CN103880901A - Preparation method of clarithromycin intermediate methide - Google Patents
Preparation method of clarithromycin intermediate methide Download PDFInfo
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- CN103880901A CN103880901A CN201210565618.3A CN201210565618A CN103880901A CN 103880901 A CN103880901 A CN 103880901A CN 201210565618 A CN201210565618 A CN 201210565618A CN 103880901 A CN103880901 A CN 103880901A
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Abstract
The invention belongs to the technical field of medicine synthesis, and discloses a preparation method of a clarithromycin intermediate methide. The method comprises the following steps: protecting the hydroxy group of erythromycin oxime through etherification via a routine process, protecting 2'-position and 4''-position hydroxy groups through silanization, dissolving the obtained substance in a water-insoluble or weakly-water-soluble polar solvent of one or more non-protons, adding a certain amount of a methylation reagent and a phase transfer catalyst, continuously stirring to uniformity, maintaining a certain temperature, gradually adding a certain amount of a powdery strong alkali, stirring for 1h, adding water, stirring, allowing the obtained solution to stand for layering, separating the obtained water phase, adding a solvent to the water phase for back extraction, mixing obtained organic phases, adding water to wash the obtained organic phase mixture, and recovering the solvent to obtain the clarithromycin intermediate methide. The method has the advantages of convenient solvent recovery, safety, environmental protection, good quality and low cost, and can be used in industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis.Especially the preparation method of first compound in the middle of a kind of clarithromycin.
Background technology
Clarithromycin has another name called CAMA A, English name: Clarithromycin is the derivative of erythromycin, by the hydroxyl selective methylation of 6 of Erythromycin A and make.Clarithromycin in vitro anti-microbial activity is similar to erythromycin, but as stronger than erythromycin in anti-microbial activities such as streptococcus aureus, suis, hemophilus influenzaes to part bacterium in vivo.And have poor resistance between erythromycin, and the also certain anti-microbial activity of tool of erythromycin-resistant bacterial strain that induction is produced.
Clarithromycin after finding for 1980, a very long course has been experienced in its synthetic development, so far formed one relatively ripe, general industrializing synthesis route, first with hydroxylammonium, the carbonyl of 9 is carried out to oximation reaction by erythromycin or Matachrom and form erythromycin oxime, protect through the rare hydroxyl to oxime position of 2-ethoxy-c again, with trimethylchlorosilane, to 2 ' position and 4, " hydroxyl of position is protected simultaneously, and then in a kind of mixed solvent being formed by superpower solvents such as the fat-soluble solvent such as ethers or aromatic hydrocarbons and dimethyl sulfoxide (DMSO), under the catalysis of sodium hydroxide or potassium hydroxide and methyl iodide, the reaction of the methylating reagent such as monobromethane or methyl tosylate, the hydroxyl of realizing 6 is methylated, again the first compound obtaining is after treatment added to the water and adds acetic acid and sodium bisulfite simultaneously, add again ethanol solubilising to be then warmed up to 60～70 ℃ of insulation reaction, slough ethoxycarbonyl propyl and trimethyl silane obtains clarithromycin by being hydrolyzed and reducing simultaneously.Reaction process is as shown in the formula (I):
（I）
Methylating of oxime etherificate silane compound is an exhausted water reaction, all uses a kind of mixed solvent: in U.S. Pat 0010128, use the mixed solvent of toluene and dimethyl sulfoxide (DMSO), take methyl iodide as methylating reagent in patent in the past; In U.S. Pat 0280230, use the mixed solvent of tetrahydrofuran (THF) and dimethyl sulfoxide (DMSO), take methyl-sulfate as methylating reagent; In Chinese patent CA102268053, with the mixed solvent of toluene and dimethyl sulfoxide (DMSO), obtain better effects take monobromethane as methylating reagent; The analogy sword soldier of Zhejiang University in 2009, with the mixed solvent of methyl tertiary butyl ether and dimethyl sulfoxide (DMSO), obtains better effects take monobromethane as methylating reagent.The 4-6 that the usage quantity of dimethyl sulfoxide (DMSO) is generally erythromycin oxime in above patent and document doubly, and dimethyl sulfoxide (DMSO) boiling point is higher 189 ℃, have water absorbability can miscible with water, stablely not easily form the character such as superoxide or self-decomposition, even in the time of Distillation recovery, blast, dimethyl sulfoxide (DMSO) is reclaimed more difficult as anhydrous solvent, dimethyl sulfoxide (DMSO) is sulfur-bearing solvent again, and environmental pollution is larger.So make the production of clarithromycin occur the series of problems such as safety, environmental protection, moisture controlled, cost control in the problem of selective methylation.And then limit a large amount of production of clarithromycin and generally applied.
