CN101376643B - Preparation of carbapenem penicillin ertapenem intermediate - Google Patents
Preparation of carbapenem penicillin ertapenem intermediate Download PDFInfo
- Publication number
- CN101376643B CN101376643B CN2007100453251A CN200710045325A CN101376643B CN 101376643 B CN101376643 B CN 101376643B CN 2007100453251 A CN2007100453251 A CN 2007100453251A CN 200710045325 A CN200710045325 A CN 200710045325A CN 101376643 B CN101376643 B CN 101376643B
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- suc
- compound
- pnz
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 *OC(c1cccc(N)c1)=O Chemical compound *OC(c1cccc(N)c1)=O 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of an intermediate for synthesizing carbapenems penicillin etapenem having the formula of VII. The preparation method comprises the following steps: allowing a compound having the formula of I and 4-methoxybenzyl chloride to react to obtain a product; reacting under the action of stannous chloride dehydrate, and regulating pH to 7; performing condensation reaction of above product and activated ester of PNZ L-hydroxyproline; reacting with methylsulfonyl chloride; reacting with potassium thioacetate; and hydrolyzing in acidic or alkaline condition, wherein PMB is shown in figure (1), PNZ is shown in figure (2), Ms is mesyl, and Ac is acetyl. The preparation method can be carried out at the room temperature, with the advantages of mild reaction condition, low cost, and easily realized industrial production.
Description
Technical field
The invention belongs to the synthetic field of organic compound, be specifically related to a kind of intermediates preparation of Carbpenem penicillin ertapenem.
Background technology
Ertapenem (ertapenem, MK-0826, L-749,345, trade(brand)name Invanz) the New-type wide-spectrum carbapenem antibiotic of developing for Merck drugmaker, have has a broad antifungal spectrum,, characteristics such as pharmacokinetic parameters good, clinical therapeutic efficacy good, better tolerance, untoward reaction few and long half time can a day be administered once stable, be used for the treatment of adult's moderate clinically, can obtain satisfactory effect the acquired polyinfection of community to the responsive microbial infection of severe to dehydropeptidase of kidney.This product is then gone on the market in Britain, Ireland, Israel and Philippines in succession first in the U.S.'s listing November calendar year 2001.
US5478820 has reported a kind of synthetic method of ertapenem.This method synthetic route is long, and yield is low, and part reagent price is higher, and polystep reaction needs column chromatography for separation, is unsuitable for suitability for industrialized production.
At present, be applied in the synthetic method of ertapenem of suitability for industrialized production, the side chain composite part adopts " one kettle way ".Relevant patent is US5872250 and US6180783.The reaction of this method need remain under the low temperature-20 ℃ to be carried out, and the industrial production condition is harsh, to the equipment requirements height; And used part reagent price is higher, as: diisopropyl ethyl amine and diphenyl phosphoryl chloride.
Summary of the invention
Technical problem to be solved by this invention is that the synthetic method of ertapenem is difficult for being applied to suitability for industrialized production in the prior art in order to overcome, and industrialized method need remain under the low temperature-20 ℃ and carries out, condition is harsh, equipment requirements is higher, the cost problem of higher, and a kind of reaction conditions gentleness and the lower Carbpenem penicillin ertapenem intermediates preparation of cost are provided.
Method of the present invention comprises the steps:
(1) in non-proton organic solvent, under the catalysis of organic bases reagent, with compound shown by formula I and the reaction of 4-methoxybenzyl chloride;
(2) in the alcoholic solvent, will be under the effect of two hydrated stannous chlorides suc as formula the compound shown in the II, heating is reacted, and adopts mineral alkali to regulate pH to alkalescence afterwards;
(3) in the non-polar solvent, the compound that will be shown in formula III and the Acibenzolar of PNZ L-oxyproline carry out condensation reaction; Wherein, PNZ L-oxyproline is suc as formula shown in the IX;
(4) in the nonpolar reagent, under the catalysis of organic bases reagent, will be suc as formula compound shown in the IV and methylsulfonyl chloride reaction;
(5) in the non-proton property polar solvent, will be suc as formula compound shown in the V and thioacetic acid potassium reacting by heating;
(6) in the solvent, will get final product suc as formula the hydrolysis under acidity or alkaline condition of the compound shown in the VI.
Formula I formula II
Formula III
Formula IX formula IV
Formula V formula VI
Formula VII
Wherein, PMB is
PNZ is
Ms is a methylsulfonyl; Ac is an ethanoyl.
In the step (1), what the mol ratio of described compound shown by formula I and 4-methoxybenzyl chloride was preferable is 1: 1.5～1: 3, and better is 1: 1.5～1: 2, and that best is 1.8-1.9; What described non-proton organic solvent was preferable is toluene, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether or isopropyl ether, and better is toluene dichloride; The consumption of non-proton organic solvent can be the twice of meltage; What described organic bases reagent was preferable is triethylamine, diisopropyl ethyl amine, pyridine, and better is triethylamine; The consumption of organic bases reagent is preferable be the compound shown by formula I molar weight 1.5-2 doubly; What the temperature of described reaction was preferable is 40～60 ℃, and better is 40-45 ℃, and best is 45 ℃; What the time of described reaction was preferable is 1～10 hour, and better is 3～7 hours, and best is 4～5 hours.After reaction finishes, available CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer, drying is filtered, and concentrates and makes solid product, can be further through the recrystallization purified product.
In the step (2), the consumption of described two hydrated stannous chlorides is preferable is suc as formula the compound molar weight shown in the II 4～6 times; What described alcoholic solvent was preferable is methyl alcohol, ethanol, n-propyl alcohol or Virahol; The consumption of alcoholic solvent can be the twice of reactant molar weight; What the temperature of described reaction was preferable is 40-75 ℃, and better is 50-55 ℃; What the time of described reaction was preferable is 30-60 minute, is more preferred from 30-45 minute; What described mineral alkali was preferable is sodium hydroxide or potassium hydroxide, and concrete operations can be made into mineral alkali the aqueous solution or the alcoholic solution use that concentration is about mass percent 8-15%; What described alkalescence was preferable is pH 〉=9, and better is pH=10～11.The conditioned reaction system is to alkalescence, and available ether and water extract, combined ether layer, and drying is filtered, and concentrates and makes solid product.
