CN103664946B - The Industrialized synthesis method of a kind of many Li Peinan - Google Patents
The Industrialized synthesis method of a kind of many Li Peinan Download PDFInfo
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- CN103664946B CN103664946B CN201210319779.4A CN201210319779A CN103664946B CN 103664946 B CN103664946 B CN 103664946B CN 201210319779 A CN201210319779 A CN 201210319779A CN 103664946 B CN103664946 B CN 103664946B
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- 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
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- 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
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Abstract
The present invention relates to a kind of preparation method preparing the many Li Peinan of carbapenems antibacterials.Formula (I) compound is dispersed in a kind of double solvents of two-phase and carries out hydrogenation deprotection, obtains enrichment many Li Peinan phase, obtain many Li Peinan crystallization with acid for adjusting pH through layering.
Description
(1) technical field
The present invention relates to organic synthesis preparative chemistry 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, have has a broad antifungal spectrum, stable to most β-lactamase, PBPSs avidity strong, to advantages such as DHP-1 are stable.Its chemistry (+)-(4R by name, 5S, 6S)-3-[[(3S, 5S)-5-[[(aminosulfonyl) is 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 preparing many Li Peinan mainly uses (2S, 4S)-1-is to nitrobenzyloxycarbonyl-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 nitrobenzyloxycarbonyl pyrrolidin-3-yl] sulfenyl-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid generates many Li Peinan of protection to nitrobenzyl ester condensation, 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 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 crystallization, be not suitable for industrialized production.
Disclose the crystallization method of a kind of many Li Peinan in EP2275424, many Li Peinan are dissolved in the water of pH10, are then adjusted to pH5, separate out the new crystallization of a kind of many Li Peinan, what find that many Li Peinan can be stable is present in the aqueous solution of pH10 simultaneously.But this patent is only that not to the hydrogenation in synthesis many Li Peinan process, the solvent especially in hydrogenation and the pH of solvent study to the crystallization of many vertical training southing row.
One hydrogenation deprotection in sodium hydrogen carbonate solution and methylene dichloride is disclosed in CN98806091; pH5-6 is regulated to prepare the method for ertapenem with Glacial acetic acid after reaction; due to ertapenem less stable; only adopt the solution of pH7-8 to carry out hydrogenation, need after simultaneous reactions to add methanol crystallization.
Summary of the invention
Technical problem to be solved by this invention obtains in the process of many Li Peinan to overcome existing intermediate (I) hydrogenation deprotection, with an organic solvent too much, obtains that product purity is not high, yield is not high, be 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 nitrobenzyloxycarbonyl 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, obtains enrichment many Li Peinan phase through layering, 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 the one of ammonia-ammonium chloride buffer, sodium carbonate-bicarbonate damping fluid, borax-sodium carbonate buffer; It can be the one of sodium carbonate solution, sodium hydrogen carbonate solution.
Organic phase can be the one of ethyl acetate, propyl carbinol.
Adopt acid for adjusting pH, described acid is hydrochloric acid, sulfuric acid, Glacial acetic acid one wherein.
Acid for adjusting pH scope is adopted to be that pH is less than 7, preferred pH=5-6.
Embodiment
Further illustrate the present invention by embodiment 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: XBridgeC18 post, 2.5 μm, 4.6 × 50mm
Gradient elution:
| Min | 0 | 1.5 | 17 | 20 |
| ％B | 0 | 3 | 26 | 100 |
Flow velocity: 1.5ml/min
Column temperature: 30 DEG C
Sampling volume: 4 μ L
Working time: working time after 25min: 5min
Determined wavelength: λ=210nm
Injector temperature: 5 DEG C
Comparative example:
Reference literature (Org.Proc.Res.Dev., 2003,7 (6), 846-850) prepares many Li Peinan.
33.6g3c, 15.8g98% vitriol oil and 140g methyl alcohol are put in reactor, be heated with stirring to 65 DEG C, temperature control reaction 2.5h, reaction solution is chilled to less than 25 DEG C, be evaporated to volume 110mL, be poured in the mixing solutions of 225g ethyl acetate and 250g water, separate organic phase, with 175g5%NaCl solution washing three times, aqueous phase 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 containing 4c.
