CN111825693B

CN111825693B - Method for synthesizing moxidectin

Info

Publication number: CN111825693B
Application number: CN202010667151.8A
Authority: CN
Inventors: 王标; 姜桥; 温军贤; 赖建龙; 陈果
Original assignee: Livzon New North River Pharmaceutical Co ltd
Current assignee: Livzon New North River Pharmaceutical Co ltd
Priority date: 2020-07-13
Filing date: 2020-07-13
Publication date: 2021-06-29
Anticipated expiration: 2040-07-13
Also published as: CN111825693A

Abstract

The invention provides a method for synthesizing moxidectin, which comprises the following steps: 1) adding a protective substance into nimustine M0 for reaction, and protecting the 3' hydroxyl of nimustine M0 to obtain an upper protection intermediate M1; 2) oxidizing the upper protection intermediate M1 by using a dessimantin oxidant to obtain an oxidation intermediate M2; 3) deprotection of oxidized intermediate M2 to give deprotected intermediate M3; 4) and carrying out oximation reaction on the deprotected intermediate M3 to obtain moxidectin MX. According to the method, the upper protective intermediate M1 is oxidized by using the dessimantin oxidant instead of a Swern oxidation system and PCC/PDC oxidation in the prior art to prepare the Moxidectin key intermediate M2, the oxidation condition is mild, the method can be carried out at normal temperature, and low temperature is not needed; moreover, the oxidation reaction has good selectivity and high yield, and the obtained oxidation intermediate M2 has high purity.

Description

Method for synthesizing moxidectin

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for synthesizing moxidectin.

Background

Moxidectin is a broad-spectrum, high-efficiency and novel macrolide anthelmintic antibiotic widely applied to veterinary clinic, is a semi-synthetic macrolide drug with single component generated by streptomyces fermentation, has good anthelmintic activity, and has the characteristics of long acting, safety and the like. Moxidectin is a derivative of nimustine, and is prepared mainly by producing nimustine through streptomyces fermentation and then modifying through four steps of protection, oxidation, oximation and deprotection.

The main oxidation systems reported in the current moxidectin preparation process are Swern oxidation and PCC/PDC oxidation (see: US 4916154A). The Swern oxidation mainly adopts dimethyl sulfoxide/oxalyl chloride, dimethyl sulfoxide/trifluoroacetic anhydride, dimethyl sulfoxide/phenoxy phosphoryl dichloride and the like as oxidants, the reaction is more classical and has certain cost advantage, but the oxidation reaction has violent heat release, needs to be carried out at low temperature, has more over-temperature side reactions, and can cause obvious increase of impurities and easy material flushing if the temperature is not accurately controlled. Furthermore, various oxidation impurities of the Swern oxidation system are difficult to remove, resulting in poor purity and yield of the oxidation intermediates and the final product moxidectin. In addition, a large amount of dimethyl sulfide as a byproduct generated by the reaction of the Swern oxidation system has malodor, influences the body health of operators and has great pollution to the environment, so that the environmental protection investment cost of enterprises is high. The PCC/PDC oxidation mainly adopts pyridinium chlorochromate or pyridinium dichromate as an oxidant, and has participation of heavy metal chromium, carcinogenicity and environmental friendliness.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention provides a method for synthesizing moxidectin, which reduces the synthesis temperature of an oxidation intermediate in the preparation process and has high selectivity and purity.

In the process of synthesizing moxidectin by taking nimustine as a raw material, firstly, hydroxyl connected with 3 'carbon in the nimustine needs to be protected to obtain an upper protection intermediate, and then the hydroxyl connected with 23' carbon in the upper protection intermediate is oxidized to form carbonyl to obtain an oxidized intermediate. Because the upper protection intermediate has 5 carbon-carbon double bonds, the carbons at the 7 'position and the 23' position respectively have one hydroxyl group, and two ester groups exist at the same time, the carbon-carbon double bonds, the hydroxyl at the 7 'position, the hydroxyl at the 23' position and the ester groups are likely to simultaneously have oxidation reactions in the process of oxidizing the upper protection intermediate, thereby reducing the selectivity of the target oxidation intermediate. Therefore, it is necessary to select the proper oxidant to selectively oxidize the hydroxyl group at the 23' position, so as to avoid other side reactions. The inventors have studied various oxidation systems and found that the dessimutan oxidant is a high-valence iodine compound oxidant, wherein pentavalent iodine has strong oxidizing property, and the dessimutan oxidant has a conjugated system, and can selectively oxidize the hydroxyl group at the 23' -position in the upper protective intermediate at normal temperature. In the process of oxidizing with the upper protection intermediate, iodine in the dessimidine oxidant is changed from pentavalent into trivalent, no other side reaction is caused, the reaction condition is mild, and the high selectivity is realized.

