CN101376633B - Carbpenem penicillin ertapenem intermediate, and preparation and use thereof - Google Patents
Carbpenem penicillin ertapenem intermediate, and preparation and use thereof Download PDFInfo
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- CN101376633B CN101376633B CN2007100453247A CN200710045324A CN101376633B CN 101376633 B CN101376633 B CN 101376633B CN 2007100453247 A CN2007100453247 A CN 2007100453247A CN 200710045324 A CN200710045324 A CN 200710045324A CN 101376633 B CN101376633 B CN 101376633B
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- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 title claims abstract description 24
- 229960002770 ertapenem Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 229930182555 Penicillin Natural products 0.000 title claims abstract description 8
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 title claims abstract description 8
- 229940049954 penicillin Drugs 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000000543 intermediate Substances 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000003513 alkali Substances 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 239000012454 non-polar solvent Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000012141 concentrate Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- 0 *OC(c1cccc([N+]([O-])=O)c1)=O Chemical compound *OC(c1cccc([N+]([O-])=O)c1)=O 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 238000003809 water extraction Methods 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 238000010792 warming Methods 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000012797 qualification Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 diethyl propyl group Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Natural products CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229940054114 invanz Drugs 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ZBOGUDPFEVIZIQ-UHFFFAOYSA-N toluene;dihydrochloride Chemical group Cl.Cl.CC1=CC=CC=C1 ZBOGUDPFEVIZIQ-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses an intermediate shown as the formula II for synthesizing carbapenem penicillin ertapenem, and a preparation method thereof. The preparation method comprises the following steps: reacting a compound shown as a formula I with 4-methoxybenzyl chloride in the presence of an organic alkali reagent as a catalyst in a nonpolar solvent. The present invention also discloses the application of the intermediate on the preparation of the carbapenem penicillin ertapenem. In the formula I and formula II, PMB is the intermediate compound which can be prepared into ertapenem side chain and then further into ertapenem. The preparation method has the advantages that the conditions of each reaction are mild, the reaction can be carried out at the room temperature, the cost is low, the method is easily applied on an industrialized production, the operation is simple, the experimental condition is simple, no expensive reagent is required, the yield is high and reaches above 90%, and the purity is high.
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.
Midbody compound of the present invention is suc as formula shown in the II:
Formula II
Wherein, PMB is
The invention still further relates to a kind of preparation method of this midbody compound, it comprises the steps: 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, gets final product.
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; Described non-proton organic solvent preferable for non-protonic solvent is toluene, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether or isopropyl ether, 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.
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 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 the productive rate height can reach more than 90%, and purity is higher.
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 ℃.Qualification result is with embodiment 1.
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 ℃.Qualification result is with embodiment 1.
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: 83-85 ℃.Qualification result is with embodiment 1.
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 ℃.Qualification result is with embodiment 1.
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: 83-85 ℃.Qualification result is with embodiment 1.
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 the ester activation products (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 (13)
1. be used for synthesizing carbapenem penicillin ertapenem suc as formula the intermediate shown in the II;
Formula II
Wherein, PMB is
2. as claimed in claim 1 suc as formula the intermediates preparation shown in the II, it is characterized in that comprising the steps: in non-proton organic solvent, under the catalysis of organic bases reagent,, get final product compound shown by formula I and the reaction of 4-methoxybenzyl chloride;
Formula I.
3. method as claimed in claim 2 is characterized in that: the mol ratio of described compound shown by formula I and 4-methoxybenzyl chloride is 1: 1.5～1: 3.
4. method as claimed in claim 3 is characterized in that: the mol ratio of described compound shown by formula I and 4-methoxybenzyl chloride is 1: 1.5～1: 2.
5. method as claimed in claim 2 is characterized in that: described non-protonic solvent is toluene, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether or isopropyl ether.
6. method as claimed in claim 2 is characterized in that: described organic bases reagent is triethylamine, diisopropyl ethyl amine or pyridine.
7. method as claimed in claim 2 is characterized in that: the consumption of described organic bases reagent is 1.5～2 times of compound shown by formula I molar weight.
8. method as claimed in claim 2 is characterized in that: the temperature of described reaction is 40～60 ℃.
9. method as claimed in claim 8 is characterized in that: the temperature of described reaction is 40-45 ℃.
10. method as claimed in claim 2 is characterized in that: the time of described reaction is 1～10 hour.
11. method as claimed in claim 10 is characterized in that: the time of described reaction is 3～7 hours.
12. method as claimed in claim 11 is characterized in that: the time of described reaction is 4～5 hours.
13. it is as claimed in claim 1 suc as formula the application of the intermediate shown in the II in the preparation Carbpenem penicillin ertapenem.
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| CN2007100453247A CN101376633B (en) | 2007-08-28 | 2007-08-28 | Carbpenem penicillin ertapenem intermediate, and preparation and use thereof |
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| CN2007100453247A CN101376633B (en) | 2007-08-28 | 2007-08-28 | Carbpenem penicillin ertapenem intermediate, and preparation and use thereof |
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| CN101376633A CN101376633A (en) | 2009-03-04 |
| CN101376633B true CN101376633B (en) | 2011-08-10 |
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| IN2013MU03862A (en) | 2013-12-11 | 2015-07-31 | Unimark Remedies Ltd | |
| CN110698477A (en) * | 2018-07-09 | 2020-01-17 | 武汉启瑞药业有限公司 | Synthetic method of ertapenem monosodium salt |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5872250A (en) * | 1997-07-30 | 1999-02-16 | Merck & Co., Inc. | Process for synthesizing carbapenem antibiotics |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5872250A (en) * | 1997-07-30 | 1999-02-16 | Merck & Co., Inc. | Process for synthesizing carbapenem antibiotics |
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