CN104788453B

CN104788453B - One-pot preparation process of monosodium ertapenem

Info

Publication number: CN104788453B
Application number: CN201410019328.8A
Authority: CN
Inventors: 蔡亚祥; 方健; 张怀宝; 林荆鑫
Original assignee: Zhejiang Jiuzhou Pharmaceutical Co Ltd
Current assignee: Zhejiang Jiuzhou Pharmaceutical Co Ltd
Priority date: 2014-01-16
Filing date: 2014-01-16
Publication date: 2017-02-15
Anticipated expiration: 2034-01-16
Also published as: CN104788453A

Abstract

The present invention relates to the technical field of medicine synthesis, especially to the technical field of monosodium ertapenem preparation, specifically to a one-pot preparation process of monosodium ertapenem. The one-pot preparation process comprises: i) carrying out a condensation reaction of a compound represented by a formula (a) and a compound represented by a formula (b) in the presence of an organic alkali, pouring the reaction solution into a halogenated alkane solvent, washing with a buffer solution, and concentrating the organic layer to obtain a compound represented by a formula (c); and ii) adding tetrahydrofuran to dissolve the concentrated compound represented by the formula (c), cooling to a temperature of -5-10 DEG C, adding a sodium bicarbonate solution with a mass fraction of 0.5-5% in a dropwise manner, adding palladium carbon, introducing hydrogen gas, filtering after completing the reaction, rinsing the filter cake with water, adjusting the pH value of the filtrate with acetic acid/methanol to 5-6, adding an alcoholic solvent/dichloromethane, carrying out stirring layering, adding a solvent A to the obtained water layer, adding a methanol/n-propanol mixed solution in a dropwise manner at a temperature of 0-5 DEG C, filtering, and rinsing the filter cake with acetone to obtain the monosodium ertapenem.

Description

Ertapenem Sodium one kettle way preparation technology

Technical field

The present invention relates to medical synthesis technical field, the more particularly, to preparing technical field of Ertapenem Sodium.

Background technology

The New-type wide-spectrum carbapenem antibiotic that ertapenem is developed for Merck drugmaker, chemical name is (4R, 5S, 6S) -3- [[(3S, 5S) -5- [[(3- carboxyl phenyl) carbamoyl] pyrrolidin-3-yl] sulphur -6- (1- hydroxyl second Base) -4- methyl -7- oxo -1- azabicyclo [3.2.0] hept-2-ene" -2- formic acid sodium salt, its structural formula is as follows：

Application No. CN93101472.7 embodiment 12 discloses the preparation method of ertapenem, the method, is with chemical combination Thing 1 is raw material, four（Triphenylphosphine）Under palladium and the effect of 10% palladium-carbon catalyst, with the mixing of oxolane, ethyl acetate and water Solution is the hydrogenated deprotection reaction of reaction dissolvent, and reaction finishes, and filters, and filtrate is extracted with ethyl acetate and ether respectively Take, water layer is concentrated again, column chromatography purifies, lyophilized obtain ertapenem solid；Four（Triphenylphosphine）Palladium can produce as catalyst Raw triphenylphosphine oxide, this catalysate is difficult to remove, and can remain always in the final product, affect product quality；And this work Skill post processing needs will arrive column chromatography technique, is unfavorable for industrialized production, its reaction equation is as follows：

Authorization Notice No. is that the Chinese patent of CN1249065C discloses a kind of preparation of Ertapenem Sodium one kettle way Technique, this preparation method is to be prepared through condensation, hydrogenation deprotection with carbapenem parent nucleus and ertapenem side chain for raw material Ertapenem Sodium, the method post-processes and is：Reaction finishes, and is filtered with activated carbon reaction mixture, with containing The isoamyl alcohol extraction filtrate of diphenylphosphoric acid and sodium hydroxide solution, extracts the remaining aqueous solution with isoamyl alcohol, twice further Extraction is required for using multistage reflux centrifugal extractor, and last crystallization obtains Ertapenem Sodium, and this brings to industrial production Inconvenience and increased industrial production cost, this preparation technology route is summarized as follows：

