A method for preparing high purity silatones

Abstract

This invention relates to the field of pharmaceutical technology, and discloses a method for preparing high-purity selamectin. This invention uses an inexpensive oxidation system, specifically a low-cost sodium hypochlorite-TEMPO system, to oxidize the reaction raw materials, avoiding the use of expensive oxidants. The reaction is also mild, highly operable, and more environmentally friendly. Furthermore, this invention involves recrystallization of the oxidation product to improve purity, laying a solid foundation for obtaining high-purity selamectin. In the purification of crude selamectin, a toluene-methanol mixed solvent is used for recrystallization, avoiding the need for liquid chromatography or column chromatography, reducing costs, and achieving a high purity of over 99.5%.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically a method for preparing high-purity selamectin. Background Technology

[0002] Selamectin is produced by fermentation of a new recombinant strain of *Streptanyces avemitilis*, and is a relatively new compound belonging to the avermectin class of drugs. Developed by Pfizer, it is obtained from doramectin as a starting material through hydrogenation, oxidation, desaccharification, and oxime reactions. Selamectin has a broad antibacterial spectrum, basically meeting the requirements for eliminating most major parasites throughout the body of animals. It is effective when administered via drops, injection, or oral administration. It is a primary internal and external parasite control agent for pet cats and dogs.

[0003] However, the current preparation process of selamectin has three drawbacks. First, the preparation process involves column chromatography or preparative liquid chromatography, which, while improving purity, also increases costs. Second, multiple recrystallizations are used instead of column chromatography, but the purity is relatively low. Third, the preparation process requires the use of oxidants, and the expensive oxidants currently used, such as activated manganese dioxide and Dess-Martin, further increase costs. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing high-purity selamectin to solve the problems mentioned in the background art.

[0005] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a method for preparing high-purity selamectin, comprising the following steps:

[0006] S1. Doramectin (I) was hydrogenated under the action of Wilkinson catalyst, and then purified by recrystallization to obtain hydrogenated doramectin (II).

[0007] S2. Hydrogenated doramectin (II) is dissolved in organic solvent A, an oxidant and a catalyst are added, an oxidation reaction is carried out and then extracted, and then recrystallized and purified to obtain oxidized doramectin (III).

[0008] S3. Disperse oxydoracin (III) in a mixed solvent of organic solvent B and pure water, add hydroxylamine hydrochloride to react, extract, recrystallize and purify to obtain selamectin (IV).

[0009] Furthermore, the preparation method of the high-purity selamectin specifically includes the following steps:

[0010] S1. Dissolve doramectin (I) in acetone, add Wilkinson catalyst and mix, fill with nitrogen, vent air and switch to hydrogen atmosphere, heat to 25-35℃, react for 15-20h, remove excess solvent by rotary evaporation, recrystallize and purify to obtain hydrogenated doramectin (II).

[0011] S2. Dissolve hydrogenated doramectin (II) in organic solvent A, add saturated sodium bicarbonate solution, maintain the temperature at 0-10℃, add oxidant and catalyst, react for 2-4 hours, extract the organic phase with dichloromethane 2-3 times, wash with sodium sulfite 2-3 times, add anhydrous sodium sulfate to dry, filter, remove excess solvent by rotary evaporation, recrystallize and purify to obtain oxidized doramectin (III).

[0012] S3. Disperse oxydralazine (III) in a mixed solvent of organic solvent B and pure water, add hydroxylamine hydrochloride, react for 4-8 hours, quench the reaction by adding saturated sodium bicarbonate solution, extract the organic phase with dichloromethane, dry with anhydrous sodium sulfate and filter, remove excess solvent by rotary evaporation, recrystallize and purify to obtain crude selamectin product, recrystallize and purify again to obtain selamectin (IV).

[0013] Furthermore, the chemical structural formula of the doramectin (I) is as follows:

[0014]

[0015] The chemical structural formula of the hydrogenated doramectin (II) is as follows:

[0016]

[0017] The chemical structural formula of the oxydoramectin (III) is as follows:

[0018]

[0019] The chemical structural formula of selamectin (Ⅳ) is as follows:

[0020] .

[0021] Furthermore, the mass ratio of doramectin (I) to Wilkinson catalyst is 1:(0.02-0.05).

[0022] Furthermore, in step S1, the hydrogen atmosphere pressure is 0.2-0.3 MPa.

[0023] Furthermore, in step S1, during recrystallization purification, the recrystallization solvent is either methanol or acetonitrile, preferably acetonitrile.

