KR910008351B1 - Process for preparation of carboxyalkenamido cephalosporinester - Google Patents

Abstract

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Description

Method for preparing carboxyalkenamidocephalosporin ester

The present invention provides amidation of 7 beta-amino-3-cepem-4-carboxylic acid compound (II) or a reactive derivative thereof using an alkenyloxycarbonylalkenic acid compound (III) or a reactive derivative thereof according to the following scheme. Antimicrobial 7 beta- (altenyloxycarbonylalkenoylamino) -3-cefe-4-carboxylic acid compound (I) or derivatives thereof.

Wherein R is an aryl or heterocyclic group; R ¹ is hydrogen or halogen; R ² is a single bond, alkylene or thiaalkylene; R ³ is alkenyl; R ⁴ is hydrogen or methoxy; R ⁵ is a tri-substituted group of hydrogen or cephalosporin; R ⁶ is a hydrogen atom or a salt- or ester-forming group; X is oxygen, sulfur or sulfinyl.)

The product (I can be easily deesterified).

The following describes various groups of the scheme.

R is preferably selected from phenyl, furyl, thienyl, oxazolyl, isoxazolyl, optionally protected aminoisoxazolyl, thiazolyl, optionally protected aminothiazolyl, thiadiazolyl, and aminothiadiazolyl, and optionally Protected aminothiazolyl is more preferred. Among the protecting groups at protected amino, 7-20C substituted aralkyl, 1-8C substituted alkyl, substituted phenylthio, 1-8C substituted alkylidene, 7-14C substituted aralkylidene, 5 ~ 8C substituted cycloalkylidene, acyl [e.g. substituted with 1 to 8C substituted alkanoyl, substituted with 2 to 12C lower alkoxycarbonyl, 8-15C optionally substituted alkoxycarbonyl, succinyl, phthaloyl], Trialkylsilyl, alkoxydialkylsilyl, trialkylstenyl and the like are preferable.

R ¹ is preferably hydrogen or chlorine.

The alkylene moiety in R ² is low gold alkylene, preferably 1 to 3 C alkylene, in particular methylene.

R ³ as alkenyl is preferably a side chain alkenyl having 2 to 5 C.

R ⁵ as a cephalosporin substituent may be hydroxy, alkanoyloxy, halogen, alkoxy, alkylthio, alkenylthio, alkel, alkenyl, substituted methyl, or may be a known cephalosporin 3-substituent. . Substituents for substituted methyl include pyridinio, substituted pyridinio, halogen, hydroxy, alkoxy, acyloxy, alkylthio, haloalkylthio, cyanoalkylthio, polycyclic thio, triazolyl, tetra Zolyl and the like, and methyl is preferable as the alkyl moiety. As R ^5, hydrogen, vinyl, carbaoyloxymethyl, tetracyclylthiamethyl or thiaziazolyl dimethyl are preferable. It is known in the art of penicillins and cephalosporins that R ⁵ as a carboxy-modifier can be introduced or removed without adversely affecting other parts of the molecule. Representative examples include alkali metal or alkaline earth metal salts, alkylamni salts, aromatic amine salts, aromatic base salts, optionally substituted 1-8C alkyl esters, 7-15C araalkyl esters, 6-12C aryl esters, 3-12C silyl esters 3 12C stenyl ester, 1-12C N-hydroxyamino ester, 2-7C alkenyl ester, and the like. R ⁶ as a carboxy protecting group is hydrogen, sodium, potassium, methyl, t-butyl, trichloroethyl, methanesulfonylethyl, phenyl, indanyl, benzyl, cyanobenzyl, halobenzyl, methylbenzyl, nitrobenzyl, phenylbenzyl, etc. This is preferred. There is no protecting group in the desired product. Thus, as long as the protecting group serves the purpose of protection, its structure has no special significance and can be replaced by various equivalent groups.

