JPS609516B2 - Cyclization method for Cefem skeleton - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides Q[(4-mercapto or substituted thio)-3
[1-(amino or substituted amino)-2-oxoazetidin-1-yl]-Q-(2-halo 1 monolayer alkylidene or 2-halo 1 monosubstituted alkyl) acetic acid or its derivative at the carboxy group is subjected to a moat reaction. 7-(amino or substituted ami/)-3-substituted-(cephem or cephaam)-4-carboxylic acid or its derivative at the carboxy group.

In the azetidine acetic acid derivative, which is the raw material of this invention, the substituent on the substituted thio group at the 4-position is an acyl group, an alkyl group, an aralkyl group, an aryl group derived from an organic or inorganic acid, and an aliphatic or aromatic group. A protecting group for a mercapto group at the 4-position, such as a mercapto group, and preferably a group that can be easily removed later can be exemplified.

More specifically, acyl groups [inorganic acyl groups such as acyl carbonate groups (alkoxycarbonyl, haloalkoxycarbonyl, aralkoxycarbonyl, etc.), acyl sulfate groups; organic acyl groups such as alkanoyl, aralkanoyl, aroyl, alkylsulfonyl, arylsulfonyl, etc. ], alkyl groups (methyl, ethyl, etc.), aralkyl groups (benzyl, diphenylmethyl, trityl, etc.), aryl groups (fenyl, chenyl, pyridyl, etc.), aliphatic or aromatic mercapto groups (methylthio, ethylthio, cyclopropyl, etc.) Methylthio, benzylthio, pyridylmethylthio, ○nitrophenylthio, 2-methyl-1, 3,
In addition to 4-thiadiazol-5-ylthio, benzothiazol-2-ylthio, quinolin-2-ylthio, acetylthio, etc., amino (propylamino, anilino, etc.) and other groups can be exemplified. Any of these groups may have a halogen, sulfur group, oxygen group, nitrogen group, carbon group, or other substituent, and may also have an unsaturated bond. Particularly desirable are groups that can produce mercapto groups, thio radicals, sulfenyl anions, etc. through mild decomposition reactions, such as acyl carbonate groups, acyl sulfate groups, aralkyl groups, aliphatic or aromatic thio groups, and amino groups. The amino substituent in the amino group or substituted amino group at the 3-position is intended to include amino substituents or equivalents thereof constituting known side chains in the chemistry of natural or synthetic penicillins and cephalosporins.

Since this substituent is generally not directly related to the mercapto group at the 4-position and the ring-closing reaction at the side chain at the Q-position, a wide range of changes is possible. Typical amino substituents are hydrocarbon groups (methyl,
Propyl, tertiary butyl, benzyl, benzhydryl,
trityl, alkylidene, benzylidene, o-oxybenzylidene, etc.), silyl group (trialkylsilyl, etc.), sulfenyl group (o-nitrophenylsulfenyl, etc.), acyl group [carbonate acyl group (alkoxycarbonyl, haloalkoxycarbonyl, aral oxycarbonyl, aryloxycarbonyl, etc.), acyl sulfate groups, acyl phosphate groups (phosphonyl, dialkoxyphosphonyl, thiophosphonyl, etc.), other inorganic acyl groups or alkanoyl, cycloalkanoyl, aralkanoyl, aroyl, alkylsulfonyl, aryl Amino substituents such as sulfonyl, alkylphosphonyl, and other organic acyl groups], which may have halogens, sulfur groups, oxygen groups, nitrogen groups, carbon groups, and other substituents, if possible. It may also have an unsaturated bond.

Groups that can be converted into amino or amide groups, such as azide, isocyanato, and isocyano groups, are also included in the definition of substituted amino groups. Among amino substituents, acyl groups (phenoxyacetyl, phenylacetyl, heptanoyl, etc.) contained in the side chain of natural benicylj, in particular
and easily removable substituents (trityl, benzylidene, phthaloyl, arylsulfenyl, trimethylsilyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, phenoxyacetyl, phenylacetyl, etc.), which are advantageous for the target compound. Groups that can be easily transformed into functional groups (N-tert-butoxy-Q-phenylglycyl, Q-(3-carbetoxy-2-ben-2-ylamino)-phenylacetyl, Q-azidophenylacetyl, etc.) is important in manufacturing.

Substituted amino groups form a cyclic group, e.g. 4-oxo-3
-imidazolidinyl group, etc. Reactive substituents can be protected by known methods. These groups correspond to the substituents at the 7-position in the product cephem compound, but may undergo partial changes under the reaction conditions. 3-substituted-4-thia2, which is a compound in which the amino group at the 3-position and the acylthio group at the 4-position share an acyl group
16-diaza-7-oxopicyclo[3.210]hept-2-en-6-yl acetic acid and the like are also substituted with the above Q-(4-acylthio-3-amino-2-oxoazetidin-1-yl)-Q- or unsubstituted) shall be included within the definition of acetic acid.

