KR20000073205A - Preparation of cephem derivatives using indium and zinc and process for the production thereof - Google Patents

Abstract

PURPOSE: A cephem derivative using indium and zinc and a preparation method thereof are provided. The cephem derivative is used as an intermediate in manufacturing beta-lactamase inhibiting agent and antibiotics CONSTITUTION: Cephem derivative as represented by formula(I) is prepared by reacting 7-oxo cephalosporin derivative as represented by formula(I'), allyl halide as represented by formula(II), acetylene halide as represented by formula(III), solvent in the presence of indium or zinc. In the formula (I): R1 is allyl derivative or acetylene derivative; R2 is hydrogen, carboxylic acid salt(sodium salt and potassium salt as inorganic salt, alkyl amine salt, aromatic amine salt as organic salt) or carboxy protecting group(4-methoxybenzyl, diphenylmethyl, 4-nitrobenzyl and useful thing as protecting group of molecule in penicillin or cephalosporin compound field); R3 is hydrogen, halogen, hydroxy or acetoxy group; and R4,R5,R6 are each hydrogen, methyl, ethyl, carboxylic acid or ester.

Description

Cefem derivatives using indium and zinc metals and methods for their preparation {PREPARATION OF CEPHEM DERIVATIVES USING INDIUM AND ZINC AND PROCESS FOR THE PRODUCTION THEREOF}

The present invention relates to a cefem derivative represented by the novel general formula (I) and a method for preparing the same, which is used as an important intermediate for preparing beta-lactamase inhibitors and antibiotics.

Wherein R ₁ is an allyl derivative ( ) Or acetylene derivatives ( R ₂ is hydrogen, a carboxylate salt (in salts, inorganic salts and organic salts, inorganic salts are sodium and potassium salts, organic salts are salts of alkylamines and aromatic amines), or carboxyl protecting groups (4-methoxybenzyl, diphenylmethyl, 4-nitrobenzyl and allyl as useful for protecting molecules in penicillin or cephalosporin compounds), and R ₃ represents a hydrogen, halogen, hydroxy or acetoxy group R _4, R ₅ and R ₆ each represent hydrogen, methyl, ethyl, carboxylic acid or ester.

Cefem derivatives represented by general formula (I) of the present invention are the main intermediates that can be easily converted to the compounds represented by general formulas (Ia) and (Ib) as follows. In particular, compounds represented by general formula (Ia) are currently known as beta-lactamase inhibitors.

A general method for preparing a compound represented by formula (Ia) is the Jötig reaction using a 7-oxo cephalosporin derivative represented by formula (I ') and an appropriate lide [J. Med. Chem., 38, 1022, (1995), Tetrahedron Letters, 40, 1281 (1999)] and mono or dihalogen penam and cephalosporin derivatives are metallized at low temperature with Grignard reagents and reacted with aldehydes A reaction for removing the alcohol produced (EP 0321187A1) is used. However, these are not industrial preparation methods because of the difficult reaction conditions such as cryogenic -78 to -60 ° C or anhydrous solvent.

From the 7-oxo cephalosporin derivative represented by the general formula (I ') to react in the presence of indium or zinc metal to prepare a cefe derivative represented by the general formula (I).

The 7-oxo cephalosporin derivative represented by the general formula (I ') is reacted with an allyl halide represented by the general formula (II) or an acetylene halide represented by the general formula (III) in the presence of indium or zinc metal. It is to prepare a cefem derivative represented by the general formula (I).

The present inventors have studied to develop a cefe derivative represented by the general formula (Ia), which is used as a beta-lactamase inhibitor, a cefe derivative represented by the general formula (I) of the present invention used as a starting material thereof, and I learned their manufacturing technology.

That is, in the present invention, as illustrated in the following reaction step, the 7-oxo cephalosporin derivative represented by general formula (I ') is represented by allyl halide or general formula (III) represented by general formula (II). The acetylene halide is reacted in the presence of indium or zinc metal to prepare a cefem derivative represented by the general formula (I) of the present invention.

In the formula (I '), R ₂ is the same as R ₂ in the formula (I), R ₃ is a hydrogen, halogen, hydroxy or acetoxy group, the general formula (II) and formula ( In III), R ₄ , R ₅ and R ₆ each represent hydrogen, methyl, ethyl, carboxylic acid or ester and X represents chloro, bromo or iodine.

