CN102731503A - Preparation method of tebipenem - Google Patents
Preparation method of tebipenem Download PDFInfo
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- CN102731503A CN102731503A CN2011100928685A CN201110092868A CN102731503A CN 102731503 A CN102731503 A CN 102731503A CN 2011100928685 A CN2011100928685 A CN 2011100928685A CN 201110092868 A CN201110092868 A CN 201110092868A CN 102731503 A CN102731503 A CN 102731503A
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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
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- 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 relates to a preparation method of an improved carbapenem compound tebipenem (shown as a formula 2). The method employs a tebipenem intermediate I as a raw material to conduct a hydrogenated deprotection reaction in a reaction solvent of a single solvent water in the presence of alkali and catalyst. The method of the invention adopts the single solvent water as the reaction solvent, and is economical, safe, environment-friendly, and more suitable for industrial scale operation.
Description
Technical field
The invention belongs to the carbapenem antibiotics field, be specifically related to the preparation method in a kind of improved carbapenem compounds Typee training south.
Background technology
Carbapenem antibiotics is the one type of Broad spectrum antibiotics that grows up the seventies in 20th century; Its anti-microbial activity is strong; Aerophil and anerobes all there are good anti-microbial effect, stable to β-Nei Xiananmei, be specially adapted to various bacteria; Especially aerophil and anerobes polyinfection, and the stationary state bacterium also had killing action.Because this type of adverse drug reaction is less, and the application time is shorter, resistance does not also have obviously to be strengthened in addition, and therefore being used as sometimes is to antibacterial last line of defense, in hospital's severe infection treatment, vital role is arranged.
A Typee training south volt ester, English Tebipenem Pivoxil by name, chemistry (1R by name; 5S; 6S)-1-methyl-6-[(1R)-the 1-hydroxyethyl]-2-[1-(1,3-thiazoles quinoline-2-yl) azetidine-3-yl] sulfo--1-carbon penicillium mould-2-alkene-3-carboxylic acid trimethylacetic acid methyl esters, structural formula is suc as formula shown in 1:
A Typee training south volt ester is the carbapenems medicine of first taking orally medication, and the same imipenum of anti-microbial activity especially has very strong active to gram positive organisms such as streptococcus pneumoniaes.In August, 2009 is at first by Japanese Meiji Seika Kaisba exploitation listing.As first oral prepns product of carbapenem antibiotic, the conformability of clinical application is significantly improved; This medical instrument has lower Mlc, is difficult for causing the appearance of bacterial drug resistance; Spinoff is little, and drug safety is high, can be used for treating childhood infection.
U.S. Pat 5886172 discloses the preparation method of a Typee training south volt ester.Wherein, Hydrogenation is that to train southern midbody with the Typee shown in the formula 3 be raw material, adopts phosphate buffered saline buffer, zinc powder catalyzer, THF system to carry out hydrogenolysis, reacting liquid filtering, washing, adjusting pH value, concentrated; Through macroporous adsorbent resin HP-40 purifying, obtain Typee training south 2 again.Reaction scheme is shown in flow process 1:
The shortcoming of this method is that at first the catalyzer zinc powder is difficult to reclaim, and environmental pollution is serious; Next adopts the phosphate buffered saline buffer reaction system, need carry out desalting refinement, and inefficiency is unfavorable for scale operation; Once more, purifying products adopts resin method, complex operation, yield low (only 64%).
J.Antibiot.2006,59 (4): 241-247, the document has been introduced the total synthesis method of a Typee training south volt ester, comprises by Typee and trains southern midbody 3 prepares Typee training south through hydrogenation method.Typee is trained southern midbody 3 and in the mixed solvent of propyl carbinol and water, 10% palladium-carbon catalyst, reaction of sodium bicarbonate system, is carried out hydrogenolysis, has reacted filtration, has regulated pH value, phase-splitting, crystallization, obtains Typee training south 2.Reaction scheme is shown in flow process 2:
Contain the organic solvent propyl carbinol in this method action solvent, its can with the palladium complexing in the catalyzer, be difficult for removing, product is very easily degraded in last handling process, we fail to obtain title product by document method operation.
Summary of the invention
In order to overcome above-mentioned defective of the prior art, main purpose of the present invention is to provide a kind of simple, economy, safety and is easy to the preparation method in industrialized improved Typee training south.
Therefore, the preparation method that a kind of Typee training south is provided of the present invention, said method comprises that training southern intermediate compound I with Typee is raw material, in the presence of alkali and catalyzer, is action solvent with single solvent water, carries out hydrogenation deprotection.Reaction scheme is shown in flow process 3:
Wherein:
Ra represents H or hydroxyl protecting group, and preferably, hydroxyl protecting group is benzyl or allyl group, and said benzyl or allyl group are randomly by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6Alkyl or C
1-C
6Alkoxyl group replaces.
