JPS604192A - Novel 7alpha-methoxycephalosporin derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 7α-methoxycephalosporin derivatives and salts thereof represented by the following general formula [wherein R1 is a hydrogen atom, a lower alkanoyl group, a lower alkoxycarbonyl group, n is an integer of 1.2, 3° 4 or 5, R2
is a hydrogen atom, an acetoxy group, a carbamoyloxy group, an optionally substituted pyridinium group, or -5R3 (where R3 means an optionally substituted 5- or 6-membered heterocycle containing N and optionally S) ). ] In the general formula (1), the lower alkanoyl group represented by R1 represents a linear or branched alkanoyl group having 5 or less carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and pivalyl group. , and the alkyl moiety in the lower alkoxycarbonyl group represented by R1 means an alkyl group having 4 or less carbon atoms, such as a methyl or ethyl group. The pyridinium group represented by R2 is carbamoyl, carboxymethyl, 2
- May be substituted with a sulfoethyl group or the like.

In SR3, the 5-membered heterocycle and 6-membered heterocycle that R3 means are, for example, 1.3.4-thiadiazole, triazole, tetrazole, 1.2.4-triazine, and these are mercapto groups, hydroxyl groups, It also includes cases where it is substituted with a lower alkyl group, or a lower alkyl group substituted with an amino group which may be substituted with a carboxyl group or a lower alkyl group.

The salts of the compound of formula (I) include pharmacologically acceptable non-toxic salts, such as sodium salts, potassium salts, calcium salts, ammonium salts, triethylamine salts, dicyclohexylamine salts, and prolactin salts. , arginine salt, hydrochloride, sulfate, oxalate, formate, trichloroacetate, trifluoroacetate, methanesulfonate, toluenesulfonate, and the like.

The compound of formula (1) and its salts are both new compounds that have excellent antibacterial activity against Durham-positive bacteria and Gram-negative bacteria, and are extremely effective against a wide range of Gram-negative bacteria, including particularly resistant Gram-negative bacteria. It has strong antibacterial activity and is useful as a medicine.

Examples of the 7α-methoxycephalosporin derivatives of the present invention include the following.

7α-methoxy-7β-(2-(3,4-diacetoxybenzoylamino)-2-(2-aminothiazole-4
-yl)acetamido]cephalosporanic acid.

7α-methoxy-7β-C2-(3,4,5-triacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid.

7α-methoxy-7β-[2-(2,3-diacetoxybenzoylamino)-2-(2-aminothiazole-4
-yl)acetamido]cephalosporanic acid.

7α-methoxy-7β-(2-(3,4-dihydroxybenzoylamino)-2-(2-aminothiazole-4
-yl)acetamido]cephalosporanic acid.

7α-methoxy-7β-(2-(3,4-diacetoxybenzoylamino)-2-(2-aminothiazole-4
-yl)acetamido]-3-(1-methyl-IH-tetrazol-5-ylthiomethyl)-3-cephem-4
-Carboxylic acid.

7α-methoxy-7β-(2-(3,4,5-triacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1
11-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.

The compound represented by formula (I) can be synthesized by the method shown below.

Tomomi, Shin) (T[) [In the formula, R4 is a hydrogen atom or a protecting group for an amino group, R
5 means a protecting group for a hydrogen atom or a carboxyl group. Rx, R2-n have the same meanings as above] Compound (m) or a reactive derivative in its carboxyl group and compound (
Compound (1) of the present invention can be obtained by reacting with II) or a salt thereof and further removing the protecting group as necessary.

In the above reaction, when using a compound (m) which is a carboxylic acid (-COOH), for example, N,N'-dicyclohexylcarbodiimide, N,N'-diethylcarbodiimide, N-cyclohexyl-N'- The reaction is preferably carried out in the presence of a dehydration condensation agent such as morpholinoethylcarbodiimide, phosphorous acid trialkyl ester, polyphosphoric acid ethyl ester, phosphorus oxychloride, or oxal chloride. In addition, when using a reactive derivative at the carboxyl group of compound (III), as the reactive derivative,
Acid halides such as acid chlorides and acid bromides; symmetrical acid anhydrides; mixed acid anhydrides with carboxylic acids such as chlorocarbonate and trimethylacetic acid; active esters with N-hydroxysuccinimide, p-nitrophenol, etc. used.

The above N-acylation reaction is carried out in an inert solvent in the presence or absence of a basic reagent or silylating agent.
It can be carried out at a temperature of 50°C to 50°C, preferably -206°C to 30°C, for 5 minutes to 24 hours. Examples of the inert solvent include tetrahydrofuran, acetone, dimethylacetamide, dimethylformamide, dioxane, dichloromethane, chloroform, ethyl acetate, benzene, or a mixed solvent thereof.

Examples of basic reagents include alkali hydroxides such as sodium hydroxide and potassium hydroxide, potassium hydrogen carbonate,
Examples include alkali hydrogen carbonates such as sodium hydrogen carbonate, and organic bases such as triethylamine, pyridine, dimethylaniline, and N-methylmorpholine.

Examples of the silylating agent include N,0-bis(trimethylsilyl)acetamide, hexamethyldisilazane, and trimethylsilylacetamide.

