KR810001428B1 - Process for preparing cephem intermediates - Google Patents

Abstract

Cephem intermediates(I; A,B = H, amino substituent; R = H, thiol substituent; X = hydroxy, carboxy protecting group; Z = sulfonyl group) were prepd. by treating compd.(II) with substituted amine. Thus, benzylchloroformate 100 mg was added in the tetrahydrofurane 3 ml soln. of methyl α-[4-mercapto-3-phthalimido-2-oxoazetidine-1-yl -α-(1-hydroxyethylidene) acetate 100 mg and then cooled to -65oC. Triethylamine 60 mg was added in the soln., heated to the room temp. and then evapd. The residue was purified with silica gel chromatography to give methyl α-[4-benzyloxycarbonylthio-3-phthalimido-2-oxoazetidine-1-yl -α-(1-benzyloxycarbonylethylidene)acetate 160 mg.

Description

Process for producing cefem ring intermediate

The present invention relates to a process for preparing the compound of formula (I).

Wherein A and B are each hydrogen or amino substituents,

R is hydrogen or a thiol substituent,

X is a hydroxy or carboxyprotecting group,

The dashed line between A and R indicates that when R and B are hydrogen and A is a carboxyl substituent, the substituents can be bonded to form an azetidinothiazoline bicyclic ring.

That is, the present invention treats the following compound of formula (II) with a substituted amine to produce enamine of the compound of formula (I) as shown in the following scheme.

Where

A, B, R, and X are as described above

Z represents a sulfonyl group.

Several tests have been reported for the synthesis of 3-cefem ring on a large scale, but no cephalosporin has been produced by synthesizing the nucleus, except for cetalexin.

The present invention provides an enamine of the above compound of formula (I) which is a heavy compound of 3-hydroxy-3-cefem compound.

In the above scheme, the ABN group is an amino group or a substituted amino group. The former substituted amino groups are acylamino, hydrocarbylamino, hydrocarbylideneamino, silylamino, sulfenylamino or cephalosporins or conventional protecting groups containing up to 20 carbon atoms in the ferricillin chemistry. .

Representative examples of the acyl group in the acylamino group include acyl carbonate (e.g., alkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl), acyl sulfate, acyl phosphate (e.g., dialkoxyphosphinyl, dialkoxythiophosphonyl or alkoxy). Inorganic acyl groups such as aminophosphoryl), cycloalkanoyl, aralkanoyl, aroyl, alkylsulfonyl, arylsulfonyl or alkylphosphonyl. These groups may, if possible, contain heteroatoms in their backbone, for example halogen (eg fluorine, chlorine or bromine), nitrogen groups (eg amino, hydrazino, azido, alkylamino, Arylamino, acylamino, alkylideneamino, acylimino, imino or nitro), oxygen group (e.g. hydroxy, alkoxy, aralkoxy, aryloxy, acyloxy or oxo), sulfur group (e.g. mercapto, alkylthio) , Aralkylthio, arylthio, acylthio, thioxo, sulfo, sulfonyl, alkoxy-sulfonyl, or aryloxysulfinyl), carbon group (e.g., alkyl, alkenyl, aralkyl, aryl, carboxy, carbo It may be unsaturated or substituted by alkoxy, carbamoyl, alkanoyl, aroyl, aminoalkyl, aralkanoyl or cyano), or by popularity (eg, phosphor or phosphoroyl). A and B may also form diacyl groups of polybasic acids (eg, phthaloyl, pyridine-2, 3-dicarbonyl, maleoyl or succinoyl).

More suitable groups of the acyl groups are acyl groups of the penicillin side chain (e.g., phenylacetyl, phenoxyacetyl, heptanoyl) or groups suitable for the antimicrobial effect of the final product (e.g., hydrogen, N-tert-butoxy-2-phenylglycineami Figure, α- (1-carbomethoxy-1-isopropen-2-yl) amino-α-phenylglycyl, 4-phenyl-2, 3-dimethyl-5-oxo-1, 3-imidazoli Din-1-yl, α-diphenylmethoxycarbonyl-α-phenylacetamido).

The hydrocarbon group represented by A and / or B can be easily removed aliphatic hydrocarbon group containing 1 to 20 carbon atoms (eg, alkyl, alkenyl, aralkyl or other aliphatic hydrocarbon group) or easily removed. Mono-cyclic aromatic hydrocarbon groups (eg phenyl or pyrimidyl). These groups may contain, if necessary, heteroatoms in their backbone, and may be unsaturated or substituted by substituents (e.g., halogen atoms or nitrogen groups, oxygen groups, sulfur groups, carbon groups or popularity).

A and B together form a divalent hydrocarbon group (e.g., alkylene, aralkylene, alkylidene, aralkylidene, α-halo- or alkoxy-aralkylidene, diarylmethylidene or cycloalkylidene) It may be conceived, and if necessary, it may contain a hetero atom in its skeleton, or may be substituted or unsaturated by the above-mentioned substituent.

When the A group is an acyl group and the B group is a hydrocarbon group, they may be bonded together with the nitrogen atom bonded to the 7 position of the cefe ring to form a ring (eg, a 4-oxo-3-imidazolidinyl ring).

Silyl groups (eg, trialkylsilyl) and sulfenyl groups (eg, phenylsulphenyl or O-nitrophenylsulphenyl) which may be represented by A and (or) B are common aminoprotecting groups.

Representative acyl groups for A and B in the above structural formula and the like include the following groups.

1) alkanoyl groups containing 1 to 5 carbon atoms,

2) haloalkanoyl groups containing 2 to 5 carbon atoms,

3) azidoacetyl group,

4) cyanoacetyl group,

5) Acyl group represented by the following formula

Ar-CQQ'-CO

Wherein Q and Q 'are each hydrogen or methyl, and Ar is a monocyclic heterocyclic aromatic group containing 1-4 heteroatoms selected from phenyl, dihydrophenyl or nitrogen, oxygen and (or sulfur atoms, Optionally substituted by acyclic groups such as alkyl or alkoxy groups containing 1 to 3 carbon atoms, chlorine, bromine, iodo, fluorine, trifluoromethyl, hydroxy, cyano, aminomethyl, amino or nitro groups) .

