CN101311178B - Synthetic method of compound panipenan - Google Patents
Synthetic method of compound panipenan Download PDFInfo
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- CN101311178B CN101311178B CN2007100412092A CN200710041209A CN101311178B CN 101311178 B CN101311178 B CN 101311178B CN 2007100412092 A CN2007100412092 A CN 2007100412092A CN 200710041209 A CN200710041209 A CN 200710041209A CN 101311178 B CN101311178 B CN 101311178B
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Abstract
The invention discloses a preparation method for a compound as shown in the formula V, that is, panipenem; the method includes the following steps: (1) in an organic solvent with organic base, a compound as shown in the formula I reacts with phosphate ester chloride as shown in the formula II; (2) a compound as shown in the formula III is added in for reaction to prepare a compound as shown in the formula IV; (3) in an organic solvent or the mixed liquid of the organic solvent and water and with the existence of protecting group receptors, the compound as shown in the formula IV carries out deprotection reaction by taking a compound containing cesium as a catalyst; wherein, R is allyl or substituted allyl, and R' is methyl, ethide or phenyl. The method of the invention has simple operation and does not need resin purification or special equipment; the obtained products have high purity and are suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of compound, be specifically related to a kind of synthetic method of compound panipenan.
Background technology
Panipenem is a kind of carbapenem antibiotic, and its chemical name is: (5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-[[(3S)-1-(1-imines ethyl)-3-pyrrolidyl]-sulfo-]-7-oxo-1-azabicyclic [3.2.0]-hept-2-ene"-2-carboxylic acid.Panipenem has the pharmacologically active of general hydrocarbon mould carbapenem antibiotic, has a broad antifungal spectrum, and anti-microbial activity is similar to imipenum.Activity to staphylococcus aureus and streptococcus aureus is better than imipenum, the activity of and negative Bacillus proteus, citrobacter, husky thunder bacterium, genera bacillus positive to intestinal bacteria, streptococcus pneumoniae, hemophilus influenza, enterobacter cloacae, indoles and imipenum is identical or strong slightly is a unique carbapenem antibiotic that children are suitable for.
At present, the preparation method of panipenem mainly contains two kinds: a kind of is first deprotection base, meets functional group again on pyrrole ring, as document and patent (J.Antibiot, 36,1034-1039,1983, JP5913757, EP0161546) reported method.Another kind is to remove protecting group at last, as the method for patent (JP5913757, EP0161546) disclosure.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 carbapenem compound is extremely unstable, easily part degraded in the concentration process, and complex operation, yield are not high, are difficult for amplifying producing.
Summary of the invention
The objective of the invention is to disclose a kind of method of new synthetic compound panipenem,, satisfy need of industrial production to overcome the shortcoming that prior art exists.
Method of the present invention comprises the steps:
(1) in the organic solvent, in the presence of organic bases, with compound shown by formula I with react suc as formula the chlorine phosphoric acid ester shown in the II;
(2) compound of adding shown in formula III makes suc as formula the compound shown in the IV through reaction;
(3) in the mixed solution of organic solvent or organic solvent and water, be catalyzer with the compound that contains palladium, in the presence of the protecting group acceptor, will carry out deprotection reaction suc as formula the compound shown in the IV, get final product;
Wherein, R is allyl group or the allyl group that replacement is arranged, and R ' is methyl, ethyl or phenyl.
In the step (1), described organic solvent is preferable is selected from the inert solvent one or more, as acetone, methylene dichloride, trichloromethane, tetrahydrofuran (THF), ethyl acetate or acetonitrile; What the temperature of reaction was preferable is-10 ℃～40 ℃; What the time of reaction was preferable is 0.5～24 hour; What described organic bases was preferable is diisopropyl ethyl amine, triethylamine or Diisopropylamine; The consumption of organic bases and chlorine phosphoric acid ester all can be 1 to 2 times of compound shown by formula I molar weight respectively; Organic bases during 1 times of add-on less than, also can be added in step (2) in step (1).