Examples of the protecting group R4 for the amino group in formula (II) include formyl, chloroacetyl, 2,2,2-1-lichloroethoxycarbonyl, t-butoxycarbonyl, triphenylmethyl, and tolumethylsilyl groups. . Examples of carboxyl-protecting groups include thi-butyl, diphenylmethyl, P-nitroethandyl, P-methoxybenzyl, trimethylsilyl, and 2°2.2-trichloroethyl groups.

Compound (1) of the present invention can be prepared by the formula (1) in addition to the method A described above, for example
Compounds in which R2 in I) is -S R3 can also be produced by method B below.

In addition, for example, compounds in which R1 in formula (I) is hydrogen can also be produced by method C below.

[In the formula of Method B, R1, R3, R4, and n have the same meanings as above] Compound (I') in which the 3-position of cephalosporin is acetoxymethyl is mixed with 1 to 10 times the mole of thiol compound (IV).
By reacting with cephalosporin in an organic solvent in the presence or absence of an acid or an acid adduct at a temperature of 0 to 100°C for 1 to 24 hours, a compound in which the 3-position of the cephalosporin is an R35CH2 group can be easily obtained. The compound (1) of the present invention is obtained by protecting the carboxyl group as an ester if necessary and then purifying it, and removing the protecting group if necessary. Organic solvents that can be used in the reaction include all organic solvents or reaction reagents themselves that do not adversely affect the reaction, such as nitroalkanes such as nitromethane and nitroethane; formic acid, acetic acid, trifluoroacetic acid, etc. Organic carboxylic acids; ketones such as acetone and methylmorpholine; ethers such as diethyl ether, dioxane, and tetrahydrofuran, and mixtures thereof. Examples of acids include protonic acids such as sulfuric acid, methanesulfonic acid, and perchloric acid; Lewis acids such as boron trifluoride, zinc chloride, and stannic chloride; and adducts of acids such as the above Lewis acids and diethyl ether. , ethylamine, acetic acid, and other complex salts. In addition, the reaction between compound (■') and compound (IV) is carried out in water, a buffer solution, in the presence of a base such as sodium bicarbonate or sodium hydroxide, at a reaction temperature of 50 to 70°C for a reaction time of 1 to 10 hours. You can also do it with

[In the formula of method C, R6 is a lower alkyl or lower alkoxy group, and R2, R4, Rs, and n have the same meanings as above] In the compound in which R1 is a hydrogen atom in formula (1), a base is added to the compound of formula (bi'). It can also be obtained by acting on Bases include alkali metal salts of weakly acidic substances such as carbonic acid, acetic acid, and phosphoric acid; lower alkyl amines or hydroxy lower alkal metal salts; lower alkyl amines or hydroxy lower alkyl amines, and organic amines such as alicyclic amines such as piperazine and morpholine. Examples include bases.

The amount of base used is usually 2 to 6 times the mole of CI"), and the reaction solvent includes water or an organic solvent containing water such as methanol, ethanol, dioxane, and tetrahydrofuran. After the reaction, protecting groups are added as necessary. Compound (1) of the present invention is obtained by eliminating .

2- in the above formula (1), (■'), (I"), (II)
The configuration of the carbon atom to which the aminothiazole group is bonded is D
It can exist in the form of 1-, L-, or racemic forms. Note that these optically active substances can be obtained by manufacturing using appropriate optically active raw materials or by optical resolution.

The 7α-methoxycephalosporin derivatives of the present invention are new substances, and the antibacterial activity of these sodium salts was compared with that of known representative cephalosporin compounds, and the minimum inhibitory concentration (M
IC1 μg/m Q ) is shown in Table 1.

Reference example 1 7α-methoxy-7β-[0L-2-amino-2-(2
-aminothiazol-4-yl)acetamide] Synthesis of cephalosporanic acid benzhydryl ester = 7-amituseph 70 suboranic acid benzhydryl ester 4.39
Crude 7α-methoxy 7β-aminocephalosporanic acid benzhydryl ester obtained from
rahedron Let, t,” 1975, 270
Dissolve 3.33 g of 2-anti-methoxyimino-2-(2-chloroacetylaminothiazol-4-yl) acetyl chloride hydrochloride in 40 mQ of tetrahydrofuran, add 4 mQ of pyridine, and stir while cooling with water. Add the solution dissolved in Q and stir at the same temperature for 20 minutes. After reaction ethyl acetate 300rs Q
was added, washed successively with ice water, aqueous sodium hydrogen sulfate solution, aqueous sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off and subjected to silica gel column chromatography, and benzene:ethyl acetate (2:1)
) was collected to obtain 4.05 g of 7α-methoxy-7β-[2-anti-methoxyimino-2-(2-chloroacetylaminothiazol-4-yl)acetamide]cephalosporanic acid benzhydryl ester.

