JPS63170384A - 7alpha-substituted cephalosporin compound - Google Patents

Abstract

NEW MATERIAL:A 7alpha-substituted-7-cyanomethylthioacetylamino-3-( 1-methyl-1H- tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid expressed by formula I [R represents (substituted) aryl or lower alkyl], salts or esters thereof. EXAMPLE:7-Cyanomethylthioacetylamino-7alpha-(4-methylphenyl)thio-3-( 1-methyl-1H- tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid expressed by formula II. USE:An intermediate for producing cefmetazole. PREPARATION:A 7alpha-substituted-7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl- 3-cephem-4-carboxylic acid (salt) or ester expressed by formula III is reacted with cyanomethylthioacetic acid (reactive derivative).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a new method for producing cefmetazole, a useful intermediate therefor, and a method for producing the same.

[Conventional technology]

- Conventionally, methods for converting the 7α substituent of a cephalosporin compound into a methoxy group include a method using chlorine or bromine and methanol (Japanese Patent Application Laid-Open No. 49-42689), a method using heavy metals such as thallium, bismuth, lead, etc., and methanol. A method using N-halogenocarboxylic acid imide or N-halogenocarboxylic acid amide and methanol (Japanese Patent Application Laid-Open No. 53-79892) is known.

[Problem that the invention seeks to solve]

In methods using chlorine or bromine and methanol as reagents, chlorine and bromine are highly corrosive, irritating, and toxic, making them difficult to handle, and in order to maintain reaction stability, the reaction temperature must be kept at 180° or above. The process must be carried out under strong cooling at -25°C, and implementation on an industrial scale requires a large amount of equipment.

The method using methanol and heavy metals such as thallium, bismuth, and lead as reagents requires the use of heavy metals that may pollute the environment, and has poor selectivity to the 7α position, making it difficult to separate and purify the 7β-methquine. However, a considerable amount of side effects are generated.

N-halogenocarboxylic acid imide or N-
The method using halogenocarboxylic acid amide and methanol has better selectivity to the 7α position than the method using heavy metals and methanol, but this selectivity is dependent on temperature to some extent and must be carried out under strict temperature control. If the reaction is not carried out, the yield will be reduced. Furthermore, during the reaction, coloring occurs that cannot be removed even with licage gel column chromatography.

The methoxylation of the present invention must be carried out under strict temperature control.
It has excellent selectivity to the α-position, and provides methoxylation in high yields without using reagents that may pollute the environment, and without requiring special equipment or factories. It's right there.

[Means to solve the problem]

In view of the above-mentioned technical situation, the present inventors conducted various studies, and the starting material of the present invention, 7α-substituted-7-amino-3-(
The present invention is accomplished by using as a reagent the sulfenyl chlorides used in the synthesis of I-methyl-114-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, its salt, or its ester. reached.

The present invention provides 7α-substituted-7-amino-3-(I-medy-IH-tetrazole-5- yl)thiomethyl-3-
Cephem-4-carboxylic acid, a salt thereof, or an ester thereof is reacted with cyanomethylthioacetic acid or a reactive derivative thereof to obtain a compound represented by the general formula (wherein R has the same meaning as above), 7α-substituted- 3- to 7-tuanomethylthioacetylamide
(l-methyl-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid or a salt thereof, or an ester thereof is obtained, and this compound is reacted with sulfenyl chloride and methanol to obtain cefmetazole or its This article relates to a method for producing salts or esters thereof.

7α-substituted-7-diazmethylthioacetylamino-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid or a salt thereof, which is the object of the present invention. All esters are new compounds.

The sulfenyl chloride used in the present invention includes 7α-substituted-7-ami/-3-(1-
Methyl-1 (formerly tetrazol-5-yl)thiomethyl-3
Methanesulfenyl chloride, phenylsulfenyl chloride, p-tolylsulfenyl chloride, etc. used in the synthesis of -cephem-4-carboxylic acid, its salt, or its ester are preferred, and p-tolylsulfenyl chloride is particularly suitable. There is.

