CN101235044B - Method for preparing faropenem daloxate - Google Patents
Method for preparing faropenem daloxate Download PDFInfo
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Abstract
The invention relates to a preparation method of faropenem medoxomil, belonging to chemical synthesis technical field, which is characterized in that faropenem and 4-halogenated methyl radical-5-methyl-1, 3-dioxane cyclopentene-2-ketone, in an alkali condition and a solvent A, via a phase transfer catalyst and a reaction promoter containing iodine are synthesized to obtain faropenem medoxomil, or the inorganic salt of faropenem medoxomil and 4-halogenated methyl radical-5-methyl-1, 3-dioxane cyclopentene-2-ketone, in a solvent B, via a phase transfer catalyst and reaction promoter containing iodine are synthesized to obtain faropenem medoxomil. The method has simple operation, mild reaction and saved cost, while the synthesized faropenem medoxomil has high yield and purity.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to a kind of preparation method of Faropenem ester.
Background technology
Faropenem ester (faropenem medoxomil), chemistry (5-methyl-2-oxo-1 by name, the 3-Dioxol-4-yl) methyl (5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran (THF)-2-yl]-4-sulfo--1-azabicyclic [3.2.0] hept-2-ene"-2-carboxylicesters.It is the penems antimicrobial drug of first oral administration, is the oral prodrugs of the rare class antibiotic Faropenum of novel carbon mould, is converted into the Faropenem with anti-microbial activity after the oral absorption in vivo.This product is by get profit (Suntory) companies exploitation of Japan three, now licenses to German Bayer company, and the research code name is Bay56-6854.This product is carried out III phase clinical study in the Germany and the U.S. at present, estimates will introduce to the market soon.
At present, relevant Faropenem ester preparation method has two kinds, and the reference that wherein a kind of method relates to has: U.S. Pat 5885981, world patent WO 9203442; Zhu Xueyan, Liu Xiangkui, Yuan Zhedong, etc. synthetic [J] of Faropenem sodium. Chinese Journal of Pharmaceuticals, 2007,38 (3): 174-176 etc., the Faropenem ester specific embodiments that provides in these documents is as follows:
With the Faropenem allyl ester is raw material, with sodium bicarbonate 36.1g and 5,5-dimethyl-hydroresorcinol 36.1g drops in the 250ml water and stirs 10min, the acetone 1.2L solution, triphenyl phosphine 5.2g and the acid chloride 2.5g that add Faropenem allyl ester 140g successively, stirring at room 2hr.Suction filtration, filtrate are cooled to 0 ℃, add small amount of seeds, have faint yellow solid to separate out, suction filtration, and (10: 3,1.3L) recrystallization got off-white color 3 pure product 128.5g, yield 85% to filter cake 139.5g with acetone-water.Get the Faropenem sodium 119g of step preparation, 700mlDMF puts in the exsiccant reaction flask, stirs down and drips 4-iodomethyl-5-methyl isophthalic acid, and 3-Er Evil cyclopentenes-2-ketone 48.3g dropwises, at room temperature stirring reaction 5hr.After reaction finishes, in reaction solution, add 500ml water, and divide three extractions with ethyl acetate 2400ml, separate organic layer.Then with 1500ml water washing organic layer, the organic layer anhydrous sodium sulfate drying, suction filtration is evaporated to driedly, and residue gets Faropenem ester 61.2g, yield 45.6% by column chromatography purification.Total recovery is in Faropenem allyl ester about 39%.
