CN102731506B - The preparation method of a kind of ertapenem and sodium salt thereof - Google Patents
The preparation method of a kind of ertapenem and sodium salt thereof Download PDFInfo
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Abstract
The present invention relates to the preparation method of the ertapenem shown in a kind of formula 1 and sodium salt thereof; the method makes action solvent with water; under alkali and catalyzer exist, the ertapenem intermediate shown in formula 2a is carried out hydrogenation deprotection, the ertapenem shown in production 1 or its sodium salt.The inventive method adopts single solvent water as action solvent, solves the problems of dissolution of action solvent to catalyzer, simplifies post-processing operation step; reduce product degraded; improve product purity, and economy, safety, environmental protection, be more suitable for industrial scale operation.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to a kind of carbapenem compounds ertapenem of improvement and the preparation method of sodium salt thereof.
Background technology
Ertapenem (Ertapenem, structural formula is such as formula 1), chemistry [4R by name, 5S, 6S]-3-[[(3S, 5S)-5-[[(3-carboxyl phenyl) is amino] carbonyl]-3-pyrryl] sulfydryl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, for the New-type wide-spectrum carbapenem antibiotic of Merck company and Astrazeneca AB's joint development, to comprising gram positive organism and Negative aerobe and anerobe, all there is good anti-microbial activity.
Chinese patent CN93101472.7 makes public for the first time compound ertapenem and disodium salt thereof and their preparation method, and disclosed synthetic route is as shown in flow process 1.Due to the difference of the protecting group of raw materials used compound 2, different deprotection methods has been selected in this invention.Wherein embodiment 4 describes the preparation method of ertapenem disodium salt, is with compound 2 (P
1, P
2and P
3be allyl group) be raw material; under tetrakis triphenylphosphine palladium catalyst action; with the mixing solutions of dimethyl sulfoxide (DMSO) (DMSO) and tetrahydrofuran (THF) (THF) be reaction solvent under argon gas and non-illuminated conditions through deprotection reaction; react complete; with ether processing reaction liquid, gained throw out after centrifugation, drying, more water-solublely carries out pH regulator; then through column chromatography purification, ertapenem disodium salt is obtained.Embodiment 12 describes the preparation method of ertapenem, is with compound 2 (P
1, P
2for to nitrobenzyl (hereinafter referred to as PNB), P
3for allyl group) be raw material; under tetrakis triphenylphosphine palladium and 10% palladium-Pd/carbon catalyst effect; with the mixing solutions of THF, ethyl acetate and water for reaction solvent is through hydrogenation deprotection; react complete; filter; filtrate extracts with ethyl acetate and ether respectively, and water layer through concentrated, column chromatography purification, freeze-drying, obtains ertapenem solid again.Front a kind of deprotection method needs to carry out under argon gas and non-illuminated conditions, severe reaction conditions; Although rear a kind of deprotection method reaction conditions is relatively gentle, there is following defect: 1) tetrakis triphenylphosphine palladium and palladium-charcoal two kinds of catalyzer need be used, and tetrakis triphenylphosphine palladium is to air-sensitive, needs lucifuge stored refrigerated; 2) catalyzer dissolves in action solvent, and aftertreatment not easily removes; 3) in last handling process there is a large amount of degraded thus affect finished product purity in product.Therefore, the ertapenem disclosed in this invention and the preparation method of sodium salt thereof are also not suitable for suitability for industrialized production.
P
1, P
2and P
3representation carboxy protecting group, M represents H or Na.
In order to overcome above-mentioned defect, domestic and international researchist has carried out a large amount of research work.
