CN103664946A - Industrial synthesis method of doripenem - Google Patents
Industrial synthesis method of doripenem Download PDFInfo
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- CN103664946A CN103664946A CN201210319779.4A CN201210319779A CN103664946A CN 103664946 A CN103664946 A CN 103664946A CN 201210319779 A CN201210319779 A CN 201210319779A CN 103664946 A CN103664946 A CN 103664946A
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- Prior art keywords
- water
- phase
- acid
- peinan
- soluble liquid
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- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 title abstract description 5
- 229960000895 doripenem Drugs 0.000 title abstract description 5
- 238000001308 synthesis method Methods 0.000 title description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 7
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- 239000000243 solution Substances 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 15
- 239000000872 buffer Substances 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 239000012071 phase Substances 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 239000007791 liquid phase Substances 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 238000013016 damping Methods 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- HDFXRQJQZBPDLF-UHFFFAOYSA-L disodium hydrogen carbonate Chemical compound [Na+].[Na+].OC([O-])=O.OC([O-])=O HDFXRQJQZBPDLF-UHFFFAOYSA-L 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- ZRBROGSAUIUIJE-UHFFFAOYSA-N azanium;azane;chloride Chemical compound N.[NH4+].[Cl-] ZRBROGSAUIUIJE-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- WOIVNLSVAKYSKX-UHFFFAOYSA-N benzyl nitrate Chemical compound [O-][N+](=O)OCC1=CC=CC=C1 WOIVNLSVAKYSKX-UHFFFAOYSA-N 0.000 claims description 2
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 11
- -1 p-nitryl benzyl Chemical group 0.000 abstract description 4
- 239000013078 crystal Substances 0.000 abstract description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 abstract 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract 1
- 239000002131 composite material Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000004845 hydriding Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical class [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 229960002770 ertapenem Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 2
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000004328 sodium tetraborate Substances 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 101150116596 dhp-1 gene Proteins 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Substances [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing a carbapenem antibacterial medicament doripenem. The method comprises the following steps: dispersing a compound of a formula (I) as shown in the specification in a two-phase composite solvent so as to be subjected to hydrogenation deprotection, layering so as to obtain an enriched doripenem phase, and adjusting the pH value by using acid so as to obtain doripenem crystal. PNZ is p-nitryl benzyl oxygroup carbonyl; PNB is p-nitryl benzyl.
Description
(1) technical field
The present invention relates to organic synthesis and prepare chemical field, particularly the industrialized process for preparing of a kind of many Li Peinan.
(2) background technology
Many Li Peinan (Doripenem, S-4661) are the carbapenems Broad spectrum antibioticss of Japanese Yan Yeyi company exploitation, there is has a broad antifungal spectrum, stable to most β-lactamases, PBPSs avidity is strong, to advantages such as DHP-1 are stable.Its chemistry (+)-(4R by name, 5S, 6S)-3-[[(3S, 5S)-5-[[(aminosulfonyl) amino] methyl]-3-tetramethyleneimine] sulphur] 6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid monohydrate, structural formula is shown below.
Present stage, the method of preparing many Li Peinan is mainly with (2S, 4S)-1-is to nitro carbobenzoxy-(Cbz)-2-(N-aminosulfonyl aminomethyl)-4-mercapto pyrrolidine and (1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-2[(3S, 5S)-5-sulfamoylamino group methyl isophthalic acid-to nitro benzyloxy carbonyl pyrrolidine alkane-3-yl] the many Li Peinans of sulfenyl-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid to nitrobenzyl ester condensation generation protection, then under the catalysis of palladium carbon, in the mixed solvent of tetrahydrofuran (THF) and water, hydrogenation deprotection obtains many Li Peinan (Org.Proc.Res.Dev., 2003, 7 (6), 846-850), as shown in the formula:
This method products obtained therefrom impurity and by product are more, purifying products difficulty, and yield is lower, from technological angle and economic benefit angle, is all not suitable for large-scale commercial production.
WO2006/117763 discloses the preparation method of a kind of many Li Peinan, the method adopts the damping fluid of pH6-7, because the solubleness of many Li Peinan in this damping fluid is limited, causes ultimate yield lower, and need to add a large amount of Virahol crystallizations, be not suitable for industrialized production.
In EP2275424, disclose the crystallization method of a kind of many Li Peinan, many Li Peinan have been dissolved in the water of pH10, be then adjusted to pH5, separated out the new crystallization of a kind of many Li Peinan, found in the aqueous solution that is present in pH10 that many Li Peinan can be stable simultaneously.But this patent is only to the crystallization of many vertical training southing row, the solvent in hydrogenation, especially hydrogenation in synthetic many Li Peinan process and the pH of solvent is not studied.