In the step (3), described shown in formula III compound and the molar ratio of the Acibenzolar of PNZ L-oxyproline preferable for to be less than or equal to for 2 (not comprising that molar ratio is 0 situation), better is 1.01～1.1; The temperature of described reaction is preferable is-10-0 ℃, and better is-5-0 ℃; What the time of described reaction was preferable is 2-5 hour, and better is 4 hours.The consumption of non-polar solvent can be 2 times of reactant molar weight.
Wherein, the Acibenzolar of described PNZ L-oxyproline can be made by following method: in the non-polar solvent, under the organic bases effect, PNZ L-oxyproline (suc as formula the compound shown in the IX) and chloro-formic ester reaction are got final product; Wherein, PNZ L-oxyproline is suc as formula shown in the IX.What described organic bases was preferable is triethylamine, diisopropyl ethyl amine, pyridine, and better is triethylamine; The consumption of described organic bases can be 1.5-3 times of PNZL-oxyproline molar weight; What described chloro-formic ester was preferable is methyl-chloroformate, Vinyl chloroformate, butyl chloroformate or isobutyl chlorocarbonate; The consumption of described PNZ L-oxyproline is preferable be chloro-formic ester molar weight 1.5-3 doubly; The time of reaction can be 1-3 hour, preferred 2 hours; Temperature of reaction can be-10 ℃-25 ℃, preferred 0 ℃.
In the step (4), the consumption of described methylsulfonyl chloride is preferable is suc as formula the molar weight of the compound shown in the IV 1～4 times, and better is 1.5～3 times, and best is 2 times; What described organic bases reagent was preferable is triethylamine, diisopropyl ethyl amine, pyridine, and better is triethylamine; The consumption of organic bases reagent can be 1.5～3 times suc as formula the compound molar weight shown in the IV; The temperature of described reaction is preferable is-10-0 ℃, and better is-5-0 ℃; What the time of described reaction was preferable is 1-4 hour, and better is 1-3 hour.After reaction finished, through washing, drying was filtered, and concentrates and makes solid product.The consumption of nonpolar reagent can be 2 times of reactant molar weight.
In the step (5), described thioacetic acid potassium be less than or equal to for 5 (not comprising that molar ratio is 0 situation) suc as formula the molar ratio of the compound shown in the V, better is 2.5～3; What the temperature of described reaction was preferable is 40～80 ℃, and better is 50～60 ℃, and best is 55-58 ℃; The time of described reaction can be more than or equal to 3 hours, and that preferable is 5-10, and better is 6 hours.The consumption of non-proton property polar solvent can be more than or equal to 4 times of feed molar amount.After reaction finishes, can with product through extraction, concentrate and recrystallization make purify after solid product.
In the step (6), what described acidic conditions was preferable is pH≤1; Regulate reagent that described acidic conditions adopts preferable be the vitriol oil; The reagent of regulating described alkaline condition employing is the NaOH or the KOH aqueous solution; Described preferred solvents be tetrahydrofuran (THF) or methylene dichloride; The consumption of solvent can be 4 times of reactant solubilized amount; What the temperature that is hydrolyzed under acidic conditions was preferable is 0-45 ℃; What the temperature that is hydrolyzed under alkaline condition was preferable is 0-5 ℃; What the time that is hydrolyzed under acidic conditions was preferable is 10-30 minute; What the time that is hydrolyzed under alkaline condition was preferable is 15-30 minute.
In the method for the present invention, intermediate II, III, IV, V, VI, VII are new compound, can be respectively referring to six parts of patent applications " intermediate of Carbpenem penicillin ertapenem and its production and application " of being applied for 2007.8.28 day by the present patent application people.
The compound that method of the present invention makes can further synthesize ertapenem by following route:
Agents useful for same of the present invention and raw material are all commercially available to be got.
Positive progressive effect of the present invention is: in the method for the present invention, each goes on foot the reaction conditions gentleness, can at room temperature carry out, and cost is lower, easily is applied to suitability for industrialized production.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
Synthesizing of embodiment 1 3-nitrobenzoic acid 4-methoxy benzyl ester (formula II)
(4.00g is 23.93mmol) in CH for formula I compound
2Cl
2Among the 50ml, add NEt
3(4.84g, 47.91mmol), (5.62g 35.89mmol), is warming up to 45 ℃, reacts 3 hours to drip 4-methoxybenzyl chloride (PMBCl) under the room temperature.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer anhydrous Na SO
4Drying is filtered, and filtrate concentrates, light yellow solid (formula II) (6.29g, productive rate 91.5%, purity〉99%).Fusing point: 82-84 ℃.Qualification result is as follows:
NMR(CDCl
3)δ：3.81(s，3H)；5.35(s，2H)；6.93(m，2H)；7.40(m，2H)；7.63(m，1H)；8.37(m，2H)；8.40(m，1H)
MS(CI)：287
Synthesizing of embodiment 2 3-nitrobenzoic acid 4-methoxy benzyl esters (formula II)
(150.00g 0.898mol) in ethyl acetate 100ml, adds NEt to formula I compound
3(181.89g, 1.797mol), (251.49g 1.605mol), is warming up to 60 ℃, reacts 5 hours to drip PMBCl under the room temperature.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets light yellow solid, and ethyl alcohol recrystallization gets white crystal (formula II) (256.53g, productive rate 99.5%, purity 100%).Fusing point: 83-85 ℃.
Synthesizing of embodiment 3 3-nitrobenzoic acid 4-methoxy benzyl esters (formula II)
(150.00g, 0.898mol) in toluene 200ml, (106.41g, 1.35mol), (422.13g 2.694mol), is warming up to 40 ℃ to formula I compound, reacts 10 hours to drip PMBCl under the room temperature to add pyridine.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer anhydrous Na SO
4Drying is filtered, and filtrate concentrates, light yellow solid, ethyl alcohol recrystallization gets white crystal (formula II) (256.00g, productive rate 99.1%, purity〉99%).Fusing point: 83-85 ℃.
