CN1023322C - Carboxyalkenamidocephalosporins - Google Patents

Abstract

The present invention relates to a preparing method of a new antiseptic agent, namely a 7 beta-(carboxyl alkene acylamino)-3-cephem-4-carboxylic acid compound (I) or derivatives thereof. The method comprises the following steps: amidating a 7 beta-amino-3-cephem-4-carboxylic acid compound (II) by using a carboxylic alkenoic acid compound (III) or reactive derivatives thereof according to a reaction formula shown in the specification; (2) selectively removing protecting groups of reaction products and/or (3) salting the reaction products to obtain the antiseptic agent. In the formula, R represents aryl or heterocyclic radicals; R1 represents hydrogen or halogen; R2 represents single bonds, alkylene or thia-alkylene; R3 represents hydrogen atoms or radicals forming salts or ester; R4 represents hydrogen or methoxyl; R5 represents hydrogen or 3-site substituents of cephalosporin; R6 represents hydrogen atoms or radicals forming salts or ester; X represents oxygen, sulfur or sulfinyl.

Description

Carboxyalkenamidocephalosporins

The invention relates to preparation new anti-bacterial agent 7 β-(carboxyl alkenoyl amino)-3-cephem-4-carboxylic acid cpd (I), the method for or derivatives thereof.Present method is with a carboxyl alkenoic acid compound (III) or its reactive derivative 7 beta-aminos-3-cephem-4-carboxylic acid cpd (II) or its activated derivative to be carried out amidation by (1) by following reaction formula; (2) take off selectively protecting group and (or) (3) make and form corresponding salt and prepare this new anti-bacterial agent:

(here, R is aryl or heterocyclic radical;

R ¹It is hydrogen or halogen;

R ²Be a singly-bound, alkylidene group, or thia alkylene;

R ³Be a hydrogen atom, or form the group of salt or ester;

R ⁴Be hydrogen or methoxyl group;

R ⁵Be hydrogen, or the substituting group of a cynnematin on the 3rd position;

R ⁶Be a hydrogen atom, or form the group of salt or ester; And X is oxygen, sulphur or sulfinyl).

Various groups in reaction formula below are described:

R preferably is selected from one of following groups: phenyl, furyl, thienyl, oxazolyl, isoxazolyl, can protected An isoxazole base, aminothiazole base, thiadiazolyl group and the amino thiadiazolyl group of thiazolyl, protection arbitrarily.Wherein be more preferably the aminothiazole base of any protection.Among many blocking groups of amino; preferably adopt the aralkyl that is optionally substituted with 7 to 20 carbon atoms; the alkyl that is optionally substituted with 1 to 8 carbon atom; substituted thiophenyl; substituted alkylidene group with 1 to 8 carbon atom; substituted arylmethylene alkyl with 7 to 14 carbon atoms; substituted ring alkylidene group with 5 to 8 carbon atoms; acyl group (for example: the alkanoyl that is optionally substituted with 1 to 8 carbon atom; the lower alkoxycarbonyl that is optionally substituted with 2 to 12 carbon atoms; have 8 to 15 aralkoxycarbonyls that carbon atom is optionally substituted; succinyl; the phthalyl base; trialkyl silyl; the alkoxyl group dialkyl silicon group; the trialkyl tinbase), and similar group.

R ¹Preferably hydrogen or chlorine.

As R ²The alkylidene group of a part is a low-grade alkylidene, preferably has the alkylidene group, particularly methylene radical of 1 to 3 carbon atom.

As the substituting group of a cynnematin, R ⁵Be the 3-bit substituent of having known of cynnematin on the 3rd position, wherein have: hydroxyl, alkanoyloxy, halogen, alkoxyl group, alkylthio, alkenyl thio, alkyl, alkenyl, substituted methyl or similar group.Here, the substituting group on the described methyl can be pyridine, halogen, hydroxyl, alkoxyl group, acyloxy, alkylthio, halogenated alkylthio, cyanogen alkylthio, heterocycle sulfenyl, triazolyl, tetrazyl or other similar gene of pyridine (Pyri d inio), replacement.The abovementioned alkyl part is methyl preferably.R ⁵Preferably hydrogen, vinyl, carbamyl oxygen methyl, tetrazyl thiomethyl or thiadiazolyl group thiomethyl.

R ³Or R ⁶As the modification group on the carboxyl, in penicillin and cynnematin field, be known, because when these groups are introduced or slough, other parts of molecule there is not undesirable action.Representational combining form is the alkyl ester with 1 to 8 carbon atom, the aralkyl ester with 7 to 15 carbon atoms, the aromatic ester with 6 to 12 carbon atoms, the stannyl ester with 3 to 12 carbon atoms, the N-hydroxylamino ester with 1 to 12 carbon atom, the alkenyl ester with 2 to 7 carbon atoms and the similar group of basic metal or alkaline earth salt, alkylamine salt, fragrant alkali salt, replacement arbitrarily.During as carboxy protective group, R ³And R ⁶Preferably: hydrogen, sodium, potassium, methyl, the tertiary butyl, three chloroethyls, methylsulfonyl ethyl, phenyl, 2,3-indanyl, benzyl, cyanobenzyl, halogen benzyl, methyl-benzyl, nitrobenzyl, phenylbenzyl or similar group.For making last product, need slough blocking group.Like this, as long as used group can play a protective role, its structure is unessential, so it can be replaced by the group of many equivalences.