Further, the amino group at the 3-position may form a salt with an acid (organic acid or inorganic acid). Derivatives of the carboxy group of azetidine acetic acid include esters [alkyl esters (methyl, ethyl, trichloroethyl ester, etc.), aralkyl esters (benzyl, methoxybenzyl, nitrobenzyl, diphenylmethyl, trityl ester, etc.), aryl esters (phenyl, naphthyl ester, etc.), metal esters (trimethylsilyl, trityltin ester, etc.), other esters, acid anhydrides,
carboxy derivatives such as salts (sodium, potassium, magnesium, aluminum salts, etc.), thiolesters, amides, hydrazides, azides, etc.

If possible, these carboxy derivatives may have substituents such as halogen, sulfur group, oxygen group, nitrogen group, carbon group, and other substituents, and may also have unsaturated bonds. It's okay. Among these carboxylic conductors,
Groups that are inert to the reaction and can be removed after the reaction without causing any unfavorable changes in other parts of the molecule (iii).

Of interest are derivatives containing alkyl-acylalkyl, alkoxyalkyl, acyloxyalkyl, aralkyl-esters, dialkyl hydrazides, alkali metal salts, alkylamine salts, etc.). The 1-position substituent of the 2-halo-1-monosubstituted alkylidene group, which is the substituent at the Q-position of azetidine-1-monoacetic acid, is a halogen (chlorine, bromine, iodine, etc.), oxygen group [hydroxy, acyloxy (alkanoic acid, algenic acid, etc.)]. , alkyl acids, cycloalkanoic acids,
Acyl groups derived from carboxyl acids such as aralkanoic acid, aralkenic acid, aromatic carboxylic acids, organic acids such as sulfonic acids, sulfinic acids, and phosphonic acids, or carbonic acid, sulfuric acid,
Acyloxy groups (having acyl groups derived from inorganic acids such as phosphoric acid and halogen acids), alkoxy groups (methoxy, ethoxy, isopropyloxy, tertiary butoxy, etc.), aralkoxy (benzyloxy, benzhydryloxy, (trityloxy, etc.), aryloxy (phenoxy, pyridyloxy, etc.)], sulfur group (mercapto,
Acylthio (acylthio group having an acyl group as described in the acyloxy section), alkylthio group (methylthio, ethylthio, etc.), aralkylthio (benzylthio, etc.),
Arylthio (phenylthio, naphthylthio, etc.)
Nitrogen group [amino, acylamino (acylamino/group having one or two acyl groups mentioned in the section of acyloxy group), alkylamino (methylamino/, jetylamino,
piberidin-1-yl, morpholin-4-yl, etc.),
Alkylacylamino (such as methylacetylamino),
Aralkylamino, arylamino, hydrazide, semicarbazide, hydroxylamino, alkoxylamino/,
aralkylamino, arylamino, etc.], phosphorus groups (diphenylphosphinyl, etc.), and other monovalent substituents.

The 1-position substituent of the 2-ha o-1 monosubstituted alkyl group, which is the substituent at the Q-position of the azetidine-1-acetic acid, is the 2-
2 of the same substituents as in the halo 1-substituted alkyl 1"dene group, or oxo, thioxo, imino, alkylimino, hydroxyimino, alkoxyimino, acyloxyimino, aralkoxyimino, arylimino, hydrazono, acylhydrazono, alkyl Substituents include divalent oxygen groups such as hydrazono and arylhydrazono, sulfur groups, nitrogen groups, and phosphorus groups.

The substituent at the Q position of these azetidine-1 monoacetic acids, 1 monolayer alkylidene or 1 monosubstituted alkyl group, and these 1-position substituents, if possible, include halogen, oxygen group, sulfur group, nitrogen group, carbon It may have a group or other substituent, and it may also have an unsaturated bond.

2-halo 1-substituted alkylidene group or 2-halo 1 which is a substituent at the Q position of the azetidine-1-acetic acid
- The halogen at the 2-position in the substituted alkyl group is a base, bromine, iodine, and a group of groups collectively called pseudohalogens or leaving groups (sulfonyloxy, alkanoyloxy, benzoyloxy, hydroxy, etc.) that have equivalent functions. ) shall also be included within the scope of this definition.
The substituents that each of the above groups may have include halogen (fluorine, chlorine, bromine, etc.), sulfur group (mercapto, alkylthio, aralkylthio, arylthio, acylthio, thioxo, sulfo, sulfonyl, sulfinyl, alkoxysulfonyl, aryloxysulfinyl, etc.) , oxygen group (
hydroxy, alkoxy, aralkoxy, aryloxy, acyloxy, oxo, etc.), nitrogen groups (amino, hydrazo, diazo, azide, alkylamino, aralkylamino, arylamino, acylamino, alkylidene amino, acylimino, imino, alkylimino, nitroso, nitro, etc.) ), carbon groups (alkyl, alkenyl,
aralkyl, aryl containing aromatic heterocyclic groups, carboxy, carbamoyl, alkyloxy, alkanoyl,
In addition to aralcanol, aroyl, cyano, etc.),
It shall include a phosphorus group (such as phosphonyl) and other substituents. The starting material for the reaction is Q-[4 monolayer thiol 3-(amino or substituted amino/)-2-oxoazetidin-1-yl]-Q-(2-halo 1-substituted alkylidene or 2-halo-1 monosubstituted alkyl) ) acetic acid or its derivatives at the carboxy group, such as penicillin.
1-oxide is decomposed with phosphite, acetic anhydride, etc. to produce Q-(azetidin-1-yl)-Q-(isoph).

