KR19980045254A - Method for producing propenyl cefem intermediate - Google Patents

Abstract

The propefecefem compound of Formula (I) is prepared by reacting a cefe compound represented by Formula (IIV) and a hydroxypropenyltin compound represented by Formula (VIII) under a palladium-based catalyst, a ligand-based catalyst, and a halogen catalyst. It is about how to.

The propenyl cefem-based compound represented by the general formula (I) of the present invention is a useful intermediate used to prepare a 3-substituted propenyl cephalosporin compound, which is a useful antibiotic having a broad antimicrobial range and excellent antimicrobial activity.

In formula (I), R ₁ represents hydrogen, phenylacetyl, phenoxyacetyl, thiophenacetyl, furanacetyl, t-butoxyacetyl, trimethylacetyl, t-butoxycarbonyl, 2- (2-aminothia Zol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (5- Amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetyl or 2- (5-amino-1,2,4-thiadiazol-3-yl)- 2- (Z) -fluoromethoxyiminoacetyl. R ₂ is hydrogen, diphenylmethyl, p-methoxybenzyl, or p-nitrobenzyl. X is in the form of hydroxy, acetoxy, chloro, or iodo, and their acid-added salts.

In formula (VII), R ₁ , R ₂ are the same as R ₁ , R _{2 as} defined in formula (I), P is trifluoromethanesulfonyloxy, methanesulfonyloxy, fluorosulfonyloxy, Chloro, bromo, or iodo.

Description

Method for producing propenyl cefem intermediate

The present invention relates to a new and advanced process for the preparation of propenyl cephem intermediates represented by general formula (I). The propenyl cefem-based intermediate represented by Formula (I) is a starting material used to prepare 3-propenyl cephalosporin compound, and more specifically, 3-substituted propenyl cephalosporin having a broad antibacterial range and excellent antimicrobial activity. Compounds Useful compounds are used when preparing antibiotics.

In formula (I), R ₁ represents hydrogen, phenylacetyl, phenoxyacetyl, thiophenacetyl, furanacetyl, t-butoxyacetyl, trimethylacetyl, t-butoxycarbonyl, 2- (2-aminothia Zol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (5- Amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetyl or 2- (5-amino-1,2,4-thiadiazol-3-yl)- 2- (Z) -fluoromethoxyiminoacetyl. R ₂ is hydrogen, diphenylmethyl, p-methoxybenzyl, or p-nitrobenzyl. X is in the form of hydroxy, acetoxy, chloro, or iodo, and their acid-added salts.

The propenyl cefempe compound of the general formula (I) is a compound useful for preparing a 3-substituted propenyl cephalosporin compound represented by the general formula (II) widely used as an antibiotic.

In the 3-substituted propenyl cephalosporin compound represented by Formula (II) useful as an antibiotic, the 3-substituted compound represented by Y has various substituents from (A) to (F) as described below. have.

(A) unsaturated heterocyclo ammonium groups, such as general formula (III):

In general formula (III), Het ₁ represents a heterocyclic compound in which five rings, six rings, or two rings thereof are bonded, including one or two or more heteroatoms selected from oxygen, nitrogen, and sulfur. R ₃ and R ₄ may each be the same or different and are hydrogen, carboxy, carboxamido, sulfonic acid, or substituents such as alkoxy, hydroxy, acyl, amino, alkylthio, mercapto, or appropriately substituted saturated or unsaturated Alkyl, saturated or unsaturated carbocyclo ring, or heterocyclo ring.

In the general formula (III), specific examples of Y include thiazolium, pyrrolinium, thiadiazolium, oxadizolium, oxazolium, pyridinium, thiazole [4,5-c] pyridinium and thie which are suitably substituted. No [2,3-b] pyridinium, isoquinolium or quinolinium.

(B) aliphatic ammonium groups, such as general formula (IV):

In formula (IV), R ₅ , R ₆ and R ₇ may be the same or different, respectively, hydrogen, alkyl, alkenyl, aryl, lower alkyl substituted with hydroxy group, carbamoyl lower alkyl, amino lower alkyl, Acylamino lower alkyl, cyano lower alkyl, or carboxy lower alkyl.

Specific examples of Y represented by general formula (IV) include triethylammonium, (1-carbamoyl-2-hydroxyethyl) dimethylammonium, (carbamoylmethyl) ethyl-methylammonium, (cyanomethyl) dimethylammonium , (2-oxopropyl) dimethylammonium, dehydroquinuclidinium, and dimethyl- (4-hydroxyethyloxazol-5-yl) -methylammonium.

(C) saturated heterocycloammonium group:

Examples of the group include 1-methylpyrrolidinium, pyrrolidinium, piperidinium, 1-methylpiperidinium, 1-methylpyrazolidinium, 1,5-diazabicyclo [3.3.0] -1-octanium , 1,4-azabicyclo [2.2.2] -1-octanium, quinuclidinium, 1-aza-5-methyl-4,6-dioxabicyclo [3.3.1] -1-nonanium, meso -3,4-dihydroxy-1-methylpyrrolidinium, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidinium, (3R, 4R) -3,4-dihydroxy -1-methylpyrrolidinium, (2S, 4R) -4-hydroxy-1-methyl-2-hydroxymethylpyrrolidinium, bis (2-hydroxyethyl) -N-methylpyrrolidinium, 3, 4-cis-dihydroxy-1-methylpiperidinium, 3,4-trans-dihydroxy-1-methylpyrrolidinium, 4-hydroxy-1-methylpiperidinium, 2-hydroxymethyl- 1-methyl piperidinium and a tripinium are mentioned.

