JPH0140826B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to azetidinone derivatives useful as synthetic intermediates for antibiotics and a method for producing the same. The azetidinone derivative provided in the present invention has the general formula More specifically, the general formula (In the above formula, R ¹ represents a hydrogen atom, an acyl group, or an aralkyl group, R ₂ represents an acyl group, an aralkyl group, or R ¹ and R ² together represent a dibasic acid acyl group, and R ³ represents a dibasic acid acyl group. Alkyl group, aralkyl group,
represents an aryl group or a heterocyclic group, -COB represents a -COOR group (R represents a hydrogen atom, a lower alkyl group, an aralkyl group, an aryl group, an organometallic group, an alkali metal or an ammonium group), and n
indicates 1 or 2. ) is a novel azetidinone derivative. R ¹ in general formulas (), ( _a ) and ( _b ),
R ² , R ³ and the formula -COB group will be specifically explained. The acyl group in R ¹ and R ² is commonly used in β-lactam synthesis chemistry, and is an aliphatic acyl group, an acyl group having an aromatic ring or a heterocycle, or an acyl group such as acyl carbonate. , such as lower alkanoyl (e.g. acetyl, propionyl, butyroyl, etc.), aroyl (e.g. benzoyl, naphthoyl, etc.), arylalkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.), heterocyclic carbonyl (e.g. thenoyl,
furoyl, nicotinoyl, etc.), alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, etc.),
Examples include acyl carbonate groups such as aralkoxycarbonyl (eg, benzyloxycarbonyl) or aryloxycarbonyl (eg, phenoxycarbonyl), and aralkyl groups such as triphenylmethyl. The above acyl group may have a suitable substituent, and examples of such substituents include halogen, hydroxy, lower alkoxy, nitro, amino, cyano, carboxy, alkoxycarbonyl, mercapto, alkylsulfonyl, arylsulfonyl, lower Alkyl etc. are mentioned,
These may further be combined. (e.g. thienylacetyl, cyanomethylthioacetyl, 2-carboxy-2-phenylacetyl,
2,2,2-trichloroethoxycarbonyl, p
-Toluenesulfonylethoxycarbonyl, etc.)
R ¹ and R ² may be taken together to form a diacyl group or a dibasic acid acyl group such as phthaloyl, maleoyl or succinyl. R ³ is an alkyl group having 1 to 8 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, octyl, etc.), an aralkyl group (e.g., benzyl, phenethyl, etc.), an aryl groups (e.g. phenyl, naphthyl, etc.), monocyclic heterocyclic groups (e.g. furyl, thienyl, thiazolyl, oxazolyl, thiadiazolyl, tetrazolyl, pyridyl, etc.), bicyclic heterocyclic groups (benzothiazolyl, benzoxazolyl, benzimidazolyl, benzo thiophenyl, benzofuranyl, quinolyl, etc.). These groups may be optionally substituted with inert groups such as lower alkyl, halogen, hydroxy, lower alkoxy, nitro, amino, cyano, carboxy, alkoxycarbonyl, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, and the like. Protected carboxy groups, which can be represented by the formula - COB, are commonly used in the synthetic chemistry of β-lactams and include esters, amides, and salts. Examples of esters include lower alkyl groups (such as methyl, ethyl, tert-butyl, etc.),
Esters such as aralkyl groups (e.g., benzyl, diphenylmethyl, etc.), aryl groups (e.g., phenyl, etc.), trisubstituted silyl groups (e.g., trimethylsilyl, tert-butyldimethylsilyl, etc.),
Examples of amides include acetamide and diisopropyl hydrazide; examples of salts include metal salts (eg, sodium salts, lithium salts, etc.) and organic salts (eg, triethylamine salts, tetrabutylammonium salts, etc.). Substituents such as alkyl, halogen, hydroxy, alkoxy, acyloxy, oxo, acylamino, nitro, cyano, alkylthio, arylthio, alkylsulfonyl, and arylsulfonyl may be present in the above carboxylic acid protecting group, and the above aryl also includes aromatic heterocycles. These carboxy-protecting groups are commonly used in the chemistry of penicillins and cephalosporins, and a wide range of changes can be made without changing the gist of the invention as long as the purpose of protection is achieved. The compound ( _a ) of the present invention is produced by reacting the compounds ( _a and _b ) shown below with a mercaptan shown by the general formula ().