X is sulphur preferably.

Two geometrical isomers that form owing to the two keys in the side chain of 7-position all are anti-microbial type compounds.Wherein, R and R ¹For the isomer of cis position is stronger antiseptic-germicide.Other geometrical isomer (trans) also is useful as the intermediate of the corresponding cis-isomeride of preparation.

With the more closely-related compounds of compound (I), be published on the Japanese Patent publication, notification number is 10,996(1967), publication number is 57-93982(1982), and on belgian patent 816408 and 888389, these compounds are in sterilizing power, intestines or the receptivity outside the intestines, and aspects such as Excretion are superior unlike compound (I).

Compound (I) is an antiseptic-germicide, can resist aerobic gram-positive microorganism and Gram-negative bacteria, also can resist anerobe.Particularly: compound (I) has that anti-Gram-negative bacteria effect is strong, absorbing power good, drainage is fast and high distributivity etc. and some other significant advantages.Therefore, this compound is the active drug of treatment infectation of bacteria.Compound (I) is as the medicine of prevention or treatment bacterial infection disease, can be oral, injection or topical application, and every day, dosage was 10 micrograms to 6 grams.If desired also can with conventional additives or the medicine that concurs for example other antiseptic-germicide together prepare.Protected compound (I) also is useful as the raw material of the antiseptic-germicide (I) that synthesizes other.Some R ²Compound (I) for methylene radical can be absorbed at digestion organs, is applicable to and makes oral cephalosporin.Especially effectively those R are thiazolamine-4-base, R ³And R ⁴Be hydrogen, and R ⁵Compound (I) and their salt for hydrogen, vinyl, acrylonitrile base, trifluoro-propenyl, acetyl-o-methyl, carbamyl oxygen methyl or thiadiazoles thiomethyl.

The present invention presses following 6 enforcements:

(1) amidation

The generality reaction of amine (II) or the same carboxylic acid of its reactive derivative (III) or its reactive derivative can draw compound (I) or derivatives thereof.

The reactive derivative of amine (II) is a 7-amino by silyl, stannyl, alkylidene group, the acyl group of easily sloughing or the similar compound of group activation, or the protected compound of other functional group in the molecule.

Free acid (III) needs to react in the presence of condensing agent (carbodiimide, carbonyl compound, isoxazolium salt, amido compounds etc.).

The reactive derivative of carboxylic acid (III) can be an acid anhydrides; for example: symmetrical anhydride or mixed anhydride (acid anhydrides that is become with mineral acid, organic acid, intramolecular anhydride etc.), acyl halide, active ester (enol ester, aryl ester, heterocyclic ester, the ester that has the N-oxy-compound, diacyl azanol ester, thioesters and analogue), or active amide (aromatic heterocycle acid amides, N-diacyl aniline).The acid scavenger that uses together with above-mentioned derivative has, for example: mineral alkali, organic bases, oxyethane, pyridinium salt, sorbent material and other analogue.

(2) blocking group such as carboxyl-protecting group sloughs.

Ester group on protected compound (I) can be sloughed ester by following common mode and form base, for example:

(a) highly active ester group usable acid, alkali, damping fluid or ion exchange resin decarboxylize protecting group in water.When it is active not enough, can increase its activity so that ester forms base is easy to take off with ordinary method.

(b) aralkyl ester can be in the presence of catalyzer, with conventional hydrogen catalysis reduction method decarboxylize protecting group.

(c) ester of aralkyl, cyclopropyl methyl, sulphonyl ethyl or similar base can be by the method decarboxylize protecting group (solvent can be used mineral acid, Lewis acid (for example: aluminum chloride, tin tetrachloride, titanium tetrachloride), sulfonic acid (for example: methylsulfonic acid, trifluoromethanesulfonic acid), strong carboxylic acid (trifluoroacetic acid) or similar solvent) of solubilizing agent decomposition.If desired, can while decarboxylize protecting group in the presence of positively charged ion scavenging agent (as: methyl-phenoxide, thiophenol).

(d) amino protecting group in compound (I), can slough by ordinary method, for example: other compound of substituted alkyl, aralkyl, alkylidene group, arylmethylene alkyl, alkanoyl, trialkyl silyl, trialkyl tinbase, thiophenyl or aqueous acids or non-aqueous acids; Alkoxyl group formyl, aralkoxy formyl, aralkyl etc. in the presence of above-mentioned acid scavenger, can be sloughed with Lewis acid; Halogen alkoxy carbonyl, aralkoxy or similar base can be sloughed through reduction; The active acetyl available bases is sloughed.