In the metal catalyst used in the present invention, indium or zinc may be used alone, respectively, and in the case of using indium, 1.0 to 3.0 equivalents to 1 equivalent of 6-oxophenam derivative represented by General Formula (I ′) are used. Preferably, it is more preferably 1.5 to 2.0 equivalents, and when zinc is used, 1.0 to 3.0 equivalents are preferred, and more preferably, relative to one equivalent of 6-oxophenam derivative represented by the general formula (I '). Is 1.0-2.0 equivalent. The solvent may be used singly or in combination of two or more solvents among water, tetrahydrofuran, acetonitrile, methanol, ethanol and isopropyl alcohol, and preferably tetrahydrofuran alone or a mixed solvent of water and tetrahydrofuran (volume ratio 1: 1) is good. However, when zinc is used, catalytic amounts of ammonium chloride, hydrochloric acid or sulfuric acid may be used, but preferably 1-3 equivalents of ammonium chloride.

The reaction conditions are allyl halide represented by general formula (II) or allyl halide represented by 1-3 equivalents of 7-oxo cephalosporin derivative (1 equivalent) represented by general formula (I '). The halide is reacted at 0 to 100 ° C. for 1 to 4 hours to produce a cefe derivative represented by the general formula (I).

As can be seen from the above detailed description and the following examples, the present invention has several advantages.

1) It is possible to obtain a cefe derivative represented by general formula (I) in high yield,

2) Since the reaction proceeds easily in an aqueous solution as well as an organic solvent, it is more economical than the reaction proceeding in anhydrous conditions, which is a preferable manufacturing method for industrialization.

3) The reaction conditions can be advanced at room temperature, so it is not only economical but also easy to operate.

Finally, the reaction using indium and zinc in the aqueous solution is environmentally friendly, in particular can be said to be a stereoselective reaction.

The present invention can obtain a cefe derivative represented by the general formula (I) in a relatively high yield at room temperature, the typical reaction examples thereof are as follows, but the scope of the present invention is not limited thereto.

Example 1

Preparation of Diphenylmethyl 7 Alpha- (2-propenyl) -7beta-hydroxycephalosporinate

Dissolve 7-oxocephalosporrenate (I ') (176 mg, 0.402 mmol) in 4 ml of solvent (water: tetrahydrofuran = 3: 1), and then allyl bromide (46 μl, 0.604 mmol) and indium (55 mg). , 0.482 mmol) was added thereto, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was passed through a neutral alumina layer, washed with dichloromethane, and the organic layer was washed with saturated NaCl, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The target compound (59%) was obtained by separation with.

Example 2

Preparation of Diphenylmethyl 7 Alpha- (2-propenyl) -7beta-hydroxycephalosporinate

Dissolve 7-oxocephalosporrenate (160 mg, 0.367 mmol), Zn (29 mg, 0.440 mmol), NH ₄ Cl (24 mg, 0.440 mmol) in 3 ml of tetrahydrofuran, and then remove allyl bromide (42 μl, 0.550 mmol) was added thereto, stirred at room temperature for 2 hours, and water was added to the reaction mixture, followed by extraction with ethyl acetate (5ml x 3). The organic layer was washed with saturated brine, dried over anhydrous manganese and concentrated under reduced pressure. The same target compound (55%) was obtained.

¹ H NMR (CDCl ₃ ) δ: 7.35 (m, 10H), 6.92 (s, 1H), 5.87 (m, 1H), 5.24 (d, J = 20 Hz, 1H), 5.20 (d, J = 6 Hz ,?), 5.10 (d, A of ABq, J = 18 Hz, 1H), 4.81 (d, B of ABq, J = 18 Hz, 1H), 4.24 (s, 1H), 3.51 (d, A of ABq , J = 15 Hz, 1H), 3.32 (d, B of ABq, J = 15 Hz), 2.75 (d, J = 9 Hz), 2.01 (s, 3H)

Example 3

Preparation of Diphenylmethyl 7alpha- (1,1-dimethyl-2-propenyl) -7beta-hydroxycephalosporinate

7-Oxocephalosporrenate (I ') (171 mg, 0.391 mmol) was dissolved in water: tetrahydrofuran (3: 1, 4 ml) and then 4-bromo-2-methyl-2-butene (75 μl, 0.586 mmol) and indium (54 mg, 0.469 mmol) were added and stirred at room temperature for 4 hours, after which the reaction mixture was passed through a neutral alumina layer, washed with dichloromethane, and the organic layer was washed with saturated brine, dried over anhydrous forget-me-not, The mixture was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (47%).