China Medicine University's journal 2007,38（4）, it is in distress that 305-310 discloses a kind of ertapenem preparation by three protections The method of Ta Peinan mono-sodium salt, the method be the ertapenem of three protections in the presence of palladium carbon, sodium acid carbonate, with oxolane and Water carries out hydrogenation for reaction dissolvent, filters after completion of the reaction, and filtrate is extracted with dichloromethane, and water layer is used after removing solvent DiaionCHP-20P purifying resin, obtains Ertapenem Sodium, and its reaction equation is as follows：

Although this route avoids using multistage reflux Centrifugical extraction technology, need for using column chromatography method, Unfavorable use industrialized production, and Chinese patent application CN102731506A reports that the method product can be degraded in a large number, gained Product purity difference and heavy metals exceeding standard.

The Chinese patent for CN100457760C for the Authorization Notice No. discloses a kind of one kettle way and prepares Ertapenem Sodium Preparation technology, this preparation technology is with carbapenem parent nucleus and ertapenem side chain for raw material through condensation, one pot of deprotection of hydrogenation Boil reaction and Ertapenem Sodium mixed solution is obtained, filter off palladium carbon, filtrate is processed with activated carbon, this post-reaction treatment extracts Take solvent to be ethyl acetate and isoamyl alcohol, gained liquid is added thereto to acetone and propyl alcohol, filter, concentrate, gained solid uses 95% Ethanol and methyl acetate washing, obtain Ertapenem Sodium after being dried, concrete reaction equation is summarized as follows：

Chinese patent application CN102731506A reports that the method product also can be degraded in a large number, the product purity of gained difference and Heavy metals exceeding standard.

It is therefore desirable to developing a kind of preparation technology of new Ertapenem Sodium so as to product purity and heavy metal contain Amount meets technique productions standard.

Content of the invention

In order to solve technical problem present in prior art, the present invention adopts the following technical scheme that：

A kind of Ertapenem Sodium one kettle way preparation technology, this preparation technology comprises the steps：

I) formula a compound is existed in organic base with formula b compound and carry out condensation reaction, reaction terminates, and reactant liquor is fallen Enter in halogenated alkanes solvents, washed with cushioning liquid, gained organic layer is concentrated to give double protection ertapenems（Formula cization Compound）,

Ii) add oxolane to dissolve double protection ertapenems of above-mentioned concentration and be cooled to -5～10 DEG C, instill matter Amount fraction 0.5%～5% sodium bicarbonate solution, adds palladium carbon, is passed through hydrogen to 1.0～2.0MPa and keeping temperature is -5～20 ℃；After completion of the reaction, filter, filter cake water wash；Filtrate adjusts pH to 5-6 with acetic acid/methyl alcohol；Add alcohols solvent/dichloromethane Alkane stirring layering, gets addition A solvent in water layer, gets water layer, instills methyl alcohol/normal propyl alcohol mixing in 0～5 DEG C of temperature range Liquid, adds Ertapenem Sodium crystal seed, filters, and filter cake acetone drip washing obtains Ertapenem Sodium.

Described A solvent is n-butanol, methyl formate, butanone, one of methyl iso-butyl ketone (MIBK) and isoamyl alcohol or two kinds with On mixture.

Organic base described in step i) is selected from 1,8- diazabicylo [5.4.0] 11 carbon -7- alkene（DBU）, 1,5- phenodiazine Miscellaneous two rings（DBN）, diisopropylethylamine, diisopropylamine, dimethylamine, triethylamine, TMG or wherein two or more Mixture；

The mole dosage of formula a compound and described organic base is than for 1：（0.5～5）；It is preferably 1：（1～2）；

The mole dosage of formula a compound and formula b compound is than for 1：（0.5～1.5）.

Step i）Described in halogenated alkanes solvents be selected from dichloromethane, dichloroethanes and the mixing containing these solvents molten Agent, such as dichloromethane or dichloroethanes and the mixed solvent of methyl alcohol or ethanol, dichloromethane or dichloroethanes and acetonitrile, diformazan Base formamide, the mixed solvent of 1-METHYLPYRROLIDONE etc., dichloromethane or dichloroethanes and the mixing of n-hexane or petroleum ether Solvent；

Step i）Described in pH value of buffer solution be 2-10, selected from phosphate sodium dihydrogen buffer solution, potassium phosphate buffer.