6) acyl group represented by the following formula,

Ar-G-CQQ'-CO-

(Wherein G is oxygen or sulfur and Ar, Q and Q 'are as described above).

7) acyl group represented by the following formula,

Ar-CHT-CO-

Wherein Ar is as defined above and T is

i) amino, ammonium, benzyloxycarbonyl, alkoxycarbonyl groups containing 1 to 4 carbon atoms, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, cyclopropylmethoxycarbonyl, methane Containing sulfonylethoxycarbonyl, triphenylmethyl, 2, 2, 2-trichloroethoxycarbonyl, guanidylcarbamoyl, 3-methanesulfonylimidazolidon-1-yl-carbonyl Optionally substituted ureido carbonyl groups, alkanoyl groups containing 1 to 5 carbon atoms, pyroncarbonyl, thiopyronecarbonyl, pyridone carbonyl, iso- or heterocyclic monocyclic aromatic acyl groups optionally substituted by hydroxy , Lower alkanoyloxy, halogen, trifluorome containing 1 to 3 carbon atoms

ii) hydroxy or acyloxy containing 1-7 carbon atoms, carbamoyloxy, or aralkyloxy containing 7-12 carbon atoms,

iii) alkoxycarbonyl, indanyloxycarbonyl, phenoxycarbonyl, or iv) azido, cyano, carbamoyl, alkoxysulfonyl, sulfo, or alkoxysulfo containing carboxyl or 2 to 7 carbon atoms Neil,

8) 2-side containing 3 to 5 carbon atoms is 3-alkanoyl,

9) (2- or 4-pyridone-1-yl) acetyl,

10) 5-aminoadipoyl, aroyl or 5-aminoadipoyl groups protected from amino groups by alkanoyls containing 1 to 10 carbon atoms, chloroalkanoyls containing 1 to 5 carbon atoms or 2 to 10 carbon atoms 5-aminoadifoyl groups, 2, 2, 2-trichloroethyl, trialkylsilyl, alkyl containing 1 to 6 carbon atoms, nitrobenzyl, protected at the carboxyl group by alkoxycarbonyl or benzhydryl containing carbon atoms Or methoxybenzyl; and

11) Acyl group represented by the following formula,

L-O-CO

[Wherein L is a readily removable and optionally substituted hydrocarbon group containing 1 to 8 carbon atoms (eg, 2, 2, 2-trichloroethyl, isobornyl, tert-butyl, 1-methylcyclohexyl , 2-alkoxy tert-butyl, benzyl, P-nitrobenzyl or P-methoxybenzyl)].

Optionally, A and B together dibasic carboxyl containing 4 to 12 carbon atoms

In the above, examples of the Ar group include furyl, thienyl, pyryl, oxazolyl, isoxazolyl, oxdiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tithiazolyl, pyrazolyl, imidazolyl , Triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl and dihydrophenyl, each of which is halogen, an alkyl group containing 1 to 3 carbon atoms, hydroxy , May be optionally substituted with aminomethyl or an alkoxy group containing 1 to 3 carbon atoms.

The carboxy protecting group represented by X contains 20 or less carbon atoms, an alkoxy group containing 1 to 8 carbon atoms (e.g., methoxyethoxy or tert-butoxy), an alkoxy group containing 7 to 20 carbon atoms ( Eg benzyloxy, methoxybenzyloxy, nitrobenzyloxy, diphenylmethoxy or trityloxy), mono- or bi-cyclic aryloxy groups (eg phenoxy or naphthyloxy), or organomethyloxy ( E.g. trimethylstannicoxy or trimethylsilyloxy), organic or inorganic acyloxy groups containing eight carbon atoms or metaloxy groups of groups I, II or III of the periodic table (e.g. sodium oxy, potassium Oxygen group, such as oxy or magnesiodioxy,

X may be selected from nitrogen groups such as forming sulfur groups, amides, hydrazides, azide groups, etc., such as forming thiol esters, thiocarboxyl groups and the like, or may be selected from other carboxy-protecting groups.

These groups may be interrupted by heteroatoms in the nucleus if possible and may be unsaturated or substituted by substituents as mentioned above (nitrogen, oxygen, sulfur, carbon or popular or halogen) as mentioned above. . Suitable among carboxyl protecting groups X include groups forming haloalkyl esters containing 1 to 5 carbon atoms, acylalkyl ester groups containing 2 to 10 carbon atoms, containing 2 to 8 carbon atoms

Antimicrobially preferred carboxy-protecting groups X are acyloxymethyl esters, phenacyl esters, benzaldooximes, N, N-dimethylaminomethyl esters, alkali metal salts, alkaline earth metal salts, acylated alkaline earth metal salts and others which actually correspond to these groups. And those that form groups of. Preferred carboxyprotecting group X includes tertiary butoxybenzyloxy, benzhydryloxy, p-nitrobenzyloxy, p-methoxybenzyloxy, 2, 2, 2-trichloroethoxy and alkali metal-oxy groups.

Thiol substituent R means groups that can be easily removed without adversely affecting other parts of the molecule before or during the cyclization reaction. Examples thereof include acyl groups, for example tert-butoxycarbonyl, carbobenzoxyl, cyclopropylmethoxycarbonyl, cyclopropylethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, 2- Methanesulfonylethoxycarbonyl:

1-alkoxy or acyloxyalkyl groups containing 2 to 10 carbon atoms (eg methoxymethyl, ethoxymethyl, acetoxymethyl, 1-benzoyloxymethyl), mono- or dicyclic aromatic thio groups (eg thia And other groups such as diazolylthio, thiazolylthio, benzothiazolylthio, phenylthio, 0-nitrophenylthio, naphthylthio).