In compound (I), the blocking group of hydroxyl or similar functional group can be used on put down in writing in various science and the patent documentation, known method is sloughed in penicillin and cephalosporin chemistry field.

(3) formation of salt

At the cephem of compound (I) nuclear last the 4th or carboxyl in the 7-substituting group, can be by alkali reaction with light metal, or with the permutoid reaction formation light metal salt (I) of the corresponding light metal salt of other carboxylic acid.Salify operation can be undertaken by the ordinary method of this area, for example: in and free acid, boil off solvent; Or free acid handled with the lower carboxylic acid salt of light metal in polar organic solvent, add the lower solvent of the sl. sol. therein polarity of these salt then and make and salt out.Solvent can be removed after filtration.

(4) reaction conditions

Above-mentioned (1), is preferably in-20 ℃ to 80 ℃ and carries out usually at-60 ℃ to 120 ℃ to the reaction of (3), and the reaction times was not waited by 10 hours according to not being all of reaction type in 10 minutes.Be reflected in the solvent and finish.Other normal condition (as: stir, vibration, with inert gas seal, drying) also can be utilized.

Typical reaction solvent is exemplified below: hydrocarbon, halohydrocarbon, ether, ketone, ester, nitro-hydrocarbon, nitrile, acid amides, sulfoxide, carboxylic acid, organic bases, alcohol, water and other industrial solvent and composition thereof.

(5) post-reaction treatment

Use ordinary method, from reaction mixture, remove impurity, can obtain product, available general post treatment method or isolate product with the method that aforesaid operations combines.

(6) raw material

The raw material that the present invention is used, described any one method obtains in the patent application case that can apply for simultaneously by applicant.

Embodiment

Set forth specific embodiments of the present invention below in 9 examples:

In an embodiment, what is called " part " (Part), be meant the part of calculating with weight, and " equivalent " is meant the mol equivalent of comparing with the beta-lactam starting materials: symbol " suitable " (cis) and negation (trans) expression be connected to the relative position of the group of (acyl) amino on the two keys of side chain and carboxyl substituted.The physicochemical constant of product collects in the table.IR is with the cm of unit in table ^-1The expression wave number; NMR represents chemical shift with the ppm of unit; J value representation coupling constant, unit is HZ.The mixture of geometrical isomer is in the NMR collection of illustrative plates, and signal produces two or more branches that split, and chemical shift differs and shows the author, separate with comma, chemical shift differs little person with splitting mark (as 2,3 ...) multiply by (X) split the branch mark (as, s, t, m etc.) represent.

All concentration operations are under reduced pressure finished.

Write the explanation of word:

The AOM=acetyl-o-methyl; The BH=diphenyl-methyl; The BU=butyl; The BOC=tert-butoxycarbonyl; The Bzl=benzyl; The Cbz=benzyloxycarbonyl; Circle on the heterocycle of structural formula=this ring is an aromatics; Exo=props up 3 on the chain acyl at 7-, 4-position of double bond isomers; The Me=methyl; MEM=methoxy ethoxy methyl; The ph=phenyl; PMB=is to methoxy-benzyl; PNB=is to nitrobenzyl; And POM=pivalyl methylol.

Embodiment 1(sodium salt)

(1) with carboxylic acid (I, a R in the table 2 ³(or) R ⁶=H) (1 gram) be dissolved in 0.5% sodium bicarbonate aqueous solution (6 milliliters), adjust PH to 7 with hydrochloric acid, with vinyl acetic monomer washing, desalination, again solution is poured in one 10 milliliters the bottle.With its lyophilize, can get corresponding sodium salts (I, R with usual method ³(or) R ⁶=Na) powder.

(2) similarly, aqueous sodium carbonate is joined carboxylic acid (I, the R of table 2 ³(or) R ⁶=H) in (1 gram) suspension in water, make PH and be 6.5 solution.With this solution desalination, and pour in 10 milliliters the bottle, lyophilize is to obtain above-mentioned same preparation of sodium.

(3) sodium salt for preparing under aseptic condition (1 gram) is dissolved in the sterilized water (4 gram), give the oral or intravenous injection twice patient's every day of suffering from infection of staphylococcus aureus, to treat above-mentioned disease.

(4) each carboxylic acid on the table 2 be dissolved in the aqueous sodium carbonate sodium salt solution check this sodium salt so that draw its minimum inhibition concentration.Standard method check with Japanese chemotherapy association obtains following numerical value: 3.1 to 0.2 mcg/ml, suis C-203 that can the antibiosis purulence; 0.8 to 0.025 mcg/ml, can Chinese People's Anti-Japanese Military and Political College's intestines escherich's bacillus.

