CN101376642B - Carbapenem penicillin ertapenem intermediate, and preparation and use thereof - Google Patents
Carbapenem penicillin ertapenem intermediate, and preparation and use thereof Download PDFInfo
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- CN101376642B CN101376642B CN2007100453196A CN200710045319A CN101376642B CN 101376642 B CN101376642 B CN 101376642B CN 2007100453196 A CN2007100453196 A CN 2007100453196A CN 200710045319 A CN200710045319 A CN 200710045319A CN 101376642 B CN101376642 B CN 101376642B
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Abstract
The invention discloses an intermediate for synthesizing carbapenems penicillin etapenem having the formula of IV, and a preparation method and application in the preparation of the carbapenems penicillin etapenem thereof. The preparation method comprises the following steps: allowing a compound having the formula of III and activated ester of PNZ L-hydroxyproline to perform condensation reactionin a nonpolar solvent, wherein the PNZ L-hydroxyproline is shown in the formula of IX, PMB is shown in figure (1), and PNZ is shown in figure (2). The intermediate can be used for preparing etapenem side chain, and further etapenem. The preparation method can be carried out at the room temperature, with the advantages of mild reaction condition, low cost, simple operation, simple experiment condition, no requirement of expensive reagent, high yield, environmental friendliness, and easily realized industrial production.
Description
Technical field
The invention belongs to the synthetic field of organic compound, be specifically related to intermediate of Carbpenem penicillin ertapenem and its production and application.
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: diethyl propyl group ethylamine 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 new midbody compound and its production and application is provided.Prepare ertapenem by this midbody compound, the reaction conditions gentleness can at room temperature be carried out, and cost is lower, and easily is applied to suitability for industrialized production.
Intermediate of the present invention is suc as formula shown in the IV:
The formula IV
Wherein, PMB is
PNZ is
The invention still further relates to a kind of preparation method of this midbody compound, it comprises the steps: in the non-polar solvent, will carry out condensation reaction suc as formula the Acibenzolar of compound shown in the III and PNZ L-oxyproline; Wherein, PNZ L-oxyproline is suc as formula shown in the IX;
Formula III formula IX
Wherein, PMB is
PNZ is
Wherein, the molar ratio of described Acibenzolar suc as formula compound shown in the III and 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 or 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 ℃.
Wherein, described compound shown in formula III can be made by following method:
(1) in non-proton organic solvent, under the catalysis of organic bases reagent,, gets final product compound shown by formula I and the reaction of 4-methoxybenzyl chloride.
Formula I
Wherein, that the mol ratio of described compound shown by formula I and 4-methoxybenzyl chloride is preferable is 1:1.5～1:3, and that 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 or 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.
(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, can make the compound shown in formula III.
Formula II
Wherein, PMB is
Wherein, 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.
The invention still further relates to the application of intermediate of the present invention in the preparation Carbpenem penicillin ertapenem.Intermediate of the present invention (formula III) can be by the synthetic ertapenem side chain that makes of following route:
Wherein, PMB is
PNZ is
Ms is a methylsulfonyl; Ac is an ethanoyl; Et is an ethyl; IBu is an isobutyl-.
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: intermediate of the present invention can make the ertapenem side chain, and then makes ertapenem.Respectively go on foot the reaction conditions gentleness in this route, can at room temperature carry out, cost is lower, easily is applied to suitability for industrialized production.Intermediates preparation of the present invention is easy and simple to handle, and experiment condition is simple, need not expensive reagent, and productive rate is higher, and is environmentally friendly.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
The preparation of reference example formula III compound
(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%).
Embodiment 1 (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 2 (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: 175-178 ℃.
Embodiment 3 (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: 175-178 ℃.
Embodiment 4 (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 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) (30.33g, 95.7%).Fusing point: 175-178 ℃.
Application 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 (11)
1. be used for synthesizing carbapenem penicillin ertapenem suc as formula the intermediate shown in the IV;
The formula IV
Wherein, PMB is
PNZ is
2. as claimed in claim 1 suc as formula the intermediates preparation shown in the IV, it is characterized in that comprising the steps: in the non-polar solvent, will carry out condensation reaction suc as formula the Acibenzolar of compound shown in the III and PNZ L-oxyproline; Wherein, PNZ L-oxyproline is suc as formula shown in the IX;
Formula III formula IX
Wherein, PMB is
PNZ is
3. method as claimed in claim 2 is characterized in that: the molar ratio of described Acibenzolar suc as formula compound shown in the III and PNZL-oxyproline is less than or equal to 2.
4. method as claimed in claim 3 is characterized in that: the molar ratio of described Acibenzolar suc as formula compound shown in the III and PNZL-oxyproline is 1.01～1.1.
5. method as claimed in claim 2 is characterized in that: the temperature of described reaction is-10-0 ℃.
6. method as claimed in claim 5 is characterized in that: the temperature of described reaction is-5-0 ℃.
7. method as claimed in claim 2 is characterized in that: the time of described reaction is 2-5 hour.
8. method as claimed in claim 2 is characterized in that: 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.
9. method as claimed in claim 8 is characterized in that: described organic bases is triethylamine, diisopropyl ethyl amine or pyridine.
10. method as claimed in claim 8 is characterized in that: described chloro-formic ester is methyl-chloroformate, Vinyl chloroformate, butyl chloroformate or isobutyl chlorocarbonate.
11. it is as claimed in claim 1 suc as formula the application of the intermediate shown in the IV in the preparation Carbpenem penicillin ertapenem.
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| CN103127097B (en) * | 2011-11-30 | 2015-09-02 | 上海医药工业研究院 | The pharmaceutical composition of ertapenem |
| IN2013MU03862A (en) | 2013-12-11 | 2015-07-31 | Unimark Remedies Ltd |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5872250A (en) * | 1997-07-30 | 1999-02-16 | Merck & Co., Inc. | Process for synthesizing carbapenem antibiotics |
| US6180783B1 (en) * | 1997-06-16 | 2001-01-30 | Merck & Co., Inc. | Stabilized carbapenem intermediates and improved process for carbapenem synthesis |
| CN1800162A (en) * | 2005-10-20 | 2006-07-12 | 上海交通大学 | N-protective ertapenem intermediate preparation method |
-
2007
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6180783B1 (en) * | 1997-06-16 | 2001-01-30 | Merck & Co., Inc. | Stabilized carbapenem intermediates and improved process for carbapenem synthesis |
| 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 (2)
| 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38 4.2007,38(4),305-310. |
| 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38 4.2007,38(4),305-310. * |
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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 |
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Free format text: CORRECT: INVENTOR; FROM: LU YANG DAN XIAOYAN SHI HUILIN TO: LU YANG DAN XIAOYAN SHI HUILIN WANG ZHAODONG LIU YONG |
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| 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 |
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| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20101201 Termination date: 20200828 |
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| CF01 | Termination of patent right due to non-payment of annual fee |