IR (Br): 1790, 1745, 1705,
1550, 1390° 1230 cm −1 NMR (CDCQ 3 ) δ: 2.00 (3H, s, OCOCH3) 3.41 (28, AB + 1,2 CH2) 3.60 (3
H,s,7α−0CH3)4.13(3t(,s,=
N-OCH3)4.24(2)1. s, C11CH2C
0)4.95(28,ABq,3'-CH2)5.1
6(it(,s,6-CH) 7.01(11(,s,Ph2CFI) 7.38(I
OH, g, Ph2CH) 7.83 (IH, s, thiazole 5- C1) 7α-methoxy-7β-[2-anti-methoxyimino-2-(
2-Chloroacetylaminothiazol-4-yl)acetamide] 3.641 g of cephalosporanic acid benzhydryl ester was dissolved in 4 vans of tetrahydrofuran, 50 m of ethanol Q, 420 mg of sodium hydrogen carbonate,
Add 761 mg of thiourea, and heat and stir at 70°C for 2.5 hours. After the reaction, 200 mQ of ethyl acetate was added, washed with ice water and then saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the mixture was subjected to silica gel column chromatography.

Collecting the eluate of benzene:ethyl acetate (3:1 to 1:1) yields 7α-methoxy-7β-[2-anti-methoxyimino-2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid. 2.467 g of benzhydryl ester are obtained.

I R (KBr): 1790, 1785, 1745
,1615,1540,15001390.1235c
m-'NMR(CDCQ3)δ: 1.99(3)1. g, 0COCH3) 3.39 (28
, broad s, 2-CH*) 3.59 (3H, S
,7CE-QC)+3)4.12(3H,s,=
N-OCH3)4.93(2H,ABq,3'-CH
2) 5.11 (18, s, 6-CI) 6.95 (IH, s, Ph2 CH-) 7.35 (IO
H, s, Phz CH) 7.44 (LH, s, thiazole 5- CH) 8.94 (IH, broad s, -
CONH-)7α-methoxy-7β-[2-anti-methoxyimino-2-(2-aminothiazol-4-yl)acetamide] 1.955 g of cephalosporanic acid benzhydryl ester was mixed with 30n ethanol + 10Q toxic acid.
While keeping the reaction temperature at 25°C, add 3.92 g of zinc powder over 5 minutes to the mQ (D'a combined solution). After stirring for 10 minutes at the same temperature after addition, the precipitate is filtered and mixed with 10 mQ of ethanol, Wash sequentially with 50+oQ of ethyl acetate, combine the filtrate and washing liquid, add ice water, and add 30 g of sodium hydrogen carbonate.
Neutralize with. After neutralization, extraction with 100 mQ of ethyl acetate, washing with saturated brine, and drying over anhydrous magnesium sulfate yields 7α.
-methoxy-7β-(DL -2-amino-2-(2-
An ethyl acetate solution of aminothiazol-4-yl)acetamide]cephalosporanic acid benzhydryl ester is obtained. This solution was used as it was without purification in Reference Example 2 7α-methoxy-7β-[DL-2-amino-2-(2
-formamidothiazol-4-yl)acetamide]
Synthesis of cephalosporanic acid monobutyl ester near β-
[2-Syn-methoxyimino-2-(2-formamidothiazol-4-yl)acetamide] 1.08 g of cephalosporanic acid monobutyl ester was dissolved in 30 mΩ of anhydrous tetrahydrofuran, and 121 t,% of lithium methoxide was dissolved at -70°C. 4.6 mQ of methanol solution, then after 15 minutes 0.4611 IQ of t-butyl hypochloride
Add. After addition, stir at the same temperature for 30 minutes, then add 0% acetic acid.
．． Add 5 mQ of tetrahydrofuran 2 + sQ, and after 10 minutes add 0.52 mQ of trimethyl phosphite and add 1
Stir for 0 minutes. Then, the reaction solution was diluted with 30+n ethyl acetate.
The ethyl acetate layer was washed with ice and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography to obtain benzene:ethyl acetate ( 1: When the eluted portion of 1) was collected, 7α-methoxy-7β-[2-syn-methoxyimino-2-(2-formamidothiazol-4-yl)acetamide]cephalosporanic acid monobutyl ester 73
3 mg is obtained.

I R (KBr): 1780, 1735J705,
1550,1390.13651250cm-1 NMR (CDCQ3) δ: 1.56 (9■, s, t-Bu) 2.09 (3H, s, 0COCH3) 3.47 (2H, broad, 2-CH2 )3.67(
3H,s, 7a -0CH3) 3.87(3H,s,
=N-OCH3)4.97(28,ABq,3'CH
2) 5.16 (it(, s, 6-CH) 7.47 (ill, s, thiazole 5-C11) 8.5
6(11(,s,HCON) 7α-methoxy-7β-[2-syn-methoxyimino-
2-(2-formamidothiazol-4-yl)acetamide]cephalosporanic acid monobutyl ester 2.8
Dissolve 48g of zinc powder in a mixed solution of 50mQ of ethanol and 15mQ of formic acid and maintain the reaction temperature at 25°C.6.
Add 54g over 5 minutes. After stirring for 5 minutes at the same temperature after addition, the precipitate was filtered off, washed sequentially with 10 mQ of ethanol and 50 mQ of ethyl acetate, the filtrate and washing solution were mixed, ice water was added, and neutralized with 60 g of sodium bicarbonate. After neutralization, extraction with ethyl acetate, washing with saturated brine, and drying over anhydrous sodium sulfate yields 7α-methoxy-7β-(DL-
,2-amino-2-(2-formamidothiazole-4
An ethyl acetate solution of monobutyl ester of cephalosporanic acid (acetamido) is obtained. This solution is used as a starting material in Example 5 without being purified.