Example 4

Preparation of diphenylmethyl 7 alpha- (1,1-dimethyl-2-propenyl) -7beta-hydroxyphenicylate

Dissolve 7-oxophenicylenate (104 mg, 0.274 mmol), Zn (22 mg, 0.329 mmol), NH ₄ Cl (18 mg, 0.329 mmol) in 3 ml of tetrahydrofuran, and then add 4-bromo-2-methyl. After adding 2-butene (53 μl, 0.411 mmol) and stirring at room temperature for 2 hours, water was added to the reaction mixture, followed by extraction with ethyl acetate (5ml x 3). The organic layer was washed with saturated brine, dried over anhydrous manganese and concentrated under reduced pressure. Column chromatography gave the target compound (61%) as in Example 3.

¹ H NMR (CDCl ₃ ) δ: 7.35 (m, 10H), 6.92 (s, 1H), 5.91 (m, 1H), 5.17 (d, J = 17 Hz, 1H), 5.13 (d, J = 10 Hz , 1H), 5.07 (d, A of ABq, J = 13.8 Hz, 1H), 4.82 (d, B of ABq, J = 13.8 Hz, 1H), 4.76 (s, 1H) 3.51 (d, A of ABq, J = 18 Hz, 1H), 3.33 (d, B of ABq, J = 18 Hz, 1H), 2.01 (s, 3H), 1.20 (s, 3H), 1.19 (s, 3H)

Example 5

Preparation of Diphenylmethyl 7 Alpha- (2-methoxycarbonyl-2-propenyl) -7beta-hydroxycephalosporinate

Dissolve 7-oxocephalosporenate (I ') (100 mg, 0.229 mmol) in water: tetrahydrofuran (3: 1, 3 ml), and then methyl-2- (bromomethyl) acrylate (41 μl). , 0.343 mmol) and indium (32 mg, 0.273 mmol) were added and stirred at room temperature for 4 hours. The reaction mixture was passed through a neutral alumina layer, washed with dichloromethane, and the organic layer was washed with saturated brine, dried over anhydrous manganese, and decompressed. Concentrated and separated by column chromatography to give the target compound (73%).

Example 6

Preparation of Diphenylmethyl 7 Alpha- (2-methoxycarbonyl-2-propenyl) -7beta-hydroxycephalosporinate

Dissolve 7-oxocephalosporrenate (I ') (75 mg, 0.171 mmol), Zn (13 mg, 0.205 mmol), NH ₄ Cl (11 mg, 0.205 mmol) in 3 ml of tetrahydrofuran, 2- (bromomethyl) acrylate (31 μl, 0.257 mmol) was added thereto, stirred at room temperature for 4 hours, water was added to the reaction mixture, extracted with ethyl acetate (5ml x 3), and the organic layer was washed with saturated brine and dried over anhydrous manganese. Drying and concentration under reduced pressure gave the target compound (80%) as in Example 5 by column chromatography.

¹ H NMR (CDCl ₃ ) δ: 7.35 (m, 10H), 6.92 (s, 1H), 6.32 (s, 1H), 5.28 (s, 1H), 5.03 (d, A of ABq, J = 15 Hz, 1H), 4.81 (s, 1H), 4.76 (d, B of ABq, J = 15 Hz, 1H), 3.79 (s, 3H), 3.51 (d, A of ABq, J = 18 Hz, 1H), 3.34 (d, B of ABq, J = 18 Hz, 1H), 2.01 (s, 3H)

Example 7

Preparation of diphenylmethyl 7 alpha- (1-methyl-2-propenyl) -7beta-hydroxycephalosporinate

Dissolve 7-oxocephalosporrenate (I ') (107 mg, 0.245 mmol) in water: tetrahydrofuran (3: 1, 3 ml), and then crotybromide (38 μl, 0.369 mmol) and indium (34) mg, 0.295 mmol) were added and stirred at room temperature for 3 hours, after which the reaction mixture was passed through a neutral alumina layer and washed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous forget-me-not, concentrated under reduced pressure and separated by column chromatography. The target compound (68%, 1.5: 1 ratio isomer) was obtained.

Example 8

Preparation of diphenylmethyl 7 alpha- (1-methyl-2-propenyl) -7beta-hydroxycephalosporinate

7-oxocephalosporenate (I ') (106 mg, 0.242 mmol), Zn (19 mg, 0.290 mmol), NH ₄ Cl (16 mg, 0.290 mmol) was dissolved in 3 ml of tetrahydrofuran and then crotyl After adding bromide (37 µl, 0.363 mmol) and stirring at room temperature for 4 hours, water was added to the reaction, followed by extraction with ethyl acetate (5ml x 3). The organic layer was washed with saturated brine, dried over anhydrous forget-me-not and concentrated under reduced pressure. The target compound (51%, isomer of 1.3: 1 ratio) like Example 7 was obtained.