Specifically, the invention adopts the following technical scheme:

a method for synthesizing moxidectin, comprising the following steps:

1) adding a protective substance into nimustine M0 for reaction, and protecting the 3' hydroxyl of nimustine M0 to obtain an upper protection intermediate M1;

2) oxidizing the upper protection intermediate M1 by using a dessimantin oxidant to obtain an oxidation intermediate M2;

3) deprotection of oxidized intermediate M2 to give deprotected intermediate M3;

4) and carrying out oximation reaction on the deprotected intermediate M3 to obtain moxidectin MX.

The synthetic route is as follows:

in the step 2), the temperature of the oxidation is 0-100 ℃, and preferably 0-60 ℃.

In the step 2), the molar ratio of the upper protection intermediate M1 to the dessimutan oxidant is 1 (1-4); preferably 1 (1.5-3.5).

In the step 2), the oxidation process is specifically that an upper protection intermediate M1 and an acid-binding agent are added into an organic solvent, and then a dessimutan oxidant is added for oxidation reaction.

The molar ratio of the upper protection intermediate M1 to the acid-binding agent is 1 (2-8), and preferably 1 (2-5).

The acid binding agent is at least one selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, silver carbonate, sodium bicarbonate, sodium acetate, trimethylamine, triethylamine, tripropylamine, tributylamine, 4-dimethylaminopyridine, N-dimethylaniline, dimethylformamide, dimethylacetamide, pyridine, piperidine, N-diisopropylethylamine, 2, 6-dimethylpyridine and imidazole.

The organic solvent is selected from non-protonation organic solvent, preferably at least one of dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane, acetonitrile, acetone, toluene and the like.

In the step 1), the reaction temperature is not higher than 0 ℃.

In the step 1), the purity of the nimustine M0 is not less than 55%.

In the step 1), the protective substance is at least one selected from 4-nitrobenzoyl chloride, 4-chlorophenoxyacetyl chloride and tert-butyldimethylchlorosilane.

In the step 1), the 3' hydroxyl of the nimustine M0 is protected, specifically, the nimustine M0 and an acid-binding agent are added into an organic solvent, and then a protective substance is dripped for reaction. Wherein the molar ratio of the nimustine M0 to the acid-binding agent is 1 (3-6); the molar ratio of the protective substance to nimustine is (2-4): 1.

In the step 3), adding the oxidation intermediate M2 into an alkali solution for reaction to deprotect the oxidation intermediate M2; the reaction temperature is-10-0 ℃; the pH value of the alkali solution is 10-11; the alkali solution is selected from sodium hydroxide solution.

In step 4), the oximation reaction is carried out by mixing the deprotected intermediate M3 with methoxyamine hydrochloride. The temperature of the oximation reaction is-10-0 ℃. The oximation reaction is carried out under the condition that the pH value is 5-6.

In the step 4), after the oximation reaction is finished, purification is performed, and the purification method comprises at least one of column chromatography and recrystallization.

The purity of the moxidectin MX is more than 98 percent.

Compared with the prior art, the invention has the following beneficial effects:

(1) according to the method, the upper protective intermediate M1 is oxidized by using the dessimantin oxidant instead of a Swern oxidation system and PCC/PDC oxidation in the prior art to prepare the Moxidectin key intermediate M2, the oxidation condition is mild, the method can be carried out at normal temperature, and low temperature is not needed; moreover, the oxidation reaction has good selectivity and high yield, and the obtained oxidation intermediate M2 has high purity.