Example 1 Synthesis of 7α-methoxy-7β-(DL-2-(3,4-diacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid: 3,4-diacetoxy 715 mg of benzoic acid to 1 part of benzene
Suspend in 0 mQ, add 1 drop of dimethylformamide and 1.09+nΩ of thionyl chloride, and heat under reflux for 1 hour.

After the reaction, the solvent is distilled off to obtain 3,4-diacetoxybenzoic acid chloride, which is dissolved in 10 IlΩ of ethyl acetate.

7α-methoxy-7β-(DL
-2-amino-2-(2-aminothiazol-4-yl)acetamide] 10 dimethylacetamide in ethyl acetate solution of cephalosporanic acid benzhydryl ester
mQ was added, and under water cooling, the ethyl acetate solution of the acid chloride prepared above was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was then washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and subjected to silica gel column chromatography using chloroform:acetone (3:1-2).
: When the eluted portion of 1) is collected, 7α-methoxy-7β-(O
L-2-(3,4-diacetoxybenzoylamino)-
2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid benzhydryl ester 1.57
6g is obtained.

IR(KBr): 17B0,1745.1670
-1620.1535, 1500°1370, 1210
cm ”-1 N M R (CDC123) δ: 1.98 (38, S, OCOCH3) 2.27 (61 (, S, 2X OCOCH3) 3.26 (
2H, broad, 2-CH2) 3.39, 3.51 (
3H, each s, 7a-OCH3) 4.94 (2H
,ABq,3'CH2)5.00(IH,s,6-C
H) 5.80 (ill, d, thiazolylglycine 2-CH
) 6.45 (LH, s, thiazole 5-C1 () 6.9
1 (IH, s, Ph2CH-) 7.32 (IOH, s, Ph2CH) 7.06-7.89 (3H, m, aromatic ring CH) 1.435 g of benzhydryl ester obtained above was mixed with anisole 2IIQ. Dissolve in a mixture of 10+n12 trifluoroacetic acid, react at room temperature for 30 minutes, concentrate to about half the volume under reduced pressure at room temperature, and add ethyl ether to obtain 7α-methoxy-7.
Trifluoroacetate of β-[DL-2-(3,4-diacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid precipitates out and is collected by filtration. Yield: 1.288g.

IR (KBr): 1780, 1690-1640
,1500,1375°1200cm-1 N M RCC'DCQ 3: DMSO-d6 =4
: 1)) δ: 2.06 (3H, s, OCOCH3) 2.30 (6H, 5, 2XOCOCH3) 3.44, 3
．． 53 (38, each s, 7a-OCf (3)5.
00 (IH, +, 6-CH) 6.86 (IH, s, thiazole 5-CH) 7.16-
8.13 (3H, m, aromatic ring H) 1.188 g (1.5 mmol) of the trifluoroacetate obtained above was added to 0.5
The solution was dissolved in water containing 6 mQ (3 mmol) of an aqueous N-sodium hydrogen carbonate solution and subjected to column chromatography on Annobelite XAD-2 to obtain 912 mg of the sodium salt from the ethanol:water (5:1) eluate.

Example 2 7α-methoxy-7β-[DL-2-(3,4,5-triacetoxybenzoylamino)=2-(2-aminothiazol-4-yl)acetamide]cephalosporar anti-methoxyimino-2 -(2-aminothiazol-4-yl)acetamide] 7α-methoxy-7β-(DL-2-amino-2-(2-aminothiazol-4-yl) prepared from 2.93 g of cephalosporanic acid benzhydryl ester) When 1.24 g of 3.4.5-triacetoxybenzoic acid was reacted with 3.4.5-triacetoxybenzoic acid in the same manner as in Example 1, 7 was obtained.
α-Methoxy-7β-(DL-2-(3°4.5-)
1.70 g of cephalosporanic acid benzhydryl ester are obtained.

I R (KBr): 17g5,1750,1525
, 1490, 1370° 1195cII+'-' N M R (CDC flood.) δ: 1.53 (9H, s, t-Bu) 2.06 (3H, s, 0COCH3) 2.26 (9H, s, 3XOCOCH3 )3.41,3
．． 53 (38, each s, 7 a -0CH3,)
4.99 (IH, s, 6-CI) 6.44 (IH, s, thiazole 5-CH) 7.66 (
28,s, aromatic ring CH) When 1.60 g of the benzhydryl ester obtained above was treated with a mixed solution of 2 mfl of anisole and 10 mμ of trifluoroacetic acid in the same manner as in Example 1, 7α-methoxy-7β was obtained.
-(DL-2-(3,4,5-triacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)
1.58 g of trifluoroacetate of cephalosporanic acid (acetamide) are obtained.

