JPS6034977A - 3,7-disubstituted-3-cephem-4-carboxylic acid compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (X is acid residue; R<2> is alkanoyloxy, carbamoyloxy or heterocyclic-thio group which may have proper substituent group; R<3> is protected carboxy). EXAMPLE:7-( 2-Hydroxyimino-3-oxo-4-bromobutylamido )-3-( 1-methyl-1H-tetrazol- 5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester. USE:Useful as a raw material for the preparation of antibacterial agent. PREPARATION:The compound of formula I can be prepared by reacting the compound of formula II with a nitrosation agent such as nitrous acid, etc. in a solvent such as benzene under cooling or at room temperature. The starting compound of formula II is novel compound.

Description

[Detailed description of the invention]

This invention discloses a general formula (wherein, X is an acid residue, R2 is an alkanoyl-reoxy group,
A kallevamoyloxy group or a heterocyclic thio group which may have an appropriate substituent, R3 means a protected carboxy group respectively] 6,7-disubstituted-5-cephem-4-carboxylic acid compound, which is the object compound of this invention, is represented by the above general formula (1) and is a syn isomer. However, there may exist anti-isomers, which are the corresponding geometric isomers of this compound. Here, the syn isomer means a geometric isomer that has a partial structure represented by the formula % (in the formula, X has the same meaning as before) in its molecule, and the corresponding anti-isomer is the formula It means the other geometric isomer having a partial structure represented by the formula % (wherein X has the same meaning as before) in its molecule. Therefore, in this specification, the syn isomer of the target compound and the starting compound is represented as a compound having a partial structure 1 -0- represented by the formula -CONH- in its molecule. The object compound (1) of the present invention is a novel compound 6D, which can be produced, for example, by the method shown below. Method (in the formula, R2, R3 and reactive derivatives or their salts

[In the formula, R2, R3 and Useful as a chemical compound. 6 (1)(V) R''(1'D (wherein, R2, R3 and X each have the same meaning as before)
(R1 means an amino group or a protected amino group) Next, the definition of the above general formula will be explained. In this book Il'III, the term "lower" is not otherwise defined and is generally used to mean prime numbers 1 to 6. Examples of the protected amino group include an acyl group, benzyl, 4-methoxybenzi's 3,
4-dimethoxybendiJV1 Aralkyl groups such as phenethyl, trityl, etc., preferably substituted with a protecting group used such as ary JV lower alkyl groups are mentioned. Examples of the acyl group include a carbamoyl group, an aliphatic acyl group, an acyl group containing an aromatic ring or a heterocycle,
More specifically, the examples include formyl, gropionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, methoxycarponyl, ethoxycarbonyl, fropoxycarponyl, 1 -cyclopropylethoxycarbonyl, isopropoxycarbonyl, ptoxycarbonyl, tertiary butoxycarbonyl, 3M benzyloxycarbonyl IV, hexyloxycarbonyl group, mesyl, ethannulfonyl, propanenulfonyl, isopropanulfonyl , 7Vn7. Arenesulfonyl groups such as sulfonyl, arenesulfonyl groups such as benzene lrefonyl, tolyenes IV fonyl, benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonylacetyl groups, aralkayl groups such as phenylpropionyl, benzyloxycarbonyl groups, etc. These groups include, for example, chlorine, bromine,
One or more suitable substituted needles such as halogens including iodine and fluorine, nitro groups, amino groups, cyano groups, methyl, ethyl, propyl, impropyl, butyl, etc.) You may have
Preferred examples include lower alkanoyl groups and trihalo lower alkanoyl groups. The heterocyclic moiety in the heterocyclic thio group which may have an appropriate substituent includes one saturated or unsaturated monocyclic or polycyclic heteroatom such as an oxygen atom, a sulfur atom, or a nitrogen atom. It means a heterocyclic group containing the above, and more specifically, pyrrolyl, pyrrolinyl, imidazolylmi-pyrazolyl, pyridyl or its N-oxide, pyrimidinyl, pyrazinyl, pyridazine IV, 4H-1.2.
