CN102304129A - Method suitable for industrially producing tebipenem - Google Patents
Method suitable for industrially producing tebipenem Download PDFInfo
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- CN102304129A CN102304129A CN 201110130624 CN201110130624A CN102304129A CN 102304129 A CN102304129 A CN 102304129A CN 201110130624 CN201110130624 CN 201110130624 CN 201110130624 A CN201110130624 A CN 201110130624A CN 102304129 A CN102304129 A CN 102304129A
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Abstract
The invention provides a method suitable for industrially producing tebipenem. Compared with the conventional method for synthesizing the tebipenem, the method has the advantages that: an organic solvent is single, convenient to recycle and low in consumption, resources are saved, environmental pollution is reduced, and the synthesized coarse tebipenem product has the purity of over 99.8 percent. When the coarse tebipenem product prepared by the method is refined, only pure water is selected as a solvent for recrystallization, and the tebipenem with the purity of over 99.9 percent and the maximum content of single impurity of less than 0.1 percent can be obtained; and the refining method is easy to implement, organic solvents are not used, environmental pollution is avoided, resources are saved further, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, further relate to a kind of preparation method of suitable suitability for industrialized production tebipenem.
Background technology
A tebipenem volt ester (L-084) is a kind of novel oral carbapenems medicine by Wyeth Pharmaceuticals's research and development.This compound is the prodrug that reactive precursor tebipenem C2 position carboxylic esterification forms, and oral back is discharged the active parent drug tebipenem by esterase hydrolyzed.The tebipenem has a broad antifungal spectrum; To most of clinical strain separated (except that few part bacterial classification such as Enterococcus faecium (faecium) and Pseudomonas aeruginosa (Pseudomonas aeruginosa)); Tebipenem all shows than penicillium mould series and the stronger bacterinertness of cephalo series; And compare with the carbapenem antibiotic of other injections, tebipenem also shows with degree or stronger antibacterial effect.Particularly show extremely strong antibacterial effect to the PRSP (penicillin resistant streptococcus pneumoniae), MRSP (anti-Oxacyclotetradecane,erythromycin deriv streptococcus pneumoniae) and the Haemophilus influenzae (hemophilus influenzae) that caused the childhood infection major cause in recent years.
A tebipenem volt ester needs to be obtained through esterification is synthetic by tebipenem, so tebipenem (I) is the important intermediate of synthetic this medicine.
Document (J.Antibiot.59 (4): 241-247,2006) has been reported the compound method of compound L-084, and synthetic route is following:
Wherein, be that the method for tebipenem does by compound I I synthetic compound I, with the i.e. (1R of compound I I; 5S; 6S)-and 6-[(1R) hydroxyethyl]-1-methyl-2-[1-(2-thiazoline-2-yl) azetidine-3-yl] sulfenyl-1-carbon generation-2-penem-3-carboxy acid mutual-nitro carbobenzoxy, propyl carbinol, water, palladium charcoal catalytic hydrogenation under 4M Pa pressure, reaction finishes and removes by filter insolubles, with reaction solution system pH regulator to 5.6; In with water impouring cold acetone;-5 ℃ are stirred down, and drip acetone and stir and separate out solid, and the quality (g) of acetone consumption (ml) and compound (II) is than being about 100: 1.This method acetone consumption is very big, and is low through the evidence product yield, about about 30%, so this method is not suitable for suitability for industrialized production, and in addition, products obtained therefrom purity is about 98%, has content to exist greater than 1% impurity, is unfavorable for carrying out next step esterification.
Summary of the invention
The invention provides a kind of compound method of tebipenem, this method is easy and simple to handle, and consumption of organic solvent is few, and purification process is simple to operation, and not with an organic solvent, product purity is fit to suitability for industrialized production up to more than 99.9%.
Provided by the invention a kind of be the method for tebipenem by compound I I synthetic compound I, it is characterized in that, comprise following steps:
1) preparation of tebipenem bullion: catalytic hydrogenation is carried out in compound I I, THF, water, alkali, the mixing of 10% palladium charcoal, and hydrogenation finishes and removes by filter insolubles, will filtrate and regulate pH to 5.6 ± 0.2; Add THF; Stirring and crystallizing is filtered drying; Wherein said alkali is sodium hydrogencarbonate, 2, in 6-lutidine, yellow soda ash, saleratus, the salt of wormwood any one;
2) recrystallization of tebipenem bullion: the tebipenem dissolving crude product that step 1) is obtained is in hot water, and said hot water temperature is 40～80 ℃, dissolving back filtered while hot, and filtrating is cooled to-15～30 ℃, and stirring and crystallizing is filtered drying.
The method of the synthetic reference literature of The compounds of this invention II (J.Antibiot.59 (4): 241-247,2006).
Further optimize technical scheme of the present invention, the preferred sodium hydrogencarbonate of the said alkali of step 1), the mass volume ratio of compound I I and solvents tetrahydrofurane and water TV is 1: 8～20 during catalytic hydrogenation, preferred 1: 10～12; The volume ratio of solvents tetrahydrofurane, water is 1～0.2: 1, preferred 1: 1; The mol ratio of compound I I, alkali is 1: 0.1～0.6, preferred 1: 0.3～0.5; The mass ratio of compound I I and palladium charcoal is 1: 0.05～0.2, preferred 1: 0.08～0.12.