Reaction formula 1:
The reference that another kind method relates to has: European patent EP 0612749, and Japanese Patent JP 1994192270 and other documents have: J shenyang pharm univ 2001,18:20-22; Bioorg Med Chem 1997,5:1389-99; J Antibiot 1988,41:1685-93 etc., the Faropenem ester specific embodiments that provides in these documents is as follows:
With N; dinethylformamide (DMF) is a solvent; 4-chloromethyl-5-methyl isophthalic acid; 3-Er Evil cyclopentenes-2-ketone (DMDO-Cl) is raw material; under the sodium bicarbonate alkaline condition; potassiumiodide is made catalyzer; reaction generates intermediate 3 with potassium formiate; intermediate 3 reflux in methyl alcohol is decomposed into 4-hydroxymethyl-5-methyl isophthalic acid; 3-Er Evil cyclopentenes-2-ketone (intermediate 4); intermediate 4 generates intermediate 5 with the oxalyl chloride effect in methylene dichloride; intermediate 5 again with Faropenem intermediate (3S; 4R)-3-[(1R)-(tertiary butyl dimethyl Si base) ethyl]-4-[(2R)-and tetrahydrofuran (THF) formyl sulfenyl] nitrogen heterocyclic din-2-ketone condensation prepared intermediate 6 under triethylamine catalysis; intermediate 6 is catalyzed into ring preparation intermediate 7 through three butoxy phosphorus in xylene solution, intermediate 7 at last in THF under tetrabutylammonium and acetic acid catalysis deprotection generate the Faropenem ester.With 4-chloromethyl-5-methyl isophthalic acid, 3-two Evil cyclopentenes-2-ketone is roughly counted, and total recovery is greatly between 30～35% scopes.
Reaction formula 2:
The preparation method who uses above document to provide prepares this product, and we find that the yield of these methods and quality are all undesirable.The final product quality aspect, HPLC (area normalization method) content is about 95%, and it is extremely difficult further to improve its quality.The reaction yield aspect differs greatly with the yield of bibliographical information generally about 15%.Make product through polystep reaction in addition, and obtain behind the product demand pole purification by chromatography, the tetrabutylammonium of mentioning in the document costs an arm and a leg, industrial production cost height.Utilize above method, by reducing or the rising temperature of reaction, change post-treatment condition, prolong methods such as reaction times, though on reaction yield and final product quality, increase, but still can not prepare the Faropenem ester that meets pharmaceutical quality, and yield and quality still can not reach the data that document provides far away.
Summary of the invention
The purpose of this invention is to provide a kind of easy and simple to handle, reaction time is short, the preparation method of cost-effective Faropenem ester, and institute's synthetic Faropenem ester has high yield, high quality, low cost and meets the characteristics of pharmaceutical quality, and the present invention is a kind of preparation method with good industrialized condition.
Purpose of the present invention can reach by following measure:
A kind of method for preparing the Faropenem ester is characterized in that Faropenem and 4-halogenated methyl-5-methyl isophthalic acid, and 3-two Evil cyclopentenes-2-ketone uses phase-transfer catalyst and contains the synthetic Faropenem ester of reaction promotor of iodide ion in solvent orange 2 A under alkaline condition; Perhaps with the inorganic salt and the 4-halogenated methyl-5-methyl isophthalic acid of Faropenem, 3-two Evil cyclopentenes-2-ketone uses phase-transfer catalyst and contains the synthetic Faropenem ester of reaction promotor of iodide ion in solvent B.
The inorganic salt of above-mentioned Faropenem are alkali-metal Faropenem salt; Wherein, be preferably Faropenem lithium, Faropenem sodium, Faropenem potassium, the most preferable method faropenem.
Above-mentioned 4-halogenated methyl-5-methyl isophthalic acid, 4-halogenated methyl-5-methyl isophthalic acid in 3-Er Evil cyclopentenes-2-ketone, 3-Er Evil cyclopentenes-2-ketone is 4-fluoro methyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone, 4-chloro methyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone, 4-bromomethyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone or 4-iodo-methyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone; Wherein, be preferably 4-chloro methyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone.
When described reaction Faropenem was raw material, reaction system was an alkalescence, and the PH preferable range is 7.5～8.5; Faropenem generates salt under alkaline condition.The reagent of control alkaline condition is alkaline carbonate, alkali metal hydrocarbonate, lithium hydroxide, the organic monoacid salt of potassium hydroxide, sodium hydroxide, tertiary amine, ring-type organic bases, tertiary amine organic monoacid salt or ring-type organic bases; Described tertiary amine is triethylamine, Trimethylamine 99, Tributylamine, N, N-dimethyl amine, N, N-dimethyl Isopropylamine, N, N-diethyl Isopropylamine; Described ring-type organic bases is the piperidines of pyridine, N-replacement, the morpholine that N-replaces, preferred N-methyl or N-ethylpiperidine, N-methyl or N-ethylmorpholine, and described tertiary amine organic monoacid salt can be triethylamine acetate; The organic monoacid salt of described ring-type organic bases can be N-methylmorpholine acetate, N-methyl piperidine acetate etc.Wherein, preferred alkalescence control reagent is salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate, Quilonum Retard, lithium bicarbonate, N-methyl or N-ethylmorpholine, N-methyl or N-ethylpiperidine; Particularly preferred alkaline reagents is a salt of wormwood, Quilonum Retard, saleratus and N-methylmorpholine; Only is N-methylmorpholine.