(D) appropriately substituted tetrazole, triazole, imidazole, pyrrolidine, or pyrazole:

Examples of groups to which they belong include 1,2,4-triazolyl, 1-methyl-1H-tetrazol-5-yl, 1-carboxymethyl-1H-tetrazol-5-yl, or 1,2,3- Triazol-5-yl.

(E) a suitably substituted heterocyclothiol, such as formula (V):

In the general formula (V), Het ₂ is a heterocyclic ring which has up to 4 heteroatoms such as oxygen, nitrogen and sulfur in each ring, and (C _1-4 ) alkyl, (C _3-4 ) al Kenyl, (C _1-4 ) alkoxy, halogen, hydroxy, acyloxy, oxo, mercap, amino, carboxy, carbamoyl, di (C _1-4 ) alkylamino, carboxymethyl, carbamoylmethyl, methi It is a 5- or 6-ring cyclic compound having a substituent such as oxycarbonylamino and a heterocyclic ring in which these rings are conjugated.

Examples of heterocycles include substituted or unsubstituted imidazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazoleyl, thiatazolyl, oxazolyl, oxadiazoleyl, benzimidazolyl, benzoxazolyl, Benzothiazolyl, triazolylpyridyl, purinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, or triazinyl; suitable heterocycles include substituted or unsubstituted 5-hydroxy-4-pyrides Don-2-yl, 5-hydroxy-1-methyl-4-pyridone-2-yl, 1,5-dihydroxy-4-pyridone-2-yl, 1-methyl-1H-tetrazol- 5-yl, 1-carbomethyl-1H-tetrazol-5-yl, 6-hydroxy-2-methyl-5-oxo-2H-1,2,4-triazin-3-yl, 1,2 , 3-triazol-5-yl, 4-methyl-thiazol-5-yl.

(F) Thiols, such as general formula (VI):

SR ₉ (VI)

In formula (VI), R ₉ represents an appropriately substituted alkyl, alkenyl, aryl, acyl, carbamoyl, thiocarbamoyl, carbaalkoxy, or thia derivative.

Examples of acid addition salts include inorganic acid salts such as hydrochloric acid and organic acid salts such as toluenesulfonic acid, acetic acid and trifluoroacetic acid.

The preparation method of the propenyl cefem compound represented by the general formula (I) of the present invention, which is used when preparing the 3-substituted propenyl cephalosporin compound represented by the general formula (II), which is useful as an antibiotic, is well described in various literatures. Known.

For example, US Pat. No. 4,139,618 produces 7-acylamino-3-acetoxypropenyl-3-cefe-4-carboxylic acid esters through a relatively multi-step reaction process. As follows.

7-Acylamino-3-acetoxypropenyl-Δ2 was added acetic acid to the compound obtained by adding vinyl magnesium bromide to the starting material, 7-acylamino-3-propyl-Δ2-sefe-4-carboxylic acid ester. -Cefe-4-carboxylic acid ester is prepared, and the Δ2 double bond of this compound isomerized to 7-thiophenacetamido-3-acetoxypropenyl-3-cefe-4-carboxylic acid ester. To prepare.

This method is difficult to industrialize because the starting material, 7-acylamino-3-formyl-Δ2-sefe-4-carboxylic acid ester, is expensive and the reaction process is very long.

On the other hand, European Patent (EP 333 154) discloses that after protecting the amino group at the 7-position of the starting material 7-amino-3-chloromethylcepem-4-carboxylic acid ester by acylation reaction, the chloromethyl group is used as an iodomethyl group. Halogen exchange was carried out and then reacted with triphenylphosphine to prepare phosphonium salts. The obtained phosphonium salt was reacted with chloroacetaldehyde and Wittig in the presence of a base to prepare 7-phenylacetamido-3-chloropropenyl-3-chefe-4-carboxylic acid ester. This preparation method is used in the industrial chloroacetaldehyde is supplied as an aqueous solution for industrial use, it is mixed with the chloroform solution and distilled together to obtain only a solution of very small concentration of chloroacetaldehyde in chloroform, the purification method is very difficult In addition, there is a disadvantage that the loss in the purification process is very large.

Finally, the Journal of Antibiotics. 45 (6), 998-1001 (1992)], after protecting the amino group at the 7-position of the starting material 7-amino-3-chloromethylcepem-4-carboxylic acid ester with a benzylidene or t-butoxycarbonyl group To prepare in the form of phosphonium salt in a similar manner to the preparation method of the European patent (EP 333 154). The phosphonium salt thus obtained was reacted with acetyloxyacetaldehyde and Wittig in the presence of a base to prepare 3-acetoxypropenyl-3-cepem-4-carboxylic acid ester. However, since the double bond of the 3-acetoxypropenyl group in the obtained material is in the cis form, the double bond of the 3-acetoxypropenyl group should be converted to the trans form by refluxing for 48 hours in a toluene solvent. At this time, since the cis-type double bond structure is not completely converted into a trans-type double bond, it has an inconvenient disadvantage to be separated. Since acetyloxyacetaldehyde is unstable and not industrially produced, it is very difficult to prepare a 1,4-diacetoxy-2-butene compound and then react with a highly toxic compound such as osmium tetraoxide. It is. In other words, it is not suitable for industrialization.