Also, the following structural formula

Wherein the sulfoxylated azetidine compound represented by (wherein R 'is an acyl group R'CO- group and X is as defined above) is the target compound of the process of the invention.

More suitable among the compounds represented by the above formulas are those wherein R 'is phenoxymethyl, X is p-nitrobenzyloxy, 2, 2, 2-trichloroethoxy, benzyloxy, or benzhydryloxy, or R' Is benzyl, X is p-nitrobenzyloxy, 2, 2, 2-trichloroethoxy, benzyloxy, or benzhydryloxy, or R 'is phenoxymethyl, X is P -nitrobenzyloxy, Or 2,2,2-trichloroethoxy is a compound.

Starting materials are prepared by the following method.

[Production Example 1]

Methyl α- [4-mercapto-3-phthalimido-2-oxoazetidin-1-yl] -α- (1-hydroxyethylidene) acetate (100 mg) dissolved in tetrahydrofuran (3 ml) Benzyl chlorophosphomate (100 mg) was added to the solution, and the mixture was cooled to -65 deg. Triethylamine (60 mg) was added to this solution, and the mixture was stirred for 1 hour. After warming to room temperature, the mixture was evaporated. The residue was purified by silica gel chromatography to give methyl a- [4-benzyloxycarbonylthio-3-phthalimido-2-oxozetadan-1-yl] -a- (1-benzyloxycarbonylethylritene Acetate (160 mg) was obtained. Yield: 94%

The product did not contain isomers at the α position.

1790, 1780, 1730㎝^-1 IR:

1790, 1780, 1730 cm ^-1

NMR: δ CDCl ₃ 8.00 to 7.50 m ₄ H, 7.4 s 5 H, 7.30 s 5 H, 6.27 d (5 Hz) 1 H, 5.90 d (5 Hz) 1 H, 5.27 s 2 H, 5.17 s 2 H, 3.70 s ₃ H, 2.47 s ₃ H.

[Production Example 2]

Methyl α- (4-mercapto-3-phthalimido-2-oxoazetidin-1-yl) -α- (1-hydroxyethylidene) acetate (50 mg) dissolved in tetrahydrofuran (2 ml) ) Was added to chloropropylmethyl chloroformate (50 mg), and the mixture was cooled to -65 deg. C, and then a solution of triethylamine (30 mg) dissolved in tetrahydrofuran (0.5 ml) was added. After stirring for 1 hour, the mixture was slowly warmed to room temperature, evaporated under reduced pressure, purified by silica gel chromatography using benzene containing 5% ether, methyl methoxycarbonyloxyethylidene) acetate (61 mg). ) Yield: 79%

The product is a mixture of geometric isomers in the α position substituent (about 3: 2).

1790, 1780, 1730㎝^-1 IR:

1790, 1780, 1730 cm ^-1

NMR: δ CDCl ₃ 8.00 to 7.70 m4H, 6.18 d (5 Hz) 3/5 H, 6.10 d (5 Hz) 2/5 H, 5.85 d (5 Hz) 3/5 H, 5.78 d (5 Hz) 2/5 H, 4.30 to 3.80 m4 H, 3.87s6 / 5H, 3.82s9 / 5H, 2.53s6 / 5H, 2.47s9 / 5H, 1.60-0.90 m2H, 0.90-0.10 m8H.

[Manufacture example 3]

An acid chloride and triethylamine were added to a solution of 2, 2, 2-trichloroethyl acetate dissolved in terahydrofuran, and the mixture was reacted for 1 to 3 hours, and then operated in a conventional manner to obtain the following ester. Got.

(1) 2, 2, 2-trichloromethyl α- [4- (2-benzothiazolyl)

1795, 1753, 1698, 1640, 1602㎝^-1.IR:

1795, 1753, 1698, 1640, 1602 cm ^-1 .

NMR: δCDCl ₃ 2.70s3H, 3.38s3H, 4.6m4H, 5.25d (5Hz) 1H, 5.78d (5H) 1H, 6.8 ~ 8.0mlOH

(2) 2, 2, 2-trichloromethyl

3420, 1780, 1770, 1685㎝^-1.IR:

3420, 1780, 1770, 1685 cm ^-1 .

NMR: δ CDCl ₃ 2.28 s ₃ H, 2.50 s ₃ H, 4.55 s 2 H, 4.63 ABq (12 Hz) 2 H, 5.08 dd (7; 5 Hz) 1 H, 5.78 (5 Hz 1 H, 6.65-8.22 ml 4 H.

(3) p-nitrobenzyl-α- [4- (2-benzothiazolyl)

3420, 1780, 1685, 1640㎝^-1.IR:

3420, 1780, 1685, 1640 cm ^-1 .

NMR: δ CDCl ₃ 0.05 to 1.52 m5H, 2.47 s3H, 3.95 + 4.02d (2H), 4.50 + 4.58 s2H, 4.80 to 5.50 m4H, 6.67 to 8.13 ml4H.

(4) 2, 2, 2-trichloroethyl α- [4- (2-benzothiazolyl) acetate.

3450, 1790, 1690, 1650㎝^-1.IR:

3450, 1790, 1690, 1650 cm ^-1 .

NMR: δ CDCl ₃ 0.13 to 1.55 m ₅ H, 2.52 s ₃ H, 4.10 d (7 Hz) 2 H, 4.53 ABq (12 Hz) 2 H, 4.62 s 2 H, 5.11 dd (7; 5 Hz) 1 H, 5.75 d (5 Hz) 1 H, 6.72 to 8.07 mlOH.

[Production Example 4]

Methanesulfonylchloride (0.26 ml) and triethylamine (0.37 ml) were added to a p-nitrobenzyl solution dissolved in a mixture (9.5 ml) of tetrahydrofuran and hexamethylphosphorotriamide (20: 1). After 2 hours, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dehydrated and evaporated to give p-nitrobenzyl. Yellow foam.

