CN1927867A - Synthesis method of biapenem - Google Patents
Synthesis method of biapenem Download PDFInfo
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- CN1927867A CN1927867A CNA200510029523XA CN200510029523A CN1927867A CN 1927867 A CN1927867 A CN 1927867A CN A200510029523X A CNA200510029523X A CN A200510029523XA CN 200510029523 A CN200510029523 A CN 200510029523A CN 1927867 A CN1927867 A CN 1927867A
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- palladium
- reaction
- biapenem
- compound
- damping fluid
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The present invention discloses process of synthesizing Biapenem. The synthesis process includes the following steps: the hydrogenation reaction of the compound shown in expression I to eliminate protecting group inside buffer solution or the mixed liquid of buffer solution and organic solvent in the presence of catalyst of Pd or Pt containing compound; and the subsequent collection of Biapenem from the reaction product. The synthesis process is simple, high in product purity and suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic method of biapenem.
Background technology
Biapenem is the hydrocarbon mould carbapenem antibiotic of a kind of a new generation, its chemical name is: 6-[(4R, 5R, 6S)-the 2-carboxyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1,2-α] [1,2,4] triazole-4-inner salt.Biapenem has the pharmacologically active of general hydrocarbon mould carbapenem antibiotic, has a broad antifungal spectrum, anti-microbial activity and the similar (Acdridge.K with meropenem of imipenum, Morice M, et al, antimicrob Agent.Chemother, 1994,38 (4): 889-890).Activity to intestinal bacilli is better than imipenum, to non-fermentation gram-negative bacteria, especially pseudomonas aeruginosa and anti-gentamicin (GM) Pseudomonas aeruginosa, its anti-microbial activity is than strong 2 times of (the western wild Wu Ke etc. of imipenum, chenotherapy, 1994,42 (4): 64-66).
At present, the preparation method of biapenem is a raw material with the compound with general formula I all, removes protecting group and obtains, and mainly contains two kinds of methods:
A kind of is with Pd (OH)
2Be catalyzer, pressure hydration in phosphate buffered saline buffer, through ion exchange resin Dowex 50-X4 purifying, concentrate, obtain product after the freeze-drying, yield is lower than 30%.
Another kind is to be catalyzer with the zinc powder, removes protecting group in the phosphate buffered saline buffer of pH=5.6, obtains product behind macroporous adsorbent resin SP-207 purifying.Two kinds of methods all need be used the resin desalting and purifying, and a large amount of elutriants need concentrate postlyophilization.The solution of hydrocarbon mould vinyl compound is extremely unstable, and the degraded of 10-20% is arranged in the concentration process, and complex operation, yield are not high, is difficult for amplifying producing.
Summary of the invention
The technical issues that need to address of the present invention are the synthetic methods that disclose a kind of biapenem, to overcome the shortcoming that prior art exists, satisfy need of industrial production.
Method of the present invention comprises the steps:
With the compound with general formula I is raw material, is catalyzer to contain palladium or to contain platinic compound in the mixed solution of damping fluid or damping fluid and organic solvent, carries out hydrogenation with H2, removes protecting group, collects biapenem then from reaction product.
Reaction pressure is 1-10Kg/m
2, the reaction times is 0.5～5h, and yield can reach more than 55%, and purity can reach more than 97.0%;
Method of the present invention, temperature of reaction are not very crucial, generally can carry out under 0～50 ℃;
Said pH of buffer value is at 3.0-7.0, preferably zinc acetate damping fluid, magnesium chloride damping fluid, magnesium acetate damping fluid, ammonium acetate buffer, Potassium ethanoate damping fluid, sodium-acetate buffer or ammonium chloride buffer;
In the reaction system, volumetric molar concentration is 0.1-5.0mol/L;
Said organic solvent is selected from a kind of or its mixture in the trimethyl carbinol, isopropylcarbinol, ethyl acetate, acetone, Virahol, tetrahydrofuran (THF), ethanol or the methyl alcohol;
Said contain palladium or platiniferous compound catalyst be hydrogenation commonly used contain palladium or platiniferous organism or inorganics, as J.antibiotic, the disclosed catalyzer of 1993,46 (12) documents, a kind of in preferred palladium carbon, palladium, platinum, platinum dioxide or the palladium hydroxide; The weight consumption of catalyzer be general formula I compound weight 5～50%.Reaction expression is as follows:
Wherein: R is the allyl group that benzyl, the allyl group of replacement is arranged on benzyl, the phenyl ring or replacement is arranged;
Preferred R is=PhCH
2, 4-O
2NPhCH
2, 3-O
2NPhCH
2, CH
3OPhCH
2, 2,4-(CH
3O)
2PhCH
2Or CH
2=CHCH
2
The compound of general formula I can adopt JP0616680 or document J.antibiotic, 1993,46 (12), 1866; EP480100, J.Org.Chem.1998,63,8145) disclosed method is prepared.