IR(KBr): 1775.1635-1690
．． 1500.1380°1200cn+-” NMR (cocn3: DMSO-d6=4:
1)) δ: 2.07 (3H, 5, OCOCH3) 2, 28 (9H, s, 3 X 0CO (j13) 3.4
g, 3.58 (3H, each s, 7α-0CH3)
5.02 (IH, s, 6-CH) 6.86 (IH, s, thiazole 5-CH) 7.82 (
Amberlite
Purification by AD-2 column chromatography yields 1.0 g of sodium salt.

7α-methoxy-7β-(DL-2-(2,3-diacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid 7α-methoxy- 7β-[2-anti-methoxyimino-2-(2-aminothiazole-4
-yl)acetamide] 7α-methoxy-7β- prepared from 1.955 g of benzhydryl cephalosporanate
[DL-2-amino-2-(2-aminothiazole-4
-yl)acetamido]cephalosporanic acid benzhydryl ester and 2,3-diacetoxybenzoic acid 0.95
When 3g is reacted in the same manner as in Example 1, 7α-methoxy-
1.102 g of 7β-(DL-2-(2,3-diacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid benzhydryl ester are obtained.

IR (KBr): 1785, 1750, 1520
, 1375.1220cm-1HMR(CDCQ3)δ
: 1.99(3H,s,0COC)+3)2.29,2.
35, 2.39 (6H, each 11, 2XOCOC
H3) 3.41, 3.52 (3H, S, 7 (E -0C
H3) 5.02 (l) I, s, 6-CH) 6.44 (ill, s, thiazole 5-CH) 6.94
(IH,s, Ph2CII-)7.35(108,s,
Ph2CH) When 1.097 g of the benzhydryl ester obtained above was treated with a mixed solution of anisole 2IIIQ and trifluoroacetic acid 10 mΩ in the same manner as in Example 1, 7α-methoxy-
0.865 g of trifluoroacetate of 7β-(DL-2-(2,3-diacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid is obtained.

IR (Br): 1780.1690-1630,
1520,1375°1200cm-1 NMR (CDCfl3: DMSO-d6=4
: 1) δ: 2.08 (3H, s, 0COCH3) 2.31, 2.36 (6B, each s, 2XOCO
CH3) 3.44, 3.54 (3H, each g, 0
COCH3) 5.03 (01, s, 6-CI) 6.74 (1B, s, thiazole 5-CH) 0.803 g of the above trifluoroacetate was dissolved in an aqueous sodium bicarbonate solution in the same manner as in Example 1. Light XAD
Purification by -2 column chromatography yields 0.566 g of sodium salt.

Example 4 7α-methoxy-7β-(DL-2-(3,4-dihydroxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid O1
""l 7α-methoxy-7β-(D
L-2-(3,4-diacetoxybenzoylamino)
-2-(2-aminothiazol-4-yl)acetamide] cephalosporanic acid trifluoroacetate 396m
g was dissolved in 20mQ of 0.5N aqueous sodium bicarbonate solution and stirred at room temperature for 2.5 hours. After the reaction, it was subjected to Amberlite XAD-2 column chromatography and the eluate of ethanol:water = 5 = 1 was collected. 7α-methoxy-7
Sodium salt of β-(DL-2-(3,4-dihydroxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide)cephalosporanic acid 228m
g is obtained.

IR (Br): 1770, 1600, 1510,
1350,1295°1240cm-1 NMR(CDCQ3:DMSOd6)δ:2
．． 00(3H,s,0COCH3) 3.31. '3.43 (3+1.5,7α-0CH3)
4.95, 4.98 (1) 1. each s, 6-CH
)6.58(IH,s,thiazole5-C1()6.
70-7.47 (3H, m, aromatic ring CH) Example 5 7α-methoxy-7β-(OL-2-(3,4-diacetoxybenzoylamino)-2-(2-aminothiazol-4-yl )acetamide)-3-(1-methyl-
1.429 g of IH-tetrazol-5-ylthiomethyl)-3-cephe3.4-diacetoxybenzoic acid is suspended in 10+nQ of benzene, 1 drop of dimethylformamide and 2.18+nR of thionyl chloride are added, and the mixture is heated under reflux for 1 hour.

After the reaction, the solvent is distilled off to obtain 3,4-diacetoxybenzoic acid chloride, which is dissolved in 10 mQ of ethyl acetate.

7α-methoxy-7β-[DL
-2-amino-2-(2-formamidothiazole-
4-yl)acetamide] Sepha 0 Add 1 part of dimethylacetamide to an ethyl acetate solution of sporanic acid t-butyl ester.
0II1Ω is added, and under water cooling, the ethyl acetate solution of the acid chloride prepared above is added and stirred at the same temperature for 15 minutes. The reaction solution was then washed successively with water, an aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the solution was subjected to silica gel column chromatography. When the eluate of chloroform:acetone (5:1 to 3:1) was collected, 7α-methoxy-7β-(DL-2-(3,
1.395 g of 4-diacetoxybenzoylamino)-2-(2-formamidothiazol-4-yl)acetamide]cephalosporanic acid tert-butyl ester are obtained.