1780, 1731, 1612, 1601㎝^-1.IR:

1780, 1731, 1612, 1601 cm ^-1 .

NMR: δ CDCl ₃ 0.2-1.25m5H, 2.57s3H, 2.72s3H, 3.09d (7Hz) 2H, 4.55s2H, 5.33-5.99m4H, 6.82-7.62m7H, 8.21d (8.5Hz) 2H.

Similar acylation produced the following compounds.

(1) p-nitrobenzyl

1780, 1731, 1643, 1612, 1601㎝^-1.IR:

1780, 1731, 1643, 1612, 1601 cm ^-1 .

NMR: δCDCl ₃ 0.2-1.33m5H, 2.34s3 / 2H, 2.50s3 / 2H, 3.74s3 / 2H, 3.83s3 / 2H, 3.97d (7Hz) 2H, 4.52s2H, 5.26s2H, 5.53-6.00m2H, 6.79-8.24 m9H.

(2) 2, 2, 2-trichloroethyl

3430, 1781, 1750sh, 1685, 1640㎝^-1.IR:

3430, 1781, 1750sh, 1685, 1640 cm ^-1 .

NMR: δ CDCl ₃ 0.2-1.4 m ₅ H, 2.50 s ₃ H, 4.13 d (8 Hz) 2 H, 4.53 ABq (12 Hz) 2 H, 4.56 s 2 H, 5.15 dd (5; 8 Hz) 1 H, 5.43 d (5 Hz) 1 H, 6.8-8.4 mlOH.

Production Example 5

A mixture of cyclopropylmethylchloroformate (480 mg) and triethylamine (180 mg) was added to a solution of 2, 2, 2-chlorochloroethyl silver salt (695 mg) dissolved in hexamethylphosphorotriamide (8 ml), The mixture was stirred for 1 hour. The reaction mixture was decanted into ice water and extracted with benzene. The extract was washed with water, dehydrated and evaporated to give a residue. The residue was purified by silica gel chromatography to give 2, 2, 2-trichloroethyl. Yield: 64.4%

This product is a mixture of a mixture of geometric isomers (about 4: 3) in the α-position substituent.

3440, 1785, 1720㎝^-1.IR:

3440, 1785, 1720 cm ^-1 .

NMR: δ CDCl ₃ 0.1-1.3 mlOH, 2.4 s ₃ H, 4.0 m ₃ H, 4.60 s ₂ H, 4.83 s ₂ H, 5.2-6.1 m ₂ H, 6.8-7.5 m ₆ H.

[Manufacture example 6]

Morpholine (0.26 ml) was added under p-nitrobenzyl ice-cooling dissolved in benzene (11 ml), and the mixture was kept at 10 ° C. overnight. The reaction mixture was washed with water, dehydrated and evaporated under reduced pressure. The obtained residue (1 g) was purified by chromatography on silica gel (10 g) using a mixture of benzene and ethyl acetate (1: 2) to obtain p-nitrobenzyl. Foam.

3430, 1774, 1694br, 1604, 1150㎝^-1.IR:

3430, 1774, 1694br, 1604, 1150 cm ^-1 .

NMR: δCDCl ₃ 0.22m5H, 2.27 + 2.40s3H, 3.43m4H, 3.77m4H, 4.02d (6.4Hz) 2H, 4.57s2H, 5.05-5.27m3H, 5.89d (5.4Hz) 1H, 4.12-77.6m7H, 8.23 (8.4 Hz) 2 H.

By a method similar to that described above, the following compounds were prepared from the corresponding methanesulfonates.

(1) 2, 2, 2-trichloroethyl

3440, 1773, 1690, 1600㎝^-1.IR:

3440, 1773, 1690, 1600 cm ^-1 .

NMR: δ CDCl ₃ 1.68brs6H, 2.4brs3H, 3.36brs4H, 4.63m4H, 5.0-5.7m2H, 6.8-8.0ml4OH.

(2) p-nitrobenzyl

NMR: δ CDCl ₃ 1.63brs6H, 2.33brs3H, 3.3brs4H, 4.53s2H, 5.0-5.5m4H, 6.8-8.2ml4H.

Similarly, the following compounds were prepared from the corresponding chlorides.

(1) 2, 2, 2-trichloroethyl

3440, 1780, 1710, 1695㎝^-1.IR:

3440, 1780, 1710, 1695 cm ^-1 .

NMR: δ CDCl ₃ 0.2-1.3 m ₅ H, 1.67 brs ₆ H, 2.40 or 2.27 s ₃ H, 3.35 br ₄ H, 3.98 (7 Hz) 1 H, 4.57 s 3 H, 4.73 s 2 H, 5.13-6.07 m 2 H.

About Isomers

(2) 2, 2, 2-trichloroethyl as described above

[Manufacture example 7]

P-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-ene- dissolved in tetrahydrofuran (8 ml) 6-day] methanesulfonyl chloride (0.13 ml) and triethylamine (0.23 ml) were added dropwise to a solution of -α- (1-hydroxyethylidene) acetate (504 mg) under ice-cooling. After 3 hours the mixture was evaporated to give a residue, which was dissolved in methylene chloride, washed with water, dehydrated with magnesium sulfate and evaporated. The residue was purified by silica gel chromatography containing 10% water (15 g) using a mixture of benzene and ethyl acetate (5: 1) to give P-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4 -Thia-2,6-diazabicyclo [3,2,0] hept-2-en-6-yl] -α- (1-methanesulfonyloxyethylidene) acetate (353 mg) was obtained. Colorless foam.

The product did not have geometric isomers at the α position.

1780, 1730㎝^-1.IR:

1780, 1730 cm ^-1 .

NMR: δ CDCl ₃ 2.60 s ₃ H, 3.18 s ₃ H, 4.58 + 4.88 a Bq (14 Hz) 2 H, 5.24 s 2 H, 5.92 + 6.08 ABq (5 Hz) 2 H, 6.73-8.20 m 9 H.