Further, step i）In condensation reaction preferred solvent be acetonitrile, dimethylformamide, N- crassitude Ketone, N- ethyl pyrrolidone or two of which or two or more mixed solvents；Setting-up point is preferably -40～-20 ℃；

Described step ii）In, the consumption of oxolane is 2～30 times of formula c compound（V/M）, preferably 5～12 times；

Described step ii）In, sodium acid carbonate with the mole dosage ratio of formula c compound is（1～5）：1；It is preferably（1～2）： 1；

Described step ii）In, preferred reaction temperature is 0～10 DEG C；

Described step ii）In, added palladium carbon with the mass ratio of formula c compound is（0.1～0.3）：1；

Described step ii）In, described alcohols solvent is preferably methyl alcohol, ethanol, isopropanol, normal propyl alcohol, n-butanol, isoamyl alcohol One or more of；

Described step ii）In, the amount ratio of described alcohols solvent and dichloromethane（V/V）For（0.5～4）:1, preferably 1:1；The consumption of described alcohols solvent is 5～40 times of formula c compound（V/M）, preferably 5～25 times；

Described step ii）In, the consumption of described A solvent is 2～50 times of formula c compound（V/M）；It is preferably 5～40 times；

Described step ii）In, methanol usage is 0.1～3 times of got aqueous phase（V/V）, normal propyl alcohol consumption is by being got 0.1～3.0 times of aqueous phase (V/V)；

Preferably described step ii）In, methyl alcohol/normal propyl alcohol mixed liquor instills at twice.

Preferably, step ii）Described crystal seed is to add during methyl alcohol/normal propyl alcohol mixed liquor dropping, described crystal seed Mole dosage ratio with formula c compound is（0.001～0.01）：1.

Described Ertapenem Sodium crystal seed is 4.63 ± 0.1 ° in the angle of diffraction 2 θ, 5.51 ± 0.1 °, 7.32 ± 0.1 °, 7.74±0.1°,8.19±0.1°,8.94±0.1°,9.59±0.1°,10.99±0.1°,11.79±0.1°,12.11± 0.1 °, 12.99 ± 0.1 °, 15.32 ± 0.1 °, at 19.10 ± 0.1 °, there is characteristic peak, specific X-ray powder diffraction collection is shown in Accompanying drawing 2.

In step i) of the present invention, the not concentrated direct stirring of gained organic layer can separate out double protection ertapenem crystal formations, this crystalline substance Type is 5.7 ± 0.2 ° in the angle of diffraction 2 θ, 6.1 ± 0.2 °, 7.1 ± 0.2 °, 8.6 ± 0.2 °, 9.3 ± 0.2 °, 12.8 ± 0.2 °, 14.3 ± 0.2 °, 15.8 ± 0.2 °, 16.7 ± 0.2 °, at 18.0 ± 0.2 °, there is characteristic peak, specific X-ray powder diffraction figure Spectrum is shown in accompanying drawing 1.Agitated can direct crystallization, illustrate to create as post processing solvent using halogenated alkanes solvents and expect not The technique effect arriving, this technique directly extracts product, scrubbed rear directly room temperature concentration with halogenated alkanes solvents, can Crystallization, filtration link, less need high temperature drying moisture content, whole operation is carried out all below low temperature, and what product generation was degraded can Energy property very little, directly prepares Ertapenem Sodium using double protection group ertapenems without isolation that the method prepares Purity is high, and HPLC purity can reach more than 99%, and present invention application halogenated alkane or the mixed solvent containing halogenated alkane Easily remove from reaction system.

Step ii) in, our post processing extracts, using the system of dichloromethane/alcohols solvent, the protection group that hydrogenation is taken off And foreign pigment, and need not " ion-pairing agent abstraction technique " or " multistage reflux Centrifugical extraction technology ", without activated carbon Decolorization process, reduces the product moisture absorption and degraded risk；The system of application dichloromethane/alcohols solvent extracts the protection that hydrogenation is taken off The product colour obtaining after base and foreign pigment is white, and content of beary metal is less than 10ppm.Compare intermediate product crystallization take out and Necessarily lead to the loss of portion of product, this technique all take part in hydrogenation because the product of condensation reaction all is extracted efficiently out Reaction, so the total recovery of this technique is high.