[0024] Furthermore, in step S2, the organic solvent A is any one or more of dichloromethane, tetrahydrofuran, and acetonitrile; the catalyst is TEMPO (2,2,6,6-tetramethylpiperidine oxide); and the oxidant is sodium hypochlorite.

[0025] Furthermore, in step S2, the molar ratio of the hydrodorafenib (II), sodium bicarbonate, oxidant and catalyst is 1:(2-3):(1.5-3):(0.2-0.5) by molar proportion.

[0026] Furthermore, in step S2, during recrystallization purification, the recrystallization solvent is a mixed liquid in which the volume ratio of solvent A to solvent B is (3-5):(0.5-5);

[0027] Solvent A is either toluene or methyl tert-butyl ether; solvent B is any one or more of methanol, ethanol, isopropanol, and acetonitrile.

[0028] Preferably, the recrystallization solvent of the present invention includes toluene and methanol.

[0029] The volume ratio of toluene to methanol is preferably 3:(0.5-4), and more preferably 3:(1-2).

[0030] Preferably, the recrystallization solvent of the present invention includes methyl tert-butyl ether and ethanol.

[0031] The volume ratio of methyl tert-butyl ether to ethanol is preferably 3:(0-6), and more preferably 3:(0-1).

[0032] Furthermore, in step S3, the molar ratio of oxydoracin (III) to hydroxylamine hydrochloride is (3-6):1.

[0033] Furthermore, in step S3, the organic solvent B is any one or more of isopropanol, methanol, and dioxane; the volume ratio of the organic solvent B to pure water is (6-10):1.

[0034] Furthermore, in step S3, during recrystallization purification, the recrystallization solvent is a mixed solution of toluene and methanol;

[0035] During the first recrystallization, the volume ratio of toluene to methanol was 3:(0-1); during the second recrystallization, the volume ratio of toluene to methanol was 3:(4-5).

[0036] Compared with existing technologies, the beneficial effects achieved by this invention are as follows: This invention uses an inexpensive oxidation system, specifically a low-cost sodium hypochlorite-TEMPO system, to oxidize the reaction raw materials, avoiding the use of expensive oxidants. Furthermore, the reaction is mild, highly operable, and more environmentally friendly. Simultaneously, this invention also recrystallizes the oxidation product to improve purity, laying a solid foundation for obtaining high-purity selamectin. In the purification of crude selamectin, a mixed solvent of toluene and methanol is used for recrystallization, avoiding the need for liquid chromatography or column chromatography, reducing costs, and achieving a high purity of selamectin, exceeding 99.5%. Attached Figure Description

[0037] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings:

[0038] Figure 1 This is the HPLC chromatogram of the hydrogenation product prepared in Example 1 of this invention;

[0039] Figure 2 This is the HPLC chromatogram of the oxidation product prepared in Example 3 of this invention;

[0040] Figure 3 This is the HPLC chromatogram of the oxidation product prepared in Example 4 of this invention;

[0041] Figure 4 This is the HPLC chromatogram of selamectin prepared in Example 6 of this invention;

[0042] Figure 5 This is the HPLC chromatogram of selamectin prepared in Comparative Example 1 of this invention. Detailed Implementation

[0043] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0044] Example 1.

[0045] The feeding ratio for this embodiment is shown in Table 1 below:

[0046] Table 1. Proportions of each feedstock for hydrogenation products

[0047]

[0048] According to the feed ratio in Table 1, add doramectin (Hubei Weideli Chemical Technology Co., Ltd., industrial grade, purity >98%), Wilkinson catalyst (Shaanxi Ruike New Material Co., Ltd., Rh content >11%), and acetone to a 500 mL hydrogenation reactor. Open the nitrogen valve and purge with nitrogen to reach a pressure of 0.2 MPa inside the reactor. After purging three times, close the nitrogen valve. Open the hydrogen valve and purge with hydrogen to reach a pressure of 0.2 MPa inside the reactor. After purging three times, increase the pressure inside the reactor to 0.2-0.3 MPa, maintain the internal temperature at 25-35℃, and maintain the pressure for 15-16 hours. HPLC analysis of the reaction is performed; a doramectin content ≤1% is considered the reaction endpoint. After the reaction is complete, open the vent valve.

[0049] The solution was concentrated under reduced pressure at 40°C in an external bath to obtain a yellow, foamy solid. 30 mL of acetonitrile was added, and the mixture was stirred at 20-30°C for 3 hours to induce crystallization. The solid was then collected by filtration and transferred to a vacuum drying oven at 60°C for 3 hours to obtain 17.8 g of solid, the hydrogenated product. HPLC analysis showed a yield of 88.74% and a purity of 97.63%. The results are shown in Table 2. Figure 1 As shown.