The present inventors have been working to develop a 3-substituted propenyl cephalosporin-based antibiotic represented by the general formula (II) having a strong and broad antimicrobial action, and there is an urgent need for effective preparation of various compounds required for their preparation. . In particular, while trying to solve various disadvantages of known methods, such as safety in the manufacturing process, reaction conditions such as having to go through various processes, purchase of raw materials that are not easy to purchase, and well-known technology A new and advanced method for preparing a propenyl cefem-based compound represented by general formula (I), which overcomes several disadvantages inherent in the present invention, has been learned.

Briefly describing the preparation method of the present invention, the cefem compound represented by the general formula (VII) and the hydroxypropenyl tin compound represented by the general formula (VIII) are combined with a catalyst such as a palladium-based catalyst (O). This is to easily and effectively prepare the propenyl cefem compound of the general formula (I) which is the target compound.

In formula (I), R ₁ represents hydrogen, phenylacetyl, phenoxyacetyl, thiophenacetyl, furanacetyl, t-butoxyacetyl, trimethylacetyl, t-butoxycarbonyl, 2- (2-aminothia Zol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (5- Amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetyl or 2- (5-amino-1,2,4-thiadiazol-3-yl)- 2- (Z) -fluoromethoxyiminoacetyl. R ₂ is hydrogen, diphenylmethyl, p-methoxybenzyl, or p-nitrobenzyl. And X is in the form of hydroxy, acetoxy, chloro, or iodo, and their acid added salts.

In formula (VII), R ₁ is phenylacetyl, phenoxyacetyl, thiophenacetyl, furanacetyl, t-butoxyacetyl, trimethylacetyl, t-butoxycarbonyl, 2- (2-aminothiazole -4-yl) -2- (Z) -methoxyiminoacetyl, 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (5-amino -1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetyl or 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 -(Z) -fluoromethoxyiminoacetyl. R ₂ is diphenylmethyl, p-methoxybenzyl, or p-nitrobenzyl. And P is trifluoromethanesulfonyloxy, methinesulfonyloxy, fluorosulfonyloxy, chloro, bromo, or iodo.

As described above, in the preparation of the cephalosporin compound, a production method using a palladium-based catalyst has been introduced in various documents. For example, according to the Journal of Organic Chemistry, 54 4962-4966 (1989) and the Journal of Antibiotics, 49 (4) 405-407 (1996) published by the inventors, the general formula (VII) When the cefem compound represented by the present invention and various kinds of vinyl tin or heterocyclic tin compounds are reacted under a palladium catalyst, a compound having a double bond or a heterocyclic compound substituted at the 3-position of the general formula (VII) compound is prepared. Announced that it can. However, the literature using the palladium-based catalyst used in the present invention for the preparation of the propenyl cefem-based compound of formula (I) for the preparation of the 3-substituted propenyl cephalosporin compound represented by formula (II) is found. Can't. Accordingly, the present inventors have formulated the cefem compound represented by the general formula (VII) and the hydroxypropenyltin compound represented by the general formula (VIII) in the presence of a palladium-based catalyst, a phosphine-based ligand, and a halogen catalyst. The propenyl cefem compound of (I) is effectively produced. Although the propenyl cephem type compound of general formula (I) will be demonstrated later, the 3-substituted propenyl cephalosporin compound represented by general formula (II) is also represented by another form of general formula (II) useful as an antibiotic 3- It can be readily used to prepare substituted propenyl cephalosporins.

Hereinafter, the present invention will be described in detail.

In order to manufacture the propenyl cefem compound of the general formula (I) of the present invention, a pemdium compound (O) catalyst, the cefem compound represented by the general formula (VII) and the hydroxypropenyl tin compound represented by the general formula (VIII), In the presence of a phosphine ligand and a halogen catalyst, a propenyl cefem compound of the general formula (I) is prepared.

In general formula (I), R <_1> is phenylacetyl, phenoxyacetyl, thiophenacetyl, furanacetyl, t-butoxyacetyl, trimethylacetyl, t-butoxycarbonyl, 2- (2-aminothiazole- 4-yl) -2- (Z) -methoxyiminoacetyl, 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (5-amino- 1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetyl or 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -fluoromethoxyiminoacetyl. R ₂ is diphenylmethyl, p-methoxybenzyl, or p-nitrobenzyl, and X is hydroxy.

In general formula (VII), R <_1> , R <_2> is the same as R <_1> , R <_2> defined by general formula (I), P is trifluoromethanesulfonyloxy, methanesulfonyloxy, fluorosolfonyloxy , Chloro, bromo, or iodo.

Cefem compound of the general formula (VII) to be used as the starting material of the present invention is described in detail in the well-known document [Journal of Organic Chemistry, 54, 4962 ~ 4966 (1989)], the preparation method thereof is 1, The 3-hydroxycefe compound can be easily prepared and used in accordance with this method, such as carrying out an amination reaction with a reagent such as trifluoromethanesulfonic anhydride, methanesulfonic anhydride, and the like.

Meanwhile, hydroxypropenyltin compound represented by general formula (VIII), which is another starting material, is also described in detail in a known document [Tetrahedron Letters, 23 (39), 3851 ~ 3854 (1982)]. It can be easily prepared by reacting -1-ol with tributyltin and a catalytic amount of azo-bis (isobutyronitrile) in the presence of distillation.