Embodiment 2(amidation)

Use 7 beta-amino compounds (2) (1 equivalent) carboxylic acid corresponding with 7 β-side chain (3) or its reactive derivative to handle, obtain acid amides (1) (table 1 or 2), method therefor is as follows:

1) with methylene dichloride (10 volume), 2-oxyethyl group-1-ethoxy carbonyl-1,2-dihydroquinoline (1.1 equivalent), N, the mixture of N '-dicyclohexyl carbodiimide (1.1 equivalent), pyridine (1.5 equivalent) and carboxylic acid (3) (1.1 equivalent) 0 ℃ under room temperature, stirred 1～6 hour.

2) mixture with vinyl acetic monomer (10 volume), two-2-pyridyl disulfide (1.1 equivalent), triphenyl phosphine (1.1 equivalent) and carboxylic acid (3) (1.1 equivalent) stirred 2～6 hours at 10 ℃ to 50 ℃.

3) with methylene dichloride (3 volume), 1,3, the mixture of 5-TPTE trichloro-compound (4 equivalent) and carboxylic acid (3) (1.1 equivalent) stirred 1～5 hour in-10 ℃ to 10 ℃.

4) mixture with tetracol phenixin (30 volume), 4-methylmorpholine (1.5 equivalent), three-diethylamino phosphine (1.1 equivalent) and carboxylic acid (3) (1.1 equivalent) kept 1～5 hour at-20 ℃ to 10 ℃.

5) mixture of the mixed acid anhydride of trichloromethane (10 volume), dimethyl ethane (10 volume), triethylamine (1.5 mol) and carboxylic acid (3) and isobutoxy formic acid was stirred 30 minutes to 6 hours between temperature-5 is ℃ to 10 ℃.

6) with vinyl acetic monomer (10 volume), 1, the mixture of the symmetric anhydride (1.1 equivalent) of 2-ethylene dichloride (10 volume), 4-methylmorpholine (1.5 equivalent) and carboxylic acid (3) refluxed 10 minutes to 2 hours.

7) with the mixture of the mixed acid anhydride (1.1 equivalent) of methylene dichloride (10 volume), pyridine (1.5 equivalent) and carboxylic acid (3) and methylsulfonic acid in-70 ℃ to stirring between the room temperature 1～3 hour.

8) mixture with the mixed acid anhydride (1.5 equivalent) of vinyl acetic monomer (10 volume), pyridine (1.5 equivalent) and diethyl phosphoric acid and carboxylic acid (3) stirred 1～5 hour for 0 ℃ to 10 ℃ in temperature.

9) with the mixture of the mixed acid anhydride (1.1 equivalent) of vinyl acetic monomer (10 volume), methylene dichloride (10 volume), N-methylmorpholine (1 equivalent) and carboxylic acid (3) and dichloro phosphoric acid in 0 ℃ under room temperature, stirred 1～3 hour.

10) mixture with the mixed acid anhydride (1.1 to 2 equivalent) of lutidine (1.5 equivalent), methylene dichloride (10 volume) and a carboxylic acid (3) and a chlorine di(2-ethylhexyl)phosphate methyl nitrosourea stirred 1～4 hour for 0 ℃ to 30 ℃ in temperature.

11) mixture with methylene dichloride (5 volume), trifluoroacetic anhydride (1.5 equivalent), pyridine (3 equivalent) and carboxylic acid (3) (1.5 equivalent) stirred 1～5 hour under room temperature for 0 ℃ in temperature.

12) mixture with acylbromide (1.2 equivalent), 4-methylmorpholine (2.5 equivalent) and the carboxylic acid (3) (1.2 equivalent) of methylene dichloride (10 volume), diethyl phosphoric acid stirred 1～3 hour under room temperature for 0 ℃ in temperature.

13) amine (2) that carboxyl is arranged on the 4th position on the cephem ring is dissolved in the aqueous solution (10 volume) of sodium bicarbonate (2.5 equivalent).The acyl chlorides (1.1 equivalent) of carboxylic acid (3) is added dropwise in the above-mentioned aqueous solution.This mixture is incubated 30 minutes to 2 hours at-5 ℃ under room temperature.

14) the amine (2) that carboxyl is arranged on the 4th position on the cephem ring, handle with trimethylammonium silicon chlorides and triethylamine (respectively being 1.2 equivalents), then, under-30 ℃, acyl chlorides (1.1 equivalent) with pyridine (4 equivalent) and carboxylic acid (3) was handled 30 minutes to 2 hours, at last with the silylation ester acid hydrolysis that obtains.

15) solution that will be dissolved in the acyl chlorides (1.2 equivalent) of interior picoline (4 equivalent) of methylene dichloride (20 volume) and carboxylic acid (3) stirred 30 minutes to 2 hours at 0 ℃ to-30 ℃.

16) with the mixture of dimethyl formamide (2 volume) and ethyl acetate (10 volume), the acyl chlorides (1.1 equivalent) of same triethylamine (1.1 equivalent) and carboxylic acid (3) is 0 ℃ to 20 ℃ in temperature together, stirs 30 minutes to 3 hours.