[expression] or

【formula】

(In the above formula, R ¹ , R ² , R ³ and -COB have the same meanings as described above.) That is, β-sulfoxide ( _a ) of 3-methylenecefam or α of 3-methylenecefam
_-A new azetidinone (
_a ) Manufacture. Solvents used include hydrocarbons (e.g. benzene, toluene, hexane),
Halogenated hydrocarbons (e.g. methylene chloride, 1,
Inert solvents that do not affect the reaction, such as ethers (eg, tetrahydrofuran, dioxane, diethyl ether), esters (eg, ethyl acetate), and amides (eg, N,N-dimethylformamide), are preferred. The amount of _a or _b may be equimolar to a or b, but adding in excess can speed up the reaction, and using 2 to 10 times the molar amount can shorten the reaction time. The reaction proceeds at room temperature, but at 60
The reaction can be accelerated by heating to ~150°C. The reaction time is usually 30 minutes by heating.
The reaction is complete in minutes to 3 hours. Another object compound ( _b ) of the present invention is the compound ( _a ) produced by the above method, which has the general formula ()
It is produced by reacting with a trivalent phosphorus compound shown in (In the above formula, R ¹ , R ² , R ³ , and COB have the same meanings as described above, and R ⁴ represents an alkyl group, an aryl group, or an alkoxy group.) R ⁴ has a carbon number of 1 to 8. Alkyl groups (e.g. methyl, ethyl, propyl, n-butyl, pentyl, octyl, etc.), aryl groups (e.g. phenyl, naphthyl, etc.), alkoxy groups (e.g. methoxy, ethoxy,
propoxy, n-butoxy, isobutoxy, etc.), and these aryl groups have substituents such as alkyl, halogen, hydroxy, alkoxy, acyloxy, oxo, acylamino, nitro, cyano, alkylthio, arylthio, alkylsulfonyl, and arylsulfonyl. May exist. The novel azetidinone ( _b ) can be prepared by reacting the disulfide ( _a ) with 1 to 5 times the molar amount of the phosphorus compound () in a solvent. The solvents used are hydrocarbons (e.g. benzene, toluene, hexane, etc.), halogenated carbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, etc.),
Inert solvents that do not affect the reaction of ethers (eg, ethyl ether, tetrahydrofuran, dioxane, etc.), esters (eg, ethyl acetate, etc.), amides (eg, N,N-dimethylformamide, etc.) are preferred. The reaction is completed within 1 hour at 0°C to room temperature. The starting compounds ( _a and _b ) of the present invention can be produced by various methods, for example, 7-amino-3
-Heterocyclic thiomethyl-3-cefem-4-carboxylic acid ester to the following reaction steps a and b
It can be manufactured according to the diagram. (In the above formula, -COB has the same meaning as described above, and Het represents a monocyclic or bicyclic heterocycle, such as 1-methyltetrazol-5-yl,
1,3,4-thiadiazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl,
1,2,3-triazol-4-yl, 1,3,
4-triazin-2-yl. (In the above formula, R ¹ , R ² , COB, and Het have the same meanings as described above.) The compounds of the present invention ( _a and _b ) are used to synthesize β-lactam compounds having various novel antibacterial activities. As an example, the conversion to 1-oxacefam is shown in the formula below. (In the above formula, R ¹ , R ² , R ³ and -COB have the same meanings as described above, and R ⁷ represents a group obtained by removing the carbonyl group from the acyl group in R ² group.) Examples are as follows. Examples and manufacturing methods of the present invention are shown by describing reference examples and reference examples, but these examples and reference examples are not intended to limit the present invention in any way. Example 1 3S-benzamide-4R-(2'-benzothiazolyldithio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-