30g2b and 143gDMF is joined in above-mentioned concentrated solution, cool to 0 DEG C, drip 9.1g diisopropyl ethyl amine, reaction mixture stirs 18h at 5 DEG C, reaction solution is poured in the mixture of 200g ethyl acetate and 225mL water, separate organic layer, and wash once with 153g0.7%HCl, 63g5% sodium bicarbonate is washed once, 90g NaCl secondary, aqueous phase with the back extraction of 90g ethyl acetate once, combined ethyl acetate layer, be concentrated into 104mL, add ethyl acetate 180g in resistates again to concentrate, again add 180g ethyl acetate, concentrating under reduced pressure removing moisture content, obtain resistates 155mL, 365g toluene is added in resistates, solid is separated out, suction filtration is dry obtains 32.5gI.
8.8gI is dissolved in 60mLTHF, 40mL deionized water, 5g10%Pd/C and 1.4g magnesium chloride hexahydrate is added in solution, above-mentioned suspension is joined in hydriding reactor, keep hydrogen pressure 0.5MPa, temperature of reaction 26 ~ 38 DEG C, reaction 2h, filters Pd-C, and wash with the mixed solvent of 18mLTHF and 12mL deionized water, 0.7g magnesium chloride hexahydrate is dissolved in filtrate.Joined by 300mLTHF in mixture, temperature control 26 DEG C, point water-yielding stratum, is cooled to 0 DEG C, is added 40mL methyl alcohol and 0.1g crystal seed, and solid is separated out.Organic phase adds 0.7g six water magnesium sulfate, and a point water-yielding stratum is merged in aqueous phase in early stage.Organic phase adds 0.7g six water magnesium sulfate again, and a point water-yielding stratum is merged in aqueous phase in early stage again.Drip in the suspension of methyl alcohol Li Peinan at the most of 75mL ,-10 DEG C, mixture stirs 1h, filters, filter cake methanol wash column, dry get Duo Lipeinan, yield 73%, HPLC:92.1%.
Embodiment one
To in hydriding reactor, add intermediate (I) 150g, dissolve with ethyl acetate 1000ml, add saturated sodium carbonate solution (pH10) 750ml, 10%Pd/C75g, after good seal kettle, first go out air in still with nitrogen replacement, three times repeatedly, hydrogen is passed into after vacuumizing, still internal pressure keeps 0.6MPa, and temperature keeps about 40 DEG C, reaction 4h.Filter, filter cake 100ml saturated sodium carbonate solution washing, filtrate layering, aqueous phase 300ml ethyl acetate washing, aqueous phase ice-water bath is cooled to less than 10 DEG C, is adjusted to pH5 with 2N hydrochloric acid, separate out solid gradually, less than 10 DEG C are stirred 2h, and filter, filter cake 80% Virahol 150ml washs, 50 DEG C of vacuum-drying (gauge pressure is not less than 0.095MPa) about 6h, obtain white crystalline powder 73.7g, HPLC purity 99.0%, yield 82.3%.
Embodiment two
To in hydriding reactor, add intermediate (I) 150g, add propyl carbinol 1500ml and stir, add saturated sodium bicarbonate solution (pH8.4) 750ml, 10%Pd/C75g, after good seal kettle, first go out air in still with nitrogen replacement, three times repeatedly, hydrogen is passed into after vacuumizing, still internal pressure keeps 0.6MPa, and temperature keeps about 40 DEG C, reaction 4h.Filter, filter cake 100ml saturated sodium bicarbonate solution washing, filtrate layering, aqueous phase 300ml ethyl acetate washing, aqueous phase ice-water bath is cooled to less than 10 DEG C, is adjusted to pH5 with 2N hydrochloric acid, separate out solid gradually, less than 10 DEG C are stirred 2h, and filter, filter cake 80% Virahol 150ml washs, 50 DEG C of vacuum-drying (gauge pressure is not less than 0.095MPa) about 6h, obtain off-white color crystalline powder 63.1g, HPLC purity 98.2%, yield 70.5%.
Embodiment three
Get ammonium chloride 54g, the 200ml that adds water adds liquor ammoniae fortis 350ml, then is diluted with water to 1000ml, obtain the ammonia-ammonium chloride buffer of pH10 after dissolving.
