CN110903335A - Preparation method of tulathromycin - Google Patents
Preparation method of tulathromycin Download PDFInfo
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- CN110903335A CN110903335A CN201811073963.9A CN201811073963A CN110903335A CN 110903335 A CN110903335 A CN 110903335A CN 201811073963 A CN201811073963 A CN 201811073963A CN 110903335 A CN110903335 A CN 110903335A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention provides a preparation method of tulathromycin, belonging to the field of pharmaceutical chemicals; the method comprises the steps of reacting erythromycin azoxide serving as a raw material with phenyl chloroformate to protect hydroxyl groups to obtain protected erythromycin azoxide, oxidizing the hydroxyl groups into ketone groups through oxidation, and reacting the ketone groups with n-propylamine to obtain tulathromycin after epoxidation and deprotection. The method has the advantages of high product purity, high yield, low cost, simple operation, and stable process.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a preparation method of tulathromycin.
Background
Tulathromycin (Tulathromycin), also known as Tulathromycin, tolamycin. The drug is a novel semi-synthetic veterinary antibiotic of erythromycins developed by the animal health products company of Peucedanum in the last 90 years of the last century. The compounds, synthesis processes and preparations thereof were respectively patented by the company pfeiri during the period from 1998 to 2003. The european union veterinary medical council (VMAC) approved talaromycin injection rake new (Draxxin) for 10/13/2004 to be marketed in the european union; 24-h.2005 Food and Drug Administration (FDA) approved the talaromycin injection, rake new, to be marketed in the united states. Tulathromycin is approved for the first time in No. 957 bulletin of China's Ministry of agriculture in China. Tulathromycin bulk drug and Tulathromycin injection are fed from Groton manufacturing plant of the California company and Ambios manufacturing plant of the Fangguo company.
Tulathromycin (Tulathromycin) is a broad-spectrum antibacterial drug, as a third-generation macrolide antibiotic, has antibacterial activity on some gram-positive bacteria and gram-positive bacteria, is particularly sensitive to pathogenic bacteria causing respiratory diseases of cattle and pigs, and has the advantages of low concentration, long acting time, low minimum inhibitory concentration, small dosage, good injection water solubility, low overall treatment cost, convenience in use and the like in the using process, so that the Tulathromycin is widely concerned by the veterinary medicine field.
The synthesis route of the pyroxene is characterized in that azaerythromycin is used as a raw material, and hydroxyl is protected by benzyl chloroformate to obtain protected azaerythromycin; oxidation of hydroxyl groups to keto groups by Omura-Sharma-Swern oxidation (-70 ℃); the resulting ketone was converted to a protected epoxide compound by the Corey-Chaykovsky reaction (-70 ℃ C.); the protected epoxy compound is hydrogenated and removed of a protecting group through Pd/C catalysis, and then reacts with n-propylamine to obtain a crude tulathromycin product.
In other existing patent reports on the synthesis routes of tulathromycin, the preparation process of the intermediate requires ultralow temperature reaction conditions, salifying purification and the like, and the operation has certain difficulty.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a preparation method of tulathromycin, which has the advantages of high product purity, high yield, low cost, simple operation and mild conditions.
According to one aspect of the invention, the invention provides a method for preparing tulathromycin, which comprises the following steps:
(1) mixing the compound shown in the formula I with an organic solvent at a certain temperature, adding phenyl chloroformate, stirring to react, evaporating the solvent to dryness to obtain a compound shown in a formula II,
(2) mixing the compound shown in the formula II, o-iodoxybenzoic acid and an organic solvent, stirring, dropwise adding trifluoroacetic acid, after the reaction is finished, adding water, extracting with dichloromethane, concentrating to obtain the compound shown in the formula III,
(3) cooling the organic solvent to a low temperature, adding Me3SBr, adding potassium tert-butoxide under the protection of nitrogen, stirring, dropwise adding a mixed solution of a compound shown in a formula III and an organic solvent, adding an ammonium chloride aqueous solution, quenching reaction, separating to obtain an organic phase, concentrating under reduced pressure to obtain a compound shown in a formula IV,
(4) mixing and stirring a compound shown as a formula IV, acid, water and an organic solvent, controlling a certain temperature to react, adding alkali to adjust the pH value after the reaction is finished, filtering to obtain a compound shown as a formula V,
(5) mixing and stirring the compound shown as the formula V and n-propylamine, heating to a certain temperature, concentrating after the reaction is finished to obtain the compound shown as the formula VI,
according to some embodiments of the present invention, the organic solvent in step (1) may be at least one of dichloromethane, chloroform, tetrahydrofuran, toluene, acetonitrile, ethyl acetate, acetone, methyl tert-butyl ether, and the like.
According to some embodiments of the invention, the certain temperature in step (1) is-20 ℃ to 30 ℃.
