WO2001098309A1

WO2001098309A1 - Process for the preparation of cephem compounds

Info

Publication number: WO2001098309A1
Application number: PCT/JP2001/005163
Authority: WO
Inventors: Katsuhiko Shinozaki; Masaru Hayashi; Masato Kitayama
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 2000-06-21
Filing date: 2001-06-15
Publication date: 2001-12-27
Also published as: AU2001274541A1; AR028744A1; JP2004149412A

Abstract

A novel industrial process for preparing 7-[2-(2- amino- thiazol-4-yl)-2-lower-alkoxycarbonylmethoxyiminoacetamido] 3-cephem compounds of the general formula (I) or salts thereof (wherein R1 is an organic group; R2 is carboxyl or protected carboxyl; and R3 is lower alkyl), characterized by reacting a 7-amino-3-cephem compound of the general formula (II), a reactive derivative thereof obtained by modifying the amino group, or a salt thereof with a compound of the general formula (III) or a salt thereof (wherein X is halogeno).

Description

Description Method for producing cefm compound

The present invention relates to a method for producing 7- [2- (2-aminothiazol-4-yl) -12-lower alkoxycarbonylmethoxyiminoacetamide] -3-3-cebum compound or a salt thereof.

More specifically, the present invention provides a compound represented by the following general formula: 7- [2_ (2-amino'thiazo-l-yl-4_yl) _2-lower alkoxycarbonyl methoxyiminoacetamide] -3-cepum compound or Of the salt thereof from the corresponding 7-amino-3-cebum compound or a salt thereof and 2- (2-aminothiazo-1-yl-4-yl) -12-lower alkoxycarbonylmethoxymethoxyminacetyl halide or a salt thereof It relates to a novel production method with high yield.

(I)

(Wherein R ¹ represents an organic group, R ² represents a carboxy group or a protected carboxy group, and R ³ represents a lower alkyl group). That is, an object of the present invention is to provide 7- [2- (2-aminothiazolyl-14-yl) 1-2-lower alkoxycarbonylmethoxyiminoacetate. A.Mid] It is an object of the present invention to provide a novel industrial production method of 1-3-cepum compound (I) or a salt thereof. ■

Disclosure of the invention

Conventionally, 7- [2- (2-aminothiazole-41-yl) -12-low alkoxycarbonylmethoxyiminoacetamide] —3-cephem compound (I) can be prepared, for example, by the following method. Had been manufactured. Method 1:

Method 2:

However, for Method 1, there are two extra steps:

However, introduction of an amino-protecting group and elimination of an amino-protecting group are required, so that the total yield of the desired cefm compound is not so high.

For Method 2, expensive cefm compounds must be used initially and therefore are very expensive to obtain the final compounds. In addition, since this method also generates an anti-isomer in the oxime moiety, an additional step of separating the anti-isomer is required.

The inventors of the present invention have proposed various processes for the industrial production of 7-C2- (2-aminothiazol-4-yl) -12-alkoxycarbonylmethoxyiminoacetamide] -13-cephum compounds. The method was studied diligently, and as a result, 2- (2-aminothiazo-l- 4-yl) -l-l-alkoxycarbonylmethyoxy misoacetyl halide or its acid addition salt was separated in a stable form. We succeeded in completing the new manufacturing method of the present invention.

The production method of the present invention has the following formula:

(Wherein, and R ₂ have the same meanings as described above), and a reactive derivative thereof or a salt thereof at the 7-amino 3-cephalum compound or amino group,

(Wherein, R ³ and X have the same meanings as described above) 2- (2-aminothiazole-4-yl) 12-lower alkoxycarbonylmethoxyiminoacetyl halide or a salt thereof And the formula:

(Wherein, RR ² and R ³ have the same meanings as described above), respectively. 7 1 [2- (2-aminothiazolyl-141-yl) 1 2 -lower alkoxycarbonylmethoxyiminoacetamide) 1 3— It is characterized by obtaining a cefm compound.

Suitable salts of the raw material compound (II) and the target compound (I) include common salts used in the field of cephalosporin and venicillin, and salts with inorganic bases, for example, sodium Salts, alkali metal salts such as potassium salts, for example, alkaline earth metal salts such as calcium salts and magnesium salts; salts with organic bases, for example, triethylamine salts, pyridine salts, picoline salts, Organic amine salts such as ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like; for example, hydrochloride, hydrobromide, Inorganic acid addition salts such as sulfates and phosphates; for example, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonic acid Salts, salts with bases or acid addition salts such as organic carboxylic acid addition salts or organic sulfonic acid addition salts such as ρ-toluenesulfonate and the like. Suitable salts of the raw material compound (III) are described above. And the acid addition salts exemplified above.