4-) riazolyl, IH-1.2.3-triazolyl,
2 H-1.2. Triazolyl such as 3-triazolyl, nitrogen-containing unsaturated monocyclic heterocyclic groups such as tetrazolyl such as IH-tetrazolyl and 2H-tetrazolyl, nitrogen-containing nitrogen-containing groups such as pyrrolidinyl, imidazolinyl, piperidino, piperazinyl, etc. Saturated monocyclic heterocyclic group, indolyl, isoindolyl, intridinyl, benzimidazolyl, quinolyl,
Nitrogen-containing unsaturated fused heterocyclic groups such as isoquinolyl, imidazolyl, benzotriazolyl, oxasilyl, inxazolyl, 1,2.4-oxadiazolyl, 1,3.4
-Oxadiazolyl, unsaturated monocyclic heterocyclic groups containing oxygen such as oxadiazolyl such as 1,2,5-oxadiazolyl, saturated monocyclic heterocyclic groups containing oxygen and nitrogen such as moI leforinyl, benzoxacylyl, benzoxa Oxygen- and nitrogen-containing unsaturated fused heterocyclic groups such as diazolyl, thiazolyl, 1, 2. 3-thiadiazolyl, 1,2.
4-Thiadiazolinone, 113.4-Thiasiasili IV
, sulfur- and nitrogen-containing unsaturated monocyclic heterocyclic groups such as thiadiazolyl, 1,2,5-thiadiazolyl, sulfur- and nitrogen-containing saturated monocyclic heterocyclic groups such as thiazolidinyl, henzothiazolinono , sulfur- and nitrogen-containing unsaturated fused heterocyclic groups such as benzothiadiazolyl, etc.
These groups include, for example, alkyl groups such as methyl, ethyl, propyl, impropynon, ptynopeisoptyl, pentyl, cyclopentyl, hexyl, cyclohexyl, alkenyl groups such as vinyl, allyl, butenyl, phenyl, tolyl, etc. Aryl groups, halogens including chlorine, bromine, iodine, fluorine, amine groups, dialkylaminos such as dinotylaminomethyl, dinotylaminoethyl, diethylaminomethyl, siethylaminoethyl, shetylaminoglobil, dimethylaminobutyl, etc. It may have one or more suitable substituents such as an alkyl group. Preferred examples of the heterocyclic moiety of the above-mentioned heterocyclic thio group having an appropriate substituent include methyltetrazolyl, ethyltetrazolyl, dimethylaminomethyltetrasily/
Examples include a tetrasilyl group substituted with a lower acyl group such as l/, dimethylaminoethyltetrazolyl, or a lower alkylamino lower alkyl group. Examples of the protected carboxyl group include esterified carboxyl groups, and examples of the ester moiety in the esterified carboxyl group include fAJ Engineering Id methyl ether, ethyl ester, propyl ester, improhyle ester, isobutyl ester, Alkyl esters such as tertiary butyl ester, benthyl ester, hexyl ester, 1-cyclopropylene ethyl ester, acetoxymethinone ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxy Methyl ester, 2-y setoxyethyl! alkanoyloxia such as rayste w, 2-propionyloxymethyl ester, hivaloyloxymethyl ester, hexanoyloxymethyl ente/L/, etc./V kyl este IV, medi IV methyl enuter, ecunnulphonyle ethyl), alkanes such as V esteno v, etc. having one or more suitable substituents, such as mono(or di- or tri)haloal-lekylene ether, such as nulfonylalkyl ester, 2-iodoethyl ester, 2,2.2-)lichloroethyl ethyl ester, etc. Sulualkyl ester, vinyl N 7/L/, 7!