Above-mentioned solvent orange 2 A is non-proton type polar solvent, and described non-proton type polar solvent can be N, dinethylformamide, methyl-sulphoxide, N,N-dimethylacetamide, 1, the 3-DMPU, acetone, tetrahydrofuran (THF), dioxane, ethyl acetate, one or more blended solvents of acetonitrile equal solvent; Wherein, preferred 1,3-DMPU, methyl-sulphoxide, acetone, one or more blended solvents in dioxane, the tetrahydrofuran (THF); Particularly preferred solvent is 1,3-DMPU, one or both blended solvents in the tetrahydrofuran (THF); Optimum solvent is 1, the 3-DMPU.
Above-mentioned reaction adds phase-transfer catalyst, and described phase-transfer catalyst is polyoxyethylene glycol, crown ether or quaternary ammonium salt; Specifically can be poly(oxyethylene glycol) 400, Polyethylene Glycol-600, C
1～C
4The straight chain quaternary ammonium salt, N, N-two replace that (substituting group is C
1～C
4Alkane) piperidines, morpholine, the formed quaternary ammonium salt of Pyrrolidine, benzo 18-hat-6, dibenzo 18-hat-6,18-hat-6 etc.Preferred Polyethylene Glycol-600,18-hat-6, N, N-lupetidine, N, N-thebaine; The best is 18-hat-6 or N, the N-thebaine.
Above-mentioned temperature of reaction is between-20 ℃～100 ℃, and preferred-10 ℃～40 ℃, the best is 0 ℃～20 ℃; The reaction times of above-mentioned reaction is 5min～24hr, is preferably 4～8hr.
Above-mentioned solvent B is an acetone, tetrahydrofuran (THF), dioxane, benzene, toluene, ethyl acetate, acetonitrile, methyl alcohol, ethanol, one or more mixed solvent in the Virahol. Wherein, wherein preferred acetone, methyl alcohol, one or more mixed solvent in tetrahydrofuran (THF) and the dioxane.The best is one or both mixed solvents in acetone and the tetrahydrofuran (THF).
The above-mentioned reaction promotor that contains iodide ion is alkali-metal iodized salt or the quaternary ammonium salt that comprises iodide ion; Described alkali-metal iodized salt is a lithium iodide, sodium iodide, potassiumiodide; The described quaternary ammonium salt that comprises iodide ion is the iodide of open chain quaternary ammonium salt, the iodide of five yuan or six-membered cyclic quaternary ammonium salt; The iodide of described open chain quaternary ammonium salt can be iodinating C
1～C
4Quaternary ammonium salt, as tetramethylammonium iodide, tetraethylammonium iodide, iodate trimethylammonium second ammonium, different third ammonium of iodate trimethylammonium, different third ammonium of iodate triethyl etc.; The iodide of described five yuan or six-membered cyclic quaternary ammonium salt can be N, and N-two replaces that (substituting group is C
1～C
4Alkane) piperidines, morpholine, the quaternary ammonium salt that Pyrrolidine and iodide ion form, as:
R
1, R
2=C
1～C
4Alkane.
The preferred sodium iodide of the present invention, potassiumiodide, different third ammonium of iodate trimethylammonium, iodate N, the N-lupetidine most preferably is iodate N, the N-lupetidine.
The present invention specifically can prepare as follows:
The method of-kind of synthetic Faropenem ester, this method comprise compound (1) and compound (2) in the presence of catalyzer (3) and reaction promotor (4), synthesize the Faropenem ester.