Chinese patent CN02803742.1, CN98806091.4, US Patent No. 6504027, world patent WO03026572 reports with the carbapenem parent nucleus (P shown in formula 3
1for PNB) and the ertapenem side chain 4 shown in formula 4 (P is HCl, P
3for H) to obtain the method for Ertapenem Sodium through condensation, hydrogenation deprotection one pot reaction for raw material.Wherein, catalyzer used in deprotection technique is palladium-charcoal, and action solvent is the mixing solutions of N-ethyl pyrrolidone (NEP) and water.Reaction postprocessing method described in foregoing invention is: react complete, filter, after filtrate activated carbon treatment, filtrate to be arranged continuously in the CINC centrifuge separator (multistage reflux centrifugal extractor) carrying out reflux extraction with hexichol trimetaphosphate ion to reagent and primary isoamyl alcohol through twice extraction at two again, and then crystallization obtains Ertapenem Sodium.These inventive methods solve defect existing in CN93101472.7 substantially, but ion pair reagent abstraction technique and/or multistage reflux Centrifugical extraction technology need use special reagent and specific installation, make troubles to industrial production and increase industrial production cost, and one of raw materials used ertapenem side chain 4 (P is HCl) relative to the ertapenem side chain 4 of other type (as P
2for PNB) expensive many, add industrial production cost.Therefore, although these methods solve prior art defect, special reagent and specific installation need be used and production cost is high, need the preparation technology finding to be more suitable for large-scale industrial and to produce for this reason.
P represents HCl or COOP
2, P
1, P
2representation carboxy protecting group, P
3representation carboxy protecting group, H or Na.
Chinese patent CN200510030660.5 reports with the carbapenem parent nucleus (P shown in formula 3
1for PNB) and the ertapenem side chain 4 (P shown in formula 4
2for PNB, P
3for allyl group) to obtain the method for Ertapenem Sodium through condensation, hydrogenation deprotection one pot reaction for raw material.The catalyzer wherein adopted in deprotection technique is 10% palladium-charcoal; action solvent is N-Methyl pyrrolidone (NMP), N; the mixing solutions of dinethylformamide (DMF) and water; last handling process is for reacting complete; filter; by activated carbon treatment under ice-water bath and nitrogen protection, then obtain Ertapenem Sodium by steps such as cold solvent extraction, crystallizatioies.
Zhang Yifeng etc. report with compound 2 (P in China Medicine University's journal (2007,38 (4): 305 ~ 310) " synthesis of carbapenem antibiotic ertapenem "
1, P
2and P
3be PNB) be raw material; under 10% palladium-Pd/carbon catalyst effect; with the mixing solutions of tetrahydrofuran (THF) and water for action solvent is through hydrogenation deprotection; react complete; filter, filtrate is steamed except organic solvent with dichloromethane extraction three times, water layer concentrating under reduced pressure; again through column chromatography purification, freeze-drying, obtain Ertapenem Sodium solid.
WO2008062279 reports with compound 2 (P
1, P
2be PNB, P
3for H or Na) be raw material, under 10% palladium-Pd/carbon catalyst effect, the method for Ertapenem Sodium and disodium salt is prepared through hydrogenation deprotection.Action solvent described in the present invention is the mixing solutions of ethyl acetate and water, or in above-mentioned mixed solvent, add one or both solvents in THF, DMF, methyl alcohol again.React complete, after filtration, with activated carbon treatment, separatory, extraction, remove the steps such as aqueous phase residual solvent, adjust pH, crystallization by outgas technique, obtain Ertapenem Sodium or disodium salt.
Above-mentioned document institute report method, adopt ertapenem side chain 4 (P is HCl) for raw material and ion pair reagent abstraction technique and/or multistage reflux Centrifugical extraction technology although avoid, and attempt the catalyzer changing action solvent or adopt in active carbon adsorption removing solution, but poor effect, and product is degraded in a large number, cause products obtained therefrom purity difference and heavy metals exceeding standard.
Summary of the invention
In order to solve the defect existing for prior art, present inventor has performed a large amount of experimental studies, as: 1) acidity (below pH4) will be adjusted to after reacting liquid filtering, although this method can remove part heavy metal palladium, but effect is still undesirable, and product is caused to degrade in a large number in acid adjustment filtration procedure repeatedly; 2) adopt pure organic solvent if ethyl acetate, ethanol etc. are as action solvent, but catalyst dissolution is serious, and deprotection weak effect.