In the step (2), what the temperature of reaction was preferable is-10 ℃～40 ℃; What the time of reaction was preferable is 0.5～24 hour; The consumption of the compound shown in formula III can be 1 to 2 times of compound shown by formula I molar weight.
In the step (3), described organism or the inorganics that contains the optional self-contained palladium of compound of palladium, preferable as palladium, Palladous nitrate, Palladous chloride, bi triphenyl phosphorus Palladous chloride or four triphenyl phosphorus palladiums; Contain the consumption of compound of palladium preferable for suc as formula 0.5～50% of the quality of the compound shown in the IV; That described protecting group acceptor is preferable is morpholine, dimedone, N, N-dimethyl malonylurea, tri-butyl tin hydride, 2 ethyl hexanoic acid or caproic acid; The consumption of protecting group acceptor is preferable is suc as formula the molar weight of the compound shown in the IV 0.75～3 times; Described organic solvent is preferable is selected from the trimethyl carbinol, isopropylcarbinol, ethyl acetate, acetone, Virahol, methylene dichloride, trichloromethane, tetrahydrofuran (THF), ethanol and the methyl alcohol one or more; What the temperature of reaction was preferable is-10 ℃～40 ℃; What the time of reaction was preferable is 0.5～24 hour.
Among the present invention, the preparation method of compound shown by formula I can be referring to patent US4382949, and the preparation method of the compound shown in formula III can be referring to patent JP6084258.Other 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: compared with prior art, method of the present invention is simple to operate, does not need resin purification and specific installation, and resultant product purity height is more suitable for suitability for industrialized production.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
Embodiment 1
Nitrogen protection, in the 1L reaction flask, (R is an allyl group with formula I compound; 20g 79.05mmol) is dissolved in acetonitrile 775ml, under-10 ℃; drip diisopropyl ethyl amine 15.1ml, 5min drips complete, drips diphenyl phosphate chloride 17.6ml again; 15min drips complete, adds diisopropyl ethyl amine 15.1ml behind the 30min again, and (R is an allyl group to the formula III compound; 19.4g, 85.3mmol), after 6 hours; impouring 800ml ethyl acetate; the 800ml salt solution, separatory, anhydrous magnesium sulfate drying; filter; concentrate, raffinate adds 40ml ethyl acetate, suction filtration; get 20.1g off-white color solid type IV compound (R is an allyl group), yield 55%.
In the 50ml reaction flask, (R is an allyl group, 0.463g to add formula IV compound, 1mmol), Virahol 23.15ml, N, N-dimethyl malonylurea (156mg, 1mmol), four triphenyl phosphorus palladium (23.11mg, 0.02mmol), room temperature reaction 0.5h filters, vacuum-drying, get the 0.29g yellow solid, yield 85.5%, purity 99.1%.
Embodiment 2
In the 150ml reaction flask, (R is an allyl group, 2g with formula I compound, 7.905mmol) be dissolved in tetrahydrofuran (THF) 80ml, under-10 ℃, drip diisopropyl ethyl amine 1.51ml, 5min drips complete, drips diethyl chloro-phosphate 1.63ml again, and 15min drips complete, add diisopropyl ethyl amine 1.51ml behind the 30min again, (R is an allyl group to the formula III compound, 2g, 8.77mmol), after 10 hours, impouring 100ml ethyl acetate, 80ml salt solution, separatory, anhydrous magnesium sulfate drying filters, and concentrates, raffinate adds the 5ml ethyl acetate, suction filtration gets 1.2g off-white color solid type IV compound (R is an allyl group), yield 32.8%.
In the 50ml reaction flask, (R is an allyl group, 0.463g to add formula IV compound, 1mmol), methylene dichloride 23.15ml, tri-butyl tin hydride (0.59ml, 2.2mmol), bi triphenyl phosphorus Palladous chloride (7.02mg, 0.01mmol),-10～0 ℃ of reaction 2h, filter, vacuum-drying gets the 0.23g yellow solid, yield 67.8%, purity 99.0%.