[0050] Table 2. HPLC of hydrogenation products

[0051]

[0052] Example 2.

[0053] The feeding ratio for this embodiment is shown in Table 3 below:

[0054] Table 3. Feed ratios of oxidation products

[0055]

[0056] Following the feed ratio in Table 2, add the hydrogenation product, dichloromethane, and TEMPO (Shanghai Aladdin Reagent Co., Ltd., AR, 98%) to a 500mL reaction flask, followed by a saturated aqueous solution of sodium bicarbonate. Stir in an ice-water bath, maintaining an internal temperature of 0-10℃. Slowly add a 10% sodium hypochlorite solution, completing the addition over approximately 30 minutes, while maintaining the internal temperature at 0-10℃. Monitor the reaction by TLC (DCM:MeOH = 20:1), and the reaction is complete in approximately 2.5 hours.

[0057] The mixture was allowed to stand and separate into layers. The organic layer was collected, and the aqueous layer was extracted with 60 mL of dichloromethane three times. The organic phases were combined and washed with 60 mL of saturated sodium sulfite solution twice. The mixture was dried over 20 g of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 35 °C in an external bath to give about 20.3 g of a pale yellow oil.

[0058] Example 3.

[0059] Take 20.3 g of the oily substance obtained in Example 2, add 60 mL of toluene and 30 mL of methanol, heat and stir, dissolve at 60 °C, and maintain the temperature for 0.5 h. Turn off the heating and slowly cool to allow crystallization to occur for 3 h. A large amount of pale yellow solid precipitated, which was filtered and collected. The solid was transferred to a vacuum drying oven at 50 °C for 4 h to obtain 13.6 g. Yield: 78.94%, purity: 94.71%. The test results are shown in Table 4. Figure 2 As shown.

[0060] Table 4. HPLC of the oxidation products in Example 3

[0061]

[0062] Example 4.

[0063] The crude oxidation product was prepared according to Examples 1 and 2, yielding 19.2 g of an oily substance. 60 mL of methyl tert-butyl ether and 60 mL of ethanol were added, and the mixture was heated and stirred until dissolved at 55 °C for 0.5 h. Heating was then turned off, and the mixture was slowly cooled to allow crystallization to occur for 1 h. Crystallization was then continued for 2 h using an ice-water bath, maintaining an internal temperature of 0-10 °C. A large amount of pale yellow solid precipitated. The solid was filtered and collected. The solid was then transferred to a vacuum drying oven at 50 °C for 4 h to yield 15.1 g. Yield: 88.39%, Purity: 96.67%. The test results are shown in Table 5. Figure 3 As shown.

[0064] Table 5. HPLC of the oxidation products in Example 4

[0065]

[0066] Example 5.

[0067] The feeding ratio for this embodiment is shown in Table 6 below:

[0068] Table 6. Feed ratios for crude selamectin

[0069]

[0070] According to the feed ratio in Table 3, the oxidation product, hydroxylamine hydrochloride, water, and isopropanol were added to a 250 mL reaction flask. The temperature was raised to 40-50℃ and the reaction was maintained for 5 h. HPLC analysis showed that the oxidation product was ≤0.6% and the impurity C was ≤8%. 108 mL of saturated sodium bicarbonate was added to quench the reaction, and the mixture was allowed to stand for phase separation. The organic layer was collected, and the aqueous layer was extracted with 20 mL of dichloromethane three times. The organic phases were combined, dried with 20 g of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40℃ in an external bath to obtain 10.9 g.

[0071] Example 6.

[0072] Take 10.9 g of crude selamectin obtained in Example 5, add 30 mL of toluene and 10 mL of methanol, heat and stir, dissolve at 70 °C, turn off the heat, and slowly crystallize for 3 hours, precipitating a large amount of white solid. Filter, collect the solid, and dry under vacuum at 60 °C to obtain 8.4 g of solid.

[0073] Take 8.4 g of the above solid, add 25 mL of toluene and 42 mL of methanol, heat and stir, dissolve at 60 °C, turn off the heat, and allow slow crystallization for 3 hours, precipitating a large amount of white solid. Filter, collect the solid, and dry under vacuum at 60 °C to obtain 7.0 g of solid. The purity of selamectin is 99.7%, and the impurity C is 0.13%. The yield is 60.6%. The test results are shown in Table 7. Figure 4 As shown.