By oxidizing this with ozone, a raw material in which the substituent at the Q position is 1-hydroxyethylidene or 1-acetyl is obtained, and if necessary, a halogenating agent, an etherifying agent, Synthesis can be achieved by converting the substituent at the 1-position using an acylating agent, aminating agent, thioetherizing agent, active nitrogenating agent, etc., and then reacting with a halogenating agent. To carry out the method of the invention, the raw material is subjected to a ring-closing reaction.

The ring-closing reaction occurs, for example, under basic, neutral, or acidic conditions, or by homogeneous phase or heterophase reaction in the presence of a contact agent, and the conditions can be appropriately selected depending on the structure of the raw material. As a raw material, the thio group at the 4-position of azetidine-1 monoacetic acid is a mercapto group or mercaptide. Anions are preferable because they have high reactivity. Therefore, if necessary, it may be preferable to first remove the protecting group from the substituted thio group to form a mercapto or mercaptide group before reacting, or to carry out the ring-closing reaction under reaction conditions in which the protecting group is removed. Further, when the raw material has a thiazolinoazetidine skeleton, the ring reaction proceeds slowly under conditions where the thiazoline ring is linked, and the target substance can be obtained in high yield. The acids used to make it acidic include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid).
Perchloric acid (sulfurous acid, etc.), sulfonic acid (alkanesulfonic acid, arylsulfonic acid, etc.), phosphonic acid, carboxylic acid (formic acid, acetic acid, haloalkanoic acid, oxalic acid, phthalic acid, etc.), other organic or inorganic acids or salts of these with weak bases (aromatic or aliphatic bases, ammonia, alkali metals, aluminum, silver, etc.), or acidic salts of the above acids with general bases.

Lewis acids are also advantageously used in proton-free solvents. The base used for basicity is preferably a weak base as described above. Strong bases (Arka IJ metal hydroxides, alkali metal carbonates, quaternary ammonium hydroxides, etc.) decompose part of the molecules of the raw material or product, especially the 8-lactam ring, and should not be used. If this happens, you need to choose a weaker condition. Additionally, Lewis bases can also be used. As the contact agent, neutral or basic silica gel, alumina, Keishoshi, Florisil, and other contact agents can be used.

In some cases, the reaction proceeds even with only a solvent (hexamethylphosphorotriamide, dimethylformamide, alcohol, water, etc.).

In this case, the reaction rate increases if a suitable solvent such as water or alcohol is present. In this case, it is thought that the hydrogen halide produced by the reaction acts as a reaction accelerator. When the raw material is thiazolinoazetidine, a ring addition reaction is required, so water, alcohol, acids that can release hydrogen ions, nucleophiles such as amines, electrophiles such as acid anhydrides, acid halides, etc. Reagents and other additives 1
Preferably, an equivalent or more is present.

In order to convert the substituted thio group into a mercapto or mercaptide group, a suitable reagent is used depending on the substituted group.

This reaction is preferably carried out in a solvent, under heat, at room temperature or under cooling.

If necessary, the reaction can be carried out with stirring in the presence of an inert gas. Reaction solvents include hydrocarbons (bentane, hexane, benzene, toluene, etc.), halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, dichlorobenzene, etc.), esters (ethyl acetate, butyl acetate, methyl benzoate, etc.), Ketones (acetone, cyclohexanone, benzophenone, etc.), ethers (diethyl ether, ethylene glycol, dimethyl ether, tetrahydrofuran, tetrahydropyran, dioxane, morpholine, anisole, etc.), alcohols (methanol, ethanol, ethylene glycol, benzyl alcohol, etc.), carvone Acids (acetic acid, propionic acid, etc.), bases (
butylamine, triethylamine, pyridine, picoline, etc.), amides (dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, etc.), nitriles (acetonitrile, benzonitrile, etc.), nitrohydrocarbons, sulfoxides (dimethylsulfoxide, etc.), water, liquid ammonia etc. and mixtures thereof are used.

In particular, highly polar solvents such as alcohols, carboxylic acids, amides, nitriles, nitrohydrocarbons, sulfoxides, and water are preferred, and the reaction is facilitated by coexisting with esters, ethers, halogenated hydrocarbons, etc. that have a high ability to dissolve raw materials. It may become.

The reaction usually proceeds relatively quickly even at room temperature, and the desired cephem or cephalic compound can be obtained in good yield. The reaction product can be obtained by removing and isolating reactants, by-products, solvents, etc. from the reaction solution using conventional methods, and then purifying it using conventional methods such as recrystallization, chromatography, reprecipitation, etc. .

The reaction product has a hydrogen or alkyl group at the 2-position; an amino group or a substituted amino group at the 3-position of the azetidine-1-acetic acid derivative, which is the raw material, at the 7-position; and the azetidine-1-acetic acid derivative, which is the raw material, at the 3-position. The 1-position substituent in the 2-halo-1 monosubstituted alkylidene or 2-halo-1 monosubstituted alkyl group substituted at the Q position of It is a conductor in

However, substituents at the 3-position, 7-position, etc. undergo changes during the reaction treatment, and the corresponding substituents of the raw material and the product may not be the same. If desired, substituents corresponding to those of the raw materials or other substituents can be changed by appropriate means. Such cases shall also be included within the scope of this invention. A double bond exists in the carbon atom at the 3rd position in the Cepham skeleton of the product, but depending on the reaction conditions and processing conditions, the double bond is directed to the 2nd or 4th position or to a substituent, or A mixture thereof is obtained.

