Synthetic method for effectively reducing impurity content in moxidectin
By using bromomethyl methyl ether and acid as a combination of protective reagents and TEMPO/TCCA oxidant system, the problems of impurities and severe oxidation reactions in the prior art were solved, and the high purity synthesis of moxikine was achieved. , reducing costs and environmental pressure.
Patent Information
- Application Number
- CN202411129541.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-16
- Publication Date
- 2024-12-27
AI Technical Summary
In the existing moxikine synthesis method, impurities are generated when deprotection under alkaline conditions, which affects product quality. In addition, oxidants such as Swern react violently and have many side reactions, and by-products are toxic, which increases cost and environmental pressure.
Use bromomethyl methyl ether as the upper protection reagent, acid as the deprotection reagent, and use tetramethylpiperidine nitrogen oxide (TEMPO)/trichloroisocyanuric acid (TCCA) system as the oxidant to avoid alkaline conditions and achieve mild Reaction conditions and high chemical selectivity.
It effectively reduces the impurity content, improves the purity of the deprotection intermediate, avoids the use of low temperatures and toxic reagents, simplifies operations, reduces costs, and makes the synthesis of moxikidetin more feasible and economical.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a synthesis method for effectively reducing impurities of moxidectin. Background Art
[0002] Moxidectin is a semi-synthetic single-ingredient new macrolide antibiotic produced by the fermentation of Streptomyces, and is a derivative of nimoctin. In the mid-1980s, moxidectin began to be used as a veterinary anthelmintic. The US FDA approved its listing in June 2018, with the trade name Moxidectin. Among the macrolide antiparasitic drugs, it belongs to the third generation of avermectins. Compared with avermectin, moxidectin has a single chemical composition, is easier to control quality, has a wide anthelmintic spectrum, high insecticidal activity, strong persistence, safe use, and has higher fat solubility and water solubility. Therefore, it is easy to combine with a variety of excipients to prepare various preparations. Moxidectin is made from nimoctin produced by the fermentation of Streptomyces, and is obtained by hydroxyl protection, oxidation, deprotection reaction and oximation reaction, in which the reaction order of oximation and deprotection can be interchanged.
[0003]
[0004] At present, the upper protection reagent reported in the literature is mainly chlorosilane and aryl formyl chloride. Patent US4916154A uses tert-butyldimethylchlorosilane as the upper protection reagent to obtain the upper protection intermediate, but the amount of this upper protection reagent is large, and the obtained upper protection intermediate has large viscosity and cannot be separated by recrystallization. It can only be separated by column chromatography, and the steps are complicated while increasing the use and processing costs of organic solvents. Patent US4988824 uses p-nitrobenzoyl chloride as the upper protection reagent. Although it can purify the intermediate by recrystallization, it also causes yield loss. And nitrobenzene compounds are toxic, have poor thermal stability, and are difficult to apply on a large scale. The upper protection reagent used by patent CN104017001A is 4-chlorophenoxyacetyl chloride, which is expensive, highly active, and easily decomposed when exposed to water, so it is low as a hydroxyl protecting group yield. The above patents all require alkaline conditions for deprotection, but the presence of alkali will cause many side reactions, produce impurities, affect product quality, and bring great difficulties to the separation and purification of subsequent products. Patent CN111592553A uses allyl chloroformate as the protecting agent and the deprotecting agents used are expensive tetrakis(triphenylphosphine)palladium and potassium borohydride, which greatly increases the cost and is not suitable for industrial production. At present, the oxidation systems used to prepare moxidectin mainly include Swern oxidation and Dess-Martin oxidation. Swern oxidation is more violent, with many side reactions, and oxidation impurities are difficult to remove, which affects product quality. In addition, the byproduct of Swern oxidation is malodorous dimethyl sulfide, which is harmful to health and increases the environmental protection cost of enterprises. Dess-Martin oxidant is relatively expensive and used in large quantities, which increases costs.
[0005] We found that bromomethyl methyl ether (MOMBr) was used as the protecting agent and acid as the deprotecting agent, avoiding the use of base, and significantly reducing impurities. When tetramethylpiperidinium N-oxide (TEMPO) / trichloroisocyanuric acid (TCCA) system was used as the oxidant, the reaction conditions were mild, with high chemical selectivity, avoiding the use of low temperature and toxic reagents, and the operation was simple and the cost was low. Summary of the invention
[0006] In order to overcome the problems in the prior art, the present invention aims to provide a method for preparing moxidectin with mild conditions, simple operation, low cost and the ability to effectively reduce the impurity content.