Rb representation carboxy protection base, preferably, Rb is benzyl or allyl group, said benzyl or allyl group are randomly by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6Alkyl or C
1-C
6Alkoxyl group replaces, and more preferably, Rb is to nitrobenzyl.
Said alkali is selected from mineral alkali, organic bases, or its arbitrary combination, and they exist with any suitable concentration.Mineral alkali is preferably sodium hydroxide, yellow soda ash, sodium hydrogencarbonate, Sodium phosphate, dibasic, more preferably sodium hydrogencarbonate; Organic bases is preferably triethylamine, pyridine, 2,6-lutidine, 3,5-lutidine, diisopropylethylamine, Diisopropylamine, ammoniacal liquor, more preferably 2,6-lutidine.The consumption of alkali is 0.5～5 molar equivalent that Typee is trained southern intermediate compound I, is preferably 2～4 molar equivalents.
Said single solvent water is any water that contains less impurity, and wherein foreign matter content is less than 10wt%, for example less than 5wt%, for example less than 1wt%, preferably less than 0.1wt%, more preferably less than 0.01wt%, also more preferably less than 0.001wt%.Said impurity comprises suspended matter, soluble material, insoluble substance, metal-salt for example, organic solvent etc.When single solvent water comprised organic solvent, the content of organic solvent should preferably less than 0.1wt%, more preferably less than 0.01wt%, also more preferably less than 0.001wt%, most preferably, not contain organic solvent less than 1wt%.Organic solvent described here is the well-known organic solvents of those skilled in the art; Comprise alcohols, ethers, ester class, replace materials such as hydro carbons, arene, ketone, amides and nitrile; For example, alcohols comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, 2-butanols, Pentyl alcohol etc.; Ethers comprises THF, ether 、 diox, methyl-phenoxide etc.; The ester class comprises methyl acetate, ETHYLE ACETATE, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, isobutyl acetate, tert.-butyl acetate etc.; Replace hydro carbons and comprise methylene dichloride, chloroform, tetracol phenixin, Nitromethane 99Min. etc.; Arene comprises toluene, ethylbenzene etc.; Ketone comprises acetone, 2-butanone, 3-methyl-2-butanone, 2 pentanone, 4-methyl-2 pentanone, methyl-n-butyl ketone; Amides comprises N, dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, N-ethyl pyrrolidone; Comprise acetonitrile with nitrile.Water described in this paper comprises soft water and hard water; Fresh water and salt water; Surface water and underground water; Preferably, single solvent water is purified water, and said purifying comprises methods well known to those skilled in the art such as throw out filtration, water softening, charcoal absorption, de-ionized, r-o-, electrodialysis, ultra-filtration, distillation, disinfection by ultraviolet light, biological chemistry processing, forward osmosis.For example, single solvent water can be tap water or like tap water, deionized water, reverse osmosis water, electrodialytic water, surpass the water of this areas such as drainage, zero(ppm) water, sterilized water purifying commonly used.The consumption of water is 5～50 times that Typee is trained southern intermediate compound I, is preferably 15～25 times, by weight.
Catalyzer is selected from palladium carbon or platinum carbon, is preferably 5～10% palladium carbon (mass percent concentration); Catalyst consumption be Typee train southern intermediate compound I 5%～80%, be preferably 10～50%, by weight.
Said method is carried out under hydrogen atmosphere, and hydrogen pressure is preferably 0.4～2.5Mpa, more preferably 1.0～2.0Mpa.
Temperature of reaction is-10～40 ℃, is preferably 10～20 ℃.
Reaction times is selected from 15min～10h, is preferably 1～5h.
Hydrogenation finishes; Can be suitable for filtration of the present invention through well known to a person skilled in the art, concentrate, a series of last handling processes such as crystallization, purifying or freeze-drying obtain the finished product; Be preferably hydrogenation liquid is filtered, in filtrating, add organic solvent then and carry out crystallization.Said organic solvent is selected from one or more in acetone, THF, methyl alcohol, ethanol, n-propyl alcohol, Virahol, the acetonitrile, is preferably acetone; The consumption of organic solvent is 2～10 times of filtrate volume, is preferably 3～5 times; Recrystallization temperature is-40～50 ℃, is preferably-10～20 ℃; The crystallization time is selected from 0.5～24h, is preferably 1～4h.
Randomly, recrystallization can be carried out once more according to purity requirement etc. in crystallization gained Typee training south, and recrystallization solvent is preferably the mixed solvent that Typee is trained southern poor solvent and optimum solvent.Wherein, optimum solvent is selected from one or both in water, the methyl alcohol; Poor solvent is selected from one or more of acetone, THF, ethanol, n-propyl alcohol, Virahol, acetonitrile, is preferably acetone.