By above-mentioned disclosed technical scheme as seen, method of the present invention, simple to operate, do not need resin purification, do not need specific installation, resultant product purity height is fit to suitability for industrialized production.
Embodiment
Embodiment 1
With the 6-[(4R of 30g (63mmol), 5R, 6S)-2-(carbobenzoxy-(Cbz))-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1,2-α] [1,2,4] triazole-4-muriate, add the 150ml trimethyl carbinol, the 50ml ethyl acetate, the magnesium chloride damping fluid (pH=5.5) of 450ml 0.30mol/L, stirring and dissolving, the weight content that adds the 10g palladium is 10% palladium carbon, control hydrogenation pressure 5Kg/m
2, react 3h down at 25 ℃, filter, water washs with ethyl acetate 300ml * 2, adds acetone 500ml, and-10 ℃ of stirring 2h filter, and solid washs with acetone 30ml * 2, and drying under reduced pressure obtains biapenem 16.5g, (yield: 75%, purity: 97.0%).
Among this embodiment, the R in the compound of general formula I is PhCH
2
Embodiment 2
6-[(4R with 30g (63mmol), 5R, 6S)-2-(carbobenzoxy-(Cbz))-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1,2-α] [1,2,4] triazole-4-muriate adds the 150ml tetrahydrofuran (THF), 450ml0.30mol/L sodium-acetate buffer (pH=5.5), stirring and dissolving, the weight content that adds the 1.5g palladium hydroxide is 20% palladium hydroxide carbon, control hydrogenation pressure 10Kg/m
2, react 2.5h down at 25 ℃, filter, water washs with ethyl acetate 300ml * 2, adds acetone 500ml, and-10 ℃ of stirring 2h filter, and solid washs with acetone 30ml * 2, and drying under reduced pressure obtains biapenem 15.4g, (yield: 70%, purity: 97.5%).
Among this embodiment, the R in the compound of general formula I is PhCH
2
Embodiment 3
6-[(4R with 30g (57.5mmol), 5R, 6S)-2-(4-nitro carbobenzoxy-(Cbz))-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1,2-α] [1,2,4] triazole-4-muriate adds Virahol 150ml, 0.35mol/L buffering salt (pH=6.0) 450ml of zinc acetate, stirring and dissolving adds platinum carbon (10%) 5g, control hydrogenation pressure 3Kg/m
2, react 4.0h down at 0 ℃, filter, add acetone 400ml in the filtrate ,-10 ℃ are stirred 1h, separate out crystal, filter, solid acetone 30ml * 2 washings, drying under reduced pressure obtains biapenem 12g, (yield: 60%, purity: 98.5%).
Among this embodiment, the R in the compound of general formula I is 4-O
2NPhCH
2
Embodiment 4
6-[(4R with 30g (57.5mmol), 5R, 6S)-2-(4-nitro carbobenzoxy-(Cbz))-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1,2-α] [1,2,4] triazole-4-muriate adds tetrahydrofuran (THF) 150ml, 0.50mol/L buffering salt (pH=6.0) 450ml of magnesium acetate, stirring and dissolving adds palladium carbon (10%) 7g, control hydrogenation pressure 2Kg/m
2, react 2.0h down at 50 ℃, filter, add acetone 400ml in the filtrate ,-10 ℃ are stirred 1h, separate out crystal, filter, solid acetone 30ml * 2 washings, drying under reduced pressure obtains biapenem 11g, (yield: 55%, purity: 98.5%).
Among this embodiment, the R in the compound of general formula I is 4-O
2NPhCH
2
Embodiment 5
With the 6-[(4R of 30g (57.5mmol), 5R, 6S)-2-(3-nitro carbobenzoxy-(Cbz))-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1,2-α] [1,2,4] triazole-4-muriate, add trimethyl carbinol 150ml, ethyl acetate 50ml, magnesium chloride damping fluid (pH=5.5) 450ml of 0.20mol/L, stirring and dissolving, add platinum dioxide carbon (5%) 10g, control hydrogenation pressure 4.5Kg/m
2, 30 ℃ of reaction 3h filter, and water adds Virahol 500ml with ethyl acetate 300ml * 2 washings,-10 ℃ are stirred 2h, separate out crystal, filter, and solid washs with Virahol 30ml * 2, drying under reduced pressure obtains biapenem 12g, (yield: 60%, purity: 98.0%).