Brief description

Fig. 1 is the double protection ertapenem X-ray powder diffraction collections preparing according to the embodiment of the present invention 1.

Fig. 2 is the Ertapenem Sodium X-ray powder diffraction collection preparing according to the embodiment of the present invention 2.

Specific embodiment

In order to be better understood from present disclosure, to be described further with reference to specific embodiment, but specifically Embodiment be not the restriction that present disclosure is done.

HPLC analytical instrument and method：

INSTRUMENT MODEL：Agilent1260

Chromatographic column：XDB-Phenyl(250*4.6*5)

Mobile phase A：0.1%H₃PO₄Solution（Adjust PH=8.0 with about 1ml50% sodium hydrate aqueous solution）

Mobile phase B：A/ acetonitrile=75：25

Flow velocity：1ml/min

Column temperature：25℃

Wavelength：230nm

Sample size：10μl

Gradient：

T	A	B
			0	94	6
3	94	6
			6	80	20
11	72	28
			15	72	28
33	40	60
			34	0	100
38	0	100
			40	94	6
50	94	6

Carbapenem parent nucleus is referred to as in an embodiment with following formula a compound, formula b compound in an embodiment referred to as strategic point he Training southern side chain, the referred to as double protection ertapenem of formula c compound：

Embodiment 1：The preparation of double protection ertapenem crystal formations

It is dried in four-hole boiling flask one, put into carbapenem parent nucleus（40.0g, 0.067mol）, dimethylformamide 60ml,

Stirred under nitrogen atmosphere dissolving clarification.It is cooled to -40～-30 DEG C, drip diisopropylethylamine（17.4g, 0.135mol）, control temperature at -40～-30 DEG C.Drip and finish, at -40～-30 DEG C, dropping is dissolved in 120ml dimethylformamide In ertapenem side chain（31.60g, 0.071mol）.Drip and finish, in -40～-30 DEG C of insulations until reacting completely, in reactant liquor Add dichloromethane 400ml, then washed with the potassium phosphate buffer that pH value is 2-10, gained organic layer is in -5～-10 DEG C stirring and crystallizing overnight, filters, wash filter cake with a small amount of dichloromethane, send 25 DEG C to be vacuum dried after being filtered dry double protect E Tapei Southern crystal formation 49.9g, yield 94.4%, HPLC purity is 98.7%, X-ray powder diffraction pattern such as Fig. 1 of product.

Embodiment 2：The preparation of Ertapenem Sodium

It is dried in four-hole boiling flask one, put into carbapenem parent nucleus（36.2g, 0.061mol）, dimethylformamide 110ml, stirred under nitrogen atmosphere dissolving clarification.It is cooled to -40～-30 DEG C, drip diisopropylethylamine（15.74g, 0.122mol）, control temperature at -40～-30 DEG C.Drip and finish, at -40～-30 DEG C, dropping is dissolved in 110ml dimethylformamide In ertapenem side chain（29.0g, 0.065mol）.Drip complete, in -40～-30 DEG C of insulations until reaction completely, adds in reactant liquor Enter dichloromethane 400ml, then washed with the potassium phosphate buffer that pH value is 2-10, gained organic layer is concentrated to dryness, plus It is cooled to about 0-5 DEG C after entering the clarification of 300ml THF stirring and dissolving, instills 5% sodium bicarbonate solution 160ml, drip and finish, this is mixed Liquid pours in 2000L autoclave, is subsequently adding 10% palladium charcoal 12.0g, this reactor nitrogen displacement, then with hydrogen exchange, puts Change and finish, be passed through hydrogen to 1.0～2.0MPa insulation reaction 5 hours at 5-10 DEG C, TLC detection filter after completion of the reaction, filter Cake 5ml pure water drip washing, filtrate adjusts PH=5-6 with acetic acid/methyl alcohol, is subsequently adding isopropanol 500ml, dichloromethane 500ml, Stirring layering in 10 minutes, gets in water layer addition n-butanol 300ml, stirring layering, gets water layer and instills methyl alcohol/just after filtering Propyl alcohol（200/100ml) mixed liquor, drips and finishes, and adds Ertapenem Sodium Form seeds 0.4g, then instills first at -5 DEG C Alcohol/normal propyl alcohol（200/300ml）Mixed liquor, drips and finishes, and in -5～-10 DEG C of stirring and crystallizing 3 hours, filters, filter cake 100ml acetone Drip washing, nitrogen purges 1 hour and extremely does to obtain Ertapenem Sodium crystal formation 23.5g.HPLC purity 99.6%, yield：77.5%, with much money Belong to content and be less than 10ppm, X-ray powder diffraction pattern such as Fig. 2 of product.