The production method of the present invention is represented by the following reaction formula.

(Π)-■

Or in the amino group

Its reactive derivative or

The salt

Or its salt

(Where RR ² and R ³ each have the same meaning as before).

Starting compound 2 _ (2-aminothiazolyl 4-yl) 12-lower alkoxycarbonylmethoxyiminoacetyl halide (III) contains novel compounds, which are represented by the following reaction formulas. It can be manufactured by a method.

Or its salt or its salt

(Wherein, R ³ and X each have the same meaning as before).

7- [2- (2-Aminothiazol) obtained by removing R ³ of the target compound (I) obtained by the production method of the present invention. 1-yl) _ 2 -Carboxymethoxyiminoacetamide]-3-cefm compound has a strong antibacterial effect, and inhibits the growth of a wide range of pathogenic bacteria including Gram-positive and Gram-negative bacteria. Useful as

Preferred examples and explanations of the definitions of RR ² and) ^-3 in the above description of this specification are described in detail below.

As used herein, "lower", unless indicated otherwise, shall mean a group having 1 to 6, preferably 1 to 4 carbon atoms.

Suitable "lower alkyl groups" include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl and hexyl.

Suitable "protected carboxy groups" include the commonly used esterified carboxy groups at the 3- or 4-position in penicillin or cephalosporin compounds.

Suitable "ester moieties" of the "esterified carboxy group" include, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary ester Lower alkyl esters such as lower-pentyl ester and hexyl ester; lower alkenyl esters such as vinyl ester and aryl ester; lower alkynyl esters such as ethynyl ester and propynyl ester; for example, methoxymethyl ester, ethoxymethyl ester and isopropoxymethyl Lower alkoxy (lower) alkyl esters such as esters, 1-methoxyl ester, 1-ethoxyl ester, etc., for example, methylthiomethyl ester, ethylthio Methyl ester Lower alkylthio (lower) alkyl esters such as ethylthioethyl ester, isopropylthiomethyl ester, etc., and mono- (or di- or tri-ethyl) esters such as 2-iodoethyl ester, 2,2,2_trichloroethyl ester and the like. I) Halo (lower) alkyl: C-ster, for example, acetomethyl ester, propionyloxymethyl ester, ptyryloxymethyl ester, isobutyryloxymethyl ester, noryloxymethyl ester, vivaloyloxy Lower alkanoyloxy (lower) alkyl esters such as methyl ester, hexanoyloxymethyl ester, 2-acetoxyl ester, 2-propionyloxetyl ester, 1-acetooxypropyl ester

For example, lower alkanesulfonyl (lower) alkyl esters such as methyl mesyl ester and 2-mesyl ethyl ester, for example, benzyl ester, 4-methoxybenzinole estenole, 4-nitropentinole estenole, fenethino lenestenole Suitable substituents such as benzhydryl ester, trityl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy_3,5-ditert-butylbenzyl ester Al (lower) alkyl esters which may have one or more substituents such as mono (or di or tri) phenyl (lower) alkyl esters which may have one or more, for example, phenyl esters, Ril ester, tertiary butyl phenyl ester, xylyl ester Aryl esters which may have one or more suitable substituents such as ter, mesityl ester, cumenyl ester, salicyl ester, etc .; heterocyclic esters such as phthalidyl ester; for example, trimethylsilyl, triethylsilyl, Tri-substituted silyls such as tri (lower) alkylsilyls such as isopropyl dimethylsilyl, tertiary butyldimethylsilyl and diisopropylmethylsilyl; trisylsilyls such as triphenyl, eg triben Trial (lower) alkylsilyl such as zirsilyl and the like. Suitable "organic groups" include those commonly used in the 3-position of cephalosporin compounds, such as aliphatic, aromatic and heterocyclic groups such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, tertiary Lower alkyl groups such as tert-butyl, pentyl, neopentyl, tertiary pentyl, and hexyl;

Lower, for example, vinyl, 1-propenyl, aryl, 1-methylaryl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4 pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl Alkenyl group;

Aryl groups such as, for example, phenyl, tolyl, xylyl, cumenyl, naphthyl;

For example, heterocyclic thiomethyl groups such as furylthiomethyl, thiazolylthiomethyl, thiadiazolylthiomethyl, tetrazolylthiomethyl, etc .; Examples thereof include a heterocyclic methyl group having a quaternary nitrogen atom such as a 1-lower alkylpyrrolidiniomethyl such as -methyl-12-rubamoyloxymethylpyrrolidiniomethyl.