As the salt used as the starting material in the present invention, commonly used basic substances can be selected depending on the solvent used, and as the carboquino protecting group, commonly used ester type protecting groups can be used. Groups that are not cleaved during the reaction by the subsequent reaction conditions of the protecting substance are preferred. For example, as groups that can be removed by catalytic reduction, pennol groups such as benzyl group, phenacyl group, p-chlorobenzyl group, p-nitrobenol group, and 0-cyanobenzyl group, and picolyl group can be removed by acid treatment. In addition to diphenylmethyl group, t-butyl group, trityl group, trimethylbenzyl group, pentamethylbenzyl group, etc., and groups that can be removed by alkali treatment include methyl group, β-
A methylthioethyl group, a phthalimidomethyl group, a noclobentyl group, etc., and a substituted silyl group such as a trimethylnoryl group, which can be removed by hydrolysis, can be mainly used.

Next, the present invention will be explained in more detail with reference to Examples. The present invention is not limited to this in any way.

Example 1 Noatu methylthioacetic acid 0.98g and pyrinone 0.59g
g was added to 2 ml of methylene chloride, and under water cooling, 0.68 ml of phosphorus chloride was added and stirred for 15 minutes. This solution was mixed with 7-amino-7α-phenylthio-3-(l-methyl-I H-tetrabul-5-yl)thiomethyl-
The mixture was added dropwise to a solution of 3.01 g of 3-cephem-4-carboxylic acid benzhydryl ester and 1 loml of methylene chloride and 2.43 ml of N,N-jedylaniline, and stirred for 1 hour and 20 minutes under water cooling. After the reaction was completed, the reaction solution was concentrated and separated between ethyl acetate and water. The aqueous layer was further separated with ethyl acetate, combined with the first ethyl acetate layer, washed twice with a 3% aqueous potassium hydrogen sulfate solution, four times with a 5% aqueous dipotassium hydrogen phosphate solution, and saturated brine, and then washed with magnesium sulfate. Dry. After filtration and concentration, purification using Norica gel column chromatography,
7-Diazmethylthioacetylamino-7α-phenylthio-3-(1-methyl-11-1-tetrazole-5
3.34 g of pale yellow crystals of benzhydryl)thiomethyl-3,cephem-4-carboxylic acid ester were obtained.

IR(KBr): 1780.1720.1680.
1380cm” NMRδ (CDC13): 3.23.3.35 (dd
S J=17Hz12H), 3.31(s,2)i),
3.67 (s, 21-D, 3.81 (813 t■),
4 24 , 4.4 2 (dd, J =
1 3Hz, 2H), 4.98 (sSIf-D, 6
．． 94 (s, IH), 6.95 (s, l) [), 7
．． 2 to 7.6 (m, l 51 ()) Example 2 In the method of Example 1, 7-aminodα-phenylthio-3(1methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4 - instead of carboxylic acid benzhydryl ester, 7-amida7a-(-4-methylphenyl)thio-3-(l-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carvone Using acid benzhydryl ester and performing the same procedure, 7-cyanomethylthioacetylamide/-7α-
(4-methylphenyl)dio3~(l-methyl-4)
3.28 g of pale yellow crystals of henzhydryl ester of -tetrazol-5-yl)thiomethyl-3-cephem-4-pJ luponate were obtained.

IR(KBr): I 780.1720,168O
S 1380cm-'NMRδ (CDC13): 2
．． 33 (s, 3H), 3.23.3.35 (dd, ,
J = 17 Hz, 2 H), 3.31 (s, 2
H), 3.67 (s.

2■D, 3.81 (s, 3H), 424.4.42 (a
d, ,, r = 13 Hz, 2 H), 4.9
8 (s, LH), 6.94 (s, IH), 7.0-7.
6(m,l 4H) Real example 3 7-tuanomethyldioacetylamide/-7α-(-1-
methylphenyl)di-3-(l-methyl-L H-tetrazol-5-yl)thiomethyl-3-cephem-・
After dissolving 365 mg of 1-carboxylic acid benzhydryl ester in 1 ml of methylene chloride and 1 ml of nitromethane, 170 mg of anisole and aluminum chloride +0 were added under water cooling.
1 ml of nidokomethane containing 0 mg was added and stirred at the same temperature for 1 hour. Next, 9 Tll of ethyl acetate and 7 m of INN hydrochloric acid were added, and the mixture was stirred for 30 minutes. The ethyl acetate layer was taken, washed with IN hydrochloric acid and water, and extracted twice with 100 ml of 1O% dipotassium hydrogen phosphate aqueous solution. The extracts were combined and diluted with 1) H1 with IN hydrochloric acid, extracted with ethyl acetate, washed with water, dried with magnesium sulfate, filtered with A6, and crystallized with methylene chloride.
7-cyazmethylthioacedylamino7α-(4-methylphenyl)thio-3-(l-methyl-1)1-tetrazol-5-yl)diomedyru-3-cephemu4-
222 mg of carboxylic acid was obtained.