In the propenyl cefem-based compound of formula (I), X is hydroxy, and R ₁ and R ₂ are the same as described above in order to prepare the same propenyl cefem-based compound of formula (I) When the cefem compound (VII) and 1-3 equivalents, preferably 1.4 equivalents of the hydroxypropenyltin compound of the general formula (VIII) are reacted in the presence of a palladium catalyst, a phosphine ligand and a halogen catalyst, the general formula (I Can be easily prepared.

The palladium catalyst used for the reaction is palladium bis (dibenzylidineacetone), tetrakis (triphenylphosphine) palladium, tris (dibenzylidineacetone) dipalladium, tris (dibenzylidineacetone) dipalladium-chloroform or palladium One or two of the acetates may be selected and used, and preferably, 0.005 to 0.5 equivalents, more preferably 0.02 equivalents of palladium bis (dibenzylideneacetone) may be used.

Phosphine ligands include tri (2-furyl) phosphine, tri (2-thienyl) phosphine, triphenylphosphine, diphenylmethylphosphine, dimethylphenylphosphine and tri (4-chlorophenyl) phosphine In addition, one or two of triphenyl phosphite may be selected and used. Preferably, 0.005 to 0.5 equivalent, more preferably 0.04 equivalent of tri (2-furyl) phosphine is used.

The halogen catalyst used in the reaction may be used one or two or more of zinc chloride, aluminum chloride, iron chloride, lithium chloride, bromolithium, preferably 0.5 to 5 equivalents, more preferably 2 equivalents of zinc chloride. Do it.

As the solvent used in the reaction, one or two or more mixed solutions of 1-methyl-2-pyrrolidone, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran, acetonitrile and chloroform may be used. 1-methyl-2-pyrrolidone is preferred.

The reaction temperature and reaction time is 5 hours to 72 hours at 15 ~ 60 ℃, preferably at 25 ℃ 24 hours to complete the reaction.

In the present invention, the propenyl cefe compound of formula (I), wherein X is a hydroxy group, is easy to convert to the propenyl cefe compound of general formula (I) having another substituent instead of a hydroxy group because of the various reactivity of the hydroxyl group. In addition, it is very easy to convert to a new substituent having an antimicrobial activity on the R ₁ at the 7-position.

Hereinafter, a process for preparing another useful intermediate from the propenyl cefem compound of the general formula (I) wherein X is a hydroxyl group will be described.

In the propenyl cefem-based compound of formula (I) wherein X is a hydroxy group, the hydroxy group can be easily converted to an acetoxy group using an acetylating agent or halogenated using a halogenating agent.

In addition, to acylate a propenyl cephem compound of Formula (I) wherein X is a hydroxy group, one or two of acetic anhydride, acetyl chloride and acetyl bromide in the presence of 0.01-5 equivalents of 4-dimethylaminopyridine The above mixture can be selected and used, and a base selected from pyridine, 2,6-lutidine, 3,5-lutidine, 2,4,6-collidine, diisopropylethylamine and triethylamine Can be used.

On the other hand, when X is a hydroxy group, if the halogenated propenyl compound of the general formula (I) can be converted to chloro and iodo, the chlorolation reaction is chlorolated using triphenylphosphine-carbon tetrachloride, In the presence of pyridine, diisopropylethylamine, triethylamine base, it can be chloroated using phosphorus trichloride, phosphorus pentachloride, and the like. In addition, when the chloropropenyl compound obtained is reacted with sodium iodide in an acetone solvent, an iodopropenyl compound of which X is iodo in the propenyl cefem compound of the general formula (I) can be easily prepared.

It will be readily apparent from the following examples how the propenyl cefem-based compound of formula (I) can be used to prepare a 3-substituted propenyl cephalosporin compound represented by formula (II) useful as an antibiotic.

In other words, when a compound of formula (IX) is to be prepared, N-methyl is a propenylcefem compound of formula (I) wherein R ₁ is phenylacetyl, R ₂ is diphenylmethyl, and X is iodo. After the reaction with -N-ethylglycineamide in a toluene solvent, trifluoroacetic acid and anisole are added in a dichloromethane solvent to remove the diphenylmethyl group, a carboxy protecting group, to prepare a compound of formula (IX).

Compounds of formula (IX) can be used as intermediates useful in the preparation of formula (X) with strong antimicrobial activity and broad antimicrobial range.

In addition, when preparing an antibiotic of formula (XI), R ₁ is 2- (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetyl, R ₂ is hydrogen and X The propenyl cefem compound of formula (I) wherein is acetoxy is reacted with N in the presence of 3.3 equivalents of bis (hexamethylsilyl) trifluoroacetamide and 2.7 equivalents of trimethylsilyl iodide, which are well known in the art. When reacted with methyl diethanolamine, it is easy to prepare antibiotics of general formula (XI).

The following examples will illustrate the invention in more detail, but the scope of the invention is not limited to the examples.

