KR20040064270A - A process for the preparation of cephalosporins side chains - Google Patents

Abstract

Processes for preparing salts of carboxylic acids of Formula 1 with organic nitrogen bases useful for preparing cephalosporin side chains:

<Formula 1>

Wherein Q and R have the meaning as defined in the specification.

Description

A process for the preparation of cephalosporins side chains}

Carboxylic acids of formula 1 are important syntons for the preparation of third and fourth generation cephalosporins with broad activity and high titers against gram-positive and gram-negative microorganisms.

Efficient methods for preparing such compounds known to date include chemical formulas by the salification of hydroxy-imino groups with sodium hydride (US Pat. No. 4,935,508) or potassium tert -butoxide (US Pat. No. 5,637,721). Derivatization of the ester of 4 and subsequent reaction with a halide of formula 5 to obtain a derivative of formula 6 (Scheme 1). The reaction yield usually does not exceed 80%. The compound of formula 6 must be converted to the acid of formula 1 by carrying out a hydrolysis reaction, which in turn must be purified as a solvate with an organic amide. The total yield usually does not exceed 60%, and the preparation method is not suitable from the viewpoint of productivity since many steps are required to properly obtain the pure acid of formula 1 for subsequent use.

In the compound of Scheme 1, Q and R are as defined above and R 'is an alkyl moiety.

As reported by Bucourt et al. In Tetrahedron 34, 2233 (1978), the reaction of an ester of formula (4) with a halide of formula (5) in the presence of a tertiary amine, on the one hand, is characterized by the N-functionalized compound of formula (7) or To yield an N, O-bis-functionalized compound of formula 8 wherein Q, R and R 'are as defined above.

Currently, by reacting a carboxylic acid of formula (2) with a halide of formula (5) in the presence of an organic nitrogen base and in an industrially inert organic solvent, the salts of the organic nitrogen base with the compound of formula (1), in high yield and purity, in a single step It has been found that it can be obtained.

The salts can be usefully used for the preparation of intermediates, which can be used in isolation or in situ for the preparation of third and fourth generation cephalosporins. Indeed, since these salts have high solubility in organic solvents commonly used in the preparation, such as methylene chloride, ethyl acetate and tetrahydrofuran, these salts can impart faster reaction rates, thus providing It is advantageous in terms of yield and purity.

The present invention relates to a process for the preparation of salts of carboxylic acids of formula (1) with organic nitrogen bases:

Wherein Q is nitrogen, hydrocarbyl (CH) or chlorocarbyl (CCl) residues;

R is trityl, benzhydryl or para-methoxy benzyl.

The preparation process starts from the compound of formula 2 and provides the compound of formula 1 in high yield and purity:

In formula, Q is as defined above.

Salts of organic nitrogen bases with acids of formula (1) can be readily converted to the corresponding free acids (formula 1) or solvates thereof, or compounds of formula (3), which are Cefdinir or Cefdin. For the preparation of third and fourth generation cephalosporanic antibiotics such as Cefdaloxime, it can be isolated or used in situ :

In the compounds of the formula (3), Q and R are the same as defined above, Z is the carboxy-activating group commonly used in the synthesis of cephalosporan antibiotics, such as anhydrides, esters, or acyl halides (carboxy-activating group).

The present invention relates to a method for preparing a salt of a carboxylic acid of Formula 1 with an organic nitrogen base, comprising reacting a carboxylic acid of Formula 2 with a halide of Formula 5 in the presence of a nitrogen organic base and an inert organic solvent. It is about:

<Formula 1>

<Formula 2>

Wherein Q is nitrogen, hydrocarbyl (CH) or chlorocarbyl (CCl) residues, preferably nitrogen;

R is trityl, benzhydryl or para-methoxy benzyl, preferably trityl;

X is a halogen selected from chlorine, bromine, and iodine.

The nitrogen organic base is tertiary amine, preferably triethylamine, tributylamine, N-ethyl diisopropylamine, N-methyl morpholine, N-methyl pyrrolidine, N-methyl piperidine , Trioctylamine; Amidines, preferably diazabicyclononene (DBN) and diazabicycloundecene (DBU); Guanidine, preferably tetramethyl guanidine. The inert organic solvents are halogenated hydrocarbons, preferably methylene chloride and dichloroethane; Carboxylic acid esters, preferably ethyl acetate and butyl acetate; Ketones, preferably acetone, diethyl ketone, and methyl ethyl ketone; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; Aromatic hydrocarbons, preferably benzene, toluene, and xylene; Ethers, preferably tetrahydrofuran, dioxane, ethylene glycol dimethyl ether; Sulfoxides or sulfones, preferably dimethyl sulfoxide, dimethyl sulfone and sulfolane; Or mixtures thereof.

The reaction can be carried out at a temperature of -50 ℃ to 200 ℃, preferably 0 ℃ to 100 ℃.

The halides (Formula 5) can usually be used in stoichiometric amounts or slightly molar excess relative to the compound of formula (2), wherein the organic base is from 1: 1 to 1:10, preferably 1 It may be present in a ratio ranging from 2 to 1: 5.

The halides which are usually added to the mixture of the compound of formula (2), the base and the inert organic solvent can be added directly at once or in several portions, or for example suitable for methylene chloride, dichloroethane, toluene, or xylene. After dissolving in an organic solvent, it can be added to the reaction mixture for a time ranging from a few minutes to several hours. When the residual compound (Formula 2) is less than 3% (HPLC analysis), the reaction is usually considered complete.

The salt, hereinafter referred to as compound (1A), is usually crystallized during the course of the reaction or upon cooling of the mixture and can thus be easily filtered off. They are usually obtained in very pure form; If necessary, halogenated hydrocarbons, preferably methylene chloride or dichloroethane; Aromatic hydrocarbons, preferably toluene or xylene; Or an inert organic solvent selected from mixtures thereof, optionally in the presence of a co-solvent such as amide, preferably N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, at 10 ° C. By treating them at temperatures in the range of from 100 ° C. to 100 ° C., preferably from 25 ° C. to 70 ° C., they can be further purified from by-products (bis- or tris-functionalized products). Salt (1A) can be further purified from traces of starting material (Formula 2) and other water soluble amine hydrochlorides by treatment with water or an aqueous solvent.

Drying of salt 1A does not require a special procedure and can be carried out at temperatures of 30 ° C. to 100 ° C., for example under vacuum or by ventilation.

Salt (1A) is prepared according to the conventional methods reported in the literature ( Liebigs Ann. 1996, 1743-1749), the corresponding free acid of the formula (1) and for example formamide, dimethylformamide, dimethyl Or solvates thereof, such as acetamide or N-methylpyrrolidone.

More advantageously, salt (1A) can be used for the preparation of reactive derivatives of formula 3, which are either isolated or according to the methods disclosed in the literature (US Pat. No. 6,093,814, Organic Process Research & Development 1997, 1 121). -123), cefdinir, ceftaloxime and other third and fourth generation cephalosporins, such as in situ in acylation reactions to obtain antibiotics.

<Formula 3>

In the compounds of formula 3, Q and R are as defined above and Z is a carboxy-activating group which, together with the C═O group to which Z is bonded, forms:

1. a mixed anhydride of formula -C (O) -OP (O) (OR ₁ ) ₂ , wherein R ₁ is an aryl group or a C ₁ -C ₆ straight or branched alkyl group; preferred anhydrides Is an anhydride with diethylphosphoric acid of the formula -C (O) -OP (O) (OEt) ₂ ( Synthetic Communication , 28 (l), 1998, 35-44));

2. Mixed anhydrides of the formula -C (O) -OP (S) (OR ₁ ) ₂ , wherein R ₁ is as defined above; preferred anhydrides are of the formula -C (O) -OP (S) (OEt ₂ ) anhydride with diethylthiophosphoric acid (EP 0812846));

3. Mixed anhydrides of the formula -C (O) -O-SO ₂ R ₁ , wherein R ₁ is as defined above; preferred mixed anhydrides are of the formula -C (O) -O-SO ₂ (pC ₆ H ₄ ) anhydride of CH ₃ with para-toluenesulfonic acid (US Pat. No. 5,589,594));

4. Mixed anhydrides of the formula -C (O) -O-COR ₁ , wherein R ₁ is as defined above; preferred mixed anhydrides are selected from blood of the formula -C (O) -O-COC (CH ₃ ) ₃ Anhydride with pivalic acid);

5. Mixed anhydrides of the formula -C (O) -O-CO ₂ R ₁ , wherein R ₁ is as defined above; preferred mixed anhydrides are ethylcarboxylic acids of -C (O) -O-CO ₂ Et (anhydrous with ethylcarbonic acid)

6. Reactive esters of formula -C (O) -OR ₂ , wherein R ₂ is pentachloro-1-phenyl, benzotriazol-1-yl, N-succinimido, N-phthali Aryl or heterocyclic moieties such as mido, preferably esters with 1-hydroxybenzotriazole ( The Journal of Antibiotics , 1990, 43 (12), 1564-1572);

7. Thioester of formula -C (O) -SR ₃ , wherein R ₃ is from 2-pyridyl, benzothiazol-2-yl, benzoxazol-2-yl, benzimidazol-2-yl Heterocyclic moiety selected, preferably a thioester with 2-mercaptobenzothiazole (EP 0037380, EP 0849269));

8. Reactive amide of formula -C (O) NR ₃ R ₄ , wherein NR ₃ R ₄ is nitrogen selected from imidazolyl, 1,2,4-triazolyl, tetrazolyl, benzotriazolyl A residue of a heterocycle, preferably an amide with benzotriazol-3-oxide-1-yl ( The Journal of Antibiotics , 1993, 46 (2), 359-361);

9. Acid chlorides of formula -C (O) Cl (wherein the amino groups of the compounds of formula 1 may be free or in the form of salts with minerals or organic acids (US Pat. 6,030,965).

Compared to the acid of formula (1), salt (1A) is generally soluble better in organic solvents commonly used in activation reactions, such as methylene chloride, ethyl acetate and tetrahydrofuran, and the reaction is usually faster and To yield a compound of formula 3, which exhibits high yield and high purity.

Therefore, salt (1A) allows to carry out the process for preparing cephalosporin of formula 9:

The method comprises the steps of converting a salt of formula (1A) to a compound of formula (3), reacting the compound of formula (3) with a suitable 7-amino-cephalosporanic acid derivative, And deprotecting the subsequent hydroxy-imino residues.

In compounds of formula 9, Q is as defined above and A is a typical residue of cephalosporin chemistry, preferably vinyl (-CH = CH ₂ ) or methoxymethylene (-CH ₂ -O-CH ₃ ) to be.

According to a preferred embodiment of the process of the invention, the compound cefdinir of Formula 9 wherein Q is a hydrocarbyl residue (-CH) and A is vinyl and Q is a hydrocarbyl residue (-CH), A is Ceftaloxime, which is methoxymethylene, is prepared.

The following examples illustrate the invention in more detail.

Example 1 Preparation of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate triethylammonium salt

To a suspension of 200 g of (Z) -2- (2-aminothiazol-4-yl) -2-hydroxyimino acetic acid in 2.2 liter of sulfolane and 500 ml of triethylamine, heated at 84 ± 90 ° C. 297 g of triphenylchloromethane dissolved in 1300 ml of toluene were added for 2.5 hours with vigorous stirring. The reaction mixture was left at 85 ± 90 ° C. for 1 hour with vigorous stirring. The suspension was cooled to 20 ° C and filtered after 1.5 hours. The solid was washed with water and toluene and dried to give 475 g of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate triethylammonium salt.

IR (KBr) _cm &lt; -1 &_gt;: 3440-3230, 3054, 1610.

¹ H-NMR (30 MHz, DMSO-d ₆ ) δ: 7.45 ÷ 7.10 (15H, mm, phenyl-H); 7.00 (2H, s, -NH ₂ ); 6.50 (1H, s, thiazole-H); 2.97 (6H, q, -CH ₂ triethylamine); 1.14 (9H, t, -CH ₃ triethylamine).

The following compound was obtained according to the procedure described in Example 1 except that triethylamine was replaced with an appropriate organic base.

(Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate tributylammonium salt;

(Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate N-methyl morpholinium salt;

(Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate N-methyl pyrrolidinium salt;

(Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate N-methyl piperidinium salt;

Example 2. Preparation of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetic acid

To a suspension of 200 g of (Z) -2- (2-aminothiazol-4-yl) -2-hydroxyimino acetic acid in 2.2 liter of sulfolane and 500 ml of triethylamine, heated at 85 ± 90 ° C. 297 g of triphenylchloromethane dissolved in 1300 ml of toluene were added for 2.5 hours with vigorous stirring. The reaction mixture was left at 84 ± 90 ° C. for 1 hour with vigorous stirring. The suspension was cooled to 20 ° C and filtered after 1.5 hours. After washing with water, the solid was placed in 150 ml of purified water and 1100 ml of ethanol. The suspension was warmed to 50 ° C. and an additional 1100 ml of ethanol was added for 30 minutes. The mixture was slowly cooled to 10 ° C. for 1 hour, acidified to pH 4.0 by addition of 20% hydrochloric acid, then left at 10 ° C. for 1 hour and then filtered. The solid was washed with water and dried to give 366 g of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetic acid.

The structure of the product was confirmed by IR and NMR analysis, compared to the data reported in Kamachi et al., The Journal of Antibiotics , 1990, 1564-1572.

Example 3. Purification of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate triethylammonium salt

A suspension of 150 g of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyiminoacetic acid triethylammonium salt in 600 ml of toluene was warmed to 65 ° C. and 60 minutes at 65 ° C. It was left stirring with. The suspension was cooled to 5 ° C. and filtered after 1 hour. The solid was washed with toluene and vacuum dried at 65 ° C. for 12 hours to give 134 g of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate triethylammonium salt. .

Example 4 Purification of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate triethylammonium salt

A suspension of 300 g of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate triethylammonium salt in 600 ml of purified water was cooled to 10 ° C. and stirred for 2 hours. It was left. The suspension was cooled to 2 ° C and filtered after 1 hour. The solid was washed with water and dried to give 192 g of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate triethylammonium salt.

Example 5. 2-benzothiazolyl- (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino Preparation of Thioacetate

To a suspension of 310 g bis (2-mercaptobenzothiazolyl) disulfide in 2250 ml methylene chloride, 244 g triphenylphosphine is added at room temperature and the suspension is left at 21 ° C. with stirring for 30 minutes. It was. Thereafter, 465 g of (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate triethylammonium salt was added to the suspension for 5 minutes. The temperature was raised to 27 ° C. The suspension was left at 23 ± 25 ° C. for 90 minutes and then filtered, the solid was washed with methylene chloride and dried to 456 g of 2-benzothiazolyl- (Z) -2- (2-aminothiazole- 4-yl) -2-trityloxyimino thioacetate was obtained.

The structure of the product was confirmed by NMR analysis, compared to the data reported in Wolflinann et al., Liebigs Ann. , 1996., 1743-1749.

¹ H-NMR (30 MHz, DMSO-d ₆ ) δ: 8.30 ÷ 8.24 (1H, d), 8.13 ÷ 8.07 (1H, d), 7.63 ÷ 7.53 (2H, m); 7.40 ÷ 7.20 (17H, m); 6.83 (I H, s).

Claims (16)