2′-propenyl)azetidin-2-one 7α-benzamide-3-methylenecefaam-
1.1 g of diphenylmethyl 4-carboxylate 1-β-oxide and 0.7 g of 2-mercaptobenzothiazole
A solution of 30 ml of benzene is refluxed for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (chloroform-ethyl acetate 4:1 and 2:1) to obtain crystalline 3S-benzamide-4R-(2'-
benzthiazolyldithio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-
0.55 g of 2'-propenyl)azetidin-2-one is obtained. Recrystallized from ethyl acetate. Melting point 172-173℃ IR (nujol): 3460, 3340, 1765, 1740, 1670cm ^-1 . NMR (CDCl ₃ ) δ: 3.64 (brs, OH), 4.33 (brs,
CH ₂ OH), 4.90 (d, d, J = 2, 7, azetidine 3-position H),

[Formula] 5.08 and 5.39 (both brs, = CH ₂ ), 5.44 (d, J =
2, azetidine 4-position H), 6.83 (s, ester
_CHPh2 ), 7.0-8.0 (m, phenyl proton). Elemental analysis: Calculated value (C ₃₅ H ₂₉ N ₃ O ₅ S): C, 62.94; H, 4.38; N, 6.29; S,
14.41% Analysis value: C, 62.86; H, 4.42; N, 6.32; S,
14.39% Example 2 3S-benzamide-4R-(2'-benzothiazolyldithio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-
2′-propenyl)azetidin-2-one 7α-benzamide-3-methylenecefaam-
100 mg of diphenylmethyl 4-carboxylate 1-α-oxide and 80 mg of 2-mercaptobenzothiazole
A solution of 3 ml of benzene is refluxed for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (chloroform-ethyl acetate 2:1).
Obtain 56 mg of crystalline 3S-benzamide-4R-(2'-benzothiazolyldithio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-2'-propenyl)azetidin-2-one. . The physical properties of the obtained compound correspond to those of Example 1. Example 3 3S-benzamide-4R-(2'-benzoxazolyldithio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-
2′-propenyl)azetidin-2-one 7α-benzamide-3-methylenecefaam-
500 mg of diphenylmethyl 4-carboxylate 1β-oxide and 300 mg of 2-mercaptobenzoxazole
A solution of 15 ml of benzene is refluxed for 2 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (chloroform-ethyl acetate 4:1 and 2:1) to obtain crystalline 3S-benzamide-4R-(2'-benzothiazolyldithio)-1. -(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-
283 mg of 2'-propenyl)azetidin-2-one are obtained. Recrystallized from benzene. Melting point 98-100℃ IR (nujol): 3440, 3290, 1755, 1730, 1660cm ^-1 . NMR (DMSO-Cl ₆ ) δ: 3.62 (bs, OH), 4.17
(brs, CH ₂ OH), 5.07 (d, d, J = 2, 8,
azetidine 3-position H),

[Formula] 5.20 and 5.38 (both brs, = CH ₂ ), 5.55 (d, J = 2, H at the 4-position of azetidine), 6.68 (s, ester CHPh ₂ ), 7.2-8.0
(m, phenyl proton), 9.33 (d, J=8,
N-H). Elemental analysis: Calculated values (C ₃₅ H ₂₉ N ₃ O ₆ S ₂ ): C, 64.50; H, 4.48; N, 6.45; S, 9.84
% Analysis value: C, 64.74; H, 4.59; N, 6.48; S, 9.72
% Example 4 3S-benzamide-4S-(2'-benzothiazolylthio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-
2′-propenyl)azetidin-2-one 3S-benzamide-4R-(2'-benzothiazolyldithio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-2'-propenyl)azetidin-2-one 300 mg and triphenylphosphine A solution of 200 mg in 6 ml of dichloromethane at room temperature.