Example 1

Preparation of diphenylmethyl 7-phenylacetamido-3- [3- (E) -hydroxy-1-propen-1-yl] -3- cefe-4-carboxylate (Ia). X = hydroxy

Diphenylmethyl 7-phenylacetamido-3-trifluuromethinesulfonyloxy-3-cepem-4-carboxylate (14.3 g, 22.6 mmol), zinc chloride (6.17 g, 45.2 mmol) and palladium bis (Dibenzylideneacetone) (412 mg, 0.45 mmol) and tris (2-furyl) phosphine (210 mg, 0.90 mmol) were dissolved in 1-methyl-2-pyrrolidone (80 mL), and then ( E) -3-tributylstanylalylic alcohol (10.67 g, 30.7 mmol) was added and stirred for one day. Ethyl acetate (150 mL) and distilled water (100 mL) were added to the reaction mixture, and the organic layer was separated. The water layer is extracted twice with 30 ml of ethyl acetate and the organic layers are combined. The residue obtained after drying and evaporating an organic layer with anhydrous magnesium sulfate is dissolved in acetonitrile (150 mL). The acetonitrile solution is washed with hexane solution (100 ml) to remove almost unnecessary tin compounds and then evaporated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1: 1) to give the title compound (7.78 g, 64%).

¹ H NMR (CDCl ₃ ) δ 7.25-7.45 (15H, m), 6.96 (1H, d, J = 16.2 Hz), 6.92 (1H, s), 6.50 (1H, d, J = 9.0 Hz), 5.90 ( 1H, dt, J = 5.4, 9.0 Hz), 4.97 (1H, d, J = 4.7 Hz), 4.15 (2H, br S), 3.64 (2H, d, J = 3.0 Hz), 3.24, 3.46 (2H, ABq, J = 17.3 Hz), 1.85 (1H, broad singlet).

Example 2

Preparation of diphenylmethyl 7-phenylacetamido-3- [3- (E) -hydroxy-1-propen-1-yl] -3- cefe-4-carboxylate (Ib). X = hydroxy

Diphenylmethyl 7-phenylacetamido-3- [3- (E) -hydroxy-1-propen-1-yl] -3-cefe-4-carboxylate (1 g, 1.85 mmol) with acetic anhydride (10 mL) was dissolved in dichloromethane (10 mL), and then to this solution, a catalytic amount of 4-dimethylaminopyridine, acetyl chloride (159 mg, 2.03 mmol) and pyridine (161 mg, 2.03 mmol) was added at 0 ° C., followed by 25 Stir for 2 h 30 min. The reaction mixture was added to a mixture of ethyl acetate (40 mL) and distilled water (30 mL) and the organic layer was separated. The organic layer was washed with distilled water, saturated aqueous NaHCO ₃ , and saturated brine, and then dried over anhydrous magnesium sulfate and evaporated to obtain the title compound (1.03 g, 95%).

¹ H NMR (CDCl ₃ ) δ 7.20-7.45 (15H, m), 6.97 (1H, s), 6.93 (1H, d, J = 16.2 Hz), 6.35 (1H, d, J = 9.0 Hz), 5.89 ( 1H, m), 5.83 (1H, dd, J = 5.0, 9.0 Hz), 4.97 (1H, d, J = 5.0 Hz), 4.54 (1H, d, J = 6.1 Hz), 3.63 (2H, d, J = 4.1 Hz), 3.42, 3.53 (2H, ABq, J = 14.7 Hz), 2.02 (3H, s).

Example 3

Preparation of diphenylmethyl 7-phenylacetamido-3- [3- (E) -chloro-1-propen-1-yl] -3-cefe-4-carboxylate (Ic). X = chloro

Method 1.

Diphenylmethyl 7-phenylacetamido-3- [3- (E) -hydroxy-1-propen-1-yl] -3-cefe-4-carboxylate (1 g, 1.85 mmol) was substituted with carbon tetrachloride ( 5 ml) and acetonitrile (5 ml), and triphenylphosphine (630 mg, 2.4 mmol) was added to the solution and refluxed for 4 hours. The solvent was evaporated off and then purified by silica gel column chromatography (n-hexane / ethyl acetate = 3: 1) to give the title compound (240 mg, 23%).

¹ H NMR (CDCl ₃ ) δ 7.25-7.45 (15H, m), 7.00 (1H, s), 6.88 (1H, d, J = 15.7 Hz), 6.11 (1H, d, J = 9.0 Hz), 5.92 ( 1H, dt, J = 7.0, 15.7 Hz), 5.85 (1H, dd, J = 4.7, 9.0 Hz), 4.99 (1H, d, J = 4.7 Hz), 3.99 (2H, d, J = 7.0 Hz), 3.65 (2H, doublet, J = 6.6 Hz), 3.47, 3.55 (2H, ABq, J = 17.6 Hz).

Method 2.

Pyridine (2.19 g, 27.7 mmol) was added to a solution of phosphorus pentachloride (5.78 g, 27.7 mmol) in dichloromethane (50 mL) at 0 ° C., stirred for 1 hour at the same temperature, and then cooled to −78 ° C. To this solution was added diphenylmethyl 7-phenylacetamino-3- [3- (E) -hydroxy-1-propen-1-yl] -3-cefe-4-carboxylate (10 g, 18.5 mmol). After stirring for 4 hours at -40 ℃ poured into cooling water. The organic layer was separated, washed sequentially with a saturated aqueous NaHCO ₃ solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The solvent was removed by evaporation and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3: 1) to give the title compound (3.78 g, 37%).