As X, sulfur is preferable. The double-bonded geometric isomers of the seventh position side chain are both antimicrobial substances, of which R and R ^{1 in the} switch are stronger antimicrobial substances.

The remaining geometric isomers (trans) are also useful as intermediates for the preparation of the corresponding cis isomers.

Known ester analogs of compound (I) are described in the corresponding Korean Patent Application No. 6314/1984. The present invention is an improvement on the protecting groups of such materials for easy protection and deprotection. As mentioned in the above application, the free acid of compound ester (I) is antimicrobial to aerobic gram-positive and -negative bacteria and is also useful as a medicament for the treatment of bacterial infections. R is 2-aminothiazol-4-yl, R ² is methylene, R ¹ , R ³ and R ⁶ are hydrogen, R ⁵ is hydrogen, vinyl, cyanovinyl, trifluoropropenyl, acetoxy Compound (I), which is methyl, carbamoyloxymethyl or thiadiazolylthiomethyl, is well absorbed through the digestive tract.

The present invention is carried out by the following method.

[Amidation]

The amine (II) of the general formula or the reactive derivative thereof is reacted with the carboxylic acid (III) of the general formula or the reactive derivative thereof by the conventional method to obtain the compound (I) of the general formula or the derivative thereof.

Reactive derivatives of amines (II) have amino groups at the 7 position activated by silyl, stanyl, alkylene, alkylidene, acids, easily removable acyl and the like, or other functional groups of the molecule are protected.

The free acid (III) is reacted in the presence of a condensed system [carbodiimide, carbonyl compound, isoxazolinium salt, acylamino compound].

Reactive derivatives of carboxylic acid (III) include acid anhydrides [eg, symmetric acid anhydrides or mixture anhydrides (inorganic acids, organic acids, molecular material anhydrides)], acid halides, reactive esters [enol esters, aryl esters, heterocyclic esters, Esters having hydroxy compounds, diacylhydroxylamine esters, thioesters] or reactive amides [heteroaromatic amides, diacylanilides]. Examples of acid scanbingers used with the derivatives include inorganic bases, organic bases, oxiranes, pyridinium salts, and adsorbents.

[Any Deprotection of Carmoxi-Protective Groups]

The carboxy or amino protecting groups in the protected compound (I) can be deprotected, for example as follows.

a) Highly reactive etsers can be deprotected by contact with acids, bases, buffers or ion exchange resins in aqueous solvents. If the reactivity is not high, it can be more easily deprotected by increasing the reactivity by known methods.

b) Aralkyl esters can be deprotected by carrying out a known catalytic reduction reaction with hydrogen in the presence of a catalyst.

c) Alkenyl as R ³ or esters such as aralkyl, cyclopropylmethyl, sulfonylethyl as R ⁶ may be solvolyzed [inorganic acid, Lewis acid, if necessary, in the presence of a cationic scanbinger (e.g., anisol, thiophenol). (E.g., aluminum chloride, tin chloride, titanium tetrachloride), sulfonic acid (e.g., methane sulfonic acid, trifluoromethanesulfonic acid), strong carboxylic acid (trifluoroacetic acid), and the like.

d) 2-alkenyl carboxy protecting groups can be removed by treatment with a palladium-triphenyl phosphine addition complex in an inert solvent such as dimethylformamide.

[Reaction condition]

The reactions (1) to (2) are typically performed at -60 ° C to 120 ° C, preferably at -20 ° C to 80 ° C for 10 minutes to 10 hours, depending on the reaction form, and are carried out in a solvent. Other conventional methods (eg, stirring, shaking, inert gas sealing, drying) can be used.

Representative reaction solvents include, for example, hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitrohydrocarbons, nitriles, amides, sulfoxides, carboxylic acids, organic bases, alcohols, water and other industrial solvents and mixtures thereof.

EXAMPLE

The following examples illustrate the invention.