I R (KBr): 1790, 1780, 174 (
]-1710, 1540, 1500° 1370, 120
5cm-' NMR(CDCQ3)δ: 1.53(91(,g,t-Bu) 2.07(3)1.S, OCOCH3)2.29(6B
, s, 2XOCOCH3) 3.33, 3.53 (3H,
each s, 1a -0CH3)5.01(LH,s
, 6-C1() 7.06(1)1. s, thiazole 5-CH) 8.5
0 (LH, s, IC0N) 3.080 g of the above t-butyl ester was added to anisole 4
7α-methoxy-7β-(DL
-2-(3,4-diacetoxybenzoylamino)-2
-(2-formamidothiazol-4-yl)acetamide]cephalosporanic acid precipitates and is collected by filtration. Yield: 2.933g.

I R (KBr): 17g0,1715,1535
,1500,1370°1205cm-1 NMR (CDCM3:DMSOd6=4:1
) δ: 2.05 (3H, S, OCOCH3) 2.29 (6H, S, 2XOCOCH3) 3.38,3
．． 54(3)1. each s,'la -0Cth
) 4.93 (2H, ABq, 3'-12) 4.99,5
．． 03 (IH, each s, 6-CH) 6.02 (I
H, d, thiazolylglycine 2-CH) 7, 23 (II
(, s, thiazole 5-CH) 7, 17-7.97 (
3)1. m, aromatic ring force) 8.47 (18, s, HCON
) 4.234 g of 7α-methoxy-7β-(DL-2-(3,4-diacetokidibenzoylamino)-2-(2-formamidothiazol-4-yl)acetamide]cephalosporanic acid was dissolved in 50 m Q of acetonitrile. Boron trifluoride ethyl ether complex 7.57mQ and 5-
Mercapto]-Methyltetrazole was stirred at room temperature for 1 hour, and ethyl acetate was added to the reaction plate, followed by water.

Wash with saturated brine, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. When ethyl ether is added to this, crude 7α-methoxy-7β-(DL-2-(3.4-diacetoxybenzoylamino)-2-(2-formamidothiazol-4-yl)acetamide]-3-(1- Methyl-IH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid precipitates and is collected by filtration. The resulting precipitate is dissolved in 50 mQ of tetrahydrofuran and 1.1.7 g of diphenyldiazomethane is added thereto overnight at room temperature. After stirring, the solvent was distilled off, and the residue was subjected to silica gel column chromatography.Chloroform:acetone (5:1 to 4:1)
) 7α-methoxy-7β-(DL-
2-(3.4-diacetoxybenzoylamino)-2-
1.451 g of (2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-IH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester are obtained.

I R (KBr): 1790, 1710, 1,54
0,1500,1375.

1205cm ""NMR' (CDC Q 3) δ: 2, 21, 2.
26(6H,'each 5,2XOCOCH3)3
, 33, 3.44 (3H, each s, 7α-OCH
3) 3,77 (311,s, Tetrazole ICH3)
4,97(IH,s,6-CH) 6,85(18,s,Ph2CH) 7,00(LH,s,thiazole 5-CH)7,31(
IOH,s,PJCtl-)8,45(IH,s,HC
ON) Dissolve 3.155 g of the above benzhydryl ester in tetrahydrofuran 8I1112 and methanol 40rnQ.
．． Add 1.293 g of P-toluenesulfonic acid hydrate and stir at room temperature for 1.5 hours. Then 200m of ethyl acetate
Q was added, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography using chloroform:acetone (4
:j~3:1) is collected, 7α-methoxy-7
β-(DL-2-(3.4-diacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide)-3-(1-methyl-IH-tetrazole-
1.957 g of 5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester are obtained.

I R (KBr): 1790,17g0,1730
, 1675, 1615, 1520.

1370, 1200 cm-' N M R (CDC Q 3 ) δ: 2, 27 (61
1,S,2XOCOCH3)3,42,3.50(3
H,each s,1a-OCH3)3,77(3
H,s,tetrazole1-Cth)4,35(2H
, ABq, 3” CH2 ) s.78 (ti+, d, thiazolylglycine 2LCH) 6, 47 (E,'s, thiazole 5-CH) 6, 88 (LH, s, Ph2CH ) 7, 33 (IOH ,s,Ph,,CI-→7,10~7
．． 90 (3H, +n, aromatic ring Cl) 1.800 g of the above benzhydryl ester was dissolved in a mixed solution of 3 mQ of anisole and 15 mQ of trifluoroacetic acid, stirred at room temperature for 30 minutes, concentrated under reduced pressure at room temperature, and dissolved in ethyl acetate and then ethyl ether. When adding 7α-methoxy-7β-[DL-2
-(3.4-diacetoxybenzoylamino)-2-(
2-aminothiazol-4-yl)acetamide)-3
The trifluoroacetate of -(1-methyl-111-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid precipitates out and is collected by filtration. Yield 1.
477g.

IR(KBr): 1780,168(1-162
0,1395,1370.

1 200 cm −' N M R (CDC Q 3 : DMSO d6=4
: 1) δ: 2, 30 (6H, s, 2XOCOCH3
)3,43,3.53(3tl,each s,7 α
-OCH3)3,93(3H,s,tetrazole ICH
3) 5,00 (IH, s, 6-CH) 6, 82 (IH, s, thiazole 5-CH) 7, 17~
Amberlite
Ethanol subjected to AD-2 column chromatography:
When the eluted portion of water (5:1) was collected, the sodium salt was 1.09
9g is obtained.