Embodiment 3：The preparation of Ertapenem Sodium

It is dried in four-hole boiling flask one, put into carbapenem parent nucleus（36.2g, 0.061mol）, dimethylformamide 60ml, Stirred under nitrogen atmosphere dissolving clarification.It is cooled to -40～-30 DEG C, drip diisopropylethylamine（15.74g, 0.122mol）, control Temperature processed is at -40～-30 DEG C.Drip and finish, at -40～-30 DEG C, dropping is dissolved in the ertapenem side in 60ml dimethylformamide Chain（27.16g, 0.061mol）.Drip and finish, in -40～-30 DEG C of insulations until reaction completely, adds dichloromethane in reactant liquor 350ml, methyl alcohol 50ml, are then washed with the potassium phosphate buffer that pH value is 2-10, gained organic layer is concentrated to dryness, and add It is cooled to about 0-5 DEG C after the clarification of 300mlTHF stirring and dissolving, instills 2% sodium bicarbonate solution 400ml, drip and finish, this mixed liquor is inclined Pour in 2000L autoclave, be subsequently adding 10% palladium charcoal 12.0g, this reactor nitrogen displacement, then with hydrogen exchange, replace Finish, be passed through hydrogen to 1.0～2.0MPa insulation reaction 5 hours at 5-10 DEG C, TLC detection filter after completion of the reaction, filter cake use 5ml pure water drip washing, filtrate adjusts PH=5-6 with acetic acid/methyl alcohol, is subsequently adding isopropanol 500ml, dichloromethane 400ml, stirring Layering in 10 minutes, gets addition n-butanol 300ml in water layer, stirring layering, gets water layer and instill methyl alcohol/normal propyl alcohol after filtering （200/100ml) mixed liquor, drips and finishes, and adds Ertapenem Sodium Form seeds 0.3g, then instills methyl alcohol/just at -5 DEG C Propyl alcohol（150/240ml）Mixed liquor, drips and finishes, and stirs 8 hours at -5～-10 DEG C, filters, filter cake 100ml acetone drip washing, nitrogen Purging extremely is done to obtain Ertapenem Sodium 22.98g for 1 hour.HPLC purity 99.6%, yield：75.8%, content of beary metal is less than 10ppm.

Embodiment 4：The preparation of Ertapenem Sodium

It is dried in four-hole boiling flask one, put into carbapenem parent nucleus（36.2g, 0.061mol）, dimethylformamide 120ml, ertapenem side chain（31.60g, 0.071mol）, stirred under nitrogen atmosphere dissolving clarification.Be cooled to -30～-20 DEG C with Under, drip diisopropylethylamine（15.74g, 0.122mol）.Drip and finish, insulation reaction below -30～-20 DEG C is until reacted Entirely, add dichloromethane 300ml in reactant liquor, then washed with the potassium phosphate buffer that 600ml pH value is 2-10, institute Obtain organic layer to concentrate, be cooled to about 0-5 DEG C after adding the clarification of 350ml THF stirring and dissolving, instill 1% sodium bicarbonate solution 600ml, drips and finishes, this mixed liquor is poured in 2000L autoclave, is subsequently adding 10% palladium charcoal 10.0g, this reactor nitrogen Displacement, then with hydrogen exchange, be replaced, it is passed through hydrogen insulation reaction 5 hours at 5-10 DEG C, TLC inspection to 1.0～2.0MPa Measured reaction filters after finishing, filter cake 5ml pure water drip washing, and filtrate adjusts PH=5-6 with acetic acid/methyl alcohol, is subsequently adding normal propyl alcohol 700ml, dichloromethane 700ml, stirring layering in 10 minutes, get addition butanone 300ml in water layer, stirring layering, get water layer Instill methyl alcohol/normal propyl alcohol after filtering（500/500ml) mixed liquor, adds ertapenem list during the dropping of this mixed solvent Sodium salt crystal seed 0.1g, drips and finishes, and stirs 7 hours at -5～-10 DEG C, filters, filter cake 100ml acetone drip washing, and nitrogen purges 1 hour Extremely do to obtain Ertapenem Sodium 22.29g.HPLC purity 99.4%, yield：73.5%, content of beary metal is less than 10ppm.

