CN102268053A - Preparation method of clarithromycin - Google Patents
Preparation method of clarithromycin Download PDFInfo
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- CN102268053A CN102268053A CN2011102557143A CN201110255714A CN102268053A CN 102268053 A CN102268053 A CN 102268053A CN 2011102557143 A CN2011102557143 A CN 2011102557143A CN 201110255714 A CN201110255714 A CN 201110255714A CN 102268053 A CN102268053 A CN 102268053A
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Abstract
The invention provides a new method for preparing clarithromycin by using a (2',4''-O-bis-trimethylsilyl)-erythromycin A-9[O-(1-ethoxy-1-methyl-ethyl)] oxime compound, and the method comprises the following two steps: A, carrying out methylation reaction; and B, carrying out one-step protecting group removal and deoximation reaction of the methylated product obtained in the step A at a certain temperature. The method has the advantages that: methyl bromide is used in the methylation reaction, the reaction temperature is low, the methylation selectivity is better, post-treatment is simple, less three wastes are generated and the cost is significantly reduced; the method is more suitable for industrial production; and acetic acid is used during the deprotection process, the acidity is weak and less by-products are generated.
Description
Technical field:
The present invention relates to a kind of by (2 ', 4 "-O-is two trimethyl silicon based)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl)] oxime compound prepares the novel process of clarithromycin.
Background technology:
Clarithromycin (having another name called clarithromycin) is a new erythromycin derivatives that makes behind 6 HMs of erythromycin.Because C
6After the hydroxyl etherificate of position, stoped the living intramolecularly ring-closure reaction generation of erythromycin environment-development erythromycin 8 under the acidic conditions, 9-dehydration-6,9-hemiketal inactivation product, thus improved anti-microbial activity.Clarithromycin is used for the treatment of upper respiratory tract infection and lower respiratory infection and skin soft-tissue infection etc., and the strong 2-4 of specific activity erythromycin times, toxicity has only the 1/2-1/24 of erythromycin.
United States Patent (USP) 4331803 carries out 6 HMs reactions after having reported dimethylin protection to 2 ' hydroxyl on the Erythromycin A and 3 ', behind the deprotection clarithromycin.Because on the Erythromycin A 11,12 and 4 " methylation reaction also easily takes place in position simultaneously, thus there is more by product to generate, influence quality product and yield.
U.S. Pat 0010128 was reported the method for 6 hydroxyl selective methylations of a kind of erythromycin, is in the mixed solvent of toluene and DMSO, makes methylating reagent with methyl iodide, 5-8 ℃ of reaction 2 hours.This technology methylation reaction time is long, easily produces by product, and the use of methyl iodide makes cost higher.
U.S. Pat 0280230 has been reported a kind of synthetic method of clarithromycin, and the methylating reagent of making 6 hydroxyls with methyl-sulfate carries out methylation reaction, gets clarithromycin behind the deprotection base.Methyl-sulfate toxicity is big in this technology, operational difficulty; The time of deprotection is long, influences the yield and the quality of product, and aftertreatment need extract with methylene dichloride, and post-processing step is many, easily produces " three wastes ", and the cost height is unsuitable for suitability for industrialized production.
The preparation method that U.S. Pat 4990602 has been reported a kind of clarithromycin makes methylating reagent with methyl iodide, and reaction times 100min carries out deprotection reaction again and gets clarithromycin.This technology methylation reaction time is long, easily produces by product; The aftertreatment of methylation reaction need be multiple extraction with ethyl acetate, and aftertreatment is loaded down with trivial details, and the cost height is unsuitable for suitability for industrialized production.
European patent EP 0272110 discloses a kind of method of effectively synthetic clarithromycin, makes the methylating reagent of 6 hydroxyls of erythromycin with methyl iodide, and reaction obtains methide, behind deprotection base and the de-oxime reaction, obtains the clarithromycin finished product through ethyl alcohol recrystallization.Also there is the high shortcoming of production cost in this technology, and simultaneously, the acidity of formic acid is stronger, has by product and generate in the high temperature deprotection reaction.