Accidental; the present inventor is when adopting single solvent water to carry out hydrogenation deprotection as action solvent, and unexpected discovery can solve catalyst dissolution problem, and does not need through removing organic solvent step due to last handling process; greatly reduce product degraded, thus improve product purity.
Therefore; the invention provides the method for the ertapenem shown in a kind of preparation formula 1 and sodium salt thereof, described method comprises with the ertapenem intermediate shown in formula 2a for raw material, under alkali and catalyzer exist; with single solvent water for action solvent, carry out hydrogenation deprotection.
Wherein:
P represents HCl or COOP
2,
P
1and P
2representation carboxy protecting group,
P
3representation carboxy protecting group or charge balance group.
Described carboxyl-protecting group be selected from benzyl or or allyl group, described benzyl or allyl group are optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces, and preferably, carboxyl-protecting group is to nitrobenzyl.
Described charge balance group is maintain the group that total charge is neutrality, is selected from H
+or a kind of salt-forming cation, described salt-forming cation is selected from monovalent metallic ion, divalent-metal ion or quaternary ammonium ion, and preferably, described monovalent metallic ion is selected from Na
+, K
+, described divalent-metal ion is selected from Ca
2+, Mg
2+, and described quaternary ammonium ion is selected from organic quaternary ammonium ion as H-TMG
+, H-TMP
+, H-DBU
+, H-DBN
+, H-DIPA
+, H-DIPEA
+, H-DCHA
+, H-NMP
+.
Described H-TMG
+, H-TMP
+, H-DBU
+, H-DBN
+, H-DIPA
+, H-DIPEA
+, H-DCHA
+, H-NMP
+represent following organic amine respectively: 1,1,3,3-tetramethyl guanidine (TMG), 2,2,6,6-tetramethyl piperidine (TMP), 1,8-diazacyclo [5,4,0] hendecene-7 (DBU), 1,5-diazabicylo [4,3,0] quaternary ammonium ion of nonene-5 (DBN), diisopropylamine (DIPA), diisopropyl ethyl amine (DIPEA), dicyclohexyl amine (DCHA), N-methyl Pyrrolidine (NMP).
P
4represent H or hydroxyl protecting group, preferably, hydroxyl protecting group is benzyl or allyl group, and described benzyl or allyl group are optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces.
Described alkali is selected from mineral alkali, organic bases, or its arbitrary combination, they exist with any suitable concentration, preferably, described mineral alkali is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, Sodium phosphate dibasic, and described organic bases is selected from TMG, TMP, DBU, DBN, DIPA, DIPEA, DCHA, NMP; Preferably, the consumption of described alkali is preferably 0.5 ~ 5 molar equivalent of compound 2a, is more preferably 1 ~ 3 molar equivalent.
Described single solvent water is any water containing less impurity, and wherein foreign matter content is for being less than 10wt%, such as, be less than 5wt%, such as, be less than 1wt%, is preferably less than 0.1wt%, is more preferably less than 0.01wt%, is also more preferably less than 0.001wt%.Described impurity comprises suspended matter, soluble material, insoluble substance, such as metal-salt, organic solvent etc.When single solvent water comprises organic solvent, the content of organic solvent should be less than 1wt%, is preferably less than 0.1wt%, is more preferably less than 0.01wt%, be also more preferably less than 0.001wt%, most preferably, not containing organic solvent.Organic solvent described here is organic solvent well known to the skilled person, comprise alcohols, ethers, ester class, replace the materials such as hydro carbons, arene, ketone, amides and nitrile, such as, alcohols comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, 2-butanols, Pentyl alcohol etc.; Ethers comprises tetrahydrofuran (THF), ether, diox, methyl-phenoxide etc.; Ester class comprises methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, isobutyl acetate, tert.-butyl acetate etc.; Replace hydro carbons and comprise methylene dichloride, chloroform, tetracol phenixin, Nitromethane 99Min. etc.; Arene comprises toluene, ethylbenzene etc.; Ketone comprises acetone, 2-butanone, 3-methyl-2-butanone, 2 pentanone, 4-methyl-2 pentanone, methyl-n-butyl ketone; Amides comprises DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, N-ethyl pyrrolidone; Acetonitrile is comprised with nitrile.Water described herein comprises soft water and hard water, fresh water and salt water, surface water and groundwater, preferably, single solvent water is through the water of purifying, and described purifying comprises the methods well known to those skilled in the art such as throw out filtration, water softening, charcoal absorption, deionization, reverse osmosis, electrodialysis, ultra-filtration, distillation, disinfection by ultraviolet light, biochemistry treatment, forward osmosis.Such as, single solvent water can be tap water or as tap water, deionized water, reverse osmosis water, electrodialytic water, exceed the water of the purifying that this areas such as drainage, distilled water, sterilized water are commonly used.The consumption of water is 5 ~ 80 times of ertapenem intermediate 2a, is preferably 10 ~ 40 times, by weight.