In CN98806091, disclose a kind of in sodium hydrogen carbonate solution and methylene dichloride hydrogenation deprotection; after reaction, with Glacial acetic acid, regulate pH5-6 to prepare the method for ertapenem; due to ertapenem less stable; only adopt the solution of pH7-8 to carry out hydrogenation, after simultaneous reactions, need to add methanol crystallization.
Summary of the invention
Technical problem to be solved by this invention is to obtain in the process of many Li Peinan in order to overcome existing intermediate (I) hydrogenation deprotection, with an organic solvent too much, obtains that product purity is not high, yield is not high, is not suitable for industrial shortcoming.The synthetic method of many Li Peinan provided by the invention, the organic solvent of use is few, and building-up process is simple, and product yield is high, and purity is good, is applicable to suitability for industrialized production.
PNZ: to nitrobenzyl oxygen base carbonyl PNB: to nitrobenzyl
Technical scheme of the present invention, the synthetic method of a kind of many Li Peinan, is characterized in that:
Intermediate (I) compound is dispersed in a kind of double solvents of two-phase and carries out hydrogenation deprotection, through layering, obtains many Li Peinan of enrichment phase, regulates pH to obtain many Li Peinan crystallization.
Method double solvents used is a kind of two-phase solvent, and one is water-soluble liquid phase mutually, and another is water-insoluble organic solvent phase mutually.
The pH of water-soluble liquid phase is greater than 7, and special pH is 810.
The aqueous solution can be a kind of damping fluid, is particularly selected from a kind of of ammonia-ammonium chloride buffer, sodium carbonate-sodium bicarbonate buffer liquid, borax-sodium carbonate buffer; Can be a kind of of sodium carbonate solution, sodium hydrogen carbonate solution.
Organic phase can be a kind of of ethyl acetate, propyl carbinol.
Adopting acid for adjusting pH, described acid is wherein a kind of of hydrochloric acid, sulfuric acid, Glacial acetic acid.
Adopting acid for adjusting pH scope is that pH is less than 7, preferred pH=5-6.
Embodiment
With embodiment, further illustrate the present invention below, but the present invention is not limited.
Many Li Peinan purity test method:
Instrument: high performance liquid chromatograph (Agilent 1100 series)
Moving phase: primary ammonium phosphate ammonium damping fluid/acetonitrile PH6.9 (97: 3)
Solvent: deionized water
Chromatographic column: XBridge C18 post, 2.5 μ m, 4.6 * 50mm
Gradient elution:
Min | 0 | 1.5 | 17 | 20 |
%B | 0 | 3 | 26 | 100 |
Flow velocity: 1.5ml/min
Column temperature: 30 ℃
Sampling volume: 4 μ L
Working time: working time after 25min: 5min
Detect wavelength: λ=210nm
Sample introduction temperature: 5 ℃
Comparative example:
[018] reference literature (Org.Proc.Res.Dev., 2003,7 (6), 846-850) prepare many Li Peinan.
33.6g 3c, 15.8g 98% vitriol oil and 140g methyl alcohol are put in reactor, be heated with stirring to 65 ℃, temperature control reaction 2.5h, reaction solution is chilled to below 25 ℃, be evaporated to volume 110mL, be poured in the mixing solutions of 225g ethyl acetate and 250g water, separate organic phase, with 175g 5%NaCl solution washing three times, water with the back extraction of 90g ethyl acetate once, combined ethyl acetate layer, be concentrated into 70g, in resistates, add 180g ethyl acetate, be again concentrated to 70g, obtain the concentrated solution that contains 4c.
30g 2b and 143gDMF are joined in above-mentioned concentrated solution, cool to 0 ℃, drip 9.1g diisopropyl ethyl amine, reaction mixture stirs 18h at 5 ℃, reaction solution is poured in the mixture of 200g ethyl acetate and 225mL water, separate organic layer, and wash once with 153g 0.7%HCl, 63g 5% sodium bicarbonate is washed once, 90g sodium-chlor washing secondary, water with the back extraction of 90g ethyl acetate once, combined ethyl acetate layer, be concentrated into 104mL, in resistates, add ethyl acetate 180g again concentrated, again add 180g ethyl acetate, concentrating under reduced pressure is removed moisture content, obtain resistates 155mL, in resistates, add 365g toluene, solid is separated out, suction filtration is dried to obtain 32.5g I.