U.S. Pat 0280230 has been reported with (2 '; 4 "-O-is two trimethyl silicon based)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl)] oxime compound makes the protection thing and reacts with methyl-sulfate in THF and DMSO, react 1h under the room temperature, deprotection reaction uses formic acid, need backflow 8h to obtain clarithromycin, this technology is used tetrahydrofuran (THF), and cost recovery is higher, while methylation reaction temperature height, by product is difficult for suppressing; The use of formic acid makes that also byproduct of reaction is more in the deprotection reaction.
U.S. Pat 6617436 has been reported with (2 ', 4 "-O-is two trimethyl silicon based)-Erythromycin A-9[O-(1-methoxyl group-1-methylethyl)] oxime compound for the protection thing in mixed solvent MTBE and DMSO with iodomethane reaction, carry out deprotection again.Though this technology has been avoided the use of solvents tetrahydrofurane, the toxicity of methyl iodide and higher cost also make this technology be unsuitable for suitability for industrialized production.
Summary of the invention:
The purpose of this invention is to provide-kind of technology is simple, yield is high, cost is low, pollution is little, good product quality, be suitable for the production method of the clarithromycin of suitability for industrialized production, the present invention includes two step: A, earlier will (2 ', 4 " O-is two trimethyl silicon based)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl)] oxime compound (I) carries out methylation reaction and obtains methide (II); B, more above-mentioned methide (II) a step is finished the deprotection base, de-oxime reaction gets clarithromycin (III), reaction formula is:
The methylation reaction of A step can be following reaction: with toluene and dimethyl sulfoxide (DMSO) is mixed solvent, Compound I and the reaction of methylating reagent monobromethane, potassium hydroxide is made catalyzer, after finishing, reaction adds the shrend reaction of going out, add extracting and demixing behind the toluene, get methide (II) through concentrating under reduced pressure.
In the A step reaction, the mol ratio of reactant is: Compound I: monobromethane: potassium hydroxide=1: (I.0-3.0): (1.0-3.0), the time of methylation reaction is 15-120 minute, and temperature of reaction is 0-15 ℃.
In the A step reaction, the concentration of Compound I in solvent should be controlled at (0.05-0.08) mol/L.
The B step is with alcoholic solvent and water as solvent, and methide and acetate and sodium bisulfite reaction get clarithromycin (III).
The mol ratio of B step reaction thing is a methide: acetate: sodium bisulfite=1: (5-12): (5-12).
B step reaction, temperature of reaction are 50-80 ℃, and the reaction times is 1-6 hour.
The B step reaction is reduced to room temperature after finishing, and transfers alkali to 10-11 with sodium hydroxide solution, separates out crystallization.
Than previous technology, technology of the present invention has following advantage: (1) makes methylating reagent with monobromethane, cost reduces greatly, and avoided the use of violent in toxicity methyl iodide, the time that methylates is short, and temperature is low, avoided shortcoming because of the more generation of long reaction time by product, and aftertreatment is simple, and " three wastes " are few, are more suitable in suitability for industrialized production.(2) the protection thing reacts with monobromethane in toluene and DMSO, and under finite concentration, reaction preference is better.(3) carry out deprotection reaction with acetate, avoided acid shortcoming of forcing product to decompose, and with the deprotection base, " treating different things alike " reaction is carried out in the reduction of oxime, has reduced operation steps and cycle, and cost is reduced, " three wastes " still less are 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 one:
In being housed, the 1000ml there-necked flask of agitator and thermometer adds 150ml toluene, under the stirring at room with 22.5g (2 ', 4 " 0-is two trimethyl silicon based)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl)] oxime compound drops in the reaction flask; moltenly add the 150ml dimethyl sulfoxide (DMSO) after clear; be cooled to below 15 ℃; add the toluene solution and the 1.5g potassium hydroxide powder of the monobromethane of 2.75g (pure) 20%-50%; under the vigorous stirring behind the reaction 15min; add 150ml water, add the toluene of 150ml again, stir 10min layering in separating funnel, the upper toluene layer gets 2 of 22.5g ', 4 after concentrating " two (trimethyl silicon based-the 6-O-methyl)-Erythromycin A-9[O-(1-oxyethyl group-1-first and second bases) of O-] oxime.
Again agitator is being housed, add 2 of the above-mentioned 22.5g that makes ' in the 500ml there-necked flask of spherical condensation tube and thermometer, 4 " two (trimethyl silicon based-the 6-O-methyl)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl) of O-] oxime and 115ml ethanol and 115ml water; 10g anhydrous acetic acid and 21g sodium bisulfite; in 75 ℃ of reactions 2 hours; reduce to room temperature; the sodium hydroxide solution of Dropwise 5 % to PH be 10-11; drip finish after crystallization 1h, filter, the washing filter cake is to filtrate PH=7, drying is after get 11.0g clarithromycin, yield 64.97%, content＞95% behind the ethyl alcohol recrystallization.
Embodiment two:
In being housed, the 1000ml there-necked flask of agitator and thermometer adds 200ml toluene, under the stirring at room with 22.5g (2 ', 4 " O-is two trimethyl silicon based)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl)] oxime compound drops in the reaction flask; moltenly add the 200ml dimethyl sulfoxide (DMSO) after clear; be cooled to below 15 ℃; add the toluene solution and the 1.5g potassium hydroxide powder of the monobromethane of 2.75g (pure) 20%-50%; under the vigorous stirring behind the reaction 15min; add 200ml water, add the toluene of 200ml again, stir 10min layering in separating funnel, the upper toluene layer gets 2 of 23.0g ', 4 after concentrating " two (trimethyl silicon based-the 6-O-methyl)-Erythromycin A-9[O-(1-oxyethyl group-1-first and second bases) of O-] oxime.
Again agitator is being housed, add 2 of the above-mentioned 23.0g that makes ' in the 500ml there-necked flask of spherical condensation tube and thermometer, 4 " two (trimethyl silicon based-the 6-O-methyl)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl) of O-] oxime and 115ml ethanol and 115ml water; 10g anhydrous acetic acid and 21g sodium bisulfite; in 75 ℃ of reactions 2 hours; reduce to room temperature; the sodium hydroxide solution of Dropwise 5 % to PH be 10-11; drip finish after crystallization 1h, filter, the washing filter cake is to filtrate PH=7, drying is after get 11.5g clarithromycin, yield 67.93%, content＞95% behind the ethyl alcohol recrystallization.
Embodiment three:
In being housed, the 1000ml there-necked flask of agitator and thermometer adds 150ml toluene, under the stirring at room with 22.5g (2 ', 4 " O-is two trimethyl silicon based)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl)] oxime compound drops in the reaction flask; moltenly add the 150ml dimethyl sulfoxide (DMSO) after clear; be cooled to below 15 ℃; add the toluene solution and the 1.6g potassium hydroxide powder of the monobromethane of 3.0g (pure) 20%-50%; under the vigorous stirring behind the reaction 15min; add 150ml water, add the toluene of 150ml again, stir 10min layering in separating funnel, the upper toluene layer gets 2 of 22.5g ', 4 after concentrating " two (trimethyl silicon based-the 6-O-methyl)-Erythromycin A-9[O-(1-oxyethyl group-1-first and second bases) of O-] oxime.
Again agitator is being housed, add 2 of the above-mentioned 22.5g that makes ' in the 500ml there-necked flask of spherical condensation tube and thermometer, 4 " two (trimethyl silicon based-the 6-O-methyl)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl) of O-] oxime and 115ml ethanol and 115ml water; 10g anhydrous acetic acid and 21g sodium bisulfite; in 75 ℃ of reactions 2 hours; reduce to room temperature; the sodium hydroxide solution of Dropwise 5 % to PH be 10-11; drip finish after crystallization 1h, filter, the washing filter cake is to filtrate PH=7, drying is after get 12.0g clarithromycin, yield 70.88%, content＞95% behind the ethyl alcohol recrystallization.
Embodiment four:
In being housed, the 1000ml there-necked flask of agitator and thermometer adds 150ml toluene, under the stirring at room with 22.5g (2 ', 4 " O-is two trimethyl silicon based)-red mould rope A-9[O-(1-oxyethyl group-1-methylethyl)] oxime compound drops in the reaction flask; moltenly add the 150ml dimethyl sulfoxide (DMSO) after clear; be cooled to below 15 ℃; add the toluene solution and the 1.6g potassium hydroxide powder of the monobromethane of 3.0g (pure) 20%-50%; under the vigorous stirring behind the reaction 15min; add 150ml water, add the toluene of 150ml again, stir 10min layering in separating funnel, the upper toluene layer gets 2 of 22.5g ', 4 after concentrating " two (trimethyl silicon based-the 6-O-methyl)-Erythromycin A-9[O-(1-oxyethyl group-1-first and second bases) of O-] oxime.
Again agitator is being housed, add 2 of the above-mentioned 22.5g that makes ' in the 500ml there-necked flask of spherical condensation tube and thermometer, 4 " two (trimethyl silicon based-the 6-O-methyl)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl) of O-] oxime and 115ml methyl alcohol and 115ml water; 10g anhydrous acetic acid and 21g sodium bisulfite; in 75 ℃ of reactions 2 hours; reduce to room temperature; the sodium hydroxide solution of Dropwise 5 % to PH be 10-11; drip finish after crystallization 1h, filter, the washing filter cake is to filtrate PH=7, drying is after get 12.0g clarithromycin, yield 69.93%, content＞95% behind the ethyl alcohol recrystallization.
Claims (11)
1. a kind of preparation method of clarithromycin, this method comprises two steps:
A, earlier will (2 ', 4 " O-is two trimethyl silicon based)-Erythromycin A-9[O-(1-oxyethyl group-1-methylethyl)] oxime compound (hereinafter to be referred as the I compound) carries out methylation reaction;
B, the methide that more above-mentioned methylation reaction is obtained carry out deprotection reaction.
2. method according to claim 1 is characterized in that: the methylation reaction of A step is to carry out under toluene and dimethyl sulfoxide (DMSO) are made the condition of solvent.
3. method according to claim 1 is characterized in that: the methylation reaction of A step is to make catalyzer at potassium hydroxide, makes methylating reagent with monobromethane, carries out methylation reaction.
4. method according to claim 3 is characterized in that: the time of methylation reaction is 15-120 minute, and temperature of reaction is 0-15 ℃.
5. method according to claim 3 is characterized in that: methylation reaction uses the toluene solution of monobromethane, and concentration is 30%-50%.
6. method according to claim 2 is characterized in that: the concentration of I compound in solvent is (0.05-0.08) mol/L.
7. according to the described method of claim 1, it is characterized in that: the B step is in the presence of alcoholic solvent and water, methide and acetate and sodium bisulfite reaction.
8. method according to claim 1 is characterized in that: the reaction times of B step is 1-6 hour, and temperature of reaction is 50-80 ℃.
9. method according to claim 3 is characterized in that: the mol ratio of reactant is: I compound: monobromethane: potassium hydroxide=1: (1.0-3.0): (1.0-3.0).
10. method according to claim 1 is characterized in that: the mole proportioning of deprotection reaction is in the B step: methide: acetate: sodium bisulfite=1: (5-12): (5-12).
11. method according to claim 7 is characterized in that: alcoholic solvent can be methyl alcohol or ethanol.
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| CN2011102557143A CN102268053A (en) | 2011-09-01 | 2011-09-01 | Preparation method of clarithromycin |
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| CN2011102557143A CN102268053A (en) | 2011-09-01 | 2011-09-01 | Preparation method of clarithromycin |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102417532A (en) * | 2011-12-20 | 2012-04-18 | 浙江国邦药业有限公司 | Method for synthesizing telithromycin key intermediate 5-deoaminyl-6-O-methylerythromycin |
| CN103992346A (en) * | 2014-05-12 | 2014-08-20 | 浙江贝得药业有限公司 | Preparation method for Clarithromycin intermediate |
| 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 |
-
2011
- 2011-09-01 CN CN2011102557143A patent/CN102268053A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102417532A (en) * | 2011-12-20 | 2012-04-18 | 浙江国邦药业有限公司 | Method for synthesizing telithromycin key intermediate 5-deoaminyl-6-O-methylerythromycin |
| CN103992346A (en) * | 2014-05-12 | 2014-08-20 | 浙江贝得药业有限公司 | Preparation method for Clarithromycin intermediate |
| 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 |
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Application publication date: 20111207 |