阅读说明：本技术 泰拉霉素的合成 (Synthesis of tulathromycin ) 是由 朱灿 杨晓瑜 裔明月 刘洁 姜军 于 2021-11-08 设计创作，主要内容包括：本发明涉及泰拉霉素的合成,具体为(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-乙基-3,4,10-三羟基-13-[[3S,4S,6R,8R]-8-甲氧基-4,8-二甲基-1,5-二氧杂螺[2,5]辛-6-基]氧基)3,5,8,10,12,14-六甲基-11-[[3,4,6-三脱氧-3-(二甲基氨基)-β-D-己吡喃木糖基]氧基]-1-氧杂-6-氮杂环十五烷-15-酮一水合物在溶剂和三氟甲磺酸镱存在下与正丙胺发生反应,实现泰拉霉素的合成。(The invention relates to synthesis of tulathromycin, in particular to (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -2-ethyl-3, 4, 10-trihydroxy-13- [ [3S,4S,6R,8R ] -8-methoxy-4, 8-dimethyl-1, 5-dioxaspiro [2,5] oct-6-yl ] oxy) 3,5,8,10,12, 14-hexamethyl-11- [ [3,4, 6-trideoxy-3- (dimethylamino) -beta-D-hexylglucopyranosyl ] oxy ] -1-oxa-6-azacyclopentadecane-15-one monohydrate which reacts with propylamine under the existence of a solvent and ytterbium trifluoromethanesulfonate, the synthesis of the tulathromycin is realized.)

1. A process for the preparation of tulathromycin, in particular (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -2-ethyl-3, 4, 10-trihydroxy-13- [ [3S,4S,6R,8R ] -8-methoxy-4, 8-dimethyl-1, 5-dioxaspiro [2,5] -oct-6-yl ] oxy ] 3,5,8,10,12, 14-hexamethyl-11- [ [3,4, 6-trideoxy-3- (dimethylamino) -beta-D-hexylglucopyranosyl ] oxy ] -1-oxa-6-azacyclopentadecan-15-one monohydrate (compound formula I) by reaction with propylamine in the presence of a solvent and an additive, the preparation of the tulathromycin is realized. The reaction formula is as follows:

2. the method of claim 1, wherein the solvent used in the reaction comprises methanol, ethanol, propylene glycol, isopropanol, or a mixture thereof.

3. The process as claimed in claim 1, wherein the additive used in the reaction is ytterbium triflate.

4. The process of claim 1 wherein the equivalents of n-propylamine used in the reaction are from 1 to 2 equivalents of the equivalent of compound of formula I.

5. The process as claimed in claim 1, wherein the reaction temperature is 40-60 ℃.

6. The process of claim 1, wherein the reaction time is 2 to 5 hours.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to synthesis of tulathromycin.

Background

Tulathromycin (Tulathromycin), also known as Tulathromycin, tolamycin, under the trade name "Draxxin" (the Chinese name "Ralshin" or "Rugoshin"). The drug is a novel erythromycin synthetic veterinary drug developed by the American pfeiffe animal health product company in the last 90 years, belongs to a special macrolide semi-synthetic antibiotic for animals, and is mainly used for treating and preventing respiratory system diseases of animals caused by actinobacillus pleuropneumoniae, mycoplasma, pasteurella, haemophilus parasuis, bordetella bronchiseptica and the like. A large number of researches find that the tulathromycin can selectively penetrate gram-negative bacteria pathogens and is used for preventing and treating respiratory infectious diseases of cattle and pigs caused by sensitive bacteria and infectious bovine keratitis caused by Moraxella bovis. The drug is approved by the European Union veterinary medical counseling committee to be marketed in the European Union in 10 months in 2004, approved by the US FDA to be marketed in the United states in 5 months in 2005, and approved for use in the No. 957 notice of Ministry of agriculture in 2008 by the Ministry of agriculture in China, and the dosage form is an injection. The tulathromycin has the advantages of low concentration, long acting time, low minimum inhibitory concentration, small dosage, good water solubility for injection, low overall treatment cost, convenient use and the like in the using process, is widely concerned by the veterinary medicine field, and is called as a revolutionary product in the industry.

The tulathromycin is complex in structure, has 18 chiral centers, and comprises a plurality of active groups (comprising 5 hydroxyl groups, one macrolide group and three amine groups), and the chemical name is as follows: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -13- [ (2, 6-dideoxy-3-C-methyl-3-O-methyl-4-C- [ (propylamino) methyl ] α -L-hexopyranosyl) oxy ] -2-ethyl-3, 4, 10-trihydroxy-3, 5,8,10,12, 14-hexamethyl-11- [ [3,4, 6-trideoxy-3- (dimethylamino) - β -D-hexopyranosyl ] oxy ] -1-oxa-6-azacyclopentadecan-15-one. The compound contains three amino groups, so that the compound is weakly electronegative in a solution, is favorable for penetrating a negative bacterial membrane, and efficiently stimulates the separation of peptidyl tRNA from ribosome, thereby inhibiting the bacterial transpeptidation process, preventing the synthesis and extension of a peptide chain, and influencing the synthesis of bacterial protein. The chemical structural formula of tulathromycin is as follows:

the tulathromycin has a complex structure, contains a plurality of chiral centers and contains a plurality of active groups, so that the synthesis difficulty is high. U.S. Perey, WO9856802/US6420536/CN1295240C, started from demethylazithromycin, the 2 "-hydroxyl group was protected with benzyl chloroformate, the 4' -hydroxyl group was oxidized using Swern oxidation conditions, and then the intermediate was subjected to epoxidation of the carbonyl group using Corey-Chaykovsky epoxidation conditions to obtain an epoxy compound. And (3) removing a Cbz protective group from the epoxy compound through Pd/C hydrogenation, and carrying out nucleophilic addition reaction on the obtained product and an epoxy tricyclic ring in the molecule through n-propylamine to realize the preparation of the tulathromycin. The relevant synthetic route is as follows:

patent CN1295240C example 5 describes the reaction of n-propylamine with a three-membered ring intermediate, specifically a monohydrate of the three-membered ring intermediate ((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -2-ethyl-3, 4, 10-trihydroxy-13- [ [3S,4S,6R,8R ] -8-methoxy-4, 8-dimethyl-1, 5-dioxaspiro [2,5] -oct-6-yl ] oxy) 3,5,8,10,12, 14-hexamethyl-11- [ [3,4, 6-trideoxy-3- (dimethylamino) - β -D-hexylglucopyranosyl ] oxy ] -1-oxa-6-azacyclopentadecan-15-one) in a large excess of n-propyl alcohol in isopropanol as solvent The reaction is completed by heating at 55-55 ℃ for 30 hours in the presence of propylamine (25 equivalents). Since the intermediate compound also contains a plurality of active groups (hydroxyl, macrolide, amine and the like), the longer the reaction time is, the more impurities are caused, in particular the isomer impurities generated when n-propylamine nucleophilically attacks epoxy. In addition, the large excess of the n-propylamine can not only increase the cost of raw materials, but also increase the content of ammonia nitrogen in the three-waste treatment, thereby bringing high cost to the green and environment-friendly treatment of wastewater and waste solvent. Because of the many impurities in the reaction, the literature mostly adopts the steps of converting the prepared crude tulathromycin into diphosphate, refining the diphosphate, and finally dissociating to prepare the relatively pure tulathromycin. The relevant synthetic route is as follows:

the document "Fine chemistry" (2012,29,795-, subsequently, phosphoric acid is added to form phosphate. The reaction conditions used only 10 equivalents of n-propylamine, but the reaction temperature was raised to 70 ℃ and the reaction time was likewise up to 30 hours.

Considering that the tulathromycin is a large variety and the market demand is more than tens tons and even hundreds tons every year, the problem that how to overcome some defects existing in the preparation of tulathromycin in the prior art and provide a preparation method which is more suitable for industrial production of tulathromycin is needed to be solved for further amplified production and market popularization of the tulathromycin is urgent.

Disclosure of Invention

The invention aims to provide a method for preparing (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -13- [ (2, 6-dideoxy-3-C-methyl-3-O-methyl-4-C- [ (propylamino) methyl ] alpha-L-ribopyranosyl) oxy ] -2-ethyl-3, 4, 10-trihydroxy-3, 5,8,10,12, 14-hexamethyl-11- [ [3,4, 6-trideoxy-3- (dimethylamino) -beta-D-xylopyranosyl ] oxy ] -1-oxa-6-azacyclopentadecane-15-one (tulathromycin).

Research shows that (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -2-ethyl-3, 4, 10-trihydroxy-13- [ [3S,4S,6R,8R ] -8-methoxy-4, 8-dimethyl-1, 5-dioxaspiro [2,5] -oct-6-yl ] oxy) 3,5,8,10,12, 14-hexamethyl-11- [ [3,4, 6-trideoxy-3- (dimethylamino) -beta-D-hexylglucopyranosyl ] oxy ] -1-oxa-6-azacyclopentadecane-15-one monohydrate (compound formula I) reacts with n-propylamine in the presence of solvent and additives, can rapidly realize the ring opening of the epoxy ring and realize the preparation of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -13- [ (2, 6-dideoxy-3-C-methyl-3-O-methyl-4-C- [ (propylamino) methyl ] alpha-L-ribopyranosyl) oxy ] -2-ethyl-3, 4, 10-trihydroxy-3, 5,8,10,12, 14-hexamethyl-11- [ [3,4, 6-trideoxy-3- (dimethylamino) -beta-D-xylopyranosyl ] oxy ] -1-oxa-6-azacyclopentadecane-15-one (tulathromycin). The relevant reaction formula is as follows:

the solvent used for the reaction includes methanol, ethanol, propylene glycol, isopropanol, and a mixed solvent of any combination of these solvents.

The additive used in the reaction is ytterbium trifluoromethanesulfonate.

The equivalents of n-propylamine used for the reaction are 1 to 2 equivalents of the compound of formula I.

The reaction temperature is 40-60 DEG C

The reaction time is 2-5 hours.

The preparation method can greatly reduce the use equivalent of the n-propylamine, shorten the reaction time, and directly obtain the tulathromycin product through simple purification without salifying and purifying the generated tulathromycin crude product by phosphate, thereby having good industrialization prospect.

Detailed Description

The following exemplary embodiments are provided to illustrate the present invention, and simple replacement and modification of the present invention by those skilled in the art are within the technical scheme of the present invention.

EXAMPLE one preparation of tulathromycin

The (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -2-ethyl-3, 4, 10-trihydroxy-13- [ [3S,4S,6R,8R ] is added into a four-mouth flask in sequence]-8-methoxy-4, 8-dimethyl-1, 5-dioxaspiro [2,5]]-oct-6-yl]Oxy) 3,5,8,10,12, 14-hexamethyl-11- [ [3,4, 6-trideoxy-3- (dimethylamino) - β -D-xylopyranosyl]Oxy radical]-1-oxa-6-azacyclopentadecan-15-one monohydrate (compound of formula I) (110g,143.8mmol) and isopropanol (500mL) were dissolved with stirring at room temperature. Then n-propylamine (12.75g,215.7mmol,1.5eq) and ytterbium triflate (8.9g,14.4mmol,0.1eq) were added to the reaction in that order. After the addition was complete, the system was heated to 50 ℃ and stirred for reaction for 3 hours. After the reaction was complete, the system was concentrated under high vacuum and reduced pressure to remove the organic solvent, DMF (450mL) was added to the residue, heated to 80 ℃ to dissolve, filtered while hot, the filtrate was slowly cooled to about 5 ℃ with stirring, crystallized with stirring for 2 hours, filtered, the solid was rinsed with n-heptane (50mL) which was previously cooled to 5 ℃ and the resulting solid was dried under high vacuum at 55 ℃ to give a white solid (87.2g, 75.2%).¹H-NMR(MeOD-D4,400MHz)δppm 0.83-1.24(m,31H),1.29(s,3H),1.35-1.43(m,1H),1.46-2.01(m,10H),2.25-2.29(m,1H),2.32(s,6H),2.53-2.57(t,2H,J＝8.0Hz),2.64-2.98(m,6H),3.22-3.27(m,1H),3.38(s,3H),3.41-3.42(m,1H),3.64-3.66(d,1H,J＝8.0Hz),3.68-3.78(m,1H),4.23-4.25(m,1H),4.51-4.55(m,2H),4.93-4.96(m,1H),5.00-5.01(d,1H,J＝4.0Hz)；¹³C-NMR(CDCl₃,150MHz)δ ppm 9.51,11.31,11.91,14.35,15.29,15.57,16.30,17.41,21.17,21.60,22.06,23.03,27.36,28.98,29.96,34.05,40.47,41.61,42.21,45.30,49.16,49.91,52.77,56.48,57.14,65.64,67.84,68.64,71.17,72.55,73.83,74.11,76.42,77.89,79.02,83.91,95.77,103.09,178.36；Mass 404,(M+2H⁺)/2。