[0074] Table 7. HPLC of selamectin

[0075]

[0076] As shown above, the purity of the selamectin product obtained by this invention is ≥99.5%. Impurity C is a pharmacopoeia-specified impurity, a process byproduct generated by the removal of one sugar molecule from selamectin. Preparative liquid chromatography (HPLC) or column chromatography is primarily used to remove this impurity. This invention uses recrystallization instead of HPLC and column chromatography; recrystallization using a toluene-methanol mixture can also effectively reduce this impurity, achieving ≤0.15% on HPLC.

[0077] Comparative Example 1.

[0078] Selamectin was prepared according to the method disclosed in patent CN111116692A. After column chromatography, activated carbon adsorption, and recrystallization with 80% methanol, the finished selamectin product was obtained. The purity of the finished product was tested to be 99.35%. The HPLC detection results are shown in Table 8. Figure 5 ;

[0079] Table 8. HPLC of selamectin in Comparative Example 1

[0080]

[0081] Compared to the method disclosed in CN111116692A, this paper uses recrystallization to replace column chromatography, activated carbon adsorption and other operations, which is easier to industrialize and greatly reduces costs.

[0082] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0083] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing high-purity selamectin, characterized in that, Includes the following steps: S1. Dissolve doramectin (I) in acetone, add Wilkinson catalyst and mix, fill with nitrogen, vent air and switch to hydrogen atmosphere, heat to 25-35℃, react for 15-20h, remove excess solvent by rotary evaporation, recrystallize and purify to obtain hydrogenated doramectin (II). S2. Dissolve hydrogenated doramectin (II) in organic solvent A, add saturated sodium bicarbonate solution, maintain the temperature at 0-10℃, add oxidant and catalyst, react for 2-4 hours, extract the organic phase with dichloromethane 2-3 times, wash with sodium sulfite 2-3 times, add anhydrous sodium sulfate to dry, filter, remove excess solvent by rotary evaporation, recrystallize and purify to obtain oxidized doramectin (III). S3. Disperse oxydralazine (III) in a mixed solvent of organic solvent B and pure water, add hydroxylamine hydrochloride, react for 4-8 hours, quench the reaction by adding saturated sodium bicarbonate solution, extract the organic phase with dichloromethane, dry with anhydrous sodium sulfate and filter, remove excess solvent by rotary evaporation, recrystallize and purify to obtain crude selamectin, and recrystallize and purify again to obtain selamectin (IV). In step S2, the organic solvent A is any one or more of dichloromethane, tetrahydrofuran, and acetonitrile; the catalyst is TEMPO; and the oxidant is sodium hypochlorite. In step S2, during recrystallization purification, the recrystallization solvent is a mixed liquid of solvent A and solvent B in a volume ratio of (3-5):(0.5-5); Solvent A is any one of toluene or methyl tert-butyl ether; solvent B is any one or more of methanol, ethanol, isopropanol, and acetonitrile. In step S3, during recrystallization purification, the recrystallization solvent is a mixed solution of toluene and methanol; During the first recrystallization, the volume ratio of toluene to methanol was 3:(0-1); during the second recrystallization, the volume ratio of toluene to methanol was 3:(4-5).

2. The method for preparing high-purity selamectin according to claim 1, characterized in that: The chemical structural formula of the doramectin (I) is as follows: The chemical structural formula of the hydrogenated doramectin (II) is as follows: The chemical structural formula of the oxydoramectin (III) is as follows: The chemical structural formula of selamectin (Ⅳ) is as follows: 。 3. The method for preparing high-purity selamectin according to claim 1, characterized in that: In step S1, the mass ratio of doramectin (Ⅰ) to Wilkinson catalyst is 1:(0.02-0.05); during recrystallization purification, the recrystallization solvent is either methanol or acetonitrile.

4. The method for preparing high-purity selamectin according to claim 1, characterized in that: In step S2, the molar ratio of hydrodorafenib (II), sodium bicarbonate, oxidant and catalyst is 1:(2-3):(1.5-3):(0.2-0.5) based on molar parts.

5. The method for preparing high-purity selamectin according to claim 1, characterized in that: In step S3, the molar ratio of oxydoracin (III) to hydroxylamine hydrochloride is (3-6):

1.

6. The method for preparing high-purity selamectin according to claim 1, characterized in that: In step S3, the organic solvent B is any one or more of isopropanol, methanol, and dioxane; the volume ratio of the organic solvent B to pure water is (6-10):1.

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