Embodiment 5：The preparation of Ertapenem Sodium

It is dried in four-hole boiling flask one, put into carbapenem parent nucleus（36.2g, 0.061mol）, 1-METHYLPYRROLIDONE 60ml, stirred under nitrogen atmosphere dissolving clarification.It is cooled to -40～-30 DEG C, drip triethylamine（7.3g, 0.072mol）, control temperature Degree is at -40～-30 DEG C.Drip and finish, at -40～-30 DEG C, dropping is dissolved in the ertapenem side chain in 60ml dimethylformamide （29.8g, 0.067mol）.Drip and finish, in -40～-30 DEG C of insulations until reaction completely, adds dichloroethanes 350ml in reactant liquor With acetonitrile 50ml, then washed with the phosphate sodium dihydrogen buffer solution that pH value is 2-10, gained organic layer concentrates, add 350ml It is cooled to about 0-5 DEG C after the clarification of THF stirring and dissolving, instills 2% sodium bicarbonate solution 350ml, drip and finish, this mixed liquor is poured into In 2000L autoclave, it is subsequently adding 10% palladium charcoal 13.0g, this reactor nitrogen displacement, then with hydrogen exchange, is replaced, Be passed through hydrogen to 1.0～2.0MPa insulation reaction 5 hours at 5-10 DEG C, TLC detection filter after completion of the reaction, filter cake 5ml Pure water drip washing, filtrate adjusts PH=5-6 with acetic acid/methyl alcohol, is subsequently adding normal propyl alcohol 600ml, dichloromethane 600ml, stirs 10 points Clock is layered, and gets addition n-butanol 300ml in water layer, stirring layering, gets water layer and instill methyl alcohol/normal propyl alcohol after filtering （400/400ml）Mixed liquor, drips and finishes, and adds Ertapenem Sodium Form seeds 0.03g, in -5～-10 DEG C of stirring and crystallizing 10 Hour, filter, filter cake 100ml acetone drip washing, nitrogen purges 1 hour and extremely does to obtain Ertapenem Sodium 23.23g.HPLC is pure Degree 99.1%, yield：76.6%, content of beary metal is less than 10ppm.

Embodiment 6：The preparation of Ertapenem Sodium

It is dried in four-hole boiling flask one, put into carbapenem parent nucleus（36.2g, 0.061mol）, acetonitrile 100ml, nitrogen is protected The lower stirring and dissolving clarification of shield.It is cooled to -30～-20 DEG C, drip DBU（15.3g, 0.1mol）, control temperature at -30～-20 DEG C. Drip and finish, at -30～-20 DEG C, dropping is dissolved in the ertapenem side chain in 100ml acetonitrile（31.44g, 0.071mol）.Drip and finish, In -30～-20 DEG C of insulations until reaction completely, adds dichloroethanes 300ml and ethanol 50ml in reactant liquor, then with pH value is The potassium phosphate buffer washing of 2-10, gained organic layer concentrates, and is cooled to about after adding the clarification of 450ml THF stirring and dissolving 0-5 DEG C, instill 3% sodium bicarbonate solution 250ml, drip and finish, this mixed liquor is poured in 2000L autoclave, is subsequently adding 10% Palladium charcoal 10.0g, this reactor nitrogen displacement, then with hydrogen exchange, be replaced, it is passed through hydrogen to 1.0～2.0Mpa in 5- Insulation reaction 5 hours at 10 DEG C, TLC detection is filtered after completion of the reaction, filter cake 5ml pure water drip washing, and filtrate is adjusted with acetic acid/methyl alcohol Section PH=5-6, is subsequently adding normal propyl alcohol 700ml, dichloromethane 400ml, stirring layering in 10 minutes, gets addition formic acid in water layer Methyl esters 300ml, stirring layering, get water layer and instill methyl alcohol/normal propyl alcohol after filtering（300/150ml）Mixed liquor, drips and finishes, and adds Ertapenem Sodium crystal formation 0.2g, instills methyl alcohol/normal propyl alcohol at -5 DEG C（280/400ml）Mixed liquor, drips and finishes, -5～- 10 DEG C are stirred 6 hours, filter, filter cake 100ml acetone drip washing, and nitrogen purges 1 hour and extremely does to obtain Ertapenem Sodium 22.98g.HPLC purity 99.5%, yield：75.8%, content of beary metal is less than 10ppm.