After stirring for 1 hour, concentrate. The residue was purified by silica gel column chromatography (chloroform-ethyl acetate 2:
1) to obtain amorphous powder 3S-benzamide-4S-(2'-benzothiazolylthio)-1-
(1′-diphenylmethoxycarbonyl-2′-hydroxymethyl-2′-propenyl)azetidine-2
- Get 285mg of On. IR (film): 3330, 1760, 1740, 1650cm ^-1 . NMR (CDCl ₃ ) δ: 3.07 (brs, OH), 4.05 (brd,
J=4, CH ₂ O),

[Formula] 4.59 and 5.17 (both brs, = CH ₂ ), 5.8 to 6.05
(m, azetidinone 3rd and 4th position H), 6.97 (s,
Ester _CHPh2 ), 7.0-8.0 (m, phenyl proton), 8.41 (d, J=7, N-H). Example 5 3S-benzamide-4S-(2'-benzoxazolylthio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-
2′-propenyl)azetidin-2-one 3S-benzamide-4R-(2'-benzoxazolyldithio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-2'-propenyl)azetidin-2-one 100 mg and triphenylphosphine A solution of 66 mg in 3 ml of dichloromethane is stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by silica gel column chromatography (chloroform-ethyl acetate 3:1 and 2:1) to give 3S-benzamide-4S-(2'-benzoxazolylthio)-1-
61 mg of (1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-2'-prop-1'-yl)azetidin-2-one are obtained as an amorphous powder. IR (nujol): 3340, 1775, 1750, 1660 ^{cm -1} . NMR (CDCl ₃ ) δ: 3.10 (brs, OH), 4.12 (brs,
_CH2O ),

[Formula] 5.00 and 5.20 (both brs, = CH ₂ ), 5.65-6.05 (m, azetidinone H at 3 and 4 positions), 6.92 (s, ester
CHPh ₂ ), 7.05−7.9 (m, phenyl proton),
8.30 (d, J=8, N-H). Reference example 1 7α-benzamide-3-methylenecepham-4-carboxylic acid diphenylmethyl-1
-β-oxide a 7β-amino-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4
-Diphenylmethyl carboxylate-1-β-oxide (Step A) 7β-amino-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl 4.9 g in dichloromethane 150 ml solution at -50° or less 85% m-chloroperbenzoic acid 2.03 g Add 50ml of dichloromethane solution and -
Stir at 50° for 1 hour. Return to 0°, wash with sodium bicarbonate solution, dry with anhydrous magnesium sulfate, and concentrate.
Crystals precipitate. This was taken up with a small amount of ethyl acetate-ethyl ether, and 7β-amino-3-
4.8 g of (1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl-1-β-oxide is obtained. IR (nujol): 3450, 1780, 1730, 1650 ^{cm -1} . NMR (CDC ₃ - DMSO - d ₆ ): 3.88 (s, N-Me
and 2nd place CH ₂ ), 4.32 (ABq, Δδ = 25Hz, J = 13.3
CH ₂ S), 4.65-4.95 (m, 6th and 7th H),
6.88 (s, ester CHPh ₂ ), 7.2-7.7 (m, phenyl proton). b 7β-Salicylideneamino-3-(1-methyltetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid diphenylmethyl-
1-β oxide (Step B) 7β-amino-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl-1-β-oxide
4.6g and salicylaldehyde 3.0g methanol 30
ml and a suspension in 30 ml of dichloromethane are stirred for 4 hours at room temperature to form a homogeneous solution. After concentrating and removing salicylaldehyde in the residue by decantation with cyclohexane, silica gel column chromatography (chloroform-methanol 20:
1) to produce 7β-salicylidene amino-3
-(1-Methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl-1-β-oxide powder 6.0 g was obtained. IR (nujol): 1790, 1720, 1625 cm ^-1 . NMR (CDCl ₃ ): 3.68 (s, N-Me and 2nd H ₂ ),
4.17 (ABq, Δδ=21Hz, J=14, 3rd place CH ₂ S),
4.51 and 5.08 (both d, J=5, H at the 6th and 7th positions), 6.65-76 (m, ester CHPh ₂ and phenyl proton), 8.37 (s, CH=N). c 7α-Salicylideneamino-3-(1-methyltetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid diphenylmethyl-
1-β-oxide (Step C) 7β-Salicylideneamino-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl-1-β
- Add 2.0 g of triethylamine to a solution of 6.0 g of oxide in 60 ml of tetrahydrofuran in a nitrogen gas atmosphere while cooling in an ice-salt bath, and stir for 50 minutes. 2.5 ml of acetic acid and a large amount of chloroform were sequentially added, washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain 7α-salicylideneamino-3-(1
-Methyltetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid diphenylmethyl-1-β-oxide is obtained. Silica gel column chromatography (chloroform-ethyl acetate 1:1 and 1:
Although the isomers can be separated by 2), the mixture can also be subjected to the next step D. IR (nujol): 1790, 1725, 1625 cm ^-1 . NMR (CDCl ₃ ) δ = 3.72 (s, N-Me), 3.77
(ABq, Δδ=32Hz, J=19, 2nd place Hz), 4.22
(ABq, Δδ=20Hz, J=14, 3rd place CH ₂ S), 4.57
and 5.12 (both BRS, 6th and 7th H), 6.7-7.6
(m, ester CHPh ₂ and phenyl proton),
8.49 (s, CH=N). d 7α-amino-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4
-Diphenylmethyl carboxylate-1-β-oxide (Step D) 7α-Salicylideneamino-3- obtained in Step C
A mixture containing diphenylmethyl-1-β-oxide (1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate was stirred with 4 g of Girard-T reagent in 60 ml of methanol and 40 ml of ethyl acetate for 2 hours at room temperature. do. The reaction solution was concentrated, and the residue was dissolved in chloroform containing a small amount of ethyl acetate and water. Separate the organic layer and wash with water (x3)
Afterwards, it is dried over anhydrous magnesium sulfate and concentrated.