According to some embodiments of the invention, the certain temperature in step (2) is 0 ℃ to 90 ℃.
According to some embodiments of the present invention, the organic solvent in step (2) may be at least one of dichloromethane, chloroform, tetrahydrofuran, toluene, DMF, DMSO, ethyl acetate, acetone, methyl tert-butyl ether, and the like.
According to some embodiments of the present invention, the organic solvent in step (3) may be at least one of dichloromethane, chloroform, C1-C8 alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, and the like.
According to some embodiments of the invention, the low temperature in the step (3) is-80 ℃ to 30 ℃.
According to some embodiments of the invention, Me in said step (3)3The mol ratio of SBr to the compound shown in the formula III is 0.5-4.5.
According to some embodiments of the invention, the molar ratio of potassium tert-butoxide to the compound of formula III in step (3) is 0.5 to 5.0.
According to some embodiments of the present invention, the acid in the step (4) is formic acid, acetic acid, oxalic acid, trifluoroacetic acid, or the like.
According to some embodiments of the present invention, the base in step (4) may be at least one of an inorganic base such as sodium carbonate, potassium phosphate, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, and potassium hydroxide, and an organic base such as triethylamine and diisopropylethylamine.
According to some embodiments of the invention, the molar ratio of the acid in step (4) to the compound of formula IV is 0.5 to 3.0.
According to some embodiments of the invention, the amount of water and the compound of formula IV in step (4) is 1.5ml/g to 15 ml/g.
According to some embodiments of the invention, the certain temperature in step (4) is 25 ℃ to 80 ℃.
According to some embodiments of the invention, the molar ratio of the base in step (4) to the compound of formula IV is 0.5 to 4.0.
According to some embodiments of the invention, the molar ratio of n-propylamine to the compound of formula V in step (5) is 2.0 to 20.0.
According to some embodiments of the invention, the certain temperature in step (5) is 20 ℃ to 90 ℃.
Definition of terms
In this specification, "g" means g.
In the present specification, "room temperature" means 10 ℃ to 35 ℃.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The conditions for measuring Mass Spectrometry (MS) data were: electrospray ionization (ESI).
Measurement conditions of H spectrum: 400MHz, deuterated DMSO.
Preparation of tulathromycin according to the examples of the invention the synthetic procedure is shown in the following synthetic scheme
EXAMPLE 1 preparation of the Compound of formula II
Adding a compound (100.00g) of a formula I and dichloromethane (700.00g) into a reaction bottle at room temperature, cooling to-5.0 ℃ under stirring, dropwise adding a mixed solution of phenyl chloroformate (22.36g) and dichloromethane (100.00g), keeping the temperature at 0 ℃, stirring for 3 hours, adding a sodium carbonate aqueous solution after the reaction is finished, separating the solution to obtain an organic phase, and concentrating to obtain a compound (II) which is directly used in the next step. Yield: 92 percent.
MS(ESI)m/z：855.51[M+H]+。
EXAMPLE 2 preparation of the Compound of formula III
Adding the compound of the formula II in example 1, o-iodoxybenzoic acid (114.32g) and DMSO (300.00g) into a reaction flask at room temperature, dropwise adding trifluoroacetic acid (23.26g), keeping the temperature at 30 ℃ after dropwise adding, stirring for reaction, cooling to below 10 ℃ after the reaction is finished, dropwise adding 900.00g of water, filtering to obtain a filtrate, cooling to below 10 ℃, dropwise adding an ammonia water solution until the pH value is about 9, separating to obtain an organic phase, and concentrating the organic phase to obtain the compound of the formula III. Yield: 85 percent.
MS(ESI)m/z：853.50[M+H]+。
EXAMPLE 3 preparation of the Compound of formula IV
Me is added into a reaction bottle at room temperature3SBr (13.80g) and tetrahydrofuran (100.00g), cooling to-15 ℃ under the protection of nitrogen, adding potassium tert-butoxide (13.13g), cooling to-70 ℃, dropwise adding a dichloromethane (70.00g) solution of the compound (25.00g) of the formula III in example 2, controlling the internal temperature not to exceed-50 ℃, dropwise adding an ammonium chloride aqueous solution for quenching reaction, stirring, separating to obtain an organic phase, and concentrating to obtain the compound of the formula IV. Yield of：92％。
MS(ESI)m/z：867.51[M+H]+。
EXAMPLE 4 preparation of the Compound of formula V
A reaction flask was charged with the compound of formula IV of example 3 (25.00g), water (100ml) and acetic acid (1.73g), heated to 40 ℃ and stirred to react, after completion of the reaction, a solution of sodium hydroxide (2.30g) in water (50ml) was added dropwise, the pH was adjusted to 11.0, and the compound of formula V was obtained by filtration. Yield: 90 percent.
