A kind of method of synthesizing moxidectin

Abstract

The invention provides a method for synthesizing moxidectin, comprising steps: 1) adding a protective substance to nimoctin M0 for reaction, and protecting the 3' hydroxyl of nimoctin M0 to obtain an upper-protected intermediate M1; 2) Using Dess Martin oxidant to oxidize the protected intermediate M1 to obtain the oxidized intermediate M2; 3) deprotect the oxidized intermediate M2 to obtain the deprotected intermediate M3; 4) subject the deprotected intermediate M3 to an oxime chemical reaction to obtain moxidectin MX. The present invention uses Dess Martin oxidant to replace the Swern oxidation system in the prior art and PCC / PDC oxidation to oxidize the protected intermediate M1 to obtain the key intermediate M2 of moxidectin. The oxidation condition is mild and can be carried out at room temperature. , no need to use low temperature; and the oxidation reaction has good selectivity and high yield, and the obtained oxidation intermediate M2 has high purity.

Description

technical field

[0001] The invention belongs to the technical field of medicinal chemistry, in particular to a method for synthesizing moxidectin. Background technique

[0002] Moxidectin is a broad-spectrum, high-efficiency, new macrolide anthelmintic antibiotic widely used in veterinary clinics. It is a single-component, semi-synthetic macrolide drug produced by Streptomyces fermentation. It has It has good insect repellent activity, and has the characteristics of long-term effect and safety. Moxidectin is a derivative of nimoctin, and the main way is to produce nimoctin through Streptomyces fermentation, and then modify it through four steps of chemical reactions of upprotection, oxidation, oximation and deprotection.

[0003]

[0004] At present, the main oxidation systems reported in the preparation process of moxidectin include Swern oxidation and PCC / PDC oxidation (see: US4916154A). Swern oxidation mainly uses dimethyl sulfoxide / oxalyl chloride, dimethyl sulfoxid...

Examples

Embodiment 1

[0035] The present embodiment provides a method for synthesizing moxidectin, comprising the steps of:

[0036] 1) Add nimoctine (50g, purity 61%, 49.7mmol, 1.0eq), dichloromethane (500mL) and acid-binding agent triethylamine (30.2g, 298.5mmol, 6.0eq) in the there-necked flask, stir After nitrogen replacement, the temperature was lowered to -10~0°C under the protection of nitrogen, and the dichloromethane (100mL) solution of 4-nitrobenzoyl chloride (23.1g, 124.25mmol, 2.5eq) was added dropwise to react. The 3'hydroxyl group of moctin M0 is protected, and the internal temperature is controlled from -10 to 0°C.

[0037] After the reaction is complete, add 25 mL of methanol dropwise to the reaction liquid to quench, add 150 mL of water, let stand to separate the liquid, wash the organic layer with 1% hydrochloric acid and 15% saline successively, dry over anhydrous sodium sulfate, filter, and the filtrate is precipitated under negative pressure , adding 250 mL of methanol for cry...

Embodiment 2

[0043] The present embodiment provides a method for synthesizing moxidectin, comprising the steps of:

[0044] 1) This step is similar to step 1) of Example 1, the only difference is that the acid-binding agent triethylamine is replaced by imidazole (20.3g, 298.5mmol, 6.0eq) of the same molar mass.

[0045] As a result, 41.5 g of the upper protected intermediate M1 powder was obtained (yield 88.0%, HPLC purity 80.4%).

[0046] 2) Add 200 mL of toluene, Dess Martin oxidant (68.5 g, 161.4 mmol, 3.0 eq) and acid-binding agent potassium carbonate (18.6 g, 134.5 mmol, 2.5 eq) into a three-necked flask. The temperature was lowered to 10±5°C, and 120 mL of toluene solution of protected intermediate M1 powder (41 g, 53.8 mmol, 1.0 eq) was added dropwise, and the reaction temperature was controlled at 10±5°C.

[0047] After the feeding is completed, after the reaction at 10±5°C, the saturated sodium thiosulfate solution is added dropwise to terminate the reaction, and the liquid is se...

Embodiment 3

[0051] The present embodiment provides a method for synthesizing moxidectin, comprising the steps of:

[0052] 1) This step is similar to the step 1) of Example 1, except that dichloromethane is replaced by equal-volume 2-methyltetrahydrofuran, and the acid-binding agent triethylamine is replaced by pyridine of the same molar mass ( 23.6 g, 298.5 mmol, 6.0 eq).

[0053] As a result, 42.0 g of the upper protected intermediate M1 powder was obtained (yield 91.5%, HPLC purity 82.6%).