Compound (1) is:
Compound (2) is:
Compound (3) is:
Compound (4) is: MI M=Li, Na, K
R
1, R
2=C
1～C
4Alkane
This is reflected in the above-mentioned solvent and carries out, temperature of reaction is at-20 ℃～100 ℃ and stirring reaction 5min～24hr, filter, filtrate adds an amount of elutriation crystalline substance, use organic solvent extraction after perhaps adding suitable quantity of water in the filtrate, organic layer saturated common salt water washing, drying and dehydrating, concentrating under reduced pressure is used the appropriate solvent recrystallization again.
After reaction finished, concrete steps can directly add isopyknic water, 0 ℃～20 ℃ following stirring and crystallizing and Faropenem ester crude product, also can after adding equal-volume water, use the organic solvent extraction that the Faropenem ester is had good solubility.For example: (first) ethyl acetate, (first) propyl acetate, (first) isopropyl acetate, (first) butylacetate, organic acid acetic kind solvents such as the special pentyl ester of (first) acetate also can be used chloroform, methylene dichloride, the mixed solvent of one or more of ether equal solvent extracts.Preferred methylene dichloride and ethyl acetate.The optimum extraction solvent is an ethyl acetate.
Above-mentioned reaction gained crude product can be at toluene, methyl alcohol, ethanol, acetone, ethyl acetate, acetonitrile, dioxane, tetrahydrofuran (THF), methylene dichloride, normal hexane, hexanaphthene, recrystallization in one or more of sherwood oil equal solvent, also can be more than aqueous recrystallization in one or more solvents.Particular methanol, ethanol, the mixing solutions of acetone and their aqueous solution and ethyl acetate and normal hexane.
The method that the present invention prepares the Faropenem ester can be with compound (1), (2), (3) and (4) be suspended in the reaction solvent, 0 ℃～20 ℃ stirring reaction a few hours add after the suitable quantity of water then again 0 ℃～20 ℃ following stirring and crystallizing, also can be after adding suitable quantity of water, use ethyl acetate extraction, the saturated common salt water washing, anhydrous magnesium sulfate drying, steaming removes ethyl acetate and gets Faropenem ester crude product then.Carry out recrystallization again and prepare the Faropenem ester that meets medicinal standard.
Beneficial effect of the present invention: use the inventive method to prepare the Faropenem ester, simple to operate, save cost, reaction temperature and, yield and finished product purity height, the inventive method provides to such an extent that the preparation method has following characteristics than document: 1) use neutrality or weakly alkaline environment low-temp reaction, avoided high temperature bring side reaction, helping final product quality must improve.2) use phase-transfer catalyst and the reaction promotor that contains iodide ion, help reacting completely.When reducing side reaction, also improve reaction yield greatly, helped the reduction of cost.3) after reaction finishes, add that isopyknic water helps unreacted raw material and inorganic salt separate with product, simplified post-processing step, improved purity and yield.
Embodiment
By the specific embodiments of following examples form, foregoing of the present invention further is elaborated, for a person skilled in the art, this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.
Embodiment 1
Add the 570g Faropenem in the 10000mL there-necked flask, 2500mL1, the 3-DMPU after the stirring at room dissolving, adds 260g K
2CO
3, 50g 18-hat-6,70g KI behind the stirring 1hr, is cooled to 0～5 ℃, drips 320g 4-methyl-5-chloro methyl isophthalic acid, 3-dioxole-2-ketone (DMDO-Cl), control reaction temperature is between 0～5 ℃.Drip and finish, the synthermal 6hr that stirs down.Add 2500mL frozen water and 3000mL ethyl acetate and stirred 20 minutes, leave standstill, divide and get organic layer, the water washing of 2500mL saturated common salt, anhydrous magnesium sulfate drying.Remove by filter siccative, be evaporated to dried under 40 ℃ of the filtrates.The residue ethyl acetate: the mixing solutions recrystallization of normal hexane=2: 1, Faropenem ester 687g, yield 86.5%, mp:122～125 ℃, [M+1]
+: 398.41.