Among this embodiment, the R in the compound of general formula I is 3-O
2NPhCH
2
Embodiment 6
6-[(4R with 30g (59.2mmol), 5R, 6S)-2-(4-methoxyl group benzyloxy carbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1,2-α] [1,2,4] triazole-4-muriate, ketone 150ml in adding, 0.40mol/L ammonia chloride damping fluid (pH=6.0) 450ml, stirring and dissolving adds palladium carbon (5%) 15g, control hydrogenation pressure 5Kg/m
2, 40 ℃ of reaction 4h, filtration adds acetone 500ml in the filtrate, and-10 ℃ are stirred 2h, filter, and solid washs with acetone 30ml * 2, and drying under reduced pressure obtains biapenem 13.7g, (yield: 66%, purity: 99%).
Among this embodiment, the R in the compound of general formula I is CH
3OPhCH
2
Embodiment 7
6-[(4R with 30g (59.2mmol), 5R, 6S)-2-(4-methoxyl group benzyloxy carbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1,2-α] [1,2,4] triazole-4-muriate adds acetone 150ml, Potassium ethanoate damping fluid (pH=6.0) 450ml of 10mol/L, stirring and dissolving adds palladium carbon (5%) 15g, control hydrogenation pressure 5Kg/m
2, 40 ℃ of reaction 4h, filtration adds acetone 500ml in the filtrate, and-10 ℃ are stirred 2h, filter, and solid washs with acetone 30ml * 2, and drying under reduced pressure obtains biapenem 13.0, (yield: 63%, purity: 99%).
Among this embodiment, the R in the compound of general formula I is CH
3OPhCH
2
Embodiment 8
With the 6-[(4R of 30g (68mmol), 5R, 6S)-2-(allyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazoles [1,2-α] [1,2,4] triazole-4-muriate, add tetrahydrofuran (THF) 400ml, 0.20mol/L ammonium chloride buffer (pH=5.0) 450ml, stirring and dissolving adds palladium 0.77g, triethyl-phosphite 4.0g, reaction 2h adds acetone 500ml, and-10 ℃ are stirred 2h, filter, solid washs with tetrahydrofuran (THF) 30ml * 2, and drying under reduced pressure obtains biapenem 19g, (yield: 80%, purity: 99%).
Among this embodiment, the R in the compound of general formula I is CH
2=CHCH
2
Embodiment 9
With the 6-[(4R of 30g (68mmol), 5R, 6S)-2-(allyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazoles [1,2-α] [1,2,4] triazole-4-muriate, add tetrahydrofuran (THF) 400ml, 2.0mol/L ammonium acetate buffer (pH=5.0) 450ml, stirring and dissolving adds palladium 0.77g, triethyl-phosphite 4.0g, reaction 2h adds acetone 500ml, and-10 ℃ are stirred 2h, filter, solid washs with tetrahydrofuran (THF) 30ml * 2, and drying under reduced pressure obtains biapenem 17.8g, (yield: 75%, purity: 99%).
Among this embodiment, the R in the compound of general formula I is CH
2=CHCH
2
Ultimate analysis:
Experimental value: C:51.53 H:5.27 N:15.76 theoretical value: C:51.42 H:5.18 N:15.99
HNMR (solvent: D
2O, in be designated as TMS)
1.297-1.313(d，3H)
1.347-1.363(d，3H)
3.418-3.460(dq，1H)
3.583-3.605(dd，1H)
4.284-4.331(q，1H)
4.347-4.370(dd，1H)
4.780-4.844(m，2H)
5.001-5.058(m，1H)
5.123-5.212(m，2H)
9.070，9.080(s，1H)
MS (EI 70ev sweep limit 40-420; Electron spray(ES))
m/z?350(M
+)
IR (pellet technique scanning 400-4000cm
-1No)
3346.16cm
-1
3124.16cm
-1
1750.72cm
-1
1601.95cm
-1
1561.74cm
-1
HPLC
HP1090, Agilent 1100 series liquid chromatograph instrument.Detector is G1314A UV-detector, DAD detector; Detect wavelength: 210nm; 40 ℃ of column temperatures; Flow velocity 1.0ml/min.Chromatographic column: (1) Hypersil BDS C18 (5 μ m, 4.6mm * 250mm); (2) TSKgelODS-100S (5 μ m, 4.6mm * 250mm).Mobile phase A is acetonitrile-10mM potassium phosphate buffer (regulating PH to 3.0 with phosphoric acid) [3: 97]; Mobile phase B is an acetonitrile.Sampling volume is 10 μ l.
Claims (8)
1. the synthetic method of a biapenem is characterized in that, comprises the steps: that with the compound with general formula I be raw material, is catalyzer to contain palladium or to contain platinic compound in the mixed solution of damping fluid or damping fluid and organic solvent, with H
2Carry out hydrogenation, remove protecting group, collect biapenem then from reaction product, reaction expression is as follows:
Wherein: R is the interior base of alkene that benzyl, the allyl group of replacement is arranged on benzyl, the phenyl ring or replacement is arranged.
2. method according to claim 1 is characterized in that, reaction pressure is 1-10Kg/m
2, the reaction times is 0.5～5h.