(2) In the process of preparing the key intermediate of moxidectin, the intermediate avoids column chromatography purification, is easy to separate and purify, or can be directly and continuously put through the idea of 'one-pot method', the separation and purification are not needed in the middle, the operation is simple, the reproducibility is good, and the product purity and the yield are higher than those of the prior art.

(3) The method has the advantages of mild reaction conditions, simple operation, safe raw materials, low cost, environmental protection, and contribution to controlling the cost and protecting the environment.

Detailed Description

The technical solution of the present invention is further illustrated by the following specific examples.

Example 1

This example provides a method for synthesizing moxidectin, comprising the steps of:

1) adding nimustine (50g, purity 61%, 49.7mmol, 1.0eq), dichloromethane (500mL) and acid-binding agent triethylamine (30.2g, 298.5mmol, 6.0eq) into a three-neck flask, stirring, replacing with nitrogen, cooling to-10-0 ℃ under the protection of nitrogen, dropwise adding a dichloromethane (100mL) solution of a protective substance 4-nitrobenzoyl chloride (23.1g, 124.25mmol, 2.5eq) for reaction, protecting the 3' hydroxyl of nimustine M0, and controlling the internal temperature to-10-0 ℃.

After the reaction, 25mL of methanol was added dropwise to the reaction solution to quench, 150mL of water was added, the mixture was allowed to stand for liquid separation, the organic phase layer was washed with 1% hydrochloric acid and 15% sodium chloride in this order, dried over anhydrous sodium sulfate, filtered, and after the filtrate was desolventized under negative pressure, 250mL of methanol was added for crystallization and vacuum-dried at 50-60 ℃ to obtain 43.1g of the upper protected intermediate M1 powder (yield 92.3%, HPLC purity 81.2%, conversion 98.8%).

2) In a three-necked flask, 200mL of methylene chloride, dessimutan oxidizer (47.8g, 112.8mmol, 2.0eq), and triethylamine (22.8g, 225.6mmol, 4.0eq), an acid-binding agent, were added. 120mL of a dichloromethane solution of protected intermediate M1 powder (43g, 56.4mmol, 1.0eq) was added dropwise at 25. + -. 5 ℃ with the reaction temperature controlled between 25. + -. 5 ℃.

After the addition is finished, after the reaction at 25 +/-5 ℃, a saturated sodium thiosulfate solution is dropwise added to terminate the reaction, standing and liquid separation are carried out, an organic phase layer is washed by 1% hydrochloric acid and 15% salt solution in sequence, anhydrous sodium sulfate is dried and filtered, after negative pressure desolventization of filtrate, 270mL of methanol is added for crystallization, and vacuum drying is carried out at 50-60 ℃ to obtain 38.4g of oxidized intermediate M2 powder (the yield is 89.5%, and the HPLC purity is 90.5%).

3) Adding the oxidized intermediate M2 powder (38.4g) obtained in the step 2) into 200mL of methanol, controlling the temperature to be minus 10-0 ℃, and dropwise adding 58mL of 5% sodium hydroxide solution for reaction, wherein the pH value is 10-11. After the low-temperature reaction is finished, acetic acid is added to adjust the pH value to 5-6, an organic solvent is used for extraction, salt water is used for washing, the organic phase is dried, negative pressure desolventization is carried out, and then the following step 4) is directly carried out (methanol, ethanol, propanol or butanol can be used for recrystallization after the negative pressure desolventization to obtain deprotected intermediate M3 powder).

4) Adding the product obtained after negative pressure desolventizing in the step 3) into 200mL of methanol, adding 19.0g of anhydrous sodium acetate, controlling the temperature to be-10-0 ℃, adding methoxyamine hydrochloride to carry out oximation reaction, and controlling the pH to be 5-6. And after the low-temperature reaction is finished, adding 50mL of 3% sodium bicarbonate solution to adjust the pH value to 7-8, extracting with an organic solvent, washing with salt water, drying the organic phase, desolventizing under negative pressure, and directly concentrating to dryness to obtain a crude moxidectin product. And then carrying out macroporous adsorption resin chromatography purification, wherein the adopted macroporous adsorption resin is SD286 resin, the sample loading amount is 30g/L, 60% acetone is prewashed, 65% acetone is eluted, the eluent is concentrated, and an ethanol/water system is crystallized to obtain 17.8g of Moxidectin refined product, the HPLC purity is 98.6%, and the total yield is 56%.