Embodiment 2
Add the 50gN-methylmorpholine in the 1000mL there-necked flask, the 500mL methylene dichloride, the 100mL methyl iodide is behind the temperature rising reflux 3hr, be evaporated to dried yellow iodate N, N-thebaine solid adds this solid in the 10000mL there-necked flask, adds 4000mL acetone, stir and add Faropenem 570g down more respectively, 50g18-hat-6, stirring at room 30 minutes is transferred pH=7.5～8.5 with N-methylmorpholine.Ice bath is cooled to 0～5 ℃, drips 320g DMDO-Cl, and control reaction temperature is between 0～5 ℃.Drip and finish, the synthermal 6hr that stirs down.Add 3000mL water, 0～5 ℃ of stirring and crystallizing 4hr.Filter, collect solid.40 ℃ of following vacuum-dryings get yellow Faropenem ester crude product, the methanol aqueous solution recrystallization with 75%, the 670g finished product, yield 84.4%, mp:123～125.5 ℃, [M+1]
+: 398.41.
Embodiment 3
Add the 57g Faropenem in the 1000mL there-necked flask, the 250mL methyl-sulphoxide after the stirring at room dissolving, adds 32gNaHCO
3, 5g 18-hat-6, the 7g sodium iodide, behind the stirring 3hr, under the cooling, (control reaction temperature is between 20～25 ℃ for 4-methyl-5-chloro methyl isophthalic acid, 3-dioxole-2-ketone (DMDO-Cl) to drip 32g.Drip and finish, the synthermal 6hr that stirs down.Add 250mL frozen water and 300mL ethyl acetate and stirred 20 minutes, leave standstill, divide and get organic layer, the water washing of 250mL saturated common salt, anhydrous magnesium sulfate drying.Remove by filter siccative, be evaporated to dried under 40 ℃ of the filtrates.The residue ethyl acetate: the mixing solutions recrystallization of normal hexane=2: 1, Faropenem ester 66g, yield 83.1%, mp:122～125 ℃, [M+1]
+: 398.41.
Embodiment 4
Add 5g N-methylmorpholine, 50mL methylene dichloride, 10mL methyl iodide in the 100mL there-necked flask, behind the temperature rising reflux 3hr, be evaporated to dried yellow iodate N, N-thebaine solid adds this solid in the 1000mL there-necked flask, add the 400mL dioxane, stir down and add Faropenem 57g more respectively, 5g N, N-lupetidine, stirring at room 30 minutes is transferred pH=7.5～8.5 with triethylamine.Be water-cooled to 15～20 ℃, drip 32g DMDO-Cl, control reaction temperature is between 15～20 ℃.Drip and finish, the synthermal 6hr that stirs down.Add 300mL water, 0～5 ℃ of stirring and crystallizing 4hr.Filter, collect solid.40 ℃ of following vacuum-dryings get yellow Faropenem ester crude product, the methanol aqueous solution recrystallization with 75%, the 65.5g finished product, yield 82.5%, mp:123～125.5 ℃, [M+1]
+: 398.41.
Embodiment 5
Add the 5g N-methylmorpholine in the 100mL there-necked flask, the 50mL methylene dichloride, the 10mL methyl iodide is behind the temperature rising reflux 3hr, be evaporated to dried yellow iodate N, N-thebaine solid adds this solid in the 1000mL there-necked flask, adds the 400mL dioxane, stir and add Faropenem 57g down more respectively, 5g dibenzo 18-hat-6, stirring at room 30 minutes is transferred pH=7.5～8.5 with 10%NaOH.Be water-cooled to 15～20 ℃, drip 32g DMDO-Cl, control reaction temperature is between 15～20 ℃.Drip and finish, the synthermal 6hr that stirs down.Add 300mL water, 0～5 ℃ of stirring and crystallizing 4hr.Filter, collect solid.40 ℃ of following vacuum-dryings get yellow Faropenem ester crude product, the methanol aqueous solution recrystallization with 75%, the 65g finished product, yield 81.9%, mp:123～125.5 ℃, [M+1]
+: 398.41.
Embodiment 6
Add 57g Faropenem, 250mLN, dinethylformamide in the 1000mL there-necked flask, after the stirring at room dissolving, add 25g N-methyl piperidine, 15g acetic acid, 5g Tetrabutyl amonium bromide, 50g iodate trimethylammonium second ammonium, after stirring 1hr, be cooled to 0～5 ℃, drip 32g 4-methyl-5-chloro methyl isophthalic acid, 3-dioxole-2-ketone (DMDO-Cl), control reaction temperature is between 0～5 ℃.Drip and finish, the synthermal 6hr that stirs down.Add 250mL frozen water and 300mL ethyl acetate and stirred 20 minutes, leave standstill, divide and get organic layer, the water washing of 250mL saturated common salt, anhydrous magnesium sulfate drying.Remove by filter siccative, be evaporated to dried under 40 ℃ of the filtrates.The residue ethyl acetate: the mixing solutions recrystallization of normal hexane=2: 1, Faropenem ester 67.5g, yield 85.0%, mp:122～125 ℃, [M+1]
+: 398.41.