[0007] When using nimoctin as a raw material to synthesize moxidectin, the hydroxyl group on the carbon at position 3 of nimoctin needs to be protected first to obtain a protected intermediate. We found that when bromomethyl methyl ether is used as a protecting agent, acid is used as its deprotecting agent, which can effectively reduce the impurity problem generated when the base is used as a deprotecting agent (see patent CN111362965A and patent CN111592553A). Then, the hydroxyl group on the carbon at position 23 of the protected intermediate needs to be oxidized to a ketone carbonyl group to obtain an oxidized intermediate. It should be noted that the intermediate also contains multiple reaction sites: a carbon-carbon double bond, an ester group, and a hydroxyl group on the carbon at position 7. Therefore, a highly selective oxidant is required to oxidize the hydroxyl group on the carbon at position 23 without causing side reactions in other groups. The TEMPO / TCCA oxidation system can oxidize primary or secondary alcohols into aldehydes and ketones under mild conditions, has high chemical selectivity, and can avoid the use of low temperatures and toxic reagents.
[0008] Specifically, the present invention adopts the following technical solutions:
[0009] A synthetic method for effectively reducing the impurities of moxidectin comprises the following steps:
[0010] 1) Add MOMBr and a base to nimoctin to carry out an upper protection reaction to obtain an upper protected intermediate M1;
[0011] 2) TEMPO / TCCA oxidizes the protected intermediate M1 to obtain the oxidized intermediate M2;
[0012] 3) deprotecting the oxidized intermediate M2 with an acid to obtain a deprotected intermediate M3;
[0013] 4) The deprotected intermediate M3 is subjected to oximation reaction to obtain moxidectin MX.
[0014] Its synthetic route is as follows:
[0015]
[0016] In step 1), the solvent is selected from a non-protonated organic solvent, preferably at least one of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, methyl tert-butyl ether and the like.
[0017] In step 1), the base is selected from triethylamine, N,N-diisopropylethylamine and the like.
[0018] The molar ratio of nimoctin, bromomethyl methyl ether and base is 1:(1.0-4.0):(2.0-4.0).
[0019] In step 1), the temperature is 10-60°C.
[0020] In step 2), the oxidation temperature is -10 to 35°C.
[0021] In step 2), the molar ratio of the upper protected intermediate M1 to tetramethylpiperidine nitrogen oxide (TEMPO) and trichloroisocyanuric acid (TCCA) is 1:(0.01-0.1):(1-3).
[0022] In step 2), the oxidation process is specifically as follows: adding the upper protected intermediate M1, TCCA and ethanol to an organic solvent, and then adding a TEMPO solution in the organic solvent to carry out an oxidation reaction.
[0023] The organic solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene and the like.
[0024] In step 3), the solvent is selected from at least one of methanol, ethanol, isopropanol and tert-butanol.
[0025] In step 3), the acid is selected from at least one of sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, citric acid, acetic acid and the like.
[0026] The molar ratio of the oxidation intermediate M2:acid is 1:(0.1-1).
[0027] The temperature of the demethylation reaction of the methyl ether protecting group is 30-90°C.
[0028] In step 4), the molar ratio of the deprotected intermediate M3: anhydrous sodium acetate: methoxyamine hydrochloride is 1:3-5:1.5-2.5.
[0029] The temperature of the oximation reaction is -10°C to 10°C.
[0030] In step 4), purification is performed after the oximation reaction is completed, and the purification method includes at least one of column chromatography and recrystallization.
[0031] The purity of the moxidectin is greater than 98%.
[0032] Compared with the prior art, the present invention has the following beneficial effects:
[0033] (1) In the present invention, when bromomethyl methyl ether is used as the protecting agent and acid is used as the deprotecting agent, the impurity problem generated when the base is used as the deprotecting agent can be effectively reduced, and the obtained deprotected intermediate M3 has high purity, which is helpful for subsequent purification.
[0034] (2) When the TEMPO / TCCA system is used as the oxidant in the present invention, the reaction conditions are mild, the reaction has high chemical selectivity, and the use of low temperature and toxic reagents is avoided.
[0035] (3) The reaction conditions of the present invention are relatively mild, the raw materials are widely available and in sufficient supply at low cost, each step of the reaction is a conventional operation that is easy to control, does not require complex equipment, and is simple to operate, making the method possible for large-scale industrial production. DETAILED DESCRIPTION
[0036] The technical solution of the present invention is further described below through specific embodiments.