Example 2

1) this step is similar to step 1) of example 1, the only difference being the replacement of the acid-binding agent triethylamine with imidazole of the same molar mass (20.3g, 298.5mmol, 6.0 eq).

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

2) Into a three-necked flask, 200mL of toluene, Desmatin oxidant (68.5g, 161.4mmol, 3.0eq), and acid-binding agent potassium carbonate (18.6g, 134.5mmol, 2.5eq) were added. The temperature is reduced to 10 +/-5 ℃, 120mL of toluene solution of the protected intermediate M1 powder (41g, 53.8mmol, 1.0eq) is added dropwise, and the reaction temperature is controlled to be 10 +/-5 ℃.

After the addition is finished, after the reaction at 10 +/-5 ℃, a saturated sodium thiosulfate solution is dropwise added to terminate the reaction, standing and liquid separation are carried out, an organic phase layer is sequentially washed by water and 15% of common salt solution, dried by anhydrous sodium sulfate, filtered, and subjected to negative pressure desolventization of filtrate, 270mL of methanol is added for crystallization, and vacuum drying is carried out at 50-60 ℃ to obtain 36.9g of oxidized intermediate M2 powder (the yield is 90.2%, the HPLC purity is 88.6%, and the conversion rate is 98.5%).

3) This step is the same as step 3) of example 1.

4) This step is the same as step 4) of example 1. As a result, 18.5g of moxidectin refined product is obtained, the HPLC purity is 98.3%, and the total yield is 58%.

Example 3

1) this step is similar to step 1) of example 1, with the exception that: the dichloromethane was replaced by an equal volume of 2-methyltetrahydrofuran and the acid-binding agent triethylamine was replaced by the same molar mass of pyridine (23.6g, 298.5mmol, 6.0 eq).

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

2) Into a three-necked flask were charged 210mL of 2-methyltetrahydrofuran, dessimutan oxidizer (46.7g, 110.2mmol, 2.0eq), and sodium hydroxide (11.0g, 275.5mmol, 5.0 eq). The temperature is raised to 50 +/-5 ℃, 120mL of 2-methyltetrahydrofuran solution of the protected intermediate M1 powder (42g, 55.1mmol, 1.0eq) is added dropwise, and the reaction temperature is controlled to be 50 +/-5 ℃.

After the addition, keeping the temperature at 50 +/-5 ℃, after the reaction is finished, dropwise adding a saturated sodium thiosulfate solution to terminate the reaction, standing and separating the liquid, washing an organic phase layer with water and 15% of salt solution in sequence, drying the organic phase layer with anhydrous sodium sulfate, filtering, desolventizing the filtrate under negative pressure, adding 270mL of methanol for crystallization, and drying the mixture in vacuum at 50-60 ℃ to obtain 30.8g of oxidized intermediate M2 powder (the yield is 87.5%, the HPLC purity is 86.3%, and the conversion rate is 94.4%).

3) This step is the same as step 3) of example 1.

4) This step is the same as step 4) of example 1. As a result, 16.2g of moxidectin refined product is obtained, the HPLC purity is 98.4%, and the total yield is 51%.

In the above examples 1 to 3, the products of the respective steps are dried and purified, and in order to examine the yield, conversion rate, purity, and the like, in the actual production process, the reaction of the steps 1) to 3) is completed and then the next reaction is directly performed, and the steps such as drying and purification are not performed.

Comparative example 1

This comparative example provides a process for synthesizing moxidectin, which is different from example 1 in that descimantin oxidant was replaced with manganese dioxide of an equal molar mass, so that the conversion of the oxidation reaction in step 2) was 0 and no oxidation intermediate M2 was produced.

This result may be due to the low oxidation activity of manganese dioxide in the system, which makes it difficult to oxidize the hydroxyl group of the protected intermediate M1 which is not conjugated with a double bond.