MS(ESI)m/z：747.49[M+H]+
1H NMR(400MHz,CDCl3),δ：3.73(dd,J＝7.4,117Hz，H-11),3.30(s,12-OH)，2.70(dq，J＝6.6,1.7Hz,H-10)，2.49(dJ＝8.75Hz,H-9),2.33(s,NMe),2.30(s,NMe2),2.04(t,H-9ax),2.02(m,8-H),1.16(d,J＝6.5Hz,10-CH3),1.09(s,12-CH3)，1.05(d,J＝7.6Hz,4-CH3),0.94(d,J＝6.7Hz,8-H3),3.05(s,NH),5.42(s,CH2),7.19(s,5H)。
EXAMPLE 5 preparation of the Compound of formula VI
The compound of formula V from example 4 (25.00g) and n-propylamine (19.78g) were charged into a reaction flask, and the reaction was stirred while the temperature was raised to 60 ℃ to complete the reaction, and concentrated to give the compound of formula VI. Yield: 94 percent.
MS(ESI)m/z：806.57[M+H]+。
In the description herein, references to the description of the term "one embodiment," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A method of preparing tulathromycin, comprising:
(1) mixing the compound shown in the formula I with an organic solvent at a certain temperature, adding phenyl chloroformate, stirring to react, evaporating the solvent to dryness to obtain a compound shown in a formula II,
(2) mixing the compound shown in the formula II, o-iodoxybenzoic acid and an organic solvent, stirring, dropwise adding trifluoroacetic acid, after the reaction is finished, adding water, extracting with dichloromethane, concentrating to obtain the compound shown in the formula III,
(3) cooling the organic solvent to a low temperature, adding Me3SBr, adding potassium tert-butoxide under the protection of nitrogen, stirring, dropwise adding a mixed solution of a compound shown in a formula III and an organic solvent, adding an ammonium chloride aqueous solution after the reaction is finished, quenching the reaction, separating the solution to obtain an organic phase, concentrating the organic phase under reduced pressure to obtain a compound shown in a formula IV,
(4) mixing and stirring a compound shown as a formula IV, acid, water and an organic solvent, controlling a certain temperature to react, adding alkali to adjust the pH value after the reaction is finished, filtering to obtain a compound shown as a formula V,
(5) mixing and stirring the compound shown as the formula V and n-propylamine, heating to a certain temperature, concentrating after the reaction is finished to obtain the compound shown as the formula VI,
2. the method according to claim 1, wherein the organic solvent in step (3) is dichloromethane, chloroform, acetone, C1-C8Alcohol, tetrahydrofuran, toluene or dioxane.
3. The method according to claim 1, wherein the low temperature in the step (3) is from-80 ℃ to 30 ℃.
4. The method according to claim 1, wherein Me in step (3) is3The mol ratio of SBr to the compound shown in the formula III is 0.5-4.5.
5. The method according to claim 1, wherein the molar ratio of potassium tert-butoxide to the compound of formula III in step (3) is from 0.5 to 4.5.
6. The method according to claim 1, wherein the acid in the step (4) is formic acid, acetic acid, oxalic acid or trifluoroacetic acid.
7. The method of claim 1, wherein the molar ratio of the acid to the compound of formula IV in step (4) is 0.5 to 3.0.
8. The method according to claim 1, wherein the base in the step (4) is sodium carbonate, potassium phosphate, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, triethylamine or N, N-diisopropylethylamine.
9. The method of claim 1, wherein the temperature in step (4) is in the range of 25 ℃ to 80 ℃.
10. A compound having a structural formula as shown in formula III:
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111253447A (en) * | 2020-03-26 | 2020-06-09 | 苏州正永生物医药有限公司 | Preparation method of tulathromycin |
| CN113861252A (en) * | 2021-11-08 | 2021-12-31 | 江苏君若药业有限公司 | Synthesis of tulathromycin |
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| WO2017124222A1 (en) * | 2016-01-18 | 2017-07-27 | 浙江海正药业股份有限公司 | Method and intermediate for preparing tulathromycin |
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| CN103664967A (en) * | 2012-09-07 | 2014-03-26 | 公安部禁毒情报技术中心 | Method for synthesizing [2H3]-morphine |
| WO2017124222A1 (en) * | 2016-01-18 | 2017-07-27 | 浙江海正药业股份有限公司 | Method and intermediate for preparing tulathromycin |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111253447A (en) * | 2020-03-26 | 2020-06-09 | 苏州正永生物医药有限公司 | Preparation method of tulathromycin |
| CN111253447B (en) * | 2020-03-26 | 2021-03-02 | 苏州正永生物医药有限公司 | Preparation method of tulathromycin |
| CN113861252A (en) * | 2021-11-08 | 2021-12-31 | 江苏君若药业有限公司 | Synthesis of tulathromycin |
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