17) with the mixture of methylene dichloride (30 volume), cyanuryl chloride (1.1 equivalent), pyridine (4 equivalent) and carboxylic acid (3) (1.1 equivalent) at-30 ℃ to 10 ℃.Stirred 5 minutes to 2 hours.

18) with the mixture of methylene dichloride (3 volume), phosphoryl chloride (1.1 equivalent), triethylamine (1.5 equivalent) and carboxylic acid (3) (1.1 equivalent) ,-10 ℃ under 10 ℃, stirred 20 minutes to 3 hours.

19) handle amine (2) with trimethylammonium silicon chlorides and acid scavenger, obtain corresponding N-trimethyl silicon based compound.This compound 0 ℃ under room temperature, handled 30 minutes to 2 hours in methylene dichloride (5 parts) with phosphoryl chloride (1.5 equivalent), carboxylic acid (3) (1.2 equivalent) and xylidine (4 equivalent).

20) mixture with methylene dichloride (8 volume), first sulfuryl chloride (1.5 equivalent), pyridine (2.5 equivalent) and carboxylic acid (3) (1.1 equivalent) stirred 1 to 1.5 hour at-30 ℃ to 0 ℃.

21) mixture with chloroform (3 volume), toluene (1 volume), picoline (2 equivalent), oxalyl chloride (1 equivalent) and carboxylic acid (3) (1.1 equivalent) stirred 10 minutes to 2 hours in-50 ℃ to 10 ℃.

22) the benzotriazole ester with methylene dichloride (20 volume), pyridine (3 equivalent) and carboxylic acid (3) (3 equivalent) stirred 5 hours to 30 hours in 10 ℃ to 50 ℃.

23) with methylene dichloride (20 volume), 2-oxyethyl group-1-ethoxycarbonyl-1,2-dihydroquinoline (2.5 equivalent) and carboxylic acid (3) (2 equivalent) were stirring at room 1 to 15 hour.

24) stir the mixture of the benzene two imide esters (2 equivalent) of diox (10 volume) and carboxylic acid (3) 2～8 hours at 10 ℃～50 ℃.

25) mixture with the succinimide ester (1.5 equivalent) of methyl iso-butyl ketone (MIBK) (10 volume) and carboxylic acid (3) stirred 2～9 hours at 0 ℃～40 ℃.

26) mixture with carbonyl dimidazoles (1.1 equivalent), tetrahydrofuran (THF) (10 volume), N,N-DIMETHYLACETAMIDE (5 volume) and carboxylic acid (3) (1.1 equivalent) arrives stirring at room 1～5 hour at 0 ℃.

27) with dimethyl formamide (5 volume), xylidine (1.3 equivalent), carboxylic acid (3) and by the mixture of your reagent (Vilsmeyer reagent) (1.1 equivalent) of the prepared Wei Ersi eyebrow of dimethyl formamide at stirring at room 1-5 hour.

28) make methylene dichloride (10 volume), dimethylformamide (5 volume), N, N '-dicyclohexyl carbodiimide (1.1 equivalent), picoline (1.2 equivalent) and carboxylic acid (3) (1.1 equivalent) reacted 2～24 hours.

29) with 7-amino-3-(1-methyl-5-tetrazyl)-thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester is dissolved in and contains 2-(2-benzyloxy amide group-4-thiazolyl)-methylene dichloride (50 parts) of 4-carbobenzoxy-(Cbz)-2-butylene acid (1 equivalent), in solution, add N, N '-dicyclohexylcarbodiimide (1 equivalent).After the stirring at room 2 hours, concentrated reaction mixture, resistates is developed in ethyl acetate, filter, remove solid, with the pure system of column chromatography, get 7-(2-benzyloxycarbonyl amino-4-thiazolyl)-4-carbobenzoxy-(Cbz)-2-butylene amido)-3-(1-methyl-5-tetrazyl) thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester.Yield: 90%.

30) at 0 ℃ sodium bicarbonate (2 equivalent), 2-(2-carbobenzoxy-(Cbz)-amino-4-thiazolyl)-4-carbobenzoxy-(Cbz)-2-butylene acid (1.2 equivalent), I-hydroxybenzotriazole (1.2 equivalent), N, N '-dicyclohexylcarbodiimide (1.2 equivalent) He diox (5 parts) join and be dissolved in water (10 parts of) are with in the solution of the 7-amino-3-pyridylmethyl-3-cephem-4-carbonyl chloride in the mixed solution of diox (15 parts).Use hydrochloric acid (5 parts) acidifying and the filtering mixt of 1N after 3.5 hours 0 ℃ of stirring.Filtrate and washing solid acetone (50 parts) are merged, use the silica gel chromatography purifying, lyophilize obtains 7-(2-(2-benzyloxycarbonyl amino-4-thiazolyl)-4-benzyloxycarbonyl-2-butylene amido)-3-picolyl-3-cephem-4-carboxylicesters.Yield: 50.8%.