In the examples, "parts" are parts by weight and "equivalents" refers to molar equivalents of betalactam starting material. The symbols "cis" and "trans" indicate the relative positions of the amido and carboxy substituents attached to the side chain double bonds. The physical chemical constants of the product are summarized in the table, where IR is the wavenumber in cm ⁻¹ , NMR is the chemical shift in ppm and J value is the constant of the bond in Hz. In NMR of a geometric isomeric mixture, two or more divided signals are represented by chemical shifts separated by commas (,), splitting numbers, and the preceding multiplication table (×). All concentrations are carried out under reduced pressure. (Abbreviation) BH = diphenylmethyl; Cbz = benzyloxycarbonyl; The circle in the heterocycle in the structural formula indicates that the ring is aromatic.

Example 1

Amidation

The 7-beta-amino compound (1 equivalent) of the following general formula (2) is reacted with a carboxylic acid or a reactive derivative thereof corresponding to the 7-beta-side chain of the following general formula (3) in the following manner to The amide of formula (1) is obtained.

1) dichloromethane (10 vol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.1 equivalent (N, N'-dicyclohexylcarbodiimide (1.1 equivalent), pyridine ( 1.5 equivalents) and carboxylic acid (3) (1.1 equivalents) are stirred for 1 to 6 hours at 0 ° C to room temperature.

2) 2 to 10-50 ° C. in a mixture of ethyl acetate (10 vol), di-2-pyridyl disulfide (1.1 equiv), triphenylphosphine (1.1 equiv), and carboxylic acid (3) (1.1 equiv) Stir for 6 hours.

3) In a mixture of dichloromethane (3 vol), 1,3,5-tripyridiniumtriazine trichloride (4 equiv) and carboxylic acid (3) (1.1 equiv), stir at −10 to 10 ° C. for 1 to 5 hours. .

4) 1-5 hours at -20 to 10 ° C. in a mixture of carbon tetrachloride (30 vol), 4-methylmorpholine (1.5 equiv), trisdiethylaminophosphine (1.1 equiv), and carboxylic acid (3) (1.1 equiv) Allow to stand.

5) 30 minutes to 6 hours at a temperature of -5 to 10 ° C. in a mixture of chloroform (10 parts) and dimethoxyethane (10 parts), triethylamine (1.5 moles), and a mixed anhydride of carboxylic acid (3) and isobutoxy formic acid. Stir while.

6) 10 minutes to 2 hours in a mixture of ethyl acetate (10 vol), 1,2-dichloroethane (10 vol), 4-methylmorpholine (1.5 equiv) and symmetric anhydride (1.1 equiv) of carboxylic acid (3) Reflux.

7) Stir for 1 to 3 hours at -70 ° C to room temperature in a mixture of dichloromethane (10 vol), pyridine (1.5 equiv), mixed anhydride (1.1 equiv) of carboxylic acid (3) and methane sulfonic acid.

8) Stir at 0 ° C. to 10 ° C. for 1 to 5 hours in a mixture of ethyl acetate (10 vol), pyridine (1.5 equiv) and a mixed anhydride (1.5 equiv) of diethyl hydrogenphosphate and carboxylic acid (3).

9) 1 to 0 ° C. to room temperature in a mixture of ethyl acetate (10 parts), dichloromethane (10 parts), N-methylmorpholine (1 equivalent), and a mixed anhydride (1.1 equivalents) of carboxylic acid (3) and dichlorophosphoric acid. Stir for ˜3 hours.

10) Stir at 0-30 ° C. for 1-4 h in a mixture of lutidine (1.5 equiv), dichloromethane (10 vol) and a mixed anhydride (1.1-2 equiv) of carboxylic acid (3) and dimethylamide monochlorophosphate do.

11) In a mixture of dichloromethane (5 vol), trifluoroacetic anhydride (1.5 equiv), pyridine (3 equiv) and carboxylic acid (3) (1.5 equiv), stir at 0 ° C to room temperature for 1-5 hours.