Alkenyl esters such as esters, aralkyl esters such as ethynyl esters and propynyl esters, benzyl esters, 4-methoxybenzyl esters, 4-
Nitrobenzyl enuter, phenyl ester, trityl ester, sipheni! Remethyl ester, diphenylethyl ester, His

[Methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-
Aralkyl esters optionally having one or more suitable substituents such as hydroxy-3,4-ditertiary butylbenzyl esters, phenyl esters, tolyl esters, tertiary 7-tylphenyl esters, and aryl esters which may have one or more suitable substituents such as 4-chlorophenyl ester IV, xylyl ester, mesityl ester, cumenyl ester, preferably lower alkanoyloxy lower alkyl ester, trihalo lower Examples include alkyl esters, diphenyl lower alkyl esters, etc. Examples of alekanoyloxy groups include acetoxy, propionyloxy, butyleneoxy, hexanoyloxy, etc., and preferred examples include lower alkanoyloxy groups. Examples of the residue include halogens including chlorine, bromine, iodine, and fluorine. Particularly preferred examples of the definitions of the general formula clarified above for the target compound (1) are listed below. Preferred examples of R2 include halogen (more preferably bromine), and preferred examples of R2 include carbamoyloxy group, lower alkanoyloxy group (more preferably acetoxy group), lower alkyl group (more preferably di-lower alkyl group) Preferred examples of R3 include a tetrasilifrethio group (more preferably a 1H-tetrazolylthio group) or a thiadiazolylthio group substituted with a V-kyleamino lower alkyl group, diphenyl such as diphenylremethoxycarbonyl JV, diphenylethoxycarbonyl, etc. Each of them includes a lower alkoxycarbonyl group. Next, a method for producing the object compound of the present invention will be described. Method Compound (1) H and compound (11) are produced by reacting a nitrosating agent with a cell. Examples of the nitrosating agent include nitrous acid, potassium nitrite such as sodium nitrite, and potassium nitrite such as sodium nitrite.
Examples include aryl nitrite esters such as Nute/L/. This reaction consists of water, acetic acid, benzene, methylene chloride, tetrahydrofuran, methanol, and ethanol.
If necessary, the reaction is often carried out in a mixed solvent of these or other solvents that do not adversely affect the reaction. The reaction temperature is not particularly limited, but it is often carried out under cooling or at room temperature. Next, a method for producing the raw material compound of this invention will be explained. Compound cn>u, compound 4! +) or a reactive derivative thereof at the amino group or a salt thereof, compound (V)
Mojiku is produced by the action of reactive derivatives at its carboxyne group. As the reactive derivative at the amino group of compound (Ill), for example, compound (Ill)
Schiff's base (imino type) or its enamine type isomer, compound side) produced by the reaction of ll) with a carbonyl compound such as acetoacetate, and a nitrogenyl compound such as bis(trimethyfuresylyl)acetamide. The silyl derivative or compound II) produced by the reaction with 3
All those commonly used in amidation reactions, such as derivatives produced by reaction with phosphorus chloride, honugen, etc., are included. Examples of the salts of compound (III) include salts with organic acids or inorganic acids. In addition, examples of reactive derivatives at the carboxyl group of the compound include acid halides, acid anhydrides, active amides, active esters, etc., but particularly frequently used derivatives include acid bromides, acid chlorides, etc. Examples include acid halides such as This reaction is usually carried out in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, or other general organic solvents that do not adversely affect the reaction. These baths can also be used in combination. When compound (g) is used in the form of a free acid or a salt thereof in this reaction, it is advantageous to carry out the reaction in the presence of a conventional condensing agent such as N,N-dicyclohexyiv carbodiimide. The reaction may be carried out in the presence of a base. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. The object compounds (1) of this invention are all new compounds, and when the compound (Vl) is reacted with the compound (W) by a conventional method, a compound (W) useful as an antibacterial substance can be obtained. Example 1 7-amino-3-(1-methyl-1H-tetrazole-
5-4t) thiomethyl-6-cephem-4 - force w
To a solution of 12.49 diphenylmethyl ester of fonic acid suspended in 200 mJ of dry tetrahydrofuran, 7.6 g of binu(tritylsilyl)acetamide was added, and the mixture was heated at -30''C.