Any case shall be included within the definition of the product of the invention. 7 Mono(amino/or substituted amino)-3 monosubstituted (cephem or cephaam)-4-carboxylic acids or their derivatives at the carboxy group have antibacterial activity and are useful as medicines, as well as for the synthesis of other useful antibacterial agents. It can be used as an intermediate.

Examples are shown below to explain embodiments of the present invention.

The physical properties of the product are shown in Table 1. The nomenclature regarding the 3-position double bond is intended to include other positional isomers as well.

Example 1 '1} Q-(4-cyclopropylmethoxycarbonylthio-3-phthalimido-2-oxoazetidin-1-yl)-Q-(2-bromo-1-cyclopropylmethoxycarbonyloxyethylidene) methyl acetate 500 mg
was dissolved in 20 parts of methylene chloride, and 51 parts of aluminum chloride was dissolved.
Add 0mp all at once and stir at room temperature.

After 1 hour, pour into 20' of cold 3% hydrochloric acid and extract with methylene chloride.

After washing the extract with water and drying over magnesium sulfate, the solvent is distilled off to give Q-(4-mercapto-3-phthalimido-2-oxoazetidin-1-yl)-Q-(2-furomo-1-hydroxyethylidene). 9 of methyl acetate 252 is obtained.
Yield: 72.5%. IR:〃Madokiso 1790, 1783
, 1728, 1670・1620ka-10NMR:6C
DC and 31.8M (11HZ) IH, 3,87s ancestor, 4
．． 2214.5MBq (10HZ) is 5.3Kd (1
1;5HZ) IH, 5,7 (5HZ)IH, 7,7 seed 4 days, 12. SI day. ■ Q-(4-mercapto 3-
If methyl phthalimide-2-oxoazedin-1-yl)-(2-furo-1-hydroxyethylidene) acetate [a) is reacted under the following conditions, it will produce 3-hydroxy-7-phthalimido-3-cephemu-4-sankirubonic acid. Methyl [
b} is obtained.

(i) (a-80 comb the fence with benzene 8 [N・N
- Add 9 parts of 20 parts of dimethylaniline and reflux in a nitrogen stream.

After 3 minutes, the reaction solution was cooled, 5% hydrochloric acid was added, and the mixture was extracted with ethyl acetate.

The extract is washed with water, dried over magnesium sulfate, and the solvent is removed. When 1 part of ethyl acetate is added to the residue 71 part of 9 and left to stand, [b}25 is precipitated. mp223-22
6℃. Yield: 38.9%. (ii) ta}9 of 150
Dissolve 1 part of hexamethylphosphorotriamide and stir at room temperature for 1 hour.

Add 6 parts of ice water and 0.5 parts of ether to the reaction solution and remove the precipitated crystals to obtain 9 of 'b-50. yield:
40.8%. (iii) 'a} 9 of 200 was spotted on a pre-coated PLC plate (silica gel F-254) manufactured by Merck & Co., and developed with a mixture of benzene and ethyl acetate (2:1).

The main product zone was extracted with ethyl acetate containing 3% methanol,
The extract was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform to remove insoluble materials, and the chloroform was removed.
}Get 9 of 62.

Yield: 37.9%. Methyl 3-oxo-7-phthalimidocephalic acid 4-carboxylate (
Dissolve b- in dioxane, add an ethereal solution of diazomethane, and stir at room temperature for 1 hour.

By concentrating the reaction solution under reduced pressure, methyl 3-methoxy-7-phthalimido-3-cephemu-4-carboxylate is quantitatively obtained. Pure crystals can be obtained by recrystallization from acetone-ether mixture. mp225-227C. Example 2 '1) Q-(4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamide 2-oxoazetidin-1-yl-Q-[2-bromo-1-(piveridin-1-yl)ethylidene]acetic acid 212. Dissolve 573 parts 9 of 2-trichloroethyl in 30 parts methanol to make 10%
Add 7-chloride of hydrochloric acid and stir at room temperature or 40-45 qo.

After 30 minutes, the reaction solution was poured into ice water and extracted with benzene.