Example 4

Preparation of diphenylmethyl 7-amino-3- [3- (E) -acetoxy-1-propen-1-yl] -3-cefe-4-carboxylate hydrochloride (Id). X = acetoxy

Pyridine (538 mg, 6.8 mmol) was added to a solution of phosphorus pentachloride (1.42 g, 6.8 mmol) in dichloromethane (30 mL) and stirred at the same temperature for 30 minutes. Diphenylmethyl 7-phenylacetamino-3- [3- (E) -acetoxy-1-propen-1-yl] -3-cefe-4-carboxylate (1.98 g, 3.4 mmol) in the reaction mixture Was added and stirred at 0 ° C. for 3 hours. The reaction mixture was cooled to -78 ° C, then methanol (1.5 mL) was added and the reaction temperature was slowly raised to -30 ° C for 90 minutes. The reaction mixture was washed sequentially with distilled water, and then dried in vacuo to diphenylmethyl 7-amino-3- [3- (E) -acetoxy-1-propen-1-yl] -3-cef-4-carboxyl. Yield hydrochloride (1.4 g, 82%) was obtained.

Example 5

7- [2- (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetamido] -3- [3- (E) -acetoxy-1-propene-1 -Yl] -3-cepem-4-carboxylic acid trifluoroacetic acid salt (Ie). X = acetoxy

Diphenylmethyl 7-amino-3- [3- (E) -acetoxy-1-propen-1-yl] -3-cepem-4-carboxylate hydrochloride prepared in Example 4 (700 mg, 1.4 mmol) ) Was added bis (trimethylsilylacetamide) to a solution of dichloromethane (20 mL) and stirred at 25 ° C. for 30 minutes. 2- (aminothiazol-4-yl) -2- (Z) -methoxyiminoacetic acid S-2-benzothiazolyl ester (37 mg, 1.5 mmol) was added to the reaction solution and stirred at 25 ° C. for 24 hours. It was. The reaction mixture was concentrated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3: 1) to diphenylmethyl 7- [2- (2-aminothiazol-4-yl) -2- (Z) -Methoxyiminoacetamido] -3- [3- (E) -acetoxy-1-propen-1-yl] -3-cepem-4-carboxylate. The compound was dissolved in dichloromethane (5 mL), trifluoroacetic acid (4 mL) and anisole (2 mL), stirred at 25 ° C. for 2 hours, and added to isopropyl ether to precipitate a solid. The resulting solid was washed three times with isopropyl ether and dried to give the title compound (635 mg, 80%).

¹ H NMR (DMSO-d ₆ ) δ 9.69 (1H, d, J = 7.8 Hz), 6.86 (1H, d, J = 15.4 Hz), 6.79 (1H, s), 6.13 (1H, dt, J = 4.7 , 15.4 Hz), 5.79 (1H, dd, J = 4.9, 7.8 Hz), 5.19 (1H, d, J = 4.9 Hz), 4.65 (2H, d, J = 4.7 Hz), 3.86 (3H, s), 3.60, 3.75 (2H, ABq, J = 17.7 Hz), 2.03 (3H, s).

Example 6

Diphenylmethyl 7- [2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyaminoacetamido] -3- [3- (E) -chloro-1-prop Preparation of phen-1-yl] -3-cepem-4-carboxylate (If). X = chloro

Pyridine (700 mg, 8.85 mmol) was added to a solution of phosphorus pentachloride (1.84 g, 8.85 mmol) in dichloromethane (50 mL) at 0 ° C. and stirred at the same temperature for 2 hours. To the reaction mixture was diphenylmethyl 7-phenylacetamido-3- [3- (E) -hydroxy-1-propen-1-yl] -3-cefe-4-carboxylate (3.3 g, 5.9 mmol). ) Was added and stirred at 0 ° C. for 1 hour 30 minutes. The reaction mixture was cooled to −40 ° C., then methanol (10 mL) was added and the reaction temperature was slowly raised to −30 ° C. for 90 minutes. Distilled water (2 mL) was added to the reaction mixture, the reaction solution was adjusted to pH 3.5 with a saturated aqueous NaHCO ₃ solution, and then extracted with chloroform. The extracted chloroform solution was dried over anhydrous magnesium sulfate, and evaporated to dichloromethanediphenylmethyl 7-amino-3- [3- (E) -acetoxy-1-propen-1-yl] -3-cepem-4- The carboxylate is prepared and then dissolved in dichloromethane (5 ml) again.

Meanwhile, 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetacetic acid hydrochloride (3.14 g, 7.08 mmol) and hydroxybenzotriazole (967 mg, 7.08 mmol ) And bis (trimethylsilyl) acetamide (2.88 g, 14.16 mmol) in 2- (2-tritylaminothiazol-4-yl) -2- (Z)- Diphenylmethyl 7-amino-3- [3- (E) -acetoxy-1-propen-1-yl] -3-cefem prepared above in methoxyiminoacetacetic acid hydroxybenzotriazole ester solution The 4-carboxylate solution was added and stirred at 25 ° C. for 24 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 2: 1) to give the title compound (1.66 g, 27%).

¹ H NMR (CDCl ₃ ) δ 7.15 to 7.50 (25H, m), 7.04 (1H, s), 7.02 (1H, s), 6.93 (1H, d, J = 15.7 Hz), 6.90 (1H, d, J = 8.4 Hz), 6.74 (1H, s), 5.96 (1H, dt, J = 6.9, 15.7 Hz), 5.95 (1H, dd, J = 4.8, 8.4 Hz), 5.20 (1H, d, J = 4.8 Hz ), 4.00 (2H, d, J = 6.9 Hz), 3.48, 3.57 (2H, ABq, J = 17.8 Hz).