[Manufacture example 8]

P-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, dissolved in dimethylformamide containing 10% tetrahydrofuran (5 ml). Toluene-P-sulfonylchloride (456 mg) was added to a solution of 0] hept-2-en-6-yl] -α- (1-hydroxyethylidene) acetate (940 mg). After cooling to -70 ° C, this solution was mixed with triethylamine (0.3 ml). The reaction mixture was slowly warmed up to room temperature, decanted with water, and extracted with ethyl acetate. The extract was washed with water and evaporated to dehydrate. The obtained residue was purified by silica gel chromatography containing 10% water using benzene containing 5% ethyl acetate to prepare P-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2,6. -Diazabacyclo [3,2,0] hept-2-en-6-yl] -α- (1-toluene-P-sulfonyloxyethylidene) acetate (644 mg) was obtained.

1785, 1735㎝^-1.IR:

1785, 1735 cm ^-1 .

NMR: δ CDCl ₃ 2.45 s ₃ H, 4.75 + 4.20 ABq (14 Hz) 2 H, 5.15 s 2 H, 5.77 s 2 H, 8.30-6.60 ml ₃ H.

[Manufacture example 9]

P-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-ene-6- dissolved in benzene (3 ml) Day] -α- (1-methanesulfonyl

The product is a mixture of geometric isomers in the α position substituent (about 1: 1).

1768, 1685, 1612, 1603㎝^-1.IR:

1768, 1685, 1612, 1603 cm ^-1 .

NMR: δ CDCl ₃ 1.90 s ₁ H, 2.42 s ₁ H, 3.17 to 3.43 m ₄ H, 3.52 to 3.83 m ₄ H, 4.87 s ₂ H, 5.21 s ₂ H, 5.58 to 6.00 m ₂ H, 6.80 to 5.22 m ₉ H.

[Production Example 10]

2, 2, 2-trichloroethyl α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2 dissolved in benzene (30 ml) Morpholine (0.48 ml) was added to a solution of -en-3-yl] -α- (1-methanesulfonyloxyethylidene) acetate (1.52 g) at 10 캜 or lower. After stirring for 1 hour, the mixture was washed with water, dehydrated and evaporated. The obtained residue was purified by silica gel chromatography to give 2, 2, 2-trichloroethyl α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazacyclo [3, 2, 0 Hept-2-en-6-yl] -α- (1-morpholinoethylidene) acetate (0.76 g) was obtained. Yield: 50%

The product is a mixture of isomers at the α-position substituent.

NMR: δ CDCl ₃ 1.88 + 2.42 s ₃ H, 3.1-3.9 m 8 H, 4.73 ABq (12 Hz) 2 H, 4.95 s 2 H, 5.7-6.2 m 2 H, 6.8-7.5 m 5 H.

[Production Example 11]

P-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3, 2, 0] hept-2-ene dissolved in tetrahydrofuran (10 ml) by stirring Methylchloroformate (200 mg) and triethylamine (216 mg) were added dropwise under ice-cooling to a stirred solution of -6-yl] -α- (1-hydroxyethylidene) acetate (500 mg). After 1 hour, the reaction mixture was decanted into ice water and extracted with ethyl acetate. The extract was washed with water, dehydrated and evaporated to give P-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2. -En-6-yl] -α- (1-methoxycarbonyloxyethylidene) acetate (546 mg) was obtained. Foam, yield: 97%

The product is a mixture of geometric isomers at the α position (about 2: 1).

1783, 1732, 1642, 1612, 1600㎝^-1.IR:

1783, 1732, 1642, 1612, 1600 cm ^-1 .

NMR: δ CDCl ₃ 1.95 s 1 H, 2.47 s 2 H, 3.68 s 1 H, 3.80 s 2 H, 4.54 + 4.86 ABq (14 Hz) 4/3 H, 4.86 s 2/3 H, 5.25 s 3 H, 5.73 to 6.03 m 2 H, 6.70 to 8.16 m 9 H.

[Manufacture example 12]

2, 2, 2-trichloroethyl α- [3-benzyl-7-oxo-2, 6-diaza-4-thiabicyclo [3, 2, 0] hept-2 dissolved in methylene chloride (7 ml) Methanesulfonylchloride (0.093 mg) and triethylamine (0.48 ml) were added to a solution of -en-6-yl] -α- (1-hydroxyethylidene) acetate (450 mg) at -25 ° C. This mixture was kept at the same temperature for 40 minutes. 2, 2, 2-trichloroethyl α- [3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] -α Morpholine (0.112 ml) was added dropwise to the resulting solution of-(1-methanesulfonyloxyethylidene) acetate, and the mixture was stirred for 1.3 hours. Reaction mixture

The product is a mixture of geometric isomers in the α position (about 1: 1.6).

NMR: δCDCl ₃ 1.67 s + 2.35 [3H], 2.83-4.00 m8H, 2.31 s2H, 4.45 + 4.88 q (12 Hz), 4,47 + 4.83 q (12 Hz) [2H], 5.60-6.12 m2H, 7.22 s + 7.23 s [5H].

[Production Example 13]

P-nitrobenzyl α- [3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-ene-6 dissolved by stirring in tetrahydrofuran (15 ml) -Yl] methanesulfonylchloride (0.18 ml) and triethylamine (0.31 ml) were added to the half solution of -α- (1-hydroxyethylidene) acetate (680 mg) under ice-cooling, and the mixture was added to 1 Stir for time. The separated crystals were filtered off and the filtrate was evaporated. The residue (800 mg) was purified by silica gel chromatography containing 10% water (25 g) and developed from a fraction developed with a mixture of zylzen and ethyl acetate (2: 1) to P-nitrobenzyl α- [3-benzyl-7 Oxo-4-thia-2,6-diazabicyclo [3,2,0] hept-2-en-6-yl] -α- (1-methanesulfonyloxyethylidene) acetate (609 mg) Got it. Yield: 76.6%

The product does not have a geometric mixture at the α position.