The residue was subjected to silica gel column chromatography (chloroform-methanol 10:1 and 5:1) to obtain an amorphous powder of 7α-amino-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-
1.9 g of diphenylmethyl 4-carboxylate-1-β-oxide) and 7β-amino compound (0.71 g of crystals) were obtained. IR (nujol): 3400, 3330, 1780, 1730, 1625 ^{cm -1} . NMR (CDCl ₃ ): 2.66 (brs, NH ₂ ), around 3.62 (ABq, H ₂ at 2nd position), 3.73 (s, N-Me), around 4.05 (ABq, CH ₂ S at 3rd position), 4.20 and 4.50 ( both
brs, 6th and 7th H), 6.96(s, ester
_CHPh2 ), 7.1-7.5 (m, phenyl proton). e 7α-benzamido-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl-1-β
-Oxide (Step E) 7α-amino-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl-1-β-oxide
Add N, N to a 1.9 g solution in 20 ml of dichloromethane under ice cooling.
- 0.6g of diethylaniline and 0.57g of benzoyl chloride
g and stir for 40 minutes. The reaction solution is diluted with chloroform, washed with an aqueous potassium bisulfate solution and an aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol 10:1) to obtain an amorphous powder.
7α-benzamido-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4
-1.9 g of diphenylmethyl carboxylate-1-β-oxide is obtained. IR (nujol): 3300, 1790, 1730, 1665 ^{cm -1} . NMR ( _CDCl3 ): 3.57 (s, N-Me), around 3.60 (2nd place _H2 ), 4.06 (ABq, Δδ=32Hz, J=13),
4.60 (brs, H at 6th position), 5.42 (brd, J=7, H at 7th position), 6.85 (s, ester CHPh ₂ ), 7.0-7.5 and 7.6-7.9 (m, phenyl proton), 8.18
(brd, J=7, N-H). f 7α-benzamide-3-methylenecepham-4-carboxylic acid diphenylmethyl-1-β-
Oxide (Step F) 7α-benzamide-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-
To a solution of 1.9 g of diphenylmethyl-1-β-4-carboxylate in 25 ml of methanol and 15 ml of acetic acid, 0.6 g of copper acetate hydrate and then 4 g of zinc powder were added little by little over 2.5 hours under ice cooling, and the mixture was left at room temperature for an additional hour. Stir. Add 150 ml of ethyl acetate, remove insoluble matter, wash with water (x3), dry (anhydrous magnesium sulfate), and concentrate. The residue was purified by silica gel column chromatography (chloroform-ethyl acetate 1:4) to obtain 1.1 g of amorphous powder of 7α-benzamide-3-methylenecepham-4-carboxylic acid diphenylmethyl-1-β-oxide and by-products. 0.17 g of the Δ3-Cefem isomer is obtained. Properties of 3-methylene cephaam compound: IR (film): 3300, 1775, 1740, 1655 ^{cm -1} . NMR (CDCl ₃ ) δ: 3.40 (ABq, Δδ=22Hz, J=
14, 2nd place H ₂ ), 4.95 (d, J = 2, 6th place H),
5.19 (d, d, J = 2, 7, 7th position H), 5.25 (s,
4th place H), 5.36 and 5.65 (both brs,=CH ₂ ),
6.80 (s, ester CHPh ₂ ), 7.28 (s, ester phenyl proton), 7.2−7.5 and 7.7−7.85
(m, _C6H5CO ) _, 8.01 (brd, J=7, N-H). Reference example 2 7α-benzamide-3-methylenecepham-4-carboxylic acid diphenylmethyl-1
-α-sulfoxide a 7β-(p-nitrobenzylidene)amino-
Diphenylmethyl 3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (Step G) Add a solution of 2.47 g of diphenylmethyl 7β-amino-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate and 755 mg of p-nitrobenzaldehyde in 40 ml of benzene using a Dean Stark water separator. Reflux for an hour.