After washing the extract with water and drying, the solvent is distilled off to give Q-(4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl)-Q-
(2-furomo-1-hydroxyethylidene)acetic acid 2.2
- Obtain 434 amounts of 2-trichloroethyl. Yield: 83
．． 5%. IR: ^ rope skin 33450, 1790, 1720
(Sh), 1700 skin-10NMR:6CDCmu0.1
-1.4m 7 days, 3.9 phantom (7HZ) 2 days, 4.27d
(5 days 2) 2 days, 4.57s 2 days, 4.82d (3HZ
) is 5.27dd (6:8HZ) IH, 5.9beni (5
Hz) IH, 6-8-7-5m Mother's Day, 11.67br-
S.I.H. ■ Q-(4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl)-Q-(2-bromo-1-hydroxyethylidene)acetic acid 2,2,2-trichloroethyl chill 3
Dissolve 9 of 30 on methylene chloride and 6 of methylene chloride, add 9 of aluminum chloride 330 while stirring at room temperature, and stir for 60 minutes. The reaction solution was poured into dilute hydrochloric acid under ice cooling and extracted with ethyl acetate. Washing the extract with dilute hydrochloric acid and water, drying, and removing the solvent yields 7-phenoxyacetamide-3.
9 of 300 2,2,2-trichloroethyl oxocepham-4-carboxylate is obtained. Foamy matter. Example 3 According to the method of Example 2 [1'] Q-(4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl) 1-yl)ethylidene] 2,2,2-trichloroethyl acetate was hydrolyzed with hydrochloric acid in methanol to produce Q-(4-carpobenzoxythio 3-phenoxyacetamide).
If 2,2,2-trichloroethyl (2-oxoazetidin-1-yl)-Q-(2-bromo-1-hydroxyethylidene)acetate is produced and cyclized with aluminum chloride in methylene chloride, 7-phenoquinacetamido-3-oxocefam-4-carboxylic acid 2,2,2 tritric as in Example 2 {2}.

Obtain Loethil. Example 4 '1) Q-(4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl)-Q-[2-furomo-1-(morpholin-4-yl)ethylidene]acetic acid p-nitrobenzyl 30
Dissolve 0.9 in 22M methanol and 3.5M methylene chloride, add 10% hydrochloric acid, and stir at room temperature in a nitrogen stream.

After 2 hours, the reaction solution was poured into ice water and extracted with chloroform.

If the extract is washed with water, dried, and the solvent is distilled off, Q-(4
-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]
-Q-(2-furomo-1-hydroxyethylidene) p-nitrobenzyl acetate 252-9 is obtained. Foam yield: 9
2.8%. IR:Rekinkami 334201781, 171 stop 1690/1601 skin-IONMR; 6CDCZ30
, 23-1.33h9 days, 3.84-4.36m4 days,
4.5$2 days, 5.10-5.32h3 days, 5.8 spots (
5 HZ) IH, 6.83-8.33h arrival, 12.
$IH. (2) Q-(4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl)-Q-(2-furomo-1-hydro.

9 of 218 p-nitrobenzyl acetate (quichetylidene) was dissolved in 2.1 of methanol-free methylene chloride, and 9 of 220 of aluminum chloride was added and stirred under ice cooling in an argon stream. After 35 minutes, the reaction solution was poured into ice water containing 4N-4M hydrochloric acid, stirred for 1 minute, and then extracted with chloroform.

After washing the extract with water and drying, the solvent is distilled off to obtain Q-(4-mercapto-3-phenoxyacetamido-2-azetidin-1-yl)-o-(2-furomo-1-hydroxyethylidene)acetic acid p-nitro You get benzyl 150 9. Yellow foam yield: 94-6%. IR: Le class Sakura 334oo,
178o, 1692/1610/163 skin-1. NMR
: 6 32.2 mother (loHZ) IH, 4.29 (2H
Z) 2 days, 4.5$2 days, 5.20-5-37m mountain days,
Arrival at 6-84-8.24m, 12-ISIH. (3)
Q-(4-mercapto-3-phenoxyacetamide 2-oxoazetidin-1-yl-Q-(2-furomo-
1-Hydroxyethylidene) p-nitrobenzyl acetate 1
06 was dissolved in 5 parts of benzene, 500 parts of silica gel F-254 manufactured by Merck was added thereto, and the mixture was shaken at room temperature for 1 hour. Remove insoluble matter from the oven and wash with chloroform several times. The washings were combined in a furnace and the solvent was distilled off under reduced pressure to obtain p-nitrobenzyl 3-hydroxy-7-phenoxyacetamide 3-cephalic acid p-nitrobenzyl 4-carboxylate 60. Yield: 66
．． 3%. '4) Q-(4-Mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl)-Q-(2-furomo-1-hydroxyethylidene)acetic acid p-nitrogen prepared in Example 4■ Dissolve 70 parts of benzyl in a mixture of 2 parts of methylene chloride and 2 parts of methanol, and stir at room temperature for 3 hours.

The reaction solution was poured into ice and extracted with methylene chloride. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off to obtain p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate 42, which is the same as the product of Example 4 [3}. . Yield: 70%. t5
} p-nitrobenzyl Q-(4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl)-Q-(2-bromo-1-hydroxyethylidene)acetate prepared in Example 4 [2} 70 The female was dissolved in a mixture of 2 parts methylene chloride, 2 parts methanol, and 0.3 parts 10% hydrochloric acid, and stirred at room temperature for 2 hours.

The reaction solution was poured into ice water and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and the solvent was removed to give p-nitrobenzyl 3-oxo-7-phenoxyacetamidocephaam-4-carboxylate, the same product as in Example 4 [3'], 44.5-9. get. Yield: 74%. Example 5
[1) Q-(4-carbobenzoxythiol-3-phenoxyacetamido-2-oxoazetidine-1-yl)-Q
Dissolve 9 of 469 of p-nitrobenzyl 1-[2-fromo 1-(morpholin-4-yl)ethylidene]acetate in a mixture of 4 parts of methylene chloride, 4 parts of methanol, and 0.8 parts of 10% hydrochloric acid for 2 hours at room temperature. Stir.