Described method is carried out in a hydrogen atmosphere, and preferably, hydrogen pressure is 0.4 ~ 2.5Mpa, is more preferably 1.0 ~ 2.0Mpa.
Described catalyzer is selected from palladium carbon or platinum carbon, and as 5 ~ 10% palladium carbon (mass percent concentration), preferably, the consumption of catalyzer is 5% ~ 80% of ertapenem intermediate 2a, is more preferably 10% ~ 50%, by weight.
Temperature of reaction is-10 ~ 40 DEG C, is preferably 10 ~ 30 DEG C; Reaction times is 0.5 ~ 10h, is preferably 1 ~ 6h.
Optionally, after hydrogenation, aftertreatment can be carried out to product.The aftertreatment of described product can by well known to a person skilled in the art method to carry out, and a series of last handling processes obtaining necessity of ertapenem and sodium salt solid thereof such as such as purifying, concentrated, crystallization and/or freeze-drying, obtain the finished product.As: as described in purifying, concentration method can refer to purifying as described in CN93101472.7, CN98806091.4, concentration method carries out; Described crystallization, freeze drying process can refer to Crystallization method described in WO03026572, CN200610004335.6, WO2008062279, CN93101472.7 to carry out, and obtains A type, Type B, C type, the ertapenem of amorphous or freeze-drying or its sodium salt.The content of above-mentioned document is hereby incorporated by.
The inventive method adopts single solvent water as action solvent; solve the problems of dissolution of action solvent to catalyzer; and do not need to remove organic solvent step through separatory, extraction, underpressure distillation or outgas technique etc.; do not need with special reagent and the equipment such as ion pair reagent, multistage reflux centrifugal extractor yet; purifying, the step such as concentrated directly can be carried out after reacting complete filtration catalizer; reduce product degraded; improve product purity; and economy, safety, environmental protection, be more suitable for industrial scale operation.
Embodiment
Compound 2a realizes initial feed of the present invention, and therefore preparing compound 2a is important for the purpose of the present invention.
The synthetic route of compound 2a is as shown in flow process 2:
Preparation example 1 P
1, P
2be PNB, P
3, P
4for the preparation of the compound 2a of H
By compound 3 (P
1for PNB) 36.0g is dissolved in 300ml DMF, adds compound 4 (P
2for PNB) 26.7g, under-35 DEG C of conditions, slowly drip diisopropyl ethyl amine 7.3g, stir lower reaction.Reaction solution is joined in the aqueous acid of pH 2 ~ 6 after completion of the reaction, obtain 46.6g compound 2a (P
1, P
2be PNB, P
3for H) solid.
P
1, P
2for other carboxyl-protecting group (comprising P is HCl), P
3for the preparation of the compound 2a of H can be carried out with reference to method described in preparation example 1.