Summary of the invention
(1) goal of the invention: object of the present invention be exactly for provide a kind of by with single or mixing compared with the solvent of lower boiling and water-insoluble or low water solubility, in the case of adding a small amount of phase-transfer catalyst, oxime etherificate silane compound is carried out to the method for selective methylation, in the method, save the application of dimethyl sulfoxide (DMSO), convenient solvent reclaiming, selectivity is good, yield is higher, safety and environmental protection, is applicable to the production of clarithromycin.
(2) technical scheme: in the middle of a kind of clarithromycin of the present invention, first the preparation method of first compound protects 2 ' position and 4 " hydroxyl of position after by conventional method through etherification protection oxime hydroxyl and silanization with erythromycin oxime, dissolve in one or more non-proton, in the water miscible polar solvent in the water-insoluble or end, between 15-20 ℃, add quantitative methylating reagent and phase-transfer catalyst, after continuing to stir, keep temperature, add gradually quantitative powdery alkali metal hydroxides, rear stirring 1 hour, stirring layering adds water, separate water, water solubilizing agent is counter to be carried, merge organic phase, add and reclaim solvent after water washing and obtain first compound in the middle of clarithromycin.Recovered solvent rectifying after molecular sieve or solid caustic soda are dry obtains qualified solvent, continues on for methylation reaction.Divide water-yielding stratum because there is no more organism, after simple process, directly go wastewater treatment.It is low that this technique is convenient to solvent recuperation, safety, environmental protection, the good cost of quality, can be used for suitability for industrialized production.
Lower mask body association reaction condition, material proportion, working method, describe the concrete application of the present invention in clarithromycin is synthetic in detail by following 4 key steps.
The first step: prepare oxime etherificate silane compound
Under normal pressure, in reactor after nitrogen replacement, add a certain amount of dry erythromycin oxime to add again the methylene dichloride of its 5 times of amounts, the pyridine hydrochloride of its 25%-30%, stirring and dissolving is to clear, cool to 10-15 ℃, add the 2-ethoxy propylene of its 35%-40%, stirring reaction 0.5-1 lab scale, then cool to 0-5 ℃, add the imidazoles of its 35%-40%, keep 0-5 ℃ of trimethylchlorosilane that drips its 45%-50%, add rear stirring 10-30 minute, add the water of its 3 times of volumes, with 30% liquid caustic soda regulate pH value to 9.5-10, rear stratification, water layer counter the carrying that add methylene chloride, combined dichloromethane layer, add water respectively, salt water washing, post-heating is concentrated, after flowing out without methylene dichloride, band vacuum pumps residual dichloromethane and residual water-content.Just obtain oxime etherificate silane compound.
Second step: selective methylation
To in the oxime etherificate silane compound of previous step gained, add the methyl tertiary butyl ether of 5 times of amounts of red oxime and the mixed solvent of methyltetrahydrofuran 1:1, stirring and dissolving is to resetting and adding into 20% monobromethane of erythromycin oxime and 0.5% trimethylammonium normal-butyl chlorination ammonium, cool to 10-15 ℃, add gradually 11% potassium hydroxide sodium mixed base of erythromycin oxime, do not make overtemperature, add rear stirring reaction 0.5-1 hour methylation reaction complete, add the salinity that water washing generates, after counter the carrying of water layer methylate tertbutyl ether, go wastewater treatment, there is which floor heating concentration and recovery solvent, residual solvent pumps by vacuum.
The 3rd step: deprotection
By the middle first compound of previous step gained under continuous stirring state, add the ethanol of 4 times of amounts of erythromycin oxime and 22% acetic acid, after dissolving, add water and its 60% sodium bisulfite of 3 times of amounts of erythromycin oxime, slowly be heated to 60-70 ℃ of insulation reaction and after 3 hours, cool to 50 ℃, maintain to stir and add 10% liquid caustic soda adjusting PH9.5-10, there are a large amount of solids to separate out, after filtration, add water washing and obtain clarithromycin crude product.
The 4th step: solvent reclaims
The mixed solvent of second step heating recovery is divided to the sheet alkali that adds its total amount 10% after water purification, be warmed up to 55 ℃ of stirring and refluxing reactions 2 hours, separate while hot lower floor's buck, then change fractionation plant, after moisture in still is qualified, directly just locate mixed solvent, after allotment ratio after testing, continuing to be applied to methylation reaction.
(3) technique effect:
The invention has the advantages that, with single or mix compared with the solvent of lower boiling and water-insoluble or low water solubility, in the case of adding aliphatic quaternary ammonium hydroxide that a small amount of toxicity is less or quaternary ammonium salt as phase-transfer catalyst, oxime etherificate silane compound is carried out to selective methylation, in the method, save the application of dimethyl sulfoxide (DMSO), convenient solvent reclaiming, selectivity is good, yield is higher, and safety and environmental protection is applicable to the suitability for industrialized production of clarithromycin.Be embodied in several respects.
1. the present invention's oxime etherificate silanization raw material used is suitable for but is not limited only to by ethoxy propylene protection oxime hydroxyl and trimethylchlorosilane protection 2 ' position and 4 " ordinary method of position hydroxyl.
2. the present invention selects the aliphatic quaternary ammonium hydroxide of aliphatics or quaternary ammonium salt as phase-transfer catalyst, and toxicity is little, effective.
The present invention use single or mix compared with the solvent of lower boiling and water-insoluble or low water solubility, the application of having saved dimethyl sulfoxide (DMSO), is adding after water stratification, solvent easily reclaims, waste water is easily processed.
4. the present invention uses the Powdered highly basic of potassium hydroxide and sodium hydroxide melting mixing, reacting balance, effective, and reaction product is water-soluble large, water saving.
5. advantage of the present invention is also embodied in due to the common use to above each optimizing process, makes the selective methylation synthesis technique of this oxime etherificate silane compound be very suitable for suitability for industrialized production, and can make cost by low.
Four, the specific embodiment of the invention is as follows:
Under normal temperature and pressure, in 500ml four-hole boiling flask after nitrogen replacement, add 39g oxime etherificate silane compound (erythromycin oxime of 30g content 96.2% is synthetic), add 140mL2-methyltetrahydrofuran and 140mL methyl tertiary butyl ether, stirring and dissolving, sampling is surveyed moisture below 0.1%, add 0.16g trimethylammonium normal-butyl chlorination ammonium and the 20mL solution containing monobromethane 5.7g, stirring cools to 10-15 ℃, by osculum glass funnel under nitrogen protection, in 0.5 hour, add several times 3.6g potassium hydroxide sodium mixed base to keep 10-15 ℃ simultaneously, add rear holding temperature stirring reaction 0.5 hour.After add water 50mL stir after layering, and then with each 30mL water washing 3 times, combining water layer is carried 2 times so that each 30mL methyl tertiary butyl ether is counter.Which floor is associated with, in 500ml four-hole boiling flask, reclaim solvent with 80 ℃ of water-bath distillations, last vacuum is drawn dry solvent, obtain first compound 39.6g and then add the first compound that under 95% ethanol 120mL and the disconnected stirring state of acetic acid 6.5g, dissolving obtains, after dissolving, add 90mL water and 18g sodium bisulfite, be heated to 60-70 ℃ of insulation reaction and after 3 hours, cool to 50 ℃, maintain to stir and add 10% liquid caustic soda 85mL adjusting PH9.5-10, there are a large amount of solids to separate out, after filtration, add water washing, be dried to obtain clarithromycin crude product 29g(content 81.5%, from erythromycin oxime meter molar yield 82%).
The mixed solvent 265mL that heating in water bath is reclaimed proceeds in 500mL separating funnel, after dividing water purification, be added in 500mL flask, add 25g sheet alkali, be warmed up to 55 ℃ of stirring and refluxing reactions 2 hours, leave standstill and after 30 minutes, use while hot glass pipette sucking-off lower floor buck, then change fractionation plant, purify and dewater again by water trap, in flask sampling analysis moisture below 0.1% after, straight run distillation goes out mixed solvent 250mL(moisture 0.7%, 2-methyltetrahydrofuran 53.2%).
Claims (8)
1. in the middle of a clarithromycin, the preparation method of first compound is characterized in that first protecting 2 ' position and 4 " hydroxyl of position after by conventional method through etherification protection oxime hydroxyl with silanization with erythromycin oxime, dissolve in one or more non-proton, in the water miscible polar solvent in the water-insoluble or end, then add quantitative methylating reagent and phase-transfer catalyst, after continuing to stir, keep certain temperature, add gradually quantitative Powdered highly basic, rear stirring 1 hour, stirring layering adds water, separate water, water solubilizing agent is counter to be carried, merge organic phase, add and reclaim solvent after water washing and obtain first compound in the middle of clarithromycin, this technique is convenient to solvent recuperation, safety and environmental protection, the good cost of quality is low, can be used for suitability for industrialized production.
2. the preparation method of the middle first compound of clarithromycin is characterized in that including but are not limited to as the water miscible polar solvent of the non-proton, water-insoluble of solvent or the end mixture of one or more solvents wherein such as 2-methyltetrahydrofuran, ether, isopropyl ether, n-butyl ether, methyl tertiary butyl ether.
3. in the middle of a clarithromycin, the preparation method of first compound is characterized in that as the reagent of phase-transfer catalyst be quaternary ammonium hydroxide or quaternary ammonium salt, include but are not limited to the quaternary ammonium hydroxides such as Tetramethylammonium hydroxide, tetraethyl ammonium hydroxide, trimethylammonium normal-butyl ammonium hydroxide, trimethyldodecane base ammonium hydroxide, and their hydrochloride, vitriol etc., wherein preferred trimethylammonium normal-butyl ammonium hydroxide.
4. it is characterized in that according to the preparation method of first compound in the middle of a kind of clarithromycin described in claim 1 and 3 phase-transfer catalyst used is their anhydride or contains 1 to 5 crystal water, wherein preferred anhydride.
5. in the middle of a kind of clarithromycin according to claim 1, the preparation method of first compound is characterized in that the amount of phase-transfer catalyst used is to drop into the 1-10% of the mole number of erythromycin oxime, wherein preferably 2.5%.
6. in the middle of a kind of clarithromycin according to claim 1, the preparation method of first compound is characterized in that methylation reaction temperature is 5～35 ℃, wherein preferably 15～20 ℃.
7. in the middle of a kind of clarithromycin according to claim 1, the preparation method of first compound is characterized in that methylating reagent used is methyl iodide, monobromethane, methyl-sulfate or methyl tosylate etc., wherein preferred monobromethane.
8. in the middle of a kind of clarithromycin according to claim 1, the preparation method of first compound is characterized in that Powdered highly basic used is potassium hydroxide, sodium hydroxide or potassium hydroxide sodium mixed base etc., wherein preferred potassium hydroxide sodium mixed base.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106905204A (en) * | 2017-02-24 | 2017-06-30 | 杭州新桂实业有限公司 | A kind of recovery method of methylation reaction solvent in CLA building-up process |
| CN116239644A (en) * | 2023-01-09 | 2023-06-09 | 浙江国邦药业有限公司 | Recycling method of protective reaction auxiliary materials on clarithromycin |
Citations (6)
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| JPH0276893A (en) * | 1988-06-15 | 1990-03-16 | Taisho Pharmaceut Co Ltd | Erythromycin-a derivative and production thereof |
| EP0272110B1 (en) * | 1986-12-17 | 1993-04-07 | Taisho Pharmaceutical Co. Ltd | Erythromycin a derivatives and method for the preparation of the same |
| CN1318548A (en) * | 2000-04-14 | 2001-10-24 | 山东新华制药股份有限公司 | Preparation of clarithromycin |
| US6617436B2 (en) * | 2000-02-29 | 2003-09-09 | Teva Pharmaceutical Industries Ltd. | Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same |
| CN102250173A (en) * | 2010-05-18 | 2011-11-23 | 上海医药工业研究院 | Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin |
| CN102718821A (en) * | 2012-06-27 | 2012-10-10 | 浙江国邦药业有限公司 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
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2012
- 2012-12-23 CN CN201210565618.3A patent/CN103880901A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0272110B1 (en) * | 1986-12-17 | 1993-04-07 | Taisho Pharmaceutical Co. Ltd | Erythromycin a derivatives and method for the preparation of the same |
| JPH0276893A (en) * | 1988-06-15 | 1990-03-16 | Taisho Pharmaceut Co Ltd | Erythromycin-a derivative and production thereof |
| US6617436B2 (en) * | 2000-02-29 | 2003-09-09 | Teva Pharmaceutical Industries Ltd. | Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same |
| CN1318548A (en) * | 2000-04-14 | 2001-10-24 | 山东新华制药股份有限公司 | Preparation of clarithromycin |
| CN102250173A (en) * | 2010-05-18 | 2011-11-23 | 上海医药工业研究院 | Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin |
| CN102718821A (en) * | 2012-06-27 | 2012-10-10 | 浙江国邦药业有限公司 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
Non-Patent Citations (3)
| Title |
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| ERNESTO BRUNET ET AL.: "preparation of clarithromycin.selective 6-O-methyllation of the novel erythromycin A 9-O-(2-pyrimidyl)oxime", 《TETRAHEDRON LETTERS》 * |
| 刘增勋: "《相转移催化剂在有机化学和农药合成中的应用》", 31 December 1987 * |
| 梁建华等: "克拉霉素的合成新方法", 《有机化学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106905204A (en) * | 2017-02-24 | 2017-06-30 | 杭州新桂实业有限公司 | A kind of recovery method of methylation reaction solvent in CLA building-up process |
| CN116239644A (en) * | 2023-01-09 | 2023-06-09 | 浙江国邦药业有限公司 | Recycling method of protective reaction auxiliary materials on clarithromycin |
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Application publication date: 20140625 |