A process for preparing a salt of a carboxylic acid of Formula 1 with an organic nitrogen base, comprising reacting a carboxylic acid of Formula 2 with a halide of Formula 5 in the presence of a nitrogen organic base and an inert organic solvent: <Formula 1> <Formula 2> <Formula 5> Wherein Q is nitrogen, hydrocarbyl (CH) or chlorocarbyl (CCl) residues; R is trityl, benzhydryl or para-methoxy benzyl; X is a halogen selected from chlorine, bromine, and iodine. The method of claim 1 wherein the nitrogen organic base is triethylamine, tributylamine, N-ethyl diisopropylamine, N-methyl morpholine, N-methyl pyrrolidine, N-methyl piperidine, and trioctyl A tertiary amine selected from amines. The method of claim 1, wherein the nitrogen organic base is amidine selected from diazabicyclononene (DBN) and diazabicycloundecene (DBU). The method according to claim 1, wherein the organic base is tetramethyl guanidine. The process according to any of claims 1 to 4, wherein the inert organic solvent is selected from halogenated hydrocarbons, carboxylic acid esters, ketones, amides, aromatic hydrocarbons, ethers, sulfoxides or sulfones, or mixtures thereof. Characterized in the manufacturing method. The method of claim 5, wherein the inert organic solvent is methylene chloride, dichloroethane, ethyl acetate, butyl acetate, acetone, diethyl ketone, methyl-ethyl ketone, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, xylene, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, dimethyl sulfone and sulfolane or mixtures thereof Manufacturing method. 7. The process according to any one of claims 1 to 6, further comprising the step of transforming the salts defined in claim 1 to the carboxylic acids of formula (I). Salts of carboxylic acids of formula 1 with organic nitrogen bases: <Formula 1> Wherein Q is a nitrogen, hydrocarbyl (CH) or chlorocarbyl (CCl) residue; R is trityl, benzhydryl or para-methoxy benzyl. The method of claim 8, wherein the nitrogen organic base is triethylamine, tributylamine, N-ethyl diisopropylamine, N-methyl morpholine, N-methyl pyrrolidine, N-methylpiperidine, and trioctyl Salt, which is a tertiary amine selected from amines. 9. A salt according to claim 8, wherein said nitrogen organic base is amidine selected from diazabicyclononene (DBN) and diazabicycloundecene (DBU). 9. The salt of claim 8 wherein said nitrogen organic base is tetramethyl guanidine. The method of claim 9, (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate triethylammonium salt; (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate tributylammonium salt; (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate N-methyl morpholinium salt; (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate N-methyl pyrrolidinium salt; (Z) -2- (2-aminothiazol-4-yl) -2-trityloxyimino acetate N-methyl piperidinium salt. A method for preparing cephalosporin of formula 9 comprising reacting a derivative of formula 3 with 7-amino-cephalosporanic acid and then deprotecting the hydroxy-imino residue. The process according to claim 3, wherein the derivative of formula 3 is obtained from the salt of any one of claims 8-12. <Formula 9> <Formula 3> Wherein Q is as defined in claim 1 and A is a vinyl or methoxymethylene moiety; R is as defined in claim 1 and Z is a carboxy-activating group. The method according to claim 13, wherein in the compound of Formula 3, Z is a carboxy-activating group which forms together with a C═O group to which Z is bonded: Mixed anhydrides of the formula -C (O) -OP (O) (OR ₁ ) ₂ , wherein R ₁ is an aryl group or a C ₁ -C ₆ straight or branched alkyl group; Mixed anhydrides of the formula -C (O) -OP (S) (OR ₁ ) ₂ , wherein R ₁ is as defined above; Mixed anhydrides of the formula -C (O) -O-SO ₂ R ₁ , wherein R ₁ is as defined above; Mixed anhydrides of the formula -C (O) -O-COR ₁ , wherein R ₁ is as defined above; Mixed anhydrides of the formula -C (O) -O-CO ₂ R ₁ , wherein R ₁ is as defined above; Reactive esters of formula -C (O) -OR ₂ , wherein R ₂ is pentachloro-1-phenyl, benzotriazol-1-yl, N-succinimido, N-phthalimido Aryl or heterocyclic moiety selected from; Thioesters of the formula -C (O) -SR ₃ , wherein R ₃ is selected from 2-pyridyl, benzothiazol-2-yl, benzoxazol-2-yl, benzimidazol-2-yl Heterocyclic moiety); Reactive amides of the formula -C (O) NR ₃ R ₄ , wherein NR ₃ R ₄ is nitrogen hetero selected from imidazolyl, 1,2,4-triazolyl, tetrazolyl, benzotriazolyl A residue of a heterocycle); Acid chlorides of the formula -C (O) Cl, wherein the amino groups of the compounds of formula 1 can be free or in the form of salts with minerals or organic acids. The method according to claim 13 or 14, wherein in the compound of Formula 9, Q is a hydrocarbyl residue (-CH) and A is a vinyl residue (-CH = CH ₂ ). The preparation according to claim 13 or 14, wherein in the compound represented by Chemical Formula 9, Q is a hydrocarbyl residue (-CH), and A is a methoxymethylene residue (-CH ₂ -O-CH ₃ ). Way.