Described catalytic hydrogenation condition is 20～50 ℃ of temperature, preferred 40 ℃; Hydrogenation pressure be normal pressure to 5MPa, preferred 2MPa; The hydrogenation time is 1～5 hour, preferred 3 hours.
After reaction finishes, preferred 1N HCl solution when regulating filtrating pH; The THF consumption is 2～5 times of volume of water during crystallization, preferred 2 times; The temperature of stirring and crystallizing is-10～25 ℃, preferred 0～5 ℃.
Step 2) bullion of tebipenem described in and quality volume ratio are 1: 5～20, preferred 1: 8～12, and preferred 60～70 ℃ of hot water temperature; Preferred-5～5 ℃ of the temperature of said stirring and crystallizing; The crystallization time is 2～12 hours, preferred 3～8 hours, can add crystal seed during crystallization, and accelerate crystallization speed.
The invention provides a kind of compound method of suitable suitability for industrialized production tebipenem; The organic solvent that this method is used than the method for existing synthetic tebipenem is single; Be convenient to recycle, and usage quantity is less, economizes on resources; Reduce environmental pollution, and the synthetic tebipenem bullion purity that obtains reaches more than 99.8%.The contriver finds through experiment accident; Only select for use pure water to carry out recrystallization as solvent during tebipenem crude product refining that the present invention prepares and can obtain purity and reach more than 99.9%, maximum single assorted content is less than 0.1% tebipenem, and process for purification is simple to operate; Not not with an organic solvent; Free from environmental pollution, further practiced thrift resource, be fit to suitability for industrialized production.
Embodiment below in conjunction with embodiment does further explain to the present invention.
Embodiment
Embodiment one
With compound I I 500g, THF 2L, water 4L, 2,6-lutidine 60g, 10% palladium charcoal 100g (weight in wet base), catalytic hydrogenation is 1 hour under 20～30 ℃, 4MPa pressure; Reaction finishes, and removes by filter insolubles, will filtrate with 1N HCl solution and regulate pH to 5.6; Add THF 12L,, filter in 20 ℃ of stirring and crystallizing; Drying makes pearl tebipenem bullion 218g, and HPLC detects purity 99.81%.
Dissolving crude product in 80 ℃ pure water 1.2L, has been dissolved the back filtered while hot, and filtrating is cooled to 0～5 ℃; Stirring and crystallizing 3 hours, suction filtration, drying; Get white crystal 190g, yield 87.2% uses Ka Shi moisture titration apparatus mensuration water cut to be: 15.7% (tetrahydrate); HPLC detects purity 99.95%, maximum single assorted content 0.08%.
Embodiment two
With compound I I 500g, THF 1L, water 5L, saleratus 20g, 10% palladium charcoal 25g (weight in wet base), catalytic hydrogenation is 5 hours under 20～30 ℃, normal pressure, and reaction finishes; Remove by filter insolubles, will filtrate with 1N HCl solution and regulate pH to 5.6, add THF 25L; In 0～5 ℃ of stirring and crystallizing; Filter, drying makes pearl tebipenem bullion 222g, and HPLC detects purity 99.83%.
Dissolving crude product in 40 ℃ pure water 4L, has been dissolved the back filtered while hot, and filtrating is cooled to-5～0 ℃; Add crystal seed, stirring and crystallizing 10 hours, suction filtration; Drying gets white crystal 190g, yield 85.6%; Use Ka Shi moisture titration apparatus mensuration water cut to be: 15.7% (tetrahydrate), HPLC detects purity 99.94%, maximum single assorted content 0.05%.
Embodiment three
With compound I I 500g, THF 4L, water 4L, sodium hydrogencarbonate 20g, 10% palladium charcoal 50g (weight in wet base), catalytic hydrogenation is 3 hours under 30～40 ℃, 2MPa pressure, and reaction finishes; Remove by filter insolubles, will filtrate with 1N HCl solution and regulate pH to 5.6, add THF 8L; In 0～5 ℃ of stirring and crystallizing; Filter, drying makes pearl tebipenem bullion 225g, and HPLC detects purity 99.85%.
Dissolving crude product in 70 ℃ pure water 2L, has been dissolved the back filtered while hot, and filtrating is cooled to-5～0 ℃; Stirring and crystallizing 8 hours, suction filtration, drying; Get white crystal 198g, yield 88.0% uses Ka Shi moisture titration apparatus mensuration water cut to be: 15.7% (tetrahydrate); HPLC detects purity 99.97%, maximum single assorted content 0.03%.
Embodiment four
With compound I I 500g, THF 3L, water 6L, salt of wormwood 40g, 10% palladium charcoal 50g (weight in wet base), catalytic hydrogenation is 4 hours under 30～40 ℃, normal pressure, and reaction finishes; Remove by filter insolubles, will filtrate with 1N HCl solution and regulate pH to 5.6, add THF 30L; In-10 ℃ of stirring and crystallizing; Filter, drying makes pearl tebipenem bullion 223g, and HPLC detects purity 99.85%.
