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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- 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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- Life Sciences & Earth Sciences (AREA)
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- 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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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 |
-
2012
- 2012-09-03 CN CN201210319779.4A patent/CN103664946B/en not_active Expired - Fee Related
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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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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