Suitable "halogen" includes chlorine, bromine, iodine and the like. Preferred embodiments of R ^1. R ² and R ³ are as follows. R ¹ is, for example, a lower alkenyl group such as vinyl; or a heterocyclic thiomethyl group, preferably a 5-membered aromatic heterocyclic ring containing one io atom and one or two nitrogen atoms such as 1,2,4-thiadiazolyl. Group;

R ² is a carboxy group or an esterified carboxy group, preferably a tri (lower) alkylsilyloxycarbonyl group, preferably a tri (-) alkyl group such as trimethylsilyloxycarbonyl. Kirsilyloxycarbonyl group;

R ³ is a lower alkyl group, preferably Mel one C ₄ alkyl group such as methyl.

The method for producing the target compound (I) of the present invention will be described in detail below. Manufacturing method 1

The compound (I) or a salt thereof can be obtained by converting the compound (II) or a reactive derivative thereof at the amino group or a salt thereof to a 2- (2-aminothiazolyl-1-4-yl) -12-alkoxycarbonyl It can be produced by reacting with toximino acetyl halide (III) or a salt thereof.

Suitable reactive derivatives at the amino group of compound (II) include compounds (II) and silyl compounds such as bis (trimethylsilyl) acetamide and mono (trimethylsilyl) acetamide. Examples include silyl derivatives generated by the reaction.

Suitable salts of the compound (II) include salts as exemplified for the compound (I).

The reaction is usually carried out with common solvents such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine. The reaction can be carried out in any other organic solvent that does not adversely affect the reaction. These conventional solvents may be used as a mixture with water.

The reaction involves inorganic or organic bases such as alkali metal bicarbonates, tri (lower) alkylamines, pyridines, N- (lower) alkylmorpholines, N, N-di (lower) alkylbenzylamines, etc. It may be done with or without it.

The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or at room temperature. Is performed.

In this reaction, the case where the carboxy protecting group of R ² is eliminated during the reaction or during the post-treatment of this production method is also included in the scope.

The compound (III) or a salt thereof used in this reaction is isolated in a stable form for the first time by the inventors of the present invention, whereby the reaction proceeds in high yield, and the step of recovering by-products is reduced. It is very convenient because it is not needed, and the amount of reactants can be easily controlled under the best conditions.

A method for producing the starting material 2- (2-aminothiazoyl-4-yl) 1-2-lower alkoxycarbonylmethoxyiminoacetyl halide (III) or a salt thereof will be described below.

Starting compound (III) or a salt thereof can be produced by reacting compound (Ilia) with a halogenating agent.

A preferred salt of compound (III) is a salt with a base, and a preferred salt of compound (Ilia) is a salt with a base or an acid addition salt as exemplified for compound (I).

Compound (Ilia) can be produced by the method described in the production method described later or by a conventional method.

Suitable halogenating agents used in this reaction include conventional ones capable of converting carboxylic acids such as phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, and phosgene into acid halides.

The reaction is usually carried out in a conventional solvent such as methylene chloride, chloroform, and the like, but the reaction can be carried out in any other solvent that does not adversely influence the reaction.

The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or at room temperature.

Acid addition salts, such as the hydrochloride salt of compound (III), can be isolated in stable crystalline form and are particularly preferred for the reaction of the present invention. Hereinafter, the present invention will be described with reference to examples.

Example 1

7-amino-3-vinyl-13-cef-14-carboxylate Benzhydryl hydrochloride (4g) in dichloromethane solution (20ml) in formic acid (1.2m1) and methanesulfonic acid (1.34g) And react for 30 minutes. Add cold water (4 Oml), stir at 0-5 ° C, adjust the pH to 8.5 with cold water, and let it stand still. Separate, remove dichloromethane and adjust the aqueous layer to pH 4.5 with dilute hydrochloric acid, then dry in vacuo in the presence of diphosphorus pentoxide to obtain 7-amino-3-vinyl-3-cefumu-4-carboxylic acid (syn isomer) ) (2.05 g) (97% yield).