Example 7

7β- [2- (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetamido] -3-[(E) -3- (carbamoyloxymethylethylmethylammonium O) -1-propen-1-yl] -3-cepem-4-carboxylate (IX), X = carbamoyloxymethylethylmethylammonio

Diphenylmethyl 7- [2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetamido prepared in Example 6] -3- [3- (E NaI (391 mg, 2.61 mmol) was added all at once to a solution of) -chloro-1-propen-1-yl] -3-cef-4-carboxylate (754 mg, 0.87 mmol) in acetone (15 mL). Stirred at 15 ° C.-25 ° C. for 1 hour. The reaction mixture was concentrated, diluted with ethyl acetate (20 mL), washed sequentially with an aqueous 10% Na ₂ S ₂ O ₃ solution and brine, dried, and evaporated. The residue obtained at this time was dissolved in toluene (10 ml), and a solution obtained by suspending N-methyl-N-ethylglycineamide (202 mg, 1.74 mmol) in toluene (5 ml) was added to this solution, followed by freezer (about -10 ° C) ) For 12 hours. The resulting solid was filtered and washed three times with ethyl ether to give a white solid. This solid was added to dichloromethane (5 mL), trifluoroacetic acid (2 mL), and anisole (2 mL), followed by stirring at 15 ° C to 25 ° C for 2 hours. The reaction mixture was concentrated and isopropyl ether (20 mL) was added to obtain a solid substance. The solid was filtered and washed three times with isopropyl ether, neutralized with 10% aqueous NaHCO ₃ solution, and purified by silica gel column chromatography (CH ₃ CH / H ₂ O = 3: 1) to give the title compound (90 mg, 19%). Got.

¹ H NMR (D ₂ O) δ 7.06 (1H, s), 6.98 (1H, d, J = 15.7 Hz), 5.95 (1H, dt, J = 7.5, 15.7 Hz), 5.87 (1H, d, J = 4.4 Hz), 5.31 (1H, d, J = 4.4 Hz), 4.25 (2H, q, J = 6.9 Hz), 4.11 (2H, d, J = 7.5 Hz), 4.04 (3H, s), 3.70, 3.74 (SH, ABq, J = 16.8 Hz), 3.62, 3.67 (2H, ABq, J = 6.3 Hz), 3.20 (3H, s), 1.42 (3H, t, J = 6.9 Hz).

Example 8

7β- [2- (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetamido] -3-[(E) -3-bis (2-hydroxyethyl) methyl Preparation of Ammonio) -1-propen-1-yl] -3-cepem-4-carboxylate (XI), X = bis (2-hydroxyethyl) methylammonio

7- [2- (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetamido] -3- [3- (E) -acetoxy- prepared in Example 5 1-propen-1-yl] -3-cef-4-carboxylic acid trifluoroacetate (400 mg, 0.7 mmol) and bis (trimethylsilyl) trifluoroacetamide (595 mg, 2.3 mmol) were dichloromethane (15 mL) and refluxed for 1 h. After cooling the reaction solution to 25 ℃, trimethylsilyl iodine (378mg, 1.85mmol) was added and stirred for 1 hour. After concentrating the reaction mixture, it was dissolved in acetonitrile (15 mL) and tetrahydrofuran (2 mL) again, and N-methyldiethanolamine (83 mg, 0.7 mmol) and bis (trimethylsilyl) trifluoroacetamide (595 mg, 2.3 mmol) was added to a solution of acetonitrile (5 mL). The reaction mixture was stirred at 25 ° C. for 3 hours, after which the resulting solid was filtered off and washed with isopropyl ether. The filtered solid was neutralized with an aqueous 10% NaHCO ₃ solution and then purified by silica gel column chromatography (CH ₃ CN / H ₂ O = 2: 1) to give the title compound (67 mg, 18%).

IR (KBr, cm ^-1 ): 3382, 1764, 1606

¹ H NMR (D ₂ O) δ 7.02 (1H, s), 6.93 (1H, d, J = 15.6 Hz), 5.95 (1H, dt, J = 6.6, 15.6 Hz), 5.83 (1H, d, J = 4.5 Hz), 5.27 (1H, d, J = 4.5 Hz), 4.17 (2H, d, J = 6.6 Hz), 4.06 (4H, br s), 3.63, 3.73 (2H, ABq, J = 16.8 Hz), 3.55 (4H, broad singlet, J = 5.1 Hz), 3.13 (3H, s).

Claims (20)