Add ice water to the reaction solution and extract with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off to give Q-(4-carpobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl)Q-(2-bromo-1). -hydroxyethylidene) p-nitrobenzyl acetate 426-9 is obtained. Yield: Quantitative. IR:
Closing bag 334o8, 1788172fu 1690161
5, 1602 skin-1. NMR: 6CDC and 34.27d
(3HZ) 2 days, 4.4 $2 days, 5.1 $2 days, 5.2
Public 2nd, 5.29hIH, 5.8 (5HZ) IH, 6
．． 748, 2 skin fields. '2' Q-(4-carbobenzoxythio 3-phenoxyacetamido-2-oxoazetidin-1-yl-Q-(2-bromo-1-hydroxyethylidene) p-nitrobenzyl acetate 480 of 9 to 20
To this, 270 parts of aluminum chloride is dissolved in 4 parts of methylene chloride containing 20% nitromethane, and the mixture is stirred at room temperature for 1 hour.

The reaction solution was poured into dilute hydrochloric acid and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and the solvent was removed to give Q-(4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl)-Q-(2
-furomor 1-hydroxyethylidene) p-nitrobenzyl acetate 376-9 is obtained. Yield: 99.5%. Example 6 Q-(4-cyclopropylmethoxycarbonylthio3
-Phenoxyacetamide 2-Oxoazetidine-1
-Ilu Q- [2-Furomo-1-(morpholin-4-yl)ethylidene p-nitrobenzyl acetate 151-9 was dissolved in 1.5 methylene chloride, and aluminum chloride 142 was added thereto, and the solution was dissolved under ice-cooling for 5. (female enemy) to stir.

Add 2 parts of ice water to the reaction solution and stir for 5 minutes, then add 15 parts of a methanol + methylene chloride (5:1) mixture [and 1
Add 0% hydrochloric acid trichloride and stir with room salt for 80 minutes. Add ice water to the reaction solution and extract with chloroform. The extract was washed with water, dried over magnesium sulfate, and then the solvent was distilled off to obtain p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-ceph-4-carboxylate p-nitrobenzyl 63-9. Yield: 63%. This product is identical to the product of Example 4, in which the 4-morpholino group is hydrolyzed and replaced by a hydroxy group in the reaction. Example 7 Q-[4-(benzothiazol-2-yl)dithio 3
-Phenoxyacetamide-2-oxoazedine-1-
]-Q-(2-furomo-1-hydroxyethylidene) 100 parts of 2,2,2-trichloroethyl acetate was dissolved in 10 parts of ethanol, and 5 parts of sodium borohydride was added at 0°C. 1 Stir.

A few drops of glacial acetic acid and water are added to the reaction mixture, and then extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off. The residue was dissolved in 4 parts of N-N-dimethylformamide, 30 parts of triphenylphosphine was added thereto, and the mixture was diluted with 1 part of triphenylphosphine at room temperature.
．． After stirring for 5 hours, dilute with ethyl acetate. After washing this solution with water and drying, the solvent was distilled off. The remaining 7-phenoxyacetamido-3-oxocephalic acid 2,2,2-trichloroethyl 4-carboxylate was dissolved in methylene chloride 4'
Add an ether solution of diluted diazomethane and stir at room temperature for 25 minutes. The residue obtained by removing the solvent is purified by thin layer chromatography to obtain 2,2,2-trichloroethyl 7-phenoxyacetamido-3-methoxy-3-cephemu-4-carboxylate. This product can be identified from a separately synthesized standard product by IR and Rf in thin layer chromatograms. Example 8 The following compound can be prepared in the same manner as in the previous example.

[1} Methyl 7-phthalimido-3-hydroxy-3-cephemu-4-carboxylate; (2) 7-phenoxyacetamido-3-(morpholin-4-yl)-3-cephemu-4-carboxylic acid 2,2,2-trichloro Ethyl; [3' Methyl 7-phthalimido-3-chloro-3-cephem-4-carboxylate: '4) 2,2,2-trichloroethyl 7-phenylacetamido-13-benzylthio-3-cephem-4-carboxylate; [5) 7- (2・
p-Methoxybenzyl 2-dimethyl-3-nitroso-4-phenyl-5-oxoimidazolidin-1-yl)-3-hydroxy-3-cephem-4-carboxylate: '6
'7-(N-tert-butoxycarbonyl-Q-phenylglycyl)amino-3-oxocephalomu-4-carboxylic acid p-nitrobenzyl.

'7} 7-Thienylacetamide 3-hydroxy-3-cephem-4-carboxylic acid 2.2.2 trit.

Loethyl; [81 p-nitrobenzyl 7-salicylideneamino-3-hydroxy-3-cephem-4-carboxylate; '9} 7-penzyloxycarbonylamino-
3-hydroxy-3-cephem-4-carboxylic acid 2.2
・2-Trichloroethyl; 007-(2.2.2-tricooethoxycarbonyl)amino-3-hydroxy-
p-nitrobenzyl 3-cephem-4-carboxylate.