¹ H NMR (CDCl ₃ ) δ: 7.35 (m, 10H), 6.92 (s, 1H), 5.87 (m, 1H), 5.20 (m, 1H), 5.07 (d, A of ABq, J = 15 Hz, 1H), 4.80 ((d, B of ABq, J = 15 Hz, 1H), 4.76 (s, 1H), 3.53 (d, A of ABq, J = 18 Hz, 1H), 3.34 (d, B of ABq , J = 18 Hz, 1H), 2.78 (m, 1H), 2.01 (s, 3H), 1.26 (d, J = 4 Hz, 3H)

Example 9

Preparation of Diphenylmethyl 7 Alpha- (1-phenyl-2-propenyl) -7beta-hydroxycephalosporinate

Dissolve 7-oxocephalosporrenate (I ') (120 mg, 0.274 mmol) in water: tetrahydrofuran (3: 1, 3 ml), and then cinnamilbromide (81 mg, 0.411 mmol) and indium (38) mg, 0.329 mmol), and the mixture was stirred at room temperature for 3 hours, and then the reaction mixture was passed through a neutral alumina layer, washed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous forget-me-not, concentrated under reduced pressure, and separated by column chromatography. The target compound (57%, isomer of 30: 1 ratio) was obtained.

Example 10

Preparation of Diphenylmethyl 7 Alpha- (1-phenyl-2-propenyl) -7beta-hydroxycephalosporinate

7-oxocephalosporenate (111 mg, 0.255 mmol), Zn (20 mg, 0.299 mmol), NH ₄ Cl (16 mg, 0.299 mmol) was dissolved in 3 ml of tetrahydrofuran and then crotylbromide (75 mg , 0.382 mmol) was added thereto, and the mixture was stirred at room temperature for 4 hours. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate (5 ml x 3). The organic layer was washed with saturated brine, dried over anhydrous manganese, and concentrated under reduced pressure. The same target compound (61%, 12: 1 ratio isomers) was obtained.

¹ H NMR (CDCl ₃ ) δ: 7.35 (m, 15H), 6.92 (s, 1H), 6.20 (m, 1H), 5.24 (s, 2H), 5.03 (d, A of ABq, J = 13.7 Hz, 1H), 4.80 (d, B of ABq, J = 13.7 Hz, 1H), 3.89 (d, J = 8 Hz, 1H), 3.47 (d, A of ABq, J = 18 Hz, 1H), 3.32 (d , B of ABq, J = 18 Hz, 1H), 2.01 (s, 3H)

Example 11

Preparation of Diphenylmethyl 7alpha-propynyl-7beta-hydroxycephalosporinate

Dissolve 7-oxocephalosporrenate (I ') (103 mg, 0.235 mmol) in water: tetrahydrofuran (3: 1, 3 ml), and then propazylbromide (39 μl, 0.353 mmol) and indium (32) mg, 0.282 mmol) and the mixture was stirred at room temperature for 3 hours, and then the reaction mixture was passed through a neutral alumina layer, washed with dichloromethane, the organic layer was washed with saturated brine, dried over anhydrous manganese, concentrated under reduced pressure, and separated by column chromatography. The target compound (42%, acetylene: allene = 6: 1) was obtained.

Example 12

Preparation of Diphenylmethyl 7alpha-propynyl-7beta-hydroxycephalosporinate

Dissolve 7-oxocephalosporrenate (109 mg, 0.249 mmol), Zn (20 mg, 0.306 mmol), NH ₄ Cl (16 mg, 0.299 mmol) in 3 ml of tetrahydrofuran, and then propazilbromide (42 μl). , 0.373 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate (5 ml x 3). The organic layer was washed with saturated brine, dried over anhydrous forget-me-not and concentrated under reduced pressure. The target compound (55%, isomer ratio = 40: 1) was obtained.

¹ H NMR (CDCl ₃ ) δ: 7.35 (m, 10H), 6.92 (s, 1H), 5.09 (d, A of ABq, J = 13.9 Hz, 1H), 4.97 (s, 1H), 4.84 (d, B of ABq, J = 13.9 Hz, 1H), 3.53 (d, A of ABq, J = 18 Hz, 1H), 3.36 (d, B of ABq, J = 18 Hz, 1H), 2.90 (m, 2H) , 2.90 (s, 3H), 2.01 (s, 3H), 1.98 (s, 1H)

Example 13

Preparation of diphenylmethyl 7 alpha- (2-butynyl) -7beta-hydroxycephalosporinate

Dissolve 7-oxocephalosporenate (I ') (102 mg, 0.233 mmol) in water: tetrahydrofuran (3: 1, 3 ml) and then 1-bromo-2-butyne (31 μl, 0.349 mmol) ) And indium (32 mg, 0.282 mmol) were added and stirred at room temperature for 3 hours. The reaction mixture was passed through a neutral alumina layer, washed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous manganese, and concentrated under reduced pressure. Chromatography gave the target compound (69%).