Embodiment 3(sloughs the carboxylic acid protecting group)

1) will be dissolved in the tertiary butyl in the table 1 in the mixed solution of methylene dichloride (0.3 to 3 part), trifluoroacetic acid (0.3 to 3 part) and methyl-phenoxide (0.5 to 5 part), the solution of methoxybenzyl or phenylbenzene methyl esters was stirred 10 minutes to 3 hours between-10 ℃ to 40 ℃.Concentrate this solution, desolvate and reagent to remove.With benzene or ether washing residue, obtain corresponding acid, its yield is 70～90%.

2) between-10 ℃～10 ℃, aluminum chloride, tin tetrachloride or titanium tetrachloride (3 to 12 equivalent) join the tertiary butyl that table 1 enumerates, benzyl, in methyl-benzyl, the solution to the methylene dichloride (5 to 9 parts) of methoxybenzyl or diphenyl methyl ester and phenylate (2 to 8 parts).Mixture was stirred 1 to 24 hour.With dilute hydrochloric acid and this mixture of water washing, drying, concentrate, obtain corresponding free acid, its yield is 80 to 95%.When t-butoxycarbonyl amino, N-tert-butoxycarbonyl-N-methoxy ethoxy methyl or benzyloxycarbonyl amino existed, then the protecting group on the amino was also sloughed and is stayed amino.

3) 90% formic acid (5 to 6 parts) and methyl-phenoxide (2 to 3 parts) be added to the tertiary butyl that table 1 enumerates, benzyl, to methyl-benzyl, in methoxy-benzyl or the diphenyl methyl ester solution.Mixture was stirred 1 to 4 hour at 50 ℃ to 60 ℃, obtain corresponding carboxylic acid, its yield is 40 to 50%.

4) acetic acid (10 parts) and zinc powder (60 parts) are added in the solution to the nitrobenzyl ester in the table 1 that is dissolved in methylene dichloride (60 parts) go.0 ℃ stir 2 hours after, mixture is filtered removing solid dilute with water, and use chloroform extraction.Extracting solution is washed with water, extract with sodium bicarbonate aqueous solution again.Water layer arrives PH=2 with the salt pickling, and uses dichloromethane extraction.Organic layer washes with water, and drying, and concentrating under reduced pressure obtain corresponding free acid, and its yield is 60～80%.

5) above-mentioned ester can be with following method decarboxylize protective material: having in the presence of 5% palladium charcoal of equal amts, logical hydrogen jolting is 2 hours in diox, under the room temperature.

6) aluminum chloride (9 equivalent) is added 7-(2-(2-benzyloxycarbonyl amino-4-thiazolyl)-4-carbobenzoxy-(Cbz)-2-butylene amido)-3-(1-methyl-5-tetrazyl) go in methyl-phenoxide (12 parts) solution of thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester.After 4 hours, with 5% sodium bicarbonate aqueous solution neutralise mixt, solids removed by filtration is washed with ethyl acetate 0 ℃ of stirring.Water layer hcl acidifying, and with ethyl acetate washing makes it pass through the synthetic adsorbent that a HP-20 or SP-207(are produced by Mitsubishi Chemical Ind) chromatographic column.The material that is adsorbed obtains 7-(2-(2-amino-4-thiazolyl-4-carboxyl-2-butylene amido)-3-(1-methyl-5-tetrazyl with 80% methanol-eluted fractions) sulphomethyl-3-cephem-4-carboxylic acid.Yield: 65%.

7) in 7-(2-(2-benzyloxycarbonyl amino-4-thiazolyl) 4-benzyloxycarbonyl-2-butylene amido)-suspension of 3-picolyl-3-cephem-4-carboxylic acid in phenylate (2 parts) in, in 0 ℃ of methyl-phenoxide (2 parts) solution that adds aluminum chloride (9 equivalent).Stir after 3.5 hours, mixture is with 10% hcl acidifying, and washs with ethyl acetate.Make water layer pass through a Diaion HP-20 chromatographic column.The adsorbed material aqueous solution wash-out that contains 5% acetone.With the eluate lyophilize, obtain 7-(2-(2-amino-4-thiazolyl)-4-carboxyl-2-butylene amido)-the 3-pyridine is for methyl-3-cephem-4-carboxylic acid.Yield: 55%.

8) to above-mentioned 1) to 7) method similar, the free carboxy compound that table 2 is cited, the compound of the corresponding carboxy protective that can enumerate by table 1.

