Cool to ℃.
Blow dry nitrogen gas onto the liquid surface. 2 To this tetrahydrofuran was added 15.06% (1.6N) butyllithium (Foot Mineral Company) 500 in hexane under stirring in a stream of dry nitrogen.
ml over 10 minutes. Cool this near solution to -5 to -10°C. 3 Substantially pure dry tetrahydrofuran
Dissolve 46.4 g of 1-methyl-5-mercaptotetrazole (recrystallized as above) in 200 ml. If it is cloudy, strain the solution and add 5
Cool to ~10°C. 4. Add the cooled solution from step 3 to the butyllithium solution under stirring in a stream of dry nitrogen over 10 minutes.
The temperature must be kept between -5°C and a maximum of +10°C. Precipitates may form. 5. Stir the mixture for 0.5 h at 0°C to +10°C under nitrogen flow. 6. Anhydrous carbon dioxide gas at external temperature (0~10℃) or +
Blow at high speed and with rapid stirring for 15 minutes below 20°C. 7. Collect the white precipitate that forms in a place with low humidity by filtration. Precipitate in tetrahydrofuran approx.
Wash with 75ml. 8 Dissolve this precipitate in 250 ml of water (PH8.5-9.5). A second layer of tetrahydrofuran may be present. This can be removed in a vacuum rotary evaporator (bath 50°C). 9 Adjust the pH of this aqueous solution to 1.6-2.0 with concentrated hydrochloric acid. 10 Extract this acid aqueous solution twice with 250 ml of ethyl acetate each time. Back-extract each 250 ml of ethyl acetate with 100 ml of water. Discard the aqueous extract. Filter the ethyl acetate extract (without the aqueous layer) and combine. 11 Combine the ethyl acetate extracts and concentrate to dryness on a vacuum rotary evaporator (bath 60°C). 12 Boil the crystals in the flask with 300 ml of chloroform for 2 minutes. The hot slurry is vacuum filtered through a heated Buchner To (11 cm-SS-604 paper). Wash the crystals with approximately 75 ml of chloroform at 50°C. The crystals are air-dried for about 3 hours at room temperature and then reduced to about 100-200 meshes. 13 Complete this process exactly as described during step 12.
Treat 100-200 meshes of crystals (hot chloroform removes most of the unreacted 1-methyl-5-mercaptotetrazole). Yield: about 45 to 50 g of crystalline 1-carboxymethyl-5-mercaptotetrazole. These crystals are
It may contain 0.02 to 0.05 mol of 1-methyl-5-mercaptotetrazole. 14 Slurry the crystals from step 13 with 250 ml of ethyl ether for 3-5 minutes at room temperature. Filter this mixture. The insoluble material (0.5-5%) may be a contaminating symmetric mercaptotetrazole ketone with the following tentative structure: CAUTION: This compound is explosive at approximately 205-210°C. 15 Evaporate the ether solution from step 14 to dryness on a vacuum rotary evaporator (bath 50°C). Approximately 0.01
about 42 to 48 crystalline 1-carboxymethyl-5-mercaptotetrazole containing ~0.05 moles of 1-methyl-5-mercaptotetrazole
g is recovered. 16 Dissolve the crystals in 420 ml of absolute ethanol (approximately 100 mg/ml). Warm the solution to 50-60°C. 17 Add 41% in isopropanol to the hot solution in step 16.
Sodium 2-ethylhexanoate (SEH)
Add 310 ml over 10 minutes with very rapid stirring. A crystalline precipitate forms. this mixture
Slurry at 50-60°C for 20 minutes. 18 Heat the mixture through a heated Buchner tube (11 cm - SS - No. 604 paper). Crystals at 50℃
Wash with 75 ml of ethanol. 19 Add 200% ethanol to the ethanol wet crystals from step 18.
Make a ~300ml medium slurry. Pass the slurry through a 200 mesh sieve. Add this slurry under rapid stirring to 50~
Heat to 60℃ for 5 minutes (unreacted 1-methyl-
Sodium 5-mercaptotetrazole is highly soluble in hot ethanol). 20 Heated Buchner Tochu 11cm-SS-604 paper top 50
Collect crystals at ~60°C. This crystal is 75～
Wash with 100ml ethanol and dry at 50-60°C for 24-48 hours. Yield: 40-48 g of 1-carboxymethyl-5-mercaptotetrazole disodium (free of 1-methyl-5-mercaptotetrazole as observed by NMR). Example 3 1-carboxyethyltetrazole-5-thiol A 2-carbethoxyethyl isothiocyanate hydrochloric acid β-alanine ethyl ester (93.6g),
Triethylamine (123.5g) and methylene chloride (400ml) were mixed and cooled to -10°C. Add chloroform to the above solution while keeping the temperature at about -10℃.
Carbon disulfide (46.5 g) dissolved in 150 ml was added during 2 hours. After the addition is complete, keep the temperature at 10℃ for about 10 minutes.
The temperature was raised to . The solution was cooled again to -10 DEG C. and 66.9 g of chloroformic acid in 60 ml of chloroform were added over 40 minutes while stirring. The temperature was allowed to rise to room temperature for 30 minutes and cooled again to 0°C. A further 61.6 g of triethylamine were added at 0° C. and the solution was then stirred for 3 hours at room temperature. Treat this mixture with water, collect the organic phase and 2N
HCl 250ml twice, NaHCO ₃ 250ml twice, then water 250ml
ml was washed twice. The organic phase was dried over Na ₂ SO ₄ and the solvent was removed under vacuum to yield 93.7 g of an oil (found to be the desired product). IR and NMR spectra were consistent with the structure. B 1-Carboxyethyltetrazole-5-thiol Sodium azide (29.7 g) was dissolved in 400 ml of water and heated to 60° C. in a nitrogen stream. Skellisolve B
2-carboethoxyethyl isothiocyanate (46.9
g) was added to the heated sodium azide solution. The solution was stirred at about 70-72°C for about 150 minutes and then cooled to 30°C in an ice bath. 50% sodium hydroxide solution was added until the pH was 12. This mixture was heated at 70°C for 40 minutes and then heated to 15°C in an ice bath.
It was cooled to Adjust the PH to 2 using concentrated HCl,
Next, it was extracted with ethyl acetate (150ml x 4). The ethyl acetate extract was washed with water and dried over sodium sulfate. The solvent was evaporated in vacuo and the product was collected as crystals from methylene chloride. 19.5 g of the title product were obtained. Melting point 147-150℃ NMR: DMSO, PPMδ; 2.9, t, 2,