3. method according to claim 1 is characterized in that, temperature of reaction is 0 ℃～50 ℃.
4. method according to claim 1 is characterized in that, said pH of buffer value is at 3.0-7.0, and in the reaction system, the damping fluid volumetric molar concentration is 0.1-5.0mol/L.
5. method according to claim 1 is characterized in that, said organic solvent is selected from a kind of or its mixture in the trimethyl carbinol, isopropylcarbinol, ethyl acetate, acetone, Virahol, tetrahydrofuran (THF), ethanol or the methyl alcohol.
6. method according to claim 1 is characterized in that, said palladium or the platiniferous compound catalyst of containing is for containing palladium or platiniferous organism or inorganics.
7. method according to claim 6 is characterized in that, catalyzer is a kind of in palladium carbon, palladium, platinum, platinum dioxide or the palladium hydroxide; The weight consumption of catalyzer be general formula I compound weight 5～50%.
8. method according to claim 1 is characterized in that R is=PhCH
2, 4-4-O
2NPhCH
2, 3-O
2NPhCH
2, CH
3OPhCH
22,4-(CH
3O)
2PhCH
2Or CH
2=CHCH
2
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|---|---|
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Family
ID=37858020
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805359A (en) * | 2010-04-10 | 2010-08-18 | 浙江华海药业股份有限公司 | Method for preparing biapenem with high purity |
| CN101311178B (en) * | 2007-05-24 | 2010-08-25 | 上海医药工业研究院 | Synthetic method of compound panipenan |
| CN102212077A (en) * | 2010-04-08 | 2011-10-12 | 上海医药工业研究院 | Preparation method of biapenem |
| CN102453044A (en) * | 2010-10-20 | 2012-05-16 | 周小明 | Method for preparing biapenem by using micro-reaction technology |
| CN102617611A (en) * | 2011-01-28 | 2012-08-01 | 江苏正大天晴药业股份有限公司 | Preparation method of biapenem aseptic powder |
| CN101768174B (en) * | 2009-01-07 | 2012-08-08 | 四川科伦药业股份有限公司 | Method for preparing biapenem |
| CN102731534A (en) * | 2011-04-13 | 2012-10-17 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of biapenem |
| CN104072523A (en) * | 2014-07-14 | 2014-10-01 | 上海新亚药业有限公司 | Preparation method of biapenem |
| CN110078745A (en) * | 2019-03-26 | 2019-08-02 | 北京晨光同创医药研究院有限公司 | The new intermediate and its preparation method and application of Faropenem sodium |
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2005
- 2005-09-08 CN CNA200510029523XA patent/CN1927867A/en active Pending
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101311178B (en) * | 2007-05-24 | 2010-08-25 | 上海医药工业研究院 | Synthetic method of compound panipenan |
| CN101768174B (en) * | 2009-01-07 | 2012-08-08 | 四川科伦药业股份有限公司 | Method for preparing biapenem |
| CN102212077B (en) * | 2010-04-08 | 2013-06-19 | 上海医药工业研究院 | Preparation method of biapenem |
| CN102212077A (en) * | 2010-04-08 | 2011-10-12 | 上海医药工业研究院 | Preparation method of biapenem |
| CN101805359B (en) * | 2010-04-10 | 2015-03-25 | 浙江华海药业股份有限公司 | Method for preparing biapenem with high purity |
| CN101805359A (en) * | 2010-04-10 | 2010-08-18 | 浙江华海药业股份有限公司 | Method for preparing biapenem with high purity |
| CN102453044B (en) * | 2010-10-20 | 2014-06-18 | 周小明 | Method for preparing biapenem by using micro-reaction technology |
| CN102453044A (en) * | 2010-10-20 | 2012-05-16 | 周小明 | Method for preparing biapenem by using micro-reaction technology |
| CN102617611B (en) * | 2011-01-28 | 2013-07-10 | 江苏正大天晴药业股份有限公司 | Preparation method of biapenem aseptic powder |
| CN102617611A (en) * | 2011-01-28 | 2012-08-01 | 江苏正大天晴药业股份有限公司 | Preparation method of biapenem aseptic powder |
| CN102731534A (en) * | 2011-04-13 | 2012-10-17 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of biapenem |
| CN102731534B (en) * | 2011-04-13 | 2016-02-03 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of preparation method of biapenem |
| CN104072523A (en) * | 2014-07-14 | 2014-10-01 | 上海新亚药业有限公司 | Preparation method of biapenem |
| CN104072523B (en) * | 2014-07-14 | 2017-10-24 | 上海上药新亚药业有限公司 | The preparation method of Biapenem |
| CN110078745A (en) * | 2019-03-26 | 2019-08-02 | 北京晨光同创医药研究院有限公司 | The new intermediate and its preparation method and application of Faropenem sodium |
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