Embodiment 3
Nitrogen protection, in the 100ml reaction flask, (R is an allyl group with formula I compound; 2g 7.95mmol) is dissolved in ethyl acetate 80ml, under-10 ℃; drip diisopropyl ethyl amine 2.63ml, 5min drips complete, drips diphenyl phosphate chloride 1.76ml again; 15min drips complete, and (R is an allyl group, 2g to add the formula III compound behind the 30min again; 8.77mmol), be warming up to 30 ℃, after 20 hours; impouring 100ml ethyl acetate; the 80ml salt solution, separatory, anhydrous magnesium sulfate drying; filter; concentrate, raffinate adds 5ml ethyl acetate, suction filtration; get 1.8g off-white color solid type IV compound (R is an allyl group), yield 49.2%.
In the 50ml reaction flask, (R is an allyl group, 0.463g to add formula IV compound, 1mmol), tetrahydrofuran (THF) 12ml, N, N-dimethyl malonylurea (156mg, 1mmol), bi triphenyl phosphorus Palladous chloride (7.02mg, 0.01mmol), 0～10 ℃ of reaction 3h rises to 30～40 ℃ of reaction 6h, filter, vacuum-drying gets the 0.31g yellow solid, yield 91.4%, purity 99.3%.
Embodiment 4
Nitrogen protection, in the 100ml reaction flask, (R is an allyl group with formula I compound; 2g 7.95mmol) is dissolved in acetone 80ml, under 40 ℃; drip diisopropyl ethyl amine 1.51ml, 5min drips complete, drips diethyl chloro-phosphate 1.90ml again; 15min drips complete, and (R is an allyl group, 2g to add the formula III compound behind the 30min again; 8.77mmol); 0.5 after hour, impouring 100ml ethyl acetate, 80ml salt solution; separatory; anhydrous magnesium sulfate drying filters, and concentrates; raffinate adds the 5ml ethyl acetate; suction filtration gets 1.8g off-white color solid type IV compound (R is an allyl group), yield 49.2%.
In the 50ml reaction flask, (R is an allyl group, 0.463g to add formula IV compound, 1mmol), trichloromethane 4ml, tetrahydrofuran (THF) 4ml, ethanol 4ml and water 1ml, morpholine (174ml, 2mmol), and bi triphenyl phosphorus Palladous chloride (7.02mg, 0.01mmol), 0～10 ℃ of reaction 24h, filter, vacuum-drying gets the 0.30g yellow solid, yield 88.5%, purity 99.0%.
Embodiment 5
Nitrogen protection, in the 100ml reaction flask, (R is an allyl group with formula I compound; 2g 7.95mmol) is dissolved in methylene dichloride 80ml, under 20 ℃; drip diisopropyl ethyl amine 1.51ml, 5min drips complete, drips diethyl chloro-phosphate 1.9ml again; 15min drips complete, adds diisopropyl ethyl amine 1.51ml behind the 15min again, and (R is an allyl group to the formula III compound; 2g, 8.77mmol), after 20 hours; impouring 100ml methylene dichloride; the 80ml salt solution, separatory, anhydrous magnesium sulfate drying; filter; concentrate, raffinate adds 5ml ethyl acetate, suction filtration; get 1.9g off-white color solid type IV compound (R is an allyl group), yield 51.6%.
In the 50ml reaction flask, (R is an allyl group, 0.463g to add formula IV compound, 1mmol), acetone 12ml, 2 ethyl hexanoic acid (319ml, 2mmol), and Palladous chloride (232mg, 1.1mmol), about 40 ℃ of reaction 0.5h, filter, vacuum-drying gets the 0.30g yellow solid, yield 88.5%, purity 98.8%.