m, p ・83-86℃ IR (KBr): 3440.1780.1720,
I b 80αm-'NMRδ (d, -DMSO)
: 2.3 3(s, 3 ト■), 3.
40 (s, 2H), 3.45 (d, J = 17
Hz, lH), 3.60(d, J=171(z,
l I-(), 3.72(s, 2H), 3.92(
s, 3H), 4.23 (dS J=13Hz, IH) 1
．． 1.38 (d, J=13Hz, IH), 5.12 (s
, I H), 7, 20 (d, J = 91
1z.

2H), 7.4 0d, J=9Hz,
2 1) Example 4 C113 7-tuanomethylthioacetylamino-7α-(,1-
Methylphenyl 1)thio-3-(1-methyl-I Ll
After dissolving 109 mg of benzhydryl ester of 3-cephem-4-carboxylic acid (tetrazol-5-yl) in 1 ml of methanol and 0.5 ml of methylene chloride, a solution of 26 mg of phenylsulfenyl chloride in methylene chloride (methylene chloride (dissolved in 0.5 ml) and stirred for 1 hour. After concentration, it was purified using silica gel column chromatography to obtain 7-cyanmethylthioacetylamino-7.
80 mg of colorless crystals of α-methquin-3-(1-methyl-I H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester were obtained.

IR(KBr): 2275.1780.1720
．． 1680cm-'NMRδ(CDCl2): 3.4
7 (s, 2H), 3.54 (s, 2H), 3.58 (s
, 3H), 3.65 (s, 2H), 3.85 (s, 3H)
), 4.2B, 4.48 (dd, J=14Hz, 2l
-I), 5, 09 (s.

IH), 6.93(s, II(), 7.2-7.
6(m,IOH) Example 5 (4)--→(6) 7-Diazmethylthioacetylamino-7α-(4-methylphenyl)thio-3-(l-methyl-IH-tetrazole-5- After dissolving 109 mg of benzhydryl thiomethyl-3-cephem-4-carboxylic acid in 1 ml of methanol and 0.5 ml of methylene chloride, a solution of 19 mg of methanesulfenyl chloride in methylene chloride (dissolved in 0.5 ml of methylene chloride) was prepared under water cooling. was added and stirred for 1.5 hours. Furthermore, methanesulfenyl chloride 25m
g of methylene chloride solution (dissolved in 0.5 ml of methylene chloride) was added and stirred for 30 minutes. - After leaving in the refrigerator overnight, it was concentrated and purified by silica gel column chromatography.
-Methyl-114-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (71 mg) was obtained. This product showed the same IRS NMR spectral values as the product of Example 4 and 1
child.

Example 6 (2)--→(6) 7-diazmethylthioacetylamino-7α-phenylthio-3-(1methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydride After dissolving 358 mg of polyester in 3 ml of methanol and 2 ml of methylene chloride, a methylene chloride solution of 119 mg of pt-lylsulfenyl chloride (dissolved in 2 ml of methylene chloride) was added under water cooling, and the mixture was stirred for 1 hour. Next, 1 ml of propylene oxide was added and after stirring for a while, it was concentrated and purified by silica gel column chromatography to give 7-diazmethylthioacetylamino-7α-methoxy-3-(l-
293 mg of colorless crystals of methyl-I l-1-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester were obtained. This product showed the same IRS NMR spectral values as the product of Example 4.

Example 7 (2)--→(6) In the method of Example 6, 87 mg of phenylsulfenyl chloride was used instead of p-tolylsulfenyl chloride + 19111 g, and the other operations were the same, and 7-cyanmethylthio Acetylamino-7α-methoxy-3-
307 mg of colorless crystals of (l-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester were obtained. This product showed the same rR, NMR spectral values as the product of Example 4.