Synthesizing of embodiment 4 3-nitrobenzoic acid 4-methoxy benzyl esters (formula II)
(150.00g, 0.898mol) in tetrahydrofuran (THF) 100ml, (202.79g, 1.572mol), (211.06g 1.347mol), is warming up to 40 ℃ to formula I compound, reacts 1 hour to drip PMBCl under the room temperature to add diisopropyl ethyl amine.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets light yellow solid, and ethyl alcohol recrystallization gets white crystal (formula II) (245.10g, productive rate 95.5%, purity 100%).Fusing point: 84-86 ℃.
Synthesizing of embodiment 5 3-nitrobenzoic acid 4-methoxy benzyl esters (formula II)
(150.00g 0.898mol) in ether 100ml, adds NEt to formula I compound
3(181.89g, 1.797mol), (281.41g 1.796mol), is warming up to 50 ℃, reacts 7 hours to drip PMBCl under the room temperature.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets light yellow solid, and ethyl alcohol recrystallization gets white crystal (formula II) (256.66g, productive rate 99.6%, purity 100%).Fusing point: 83-85 ℃.
Synthesizing of embodiment 6 3-nitrobenzoic acid 4-methoxy benzyl esters (formula II)
(150.00g 0.898mol) in isopropyl ether 100ml, adds NEt to formula I compound
3(181.89g, 1.797mol), (251.49g 1.605mol), is warming up to 45 ℃, reacts 4 hours to drip PMBCl under the room temperature.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer anhydrous Na SO
4Drying is filtered, and filtrate concentrates, light yellow solid, ethyl alcohol recrystallization gets white crystal (formula II) (254.00g, productive rate 98.5%, purity〉99%).Fusing point: 83-86 ℃.
Synthesizing of embodiment 7 3-benzaminic acid 4-methoxy benzyl esters (formula III)
(10.00g is 34.81mmol) in SnCl for compound shown in the formula II
2.2H
2(39.33g among ethanol 70ml 174.05mmol), is warming up to 50 ℃ to O, reaction 30min.Alcoholic solution with 8wt%NaOH is transferred pH=9, filters, with ether and water extraction, combined ether layer, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets light yellow solid (formula III) (8.10g, 90.5%).Fusing point: 45-47 ℃.
NMR(CDCl
3)δ：3.77(s，3H)；5.25(s，2H)；6.80(m，1H)；6.89(m，2H)；7.16(m，1H)；7.33(m，2H)；7.41(m，1H)；7.43(m，1H)
MS(CI)：258[M+H]
Synthesizing of embodiment 8 3-benzaminic acid 4-methoxy benzyl esters (formula III)
(40.93g is 142.47mmol) in SnCl for compound shown in the formula II
2.2H
2(161.0g among ethanol 300ml 712.37mmol), is warming up to 50 ℃ to O, reaction 50min.Alcoholic solution with 15%NaOH is transferred pH=11, with ether and water extraction, combined ether layer, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets light yellow solid (formula III) (33.84g, 92.3%).Fusing point: 47-49 ℃.
Synthesizing of embodiment 9 3-benzaminic acid 4-methoxy benzyl esters (formula III)
(10.00g is 34.81mmol) in SnCl for compound shown in the formula II
2.2H
2(47.196g among methyl alcohol 70ml 208.86mmol), is warming up to 40 ℃ to O, reaction 60min.Alcoholic solution with 8wt%KOH is transferred pH=10, filters, with ether and water extraction, combined ether layer, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets light yellow solid (formula III) (7.61g, 85.0%).Fusing point: 46-47 ℃.
Synthesizing of embodiment 10 3-benzaminic acid 4-methoxy benzyl esters (formula III)
(10.00g is 34.81mmol) in SnCl for compound shown in the formula II
2.2H
2(31.464g among n-propyl alcohol 70ml 139.24mmol), is warming up to 75 ℃ to O, reaction 40min.Alcoholic solution with 8wt%KOH is transferred pH=10.5, filters, with ether and water extraction, combined ether layer, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets light yellow solid (formula III) (7.12g, 80.0%).Fusing point: 45-47 ℃.
Synthesizing of embodiment 11 3-benzaminic acid 4-methoxy benzyl esters (formula III)
(10.00g is 34.81mmol) in SnCl for compound shown in the formula II
2.2H
2(31.464g among Virahol 70ml 139.24mmol), is warming up to 55 ℃ to O, reaction 50min.Transfer pH=11 with the 8wt%NaOH aqueous solution, filter, with ether and water extraction, combined ether layer, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets light yellow solid (formula III) (7.51g, 83.86%).Fusing point: 44-46 ℃.
Embodiment 12 (2S, 4R)-4-hydroxyl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical] tetramethyleneimine (formula IV) synthetic
(5.00g is 16.12mmol) in CH for PNZ L-oxyproline
2Cl
2Among the 80ml, add NEt
3(2.45g, 24.17mmol) ,-8 ℃-10 ℃ drip ClCOOCH
3(3.30g, 24.17mmol), the reaction 1h, make the PNZL-oxyproline Acibenzolar (6.61g, 16.10mmol).(8.29g 32.24mmol), continues reaction 2h to compound shown in the disposable adding formula III.Use 1NHCl in succession, the saturated NaHCO of saturated NaClaq
3Aq washes, and merges CH
2Cl
2Layer usefulness, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets white powder solid (formula IV) 8.23g, productive rate 92.9%.Fusing point: 180-182 ℃.