8.8g I is dissolved in 60mLTHF, in solution, add 40mL deionized water, 5g 10%Pd/C and 1.4g magnesium chloride hexahydrate, above-mentioned suspension is joined in hydriding reactor, keep hydrogen pressure 0.5MPa, 26~38 ℃ of temperature of reaction, reaction 2h, filters Pd-C, and wash with the mixed solvent of 18mL THF and 12mL deionized water, 0.7g magnesium chloride hexahydrate is dissolved in filtrate.300mL THF is joined in mixture, 26 ℃ of temperature controls, minute water-yielding stratum, is cooled to 0 ℃, adds 40mL methyl alcohol and 0.1g crystal seed, and solid is separated out.Organic phase adds 0.7g six water magnesium sulfates, and a minute water-yielding stratum is merged in water in early stage.Organic phase adds 0.7g six water magnesium sulfates again, and a minute water-yielding stratum is merged in water in early stage again.The methyl alcohol that drips 75mL is at the most in the suspension of Li Peinan, and 1h is stirred in mixture-10 ℃, filters, and filter cake methyl alcohol is washed, dry get Duo Lipeinan, yield 73%, HPLC:92.1%.
Embodiment mono-
In hydriding reactor, add intermediate (I) 150g, with ethyl acetate 1000ml, dissolve, add saturated sodium carbonate solution (pH10) 750ml, 10%Pd/C 75g, after good seal kettle, first with nitrogen replacement, go out air in still, three times repeatedly, after vacuumizing, pass into hydrogen, still internal pressure keeps 0.6MPa, and temperature keeps 40 ℃ of left and right, reaction 4h.Filter 100ml saturated sodium carbonate solution washing for filter cake, filtrate layering, 300ml ethyl acetate washing for water, water is cooled to below 10 ℃ with ice-water bath, with 2N hydrochloric acid, is adjusted to pH 5, separate out gradually solid, 10 ℃ of following 2h that stir, filter, and filter cake washs with 80% Virahol 150ml, the about 6h of 50 ℃ of vacuum-dryings (gauge pressure is not less than 0.095MPa), obtain white crystalline powder 73.7g, HPLC purity 99.0%, yield 82.3%.
Embodiment bis-
In hydriding reactor, add intermediate (I) 150g, add propyl carbinol 1500ml to stir, add saturated sodium bicarbonate solution (pH8.4) 750ml, 10%Pd/C 75g, after good seal kettle, first with nitrogen replacement, go out air in still, three times repeatedly, after vacuumizing, pass into hydrogen, still internal pressure keeps 0.6MPa, and temperature keeps 40 ℃ of left and right, reaction 4h.Filter 100ml saturated sodium bicarbonate solution washing for filter cake, filtrate layering, 300ml ethyl acetate washing for water, water is cooled to below 10 ℃ with ice-water bath, with 2N hydrochloric acid, is adjusted to pH 5, separate out gradually solid, 10 ℃ of following 2h that stir, filter, and filter cake washs with 80% Virahol 150ml, the about 6h of 50 ℃ of vacuum-dryings (gauge pressure is not less than 0.095MPa), obtain off-white color crystalline powder 63.1g, HPLC purity 98.2%, yield 70.5%.
Embodiment tri-
Get ammonium chloride 54g, add after water 200ml dissolving, add liquor ammoniae fortis 350ml, then be diluted with water to 1000ml, obtain ammonia-ammonium chloride buffer of pH10.
In hydriding reactor, add intermediate (I) 150g, add ethyl acetate 1000ml to stir, add ammonia-ammonium chloride buffer 750ml, 10%Pd/C 75g, after good seal kettle, first with nitrogen replacement, go out air in still, three times repeatedly, after vacuumizing, pass into hydrogen, still internal pressure keeps 0.6MPa, and temperature keeps 40 ℃ of left and right, reaction 4h.Filter the washing of 100ml ammonia for filter cake-ammonium chloride buffer, filtrate layering, 300ml ethyl acetate washing for water, water is cooled to below 10 ℃ with ice-water bath, with 2N hydrochloric acid, is adjusted to pH 5, separate out gradually solid, 10 ℃ of following 2h that stir, filter, and filter cake washs with 80% Virahol 150ml, the about 6h of 50 ℃ of vacuum-dryings (gauge pressure is not less than 0.095MPa), obtain white crystalline powder 78.5g, HPLC purity 98.4%, yield 87.6%.
Embodiment tetra-
Get anhydrous sodium carbonate 5.30g, add water and make to be dissolved into 1000ml; Separately get borax 1.91g, add water and make to be dissolved into 100ml, get before use sodium carbonate solution 973ml, with borax soln 27ml, mix, obtain borax-sodium carbonate buffer of pH10.