The cefem compound represented by formula (VII) and hydroxypropenyltin compound represented by formula (VIII) are reacted in the presence of a palladium (O) catalyst, a phosphine-based ligand and a halogen catalyst. A method for producing a propenyl cefem compound of I). In formula (I), R ₁ represents hydrogen, phenylacetyl, phenoxyacetyl, thiophenacetyl, furanacetyl, t-butoxyacetyl, trimethylacetyl, t-butoxycarbonyl, 2- (2-aminothia Zol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (5- Amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetyl or 2- (5-amino-1,2,4-thiadiazol-3-yl)- 2- (Z) -fluoromethoxyiminoacetyl. R ₂ is hydrogen, diphenylmethyl, p-methoxybenzyl, or p-nitrobenzyl, and X is hydroxy. In formula (VII), R ₁ is phenylacetyl, phenoxyacetyl, thiophenacetyl, furanacetyl, t-butoxyacetyl, trimethylacetyl, t-butoxycarbonyl, 2- (2-aminothiazole- 4-yl) -2- (Z) -methoxyiminoacetyl, 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (5-amino- 1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetyl or 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -fluoromethoxyiminoacetyl. R ₂ is diphenylmethyl, p-methoxybenzyl, or p-nitrobenzyl. And P is trifluoromethanesulfonyloxy, methinesulfonyloxy, fluorosulfonyloxy, chloro, bromo, or iodo. The palladium catalyst according to claim 1, wherein the palladium catalyst is palladium bis (dibenzylidineacetone), tetrakis (triphenylphosphine) palladium, tris (dibenzylidineacetone) dipalladium, tris (dibenzylidineacetone) dipalladium-chloroform, Or a method for producing a propenyl cefem compound of the general formula (I) characterized by using a catalyst such as palladium acetate. The process for producing the propenyl cefem compound of formula (I) according to claim 2, wherein the amount of catalyst added is 0.005 to 0.5 equivalents. The method of claim 1, wherein the phosphine-based ligand is tri (2-furyl) phosphine, tri (2-thienyl) phosphine, triphenylphosphine, methyldiphenylphosphine, dimethylphenylphosphine, tri (4- Formula (I), characterized in that selected from chlorophenyl) phosphine, triphenylphosphine, methyldiphenylphosphine, dimethylphenylphosphine, tri (4-chlorophenyl) phosphine, triphenyl phosphite Method for preparing a phenylcefe compound. The method for producing propenyl cefem compound of formula (I) according to claim 4, wherein the phosphine-based ligand addition amount is used in an amount of 0.005 to 0.5 equivalents. The method of claim 1, wherein the halogen catalyst is selected from zinc chloride, aluminum chloride, iron chloride, lithium chloride, and bromolithium. The method for producing propenyl cefem-based compound of formula (I) according to claim 6, wherein the amount of halogen catalyst added is 0.5 to 5 equivalents. The reaction solvent according to claim 1, wherein the reaction solvent is one of 1-methyl-2-pyrrolidone, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran, acetonitrile, and chloroform. A process for producing a propenyl cefem compound of formula (I) The process for producing a propenyl cefem compound of formula (I) according to claim 1, wherein the reaction temperature is reacted at 15 to 60 ° C. The process for producing a propenyl cefem compound of formula (I) according to claim 1, wherein the reaction time is 5 to 72 hours. In the propenyl cefem-based compound of formula (I), X is an acetoxy group, wherein X is an acetoxy group, wherein the propenyl cefem-based compound of formula (I) wherein X is a hydroxy group is reacted with an organic solvent. A method for producing a propenyl cefem compound of I). In formula (I), R ₁ represents hydrogen, phenylacetyl, phenoxyacetyl, thiophenacetyl, furanacetyl, t-butoxyacetyl, trimethylacetyl, t-butoxycarbonyl, 2- (2-aminothia Zol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (5- Amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetyl or 2- (5-amino-1,2,4-thiadiazol-3-yl)- 2- (Z) -fluoromethoxyiminoacetyl. R ₂ is hydrogen, diphenylmethyl, p-methoxybenzyl, or p-nitrobenzyl. And X is in the form of a salt with the addition of an acetoxy group and an acid. 12. The method for producing propenyl cefem-based compound of formula (I) according to claim 11, wherein X is acetoxy, wherein one or two or more of acetic anhydride, acetyl chloride and acetyl bromide are used as the organic solvent. X according to claim 11, characterized in that selected from pyridine, 2,6-lutidine, 3,5-lutidine, 2,4,6-collidine, diisopropylethylamine, triethylamine as a salt. A process for producing a propenyl cefem compound of formula (I) wherein is acetoxy. The process for producing a propenyl cefem compound of formula (I) according to claim 11, wherein X is an acetoxy group, wherein the reaction temperature is reacted at 15 to 60 ° C. The process for producing a propenyl cefem compound of formula (I) according to claim 11, wherein X is an acetoxy group, wherein the reaction time is 5 to 72 hours. In the propenyl cefem compound of formula (I), the prophenyl cefem compound of formula (I), wherein X is a hydroxy group, is halogenated in the presence of a base. Method for preparing a phenylcefe compound. In formula (I), R ₁ represents hydrogen, phenylacetyl, phenoxyacetyl, thiophenacetyl, furanacetyl, t-butoxyacetyl, trimethylacetyl, t-butoxycarbonyl, 2- (2-aminothia Zol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetyl, 2- (5- Amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetyl or 2- (5-amino-1,2,4-thiadiazol-3-yl)- 2- (Z) -fluoromethoxyiminoacetyl. R ₂ is hydrogen, diphenylmethyl, p-methoxybenzyl, or p-nitrobenzyl. And X is in the form of a salt with the addition of a chloro group and an acid. 17. The process for producing propenyl cefem-based compound of formula (I) according to claim 16, wherein X is a chloro group, which is selected from pyridine, diisopropylethylamine and triethylamine as bases. 17. The method for producing propenyl cefem-based compound of formula (I) according to claim 16, wherein the halogenation catalyst is selected from triphenylphosphine-carbon tetrachloride, phosphorus trichloride, and phosphorus pentachloride. The process for producing propenyl cefem-based compound of formula (I) according to claim 16, wherein X is a chloro group, wherein the reaction temperature is reacted at 15 to 60 ° C. The process for producing propenyl cefem-based compound of formula (I) according to claim 16, wherein X is a chloro group, wherein the reaction time is 5 to 72 hours.