NMR(CDCl
3)δ：2.01(m，2H)；2.33(s，1H)；3.34(m，1H)；3.56(m，2H)3.74(s，3H)；4.40(m，1H)；5.32(s，2H)；5.51(s，2H)；6.70(m，2H)；7.10(m，2H)，7.28(m，1H)；7.44(m，2H)；7.68(m，1H)；7.90(m，1H)；8.00(s，1H)；8.05(m，2H)；8.40(s，1H)
MS(CI)：549
Embodiment 13 (2S, 4R)-4-hydroxyl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical] tetramethyleneimine (formula IV) synthetic
(17.91g is 57.72mmol) in CH for PNZ L-oxyproline
2Cl
2Among the 120ml, add diisopropyl ethyl amine (8.19g, 63.49mmol), 0 ℃--2 ℃ drip ClCOOi-Bu (7.96g, 58.30mmol), reaction 4h, make PNZ L-oxyproline Acibenzolar (23.66g, 57.70mmol).(125.00g 58.30mmol), continues reaction 2h to compound shown in the disposable adding formula III.Use 1N Hclaq, saturated NaClaq and saturated NaHCO in succession
3Aq washes, and merges CH
2Cl
2Layer usefulness, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets white powder solid (formula IV) (26.7,94.2%).Fusing point: 177-178 ℃.
Embodiment 14 (2S, 4R)-4-hydroxyl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical] tetramethyleneimine (formula IV) synthetic
(17.91g is 57.72mmol) in CH for PNZ L-oxyproline
2Cl
2Among the 120ml, add pyridine (5.02g, 63.49mmol), 0 ℃--5 ℃ drip ClCOOn-Bu (7.96g, 58.30mmol), reaction 1h, make the PNZL-oxyproline Acibenzolar (23.67g, 57.71mmol).(125.00g 58.30mmol), continues reaction 5h to compound shown in the disposable adding formula III.Use 1N Hclaq, saturated NaClaq and saturated NaHCO in succession
3Aq washes, and merges CH
2Cl
2Layer usefulness, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets white powder solid (formula IV) (29.52g, 93.5%).Fusing point: 177-179 ℃.
Embodiment 15 (2S, 4R)-4-hydroxyl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical] tetramethyleneimine (formula IV) synthetic
(17.91g is 57.72mmol) in CH for PNZ L-oxyproline
2Cl
2Among the 120ml, add NEt
3(6.43g, 63.49mmol), 0 ℃--5 ℃ drip ClCOOCH
2CH
3(6.33g, 58.30mmol), the reaction 1h, make PNZ L-oxyproline Acibenzolar (21.74g, 53mmol).(125.00g 58.30mmol), continues reaction 3.5h and uses 1N Hclaq, saturated NaClaq and saturated NaHCO in succession compound shown in the disposable adding formula III
3Aq washes, and merges CH
2Cl
2Layer usefulness, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets white powder solid (formula IV) (30.33g, 95.7%).Fusing point: 178-181 ℃.
Embodiment 16 ((2S, 4R)-4-mesyloxy-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula V) synthetic
(8.23g is 16.12mmol) in CH with formula IV compound
2Cl
2Among the 120ml, add triethylamine (NEt
3) (2.00g, 19.76mmol), (2.22g 19.67mmol), reacts 1h to-5 ℃～-10 ℃ dropping methylsulfonyl chlorides (MsCl).Use 1M HCl in succession, the alcoholic solution of saturated NaCl, saturated NaHCO
3Alcoholic solution wash, merge CH
2Cl
2Layer usefulness, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets off-white color crystal (formula V) 13.2g, productive rate 90.4%, purity〉95%.Fusing point: 81-85 ℃.Qualification result is as follows:
NMR(CDCl
3)δ：1.99(m，2H)；2.85(s，3H)；3.50(m，2H)；3.70(s，3H)；4.18(m，1H)；4.77(m，1H)；5.38(s，2H)；5.68(s，2H)；6.66(m，2H)；7.12(m，2H)，7.39(m，1H)；7.40(m，2H)；7.78(m，1H)；7.82(m，1H)；8.00(s，1H)；8.15(m，2H)；8.42(s，1H)
MS(CI)：627
Embodiment 17 ((2S, 4R)-4-mesyloxy-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula V) synthetic
(24.00g is 43.68mmol) in CH with formula IV compound
2Cl
2Among the 220ml, add NEt
3(6.63g, 65.51mmol), (12.89g 109.6mmol), reacts 2h to 0 ℃～-5 ℃ dropping MsCl.Use CH
2l
2With the water extraction, merge CH
2Cl
2Layer usefulness concentrates, off-white color crystal (formula V) (27.4g, productive rate 100%, purity〉95%).Fusing point: 84-86 ℃.
Embodiment 18 ((2S, 4R)-4-mesyloxy-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula V) synthetic
(24.00g is 43.68mmol) in CH with formula IV compound
2Cl
2Among the 220ml, add NEt
3(6.63g, 65.51mmol), (10.01g 87.36mmol), reacts 2h to 0 ℃～-2 ℃ dropping MsCl.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer usefulness concentrates, off-white color crystal (formula V) (25.8g, productive rate 94%, purity〉95%).Fusing point: 85-87 ℃.
Embodiment 19 ((2S, 4R)-4-mesyloxy-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula V) synthetic
(24.00g is 43.68mmol) in CH with formula IV compound
2Cl
2Among the 220ml, (5.18g, 65.51mmol), (7.51g 65.51mmol), reacts 4h to-10 ℃～-8 ℃ dropping MsCl to add pyridine.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer usefulness concentrates, off-white color crystal (formula V) (24.7g, productive rate 95%, purity〉95%).Fusing point: 84-86 ℃.
Embodiment 20 ((2S, 4R)-4-mesyloxy-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula V) synthetic
(24.00g is 43.68mmol) in CH with formula IV compound
2Cl
2Among the 300ml, (8.45g, 65.51mmol), (15.02g 131.04mmol), reacts 3h to-7 ℃～-5 ℃ dropping MsCl to add diisopropyl ethyl amine.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer usefulness concentrates, off-white color crystal (formula V) (25.2g, productive rate 96%, purity〉95%).Fusing point: 86-87 ℃.
Embodiment 21 ((2S, 4R)-4-mesyloxy-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula V) synthetic
(24.00g is 43.68mmol) in CH with formula IV compound
2Cl
2Among the 200ml, add NEt
3(6.63g, 65.51mmol), (5.01g 43.68mmol), reacts 1h to-6 ℃～-4 ℃ dropping MsCl.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer usefulness concentrates, off-white color crystal (formula V) (25.2g,, productive rate 92%, purity 95%).Fusing point: 85-87 ℃.
Embodiment 22 ((2S, 4R)-4-mesyloxy-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula V) synthetic
(24.00g is 43.68mmol) in CH with formula IV compound
2Cl
2Among the 320ml, add NEt
3(6.63g, 65.51mmol), (20.03g 174.72mmol), reacts 1h to 0 ℃～-3 ℃ dropping MsCl.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer usefulness concentrates, off-white color crystal (formula V) (27.4g,, productive rate 100%, purity 95%).Fusing point: 85-88 ℃.
Embodiment 23 ((2S, 4R)-4-ethanethioyl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VI) synthetic
(5.00g, 7.97mmol) in DMF20ml, among the toluene 20ml, (4.09g 35.86mmol), is heated to 55 ℃, reaction 8h to add thioacetic acid potassium (AcSK) with formula V compound.With EA and water extraction, the combined ethyl acetate layer concentrates, and is brown semi-solid with ethyl acetate and normal hexane recrystallization, gets product (formula VI) (3.6g, productive rate 74%).Fusing point: 140-142 ℃.Qualification result is as follows:
NMR(CDCl
3)δ：2.25(s，3H)；2.50(m，2H)；2.87(m，1H)；3.78(s，3H)；4.10(m，1H)；4.30(m，2H)；5.30(s，2H)；5.45(s，2H)；6.68(m，2H)；7.10(m，2H)，7.30(m，1H)；7.40(m，2H)；7.67(m，1H)；7.80(m，1H)；8.05(s，1H)；8.18(m，2H)；8.30(s，1H)
MS(CI)：629.9(M+Na)
Embodiment 24 ((2S, 4R)-4-ethanethioyl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VI) synthetic
(34.00g, 54.59mmol) in DMF120ml, among the ethyl acetate 100ml, (22g 192.78mmol), is heated to 58 ℃, reaction 5h to add AcSK with formula V compound.With ethyl acetate and water extraction, the combined ethyl acetate layer concentrates, and brown semisolid is washed with methyl alcohol, gets product (formula VI) (29g, productive rate 88%).Fusing point: 144-145 ℃.
Embodiment 25 ((2S, 4R)-4-ethanethioyl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VI) synthetic
(34.00g, 54.59mmol) in DMF120ml, among the ethyl acetate 100ml, (18.69g 163.77mmol), is heated to 40 ℃, reaction 10h to add AcSK with formula V compound.With ethyl acetate and water extraction, the combined ethyl acetate layer concentrates, and brown semisolid is washed with methyl alcohol, gets product (formula VI) (15g, productive rate 45%).Fusing point: 143-145 ℃.
Embodiment 26 ((2S, 4R)-4-ethanethioyl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VI) synthetic
(34.00g, 54.59mmol) in DMF120ml, among the ethyl acetate 100ml, (28.03g 245.66mmol), is heated to 80 ℃, reaction 5h to add AcSK with formula V compound.With ethyl acetate and water extraction, the combined ethyl acetate layer concentrates, and brown semisolid is washed with methyl alcohol, gets product (formula VI) (25g, productive rate 75%).Fusing point: 142-144 ℃.
Embodiment 27 ((2S, 4R)-4-ethanethioyl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VI) synthetic
(34.00g, 54.59mmol) in DMF120ml, among the ethyl acetate 100ml, (15.57g 136.48mmol), is heated to 50 ℃, reaction 9h to add AcSK with formula V compound.With ethyl acetate and water extraction, the combined ethyl acetate layer concentrates, and brown semisolid is washed with methyl alcohol, gets product (formula VI) (30g, productive rate 91%).Fusing point: 144-145 ℃.
Embodiment 28 ((2S, 4R)-4-ethanethioyl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VI) synthetic
(34.00g, 54.59mmol) in DMF120ml, among the ethyl acetate 100ml, (31.15g 272.95mmol), is heated to 60 ℃, reaction 6h to add AcSK with formula V compound.With ethyl acetate and water extraction, the combined ethyl acetate layer concentrates, and brown semisolid is washed with methyl alcohol, gets product (formula VI) (27g, productive rate 81%).Fusing point: 146-147 ℃.
Embodiment 29 ((2S, 4R)-4-sulfydryl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VII) synthetic
(3.00g 4.94mmol) in methylene dichloride 15ml, adds 98wt% vitriol oil 0.4g, pH value of solution=1.0, room temperature reaction 10 minutes with formula VI compound.Add water crystallization, filter, get off-white color solid (formula VII) (2.30g, productive rate 82%).Qualification result is as follows:
NMR(CDCl
3)δ：1.45(s，1H)；2.09(m，2H)；2.60(m，1H)；3.60(m，2H)；3.80(s，3H)；4.30(m，1H)；5.36(s，2H)；5.56(s，2H)；6.73(m，2H)；7.11(m，2H)，7.42(m，1H)；7.51(m，2H)；7.7(5m，1H)；7.90(m，1H)；8.01(s，1H)；8.18(m，2H)；8.30(s，1H)
MS(CI)：565
Embodiment 30 ((2S, 4R)-4-sulfydryl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VII) synthetic
(3.00g 4.94mmol) in tetrahydrofuran (THF) 15ml, adds 98wt% vitriol oil 1g, and pH value of solution is 0.2,0 ℃ of reaction 1 hour with formula VI compound.Add water crystallization, filter, get off-white color solid (formula VII) (1.6 g, productive rate 57%).
Embodiment 31 ((2S, 4R)-4-sulfydryl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VII) synthetic
(3.00g 4.94mmol) in methylene dichloride 15ml, adds 98wt% vitriol oil 0.4g, and pH value of solution is 1,45 ℃ of reaction 20 minutes with formula VI compound.Add water crystallization, filter, get off-white color solid (formula VII) (2.35g, productive rate 84%).
Embodiment 32 ((2S, 4R)-4-sulfydryl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VII) synthetic
(3.00g 4.94mmol) in tetrahydrofuran (THF) 15ml, adds 98wt% vitriol oil 0.5g, and pH value of solution is 1,20 ℃ of reaction 30 minutes with formula VI compound.Add water crystallization, filter, get off-white color solid (formula VII) (1.4g, productive rate 50%).
Embodiment 33 ((2S, 4R)-4-sulfydryl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VII) synthetic
(3.00g 4.94mmol) in methylene dichloride 15ml, adds 4NNaOH solution 1.3ml, 0 ℃, reacts 15 minutes with formula VI compound.Transfer pH to acid, water and dichloromethane extraction, organic layer concentrates, and gets off-white color solid (formula VII) (2.15g, productive rate 76%).
Embodiment 34 ((2S, 4R)-4-sulfydryl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VII) synthetic
(3.00g 4.94mmol) in methylene dichloride 15ml, adds 4N KOH solution 1.3ml, 5 ℃, reacts 30 minutes with formula VI compound.Transfer pH to acid, water and dichloromethane extraction, organic layer concentrates, and gets off-white color solid (formula VII) (2.3g, productive rate 81.32%).
Embodiment 35 ((2S, 4R)-4-sulfydryl-1-(4-nitro carbobenzoxy-(Cbz))-2-[3-(4-methoxy-benzyl) phenyl amino formyl radical]-tetramethyleneimine) (formula VII) synthetic
(3.00g 4.94mmol) in methylene dichloride 15ml, adds 4NNaOH solution 1.3ml, 2 ℃, reacts 25 minutes with formula VI compound.Transfer pH to acid, water and dichloromethane extraction, organic layer concentrates, and gets off-white color solid (formula VII) (2.2g, productive rate 77.76%).
Reference example [4R, 5S, 6S]-3-[[(3S, 5S)-5-[[(S-carboxyl toluene) amino] carbonyl]-the 3-pyrrolidyl] sulfenyl]-6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-azabicyclic [3.2.0] hept-2-ene"-2-carboxylic acid list sodium salt (ertapenem list sodium salt)
(26.5g is 157.9mmol) in CH for formula I compound
2Cl
2Among the 350ml, add NEt
3(32g, 316.1mmol), (44.4g 283.6mmol), is warming up to 45 ℃, reacts 3 hours to drip 4-methoxybenzyl chloride (PMBCl) under the room temperature.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer anhydrous Na SO
4Drying is filtered, and filtrate concentrates, light yellow solid (formula II) (41.5g, productive rate 91.5%, purity〉99%).
(40.93g is 142.47mmol) in SnCl for compound shown in the formula II
2.2H
2(161.0g among ethanol 300ml 712.37mmol), is warming up to 50 ℃ to O, reacts to solid all to dissolve.Alcoholic solution with 15%NaOH is transferred pH=11, with ether and water extraction, combined ether layer, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets light yellow solid (formula III) (33.84g, 92.3%).
(17.91g is 57.72mmol) in CH for PNZ L-oxyproline
2Cl
2Among the 120ml, add NEt
3(6.43g, 63.49mmol), 0 ℃--5 ℃ drip ClCOOi-Bu (7.96g, 58.30mmol), reaction 4h, make PNZ L-oxyproline Acibenzolar (23.66g, 57.70mmol).(125.00g 58.30mmol), continues reaction 2h to compound shown in the disposable adding formula III.Use 1N Hclaq, saturated NaClaq and saturated NaHCO in succession
3Aq washes, and merges CH
2Cl
2Layer usefulness, anhydrous Na SO
4Drying is filtered, and filtrate concentrates, and gets white powder solid (formula IV) (26.7,94.2%).
(24.00g is 43.68mmol) in CH with formula IV compound
2Cl
2Among the 220ml, add NEt
3(6.63g, 65.51mmol), (10.01g 87.36mmol), reacts 2h to 0 ℃～-2 ℃ dropping MsCl.Use CH
2Cl
2With the water extraction, merge CH
2Cl
2Layer usefulness concentrates, off-white color crystal (formula V) (25.8g, productive rate 94%, purity〉95%).
(25g, 40.14mmol) in DMF90ml, among the ethyl acetate 75ml, (11.45g 100.35mmol), is heated to 50 ℃, reaction 9h to add AcSK with formula V compound.With ethyl acetate and water extraction, the combined ethyl acetate layer concentrates, and brown semisolid is washed with methyl alcohol, gets product (formula VI) (22g, productive rate 91%).
(3.00g 4.94mmol) in methylene dichloride 15ml, adds vitriol oil 0.4g, pH value of solution=1.0, room temperature reaction 10 minutes with formula VI compound.Add water crystallization, filter, get off-white color solid (formula VII) (2.30g, productive rate 82%).
(4R; 5S; 6S; 8R)-and the 3-[(hexichol oxygen acyl of seeing) oxygen-6-(1-hydroxyethyl)-4-methyl-7-oxygen-1-azabicyclic [3.2.0]-hept-2-ene"-2-carboxylic acid (4-nitrophenyl) methyl esters (0.595g; 1mmol) (commercially available getting) is dissolved in NMP+DMF10ml (v/v=3:1); stir down in 0 ℃ of adding (2S; 4R)-1-(4-nitro carbobenzoxy-(Cbz))-2-(3-(4-methoxy-benzyl) formamyl) tetramethyleneimine-4-mercaptan (formula VII) (0.565g; NMP+DMF10ml 1mmol) (v/v=3:1) solution; be cooled to-40 ℃; (0.38ml 2.2mmol), reacted 4 hours to add DIPEA after 10 minutes fast.
Add the deionized water that 20ml is ultrasonic and nitrogen bubble is handled in the hydrogenation still, add anhydrous sodium bicarbonate (84mg, 1mmol), (0.29g 0.2mmol), pours the appeal reaction solution under 0 ℃ of nitrogen protection to 10%Pd/C, and 20atm is insulation 5h down.