Example 8 CH3 7-cyanmethylthioacetylamino-7α-methylthio-3-(1 methyl-IM-tetrazol-5-yl)
After dissolving 262 mg of thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester in 2 ml of methanol and 1 ml of methylene chloride, a methylene chloride solution of 78 mg of p~tolylsulfenyl chloride (dissolved in 1 ml of methylene chloride) was added under water cooling for 1 hour. Stirred. Next, 0.5 ml of propylene oxide was added and after stirring for a while, it was concentrated and purified by silica gel column chromatography.
Methyl-IH-tetrazol-5-yl)thiomethyl-
254 mg of colorless crystals of 3-cephem-4-pJ carboxylic acid benzhydryl ester were obtained.

Example 9 CHs 7-cyanomethylthioacedylamino-7α-(4-methylphenyl)thio-3-(l-methyl-1)T-tetrazol-5-yl)thiomethyl-3-cephem-4-
After dissolving 1.126 g of carboxylic acid in 10 ml of acetonitrile, 5 ml of BSAo was added and stirred for 1 hour under water cooling. Then, under water cooling, p-tolylsulfenyl chloride 50
7 mg of acetonitrile solution (dissolved in 2 ml of acetonitrile) was added. This solution was added over 15 minutes to 20 ml of a methanol solution containing 1.08 g of dicyclohexylamine under water cooling, and stirred at the same temperature for 1 hour. After distilling off the solvent under reduced pressure, 20 ml of ethyl acetate and 20 ml of water were added, and 6N
1) H1 was adjusted to 5 with hydrochloric acid, sodium chloride was added until salting out, and after stirring for 30 minutes, the precipitate was filtered off.

The ethyl acetate layer was separated and extracted twice with ethyl acetate again. The extracts were combined, washed with saturated saline, dried over magnesium sulfate, filtered and concentrated, then dissolved in 4 ml of acetonitrile, 0.3 g of dicyclohexylamine was added, and the mixture was left in the refrigerator overnight. The precipitated crystals were collected by filtration and washed successively with acetonitrile and isopropyl ether to give 7-diazmethylthioacetylamino-7α-methquin-3-(1-methyl-IH-
Tetrazol-5-yl)thiomethyl-3-cephem-
Colorless crystals of 4-carboxylic acid dichlorohequinylamine salt 0
．． 89g was obtained.

m, p, 152℃ IR (KBr) 2 1770, l 685, 1
600cm-'NMRδ(da-DMSO):
l, 0-2.0 (m, 20H), 3.05 (ml
2tI), 3.25(d, J=18Hz, I
H), 3.40 (s.

3H), 3.48 (S, 2H), 3.60 (dl J=
18Hz, IH) 3.75 (s, 2 ■]), 3.92 (
s, 3H), 4.30 (s, 2H), 4.98 (s, I
I (), 9.00 (bs, L H), 9.50 (s
, IH) Sanni Example CR3 7-cyanomethylthioacetylamino-7α-methoxy-3-(1-methyl-IH-tetrazol-5-yl)
After dissolving 0.32 g of thiomethyl-3-cephem-4-carboxylic acid henzhydryl ester and 0.17 g of anisole in 2 ml of methylene chloride, a solution of aluminum chloride (dissolved in 1 ml of tromethane) was added dropwise to a nitromethane solution of aluminum chloride with stirring under water cooling, and the mixture was heated at the same temperature. The mixture was stirred for 30 minutes. Next, at room temperature, 9 ml of ethyl acetate and 6 ml of IN hydrochloric acid were added and stirred. After the insoluble matter was completely dissolved, the ethyl acetate layer was taken, washed with water, and
Extracted twice with 0% dipotassium hydrogen phosphate aqueous solution. Combine the extracts, wash with ethyl acetate, make 1) H1 with 6N hydrochloric acid, salt out with sodium chloride, extract with ethyl acetate, wash with saturated brine, dry magnesium sulfate, filter, remove ethyl acetate, and add toluene to the residue. The residue was added and distilled off to obtain 210 mg of colorless crystals of cefmetazole.

Claims (1)

[Claims] (1) A compound or a salt thereof represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R means a substituted or unsubstituted aryl group or lower alkyl group.) or its ester (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. There are general formulas ▲mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R has the same meaning as above), or a salt thereof, or an ester thereof, which is characterized by reacting reactive derivatives. Manufacturing method (3) Reacting a compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R has the same meaning as above.) or a salt thereof, or an ester thereof, with sulfenyl chloride and methanol. A method for producing a compound, a salt thereof, or an ester thereof, represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, which is characterized by the following: