The preparation method of a kind of Erythromycin A (E) oxime
Technical field
The present invention relates to the new synthetic process of a kind of Erythromycin A (E) oxime, Erythromycin A (E) oxime is the key intermediate of synthetic Azythromycin, clarithromycin and Roxithromycin.
Background technology
Erythromycin A-9 oxime is the key intermediate of synthetic Roxithromycin, Azythromycin and clarithromycin and dirithromycin, plays the part of and important role in the antibiotic synthetic field of erythromycin series.
People such as Michael B.G. make solvent with pyridine and prepare erythromycin oxime in EP10952.This technology is dissolved erythromycin in pyridine, add the oxammonium hydrochloride reaction.Through vacuum concentration, obtain product behind cold filtration and the Virahol recrystallization.This method exists following defective: the cost height, environmental pollution is serious, is not suitable for large-scale production.
People such as Takashi A. with imidazoles free hydrochloric acid azanol, react in methyl alcohol with erythromycin under the room temperature in JP62081399, obtain erythromycin oxime.In JP62087599, replace imidazoles to react, obtain identical yield with sodium-acetate.These class methods exist following defective: the cost height; Be not suitable for large-scale production.
Gasc E.C. is at J.Antibio.1991, and 44 (3), adopting triethylamine among the 313-330 is in the free alkali and oxammonium hydrochloride prepares erythromycin oxime.This technology is dissolved in methyl alcohol with erythromycin, adds triethylamine and oxammonium hydrochloride back flow reaction.Cooling is filtered, and the ammoniacal liquor neutralization obtains erythromycin oxime.This method exists following defective: prepared erythromycin oxime E/Z ratio low (≤20), quality product is bad.Environmental pollution is serious, is not suitable for large-scale production.
The degradation problem of the erythromycin of existence during US5808017 prepares for fear of the traditional preparation process erythromycin oxime, introduced the employing aqueous hydroxylamine and replace oxammonium hydrochloride, formic acid or acetate to replace hydrochloric acid in its patent, the Virahol of middle polarity replaces methyl alcohol to prepare the method for erythromycin oxime.This method exists following defective: product yield is low, prepared erythromycin oxime E/Z ratio low (≤15), and quality product is bad.
People such as Yao Guowei are at Chinese pharmaceutical chemistry magazine .2003, and 13 (2), introduced the method that adopts synthesis of erythromycin oxime in the soda acid buffer system among the 89-96.This technology is dissolved in erythromycin and adds Glacial acetic acid in the ethanol, and oxammonium hydrochloride and suitable buffer system are reacted, and obtain product.This method exists following defective: the cost height is not suitable for large-scale production.
Leaf east is in master thesis " study on the synthesis of erythromycin oxime and derivative Roxithromycin thereof ", Beijing, Beijing Institute of Technology, 2002.Introduced with the Matachrom is that raw material carries out the method that oximation reaction prepares erythromycin oxime.This technology is scattered in Matachrom in the ethanol, adds free alkali, adds the glacial acetic acid reaction behind the oxammonium hydrochloride again, and through cooling, the neutralization extraction obtains product behind the evaporated under reduced pressure solvent.This method exists following defective: product yield is low, the cost height, and prepared erythromycin oxime E/Z ratio low (≤12), quality product is bad.
Summary of the invention
The technical problem to be solved in the present invention provides that a kind of technology is simple, yield is high, cost is low, environmental pollution is little, good product quality (erythromycin oxime E/Z 〉=45), be fit to the synthetic method of Erythromycin A (E) oxime of suitability for industrialized production.
In order to solve the problems of the technologies described above, the invention provides the synthetic method of a kind of Erythromycin A (E) oxime, may further comprise the steps:
1), in organic solvent A, oxammonium hydrochloride and molecular structural formula are that the acid binding agent of III at room temperature reacted 20~40 minutes, the mol ratio of oxammonium hydrochloride and acid binding agent is 1:1; And then to add molecular structural formula be that the Matachrom of II reacts, and the mol ratio of Matachrom and oxammonium hydrochloride is 1:2.95~8, and temperature of reaction is 20~80 ℃, and the reaction times is 24~80 hours; Then, obtain the Erythromycin A that molecular structural formula is IV (E) oxime thiocyanate-through crystallization, filtration and washing;
In the molecular structure formula III: described M
N+Be that valence state is the metallic cation of n valency or the positively charged ion that contains positive valence state, n=1; Y
X-Be that valence state is the negatively charged ion of x valency, any one integer in x=1~3;
2), Erythromycin A (E) the oxime thiocyanate-of step 1) gained added alkali carry out neutralization reaction in organic solvent B, the mol ratio of Erythromycin A (E) oxime thiocyanate-and alkali is 1:1~3, the neutralization reaction temperature is that 0~30 ℃, reaction times are 1~24 hour; Through crystallization, filtration and washing, obtain the Erythromycin A that molecular structural formula is I (E) oxime then.
Improvement as the preparation method of Erythromycin A of the present invention (E) oxime: the M in the acid binding agent
N+Be Na
+, K
+Or NH
4 +Y
X-Be HCO
3 -, HPO
4 2-, H
2PO
4 -Or PO
4 3-
Further improvement as the preparation method of Erythromycin A of the present invention (E) oxime: the crystallization in the step 1) is: the product that will react gained earlier is cooled to 35~45 ℃, adds water then to carry out crystallization, and the volume ratio of described water and organic solvent A is 1~4:1.
Further improvement as the preparation method of Erythromycin A of the present invention (E) oxime: the crystallization step 2) is: drip water to carry out crystallization in the product of reaction gained, the volume ratio of described water and organic solvent B is 1~3:1.
Further improvement as the preparation method of Erythromycin A of the present invention (E) oxime: organic solvent A and step 2 in the step 1)) organic solvent B in is C
1~C
6Fatty Alcohol(C12-C14 and C12-C18); The consumption of organic solvent A is: 100~300ml organic solvent A/100g Matachrom, the consumption of organic solvent B is: 200~400ml organic solvent B/100g Erythromycin A (E) oxime thiocyanate-.
Further improvement as the preparation method of Erythromycin A of the present invention (E) oxime: the alkali step 2) is aqueous sodium hydroxide solution.
Further improvement as the preparation method of Erythromycin A of the present invention (E) oxime: the acid binding agent in the step 1) is Secondary ammonium phosphate or sodium bicarbonate, organic solvent A is methyl alcohol, ethanol or Virahol, the mol ratio of Matachrom and oxammonium hydrochloride is 1:7, and adding the temperature of reacting behind the Matachrom and be 50~70 ℃, time is 24~40 hours; Step 2) organic solvent B in is methyl alcohol, ethanol or Virahol, and the mol ratio of Erythromycin A (E) oxime thiocyanate-and sodium hydroxide is 1:2, and the neutralization reaction temperature is that 15~25 ℃, reaction times are 2~6 hours.
The preparation method of Erythromycin A of the present invention (E) oxime has following advantage: technology is simple, the reaction conditions gentleness, and raw materials cost is low, and quality is good, and product E/Z ratio height reaches as high as erythromycin oxime E/Z=90, is easy to industrialization, is with a wide range of applications.
Embodiment
Below among all embodiment the molecular structural formula of used Matachrom shown in II; The Erythromycin A of step 1) gained (E) oxime thiocyanate-molecular structural formula is shown in IV; The molecular structural formula of Erythromycin A (z) oxime of final gained is shown in I.
The preparation method of embodiment 1, a kind of Erythromycin A (E) oxime, following steps successively:
1) in the 500ml four-hole boiling flask, add successively, earlier 140ml methyl alcohol, oxammonium hydrochloride (42.3g, 0.61mol) and Secondary ammonium phosphate (81.1g, 0.61mol), room temperature (being generally 0~40 ℃) is reaction 30min down.(65g 0.087mol), is warming up to 60 ℃ of reaction 32h to add Matachrom then.Add water 220ml after then above-mentioned reaction product being cooled to 40 ℃ and carry out crystallization.Add water and finish, be cooled to 20 ℃ of filtrations, after the 100ml*3 water washing three times, Erythromycin A (E) oxime thiocyanate-55.2g.HPLC is: Erythromycin A (E) oxime 97.5%, Erythromycin A (z) oxime 0.9%.
2), in the 500ml four-hole boiling flask, add Erythromycin A (E) oxime thiocyanate-55.0g (0.068mol) and methyl alcohol 170ml successively, being cooled to after 20 ℃ and slowly dripping mass concentration is 25% aqueous sodium hydroxide solution 21.8g (0.136mol), 1h drips off, and drips to finish, behind the stirring reaction 4h; Slowly drip 270ml water (about 2~3h drips off) again to carry out crystallization.Drip to finish, filter, after the 100ml*3 water washing three times Erythromycin A (E) oxime 41.5g, HPLC is an E oxime 96.5%, z oxime 0.8%.
The preparation method of embodiment 2, a kind of Erythromycin A (E) oxime, following steps successively:
1) in the 500ml four-hole boiling flask, add successively, earlier 70ml Virahol, oxammonium hydrochloride (48.4g, 0.696mol) and saleratus (69.6g 0.696mol), reacts 30min under the room temperature.(65g, 0.087mol), 40 ℃ are reacted 80h to add Matachrom then.Add water 220ml after then above-mentioned reaction product being cooled to 38 ℃ and carry out crystallization.Add water and finish, be cooled to 20 ℃ of filtrations, after the 100ml*3 water washing three times, Erythromycin A (E) oxime thiocyanate-53.6g.HPLC is: Erythromycin A (E) oxime 93.5%, Erythromycin A (z) oxime 2.0%.
2), in the 500ml four-hole boiling flask, add Erythromycin A (E) oxime thiocyanate-55.0g (0.068mol) and ethanol 170ml successively, being cooled to after 20 ℃ and slowly dripping mass concentration is 25% aqueous sodium hydroxide solution 30.0g (0.187mol); Drip and finish, behind the stirring reaction 22h; Slowly drip 270ml water (about 2~3h drips off) again to carry out crystallization.Drip to finish, filter, after the 100ml*3 water washing three times Erythromycin A (E) oxime 42.2g, HPLC is an E oxime 95.8%, z oxime 0.9%.
The preparation method of embodiment 3, a kind of Erythromycin A (E) oxime, following steps successively:
1) in the 500ml four-hole boiling flask, add successively, earlier 90ml ethanol, oxammonium hydrochloride (18.1g, 0.26mol) and disodium-hydrogen (36.9g 0.26mol), reacts 30min under the room temperature.(65g 0.087mol), is warming up to 80 ℃ of reaction 24h to add Matachrom then.Add water 220ml after then above-mentioned reaction product being cooled to 40 ℃ and carry out crystallization.Add water and finish, be cooled to 20 ℃ of filtrations, after the 100ml*3 water washing three times, Erythromycin A (E) oxime thiocyanate-43.8g.HPLC is: Erythromycin A (E) oxime 94.8%, Erythromycin A (z) oxime 1.8%.
2), in the 500ml four-hole boiling flask, add Erythromycin A (E) oxime thiocyanate-40.4g (0.05mol) and Virahol 100ml successively, being cooled to after 5 ℃ and slowly dripping mass concentration is 25% aqueous sodium hydroxide solution 10.0g (0.062mol), drip and finish, behind the stirring reaction 20h; Slowly drip 160ml water again to carry out crystallization.Drip and finish, filter, get Erythromycin A (E) oxime 30.2g after 100ml*3 washs three times, HPLC is 93.6%, z oxime 1.4%.
At last, it is also to be noted that what more than enumerate only is several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.