9) 2-ethylhexoate (1.5 mol equivalent), triphenylphosphine (0.5 equivalent) and four triphenylphosphine palladium complexs (125 milligrams) are added to 7 β-(2-(2-carbobenzoxy-(Cbz)-aminothiazole-4-yl)-4-allyloxy carbonyl-2-butylene amido)-go in methylene dichloride (30 milliliters) solution of 3-cephem-4-carboxylic acid benzhydryl ester (3.75 gram) (5 millimole).After 1 hour, use ether diluted mixture thing, 25 ℃ of stirrings to isolate 7 β-(2-(2-carbobenzoxy aminothiazole-4-yl)-4-sodium for hydroxycarbonyl group-2-butylene amido-3-cephem-4-carboxylic acid benzhydryl ester.Yield 94%.This compound is suspended in the water (10 parts), and the phosphate aqueous solution acidifying with 4% is to isolate 7 β-(2-(2-carbobenzoxy aminothiazole base-4-yl)-4-carboxyl-2-butylene amido)-3-cephem-4-carboxylic acid benzhydryl ester.

Sloughing of embodiment 4(amino protecting group)

1) solution that the tert-butoxycarbonyl aminocompound of table 1 being enumerated is dissolved in the mixed solvent of methylene dichloride (0.3 to 3 part), trifluoroacetic acid (0.3 to 3 part) and methyl-phenoxide (0.5 to 5 part) stirred 10 minutes～3 hours at-10 ℃～40 ℃.This solution concentration is desolvated and reagent to remove.Residue washs with benzene, then obtains the corresponding aminocompound enumerated in table 1 or the table 2, and its yield is 70～80%.

2) tert-butoxycarbonyl, benzyloxycarbonyl amino, methyl benzyloxycarbonyl amino, methoxy ethoxy methylamino or the trityl compound of enumerating in the table 1 (1 part) is dissolved in methylene dichloride (5～9 parts), in the mixed solvent of methyl-phenoxide (2～8 parts), aluminum chloride, tin tetrachloride or titanium tetrachloride (3～12 equivalent) are added in the above-mentioned solution at-10 ℃～10 ℃, again mixture were stirred 1 to 24 hour.This mixture by a HP-20 sorbent material post, then obtains the corresponding free aminocompound of enumerating with water layer with dilute hydrochloric acid and water extraction in table 1 or table 2.Its yield is 60～80%.As a tertiary butyl, benzyl, to xylyl, when the ester group of methoxybenzyl or diphenyl-methyl etc. is existed, then the protecting group on the carboxyl is also sloughed and is stayed the free carboxyl.

3) thiocarbamide or N-methyl dithiocarbamate (4 equivalent) and sodium-acetate (2 equivalent) being added to the chloroacetoamide-based compounds of enumerating in the table 1 is dissolved in the solution of tetrahydrofuran (THF) (15 parts) and methyl alcohol (15 parts), placed liquid in room temperature, enriched mixture, dilute with ethyl acetate, the salt water washing, drying, reconcentration.Residue is through chromatographic purification.Obtain corresponding aminocompound.

4) 1 to 3N hydrochloric acid (0.1 to 3 part) is added in the solution of formic acid, acetate or ethanol (10 parts) of formamido-, Schiff's base, silyl amino or the trityl aminocompound enumerated in the table 1.Mixture was at room temperature stirred 1～3 hour.Concentrated reaction mixture with the methylene dichloride dilution, is used sodium bicarbonate aqueous solution and water washing again, is dried and concentrates.Residue ordinary method purifying, the corresponding free amine group compound that obtains enumerating on table 1 or the table 2.

5) 5% palladium charcoal (0.5 part) is added in the solution of the ethanol of benzyloxycarbonyl amino compound cited on the table 1 and ethyl acetate (30 parts, 1: 1).With the hydrogenation mixture jolting, exhaust up to raw material.Reaction mixture is filtered removing solid, and concentrate, promptly get corresponding aminocompound cited on table 1 or the table 2.

Embodiment 5(esterification)

(R ³(or) R ⁶=diphenyl-methyl)

1) diphenyl diazomethane (2 equivalent) is added to compound (I, R ³And/or R ⁶In=methylene dichloride H) and the solution of methyl alcohol (each 10 parts of weight).Stir after 1 hour, with hydrochloric acid and water washing mixture, drying, reconcentration.The residue re-crystallizing in ethyl acetate promptly obtains corresponding benzhydryl ester (I, R ³(or) R ⁶=POM).

2), under the icy salt solution cooling, be added to compound (I, R PIVALIC ACID CRUDE (25) iodomethyl ester (1 to 2 equivalent) ³And/or R ⁶=K) N is in the solution of N-dimethylformamide (2～5 parts).Stirred 15 minutes to 2 hours, and with mixture diluted, washed drying, vacuum concentration with frozen water and sodium bicarbonate aqueous solution with ethyl acetate.Residue is recrystallization from ethyl acetate, promptly gets the oxy acid methyl neopentyl ester of carboxylic acid cited in the table 3.

3) with top 2) described in sylvite replace with sodium salt, under similarity condition, can obtain same product.

4) with top 2) described in oxy acid methyl neopentyl ester (250 milligrams), cereal starch (150 milligrams) and Magnesium Stearate (5 milligrams) mix mutually, make particulate state, incapsulate with ordinary method.This capsule (2～3 capsules) can be oral for the patient who suffers from intestinal bacteria (E.Coli) infection, treats this disease.