Embodiment 6
Nitrogen protection, in the 100ml reaction flask, (R is an allyl group with formula I compound; 2g 7.95mmol) is dissolved in trichloromethane 80ml, under-10 ℃; drip diisopropyl ethyl amine 1.51ml, 5min drips complete, drips diphenyl phosphate chloride 1.76ml again; 15min drips complete, adds diisopropyl ethyl amine 1.51ml behind the 5h again, and (R is an allyl group to the formula III compound; 2g 8.77mmol), is warming up to 30 ℃; after 20 hours, impouring 100ml trichloromethane, 80ml salt solution; separatory; anhydrous magnesium sulfate drying filters, and concentrates; raffinate adds the 5ml ethyl acetate; suction filtration gets 2.3g off-white color solid type IV compound (R is an allyl group), yield 62.5%.
In the 50ml reaction flask, (R is an allyl group, 0.463g to add formula IV compound, 1mmol), ethyl acetate 6ml, tetrahydrofuran (THF) 6ml, caproic acid (250ml, 2mmol), Palladous nitrate (50mg), 0～10 ℃ of reaction 3h rises to 30～40 ℃ of reaction 6h, filters, vacuum-drying, get the 0.27g yellow solid, yield 79.6%, purity 98.8%.
Embodiment 7
Nitrogen protection, in the 100ml reaction flask, (R is an allyl group with formula I compound; 2g 7.95mmol) is dissolved in 40ml ethyl acetate and the 40ml acetone, under-10 ℃; drip diisopropyl ethyl amine 1.51ml, 5min drips complete, drips diphenyl phosphate chloride 1.76ml again; 15min drips complete, adds diisopropyl ethyl amine 1.51ml behind the 24h again, and (R is an allyl group to the formula III compound; 2g 8.77mmol), is warming up to 30 ℃; after 20 hours, impouring 100ml ethyl acetate, 80ml salt solution; separatory; anhydrous magnesium sulfate drying filters, and concentrates; raffinate adds the 5ml ethyl acetate; suction filtration gets 2.1g white solid formula IV compound (R is an allyl group), yield 57.1%.
In the 50ml reaction flask, (R is an allyl group, 0.463g to add formula IV compound, 1mmol), isopropylcarbinol 12ml, dimedone (140mg, 1mmol), and palladium (22mg, 0.1mmol), 0～10 ℃ of reaction 3h rises to 30～40 ℃ of reaction 6h, filters, vacuum-drying, get the 0.28g yellow solid, yield 82.6%, purity 98.8%.
Embodiment 8
Nitrogen protection, in the 100ml reaction flask, (R is an allyl group with formula I compound; 2g 7.95mmol) is dissolved in acetonitrile 80ml, under-10 ℃; drip diisopropyl ethyl amine 1.51ml, 5min drips complete, drips diphenyl phosphate chloride 1.76ml again; 15min drips complete, adds diisopropyl ethyl amine 1.51ml behind the 30min again, and (R is an allyl group to the formula III compound; 2.5g, 11.0mmol), be warming up to 30 ℃; after 24 hours, impouring 100ml ethyl acetate, 80ml salt solution; separatory; anhydrous magnesium sulfate drying filters, and concentrates; raffinate adds the 5ml ethyl acetate; suction filtration gets 2.4g off-white color solid type IV compound (R is an allyl group), yield 65.2%.
In the 50ml reaction flask, (R is an allyl group, 0.463g to add formula IV compound, 1mmol), trimethyl carbinol 12ml, N, N-dimethyl malonylurea (156mg, 1mmol), four triphenyl phosphorus palladium (23.11mg, 0.02mmol), 0～10 ℃ of reaction 3h rises to 30～40 ℃ of reaction 6h, filter, vacuum-drying gets the 0.33g yellow solid, yield 97.3%, purity 99.3%.
Embodiment 9
Nitrogen protection, in the 1L reaction flask, (R is an allyl group with formula I compound; 20g 79.05mmol) is dissolved in acetonitrile 775ml, under-10 ℃; drip diisopropyl ethyl amine 15.1ml, 5min drips complete, drips diphenyl phosphate chloride 17.6ml again; 15min drips complete, adds diisopropyl ethyl amine 15.1ml behind the 30min again, and (R is an allyl group to the formula III compound; 25g, 110mmol), after 6 hours; impouring 800ml ethyl acetate; the 800ml salt solution, separatory, anhydrous magnesium sulfate drying; filter; concentrate, raffinate adds 40ml ethyl acetate, suction filtration; get 23.6g off-white color solid type IV compound (R is an allyl group), yield 64.1%.