Example 9 Q-(3-phenoxymethyl-7-oxo-4-thia-
2,6-diazabicyclo[3.2.0]heptot-2-en-6-yl)-Q-[2-furomo-1-(morpholin-4-yl)ethylidene]acetic acid 2.2.2-trichoo
Dissolve 6.00 g of methyl in a mixture of 150 g of chloroform and 200 g of methanol, and add 40 g of 10% hydrochloric acid at room temperature.
Add '' and stir for 6 minutes.

Pour the reaction solution into ice water and extract with chloroform. After washing the extract with water and drying, the solvent is distilled off to obtain 3-oxo-7-phenoxyacetamidocepham-4-carboxylic acid 2.2.
Obtain 4.70 ml of 2-trichloroethyl. Foamy matter. Yield: 99.8%. Example 10Q-3-phenoxymethyl-7
-oxo-4-thia2,6-diazabicyclo [3,2
・0]hept-2-en-6-yl]1Q1[2-fromo11(morpholine-4-yl)ethylidene]acetic acid p
Nitrobesodil 63 female was dissolved in a mixture of 4 parts of methanol and 3 parts of methylene chloride, and this was mixed with 0.3 parts of 10% hydrochloric acid.
Add 8' and stir at room temperature for 75 minutes.

Pour the reaction solution into ice water and extract with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamide 3-cephemu-4-carboxylate 41.
get 9. mp95.5-99.5°C. Yield: 82.
9%. Example 11 Q-(3-phenoxymethyl-7-oxo-4-thia-
2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-Q-[2-chloro1-(morpholin-4-yl)ethylidene]p-nitrobenzyl acetate 10
Dissolve 9 of 6 in a mixture of methanol and methylene chloride (2:1), add 0.93 g of Su-hydrochloric acid, and stir at room temperature in an argon stream.

After 40 minutes, dilute with ice water and extract with methylene chloride.

The extract was washed with water, dried over magnesium sulfate, and the solvent was removed to give a yellow oil. This was purified by thin layer chromatography on silica gel, and the fractions flowing out with benzene + ethyl acetate (1:2) were collected from 3-hydroxy-7-phenoxyacetamide 3-cephem-4.
-9 of p-nitrobenzyl carboxylate 20 is obtained. Yield: 22%. Example 12 Q1(3-benzyl-7-oxo4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-Q1[2-bromo11(morpholine-4yl)ethylidene] 2,2,2-trichloroethyl acetate 1
9 of 17 methanol + chloroform (1:1) tear fluid 4
Add 10% hydrochloric acid (0.5M) and stir at room temperature for 2 hours.

Extract the reaction solution with chloroform. After washing the extract with water and drying, the solvent is distilled off. Purification of the residue by silica gel chromatography yields 9 of 2,2,2-trichloroethyl 3-oxo-7-phenylacetamidocephalic acid 4-carboxylate 41. Yield: 44%. Example 13 Q1 (3-benzyru7-oxo4-thia2.6-
Diazabicyclo[3.2.0]hept-2-en-6-yl)-Q-[2-bromo-1-(morpholin-4-yl)ethylidene]p-nitrobenzyl acetate (248 mg) was mixed with 8 parts of methanol and 6 parts of methylene chloride. Dissolve in falcon solution, add 1.5 g of 10% hydrochloric acid under ice, and stir for 2 hours.

Pour the reaction solution into ice water and extract with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The resulting residue 184:9 was purified by chromatography on 10% aqueous silica gel and purified with benzene-ethyl decacetate (
2:1) If the solvent is removed from the fraction flowing out of the mixed solution, 7-phenylacetamido-3-hydroxy-3-cephem-4 is obtained.
-P-nitrobenzyl carboxylate 6 and 9 were obtained. Oily substance. Yield: 35%. Example 14 The following compound can be prepared similarly to the previous example.

[1] 7-acetamido 3-oxocephalomu 4-
Carboxylic acid 1,2-disop. Pyrhydrazide; (2}
7-Phenoxyacetamide 3-hydroxy-3-cephemu 4-carboxylic acid diphenylmethyl: [3}
7-phenylacetamido-3-hydroxy-3-cephemu-4-carboxylic acid.

Example 15 Q-(3-phenoxymethyl-7-oxo-4-thia-
2,6-diazabicyclo[3.2.0]hepto-2-en-6-yl)-Q-[2-furomo-1-(morpholin-4-yl)ethylidene]p-nitrobenzyl acetate 58
Dissolve 9 of 0 in 10 of tetrahydrofuran, and add 1.5 w of 60% perchloric acid aqueous solution while cooling to -10 qo.
Add and stir for 30 minutes.