[0054] 2) Add 210 mL of 2-methyltetrahydrofuran, Dess Martin oxidizer (46.7 g, 110.2 mmol, 2.0 eq), and sodium hydroxide (11.0 g, 275.5 mmol, 5.0 eq) into a three-necked flask. The temperature was raised to 50±5°C, and 120 mL of 2-methyltetrahydrofuran solution of protected intermediate M1 powder (42 g, 55.1 mmol, 1.0 eq) was added dropwise, and the reaction temperature was controlled at 50±5°C.

[0055] After the feeding is completed, keep warm at 50±5°C. After the reaction is completed, add sat...

technical field

[0001] The invention belongs to the technical field of medicinal chemistry, in particular to a method for synthesizing moxidectin. Background technique

[0002] Moxidectin is a broad-spectrum, high-efficiency, new macrolide anthelmintic antibiotic widely used in veterinary clinics. It is a single-component, semi-synthetic macrolide drug produced by Streptomyces fermentation. It has It has good insect repellent activity, and has the characteristics of long-term effect and safety. Moxidectin is a derivative of nimoctin, and the main way is to produce nimoctin through Streptomyces fermentation, and then modify it through four steps of chemical reactions of upprotection, oxidation, oximation and deprotection.

[0003]

[0004] At present, the main oxidation systems reported in the preparation process of moxidectin include Swern oxidation and PCC / PDC oxidation (see: US4916154A). Swern oxidation mainly uses dimethyl sulfoxide / oxalyl chloride, dimethyl sulfoxid...

Examples

Embodiment 1

[0035] The present embodiment provides a method for synthesizing moxidectin, comprising the steps of:

[0036] 1) Add nimoctine (50g, purity 61%, 49.7mmol, 1.0eq), dichloromethane (500mL) and acid-binding agent triethylamine (30.2g, 298.5mmol, 6.0eq) in the there-necked flask, stir After nitrogen replacement, the temperature was lowered to -10~0°C under the protection of nitrogen, and the dichloromethane (100mL) solution of 4-nitrobenzoyl chloride (23.1g, 124.25mmol, 2.5eq) was added dropwise to react. The 3'hydroxyl group of moctin M0 is protected, and the internal temperature is controlled from -10 to 0°C.

[0037] After the reaction is complete, add 25 mL of methanol dropwise to the reaction liquid to quench, add 150 mL of water, let stand to separate the liquid, wash the organic layer with 1% hydrochloric acid and 15% saline successively, dry over anhydrous sodium sulfate, filter, and the filtrate is precipitated under negative pressure , adding 250 mL of methanol for cry...

Embodiment 2

[0043] The present embodiment provides a method for synthesizing moxidectin, comprising the steps of:

[0044] 1) This step is similar to step 1) of Example 1, the only difference is that the acid-binding agent triethylamine is replaced by imidazole (20.3g, 298.5mmol, 6.0eq) of the same molar mass.

[0045] As a result, 41.5 g of the upper protected intermediate M1 powder was obtained (yield 88.0%, HPLC purity 80.4%).

[0046] 2) Add 200 mL of toluene, Dess Martin oxidant (68.5 g, 161.4 mmol, 3.0 eq) and acid-binding agent potassium carbonate (18.6 g, 134.5 mmol, 2.5 eq) into a three-necked flask. The temperature was lowered to 10±5°C, and 120 mL of toluene solution of protected intermediate M1 powder (41 g, 53.8 mmol, 1.0 eq) was added dropwise, and the reaction temperature was controlled at 10±5°C.

[0047] After the feeding is completed, after the reaction at 10±5°C, the saturated sodium thiosulfate solution is added dropwise to terminate the reaction, and the liquid is se...

Embodiment 3

[0051] The present embodiment provides a method for synthesizing moxidectin, comprising the steps of:

[0052] 1) This step is similar to the step 1) of Example 1, except that dichloromethane is replaced by equal-volume 2-methyltetrahydrofuran, and the acid-binding agent triethylamine is replaced by pyridine of the same molar mass ( 23.6 g, 298.5 mmol, 6.0 eq).

[0053] As a result, 42.0 g of the upper protected intermediate M1 powder was obtained (yield 91.5%, HPLC purity 82.6%).

[0054] 2) Add 210 mL of 2-methyltetrahydrofuran, Dess Martin oxidizer (46.7 g, 110.2 mmol, 2.0 eq), and sodium hydroxide (11.0 g, 275.5 mmol, 5.0 eq) into a three-necked flask. The temperature was raised to 50±5°C, and 120 mL of 2-methyltetrahydrofuran solution of protected intermediate M1 powder (42 g, 55.1 mmol, 1.0 eq) was added dropwise, and the reaction temperature was controlled at 50±5°C.

[0055] After the feeding is completed, keep warm at 50±5°C. After the reaction is completed, add sat...

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