In the 50ml reaction flask, (R is an allyl group, 0.463g to add formula IV compound, 1mmol), tetrahydrofuran (THF) 23.15ml, N, N-dimethyl malonylurea (117mg, 0.75mmol), four triphenyl phosphorus palladium (115.75mg, 0.1mmol) ,-10 ℃ of reaction 24h filter, vacuum-drying, get the 0.26g yellow solid, yield 76.7%, purity 98.8%.
Embodiment 10
Nitrogen protection, in the 100ml reaction flask, (R is an allyl group with formula I compound; 2g 7.95mmol) is dissolved in acetonitrile 80ml, under-10 ℃; drip diisopropyl ethyl amine 1.51ml, 5min drips complete, drips diphenyl phosphate chloride 1.76ml again; 15min drips complete, adds diisopropyl ethyl amine 1.51ml behind the 30min again, and (R is an allyl group to the formula III compound; 2.5g, 11.0mmol), be warming up to 30 ℃; after 20 hours, impouring 100ml ethyl acetate, 80ml salt solution; separatory; anhydrous magnesium sulfate drying filters, and concentrates; raffinate adds the 5ml ethyl acetate; suction filtration gets 2.4g white solid formula IV compound (R is an allyl group), yield 65.2%.
In the 50ml reaction flask, (R is an allyl group, 0.463g to add formula IV compound, 1mmol), methyl alcohol 12ml, tri-butyl tin hydride (0.80ml, 3mmol), and four triphenyl phosphorus palladiums (185.2mg, 0.16mmol), 0～10 ℃ of reaction 3h rises to 30～40 ℃ of reaction 6h, filters, vacuum-drying, get the 0.31g yellow solid, yield 91.4%, purity 99.0%.
Embodiment 11
Nitrogen protection, in the 100ml reaction flask, (R is a 2-alkene butyl with formula I compound; 2g 7.49mmol) is dissolved in methylene dichloride 80ml, under 20 ℃; drip diisopropyl ethyl amine 1.51ml, 5min drips complete, drips chlorine dimethyl phosphate 1.9ml again; 15min drips complete, adds diisopropyl ethyl amine 1.51ml behind the 15min again, and (R is a 2-alkene butyl to the formula III compound; 2g, 8.26mmol), after 20 hours; impouring 100ml methylene dichloride; the 80ml salt solution, separatory, anhydrous magnesium sulfate drying; filter; concentrate, raffinate adds 5ml ethyl acetate, suction filtration; get 1.8g off-white color solid type IV compound (R is an allyl group), yield 48.9%.
In the 50ml reaction flask, (R is an allyl group, 0.491g to add formula IV compound, 1mmol), acetone 12ml, tri-butyl tin hydride (0.80ml, 3mmol), and four triphenyl phosphorus palladiums (2.455mg, 0.0021mmol), about 10 ℃ of reaction 0.5h, filter, vacuum-drying gets the 0.3g yellow solid, yield 88.5%, purity 98.7%.
Claims (8)
1. the preparation method suc as formula the compound panipenan shown in the V is characterized in that comprising the steps:
(1) in the organic solvent, in the presence of organic bases, with compound shown by formula I with react suc as formula the chlorine phosphoric acid ester shown in the II;
(2) compound of adding shown in formula III makes suc as formula the compound shown in the IV through reaction;
(3) in the mixed solution of organic solvent or organic solvent and water, be catalyzer with the compound that contains palladium, in the presence of the protecting group acceptor, will carry out deprotection reaction suc as formula the compound shown in the IV, get final product;
Wherein, R is an allyl group, and R ' is methyl, ethyl or phenyl; Described protecting group acceptor is morpholine, dimedone, N, N-dimethyl malonylurea, tri-butyl tin hydride, 2 ethyl hexanoic acid or caproic acid.