In hydriding reactor, add intermediate (I) 150g, add ethyl acetate 1000ml to stir, add borax-sodium carbonate buffer 750ml, 10%Pd/C 75g, after good seal kettle, first with nitrogen replacement, go out air in still, three times repeatedly, after vacuumizing, pass into hydrogen, still internal pressure keeps 0.6MPa, and temperature keeps 40 ℃ of left and right, reaction 4h.Filter 100ml sodium carbonate-sodium bicarbonate buffer liquid washing for filter cake, filtrate layering, 300ml ethyl acetate washing for water, water is cooled to below 10 ℃ with ice-water bath, with 2N hydrochloric acid, is adjusted to pH 5, separate out gradually solid, 10 ℃ of following 2h that stir, filter, and filter cake washs with 80% Virahol 150ml, the about 6h of 50 ℃ of vacuum-dryings (gauge pressure is not less than 0.095MPa), obtain white crystalline powder 75.5g, HPLC purity 99.1%, yield 84.4%.
Embodiment five
The sodium carbonate solution 700ml of preparation 0.1mol/L, the sodium hydrogen carbonate solution 300ml of preparation 0.1mol/L, mixes before use, obtains sodium carbonate-sodium bicarbonate buffer liquid of pH10.
In hydriding reactor, add intermediate (I) 150g, add propyl carbinol 1500ml to stir, add sodium carbonate-sodium bicarbonate buffer liquid 750ml, 10%Pd/C 75g, after good seal kettle, first with nitrogen replacement, go out air in still, three times repeatedly, after vacuumizing, pass into hydrogen, still internal pressure keeps 0.6MPa, and temperature keeps 40 ℃ of left and right, reaction 4h.Filter the washing of 100ml glycine for filter cake-sodium hydrate buffer solution, filtrate layering, 300ml ethyl acetate washing for water, water is cooled to below 10 ℃ with ice-water bath, with 2N hydrochloric acid, is adjusted to pH 5, separate out gradually solid, 10 ℃ of following 2h that stir, filter, and filter cake washs with 80% Virahol 150ml, the about 6h of 50 ℃ of vacuum-dryings (gauge pressure is not less than 0.095MPa), obtain white crystalline powder 78g, HPLC purity 98.7%, yield 87.2%.
Claims (12)
1. the preparation method of Li Peinan more than, is characterized in that: formula (I) compound is dispersed in a kind of double solvents of two-phase and carries out hydrogenation deprotection, through layering, obtains many Li Peinan of enrichment phase, with acid for adjusting pH, obtains many Li Peinan crystallization;
PNZ: to nitrobenzyl oxygen base carbonyl PNB: to nitrobenzyl.
2. the double solvents of two-phase described in claim 1, is characterized in that, comprises a kind of water-soluble liquid phase and a kind of water-insoluble organic phase.
3. described in claim 2, the pH value of water-soluble liquid phase is greater than 7.
4. described in claim 3, the pH value of water-soluble liquid phase is 8-10.
5. described in claim 2, water-soluble liquid phase is a kind of damping fluid.
6. described in claim 5, damping fluid is a kind of of ammonia-ammonium chloride buffer, sodium carbonate-sodium bicarbonate buffer liquid, borax-sodium carbonate buffer.
7. described in claim 2, water-soluble liquid phase is a kind of of sodium carbonate solution, sodium hydrogen carbonate solution.
8. described in claim 2, organic phase is ethyl acetate.
9. described in claim 2, organic phase is propyl carbinol.
10. described in claim 1, acid is hydrochloric acid, sulfuric acid, Glacial acetic acid.
Described in 11. claims 1, acid for adjusting pH is for regulating pH to be less than 7.
Described in 12. claims 11, regulate pH to regulate pH to 5-6.
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CN105175420A (en) * | 2015-10-14 | 2015-12-23 | 山东罗欣药业集团股份有限公司 | Doripenem preparation method |
CN105541846A (en) * | 2016-02-05 | 2016-05-04 | 青岛麦瑞特医药技术有限公司 | Method for preparing high purity doripenem |
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CN101935321A (en) * | 2010-07-20 | 2011-01-05 | 深圳市海滨制药有限公司 | Method for synthesizing 1 beta methyl carbapenem antibiotic |
EP2275424A1 (en) * | 2009-07-17 | 2011-01-19 | Sandoz AG | Doripenem crystallization process |
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EP2275424A1 (en) * | 2009-07-17 | 2011-01-19 | Sandoz AG | Doripenem crystallization process |
CN101935321A (en) * | 2010-07-20 | 2011-01-05 | 深圳市海滨制药有限公司 | Method for synthesizing 1 beta methyl carbapenem antibiotic |
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CN105541846A (en) * | 2016-02-05 | 2016-05-04 | 青岛麦瑞特医药技术有限公司 | Method for preparing high purity doripenem |
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