Filtering Pd/C; filtrate is used activated carbon treatment down in ice-water bath and nitrogen protection; after once use cold ethyl acetate and each extracting twice of primary isoamyl alcohol; get solution to wherein adding each 50ml of acetone and propyl alcohol, leave standstill, filter, filtrate concentrates; filter; solid is washed with ethanol and methyl acetate, the dry ertapenem list sodium salt (0.33g, 66%) that gets.
Fusing point: 262-263 ℃
1H?NMR(CDCl
3)δ：1.17(d，3H)；1.27(d，3H)；2.20(m，1H)；3.00(m，1H)；3.31(m，1H)；3.45(m，2H)；3.80(dd，1H)；4.05(m，1H)；4.20(m，2H)；4.60(t，1H)；7.47(t，1H)；7.65(d，1H)；7.71(d，1H)；7.86(s，1H)
MS(ESI)：476.0(M+1)，498.1(M+Na)
Claims (34)
1. one kind suc as formula the intermediates preparation shown in the VII, it is characterized in that comprising the steps:
(1) in non-proton organic solvent, under the catalysis of organic bases reagent, with compound shown by formula I and the reaction of 4-methoxybenzyl chloride;
(2) in the alcoholic solvent, will be under the effect of two hydrated stannous chlorides suc as formula the compound shown in the II, heating is reacted, and adopts mineral alkali to regulate pH to alkalescence afterwards;
(3) in the non-polar solvent, the compound that will be shown in formula III and the Acibenzolar of PNZ L-oxyproline carry out condensation reaction; Wherein, PNZ L-oxyproline is suc as formula shown in the IX;
(4) in the nonpolar reagent, under the catalysis of organic bases reagent, will be suc as formula compound shown in the IV and methylsulfonyl chloride reaction;
(5) in the non-proton property polar solvent, will be suc as formula compound shown in the V and thioacetic acid potassium reacting by heating;
(6) in the solvent, will get final product suc as formula the hydrolysis under acidity or alkaline condition of the compound shown in the VI;
Formula I formula II
Formula III
Formula IX formula IV
Wherein, PMB is
PNZ is
Ms is a methylsulfonyl; Ac is an ethanoyl.
2. the method for claim 1, it is characterized in that: in the step (1), the mol ratio of described compound shown by formula I and 4-methoxybenzyl chloride is 1:1.5～1:2.
3. the method for claim 1, it is characterized in that: in the step (1), described non-protonic solvent is toluene, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether or isopropyl ether.
4. the method for claim 1, it is characterized in that: in the step (1), the consumption of described organic bases reagent is 1.5～2 times of compound shown by formula I molar weight.
5. the method for claim 1, it is characterized in that: in the step (1), the temperature of described reaction is 40～60 ℃.
6. the method for claim 1, it is characterized in that: in the step (1), the time of described reaction is 4-7 hour.
7. the method for claim 1, it is characterized in that: in the step (2), the consumption of described two hydrated stannous chlorides is 4～6 times suc as formula the compound molar weight shown in the II.
8. the method for claim 1, it is characterized in that: in the step (2), described alcoholic solvent is methyl alcohol, ethanol, n-propyl alcohol or Virahol.
9. the method for claim 1, it is characterized in that: in the step (2), the temperature of described heating is 50-75 ℃.
10. the method for claim 1, it is characterized in that: in the step (2), the time of described reaction is 30～60 minutes.
11. the method for claim 1 is characterized in that: in the step (2), described mineral alkali is sodium hydroxide or potassium hydroxide.
12. the method for claim 1 is characterized in that: in the step (2), described alkalescence is pH 〉=9.
13. method as claimed in claim 12 is characterized in that: in the step (2), described alkalescence is pH=10～11.
14. the method for claim 1 is characterized in that: in the step (3), described shown in formula III compound and the molar ratio of the Acibenzolar of PNZ L-oxyproline be less than or equal to 2.
15. method as claimed in claim 14 is characterized in that: in the step (3), described shown in formula III compound and the molar ratio of the Acibenzolar of PNZ L-oxyproline be 1.01～1.1.
16. the method for claim 1 is characterized in that: in the step (3), the temperature of described reaction is-10-0 ℃.
17. the method for claim 1 is characterized in that: in the step (3), the time of described reaction is 2-5 hour.
18. the method for claim 1, it is characterized in that: in the step (3), the Acibenzolar of described PNZ L-oxyproline is made by following method: in the non-polar solvent, under the organic bases effect, PNZ L-oxyproline and chloro-formic ester reaction are got final product; Wherein, PNZ L-oxyproline is suc as formula shown in the IX.
19. method as claimed in claim 18 is characterized in that: described chloro-formic ester is methyl-chloroformate, Vinyl chloroformate, butyl chloroformate or isobutyl chlorocarbonate.
20. the method for claim 1 is characterized in that: in the step (4), the consumption of described methylsulfonyl chloride is 1～4 times suc as formula the molar weight of the compound shown in the IV.
21. method as claimed in claim 20 is characterized in that: in the step (4), the consumption of described methylsulfonyl chloride is 1.5～3 times suc as formula the molar weight of the compound shown in the IV.
22. the method for claim 1 is characterized in that: in the step (4), the temperature of described reaction is-10-0 ℃.
23. the method for claim 1 is characterized in that: in the step (4), the time of described reaction is 1-4 hour.
24. as claim 1 or 18 described methods, it is characterized in that: described organic bases reagent is triethylamine, diisopropyl ethyl amine or pyridine.
25. the method for claim 1 is characterized in that: in the step (5), described thioacetic acid potassium with suc as formula the molar ratio of the compound shown in the V for being less than or equal to 5.
26. method as claimed in claim 25 is characterized in that: in the step (5), described thioacetic acid potassium be 2.5～3 suc as formula the molar ratio of the compound shown in the V.
27. the method for claim 1 is characterized in that: in the step (5), the temperature of described reaction is 45-78 ℃.
28. the method for claim 1 is characterized in that: in the step (5), the time of described reaction is 5-10 hour.
29. the method for claim 1 is characterized in that: in the step (6), described acidic conditions is pH≤1.