Said Typee is trained southern intermediate compound I can be with reference to art methods such as US5886172, J.Antibiot.2006, and 59 (4): the disclosed method of documents such as 241-247 prepares, and above-mentioned literature content is hereby incorporated by.
Products obtained therefrom Typee training of the present invention south can directly be developed as bulk drug; Also can further react and make the bulk drug Typee and train southern ester or its salt; As with reference to US5886172, J.Antibiot.2006,59 (4): the disclosed method of documents such as 241-247 prepares Typee training south volt ester (formula 1 a compound) hydrochloride.
The inventive method adopts single solvent-water as action solvent; Train southern intermediate compound I through Typee and in the dynamic buffering system, carry out hydrogenation; Solved the problems of dissolution of action solvent, reduced the product degraded, improved product purity catalyzer; And economy, safety, environmental protection are more suitable for operating in industrial scale.
Embodiment
Below in conjunction with embodiment the present invention is done further elaboration, but these embodiment do not constitute any restriction to the present invention.
The X-ray diffraction spectrum test condition that embodiment of the invention gained Typee is trained southern crystal formation is following:
Instrument: XRD D8 ADVANCE
Condition: Cu-K α radiation, pipe is pressed 40kV, pipe stream 50mA, 2-60 ° of 2 θ sweep limit, 0.02 ° at step angle, 0.3 second computing time.
The preparation in embodiment 1 Typee training south
In 50L hydrogenation still, add deionized water 20.0L successively, Typee is trained southern midbody 3 1.0Kg (2.01mol), 2,6-lutidine 0.8L (6.87mol), 10% palladium carbon 0.5Kg.Nitrogen replacement several, hydrogen exchange lead to hydrogen to still internal pressure 1.8MPa for several times at last, and 20 ℃ of temperature controls stir 4.5h.Stop stirring, row's hydrogen is used nitrogen replacement.Filter the filter cake recycling; Add acetone 80L in the filtrating, in 0 ℃ of following stirring and crystallizing 2h.Filter, vacuum-drying gets Typee training south type white solid 0.56Kg, and molar yield is 75.7%, HPLC purity 98.9%, heavy metal content＜10ppm.
The preparation in embodiment 2 Typees training south
In 10L hydrogenation still, add deionized water 3.0L successively, Typee is trained southern midbody 4 0.2Kg (0.47mol), sodium hydrogencarbonate 0.12Kg (1.43mol), 10% palladium carbon 0.08Kg.Nitrogen replacement several, hydrogen exchange lead to hydrogen to still internal pressure 1.5MPa for several times at last, and 13 ℃ of temperature controls stir 2.5h.Stop stirring, row's hydrogen is used nitrogen replacement.Filter, filter cake is with the washing of 0.5L purified water, recycling; Merging filtrate and washings add THF 3.5L earlier, in 10 ℃ of following stirring and crystallizing 2h, drip THF 7L again.Filter, vacuum-drying gets Typee training south type white solid 0.14Kg, and molar yield is 78.9%, HPLC purity 98.5%, heavy metal content＜10ppm.
The preparation in embodiment 3 Typees training south
In 50L hydrogenation still, add deionized water 25.0L successively, Typee is trained southern midbody 3 1.0Kg (2.01mol), yellow soda ash 0.32 (3.02mol) Kg, 10% palladium carbon 0.5Kg.Nitrogen replacement several, hydrogen exchange lead to hydrogen to still internal pressure 2.0MPa for several times at last, and 8 ℃ of temperature controls stir 5h and stop stirring, and arrange hydrogen, use nitrogen replacement.Filter the filter cake recycling; Slowly add ethanol 70L in the filtrating, in-10 ℃ of following stirring and crystallizing 5h.Filter, vacuum-drying gets Typee and trains southern white solid 0.52Kg, and molar yield is 70.3%, HPLC purity 99.0%, heavy metal content＜10ppm.
The preparation in embodiment 4 Typees training south
In 50L hydrogenation still, add deionized water 16.0L successively, Typee is trained southern midbody 3 1.0Kg (2.01mol), THF160mL, pyridine 0.53Kg (6.71mol), 10% palladium carbon 0.4Kg.Nitrogen replacement several, hydrogen exchange lead to hydrogen to still internal pressure 2.0MPa for several times at last, and 15 ℃ of temperature controls stir 3h.Stop stirring, row's hydrogen is used nitrogen replacement.Filter the filter cake recycling; Slowly add Virahol 80L in the filtrating, in 5 ℃ of following stirring and crystallizing 3h.Filter, vacuum-drying gets Typee and trains southern white solid 0.60Kg, and molar yield is 81.1%, HPLC purity 99.2%, heavy metal content＜10ppm.