Embodiment 7
Add 57g Faropenem, 100mL tetrahydrofuran (THF) and 150mL1,3-DMPU in the 1000mL there-necked flask, after the stirring at room dissolving, add the 14g triethylamine, 15g acetic acid, 5g poly(oxyethylene glycol) 400,7gKI, after stirring 1hr, be cooled to 0～5 ℃, drip 32g 4-methyl-5-chloro methyl isophthalic acid, the 40ml mixing solutions of 3-dioxole-2-ketone (DMDO-Cl) and methyl alcohol, control reaction temperature is between 0～5 ℃.Drip and finish, the synthermal 6hr that stirs down.Add 250mL frozen water and 300mL ethyl acetate and stirred 20 minutes, leave standstill, divide and get organic layer, the water washing of 250mL saturated common salt, anhydrous magnesium sulfate drying.Remove by filter siccative, be evaporated to dried under 40 ℃ of the filtrates.The residue ethyl acetate: the mixing solutions recrystallization of normal hexane=2: 1, Faropenem ester 67.8g, yield 85.4%, mp:122～125 ℃, [M+1]
+: 398.41.
Embodiment 8
Add the 614g Faropenem sodium in the 10000mL there-necked flask, 1500mL tetrahydrofuran (THF) (THF) and 1000mL acetone, the stirring at room dissolving, add the 50g Polyethylene Glycol-600, the 80g tetramethylammonium iodide, after stirring, ice bath is cooled to 0～5 ℃, drip 320g DMDO-Cl, control reaction temperature is between 0～5 ℃.Drip and finish, the synthermal 8hr that stirs down.Add 2500mL frozen water and 2500mL ethyl acetate and stirred 30 minutes, leave standstill, divide and get organic layer, organic layer 2500mL saturated common salt water washing, anhydrous magnesium sulfate drying.Remove by filter siccative, be evaporated to dried under 40 ℃ of the filtrates.The residue ethyl alcohol recrystallization, Faropenem ester 577g, yield 83.3%, mp:120～123 ℃, [M+1]
+: 398.41.
Embodiment 9
Add 48g N-methyl piperidine in the 1000mL there-necked flask, the 500mL methylene dichloride, the 100mL methyl iodide behind the temperature rising reflux 3hr, is evaporated to dried.Get yellowish brown iodate N, N-lupetidine solid, this solid is added in the 10000mL there-necked flask, add 4000mL acetone, stir and distinguish addition method faropenem 614g down again, 50g N, the N-lupetidine stirred 30 minutes under the room temperature, and ice bath is cooled to 0～5 ℃, drip 285g DMDO-F, control reaction temperature is between 0～5 ℃.Drip and finish, 0～5 ℃ is stirred 8hr.Add 3000mL water, 5 ℃ of following stirring and crystallizing 6hr.Filter, collect and separate out solid.40 ℃ of following vacuum-dryings, gained Faropenem ester crude product acetone: the mixed solvent recrystallization of hexanaphthene=2: 1, the 596g finished product, yield 86.1%, mp:120～124 ℃, [M+1]
+: 398.41.
Embodiment 10
Add 64.2g Faropenem potassium in the 1000mL there-necked flask, 250ml toluene, the stirring at room dissolving, add the 5g cetyl trimethylammonium bromide, different third ammonium of 8g iodate trimethylammonium after stirring, is water-cooled to 15～20 ℃, the 40ml mixing solutions of Dropwise 5 2gDMDO-I and methyl alcohol, control reaction temperature is between 15～20 ℃.Drip and finish, the synthermal 8hr that stirs down.Add 250mL frozen water and 250mL ethyl acetate and stirred 30 minutes, leave standstill, divide and get organic layer, organic layer 250mL saturated common salt water washing, anhydrous magnesium sulfate drying.Remove by filter siccative, be evaporated to dried under 40 ℃ of the filtrates.The residue ethyl alcohol recrystallization, Faropenem ester 56.5g, yield 81.6%, mp:120～123 ℃, [M+1]
+: 398.41.