12) 1 to 0 ° C to room temperature in a mixture of dichloromethane (10 vol), diethyl hydrogenphosphate bromide (1.2 equiv), 4-methylmorpholine (2.5 equiv), and carboxylic acid (3) (1.2 equiv) Stir for 3 hours.

13) An amine (2) having carboxy at position 4 of the cefme ring is dissolved in an aqueous solution of sodium hydrogencarbonate (2.5 equivalents) (10 vol). Chloride (1.1 equivalents) of carboxylic acid (3) is added dropwise to the solution, and the mixture is left at -5 ° C to room temperature for 30 minutes to 2 hours.

14) The amine (2) having carboxy at the 4 position of the cefe ring is reacted with trimethylsilyl chloride and triethylamine (1.2 equivalents each), followed by pyridine (4 equivalents) and carboxylic acid at 30 ° C. for 30 minutes to 2 hours. After reacting with the chloride of (3) (1.1 equiv), the resulting silyl ester is hydrolyzed functionally.

15) A solution of picoline (4 equivalents) and carboxylic acid (3) chloride (1.2 equivalents) in dichloromethane (20 volumes) is stirred for 30 minutes to 2 hours at 0 ° C to -30 ° C.

16) For 30 minutes to 3 hours at 0 ° C to 20 ° C with triethylamine (1.1 equiv) and carboxylic acid (3) chloride (1.1 equiv) in a mixture of dimethylformamide (2 vol) and ethyl acetate (10 vol) Stir.

17) Stir at −30 ° C. to 10 ° C. for 5 minutes to 2 hours in a mixture of dichloromethane (30 vol), cyanuric chloride (1.1 equiv), pyridine (4 equiv), and carboxylic acid (3) (1.1 equiv) do.

18) 20 minutes to 2 hours at -10 ° C to 10 ° C in a mixture of dichloromethane (3 vol), phosphorus oxychloride (1.1 equiv), triethylamine (1.5 equiv), and carboxylic acid (3) (1.1 equiv) Stir.

19) Treatment of amine (2) with trimethylsilyl chloride and oxygen vaccum affords the corresponding N-trimethylsilyl compound, which is converted to phosphorus oxychloride (1.5 equivalents), carboxylic acid (3) (in dichloromethane (5 parts)). 1.2 equivalents), and dimethylaniline (4 equivalents) at 0 ° C to room temperature for 30 minutes to 2 hours.

20) Stir in a mixture of dichloromethane (8 vol), thionyl chloride (1.5 equiv), pyridine (2.5 equiv), and carboxylic acid (3) (1.1 equiv) at −30-0 ° C. for 1-5 h.

21) 10 minutes in a mixture of chloroform (3 volumes), toluene (1 volume), picoline (2 equivalents), oxalyl chloride (1 equivalent), and carboxylic acid (3) (11 equivalents) Stir for ˜2 hours.

22) Stir at 10-50 ° C. for 5-30 hours in a mixture of dichloromethane (20 vol), pyridine (3 equiv), and benzotriazolyl ester of carboxylic acid (3 equiv).

23) 1-15 hours at room temperature in a mixture of dichloromethane (20 vol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.5 equiv) and carboxylic acid (3) (2 equiv) Stir while.

24) Stir for 2-8 hours at 10-50 ° C. in a mixture of phthalimido ester (2 equiv) of dioxane (10 vol) and cappoxy acid (3).

25) A mixture of methyl isobutyl ketone (10 vol) and succinimido ester of carboxylic acid (3) (1.5 sugars) is stirred at 0-40 DEG C for 2-9 hours in a mixture.

26) Stir for 1 to 5 hours at 0 ° C. to room temperature in a mixture of carbonyldiimidazole (1.1 equiv), tetrahydrofuran (10 vol), dimethylacetamide (5 vol) and carboxylic acid (3) (1.1 equiv) do.

27) Stir for 1-5 hours at room temperature in a mixture of dimethylformamide (5 vol), dimethylaniline (1.3 equiv) of carboxylic acid (3), and Vilsmeier reagent (1.1 equiv) prepared from dimethylformamide.