IR (Nudiol): 2620, 2050, 1810, 1790, 1640, 1610 cm- ¹ NMR (MSO-d (5): 3.51, 3.82 (2H, ABq, J = 18 Hz), 4.77 (1H, d, J = 5Hz), 5.01 (lH, d, J = 5Hz), 5.26 (1H, d, J = llHz), 5.54 (1H, d, J = 18Hz), 6.88 (1H, dd, J = 18Hz, 11Hz)

Example 2

2-Phosphorus pentachloride (58.Og) was added to a dichloromethane (350 ml) solution of 2- (2-aminothiazoyl 4-yl) -1-2-methoxycarbonylmethoxyaminoacetic acid (syn isomer) (68.8 g). Continue stirring at 25-30 ° C for 60 minutes. Diisopropyl ether (1240πι1) is added to the reaction solution over 60 minutes. The resulting precipitate is filtered, washed with diisopropylpropyl ether, and then dried under vacuum in the presence of diphosphorus pentoxide to give 2- (2-aminothiazole_4-yl) -12-methoxycarbonylmethoxyamino acetyl. Chloride hydrochloride (syn isomer) (83.4 g) is obtained.

I R (Nudiol): 3375, 3200, 1780, 1750, 1650, 1630, 1600,

1580 cm- ¹

mp: 91 ° C

Example 3 7-Amino_3-vinyl-1-3-fuemu-4-carboxylic acid (30. Og) and 1 [, N-bistrimethylsilylurea (54.2 g) are suspended in dichloromethane (450 ml) for 90 minutes. Reflux to silylate and dissolve. Cool the reaction mixture to -20 ° C, add 2- (2-aminothiazole-41-yl)-2-methoxycarbonylmethoxyamino acetyl chloride hydrochloride (cin isomer) and react for 30 minutes I do. Cold water (450 ml) is added to the reaction solution, and the solution is dropped with a 10% aqueous sodium carbonate solution until the pH becomes 6 to 7 to dissolve the precipitated crystals. The dichloromethane layer was separated and removed, and the aqueous layer was adjusted to pH 3.0 with diluted hydrochloric acid, and then stirred at 0 to 5 ° C for 30 minutes. The precipitate is collected by filtration, washed with cold water, and then dried under vacuum in the presence of diphosphorus pentoxide to give 7- [2- (2-aminothiazo-l- 4-yl) -12-methoxy-l-ponylmethoxime. Noacetamide] 1-3-vinyl-3-serum-IV (55.55 g) was obtained (yield 89.6%).

IR (Nudiol): 3575, 3250, 1760, 1730, 1660, 1550 cm " ¹ NMR (DMS0-d6, <5): 3.57,3.85 (2H, ABq, J = 18Hz), 3.68 (3H, s),

4.69 (2H, s), 5.20 (1H, d, J = 5Hz), 5.32 (1H, d, J = llHz), 5.60 (1H, d, J = 18Hz), 5.79 (1H, dd, J = 5, 8Hz), 6.80 (lH, s), 6.92 (1H, dd, J = ll, 18Hz), 7.27 (2H, s), 9.63 (1H, d, J = 8Hz)

Example 4

7- [2- (2-aminothiazoyl 4-yl) 1-2-methoxycarbonyl methoxyminoacetamide] 1-3-vinyl-13-sephemu 4 One-strength rubonic acid (35.4g) in water ( 400ml) and stirred at ~ 5 ° C. Dissolve crystals by adjusting the pH to 7 using a 10% aqueous sodium carbonate solution. Add methanol (150 ml) and cool to -12 ° C. 24 Stir for 5 minutes at pH 14 using aqueous sodium hydroxide solution. After the reaction, adjust the pH to 5 using concentrated hydrochloric acid. Add water (450ml) and adjust the pH to 2.2 using dilute hydrochloric acid while stirring at 20 ° C. After stirring at 0-5 ° C The precipitate is filtered, washed with water, and then dried under vacuum in the presence of diphosphorus pentoxide.

, 7— [2- (2-aminothiazole-1-yl) _.2 _carboxymeximinoiminoacetamide] 13 _vinyl-3- cefm-14 4 rubonic acid (syn isomer) (32.9 g) (95.9% yield).