Embodiment 11
Add 4.8g N-methyl piperidine in the 100mL there-necked flask, 50mL methylene dichloride, 10mL methyl iodide, behind the temperature rising reflux 3hr, be evaporated to dried, yellowish brown iodate N, N-lupetidine solid adds this solid in the 1000mL there-necked flask, adds the 400mL dioxane, stir and add Faropenem lithium 58.6g down more respectively, 5g benzo 18-hat-6 stirred 30 minutes under the room temperature, was water-cooled to 15～20 ℃, drip 42g DMDO-Br, control reaction temperature is between 15～20 ℃.Drip and finish, 0～5 ℃ is stirred 8hr.Add 300mL water, 5 ℃ of following stirring and crystallizing 6hr.Filter, collect and separate out solid.40 ℃ of following vacuum-dryings, gained Faropenem ester crude product acetone: the mixed solvent recrystallization of hexanaphthene=2: 1, the 59g finished product, yield 85.4%, mp:120～124 ℃, [M+1]
+: 398.41.
Embodiment 12
Add 4.2g N-methylpyrrole in the 100mL there-necked flask, 50mL methylene dichloride, 8.6mL methyl iodide, behind the temperature rising reflux 3hr, be evaporated to dried, yellowish brown iodate N, N-dimethyl pyrrole solid adds this solid in the 1000mL there-necked flask, adds the 400mL dioxane, stir down and add Faropenem lithium 58.6g more respectively, 5gN, N-thebaine, stirred 30 minutes under the room temperature, be water-cooled to 15～20 ℃, drip 42g DMDO-Br, control reaction temperature is between 15～20 ℃.Drip and finish, 0～5 ℃ is stirred 8hr.Add 300mL water, 5 ℃ of following stirring and crystallizing 6hr.Filter, collect and separate out solid.40 ℃ of following vacuum-dryings, gained Faropenem ester crude product acetone: the mixed solvent recrystallization of hexanaphthene=2: 1, the 58.6g finished product, yield 84.6%, mp:120～124 ℃, [M+1]
+: 398.41.
Claims (14)
1. method for preparing the Faropenem ester, it is characterized in that with Faropenem and 4-halogenated methyl-5-methyl isophthalic acid 3-two Evil cyclopentenes-2-ketone uses phase-transfer catalyst and contains the synthetic Faropenem ester of reaction promotor of iodide ion under alkaline condition in solvent orange 2 A; Perhaps with the inorganic salt and the 4-halogenated methyl-5-methyl isophthalic acid of Faropenem, 3-two Evil cyclopentenes-2-ketone uses phase-transfer catalyst and contains the synthetic Faropenem ester of reaction promotor of iodide ion in solvent B; Wherein, described solvent orange 2 A is non-proton type polar solvent, described solvent B is one or more mixed solvents in acetone, tetrahydrofuran (THF), dioxane, benzene, toluene, ethyl acetate, acetonitrile, methyl alcohol, ethanol, the Virahol, the inorganic salt of described Faropenem are alkali-metal Faropenem salt, and described alkaline condition pH scope is 7.5～8.5; Described phase-transfer catalyst is a polyoxyethylene glycol, crown ether or quaternary ammonium salt, and the described reaction promotor that contains iodide ion is alkali-metal iodized salt or the quaternary ammonium salt that comprises iodide ion.
2. the method for preparing the Faropenem ester according to claim 1, it is characterized in that described 4-halogenated methyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone is 4-fluoro methyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone, 4-chloro methyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone, 4-bromomethyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone or 4-iodo-methyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone.
3. the method for preparing the Faropenem ester according to claim 2 is characterized in that described 4-halogenated methyl-5-methyl isophthalic acid, is 4-chloro methyl-5-methyl isophthalic acid in 3-two Evil cyclopentenes-2-ketone, 3-two Evil cyclopentenes-2-ketone.