Example 6 7α-methoxy-7β-[DL-2-(3,4,5-triacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide)-3-(1-methyl-LH -tetrazol-5-ylthiomethyl)-3-
〇COCH3 7α-methoxy-7β-[2-syn-methoxyimino-2-(2-formamidothiazol-4-yl)acetamide]cephalosporanic acid 2.
7α-methoxy-7β-(DL-
2-amino-2-(2-formamidothiazole-4-
yl)acetamide]cephalosporanic acid t-butyl ester and 3.4.5-triacetoxybenzoic acid 1.77
When 7g was reacted in the same manner as in Example 5, 7α-methoxy-
513 g of 7β-[DL-2-(3,4,5-triacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid t-butyl ester is obtained.

I R (KBr): 1790, 1785, 1735
, 1540, 1490, 1375° 1190 cm -” NMR (CDCQ 3 ) δ: 1.51 (98, s, t-Bu) 2.06 (3H, s, 0COCH3) 2.28 (98, s, 3XOCOCth )3.32,
3.50 (3H, each, 7α-0CH3) 4.9
1(2)1. ABq, 3' CH2) 4.99 (11 (
, s, 6-C1+) 6.05 (IH, d, thiazolylglycine 2- CH)
7.01 (IH,s, thiazole 5-C)I) 7.6
6 (2H, s, aromatic ring C0) 8.48 (IH, s, HCON) 2.513 g of monobutyl ester obtained above was added to a mixed solution of 3 mQ of anisole and 15 mQ of trifluoroacetic acid in the same manner as in Example 5. When treated with 7α-methoxy-7β-
(DL-2-(3,4,5-triacetoxybenzoylamino)-2-,,(2-formamidothiazole-
4-yl)acetamido]cephalosporanic acid 2.31
9g is obtained.

IR (KBr): 1790, 1710, 1540
, 1490, 1375°1190cm-”NMR(CDCQ3: DMSO-d6=5
: 1) δ: 2.07 (3H, s, 0COCH3) 2.30 (9H, 5, 3X0COCI (3) 3.42,
3.57 (3tl, each s, 7a -0Cth
) 5.01 (IH, ABq, 3' CHx ) 5.0
5 (18, s, 6-CH) 6.04 (LH, d, thiazolylglycine 2-CH) 7
．． 27 (LH,s, thiazole 5-CH) 7.72 (2
H, s, aromatic ring CH) 8.49 (1) 1. s, IC0N) 1.679 g of the above carboxylic acid was added to 5-mercapto-1- in the same manner as in Example 5 in the presence of boron fluoride ethyl ether complex 2.73 + nQ in acetonitrile IFIII Q.
Reaction with 1.254 g of methyltetrazole followed by esterification with diphenyldiazomethane yields 7α-methoxy-7β-[DL-2-(3,4,57 triacetoxybenzoylamino)-2-(2-formamidothiazol-4-yl). acetamido)-3-(1-methyl-IH
-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester 1.018G
is obtained.

I R (KBr): 1790, 1715, 1540
,1490,1375°1190cm-' NMR(CDCΩ3)δ: 2.21,2.26(9H,each 5,3XOCO
CH3) 3.38, 3.48 (3H, each S, 7
(E -0CH3) 3.79 (3H, s, tetrazole 1-CH5) 4.31 (2H, broad, 3' -C
H2) 5.00 (LH, s, 6-CH) 6.04 (LH, m, thiazolylglycine 2-CI+)
6.86 (IH, s, Ph2CH) 6.98 (III, s, thiazole 5-CI () 7.3
2(IOH,s, Ph2CH-)7.67(2H,s,
Aromatic ring C11) 8.41 (LH, s, HCON) 1.018 g of the benzhydryl ester obtained above was mixed with P-toluenesulfonic acid-water in the same manner as in Example 5 in a mixed solution of 3 + nQ of tetrahydrofuran and 15 mQ of methanol. When reacted with 0.392g of 7α-methoxy-
7β-(DL-2-(3,4,5-triacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide)-3-(1-methyl-IH-tetrazol-5-ylthiomethyl) 0.614 g of -3-cephem-4-carboxylic acid benzhydryl ester is obtained.

IR (Br): 1790J740. ．． 1680,
1620, 1530, 1490° 1380, 1190c
m −1 N M R (CDCQ 3) δ: 2.24, 2.27 (9H, each s, 3XOCO
Hz) 3.43, 3.51 (3H, each S,
7(E-0CH3)3.78(38,s,tetrazole1-CH5)4.38(2H,AB(1,3' CH
2) 4.98 (IH, 5,6-CH) 5.78 (IH, d, thiazolylglycine 2-CH)
6.45 (IH, s, thiazole 5-CH) 6.88
(IH, s, Ph2Cf () 7.33 (10) 1.s, Ph2CH) 7.67 (28
, s, aromatic ring CH) When 1.335 g of the above benzhydryl ester was treated with a mixed solution of anisole 2+nQ and trifluoroacetic acid 10 mQ in the same manner as in Example 5, 7α-methoxy-7β-(
DL-2-(3,4,5-triacetoxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamide)-3-(1-methyl-IH-tetrazole-
1.165 g of trifluoroacetate of 5-ylthiomethyl)-3-cephem-4-carboxylic acid are obtained.