I R: 3450, 3275, 3180, 1780, 1660, 1620, 1540 cm

NMR (DMS0-d6, δ: 3.57, 3.85 (2Η, dd, J = 18Hz), 4.59 (2H, s), 5.21 (1H, d, J = 5Hz), 5.32 (1H, d, J = llHz), 5.60 (1H, d, J = 17Hz), 5.81 (1H, dd, J = 5, 8Hz), 6.81 ((lH, s), 6.92 (1H, dd, J = ll, 17Hz) 7.27

(2H, s), 9.56 (lH, d, 8Hz))

Example 5 '

7-Amino 3-vinyl-3-sefum 4-Hensyl benzoyl hydryl hydrochloride (50 Og) is suspended in acetone (750 ml) and stirred at 0-5 ° C. 2- (2-Aminothiazole_4-yl) -1-2-Methoxycarbonyl methoxyminosetylc mouth lido hydrochloride (syn isomer) (73.24 g) is added, and the mixture is added with a 20% aqueous sodium carbonate solution. Maintain pH 6-7. After the reaction is completed, cold water (200 ml) is added, and acetone in the reaction solution is distilled off under reduced pressure. Add water (300ml) to the distillate and stir at 0-5 ° C for 1 hour. The precipitate was washed with cold water in consideration of the precipitate, and then dried in vacuo over diphosphorus pentoxide to give 7- [2- (2-aminothiazol-4-yl) -2-methoxycarbonylmethoxyiminoacetamide. ] Benzhydryl (70 · Og) (70 · Og) (1-vinyl-3-carboxy-4) is obtained (94.7%).

IR (Nujor): 1780, 1750, 1730, 1710, 1670, 1620, 1530 cm " ¹

NMR (DMS 0-d6, (5): 3.62, 3.91 (2H, ABq, J = 18Hz), 3.68 (3H, s), 4.69 (2H, s), 5.28 (1H, d, J = 5Hz), 5.32 (1H, d, J = llHz), 5.6 6 (lH, d, J = 18Hz), 5.90 (1H, dd, J = 5, 8Hz), 6.75 (1H, dd, J = 11, 18Hz), 6.81 (lH, s), 6.95 (lH, s) , 7.27-7.50 (12H, m), 9.67 (1H, d, J = 8Hz)

Example 6

7- [2- (2-aminothiazol-1-yl) -1-2-methoxycarbonylmethoxyiminoacetamide] _3-vinyl-1-3-cephem_4 Benzhydryl rubonate (48. Og) is suspended in anisol (150 ml) and stirred at -20 ° C. Boron trifluoride etherate (37.6g) is added and reacted. The reaction-terminated liquid is poured into water (450 ml), and the pH is adjusted to 7 using a 24% aqueous sodium hydroxide solution. The reaction solution is separated, and the aqueous layer is adjusted to pH 3 with dilute hydrochloric acid and stirred at 0 to 5 ° C for 1 hour. The precipitate is collected by filtration, washed with water, and then dried under vacuum in the presence of diphosphorus pentoxide to give 7- [2- (2-aminothiazole-4-yl) -12-methoxycarbonylmethoxyaminoacetamide]. 1-vinyl-13-cef-14-carboxylic acid (33.6 g) (95% yield) was obtained.

IR (nujol): 3575, 3250, 1760, 1730, 1660, 1550 cm ' ¹ NMR (DMS0-d6, <5): 3.57, 3.85 (2H, dd, J = 18Hz), 3.68 (3H, s), 4.69 (2H, s), 5.20 (1H, d, J = 5, Hz), 5.32 (1H, d, J = llHz), 5.60 (1H, d, J = 18Hz), 5.79 (lH, dd, J = 5, 8Hz), 6.80 (1H, s), 6.92 (1H, dd, J = ll, 18Hz), 7.27 (2H, s), 9.63 (1H, d, J = 8Hz)

Claims

Claim formula

(Wherein, R ¹ represents an organic group, and R ² represents a carboxy group or a protected carboxy group)

A 7-amino-3-septum compound represented by the formula or a reactive derivative thereof or a salt thereof at the amino group is represented by the formula:

Wherein R ³ is a lower alkyl group and X represents a halogen, or a salt thereof.

(Where RR ² and R ³ have the same meaning as before)

7- [2- (2-aminothiazol-4-yl) -12-lower alkoxycarbonylmethoxyiminoacetamide] represented by the following formula: 3-Cephem compound or a salt thereof.

2. Expression

(Wherein, R ³ represents a lower alkyl group and X represents a halogen) or a salt thereof.