[0037] Embodiment 1:
[0038] This embodiment provides a method for synthesizing moxidectin, comprising the following steps:
[0039] 1) Nimoctin (10 g, purity 67%, 10.9 mmol, 1.0 eq) and dichloromethane (150 mL) were added to a three-necked flask, and the atmosphere was replaced with nitrogen under stirring. N,N-diisopropylethylamine (DIEA) (4.2 g, 32.79 mmol, 3.0 eq) and MOMBr (2.7 g, 21.9 mmol, 1.0 eq) were added dropwise at room temperature to protect the 3' hydroxyl group of nimoctin M0. The internal temperature was controlled at 15°C to 25°C. After the reaction was completed, saturated NH4Cl aqueous solution (40 mL) was added to the reaction solution, stirred, and allowed to stand for separation. The organic phase was then washed with water (100 mL) and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under negative pressure, and 50 mL of methanol was added for crystallization. The solution was dried in vacuo at 50-60°C to obtain the upper protected intermediate M1: 7.9 g (yield 90.8%, HPLC purity 82.3%, conversion rate 98.5%).
[0040] 2) Add intermediate M1 (7.2 g, 9 mmol, 1.0 eq), trichloroisocyanuric acid (TCCA) (2.1 g, 9 mmol, 1.0 eq), ethanol (2.14 g, 9.5 mmol), and dichloromethane (150 mL) into a three-necked flask, replace with nitrogen under stirring, cool to -10 to 0 ° C under nitrogen protection, add TEMPO (0.014 g, 0.09 mmol, 0.01 eq) in dichloromethane (5 mL) while maintaining this temperature, slowly warm the reaction solution to room temperature and stir until the reaction is completed. After the reaction is completed, the reaction solution is first filtered with diatomaceous earth, and the organic phase in the filtrate is washed with saturated NaHCO3 (100 mL) solution, 1N HCl (100 mL) and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate is desolvated under negative pressure to obtain 6.2 g of oxidation intermediate M2 (yield 95%, HPLC purity 90.3%), without further purification.
[0041] 3) In a three-necked flask at room temperature, the oxidized intermediate M2 (6.2 g, 8.55 mmol, 1.0 eq) obtained in step 2) was dissolved in methanol (50 mL), and concentrated hydrochloric acid (0.35 mL, 4.27 mmol, 0.5 eq) was added thereto. The temperature was raised to 60-65°C and stirred until the reaction was complete. After the reaction was completed, the temperature was lowered to room temperature, saturated NaHCO3 (100 mL) and an organic solvent (200 mL) were added to the reaction solution, and the aqueous phase was extracted with an organic solvent (50 mL*3), the organic phases were combined and washed with water (50 mL*3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under negative pressure to obtain the deprotected intermediate M3, and then directly proceeded to step 4.
[0042] 4) The intermediate M3 was dissolved in 50 mL of dichloromethane, anhydrous sodium acetate (2.1 g, 25.65 mmol, 3.0 eq) was added, the temperature was controlled at 0-10°C, methoxyamine hydrochloride (1.07 g, 12.8 mmol, 1.5 eq) was slowly added, and finally glacial acetic acid was slowly added to adjust the pH to 5-6. After the reaction was complete, 3% sodium bicarbonate solution was added to adjust the pH to 7-8, organic solvent extraction (50 mL*3) was performed, the organic phases were combined and washed with water (50 mL*3), washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was desolvated under negative pressure to obtain crude moxidectin. The crude product was purified by adsorption with a macroporous resin, and the macroporous resin used was LK20SS-100. The sample amount was 40 g / L, pre-washed with 60% acetone, eluted with 65% acetone, the eluate was concentrated, and crystallized in ethanol / water system to obtain 3.8 g of pure moxidectin with HPLC purity of 98.4% and a total yield of 53%.
[0043] Embodiment 2:
[0044] This embodiment provides a method for synthesizing moxidectin, comprising the following steps:
[0045] 1) Nimoctin (10 g, purity 67%, 10.9 mmol, 1.0 eq) and chloroform (150 mL) were added to a three-necked flask, and nitrogen was replaced under stirring. Triethylamine (3.3 g, 32.79 mmol, 3.0 eq) and MOMBr (5.4 g, 43.8 mmol, 2.0 eq) were added dropwise at room temperature to protect the 3' hydroxyl group of nimoctin M0, and the internal temperature was controlled at 15°C to 25°C. After the reaction was completed, the post-treatment method was the same as step 1) of Example 1.
[0046] As a result, the protected intermediate M1 was obtained: 7.74 g (yield 88%, HPLC purity 81.4%, conversion rate 96%).
[0047] 2) Add intermediate M1 (7.2 g, 9 mmol, 1.0 eq), trichloroisocyanuric acid (TCCA) (6.3 g, 27 mmol, 3.0 eq), ethanol (2.14 g, 9.5 mmol), acetonitrile (200 mL) into a three-necked flask, replace with nitrogen under stirring, cool to -10 to 0 ° C under nitrogen protection, add TEMPO (0.14 g, 0.9 mmol, 0.1 eq) in acetonitrile (5 mL) while maintaining this temperature, slowly warm the reaction solution to room temperature and stir until the reaction is complete. After the reaction is completed, the post-treatment method is the same as step 2) of Example 1.