1784, 1700, 1614㎝^-1.IR:

1784, 1700, 1614 cm ^-1 .

NMR: δCDCl ₃ 2.58s3H, 3.00s3H, 3.79s2H, 5.18s2H,

Production Example 14

P-nitrobenzyl α- [3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-en-6-yl dissolved in methylene chloride (2 ml) To a solution of?-(1-methanesulfonyloxyethylidene) acetate (609 mg) was added morpholine (0.2 ml) at -15 ° C, and the mixture was stirred at the same temperature for 50 minutes. The reaction mixture was inclined to ice water and extracted with methylene chloride. The extract solution was washed with water, dehydrated and evaporated. The resulting foam (569 mg) was purified by silica gel (25 g) chromatography and developed from a fraction developed with a mixture of benzene and ethyl acetate (2: 1) to P-nitrobenzyl-α- [3-benzyl-7-oxo-4 -Thia-2,6-diazabicyclo [3,2,0] hept-2-en-6-yl] -α- (1-morpholinoethylidene) acetate (452 mg) was obtained. Yield 75.5% foam.

The product does not have geometric isomers at the α position.

1778, 1695, 1615㎝^-1.IR:

1778, 1695, 1615 cm ^-1 .

NMR: δCDCl ₃ 2.37 s ₃ H. 3.00 to 3.73 m 8 H, 3.86 s 2 H, 5.20 s 3 H, 5.73 + 5.88 ABq (5 Hz) 2 H, 7.15 to 8,28 m 9 H.

Example 1

P-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazacyclo [3, 2, 0] hept-2-en-6-yl] -α- (1 -Hydroxyethylidene) acetate (939 mg) was dissolved in tetrahydrofuran (14 ml), cooled to -40 ° C, to which triethylamine (0.67 ml) and methanesulfonylchloride (0.178 ml) were added Stir at -40 ° C for 30 minutes and at 0 ° C for 30 minutes. To this solution, morpholine (0.209 ml) was added and stirred at 0 ° C. for 2 hours, N-bromosuccinimide (393 mg) was added, followed by stirring at 0 ° C. for 1.5 hours.

Example 2

P-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] butt-2-en-6-yl] -α- (1 -Hydroxyethylidene) acetate (278 mg) was dissolved in methylene chloride (2.9 ml), cooled to -20 ° C, and methanesulfonyl chloride (0.05 ml) and triethylamine (0.20 ml) were added with stirring, Stir for 10 minutes in the presence of argon gas. To this solution, morpholine (0.062 ml) was added under ice cooling, stirred for 15 minutes, and then N-chlorosuccinimide (97 mg) was added, stirred at -20 ° C for 2 hours, and then washed with water. It is then dehydrated and evaporated. The obtained residue (368 mg) was purified by silica gel chromatography containing 10% water (18.4 g) using a mixture of benzene and ethyl acetate (1: 1) to give p-nitrobenzyl α- [3-phenoxymethyl -7-oxo-4-thia-2, 6-azabicyclo [3, 2, 0] hept-2-ene-60yl] -α- (1-morpholino-2-chloroethylidene) acetate (106 mg; 31.2%) with p-nitrobenzyl-α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-ene-6 -Yl] -α- (1-morpholinoethylidene) acetate (134 mg; 42.0%) was obtained.

Example 3

p-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] -α- (1 -Hydroxyethylidene) acetate (940 mg) was dissolved in dichloromethane (14 ml), cooled to -25 ° C, then triethylamine (0.97 ml) and methanesulfonylchloride (0.187 ml) were added 1.5 React for hours. To this solution morpholine (0.209 ml) was added and maintained at -25 [deg.] C. for 1 hour, followed by addition of bromine solution (3.2 mmol bromine) in carbon tetrachloride. After 30 minutes, the reaction mixture is washed with 5% aqueous sodium hydrogen carbonate solution and water, then dehydrated and then evaporated. The obtained residue (1457 mg) was purified by silica gel chromatography containing 10% water (100 g) using a mixture of benzene and ethyl acetate (2: 1) to give p-nitrobenzyl a- [3-phenoxymethyl- 7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] -α- (dibromoacetyl) -methanesulfonyl acetate (132.8 mg, 8.8%) and p-nitrobenzyl-α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 3] hept-2-en-6-yl] -α- (1-monolino-2-bromoethylidene) acetate (1033.5 mg; 83.7%) was obtained.

Example 4

p-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] -α- (1 -Hydroxyethylidene) acetate (940 mg) was dissolved in dichloromethane (14 ml), cooled to -25 [deg.] C., then triethylamine (0.61 ml) and methanesulfonylchloride (0.17 ml) were added 1.5 Stir for time. Morpholine (0.209 ml) was added to the solution, held at -25 ° C for 1.5 hours, and then bromine (2.2 mmol) dissolved in carbon tetrachloride (2.2 ml) was added and held at -25 ° C for 30 minutes. Then 5% aqueous sodium hydrogen carbonate solution is added, washed with water, then dehydrated and evaporated. The obtained residue (1.134 g) was mixed with benzene and

Example 5

dissolved in p-nitrobenzene tetrahydrofuran (10 ml), cooled to −40 ° C. under nitrogen pressure, and then dissolved in triethylamine (489 mg) and tetrahydrofuran (1 ml) dissolved in tetrahydrofuran (1 ml). Methanesulfonylchloride (252 mg) was added and stirred at −40 ° C. for 30 minutes and at 0 ° C. for 45 minutes. To this solution, morpholine (209 mg) dissolved in tetrahydrofuran (1 ml) was added, maintained at 0 ° C. for 1.5 hours, and then water was added to remove the separated oily substance and extracted with ethyl acetate. . The extracted solution and the removed oily substance were combined, dehydrated with magnesium sulfate, and evaporated. The obtained residual oil (1.4 g) was purified by silica gel chromatography containing 5% water (20 g) to yield p-nitrobenzene; 52%) and p-nitrobenzyl yield; 14%).