Concentrate the reaction solution to obtain an amorphous powder of 7β-(p-
Diphenylmethyl nitrobenzylidene)amino-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate is obtained. b 7α-(p-nitrobenzylidene)amino-
Diphenylmethyl 3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (Step H) 7β-(p-nitrobenzylidene)amino-3-(1-methyltetrazole-) obtained in Step G
0 to a solution of diphenylmethyl 5-yl)thiomethyl-3-cephem-4-carboxylate in THF (50 ml).
Add 645 mg of diisopropylethylamine at ~3°C;
Stir for 1 hour. Add 0.5 ml of acetic acid, concentrate, dissolve the residue in ethyl acetate and water, and separate the organic layer. After drying with anhydrous magnesium sulfate, concentrate
7α-(p-nitrobenzylidene)amino-3-
An approximately 1:1 mixture of diphenylmethyl (1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate and 7β-(p-nitrobenzylidene) amino isomer is obtained. The next step is carried out without separating the isomers. c 7α-amino-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4
-Diphenylmethyl carboxylate (process) 7α-(p-nitrobenzylidene)amino-3-(1-methyltetrazole-) obtained in Step H
Mixture of diphenylmethyl 5-yl)thiomethyl-3-cephem-4-carboxylate and 7β-(p-nitrobenzylidene) amino isomer and Girard T
A suspension of 4.5 g of reagent in 50 ml of ethyl acetate-50 ml of methanol is stirred overnight at room temperature. The reaction solution was concentrated, the residue was dissolved in ethyl acetate-water, the ethyl acetate layer was separated, washed with water (x3), dried (anhydrous magnesium sulfate), and then concentrated to give 7α-amino-3-
A mixture (2.4 g) of diphenylmethyl (1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate and the 7β-amino isomer is obtained. Perform the next step J without separating the isomers. d 7α-benzamido-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl (Step J) Diphenylmethyl 7α-amino-(3-1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate obtained in the previous step and 7β-
2.4 g of amino isomer mixture in 30 ml of dichloromethane
Dissolved in N,N-diethylaniline 0.75 under ice cooling.
g, and 0.71 g of benzoyl chloride were added, and the mixture was stirred for 1.5 hours. The reaction solution is diluted with chloroform, washed with an aqueous potassium bisulfate solution and aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, concentrated, and separated and purified using silica gel column chromatography (chloroform-ethyl acetate 4:1). Amorphous 7α-benzamide-3-
(1-Methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl 1.34g and its 7β-benzamide isomer 0.87g
get. NMR of 7α-benzamide (CDCl ₃ ) δ = 3.66
(brs, 2nd H ₂ ), 3.87 (s, N-Me), 4.27 (ABq,
Δδ=19Hz, J=13, 3rd place CH ₂ S), 4.77 (d, J=
2, 6-position H), 5.12 (d, d, J = 2, 8, 7-position H), 7.00 (1H, ester CHPh ₂ ), 7.2-8.0 (m,
phenyl proton). e 7α-benzamide-3-methylenecephaam-4-carboxylic acid diphenylmethyl (Step K) 7α-benzamide-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-
1.3 g of diphenylmethyl 4-carboxylate acetic acid 9
Add 0.3 g of copper acetate hydrate and 2.0 g of zinc powder to a solution of 15 ml of methanol under ice cooling, stir for 1.5 hours, and then bring to room temperature, add 1.8 g of zinc powder, 4 ml of acetic acid, and 10 ml of methanol, and stir for 2.5 hours. Stir. Ethyl acetate was added to the reaction solution to remove insoluble matter, the solution was washed with water (×5), dried (anhydrous magnesium sulfate), concentrated, and the residue was subjected to silica gel column chromatography (chloroform-ethyl acetate 10:1). 0.45 g of diphenylmethyl 7α-benzamide-3-methylenecephaam-4-carboxylate and 0.19 g of its Δ3 isomer are obtained as amorphous powder. NMR of 3-methylenecephalic compound (CDCl ₃ )