Cool to Separately, diketene 2,5+1 was dissolved in 5 ml of dry methylene chloride, and a solution of 4.8 g of bromine dissolved in 3 ml of dry methylene chloride was added thereto at 130"C, then filtered at the same temperature and stirred for 6-0 minutes. A solvent containing oxo-4-promoptylino V filomide is obtained. This solution is added to the previously obtained tetrahydrofuran solution from -30 to -
After dropping at 20'C, the mixture is stirred at -20 to -10'C for 2 hours. -5, (7)thiomethyl-5-cenitrite)
A solution of 1.9 g of IJum dissolved in 4 ml of water was heated to O~7
When the resulting mixture was stirred at the same temperature for 1 hour, 7-(2-hydroxyimino-3-oxo-4-
Diphenylmethyl ester (syn isomer) of bromobutyramide]-6-(1-methyzv-1H-tetrazol-5-inoV]thiomethyl-rosefemu-4-carboxylic acid (syn isomer)=e to obtain a solution containing 'Fi'. Example 2 7-amino-ro-t'1,3.4-thiadiazole jV
A suspension of 225 mlK of dry tetrahydrofuran in 8.5!9 of the diphenylmethyl ester of vinyl(trimethylsilyl)acetamide-2-yl)thiomethyl-ro-cephem-4-force/V-poic acid was added to 25 mL of dry tetrahydrofuran. Cool to °C. On the other hand, 2.81 g of diketene was added to 6 g of dry methylene chloride, and a solution of 5.44 g of bromine dissolved in 2.5 g of dry methylene chloride was added dropwise at 25°C, followed by stirring at the same temperature for 30 minutes. 6-oxo-
A solution containing 4-glomoptylinonobromide is obtained. This solution was added dropwise to the previously obtained tetrahydrofuran solution at -25°C over 5 minutes, and then at the same temperature for 30 minutes.
Stir for a minute. Diphenyl of 7-(3-oxo-4-bromobutyramide J-3-(1,3.4-thiacyazol-2-yl]thiomethy)V-3-cephem-4-carboxylic acid thus obtained After adding 6 g of water to the mixed solution containing Remethyl Nter, a solution of 2.31 g of sodium nitrite dissolved in 6 L of water was added over 15 minutes while cooling with water. The mixed solution was stirred at the same temperature for 50 minutes. 7-(2-hydroxyimino-3
-oxo-4-bromobutyramide)-3-tl,5.
4-Thiadiazole-2-I/S]thiomethi)v
A solution containing -3-cephem-4-kaponic acid nosipheni IV methyl ether (syn isomer) is obtained. Example 3 11.0 g of diphenylmethylester Jv of 7-aminocephalosporanic acid, 2.4 M of diketene, 4.8 g of bromine and 1.91 g of sodium nitrite. When treated as in Examples 1 and 2, 7-(2- A solution containing hydroxyimino-oxo-4-gromoguchi IV amide) (the diphenylmethyl ester of cepharonuporanic acid) is obtained. Reference Example 1 7-(2-hydroxyimino-6- obtained in Example 1)
Oxo-4-bromobuty JV amide]-6-(1-methyl-1H-tetrazol-5-inoV]thiomethyl-6
-Cephem-4-force IV (diphenylation of bonic acid) Add 19 g of urea and stir at room temperature for 1.5 hours.The resulting reaction solution is concentrated, and the residue is dissolved in ethyl acetate/V2 [
Wash with ID ml. The ethyl acetate layer was then removed by decanting, and 400 ml of ethyl acetate and 2,10 ml of water were added to the residue.
The mixed solution was adjusted to pH 7 with an aqueous solution of sodium hydrogen suboxide, and extracted with ethyl acetate. Add water IV to ethyl acetate +
10 (Jprl×2). The ethyl acetate (V) extracts are combined, washed with water and a saturated chlorinated (IJ) aqueous solution, and then dried over magnesium sulfate. The solution is red-shrinked to a volume of 7 to 8 Jul, and then cooled to precipitate crystals. The crystals are collected, washed with ethyl acetate, and dried.
7-(2-hydroxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methino V
-IH-tetrazonon-5-yl]thiomethyl-3-
Cephem-4-carciboxylic acid nocyphenylmethyl enutenone (syn isomer) 3.7 Obtains Q. 1, R, Spectrum (Nujol) 335[], 3260.filter 180.178D, 1705
．． 165D. 161[], 1520c1++ N, M, R, spectrum Ld6=DMSO, δ)11.