The former product (100 mg) was stirred with 10% hydrochloric acid (0.3 ml) in a mixture of methanol (2 ml) and tetrahydrofuran (1 ml) at 0 ° C. for 90 minutes, then diluted with water to separate, evaporated and chloroform In water, washed with water and then dehydrated with magnesium sulfate and then evaporated to p-nitrobenzyl α- [4-methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl ] -α- (1-hydroxy-2-bromoethylidene) acetate (70 mg) was obtained. Yield: 78%

Example 6

p-nitrobenzyl α- [3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 3] hept-2-en-6-yl] -α- (1-hydro Roxyethylidene) acetate (827 mg) was dissolved in methylene chloride (10 ml), cooled to -20 ° C, a solution of methanesulfonyl chloride (1 M in methylene chloride: 2.2 m) and triethylamine (1 M in methylene chloride) : 2.2 ml) of solution, stirred for 90 minutes, then cooled to -25 [deg.] C., morpholine (0.35 ml) added, stirred for 65 minutes, and then N-bromosuccinimide (340 mlg) is added and stirred for 1 hour. The reaction mixture is washed with water, dehydrated with magnesium sulfate and evaporated. The obtained residue was purified by silica gel chromatography containing 10% water (30 g) to obtain p-nitrobenzyl a- [3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2]. , 3] hept-2-en-6-yl] -α- (1-morpholino-2-bromoethylidene (710 mg) was obtained.Yield: 65%

Example 7

p-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3, 2, 3] hept-2-en-6-yl] -α- (1 -Hydroxyethylidene) acetate (940 mg) was dissolved in tetrahydrofuran (14 ml), followed by addition of triethylamine (0.61 mg) and methanesulfonyl chloride (0.172 mg), -15 ° C to -20 ° C. Stir for 1 h at. p-nitrobenzyl α- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3, 2, 3] hept-2-en-6-yl] -α- (1 Morpholine (0.209 ml) was added to the resulting solution of methanesulfonyloxyethylidene) acetate, and stirred at -15 ° C to 20 ° C for 1.5 hours, followed by stirring at 0 ° C for 2 hours to form p-nitrobenzyl. α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] -α- (1-

Similar reactions using N, N-dimethylformamide (14 ml) instead of tetrahydrofuran gave the same product (910 mg; 73.6% and 100 mg; 9.0% respectively).

Example 8

P-nitrobenzyl α- [3-benzene-7-oxo-ethylidene-2, 6-diaza-4-thiabicyclo [3, 2, 0] hept-2-ene in anhydrous tetrahydrofuran (30 ml) -6-yl] -α- (1-hydroxyethylidene) acetate (2.265 g) suspended and triethylamine (1.11 g) and methanesulphate dissolved in tetrahydrofuran (2 ml) at 1-2 ° C. A solution of polyvinylchloride (630 mg) is added dropwise and stirred for 25 minutes. p-nitrobenzyl α- [3-benzyl-7-oxo-2, 6-diaza-4-thiabicyclo [3, 2, 0] hept-2-en-6-yl] -α- (1- To a solution of methanesulfonyloxyethylidene) acetate, a solution of morpholine (480 mg) dissolved in tetrahydrofuran (2 ml) was added and stirred for 15 minutes, followed by p-nitrobenzyl α- [3-benzyl- 7-oxo-2, 6-diaza-4-thia

Dilute with 5% hydrochloric acid (10 molar equivalents) and methanol without isolation from solution and stir at room temperature for 3 hours to yield p-nitrobenzyl 7-phenylacetamido-2-hydroxy-3- in yield of at least 70%. Cefem-4-carboxylate was obtained.

Example 9

Diphenylmethyl α- [3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] in tetrahydrofuran (60 ml)- α- (1-hydroxyethylidene) acetate (4.84 g) was dissolved, cooled to -20 ° C, and then triethylamine (2.84 ml) was added with stirring to methanesulfonyl chloride in the resulting yellow solution. (0.82ml) was added dropwise and reacted for 30 minutes. Diphenylmethyl α- [3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] -α- (1-methanesulphate Morpholine (0.96 ml) was added to the resulting solution of phenyloxyethylidene) acetate at −40 ° C., stirred for 3.5 hours, and then diphenylmethyl α- [3-benzyl-7-oxo-4-thia- Pyridine (077 ml) was added to a solution for producing 2, 6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] -α- (1-morpholinoethylidene) acetate, Cool to −40 ° C., add bromine (0.49 ml), and

3410, 1782, 1674, 1610㎝^-1.IR:

3410, 1782, 1674, 1610 cm ^-1 .

NMR: δ CDCl ₃ 3.20 s ₂ H, 3.64 s 2 H, 4.97 d (4 Hz) 1 H, 5.66 dd (9: 4) 1 H, 6.77 d (9 Hz) 1 H, 6.90 s 1 H, 7.35 ml 6 H.

Example 10

Diphenylmethyl α- [3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-ene-6- dissolved in tetrahydrirofuran (60 ml) (1) dissolve α- (1-hydroxyethylidene acetate (4.84 g), cool to −20 ° C., add triethylamine (2.84 ml) with stirring, and then methanol to the resulting yellow solution. Ponylchloride (0.82 ml) was added and left for 30 minutes Diphenylmethyl- [alpha]-[3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept -2-en-6-yl] -Production solution of α- (1-methanesulfonyloxyethylidene) acetate Add morpholine (0.96 ml) at −40 ° C., stir for 3.5 hours, and then pyridine ( 0.77 ml) was added to diphenylmethyl α- [3-benzyl-7-oxo-4-thia-2, 6-diazabi

3410, 1782, 1674, 1610㎝^-1.IR:

3410, 1782, 1674, 1610 cm ^-1 .

NMR: δ CDCl ₃ 3.20 s ₂ H, 3.64 s 2 H, 4.97 d (4 Hz) 1 H, 5.66 dd (9: 4 Hz) 1 H, 6.77 d (9 Hz) 1 H, 6.90 s 1 H, 7.35 ml 5 H.