(R ³And/or R ⁶=AOM)

5) with acetate iodomethyl ester alternative above 2) in PIVALIC ACID CRUDE (25) iodomethyl ester, under same reaction conditions, can obtain the cited corresponding acetoxyl methyl ester of table 3.

Embodiment 6(amine salt)

In table 2, add acetonitrile in the dilute hydrochloric acid solution of cited aminocompound,, obtain the very high corresponding hydrochloride of yield with filter method collecting precipitation thing.

Claims (7)

1, the preparation method of 7 β shown in the following formula-(carboxyl alkenoyl amino)-3-cephem-4-carboxylic acid cpd:

R is amino or the thiazolyl or the thiadiazolyl group of the amino replacement of protection in the formula,

R ¹Be hydrogen,

R ²Be low-grade alkylidene,

R ³Be hydrogen atom, the salify metal, or ester forms group,

R ⁴Be hydrogen or methoxyl group,

R ⁵Be hydrogen, vinyl, cyano group vinyl, trifluoro-propenyl, acetyl-o-methyl, carbamyl oxygen methyl, triazole thiomethyl, methyltetrazole sulfidomethyl, or not by or by amino, aminomethyl or methyl substituted thiadiazoles thiomethyl,

R ⁶Be hydrogen atom, salify metal, or ester formation group,

X is sulphur or sulfinyl,

Amido and carboxyl substituent are cis position on the two keys of 7-amido,

This method comprises: use the carboxyl alkenoic acid shown in the following formula:

(R, R in the formula ¹, R ²And R ³Definition as mentioned above) or its easy response derivative with 7 beta-aminos shown in the following formula-3-cephem-4-carboxylic acid derivative:

(R in the formula ⁴, R ⁵, R ⁶Same as above with the meaning of X) or its easy response derivative amidation, use 3～30 parts of volumes to be selected from the solvent of hydrocarbon, ester, ketone, acid amides and water in this amidate action,

Also use 1～4 equivalent to be selected from the condensing agent of dewatering agent and halogenating agent in this amidate action,

Also use 1～4 equivalent to be selected from tertiary amine in this amidate action, the alkali of aromatic base and mineral alkali,

Also use the acid derivative of 1～3 normal easy reaction in this amidate action, it is selected from:

The ester that free acid, carboxylic acid halides and hydroxylamine derivative form, symmetric anhydride, the nitration mixture acid anhydride that forms with halogenated-chain acid or phosphoric acid derivatives.

This amidate action carried out between-70 ℃ and 67 ℃ 10 minutes to 24 hours;

With in the alkali and following formula shown in 7 β-(carboxyl alkenoyl amino)-3-cephem-4-carboxylic acid

R in the formula, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶As above define with X, but R ³And R ⁶At least one is a hydrogen;

Following formula 7 β-(carboxyl alkenoyl the amino)-3-cephem-4-carboxylic acid that maybe will have protecting group goes protection

X in the formula, R, R ¹, R ², R ³, R ⁴, R ⁵And R ⁶As above definition, but R ³, R ⁵And R ⁶In at least one has a protecting group.

2, according to the method for claim 1, obtain one of following compounds:

7 β-(2-(2-aminothiazole-4-yl)-4-carboxyl-2-butylene amido)-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-4-carboxyl-2-butylene amido)-3-vinyl-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-4-carboxyl-2-butylene amido)-3-trifluoro-propenyl-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-4-carboxyl-2-butylene amido)-3-acetyl-o-methyl-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-4-carboxyl-2-butylene amido)-3-carbamyl oxygen methyl-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-4-carboxyl-2-butylene amido)-3-triazole thiomethyl-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-4-carboxyl-2-butylene amido)-3-thiadiazoles thiomethyl-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-4-carboxyl-2-butylene amido)-3-methyltetrazole sulfidomethyl-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-5-carboxyl-2-amylene amido)-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-6-carboxyl-2-hexenoyl amino)-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-4-carboxyl-2-amylene amido)-3-cephem-4-carboxylic acid,

7 β-(2-(2-aminothiazole-4-yl)-4-carboxyl-4-methyl-2-amylene amido)-3-cephem-4-carboxylic acid,

3, according to the process of claim 1 wherein that R is the aminothiazole base that can be protected with carbobenzoxy-(Cbz), tertbutyloxycarbonyl, methyl carbobenzoxy-(Cbz) formyl radical, chloracetyl or benzylidene.

4, according to the process of claim 1 wherein R ²For can branched C _1-3Alkylidene group.

5, according to the process of claim 1 wherein R ²Be methylene radical.

6, according to the process of claim 1 wherein R ³For hydrogen, methyl, the tertiary butyl, benzyl, methyl-benzyl, to methoxybenzyl or to nitrobenzyl.

7, according to the process of claim 1 wherein R ⁶For hydrogen, diphenyl-methyl or to methoxybenzyl.