37(IH,s), 9.50tIH,d,, J=8Hz
l. 7.73-7.17tlQH,m), 6.9[]LIH
,s). 6.68t IH, +q), 5.92t 1t(, aa
, J=5°8Hz), 5.20(In, d, J=5az
34.25t 2H, ABq, J=1roH2), 3
．． 33t 3H. p], 3.75t 2H, broad PI]
Reference Example 7-(2-hydroxyimino-ro-
Oxo-4-bromobutyramide]-5-tl, 3.4
-Thiadiazo-l-2-I) thiomethyl-ro-cephemu-4-carboxylic acid nodiphenylmethyl ester (
The pH of the solution containing the syn isomer was adjusted to about 5 with an aqueous sodium hydrogen acid solution, and 2.12 g of the original thio
Add. The resulting mixture is stirred at 10-15° C. for 1 hour and then concentrated, and the residue is washed with ethyl acetate 100#+/-. Add ethyl acetate to the residue (25 [3 g/and 250 ml of U7K)
'r7111. After rinsing, the pH was adjusted to 7 with an aqueous sodium hydrogen hypooxide solution, and the mixture was extracted with ethyl acetate. The aqueous layer is further extracted with 200 tut of ethyl acetate. Combine the extracts, add 1 part water
After washing with 100 AJ of a saturated aqueous solution of IJ chloride and drying with magnesium sulfate. After the ethyl acetate solution has been fully activated, it is concentrated to a volume of about 70 ml. After taking the precipitate + p and washing with 50 ml of ethyl acetate, 7
-[2-hydroxyimino-2-

[2-aminothiazo-
)V-4-yl]acetamido]-3-t i, 6.4
-thiadiazol-2-yl)thiomethytv 3-cephem-4-carboxylic acid diphenylmethylenthel (syn isomer 32.45 g2-4). Concentrate the furnace solution, add the precipitate, and obtain the same objective compound 0. .2
get g. Furthermore, in the same manner, 0 of the same objective compound was extracted from the furnace liquid.
．． Get 29. ■, R, Nuvector (Nugeot/l/) 3400-31
00.1755.1715.1645,160shi "1N
, M, R, spectrum d6-DMSO, δ) 9.5
0 (2H, broads), 7.68-6.9
5f 10H. m), 6.92 (IH, sl, 6.72 (IH, s). 5.92 [IH, da, J==5.8Hz), 5.2
4 (IH. d, J=5Hz), 435 (:2H, AEq, J=13
Hz). 3.6612H, brOads) Reference example 7-(2-hydroxyimino-
A solution containing diphenyone methyl ester (syn isomer) of 3-oxo-4-bromobutyramide]cephalonuporanic acid was diluted to pH 6 with a saturated aqueous sodium hydrogen chloride solution.
Then, 1.9 fe of thiourea was added to this and 1.9 fe of thiourea was added at room temperature.
．． Stir for 5 hours. When the reaction solution was post-treated in the same manner as in Reference Example 1, 7-[2-hydroxyimino-2-+2-aminothiazol-4-yl)acetamide]cephalonuboranic acid dipheny)V
Methyl entel (34.25 g of syn-14-mer is obtained. ■, R6 spectrum (nujol) 3350.3270.3180.1780.1715,
1655゜1610.1520m N, M, R, spectrum d6-DMSO, δ〕11
．． 34 (IH, s), 9.50 (IH, d, J-8az
). 7.1-7.64 (10H, m), 6.94 (IH, s
3゜6.7[]tIH,8), 5.82(IH,dd,
J = = 5.8Hz 1.5.22 (IH, d, J = 5Hz
), 4.78 (2a, ABq, r=13az), 3.6
0t2a. ABq,,T=17Hz), 1.98(3I(,81 Applicant Fujisawa Pharmaceutical Co., Ltd.

Claims (1)

[Claims] General formula (wherein, X is an acid residue, R2 is an alecanoyloxy group,
Power! a levamoylreoxy group or a heterocyclic thio group optionally having a suitable substituent, R3 means a protected levoxy group]
3-cephem-4-carboxylic acid compound.