Preparation example 2 P
1, P
2be PNB, P
3for Na
+, P
4for the preparation of the compound 2a of H
By compound 3 (P
1for PNB) 100g and compound 4 (P
2for PNB, P
3for H) 73.8g is dissolved in DMF, the DMF solution 60mL of DBU is added at-50 DEG C, stir, after reacting completely, reaction solution is poured in the mixed solution of ethyl acetate and buffered soln (175g potassium primary phosphate water-soluble or dipotassium hydrogen phosphate damping fluid), the pH value of two-phase system is adjusted to 4.5, separatory, the ethyl acetate solution of Sodium isooctanoate (32g) is added in organic phase, obtain pasty substance, slowly pour out organic layer, pasty substance dissolve with methanol, in methanol solution, add isopropyl ether again, obtain 110g compound 2a (P
1, P
2be PNB, P
3for Na
+) solid.
P
1, P
2for other carboxyl-protecting group (comprising P is HCl) and P
3for the preparation of other cationic compound 2a can be carried out with reference to method described in preparation example 2.
Preparation example 3 P
1, P
2, P
3be PNB, P
4for the preparation of the compound 2a of H
In reaction flask, add anhydrous acetonitrile 2L, under drying nitrogen protection, be cooled to-20 DEG C, add compound 3 (P
1for PNB) 59.5g, compound 4 (P
2, P
3be PNB) 69.7g and diisopropylamine 12.1g, 4h is reacted in less than-15 DEG C, reaction solution is poured in 2.5L frozen water, extract with methylene dichloride (1L × 3), merge organic phase, then use saturated brine (1L × 3) to wash, anhydrous sodium sulfate drying, filter, concentrate to obtain 64.5g compound 2a (P
1, P
2, P
3be PNB) solid.
P
1, P
2, P
3the preparation being the compound 2a of other carboxyl-protecting group can be carried out with reference to method described in preparation example 3.
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiments do not form any restriction to the present invention.
The preparation of embodiment 1 Ertapenem Sodium
To in hydriding reactor, add deionized water 150ml, 10%Pd/C 5g and sodium bicarbonate 1.1g (13.1mmol), then by compound 2a (P
1, P
2be PNB, P
3for H) 10g (12.7mmol) joins in hydriding reactor, nitrogen replacement, hydrogenation 2.0MPa, at 10 DEG C of reaction 2h, filter, solution is light yellow clear, concentrating under reduced pressure, concentrated solution through non-polar resin purification process, concentrating under reduced pressure, PH to 5.5 adjusted by concentrated solution acetic acid, adds isopyknic methyl alcohol and n-propyl alcohol, crystallization, obtain Ertapenem Sodium white crystal 3.2g, yield 50.8%, HPLC purity 97.4%, heavy metal content < 10ppm.NMR(D2O)：7.86(s，1H)，7.71(d，1H)，7.65(d，1H)，7.47(t，1H)，4.60(t，1H)，4.23～4.17(m，2H)，4.05(m，1H)，3.80(dd，1H)，3.47～3.42(m，2H)，3.31(m，1H)，3.00(m，1H)，1.27(d，3H)，1.17(d，3H)。
The preparation of embodiment 2 Ertapenem Sodium
In hydriding reactor, add deionized water 150ml, add 10%Pd/C 5g, sodium hydroxide 1.1g (27.5mmol) and compound 2a (P
1, P
2be PNB, P
3for H) 10g (12.7mmol), nitrogen replacement, hydrogenation 1.0MPa, at 20 DEG C of reaction 6h, in process, logical carbonic acid gas maintains PH < 9, reacts complete, filter, solution is light yellow clear, concentrating under reduced pressure, PH to 5.5 adjusted by concentrated solution acetic acid, adds isopyknic methyl alcohol and n-propyl alcohol, crystallization, obtain Ertapenem Sodium white crystal 3.3g, yield 52.4%, HPLC purity 96.7%, heavy metal content < 10ppm.