2. the method for claim 1, it is characterized in that: in the step (1), described organic solvent is one or more in the inert solvent.
3. the method for claim 1, it is characterized in that: in the step (3), the described compound that contains palladium is palladium, Palladous nitrate, Palladous chloride, bi triphenyl phosphorus Palladous chloride or four triphenyl phosphorus palladiums.
4. the method for claim 1 is characterized in that: in the step (3), the consumption of the described compound that contains palladium is for suc as formula 0.5～50% of the quality of the compound shown in the IV.
5. the method for claim 1, it is characterized in that: in the step (3), the consumption of described protecting group acceptor is 0.75～3 times suc as formula the molar weight of the compound shown in the IV.
6. the method for claim 1, it is characterized in that: in the step (3), described organic solvent is selected from one or more in the trimethyl carbinol, isopropylcarbinol, ethyl acetate, acetone, Virahol, methylene dichloride, trichloromethane, tetrahydrofuran (THF), ethanol and the methyl alcohol.
7. the method for claim 1 is characterized in that: among one or more in step (1), (2) and (3), the temperature of described reaction is-10 ℃～40 ℃.
8. the method for claim 1 is characterized in that: among one or more in step (1), (2) and (3), the time of described reaction is 0.5～24 hour.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101885727A (en) * | 2010-07-02 | 2010-11-17 | 深圳市海滨制药有限公司 | Method for preparing penipenem |
| 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 |
| CN104860996B (en) * | 2015-05-06 | 2017-04-12 | 浙江师范大学 | Panipenem intermediate and synthetic method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0161546A1 (en) * | 1984-04-30 | 1985-11-21 | Merck & Co. Inc. | Combination of 2-substituted carbapenems with dipeptidase inhibitors |
| CN1752090A (en) * | 2005-10-20 | 2006-03-29 | 上海交通大学 | Preparation method of ertabeinan sodium salt |
| CN1927867A (en) * | 2005-09-08 | 2007-03-14 | 上海医药工业研究院 | Synthesis method of biapenem |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0161546A1 (en) * | 1984-04-30 | 1985-11-21 | Merck & Co. Inc. | Combination of 2-substituted carbapenems with dipeptidase inhibitors |
| CN1927867A (en) * | 2005-09-08 | 2007-03-14 | 上海医药工业研究院 | Synthesis method of biapenem |
| CN1752090A (en) * | 2005-10-20 | 2006-03-29 | 上海交通大学 | Preparation method of ertabeinan sodium salt |
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Effective date of registration: 20160512 Address after: 200040 Beijing West Road, Shanghai, No. 1320 Patentee after: Shanghai Institute of pharmaceutical industry Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 200040 Beijing West Road, Shanghai, No. 1320 Patentee before: Shanghai Institute of pharmaceutical industry Effective date of registration: 20160512 Address after: 200040 Beijing West Road, Shanghai, No. 1320 Patentee after: Shanghai Institute of pharmaceutical industry Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 200040 Beijing West Road, Shanghai, No. 1320 Patentee before: Shanghai Institute of pharmaceutical industry |
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Effective date of registration: 20180521 Address after: No. 1320, Beijing West Road, Jing'an District, Shanghai City, Shanghai Patentee after: Shanghai Institute of pharmaceutical industry Address before: 200040 No. 1320 West Beijing Road, Shanghai Co-patentee before: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Patentee before: Shanghai Institute of pharmaceutical industry Effective date of registration: 20180521 Address after: No. 1320, Beijing West Road, Jing'an District, Shanghai City, Shanghai Patentee after: Shanghai Institute of pharmaceutical industry Address before: 200040 No. 1320 West Beijing Road, Shanghai Co-patentee before: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Patentee before: Shanghai Institute of pharmaceutical industry |
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| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100825 Termination date: 20190524 |