δ: 3.04 (ABq, Δδ=22Hz, J=14, 2nd place H ₂ ), 4.8
−5.3 (m, 4, 6, 7 H and =CH ₂ ), 6.71 (1H,
s, ester _CHPh2 ), 7.0-7.8 (m, phenyl proton). f 7α-benzamide-3-methylenecepham-4-carboxylic acid diphenylmethyl-1-α-
Oxide (Step L) 7α-benzamide-3-methylenecefaam-
To a solution of 0.41 g of diphenylmethyl 4-carboxylate in 5 ml of tetrahydrofuran and 5 ml of methanol was added 120 mg of tert-butylhypochloride at -50°C under a nitrogen gas atmosphere, and the mixture was stirred for 1 hour. After the reaction, add 0.85 ml of 1N lithium methoxide-methanol solution, followed by 1 ml of acetic acid, and dilute with ethyl acetate. The reaction solution was washed with water (x3), dried (anhydrous magnesium sulfate), and concentrated. The residue was purified by silica gel column chromatography (chloroform-ethyl acetate 1:2) to obtain 7α-benzamide-3- as an amorphous powder.
0.112 g of diphenylmethyl-1-α-oxide of methylenecephame-4-carboxylate is obtained. NMR (CDCl ₃ ) δ: 3.60 (ABq, Δδ=24Hz, J=
12, 2nd place H ₂ ), 4.88 (d, J = 1, 6th place H),
5.10 (s, 4th place H), 5.1-5.5 (m, 7th place H and =
_CH2 ), 6.87 (s, ester _CHPh2 ), 7.1−8.1
(m, phenyl proton and N-H). Reference example 3 7α-benzamide-3-methylene-
1-Oxadethiacefam-4-carboxylic acid diphenylmethyl a 2-(3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl )-4-hydroxy-3-exomethylenebutyrate diphenylmethyl 3S-benzamide-4R-(2'-benzothiazolyldithio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-2'-propenyl ) Production from azetidin-2-one (Step L) 3S-benzamide-4R-(2'-benzothiazolyldithio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-2'-propenyl)azetidin-2-one 100 mg dichloromethane 3.2 ml, A solution of 0.4 ml of propylene oxide was cooled in an ethanol-dry ice bath under a nitrogen gas atmosphere, and 0.28 ml of a 10% chlorine-carbon tetrachloride solution was added.
Stir for 30 minutes. The reaction solution is washed with water and aqueous sodium bicarbonate, dried (anhydrous magnesium sulfate), and then concentrated. The residue was purified by silica gel column chromatography (chloroform-ethyl acetate 1:1 and 1:2) to obtain 2-(3
-Phenyl-7-oxo-4-oxa-2,6-
20 mg of diphenylmethyl diazabicyclo[3,2,0]hept-2-en-6-yl)-4-hydroxy-3-exomethylenebutyrate is obtained. NMR (CDCl ₃ ) δ: 2.46 (brs, OH), 4.13 (brs,
CH ₂ O), 4.92 (s, N-CH-CO), 5.07 and 5.32
(both brs, = CH ₂ ), 5.19 and 5.93 (both d, J = 3,5, azetidine ring proton),
6.77 (s, ester _CHPh2 ), 7.1-8.0 (m, phenyl proton). Production from 3S-benzamide-4S-(2′-benzothiazolylthio)-1-(1′-diphenylmethoxycarbonyl-2′-hydroxymethyl-2′-propenyl)azetidin-2-one (Step M) 3S-benzamide-4S-(2'-benzothiazolylthio)-1-(1'-diphenylmethoxycarbonyl-2'-hydroxymethyl-2'-propenyl)azetidin-2-one 200 mg propylene oxide 1 ml, dichloro Add 0.38 ml of a 10% chlorine-carbon tetrachloride solution to a solution of 4 ml of methane under cooling in an ethanol-dry ice bath, and stir for 30 minutes. Add 1 ml of cyclohexene, wash with aqueous sodium bicarbonate, and dry over anhydrous magnesium sulfate. After concentrating the solution, it was purified by silica gel column chromatography (chloroform-ethyl acetate 1:1 and 1:2) to obtain 2-(3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2 ,0] 50 mg of diphenylmethyl hept-2-en-6-yl)-4-hydroxy-3-exomethylenebutyrate is obtained. b 7α-Benzamide-3-methylene-1-oxadethiacefam-4-carboxylic acid diphenylmethyl 2-3-phenyl-7-oxo-4-oxa-
2,6-diazabicyclo[3,2,0]hepter
To a dichloromethane solution of 74 mg of diphenylmethyl 2-en-6-yl)-4-hydroxy-3-exomethylenebutyrate is added 3μ of boron trifluoride etherate under ice cooling, and the mixture is stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (chloroform-ethyl acetate 10:1).