[Formula] 3.4, t, 2 (C H ₂ ) IR (KBr) cm ^-1 ; 2400, 3200 (OH, SH); 1720
(C=0) Example 4 Preparation of 1-carboxyalkyltetrazole-5-thiol In place of the β-alanine ethyl ester used therein in the operation for the preparation of 1-carboxyethyltetrazole in Example 3, equimolar the corresponding 1-carboxy(C ₁ -C ₉ alkyl)tetrazole-5-thiol; i.e. 1-carboxypropyltetrazole-5-thiol, using a suitably substituted amino acid ester of 4 to 10 carbon atoms in an amount of 1-Carboxybutyltetrazole-
5-thiol, 1-carboxypentyltetrazole-5-thiol, 1-carboxyhexyltetrazole-5-thiol, 1-carboxyheptyltetrazole-5-thiol, 1-
Carboxyoctyltetrazole-5-thiol and 1-carboxynonyltetrazole-5-thiol were obtained. 1-carboxypropyltetrazole-5-thiol NMR: DMSO, PPMδ; 1.9-2.4, m, 4

[Formula] 4.3, t(C H ₂ −N)

Claims (1)

[Claims] 1 formula (a) Treating 1-methyl-5-mercaptotetrazole with an organolithium compound to obtain the corresponding lithio derivative; (b) Treating the lithio derivative with carbon dioxide, which is then hydrolyzed. A process characterized in that the desired product is produced by: 2 formulas (wherein n is 1 to 9) In the method for producing a compound of formula (a) (wherein n is as defined above and R ¹⁰⁰ is alkyl, phenyl, phenylalkyl or substituted phenyl or phenylalkyl of 1 to 6 carbon atoms) with sodium azide. process and expression (b) hydrolyzing the thiol ^ester to produce the desired thiol acid.