The preparation of embodiment 3 ertapenem
In hydriding reactor, add deionized water 150ml, add 10%Pd/C 5g, sodium bicarbonate 0.55g (6.5mmol) and compound 2a (P
1, P
2be PNB, P
3for H) 10g (12.7mmol), nitrogen replacement, hydrogenation 1.5MPa, at 30 DEG C of reaction 2h, react complete, filter, solution is light yellow clear, concentrating under reduced pressure, and concentrated solution is through non-polar resin purification process, PH to 2.5 is adjusted, concentrating under reduced pressure, freeze-drying with hydrochloric acid, obtain off-white color solid 3.2g, yield 53.3%, HPLC purity 95.8%, heavy metal content < 10ppm.
The preparation of embodiment 4 ertapenem
In hydriding reactor, add deionized water 150ml, add 10%Pd/C 5g, sodium hydroxide 2.0g (50mmol) and compound 2a (P
1, P
2be PNB, P
3for H) 10g (12.7mmol), nitrogen replacement, hydrogenation 1.8MPa, at 10 DEG C of reaction 2.5h, in process, logical carbonic acid gas maintains PH < 9, reacts complete, filter, solution is light yellow clear, concentrating under reduced pressure, concentrated solution hydrochloric acid adjusts PH to 2.5, freeze-drying, obtains off-white color solid 3.4g, yield 56.7%, HPLC purity 96.2%, heavy metal content < 10ppm.
The preparation of embodiment 5 ertapenem disodium salt
In hydriding reactor, add deionized water 150ml, add 10%Pd/C 5g, sodium bicarbonate 3.2g (38.1mmol) and compound 2a (P
1, P
2be PNB, P
3for H) 10g (12.7mmol), nitrogen replacement, hydrogenation 2.0MPa, at 20 DEG C of reaction 1.5h, react complete, filter, solution is light yellow clear, concentrating under reduced pressure, is added in 1L Virahol by concentrated solution, stir, obtain white solid 3.1g, yield 47.1%, HPLC purity 97.3%, heavy metal content < 10ppm.
The preparation of embodiment 6 ertapenem disodium salt
In hydriding reactor, add deionized water 150ml, add 10%Pd/C 5g, sodium hydroxide 2.5g (62.5mmol) and compound 2a (P
1, P
2be PNB, P
3for H) 10g (12.7mmol), nitrogen replacement, hydrogenation 1.5MPa, at 10 DEG C of reaction 3h, in process, logical carbonic acid gas maintains PH < 9, reacts complete, filter, solution is light yellow clear, concentrating under reduced pressure, concentrated solution is through non-polar resin purification process, and concentrating under reduced pressure, is added in 1L Virahol by concentrated solution, stir, obtain white solid 2.8g, yield 42.4%, HPLC purity 95.6%, heavy metal content < 10ppm.
Embodiment 7 ~ 9 with other compound 2a for Ertapenem Sodium prepared by raw material
With reference to embodiment 1 preparation method, by compound 2a (P
1, P
2be PNB, P
3for H) change the compound 2a (specifically in table 1) that other protect forms into, obtain Ertapenem Sodium white crystal, experimental result is in table 1.
Table 1 embodiment 7 ~ 9 experimental result
Conclusion: with different compound 2a for raw material, all can adopt the inventive method to carry out the preparation of ertapenem and sodium salt thereof.
The preparation of Ertapenem Sodium under other alkali condition of embodiment 10 ~ 14
With reference to embodiment 1 preparation method, change sodium bicarbonate into sodium carbonate, or with reference to embodiment 2 preparation method, sodium hydroxide is changed into Sodium phosphate dibasic, DIPEA, TMG, DBU, obtain Ertapenem Sodium white crystal, experimental result is in table 2.
Table 2 embodiment 10 ~ 14 experimental result
Conclusion: under Different Alkali condition, all can adopt the inventive method to carry out the preparation of ertapenem or its sodium salt.