Example 14

Preparation of diphenylmethyl 7 alpha- (2-butynyl) -7beta-hydroxycephalosporinate

Dissolve 7-oxocephalosporrenate (I ') (107 mg, 0.245 mmol), Zn (20 mg, 0.306 mmol), NH ₄ Cl (16 mg, 0.299 mmol) in 3 ml of tetrahydrofuran, and then After adding bromo-2-butyne (32 µl, 0.367 mmol) and stirring at room temperature for 4 hours, water was added to the reaction, followed by extraction with ethyl acetate (5ml x 3). The organic layer was washed with saturated brine, dried over anhydrous manganese, and decompressed. Concentration was carried out by column chromatography to obtain the target compound (55%) as in Example 13.

¹ H NMR (CDCl ₃ ) δ: 7.35 (m, 10H), 6.92 (s, 1H), 5.09 (d, A of ABq, J = 13.7 Hz, 1H), 4.97 (m, 3H), 4.82 (d, B of ABq, J = 13.7 Hz, 1H), 3.52 (d, A of ABq, J = 18 Hz, 1H), 3.36 (d, B of ABq, J = 18 Hz, 1H), 2.01 (s, 3H) , 1.89 (m, 3 H)

As the preparation of the penam derivative represented by the novel general formula (I), it will be used as an important intermediate for the preparation of beta-lactamase inhibitors and antibiotics.

Claims (6)

Sepem derivatives represented by general formula (I). Wherein R ₁ is an allyl derivative ( ) Or acetylene derivatives ( R ₂ is hydrogen, a carboxylate (the salt is divided into an inorganic salt and an organic salt, the inorganic salt is a sodium and potassium salt, the organic salt refers to a salt of an alkylamine, an aromatic amine), or a carboxy protecting group (4-methoxybenzyl, diphenylmethyl, 4-nitrobenzyl and allyl as useful for protecting molecules in penicillin or cephalosporin compounds), and R ₃ represents a hydrogen, halogen, hydroxy or acetoxy group R _4, R ₅ and R ₆ each represent hydrogen, methyl, ethyl, carboxylic acid or ester. A 7-oxo cephalosporin derivative represented by formula (I ') is reacted with an allyl halide represented by formula (II) or an acetylene halide represented by formula (III) together with a solvent in the presence of indium or zinc metal. Method for producing a cefem derivative represented by the general formula (I) characterized in that. In the formula (I), R ₁ is an allyl derivative ( ) Or acetylene derivatives ( R ₂ is hydrogen, a carboxylate salt (in salts, inorganic salts and organic salts, inorganic salts are sodium and potassium salts, organic salts are salts of alkylamines and aromatic amines), or carboxyl protecting groups (Which is useful as a protecting group for molecules in the field of penicillin or cephalosporin compounds such as 4-methoxybenzyl, diphenylmethyl, 4-nitrobenzyl and allyl, for example) and R ₃ represents hydrogen, halogen, hydroxy or ace In the formula (I '), R ₂ is the same as R ₂ in formula (I), and in formula (II) and formula (III), R ₄ , R ₅ and R ₆ represents hydrogen, methyl, ethyl, carboxylic acid or ester, respectively, and X represents chloro, bromo or iodine. 7. The 7-oxo cephalosporin derivative represented by the general formula (I '): allyl halide represented by the general formula (II) or acetylene halide represented by the general formula (III): of indium or zinc metal A method for producing a cefe derivative represented by the general formula (I), wherein the addition amount is reacted at an equivalent ratio of 1: 1 to 3: 1. The method for producing a cefe derivative represented by the general formula (I) according to claim 2, wherein when zinc metal is used as a catalyst, 1-3 equivalents of ammonium chloride are used. The method of claim 2, wherein the solvent is a water, tetrahydrofuran, acetonitrile, methanol, ethanol, isopropyl alcohol to be used alone or two or more mixed solvents of the preparation of the cefe derivative represented by the general formula (I) Way. The method for producing a cefe derivative represented by the general formula (I) according to claim 2, wherein the reaction is carried out at 0 to 100 ° C for 1 to 4 hours.