The reaction solution was diluted with excess water and then extracted with methylene chloride. The extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is removed to obtain 512-9 as a pale yellow foam. This is 1
50% hydrated silica gel. After separation and purification by chromatography, the fraction flowing out with a mixture of benzene and ethyl acetate (1:1) was extracted from Q-(3-phenoxymethyl-7-oxo-4-thia2,6-diazabicyclo[3.2.0]
hepto-2-en-6-yl)-Q-(2-fromo-1
-hydroxyethylidene) p-nitrobenzyl acetate 20
7c (foam: yield 40%) is obtained. IR: Tokibukuro 3
1781 Skin-I. NMR: 6CDC and 33.75 13.
9matsu Bq (10 days 2) 2 days, 4.77s 2 days, 5.2 dollars
2nd, 5.7 red (4th 2nd) IH, 6.07d (4HZ)
IH, 6.73-8.18h crucian carp, 12.07sIH. In addition, Q-(3-phenoxyacetamido-2-mercapto-4-oxoazetidin-1-yl-Q-(2-furomo-1-hydroxyethylidene) p-nitrobenzyl acetate is produced as a by-product.

9 of the main product 84 is dissolved in 2 parts of tetrahydrofuran, 0.2 parts of S-HCl is added thereto, and the mixture is left at 0° C. for 30 minutes and at room temperature for 1 hour.

After diluting the reaction solution with excess water, it is extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate, and then the solvent was removed. Residue 75 is identified by IR and NM as p-nitrobenzyl 7-phenoxyacetamido-3-oxocephalic acid 4-carboxylate. Example 16 Q-(3-benzy-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]buto-2-en-6-
Dissolve 4.84 g of diphenylmethyl 1-(1-hydroxyethylidene)acetate in 60 g of tetrahydrofuran, add 2.84 g of triethylamine while stirring at 12,000 g, and add methane chloride to the yellow solution. After dropping Z of 0.82 sulfonyl, the mixture is allowed to react for 30 minutes.

of the produced Q-(3-penzyl-7-oxo-4-thia-2,6-diazabicyclo[3,200]hept-2-eso-6-yl)-Q-(1-methanesulfonyloxyethylidene) diphenylmethyl acetate. Cool the solution to -40oo, add morpholine 0.96M and stir for 3.5 hours. The generated Q-(3-benzyl-7-oxo-4-thia2,6-diazapicyclo[3.2.0]
Hept-2-en-6-yl)-Q-(1-morpholinoethylidene)diphenylmethyl acetate in a solution of pyridine 0
．． Add 77M and cool to -40°C to remove 0.49' of bromine.
If you add and stir for 30 minutes, Q1 (3-benzyl-7
-oxo-4-thia-216-diazabicyclo[3'2
A solution of 0]hept-2-en-6-yl)-Q-(2-furomo-1-morpholinoethylidene)diphenylmethyl acetate is obtained. After adding 72 parts of 5% hydrochloric acid and 60 parts of methanol dropwise to this solution, the mixture was stirred at room temperature for 3 hours, and then left in an ice chamber overnight. Concentrate the reaction solution under reduced pressure,
The residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate and stripped of the solvent. Residue 5.83 10
Purification is achieved by column chromatography on 150% hydrous silica gel, and the resulting fraction is crystallized with n-hexane using a mixture of benzene and ethyl acetate (4:1) to yield 7-phenylacetamide 3-hydroxy-3-cephemu. 3.519 diphenylmethyl 4-carboxylate is obtained. mp93
~96℃. Yield: 70%. IR: Hi-anchor fin 3341o, 1
782, 1674, 1610 skin-1. Nh rank: 6CDC
3.2$2 days, 3.6$ is 4.97d(4HZ)I
H, 5.6 mother d (9:4) IH, 6.77 d (9) IH
, 6.9$ IH, 7.35ml plaque. Example 17Q-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-Q
Suspend 9.06 g of p-nitrobenzyl mono(11-hydroxyethylidene)acetate in 120 g of tetrahydrofuran, stir at 12,000 g in a nitrogen stream, and add 5.6 g of triethylamine and stir to form a clear solution.

Add 1.65 g of methanesulfonyl chloride to this and stir at the same temperature for 30 minutes. After adding 1.92% of morpholine to this and raising the temperature to 0°C, 3. Stir the insect time. Next, cool the internal temperature to -30 to -3500, and
．． Add 54 ml and 3.12 ml of bromine. After stirring for 20 minutes, the temperature was raised to ice water temperature and 144 parts of 5% hydrochloric acid and 120 parts of methanol were added.

The solution was stirred at room temperature for 3 hours, left at 0°C overnight, and the precipitated crystals were examined to form 7-phenylacetamide-3.
6.678 g of p-nitrobenzyl-hydroxy-3-cephem-4-carboxylate are obtained. mp20100. Yield: 71%. Example 18Q-(3-benzy-7-oxo-
38
Dissolve 9 of 0 in 10 of tetrahydrofuran and add 5 to this.
Add 12M % sulfuric acid and 10% methanol and stir at room temperature for 2 hours.

Claims (1)

[Scope of Claims] 1 α-[4-mercapto or substituted thio)-3-(amino or substituted amino)-2-oxoazetidine-1-
yl]-α-(2-halo-1-substituted alkylidene or 2-halo-1-substituted alkyl)acetic acid or its derivative at the carboxy group is subjected to a cyclization reaction to form 7-(amino or substituted amino)-3 -Substituted-(cephem or cephaem)-4-carboxylic acid or its derivative at the carboxy group is produced. A process for cyclization of a cepheme skeleton.