Dissolving crude product in 60 ℃ pure water 2L, has been dissolved the back filtered while hot, and filtrating is cooled to-5～0 ℃; Stirring and crystallizing 8 hours, suction filtration, drying; Get white crystal 196g, yield 88.0% uses Ka Shi moisture titration apparatus mensuration water cut to be: 15.7% (tetrahydrate); HPLC detects purity 99.96%, maximum single assorted content 0.04%.
Claims (10)
1. one kind is the method for tebipenem by compound I I synthetic compound I, it is characterized in that, comprises following steps:
1) preparation of tebipenem bullion: catalytic hydrogenation is carried out in compound I I, THF, water, alkali, the mixing of 10% palladium charcoal, and hydrogenation finishes and removes by filter insolubles, will filtrate and regulate pH to 5.6 ± 0.2; Add THF; Stirring and crystallizing is filtered drying; Wherein said alkali is sodium hydrogencarbonate, 2, in 6-lutidine, yellow soda ash, saleratus, the salt of wormwood any one;
2) recrystallization of tebipenem bullion: the tebipenem dissolving crude product that step 1) is obtained is in hot water, and said hot water temperature is 40～80 ℃, dissolving back filtered while hot, and filtrating is cooled to-15～30 ℃, and stirring and crystallizing is filtered drying.
2. method according to claim 1, said alkali is sodium hydrogencarbonate when it is characterized in that in the step 1) catalytic hydrogenation.
3. according to claim 1,2 or 3 described methods; The mass volume ratio of compound I I and solvents tetrahydrofurane and water TV is 1: 8～20 when it is characterized in that catalytic hydrogenation in the step 1); The volume ratio of solvents tetrahydrofurane and water is 1～0.2: 1; The mol ratio of compound I I and alkali is 1: 0.1～0.6, and the mass ratio of compound I I and palladium charcoal is 1: 0.05～0.2.
4. according to claim 1,2 or 3 described methods; The mass volume ratio of compound I I and solvents tetrahydrofurane and water TV is 1: 10～12 when it is characterized in that catalytic hydrogenation in the step 1); The volume ratio of THF and water is 1: 1; The mol ratio of compound I I and alkali is 1: 0.3～0.5, and the mass ratio of compound I I and palladium charcoal is 1: 0.08～0.12.
5. method according to claim 1 is characterized in that the catalytic hydrogenation temperature is 20～50 ℃ in the step 1), hydrogenation pressure be normal pressure to 5MPa, the catalytic hydrogenation time is 1～5 hour.
6. method according to claim 5 is characterized in that the catalytic hydrogenation temperature is 40 ℃ in the step 1), and hydrogenation pressure is 2MPa, and the catalytic hydrogenation time is 3 hours.
7. method according to claim 1, the volume of THF is 2～5 times of volume of water when it is characterized in that crystallization in the step 1), recrystallization temperature is-10～25 ℃.
8. method according to claim 7, the volume of THF is 2 times of volume of water when it is characterized in that crystallization in the step 1), recrystallization temperature is-5～5 ℃.
9. method according to claim 1 is characterized in that step 2) in tebipenem bullion and quality volume ratio be 1: 5～20, said hot water temperature is 60～70 ℃, the temperature of said stirring and crystallizing is-5～5 ℃, the crystallization time is 2～12 hours.
10. method according to claim 9 is characterized in that step 2) in tebipenem bullion and quality volume ratio be 1: 8～12, the crystallization time is 3～8 hours.
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| CN 201110130624 CN102304129B (en) | 2011-05-18 | 2011-05-18 | Method for adapting to industrially producing tebipenem |
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| CN 201110130624 CN102304129B (en) | 2011-05-18 | 2011-05-18 | Method for adapting to industrially producing tebipenem |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012139424A1 (en) * | 2011-04-13 | 2012-10-18 | 石药集团中奇制药技术（石家庄）有限公司 | Crystalline forms of tebipenem, preparation methods and uses thereof in the preparation of medicines |
| CN103059027A (en) * | 2012-12-20 | 2013-04-24 | 安徽悦康凯悦制药有限公司 | Method for preparing tebipenem pivoxil |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08253482A (en) * | 1994-12-28 | 1996-10-01 | Lederle Japan Ltd | Crystalline carbapenem compound |
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2011
- 2011-05-18 CN CN 201110130624 patent/CN102304129B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08253482A (en) * | 1994-12-28 | 1996-10-01 | Lederle Japan Ltd | Crystalline carbapenem compound |
Non-Patent Citations (1)
| Title |
|---|
| 《J. Antibiot.》 20061231 Takeshi Isoda, et al. Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084 241-247 1-10 第59卷, 第4期 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012139424A1 (en) * | 2011-04-13 | 2012-10-18 | 石药集团中奇制药技术（石家庄）有限公司 | Crystalline forms of tebipenem, preparation methods and uses thereof in the preparation of medicines |
| CN103059027A (en) * | 2012-12-20 | 2013-04-24 | 安徽悦康凯悦制药有限公司 | Method for preparing tebipenem pivoxil |
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