To in hydriding reactor, add intermediate (I) 150g, add ethyl acetate 1000ml and stir, add ammonia-ammonium chloride buffer 750ml, 10%Pd/C75g, after good seal kettle, first go out air in still with nitrogen replacement, three times repeatedly, hydrogen is passed into after vacuumizing, still internal pressure keeps 0.6MPa, and temperature keeps about 40 DEG C, reaction 4h.Filter, filter cake 100ml ammonia-ammonium chloride buffer washing, filtrate layering, aqueous phase 300ml ethyl acetate washing, aqueous phase ice-water bath is cooled to less than 10 DEG C, is adjusted to pH5 with 2N hydrochloric acid, separate out solid gradually, less than 10 DEG C are stirred 2h, and filter, filter cake 80% Virahol 150ml washs, 50 DEG C of vacuum-drying (gauge pressure is not less than 0.095MPa) about 6h, obtain white crystalline powder 78.5g, HPLC purity 98.4%, yield 87.6%.
Embodiment four
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 sodium carbonate solution 973ml before use, with borax soln 27ml, mixing, obtains the borax-sodium carbonate buffer of pH10.
To in hydriding reactor, add intermediate (I) 150g, add ethyl acetate 1000ml and stir, add borax-sodium carbonate buffer 750ml, 10%Pd/C75g, after good seal kettle, first go out air in still with nitrogen replacement, three times repeatedly, hydrogen is passed into after vacuumizing, still internal pressure keeps 0.6MPa, and temperature keeps about 40 DEG C, reaction 4h.Filter, filter cake 100ml sodium carbonate-bicarbonate buffer solution, filtrate layering, aqueous phase 300ml ethyl acetate washing, aqueous phase ice-water bath is cooled to less than 10 DEG C, is adjusted to pH5 with 2N hydrochloric acid, separate out solid gradually, less than 10 DEG C are stirred 2h, and filter, filter cake 80% Virahol 150ml washs, 50 DEG C of vacuum-drying (gauge pressure is not less than 0.095MPa) about 6h, 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, use forward slip value even, obtain the sodium carbonate-bicarbonate damping fluid of pH10.
To in hydriding reactor, add intermediate (I) 150g, add propyl carbinol 1500ml and stir, add sodium carbonate-bicarbonate damping fluid 750ml, 10%Pd/C75g, after good seal kettle, first go out air in still with nitrogen replacement, three times repeatedly, hydrogen is passed into after vacuumizing, still internal pressure keeps 0.6MPa, and temperature keeps about 40 DEG C, reaction 4h.Filter, filter cake 100ml Glycine-NaOH buffer solution, filtrate layering, aqueous phase 300ml ethyl acetate washing, aqueous phase ice-water bath is cooled to less than 10 DEG C, is adjusted to pH5 with 2N hydrochloric acid, separate out solid gradually, less than 10 DEG C are stirred 2h, and filter, filter cake 80% Virahol 150ml washs, 50 DEG C of vacuum-drying (gauge pressure is not less than 0.095MPa) about 6h, obtain white crystalline powder 78g, HPLC purity 98.7%, yield 87.2%.
Claims (1)
1. the preparation method of Li Peinan more than, it is characterized in that: formula I compound is dispersed in the aqueous solution of ethyl acetate and a kind of pH=10 and carries out hydrogenation deprotection, still internal pressure keeps 0.6MPa, temperature keeps about 40 DEG C, and reaction 4h, filters, enrichment many Li Peinan phase is obtained through layering, regulate pH=5 with 2N hydrochloric acid, less than 10 DEG C are stirred 2h, obtain many Li Peinan crystallization;
（Ⅰ）
PNZ: to nitrobenzyloxycarbonyl PNB: to nitrobenzyl
Wherein the aqueous solution of pH=10 is the one of ammonia-ammonium chloride buffer, sodium carbonate-bicarbonate damping fluid, borax-sodium carbonate buffer, sodium carbonate solution.
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| CN105175420B (en) * | 2015-10-14 | 2017-11-28 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of donipenem |
| CN105541846B (en) * | 2016-02-05 | 2017-06-09 | 高霞 | A kind of preparation method of high-purity donipenem |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1995040A (en) * | 2006-01-05 | 2007-07-11 | 上海医药工业研究院 | 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method |
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1995040A (en) * | 2006-01-05 | 2007-07-11 | 上海医药工业研究院 | 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method |
| 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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Effective date of registration: 20181228 Address after: 250101 989 Xinjie street, Ji'nan high tech Zone, Shandong Patentee after: Pharmaceutical Sciences, Shandong Province Address before: 250101 989 Xinjie street, Ji'nan high tech Zone, Shandong Patentee before: Ling Peixue |
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