Although have been incorporated with specific embodiment the present invention has been carried out sufficient description it shall be noted that be for this For skilled person, its variations and modifications is obvious.Such change and modifications it will be appreciated that be including In the scope of the present invention defined in claims.

Claims

1. a kind of Ertapenem Sodium one kettle way preparation technology, this preparation technology comprises the steps：

I) formula a compound is existed in organic base with formula b compound and carry out condensation reaction, reaction terminates, and reactant liquor is poured into halogen For in alkane solvents, washed with cushioning liquid, gained organic layer is concentrated to give formula c compound,

Ii) add oxolane to dissolve double protection ertapenems of above-mentioned concentration and be cooled to -5～10 DEG C, instill quality and divide Number 0.5%～5% sodium bicarbonate solution, adds palladium carbon, is passed through hydrogen to 1.0～2.0MPa and keeping temperature is -5～20 DEG C； After completion of the reaction, filter, filter cake water wash；Filtrate adjusts pH to 5-6 with acetic acid/methyl alcohol；Alcohols solvent/dichloromethane is added to stir Mix layering, get addition A solvent in water layer, get water layer, in 0～5 DEG C of temperature range, instill methyl alcohol/normal propyl alcohol mixed liquor, Add Ertapenem Sodium crystal seed, filter, filter cake acetone drip washing obtains Ertapenem Sodium；

Described A solvent is n-butanol, methyl formate, butanone, one of methyl iso-butyl ketone (MIBK) and isoamyl alcohol or two or more Mixed solvent.

2. preparation technology according to claim 1, organic base described in described step i) is selected from 1,8- diazabicylo [5.4.0] 11 carbon -7- alkene, 1,5- diazabicylo, diisopropylethylamine, diisopropylamine, dimethylamine, triethylamine, tetramethyl Base guanidine or many of mixture.

3. preparation technology according to claim 1, halogenated alkanes solvents described in described step i) be selected from dichloromethane, Dichloroethanes or the mixed solvent containing these solvents.

4. preparation technology according to claim 1, cushioning liquid described in described step i) is selected from sodium dihydrogen phosphate and buffers Liquid, potassium phosphate buffer.

5. preparation technology according to claim 4, described pH value of buffer solution is 2-10.

6. preparation technology according to claim 4, the solvent of the condensation reaction in described step i) is acetonitrile, dimethyl methyl Acid amides, 1-METHYLPYRROLIDONE, N- ethyl pyrrolidone or two of which or two or more mixed solvents.

7. preparation technology according to claim 1, described step ii) in, described alcohols solvent is isopropanol, normal propyl alcohol, One or more of n-butanol, isoamyl alcohol.

8. preparation technology according to claim 1, described step ii) in, methyl alcohol/normal propyl alcohol mixed liquor instills at twice.

9. preparation technology according to claim 1, described step ii) in, crystal seed is in methyl alcohol/normal propyl alcohol mixed liquor dropping During add.

10. preparation technology according to claim 9, the mole dosage of described crystal seed and formula c compound than for 0.001～ 0.01：1.

11. preparation technologies according to claim 3, in described step i), halogenated alkanes solvents are selected from dichloromethane or two Chloroethanes and the mixed solvent of methyl alcohol or ethanol, dichloromethane or dichloroethanes and acetonitrile, dimethylformamide, N- methylpyrrole The mixed solvent of alkanone, dichloromethane or dichloroethanes and the mixed solvent of n-hexane or petroleum ether.