28) dichloromethane (10 vol), dimethylformamide (5 parts), a mixture of N, N'-dicyclohexylcarbodiimide (1.1 equiv), picoline (1.2 equiv) and carboxylic acid (3) (1.1 equiv) In the reaction for 2 to 24 hours.

29) In a similar manner to Examples 1) to 28) above, the amides (1) of Table 1 are prepared from the corresponding carboxylic acid (3) derivatives and amines (2).

Example 2

Carboxy-deprotection

1) The lower alkenyl and / or diphenylmethyl esters of Table 1 were dissolved in a mixture of dichloromethane (0.3-3 parts), trifluoroacetic acid (0.3-3 parts) and anazole (0.5-5 parts). The solution is stirred for 10 minutes to 3 hours at a temperature of -10-40 ° C. The solution is concentrated to remove solvent and reagents. The residue is washed with benzene or ether to give 70-90% of the corresponding acid.

2) A solution of the lower alkenyl or diphenylmethyl esser shown in Table 1 in a mixture of dichloromethane (5-9 parts) and anisol (2-8 parts) was treated with aluminum chloride at -10 ° C to 10 ° C, Tin tetrachloride or titanium tetrachloride (3-12 equiv) is added and the mixture is stirred for 1-24 h. The mixture is washed with dilute hydrochloric acid and water, dried and concentrated to yield the corresponding free acid with a yield of 80-95%.

When a t-butoxycarbonylamino or benzyloxycarbonylamino group is present, it is deprotected and made into an amino group.

3) 90% formic acid (5-6 parts) and anazole (2-3 parts) are added to the diphenylmethyl ester solution shown in Table 1. The mixture is stirred at 50-6 ° C. for 1-4 hours yielding a corresponding carboxylic acid with a yield of 40-50%.

4) 7- [2-) 2-benzyloxycarbonylamino-4-thiazolyl4-allyloxycarbonyl-2-butenoylamino] -3-cepem-4-carboxylic acid di dissolved in dichloromethane (30 ml) To the phenyl methyl ester solution was added 2-ethylhexanoate (1.5 equiv) and a mixture of triphenylphosphine palladium (125 mg). After 1 h of stirring at 25 ° C., the mixture was diluted with ether to give 7beta- [2- (2-benzyloxycarbonylaminothiazol-4-yl) -4-siooxycarbonylbutenoylamino]- 3-Sefem-4-carboxylic acid diphenylmethyl ester (yield 94%) is isolate | separated. The material is suspended in water (10 parts) and acidified with 4% aqueous phosphoric acid solution to obtain 7-keta- [2- (2-benzyloxycarbonylaminothiazol-4-yl) -4-carboxy-2-butenoyl. Amino] -3-cepem-4-carboxylic acid diphenylmethyl ester is isolated.

5) A corresponding free carboxy compound is prepared from the carboxy protection compounds shown in Table 1 in a similar manner as in Examples 1) to 4) above.

TABLE 1

TABLE 2

Claims (1)

Characterized by amidating the 7-beta-amino-3-cepem-4-carboxylic acid compound of the general formula (II) or its reactive derivative with the alkenyloxycarbonylalkenic acid compound of the general formula (III) or the reactive derivative thereof The method for producing an antimicrobial intermediate 7 beta- (alkenyloxycarbonylalkenoylamino) -3-cefe-4-carboxylic acid compound of the following general formula (I).

Wherein R is an aryl or heterocyclic group; R ¹ is hydrogen or halogen; R ² is a single bond, alkylene or thiaalkylene; R ³ is alkenyl; R ⁴ is hydrogen or methoxy; R ⁵ is a 30 substituent of hydrogen or cephalosporin; R ⁶ is a hydrogen atom or a salt- or ester-forming group; X is oxygen, sulfur or sulfinyl).