Comparative example 2

This comparative example provides a process for the synthesis of moxidectin, which differs from example 1 in that the descimetidine oxidant is replaced by potassium permanganate of equimolar mass, so that the conversion of the oxidation reaction in step 2) is 0 and no intermediate M2 is formed.

This result may be due to the fact that potassium permanganate has too strong oxidizing activity, which leads to deterioration of intermediates and oxidative degradation of various groups in the system.

Comparative example 3

The comparison example provides a method for synthesizing moxidectin, which is different from the method in example 1 in that a tesmadin oxidant is replaced by a tempo (tetramethylpiperidine oxynitride)/sodium hypochlorite/sodium bromide oxidation system with the same molar mass, and the result shows that the conversion rate of the oxidation reaction in the step 2) is 20-30%, which is lower than that of the method.

This result may be due to the presence of multiple double bonds in the structure of the upper protected intermediate M1, which causes a side reaction of double bond addition after reacting with the tempo/sodium hypochlorite/sodium bromide oxidation system, resulting in poor reaction selectivity.

Comparative example 4

This comparative example provides a process for synthesizing moxidectin, which is different from example 1 in that descimantin oxidant was replaced with pyridinium chlorochromate of equal molar mass, and shows that the conversion of the oxidation reaction in step 2) was 70%. Although the oxidation effect is good, the heavy metal chromium is introduced, so that the toxicity is high.

Comparative example 5

This comparative example provides a process for the synthesis of moxidectin, which differs from example 1 in that descimantin oxidant is replaced by N-bromosuccinimide of equimolar mass, showing a conversion of the oxidation reaction in step 2) of 9%.

The lower oxidation conversion rate of the N-bromosuccinimide to the upper protection intermediate M1 is mainly caused by the poor reaction selectivity caused by the double bond addition side reaction of a plurality of double bonds existing in the structure of the upper protection intermediate M1.

Comparative example 6

The comparative example provides a method for synthesizing moxidectin, which is different from the method in example 1 in that the descimantin oxidant is replaced by TPAP-NMO with equal molar mass, and the result shows that the conversion rate of the oxidation reaction in the step 2) is 0, mainly because the TPAP-NMO has strict requirement on moisture, the presence of water can hinder the oxidation reaction of the TPAP-NMO, and the presence of moisture can not be avoided under the non-harsh reaction environment of example 1, so that the TPAP-NMO can not oxidize the upper protective intermediate M1.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims

1. A method for synthesizing moxidectin, which is characterized by comprising the following steps: the method comprises the following steps:

1) adding a protective substance into nimustine for reaction, and protecting the 3' hydroxyl of nimustine to obtain a compound with the structural formula

The upper protected intermediate M1;

2) adding the upper protection intermediate M1 and an acid-binding agent into an organic solvent, and then adding a dessimutan oxidant for oxidation reaction to obtain a compound with a structural formula

Intermediate M2 of Oxidation of(ii) a The temperature of the oxidation reaction is 0-100 ℃, and the acid-binding agent is at least one selected from triethylamine, potassium carbonate and sodium hydroxide;

3) deprotection of the oxidized intermediate M2 to give a compound of formula

Deprotected intermediate M3;

4) the deprotected intermediate M3 is subjected to an oximation reaction to give moxidectin.

2. The method of synthesizing moxidectin according to claim 1, wherein: in the step 2), the temperature of the oxidation is 0-60 ℃.

3. The method of synthesizing moxidectin according to claim 1, wherein: in the step 2), the molar ratio of the upper protection intermediate M1 to the dessimutan oxidant is 1 (1-4).

4. A method of synthesizing moxidectin according to claim 3, wherein: in the step 2), the molar ratio of the upper protection intermediate M1 to the dessimutan oxidant is 1 (1.5-3.5).

5. The method of synthesizing moxidectin according to claim 1, wherein: the molar ratio of the upper protection intermediate M1 to the acid-binding agent is 1 (2-8).

6. The method of synthesizing moxidectin according to claim 5, wherein: the organic solvent is selected from the group consisting of non-protonated organic solvents.

7. A process for the synthesis of moxidectin according to any one of claims 1 to 6, wherein: the purity of the moxidectin is more than 98 percent.