4. the method for preparing the Faropenem ester according to claim 1, it is characterized in that described non-proton type polar solvent is N, dinethylformamide, methyl-sulphoxide, N, N-N,N-DIMETHYLACETAMIDE, 1, one or more mixed solvents in 3-DMPU, acetone, tetrahydrofuran (THF), dioxane, ethyl acetate, the acetonitrile.
5. the method for preparing the Faropenem ester according to claim 4 is characterized in that described non-proton type polar solvent is 1, one or more mixed solvents in 3-DMPU, methyl-sulphoxide, acetone, dioxane, the tetrahydrofuran (THF).
6. the method for preparing the Faropenem ester according to claim 1, the reagent that it is characterized in that controlling alkaline condition is the organic monoacid salt of alkaline carbonate, alkali metal hydrocarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, tertiary amine, ring-type organic bases, tertiary amine organic monoacid salt or ring-type organic bases.
7. the method for preparing the Faropenem ester according to claim 6 is characterized in that described alkaline carbonate is salt of wormwood, yellow soda ash, Quilonum Retard; Alkali metal hydrocarbonate is saleratus, sodium bicarbonate, lithium bicarbonate; Tertiary amine is triethylamine, Trimethylamine 99, N, N-dimethyl amine, N, N-dimethyl Isopropylamine, N, N-diethyl Isopropylamine; Described ring-type organic bases is the piperidines of pyridine, N-replacement, the morpholine that N-replaces; Described tertiary amine organic monoacid salt is triethylamine acetate; The organic monoacid salt of described ring-type organic bases is N-methylmorpholine acetate, N-methyl piperidine acetate.
8. the method for preparing the Faropenem ester according to claim 6 is characterized in that described ring-type organic bases is N-methyl or N-ethylmorpholine, N-methyl or N-ethylpiperidine.
9. the method for preparing the Faropenem ester according to claim 1 is characterized in that described phase-transfer catalyst is Polyethylene Glycol-600,18-hat-6.
10. the method for preparing the Faropenem ester according to claim 1, the inorganic salt that it is characterized in that described Faropenem are Faropenem lithium, Faropenem sodium, Faropenem potassium.
11. the method for preparing the Faropenem ester according to claim 1 is characterized in that described alkali-metal iodized salt is lithium iodide, sodium iodide or potassiumiodide; The iodide of the iodide that the described quaternary ammonium salt that comprises iodide ion is the open chain quaternary ammonium salt, five yuan or six-membered cyclic quaternary ammonium salt.
12. the method for preparing the Faropenem ester according to claim 11, the iodide that it is characterized in that described open chain quaternary ammonium salt are tetramethylammonium iodide, tetraethylammonium iodide, iodate trimethylammonium second ammonium, different third ammonium of iodate trimethylammonium, different third ammonium of iodate triethyl; The iodide of described five yuan or six-membered cyclic quaternary ammonium salt are
13. the method for preparing the Faropenem ester according to claim 1 is characterized in that the reaction times is 5min～24hr, temperature of reaction is-20 ℃～100 ℃.
14. the method for preparing the Faropenem ester according to claim 13 is characterized in that the reaction times is 4～8hr, temperature of reaction is 0～20 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5885981A (en) * | 1990-08-20 | 1999-03-23 | Suntory Limited | Antibacterial penem esters derivatives |
| CN1884284A (en) * | 2005-06-21 | 2006-12-27 | 浙江金华康恩贝生物制药有限公司 | Process for the preparation of sodium faropenem |
| CN1887886A (en) * | 2005-06-29 | 2007-01-03 | 上海医药科技发展有限公司 | Prepn of carbapenum type antibiotic Faropenum sodium |
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2008
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5885981A (en) * | 1990-08-20 | 1999-03-23 | Suntory Limited | Antibacterial penem esters derivatives |
| CN1884284A (en) * | 2005-06-21 | 2006-12-27 | 浙江金华康恩贝生物制药有限公司 | Process for the preparation of sodium faropenem |
| CN1887886A (en) * | 2005-06-29 | 2007-01-03 | 上海医药科技发展有限公司 | Prepn of carbapenum type antibiotic Faropenum sodium |
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| CN 1887886 A,说明书全文. |
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| 朱雪焱等.法罗培南钠的合成.中国医药工业杂志38 3.2007,38(3),174-176. * |
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