Example 11

Triethylamine (5.68 ml) was suspended in p-nitrobenzyl α- [3-benzyl-7-oxo-4-thia-2, 6-dia, suspended by stirring in tetrahydrofurin (120 ml) at −20 ° C. in a nitrogen stream. To a stirred suspension of jabacyclo [3, 2, 0] hept-2-en-6-yl] -α- (1-hydroxyethylidene) acetate (9.06 g) was added to form a clear solution, which was added to this solution. Methanesulfonylchloride (1.65 ml) was added and stirred at the same temperature for 30 minutes, followed by the addition of morpholine (1.92 ml), warmed to 0 ° C. and stirred for 5 hours and then to −30 to 35 ° C. Cool, then

(1) Diphenylmethyl α- [3-phenoxymethyl-7-oxo-2, 6-diaza-4-thiabicyclo [3, in a mixture of methylene chloride (3.2 ml) and methanol (0.3 ml) 20] Hept-2-en-6-yl] -α- (1-chloro-2-propen-2-yl) acetate (160 mg) in anhydrous acetone cooling solution is introduced ozone until the reaction mixture is blue. did. The excess ozone was then purified with oxygen, then mixed with an aqueous solution of 95% sodium hydrogen sulfite (100 mg), then warmed to room temperature to decompose the ozonate. After 1.5 hours, the solution was washed with 5% aqueous sodium hydrogen carbonate solution and water, dehydrated and concentrated to remove methylene chloride. The resulting oil (132 mg) was purified by larva chromatography (Merck 60F-254) using a mixture of benzene and ethyl acetate (1: 1) as a developing agent to diphenylmethyl α- [3-phenoxymetal-7 Oxo-2,6-diaza-4-thiabicyclo [3,2,0] hept-2-en-6-yl] -α- (2-chloro-1-hydroxyethylidene) acetate ( 44 mg) was obtained in a vitreous form.

1784, 1672, 1620, 1603㎝^-1.IR:

1784, 1672, 1620, 1603 cm ^-1 .

MNR: δ CDCl ₃ 4.00 s ₂ H, 4.66 + 4.96 ABq (14 Hz) 2 H, 5.23 s 2 H.

(2) Diphenylmethyl α- [3-phenoxymethyl-7-oxo-2, 6-diaza-4-thiabacyclo [2] in a mixture of methanol and tetrahydrofuran (1: 1) (1.1 ml) [ 3, 2, 0] hept-2-en-6-yl]-α- (2-chloro-1-hydroxyethylidene) acetate (36 mg)

3420, 1788, 1738, 1692, 1600㎝^-1.IR:

3420, 1788, 1738, 1692, 1600 cm ^-1 .

NMR: δ CCCl ₃ 3.33 s ₂ H, 4.54 s 2 H, 5.02 d (4 Hz) 1 H, 5.26 s 2 H, 5.62 dd (10; 4 Hz) 1 H, 6.81-7.45 mlOH, 11.5 brs 1 H.

Example 12

Benzyl α- [3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] dissolved in tetrahydrofuran (15 ml)- To a solution of α- (1-hydroxyethylidene) acetate (1.424 g) was added -30 to 20 DEG C. triethylamine (0.96 ml) and methanesulfonyl toourolide (0.28 ml) and stirred for 55 minutes. Benzyl α- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] -α- (1-methanesulfonyl Oxyethylidene) acetate, to which morpholine (0.40 ml) was added, followed by stirring at −10 to 30 ° C. for 5 hours to benzyl α- [3-benzyl-7-oxo-4-thia-2-2 , 6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] -α- (1-morpholinoethylidene) acetate was obtained and cooled to -35 to -30 ° C. Then pyridine (0.27 ml) and bromine in carbon tetrachloride (1 mmol / l: 3.2 ml) were added and stirred for 20 minutes to benzyl α- [3-benzyl-7-oxo-4-thia-2 , 6-diazabicyclo [3, 2, 0] hept-2-en-6-yl] -α- (1-morpholino-2-bromoethylidene) acetate, followed by 5% hydrochloric acid (13 ml )and

NMR: δ CDCl ₃ 3.28 d ₂ H, 3.63 s 2 H, 4.98 d (5 Hz) 1 H, 5.30 s 2 H, 5.60 dd (5; 8 Hz) 1 H, 6.37 d (8 Hz) 1 H, 7.4 s + 7.4 s 10 H, 11.6 brs 1 H.

3420, 1785, 1680, 1615㎝^-1.IR:

3420, 1785, 1680, 1615 cm ^-1 .

Example 13

(1) benzyl α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2 dissolved in dichloromethane and methanol (5: 1) -En-6-yl] Ozone-oxygenated oxygen was introduced into a solution of -α-isopropenyl acetate (4.22 g) until the blue color of the solution did not fade. This solution was then mixed with dimethylsulfide, washed with water, dehydrated and concentrated. The residue obtained was purified by silica gel chromatography containing 10% water to yield benzyl a- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept. -2-en-6-yl] -α- (1-hydroxyethylidene) acetate (2.9 g; 70.28%) was obtained.

(ii) benzyl α- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-ene-6- in tetrahydrofuran (30 ml) To the solution of [alpha]-(1-hydroxyethylidene) acetate (2.12 g), triethylamine (1.42 ml) and methanesulfonyl chloride (0.41 ml) were added at -30 DEG C and stirred for 70 minutes. Benzyl α- [3-

Claims (1)

A process for preparing enamine of the following compound of formula (I), wherein the compound of formula (II) is treated with substituted amine.

Where A and B are each hydrogen or amino substituents, R is hydrogen or a thiol substituent, X is a hydroxy or carboxy protecting group, The inspection line between A and R is that R and B are hydrogen, When A is a carboxyl substituent, it indicates that the substituent can be combined to form an azetiminothiazoline dicyclic, Z represents a sulfonyl group.