Comparative example 1: the experimental result of pertinent literature China Medicine University journal (2007,38 (4), 305 ~ 310,2.10)
By P
1, P
2, P
3be the compound 2a 7.9g (10mmol) of PNB, 10%Pd/C 1.20g, NaHCO
31.0g (12mmol), join in tetrahydrofuran (THF) (200mL) and water (200mL), in 5 DEG C of normal pressure hydrogenation reaction 6h, filter, filtrate is black, extract with methylene dichloride (100mL × 3), water layer concentrating under reduced pressure steams except organic solvent, then through Diaion CHP-20P resin purification, lyophilize, obtaining gray solid 3.0g, HPLC purity is 83.1%, heavy metal content > 20ppm.
Comparative example 2: with reference to the experimental result of CN200510030660.5 embodiment 1 hydrogenation deprotection technique gained
In hydriding reactor, add 20mL through ultrasonic and deionized water that is nitrogen bubble process, 3.5mLDMF, anhydrous sodium carbonate 84mg (1mmol), 10%Pd/C 0.29g, then add compound 2a (P in 0 DEG C
1, P
2be PNB, P
3for H) 0.79g (1mmol), then under 2.0MPa, be incubated 5h.Elimination Pd/C, filtrate uses activated carbon treatment under ice-water bath and nitrogen atmosphere, solution is black, then successively with cold ethyl acetate (50mL × 2) and primary isoamyl alcohol (50mL × 2) each extracting twice, gained liquid adds acetone and each 50mL of propyl alcohol wherein, leave standstill, filter, filtrate is concentrated into 10mL, filter, solid is respectively with 95% ethanol and methyl acetate washing, and vacuum-drying obtains gray solid 0.30g, HPLC purity is 84.0%, heavy metal content > 20ppm.
Conclusion: from comparative example experimental result, adopt China Medicine University's journal (2007,38 (4), 305 ~ 310) and the hydrogenation deprotection technique reported of CN200510030660.5 prepare ertapenem, last handling process all needs to use extraction and waits and remove organic solvent step; Action solvent is to catalyst dissolution and aftertreatment effect is undesirable, causes products obtained therefrom purity difference and heavy metals exceeding standard.
Claims (32)
1. a method for the ertapenem shown in preparation formula 1 and sodium salt thereof, described method comprises with the ertapenem intermediate shown in formula 2a for raw material, under alkali and catalyzer exist, with single solvent water for action solvent, carries out hydrogenation deprotection,
Wherein:
P represents HCl or COOP
2,
P
1and P
2representation carboxy protecting group,
P
3representation carboxy protecting group or charge balance group,
P
4represent H or hydroxyl protecting group;
Wherein carboxyl-protecting group is selected from benzyl or allyl group, and described benzyl or allyl group are optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces;
Wherein hydroxyl protecting group is benzyl or allyl group, and described benzyl or allyl group are optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces;
Wherein said alkali is selected from mineral alkali, organic bases, or its arbitrary combination, and wherein mineral alkali is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, Sodium phosphate dibasic, and organic bases is selected from TMG, TMP, DBU, DBN, DIPA, DIPEA, DCHA, NMP;
Wherein catalyzer is selected from palladium carbon or platinum carbon, and the consumption of catalyzer is 5% ~ 80% of ertapenem intermediate 2a, by weight;
Wherein said method is carried out in a hydrogen atmosphere, and hydrogen pressure is 0.4 ~ 2.5Mpa;
Wherein temperature of reaction is-10 ~ 40 DEG C.
2. method as claimed in claim 1, wherein carboxyl-protecting group is to nitrobenzyl.
3. method as claimed in claim 1, wherein works as P
3h is selected from for during charge balance group
+or a kind of salt-forming cation.
4. method as claimed in claim 3, wherein salt-forming cation is selected from monovalent metallic ion, divalent-metal ion or quaternary ammonium ion.
5. method as claimed in claim 4, wherein monovalent metallic ion is selected from Na
+, K
+.
6. method as claimed in claim 4, wherein divalent-metal ion is selected from Ca
2+, Mg
2+.
7. method as claimed in claim 4, wherein quaternary ammonium ion is selected from organic quaternary ammonium ion.