Claims (10)
1. the preparation method in the training of the Typee shown in the formula 2 south,
Said method comprises that training southern intermediate compound I with Typee is raw material, in the presence of alkali and catalyzer, is action solvent with single solvent water, carries out hydrogenation deprotection.
Wherein:
Ra represents H or hydroxyl protecting group, and preferably, said hydroxyl protecting group is benzyl or allyl group, and said benzyl or allyl group are optional by nitro, fluorine, chlorine, bromine, iodine, C
1～C
6Alkyl, C
1～C
6Alkoxyl group replace;
Rb representation carboxy protection base is preferably benzyl or allyl group, and said benzyl or allyl group are optional by nitro, fluorine, chlorine, bromine, iodine, C
1～C
6Alkyl, C
1～C
6Alkoxyl group replace, more preferably to nitrobenzyl.
2. method according to claim 1, it is characterized in that: said single solvent water is any water that contains less impurity, for example, tap water, tap water, deionized water, reverse osmosis water, electrodialytic water, surpasses drainage, zero(ppm) water, sterilized water or its combination.
3. method according to claim 1, it is characterized in that: the consumption of said aqueous solvent is 5～50 times that Typee is trained southern intermediate compound I, is preferably 15～25 times, by weight.
4. method according to claim 1, it is characterized in that: said alkali is selected from mineral alkali, organic bases, or its arbitrary combination; They exist with any suitable concentration; Preferably, the consumption of said alkali is 0.5～5 molar equivalent that Typee is trained southern intermediate compound I, is preferably 2～4 molar equivalents.
5. like the said method of claim 4, it is characterized in that: said mineral alkali is selected from sodium hydroxide, yellow soda ash, sodium hydrogencarbonate, Sodium phosphate, dibasic; Said organic bases is selected from triethylamine, pyridine, 2,6-lutidine, 3,5-lutidine, diisopropylethylamine, Diisopropylamine, ammoniacal liquor.
6. method according to claim 1, it is characterized in that: said catalyzer is selected from palladium carbon or platinum carbon, is preferably 5～10% palladium carbon.
7. method according to claim 1 is characterized in that: catalyst consumption be Typee train southern intermediate compound I 5～80%, be preferably 10～50%, by weight.
8. method according to claim 1, it is characterized in that: hydrogen pressure is 0.4～2.5Mpa, is preferably 1.0～2.0Mpa.
9. method according to claim 1, it is characterized in that: temperature of reaction is-10～40 ℃, is preferably 10～20 ℃.
10. method according to claim 1; It is characterized in that: hydrogenation finishes, and product is carried out aftertreatment, preferably hydrogenation liquid is filtered; In filtrating, add organic solvent then and carry out crystallization; Get Typee training south, more preferably, said organic solvent is selected from one or more in acetone, THF, methyl alcohol, ethanol, n-propyl alcohol, Virahol, the acetonitrile.
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| CN201110092868.5A CN102731503B (en) | 2011-04-13 | 2011-04-13 | A kind of preparation method of tebipenem |
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| CN201110092868.5A CN102731503B (en) | 2011-04-13 | 2011-04-13 | A kind of preparation method of tebipenem |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017197484A (en) * | 2016-04-28 | 2017-11-02 | 株式会社トクヤマ | Debenzylation method |
| CN112513043A (en) * | 2018-05-30 | 2021-03-16 | 维纳拓尔斯制药公司 | Broad spectrum carbapenems |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0717042A1 (en) * | 1994-12-12 | 1996-06-19 | LEDERLE (JAPAN), Ltd. | 1-(4,5-Dihydro-2-thiazolyle)-3-azetidine thiol derivatives |
| 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 |
-
2011
- 2011-04-13 CN CN201110092868.5A patent/CN102731503B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0717042A1 (en) * | 1994-12-12 | 1996-06-19 | LEDERLE (JAPAN), Ltd. | 1-(4,5-Dihydro-2-thiazolyle)-3-azetidine thiol derivatives |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| TAKESHI ISODA ET AL: "Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084", 《J. ANTIBIOT.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017197484A (en) * | 2016-04-28 | 2017-11-02 | 株式会社トクヤマ | Debenzylation method |
| CN112513043A (en) * | 2018-05-30 | 2021-03-16 | 维纳拓尔斯制药公司 | Broad spectrum carbapenems |
| EP3802538A4 (en) * | 2018-05-30 | 2022-01-12 | Venatorx Pharmaceuticals, Inc. | Broad-spectrum carbapenems |
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