[0048] As a result, the protected intermediate M2 was obtained: 6.13 g (yield 93.2%, HPLC purity 89.9%) without further purification.
[0049] 3) This step is similar to step 3) of Example 1, except that the acid is replaced with concentrated sulfuric acid (0.46 mL, 8.4 mmol, 1.0 eq).
[0050] 4) This step is the same as step 4) of Example 1. 3.6 g of pure dermoxidectin was obtained, with a HPLC purity of 98.8% and a total yield of 50.8%.
[0051] Embodiment 3:
[0052] This embodiment provides a method for synthesizing moxidectin, comprising the following steps:
[0053] 1) This step is similar to step 1) of Example 1, except that N,N-diisopropylethylamine is replaced with triethylamine of the same molar mass (3.3 g, 32.79 mmol, 3.0 eq), and MOMBr is increased to 3 equivalents (8.1 g, 65.7 mmol, 3.0 eq).
[0054] As a result, the protected intermediate M1 was obtained: 7.74 g (yield 93%, HPLC purity 86%, conversion rate 97%).
[0055] 2) This step is similar to step 2) of Example 1, except that the amounts of TCCA and TEMPO are increased: TCCA (4.2 g, 18 mmol, 2.0 eq), TEMPO (0.07 g, 0.45 mmol, 0.05 eq).
[0056] As a result, the protected intermediate M2 was obtained: 6.26 g (yield 96.0%, HPLC purity 90.5%).
[0057] 3) This step is the same as step 3) of Example 1.
[0058] 4) This step is similar to step 4) of Example 1, except that the amount of methoxyamine hydrochloride (1.52 g, 18.1 mmol, 2.1 eq) is increased. 4.0 g of pure demoxidectin, yield of about 60.4%, HPLC purity of 98.5%, m / z 641 (M+H) + .
[0059] In summary, the present invention uses acid instead of the prior art base for deprotection, and the impurity content is significantly reduced. The present invention has mild reaction conditions, high chemical selectivity, can avoid the use of low temperature and toxic reagents, is simple to operate, and has low cost.
Claims
1. A synthetic method for effectively reducing the impurity content in moxidectin, characterized in that: The steps include: 1) Add bromomethyl methyl ether to nimoctin to protect the 3' hydroxyl group of nimoctin to obtain the structural formula: The protected intermediate M1; 2) Using tetramethylpiperidine nitrogen oxide and trichloroisocyanuric acid oxidation system to oxidize the 23' hydroxyl group of the protected intermediate M1, the structural formula is obtained The protected intermediate M2; 3) Deprotect the oxidized intermediate M2 with acid to obtain the structural formula: The deprotected intermediate M3; 4) The deprotected intermediate M3 is subjected to oximation reaction to obtain moxidectin.
2. The method for synthesizing moxidectin according to claim 1, characterized in that: In step 1), the solvent is selected from a non-protonated organic solvent, preferably at least one of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, and methyl tert-butyl ether.
3. The method for synthesizing moxidectin according to claim 1, characterized in that: In step 1), the base is selected from triethylamine and N,N-diisopropylethylamine.
4. The method for synthesizing moxidectin according to claim 1, characterized in that: In step 1), the molar ratio of nimoctin, bromomethyl methyl ether and base is 1:(1.0-4.0):(2.0-4.0).
5. The method for synthesizing moxidectin according to claim 1, characterized in that: In step 2), the oxidation process is specifically as follows: adding the upper protected intermediate M1, trichloroisocyanuric acid and ethanol to an organic solvent, and then adding a tetramethylpiperidine nitrogen oxide solution in the organic solvent to carry out an oxidation reaction.
6. The method for synthesizing moxidectin according to claim 5, characterized in that: The molar ratio of the upper protected intermediate M1 to tetramethylpiperidine nitrogen oxide and trichloroisocyanuric acid is 1:(0.01-0.1):(1-3).
7. The method for synthesizing moxidectin according to claim 5, characterized in that: The organic solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene and the like.
8. The method for synthesizing moxidectin according to claim 1, characterized in that: In step 3), the solvent is selected from at least one of methanol, ethanol, isopropanol and tert-butanol.
9. The method for synthesizing moxidectin according to claim 1, characterized in that: In step 3), the acid is selected from at least one of sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, citric acid and acetic acid.
10. The method for synthesizing moxidectin according to claim 1, characterized in that: In step 3), the molar ratio of the oxidation intermediate M2:acid is 1:(0.1-1).