8. method as claimed in claim 7, wherein organic quaternary ammonium ion is selected from H-TMG
+, H-TMP
+, H-DBU
+, H-DBN
+, H-DIPA
+, H-DIPEA
+, H-DCHA
+, H-NMP
+.
9. method as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 10wt%.
10. method as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 5wt%.
11. methods as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 1wt%.
12. methods as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 0.1wt%.
13. methods as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 0.01wt%.
14. methods as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 0.001wt%.
15. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 10wt%.
16. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 5wt%.
17. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 1wt%.
18. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 0.1wt%.
19. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 0.01wt%.
20. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 0.001wt%.
21. as arbitrary in claim 9-20 as described in method, it is characterized in that: described single solvent wet concentration from tap water, tap water, deionized water, reverse osmosis water, electrodialytic water, exceed drainage, distilled water, sterilized water or its combination.
22. methods as claimed in claim 1, is characterized in that: the consumption of described aqueous solvent is 5 ~ 80 times of ertapenem intermediate 2a, by weight.
23. methods as claimed in claim 22, is characterized in that: the consumption of described aqueous solvent is 10 ~ 40 times of ertapenem intermediate 2a, by weight.
24. methods as claimed in claim 1, the consumption of wherein said alkali is 0.5 ~ 5 molar equivalent of ertapenem intermediate 2a.
25. methods as claimed in claim 24, wherein the consumption of alkali is 1 ~ 3 molar equivalent of ertapenem intermediate 2a.
26. methods according to claim 1, wherein catalyzer is selected from 5 ~ 10% palladium carbon.
27. methods according to claim 1, wherein the consumption of catalyzer is 10% ~ 50% of ertapenem intermediate 2a, by weight.
28. methods according to claim 1, wherein hydrogen pressure is 1.0 ~ 2.0Mpa.
29. methods according to claim 1, wherein temperature of reaction is 10 ~ 30 DEG C.
30. methods according to claim 1, wherein carry out aftertreatment to product after hydrogenation, obtain ertapenem or its sodium salt.
31. methods according to claim 30, wherein said aftertreatment is purifying.
32. methods according to claim 30, wherein said aftertreatment is concentrated, crystallization and/or freeze-drying.
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| WO2014082226A1 (en) * | 2012-11-28 | 2014-06-05 | 上海创诺医药集团有限公司 | Purification method of ertapenem sodium |
| CN103159770A (en) * | 2013-03-22 | 2013-06-19 | 成都自豪药业有限公司 | Crystal form of ertapenem monosodium salt |
| CN106279175A (en) * | 2016-08-12 | 2017-01-04 | 上海龙翔生物医药开发有限公司 | A kind of preparation method of Ertapenem Sodium |
| CN110423237B (en) * | 2019-09-10 | 2021-12-31 | 石药集团中诺药业（石家庄）有限公司 | Method for refining ertapenem sodium |
| CN114105988B (en) * | 2022-01-24 | 2022-04-29 | 深圳市海滨制药有限公司 | Synthetic method of ertapenem sodium |
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| CN101376636A (en) * | 2007-08-28 | 2009-03-04 | 上海医药工业研究院 | Carbpenem penicillin ertapenem intermediate, and preparation and use thereof |
| CN101376643A (en) * | 2007-08-28 | 2009-03-04 | 上海医药工业研究院 | Preparation of carbapenem penicillin ertapenem intermediate |
| CN101935321A (en) * | 2010-07-20 | 2011-01-05 | 深圳市海滨制药有限公司 | Method for synthesizing 1 beta methyl carbapenem antibiotic |
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| CN101376636A (en) * | 2007-08-28 | 2009-03-04 | 上海医药工业研究院 | Carbpenem penicillin ertapenem intermediate, and preparation and use thereof |
| CN101376643A (en) * | 2007-08-28 | 2009-03-04 | 上海医药工业研究院 | Preparation of carbapenem penicillin ertapenem intermediate |
| CN101935321A (en) * | 2010-07-20 | 2011-01-05 | 深圳市海滨制药有限公司 | Method for synthesizing 1 beta methyl carbapenem antibiotic |
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