30. the method for claim 1 is characterized in that: in the step (6), the reagent of regulating described acidic conditions employing is the vitriol oil.
31. the method for claim 1 is characterized in that: in the step (6), the reagent of regulating described alkaline condition employing is the NaOH or the KOH aqueous solution.
32. the method for claim 1 is characterized in that: in the step (6), the described temperature that is hydrolyzed under acidic conditions is 0-45 ℃; The described temperature that is hydrolyzed under alkaline condition is 0-5 ℃.
33. the method for claim 1 is characterized in that: in the step (6), the described time that is hydrolyzed under acidic conditions is 10-30 minute; The described time that is hydrolyzed under alkaline condition is 15-30 minute.
34. the method for claim 1 is characterized in that: in the step (6), described solvent is methylene dichloride or tetrahydrofuran (THF).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100453251A CN101376643B (en) | 2007-08-28 | 2007-08-28 | Preparation of carbapenem penicillin ertapenem intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100453251A CN101376643B (en) | 2007-08-28 | 2007-08-28 | Preparation of carbapenem penicillin ertapenem intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101376643A CN101376643A (en) | 2009-03-04 |
| CN101376643B true CN101376643B (en) | 2011-04-06 |
Family
ID=40420388
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007100453251A Expired - Fee Related CN101376643B (en) | 2007-08-28 | 2007-08-28 | Preparation of carbapenem penicillin ertapenem intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101376643B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731506B (en) * | 2011-04-13 | 2015-08-12 | 石药集团中奇制药技术（石家庄）有限公司 | The preparation method of a kind of ertapenem and sodium salt thereof |
| CN102690266B (en) * | 2011-09-02 | 2014-06-18 | 深圳市海滨制药有限公司 | Method for preparing ertapenem sodium |
| CN102363617B (en) * | 2011-11-09 | 2013-09-18 | 上海希迈医药科技有限公司 | Ertapenem monosodium salt crystal and preparation method thereof |
| IN2013MU03862A (en) | 2013-12-11 | 2015-07-31 | Unimark Remedies Ltd |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5872250A (en) * | 1997-07-30 | 1999-02-16 | Merck & Co., Inc. | Process for synthesizing carbapenem antibiotics |
| CN1800162A (en) * | 2005-10-20 | 2006-07-12 | 上海交通大学 | N-protective ertapenem intermediate preparation method |
-
2007
- 2007-08-28 CN CN2007100453251A patent/CN101376643B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5872250A (en) * | 1997-07-30 | 1999-02-16 | Merck & Co., Inc. | Process for synthesizing carbapenem antibiotics |
| CN1800162A (en) * | 2005-10-20 | 2006-07-12 | 上海交通大学 | N-protective ertapenem intermediate preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 张义凤等.碳青霉烯类抗生素厄他培南的合成.《中国药科大学学报》.2007,第38卷(第4期),305-310. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101376643A (en) | 2009-03-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK170073B1 (en) | Analogous Process for the Preparation of Carbapenem Derivatives | |
| CN101376643B (en) | Preparation of carbapenem penicillin ertapenem intermediate | |
| CN106967042B (en) | Synthesis method of eligerlat and intermediate compound thereof | |
| JP2007520453A5 (en) | ||
| WO2007102512A1 (en) | Method for producing 4-oxoquinoline compound | |
| ES2582643T3 (en) | Process for the preparation of 1-acyl-4-phenylsulfonylprolinamide derivatives and new intermediates | |
| US4771054A (en) | Antibacterial agents | |
| CN101376641B (en) | Carbapenem penicillin ertapenem intermediate, and preparation and use thereof | |
| CN101376642B (en) | Carbapenem penicillin ertapenem intermediate, and preparation and use thereof | |
| CN101376633B (en) | Carbpenem penicillin ertapenem intermediate, and preparation and use thereof | |
| CN101376644B (en) | Carbapenem penicillin ertapenem intermediate, and preparation and use thereof | |
| CN101376645B (en) | Carbapenem penicillin ertapenem intermediate, and preparation and use thereof | |
| CN101481346B (en) | Preparation of carbapenem antibiotic side chain | |
| CN101565428B (en) | Preparation method of prulifloxacin | |
| CN101376636A (en) | Carbpenem penicillin ertapenem intermediate, and preparation and use thereof | |
| JP2009035513A (en) | Method for producing 4-n-(methylbenzoyl)amino-2-methylbenzoic acid | |
| CN102558094A (en) | Method for preparing ceftaroline side-chain acid | |
| CN100422170C (en) | Process for porducing quinolonecarboxylic acid derivative | |
| CN111961083A (en) | Montelukast sodium intermediate compound | |
| CN105777681A (en) | Preparation methods of himbacine analogue and intermediate thereof | |
| JPS5913757A (en) | 3-mercaptopyprolidine derivative and its preparation | |
| CN101367830B (en) | Synthesis of sulfomycin derivant | |
| CN103044383A (en) | Method for preparing Penicillide racemate natural product | |
| JPH06104672B2 (en) | Penems production method | |
| CN101367831A (en) | Midbody for preparing carbpenem antibiotics and method of preparing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: WUHAN QIRUI PHARMACEUTICALS CO., LTD. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| C53 | Correction of patent for invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Lu Yang Inventor after: Dan Xiaoyan Inventor after: Shi Huilin Inventor after: Wang Chaodong Inventor after: Liu Yong Inventor before: Lu Yang Inventor before: Dan Xiaoyan Inventor before: Shi Huilin |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: LU YANG DAN XIAOYAN SHI HUILIN TO: LU YANG DAN XIAOYAN SHI HUILIN WANG ZHAODONG LIU YONG |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20110511 Address after: 200040 Beijing West Road, Shanghai, No. 1320 Co-patentee after: Wuhan Qirui Pharmaceuticals Co., Ltd. Patentee after: Shanghai Institute of pharmaceutical industry Address before: 200040 Beijing West Road, Shanghai, No. 1320 Patentee before: Shanghai Institute of pharmaceutical industry |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110406 Termination date: 20200828 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |