CN101168553A - Method for purifying 3-hydroxyclarithromycin - Google Patents
Method for purifying 3-hydroxyclarithromycin Download PDFInfo
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- CN101168553A CN101168553A CNA2007101784618A CN200710178461A CN101168553A CN 101168553 A CN101168553 A CN 101168553A CN A2007101784618 A CNA2007101784618 A CN A2007101784618A CN 200710178461 A CN200710178461 A CN 200710178461A CN 101168553 A CN101168553 A CN 101168553A
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Abstract
The invention relates to a novel purity method for 3-hydroxy clarithromycin, and belongs to the synthesis field of pharmaceutical intermediate. The 3-hydroxy clarithromycin can be gained by adopting clarithromycin as the raw material through acid hydrolysis. Through the analysis and the comparison to the physico-chemical properties of the principal product and the by product, the 3-hydroxy clarithromycin is purified by respectively adopting a one-time sedimentation method, a two-time sedimentation method, and a purge method. The invention has the advantages that a synthetic route of clarithromycin with simple operation, high productivity, and low cost is provided, the reaction time of the synthetic route is short, the product productivity is high, the subsequent process is simple and easy to be operated, and the productive efficiency of ketolide antibiotics can be greatly improved.
Description
Technical field
The present invention relates to a kind of purification process of new 3-hydroxyl clarithromycin.Obtain 3-hydroxyl clarithromycin with the clarithromycin for the raw material salt acid hydrolysis.By relatively, adopt primary sedimentation method, twice precipitator method and washing method purifying 3-hydroxyl clarithromycin respectively to the analysis of the physico-chemical property of principal product and by product.The synthetic field that belongs to pharmaceutical intermediate.
Background technology
Ketone lactone microbiotic has broad spectrum antibiotic activity and lower selection resistance, and with the cross resistance of other macrolide antibiotics, particularly common pathogenic organisms of respiratory tract is had strong active.Ketek successfully goes on the market as the ketone lactone microbiotic of first clinical application, but owing to reasons such as its complex manufacturing, productive rate are lower, causes existing market price very high, also is not used widely.The antibiotic production major part of ketone lactone is, and to be raw material with the clarithromycin make through hydrolysis, protection, oxidation and 11,12 s' formylation.And 3-hydroxyl clarithromycin is the antibiotic important intermediate of ketone lactone.The preparation and the purifying process complexity of 3-hydroxyl clarithromycin are one of higher reasons of ketone lactone microbiotic price at present.The hydrolysis clarithromycin all is hydrolysis under methyl alcohol/hydrochloric acid or the ethanol/hydrochloric acid normal temperature condition at present, and reaction formula is
But this method for hydrolysis productive rate is low and easily generate by product:
Especially the purifying of 3-hydroxyl clarithromycin is adopted ethyl acetate extraction, not only productive rate can reduce greatly and also ethyl acetate to by product also slightly soluble, can not obtain very pure hydrolysate.
Summary of the invention
The objective of the invention is to adopt three kinds of different purification process to obtain highly purified 3-hydroxyl clarithromycin.This route reaction time is short, the product yield height, and aftertreatment is simple to operation, can improve the antibiotic production efficiency of ketone lactone greatly.
For achieving the above object, the present invention adopts acid hydrolysis method to realize the hydrolysis reaction of clarithromycin.
The acid of being adopted comprises: hydrochloric acid, acetate, formic acid, Phenylsulfonic acid, sulfurous acid, dilute sulphuric acids etc. are taken all factors into consideration reaction effect and economic factors, with hydrochloric acid as H is provided
+With clarithromycin salify best results.
The present invention takes methyl alcohol, ethanol, and water, methanol, ethanol/waters etc. are as nucleophilic reagent.What the clarithromycin main ring was connected with cladinose is ehter bond, and H+ and clarithromycin salify under acidic conditions, methyl alcohol, ethanol, water methanol/water, ethanol/water etc. be as the central carbon atom of nucleophilic reagent attack substrate, thereby impels the cladinose hydrolysis.But with methyl alcohol, ethanol, methanol, ethanol/waters etc. are easy to generate by product as nucleophilic reagent, and productive rate is low, so water is as the nucleophilic reagent best results.
The pH value that reaction process of the present invention adopts is 1-7, takes all factors into consideration reaction effect, and the pH value of recommendation response process is 3.
Of the present inventionly be reflected between 10-40 ℃ reaction, temperature begins reaction when low slower, thus at the beginning the time can temperature transfer suitably higher.But temperature should not surpass 40 ℃, the too high easy generation by product of temperature.
Reaction times of the present invention carries out between 60min-180min, and temperature of reaction needs the long reaction times when low.
Twice precipitator method, primary sedimentation method, washing method are adopted in aftertreatment of the present invention respectively.
(1) twice precipitator method
Be transferred to pH=7 and pH=9 respectively.PH value=7 o'clock have a small amount of flocks generate, and organic solvent extraction is collected the aqueous solution, and water transfer solution is to pH=9, with organic solvent extraction.Organic solvent is used saturated aqueous common salt respectively, saturated Repone K, and saturated sodium bicarbonate, the washing of inorganic salts saturated solutions such as saturated potassium hydrogen carbonate, last underpressure distillation, recrystallization obtain white needle-like crystals.Temperature of reaction is 20-50 ℃, and the reaction times is 3-5h.The product purity that this method was handled is very high.
Aftertreatment of the present invention adopts organic extractant to comprise water-insoluble organic solvents such as ethyl acetate, methylene dichloride, normal hexane, normal heptane, trichloromethane and ether etc.
(2) primary sedimentation method
Transfer treatment solution to pH value 〉=9, separate out a large amount of precipitations, filter, use saturated aqueous common salt, saturated Repone K, saturated sodium bicarbonate, the washing of inorganic salts saturated solutions such as saturated potassium hydrogen carbonate, recrystallization obtains white needle-like crystals.This last handling process is simple, the yield height, and purity satisfies next step reaction.
Aftertreatment adjust pH of the present invention adopts ammoniacal liquor, anhydrous sodium carbonate, and anhydrous sodium bicarbonate, pyridine, dimethyl formamide (DMF) etc. are regulated treatment solution pH value.
(3) washing method
Precipitating the product that obtains for the first time, adopt distilled water/normal hexane or distilled water/normal heptane washing.Vacuum-drying obtains white solid.This last handling process has been avoided recrystallization, and is simple to operate, and the product purity that obtains satisfies next step reaction.
The solvent that the primary sedimentation after scouring adopts comprises: distilled water, normal heptane, normal hexane, sherwood oil, water-insoluble organic solvents such as ether.
Beneficial effect of the present invention: the present invention contrasts prior art, has the reaction times weak point, the productive rate height, and last handling process is simple, and the purity height is applicable to suitability for industrialized production.
Embodiment
The invention will be further described below in conjunction with embodiment.
Embodiment 1
3g clarithromycin, 80ml water and 2.4m138% concentrated hydrochloric acid, 25 ℃ are stirred 120min; Dropping ammonia adjust pH to 9.0, it is saturated to solution to add sodium-chlor, 30ml * 3 ethyl acetate extractions: saturated common salt water washing; Suction filtration, underpressure distillation; At acetone/sherwood oil system recrystallization; Filter, oven dry obtains white needle-like crystals 2.12g (productive rate 89.7%, purity 95%) at last
Embodiment 2
38% concentrated hydrochloric acid of 3g clarithromycin, 80ml water and 2.4ml, 25 ℃ are stirred 120min; Dropping ammonia adjust pH to 9.0, the adularescent flocks is separated out; It is saturated to solution to add sodium-chlor, and precipitation is separated out; Suction filtration, the saturated aqueous common salt washing leaching cake; Oven dry filter cake, acetic acid ethyl dissolution, suction filtration, anhydrous magnesium sulfate drying 12h; Underpressure distillation, 40 ℃ of oven dry obtain white needle-like crystals 1.87g (productive rate 79.0%, purity 96.5%)
Embodiment 3
With the hydrochloric acid of 2.0g clarithromycin, 53ml distilled water and 1.0ml 38%, 30 ℃ are stirred 90min; Dropping ammonia adjust pH to 7.0 is with ethyl acetate 15ml extraction; Dropping ammonia is transferred the pH value to 8.0 of extraction back water again, adds sodium-chlor to saturated, and ethyl acetate 15ml * 3 extract once more; Saturated sodium bicarbonate solution flushing twice, twice of saturated nacl aqueous solution flushing; Anhydrous magnesium sulfate drying; Suction filtration, underpressure distillation; At acetone/sherwood oil system recrystallization; Filter, oven dry obtains white needle-like crystals 1.39g (productive rate 88%, purity 99.0%) at last
Embodiment 4
The hydrochloric acid of 2g clarithromycin, 53ml distilled water and 1.2ml 38%, 30 ℃ are stirred 85min down; Dropping ammonia adjust pH to 9.0 leaves standstill and separates out white solid, suction filtration, distilled water wash solid; At acetone/sherwood oil system recrystallization; Filter, oven dry obtains white needle-like crystals 1.21g (productive rate 80%, purity 97.0%) at last
Embodiment 5
The 2g clarithromycin adds 53ml distilled water and fully stirs at 28 ℃, and the hydrochloric acid that adds 1.2ml 38% stirs 90min; Dropping ammonia adjust pH to 9.0 is separated out white solid under condition of ice bath, leave standstill, and suction filtration, drying is at acetone/sherwood oil system recrystallization; Filter, oven dry obtains white needle-like crystals 1.31g (productive rate 83.4%, purity 97.5%)
Embodiment 6
2 g clarithromycins add 53ml distilled water and stir 5min at 22 ℃, and the hydrochloric acid that adds 1.2ml38% stirs 80min under 28 ℃ of water-baths; Dropping ammonia adjust pH to 9.0 is separated out white solid, leaves standstill, and suction filtration, washing is at acetone/sherwood oil system recrystallization; Filter, oven dry obtains white needle-like crystals 1.34g (productive rate 84.9%, purity 98.0%)
Embodiment 7
The 2g clarithromycin adds 53ml distilled water and fully stirs at 28 ℃, and the hydrochloric acid that adds 1.2ml38% stirs 90min; Dropping ammonia adjust pH to 9.0 is separated out white solid under condition of ice bath, leaves standstill, and suction filtration adopts normal heptane, distilled water to wash successively, and vacuum-drying obtains white powder solid 1.31g (productive rate 83.4%, purity 95.0%)
Claims (4)
1.3-the purification process of hydroxyl clarithromycin is characterized in that mainly comprising: twice precipitator method, primary sedimentation method, washing method;
Operation steps is as follows:
(1) twice precipitator method: be transferred to pH=7 and pH=9 respectively; PH value=7 o'clock organic solvent extraction is collected the aqueous solution, and water transfer solution is during to pH=9, with organic solvent extraction; Organic solvent is respectively with comprising saturated aqueous common salt, saturated Repone K, and saturated sodium bicarbonate, the washing of inorganic salts saturated solutions such as saturated potassium hydrogen carbonate, last underpressure distillation, recrystallization obtain white needle-like crystals; Temperature of reaction is 20-50 ℃, and the reaction times is 3-5h;
(2) primary sedimentation method: transfer treatment solution to pH value 〉=9, separate out a large amount of precipitations, filtration, with comprising saturated aqueous common salt, saturated Repone K, saturated sodium bicarbonate, inorganic salts saturated solutions such as saturated potassium hydrogen carbonate wash, and recrystallization obtains white needle-like crystals;
(3) washing method: comprise distilled water/normal hexane or distilled water/normal heptane washing precipitating the product that obtains for the first time, adopting, vacuum-drying obtains white solid.
2. a kind of clarithromycin according to claim 1 takes off the method for the aftertreatment of cladinose acid hydrolytic reaction, it is characterized in that: the aftertreatment adjust pH adopts and comprises ammoniacal liquor, anhydrous sodium carbonate, anhydrous sodium bicarbonate, pyridine, dimethyl formamide (DMF) etc. are regulated treatment solution pH value.
3. a kind of clarithromycin according to claim 1 takes off the method for the aftertreatment of cladinose acid hydrolytic reaction, it is characterized in that: the extraction agent that aftertreatment is adopted comprises ethyl acetate, methylene dichloride, normal hexane, normal heptane, trichloromethane, water-insoluble organic solvents such as ether.
4. a kind of clarithromycin according to claim 1 takes off the method for the aftertreatment of cladinose acid hydrolytic reaction, it is characterized in that: the solvent that the primary sedimentation after scouring adopts comprises: distilled water, normal heptane, normal hexane, sherwood oil, water-insoluble organic solvents such as ether.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101784618A CN101168553A (en) | 2007-11-30 | 2007-11-30 | Method for purifying 3-hydroxyclarithromycin |
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| CNA2007101784618A CN101168553A (en) | 2007-11-30 | 2007-11-30 | Method for purifying 3-hydroxyclarithromycin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109021047A (en) * | 2018-09-27 | 2018-12-18 | 中国药科大学 | A method of preparing clarithromycin impurity K |
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2007
- 2007-11-30 CN CNA2007101784618A patent/CN101168553A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109021047A (en) * | 2018-09-27 | 2018-12-18 | 中国药科大学 | A method of preparing clarithromycin impurity K |
| CN109021047B (en) * | 2018-09-27 | 2020-09-29 | 中国药科大学 | Method for preparing clarithromycin impurity K |
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Open date: 20080430 |