IR (Br): 1780.1690-1630,
1395,1375°1190cm-' NMR (CDCQ: DMSO-da =4:1)
δ: 2.29 (9H, s, 3XOCOCH3) 3.44
,3.52(3H,each s,7(E-OCH3)
4.98 (IH, s, 6-CH) 6.90 (III, s, thiazole 5-CH) 7.81
(28,s, aromatic ring CH) 1.087 g of the above trifluoroacetate was dissolved in an aqueous sodium bicarbonate solution in the same manner as in Example 5, and purified by Amberlite XAD-2 column chromatography, resulting in 0.0% sodium salt. 773 g is obtained.

Example 7 7α-Methoxy-7β-[DL-2-(3,4-dihydroxybenzoylamino)-2-(2-aminothi,azol-4-yl)acetamide)-3-(1-methyl-
Synthesis of IH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid: 7α-methoxy-7β-(D
L-2-(3,4-diacetoxybenzoylamino)-
585 mg of trifluoroacetic acid of 2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-IH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was added to 0.5N of 32IIIQ. - Dissolve in aqueous sodium hydrogen carbonate solution and stir at room temperature for 2.5 hours. After the reaction, it was subjected to Amberlite XAD-2 column chromatography and the eluate of ethanol:water = 5:l was collected, and 7α-methoxy-7β-(DL-2-(3,4
-dihydroxybenzoylamino)-2-(2-aminothiazol-4-yl)acetamido)-3-(1-methyl-IH-tetrazol-5-ylthiomethyl)-3
- Sodium salt of cephem-4-carboxylic acid 417 mg
is obtained.

I R (KBr) knee 1775.1705,1605
,1510,1400,1360゜1300cm+ -
1 NMR (DMSOda) δ: 3.30, 3.42 (38, each s, “Ia −
0CH3) 3.93(3H,s, tetrazole 1-CH
5) 4.94 (18,s, 6-CI) 6.57 (LH,s, thiazole 5-CH) 6.70~
7.45 (3H, m, aromatic ring CH) Example 8 7α-methoxy-7β-(DL-2-(3,4-jethoxycarbonyloxybenzoylamino)-2-(2-
7α-methoxy-7β-[2-anti-methoxyimino-2-(2-aminothiazole-4
7α-methoxy-7β-(OL-2-amino-2-(2-aminothiazol-4·-yl)acetamide)cephalosporanic acid benzhydryl ester prepared from 955 g of cephalosporanic acid benzhydryl ester 1 When 7α-methoxy-7β-(OL-2-(3,
4-Jethoxycarbonyloxybenzoylamino)-
2-(2-aminothiazol-4-yl)acetamide]cephalosporanic acid benzhydryl ester 1.18
4g is obtained.

I R (KB'r): 1780, 1670, 152
5,1500,1370,1260゜1.185cm"
-1 NMR (CDCQ 3 ) δ: 1.38 (6H, CH3C1h) 1.99 (38
,s,0COCH3) 3.43,3.54(3H,each s,7a -0
CH3) 4.33 (48,q, CH3C piece 2-) 5.0
3 (IH, s, 6-CH) 6.48 (IH, s, thiazole 5-CH) 6.94 (
LH, s, Ph2Ct () 7.36 (IOH, s, Ph, CH-) 1.184 g of benzhydryl ester obtained above was added to 2 m of anisole.
When treated in the same manner as in Example 1 with a mixed solution of Q and 10 mQ of trifluoroacetic acid, 7α-methoxy-7β-(DL-2
-(3,4-Jethoxycarbonyloxybenzoylamino)-2-(2-7minothiazol-4-yl)acetamide] Cephalosporanic acid trifluoroacetate 0
．． 858 g are obtained.

IR(KBr): 1780.1680-1650
, 1505, 1375, 1260° 1190 cm-1 NMR (CDCQ3:DMSOd6=4:1) δ:1
．． 38 (6H, t, c and 3CH2-) 2.07 (3H,
5, OCOCH3) 3.45, 3.54 (3H, each s, “Ia -
0CH3)4.33(4H,q,CH3C1h)5.
02 (IH, s, 6-CH) 6.89 (IH, s, thiazole 5-CH) Dissolve 0.425 ml of the above trifluoroacetate in an aqueous sodium hydrogen carbonate solution in the same manner as in Example 1 to obtain Amberley 1. ~XA
Purification by D-2 column chromatography yields 0.276 g of sodium salt.

Patent applicant Kaken Pharmaceutical Co., Ltd.

Claims (1)

[Claims] [In the formula, R1 is a hydrogen atom or a lower alkanoyl group. a lower alkoxycarbonyl group, n is an integer of 1.2.3°4 or 5, R2 is a hydrogen atom, an acetoxy group, a carbamoyloxy group, an optionally substituted pyridinium group or -8-R3 (herein R3 represents an optionally substituted 5- or 6-membered heterocycle containing N and optionally S, and salts thereof.