18 mg of diphenylmethyl 7α-benzamido-3-methylene-1-oxadethiacefam-4-carboxylate is obtained. NMR (CDCl ₃ ) δ: 4.32 (s, 2nd H ₂ ), 5.09 (d,
J = 7, 7-position H), 5.27, 5.42 and 5.46 (s, 4-, 6-position H and =CH ₂ ), 6.97 (s, ester
CHPh ₂ ), 7.2−8.0 (m, phenyl proton and
NH).

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents a hydrogen atom, an acyl group, or an aralkyl group, R ² represents an acyl group, an aralkyl group, or R ¹ and R ² together represent a dibasic acid acyl group, and R ³ represents an alkyl group. group, aralkyl group, aryl group or heterocyclic group, -COB group is -
A COOR group (R represents a hydrogen atom, a lower alkyl group, an aralkyl group, an aryl group, an organometallic group, an alkali metal or an ammonium group), and n represents 1 or 2. ) Azetidinone derivatives. 2 General formula (In the formula, R ¹ represents a hydrogen atom, R ² represents an acyl group or R ¹ and R ² together represent a dibasic acid acyl group, and R ³ represents an alkyl group, an aryl group, or a heterocyclic group. and the -COB group represents a -COOR group (R represents a hydrogen atom, a lower alkyl group, an aralkyl group, an aryl group, an organometallic group, an alkali metal or an ammonium group). Azetidinone derivative according to item 1. 3 General formula (In the formula, R ¹ represents a hydrogen atom, R ² represents an acyl group or R ¹ and R ² together represent a dibasic acid acyl group, and R ³ represents an alkyl group, an aryl group, or a heterocyclic group. and the -COB group represents a -COOR group (R represents a hydrogen atom, a lower alkyl group, an aralkyl group, an aryl group, an organometallic group, an alkali metal or an ammonium group). Azetidinone derivative according to item 1. 4 General formula (In the formula, R ¹ represents a hydrogen atom, an acyl group, or an aralkyl group, R ² represents an acyl group, an aralkyl group, or R ¹ and R ² together represent a dibasic acid acyl group, and the -COB group represents -COOR group (R represents a hydrogen atom, lower alkyl group, aralkyl group, aryl group, organometallic group, alkali metal or ammonium group)) has the general formula R ³ SH (in the formula, A general formula characterized by reacting a mercaptan represented by R ³ represents an alkyl group, an aralkyl group, an aryl group, or a heterocyclic group. A method for producing an azetidinone derivative represented by the formula (wherein R ¹ , R ² , R ³ and the -COB group have the same meanings as described above). 5 General formula (In the formula, R ¹ represents a hydrogen atom, an acyl group, or an aralkyl group, R ² represents an acyl group, an aralkyl group, or R ¹ and R ² together represent a dibasic acid acyl group, and R ³ represents an alkyl group. group, aralkyl group, aryl group or heterocyclic group, -COB group is -
COOR group (R represents a hydrogen atom, a lower alkyl group, an aralkyl group, an aryl group, an organometallic group, an alkali metal group, or an ammonium group). ) is reacted with a trivalent phosphorous compound represented by the general formula (R ⁴ ) ₃ P (wherein R ⁴ represents an alkyl group, an aryl group, or an alkoxy group). A method for producing an azetidinone derivative represented by the formula (wherein R ¹ , R ² , R ³ and the -COB group have the same meanings as described above).