阅读说明：本技术 一种23-酮阿维菌素B2a/B2b衍生物的制备方法 (Preparation method of 23-ketone avermectin B2a/B2B derivative ) 是由 田学芳 杨泽宇 王博 张明珠 侯红欣 贾成国 于 2021-09-01 设计创作，主要内容包括：本发明公开了一种23-酮阿维菌素B2a/B2b衍生物的制备方法,在惰性溶剂中一定温度下,5位和4”位至少有一个羟基的阿维菌素B2a/B2b衍生物与烷基氯硅烷进行反应,得到保护的阿维菌素B2a/B2b衍生物,再加入氧化剂将23-羟基氧化为羰基,最后在酸性条件下脱去保护基,得到目标产物式Ⅰ,本发明制备方法简单易操作,避免了传统脱保护方法将23-羰基还原为羟基的情况。(The invention discloses a preparation method of a 23-keto abamectin B2a/B2B derivative, which comprises the steps of reacting an abamectin B2a/B2B derivative with at least one hydroxyl at the 5-position and the 4' -position with alkyl chlorosilane in an inert solvent at a certain temperature to obtain a protected abamectin B2a/B2B derivative, adding an oxidant to oxidize 23-hydroxyl into carbonyl, and removing a protecting group under an acidic condition to obtain a target product, namely a formula I.)

1. A preparation method of a 23-ketone avermectin B2a/B2B derivative is characterized by comprising the following steps: the 23-ketone avermectin B2a/B2B derivative is a compound shown as a formula I:

wherein:

R¹is hydrogen or methyl;

R²is hydroxy or other group;

R³is hydroxy or other group;

R²or R³At least one is hydroxyl;

the preparation method comprises the following steps:

s1, dissolving the compound shown in the formula II in an inert solvent, adding a protective agent and organic alkali at a certain temperature, and protecting the hydroxyl at the 5-position and/or the 4-position;

wherein:

R¹is hydrogen or methyl;

R²is hydroxy or other group;

R³is hydroxy or other group;

R²or R³At least one is hydroxyl;

s2, adding organic alkali and a certain amount of oxidant and pro-oxidant into S1, oxidizing the hydroxyl at the 23 position into carbonyl, adding alkali to remove excessive oxidant, washing with water to remove salt generated by the reaction, and layering to obtain an organic phase;

and S3, adding a certain amount of acid into the organic phase, removing the protective agent, washing with water for layering, and evaporating the solvent from the organic phase to obtain the target product shown in the formula I.

2. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 1, wherein: the protective agent in the step S1 is alkoxy chlorosilane, the molar ratio of the protective agent to the raw material formula II is 1.0-3.0: 1.0, and the reaction temperature is-20-10 ℃.

3. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 2, wherein: the protective agent in the step S1 is trimethylchlorosilane or triethylchlorosilane.

4. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 1, wherein: the inert solvent in the step S1 is dichloromethane, dichloroethane, toluene, sec-butyl acetate or isopropyl acetate, and the weight ratio of the inert solvent to the raw material formula II is 2-5: 1.

5. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 1, wherein: the organic base in the steps S1 and S2 is triethylamine, tetramethyl ethylene diamine or diisopropylamine, and the molar ratio of the organic base to the protective agent is 1-1.5: 1.

6. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 1, wherein: the oxidant in step S2 is dimethyl sulfoxide; the pro-oxidant is solid phosgene or phenyl phosphate diacid chloride, the molar ratio of the oxidant to the pro-oxidant to the raw material formula II is 1.0-5.0: 0.5-4.0: 1.0, and the reaction temperature is as follows: -20 ℃ to 30 ℃.

7. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 6, wherein: the pro-oxidant is phenyl phosphate diacid chloride.

8. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 1, wherein: the acid in the step S3 is organic strong acid and inorganic strong acid, and the molar ratio of the acid to the raw material formula II is 0.1-2.0: 1.0, the reaction temperature is: 0 to 30 ℃.

9. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 8, wherein: the acid is trifluoroacetic acid.

Technical Field

The invention relates to a preparation method of a 23-ketoavermectin B2a/B2B derivative, belonging to the field of organic synthesis reaction.

Background

With the research on the abamectin series compounds, the abamectin B2 series compounds with high content can be separated at present. Researches show that the abamectin B2 series compounds and abamectin B1 series compounds have different insecticidal spectrums and insecticidal effects, so that the abamectin B2 series compounds have high research significance.

For example, the abamectin B2a has good insecticidal activity on underground nematodes, after the abamectin B2a is metabolized into 23-keto abamectin B2a, the 23-keto abamectin B2a is further researched to obtain the 23-keto abamectin B2a/B2B derivative, and the 23-keto abamectin B2a/B2B derivative such as the compound formula I has certain insecticidal activity on pests, so that the compound formula I has great research value.

Wherein:

wherein:

R¹is hydrogen or methyl;

R²is hydroxy or other group;

R³is hydroxy or other group;

R²or R³At least one is a hydroxyl group.

The avermectin B1 compounds also relate to protection oxidation and reduction deprotection of hydroxyl, which is to use allyl chloroformate to protect the hydroxyl of avermectin B2a, oxidize light and dimethyl sulfoxide, and reduce and deprotect by using sodium borohydride, but during deprotection reaction, the carbonyl at the 23-position is also reduced to hydroxyl, and a target product shown in formula I cannot be obtained.

In addition, the target product of formula I can be obtained by performing a protection reaction on abamectin B2a and phenoxyacetyl chloride under the action of pyridine and performing an oxidation reaction under the action of dimethyl sulfoxide, oxalyl chloride and triethylamine. However, the reaction carried out in this way gives only a very small amount of the desired product.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a preparation method of the 23-keto abamectin B2a/B2B derivative, and the yield of the obtained 23-keto abamectin B2a/B2B derivative formula I is more than 80%.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows:

a preparation method of a 23-ketoavermectin B2a/B2B derivative is disclosed, wherein the 23-ketoavermectin B2a/B2B derivative is a compound shown as a formula I:

wherein:

R¹is hydrogen or methyl;

R²is hydroxy or other group;

R³is hydroxy or other group;

R²or R³At least one is hydroxyl;

the preparation method comprises the following steps:

s1, dissolving the compound shown in the formula II in an inert solvent, adding a protective agent and organic alkali at a certain temperature, and protecting the hydroxyl at the 5-position and/or the 4-position;

wherein:

R¹is hydrogen or methyl;

R²is hydroxy or other group;

R³is hydroxy or other group;

R²or R³At least one is hydroxyl;

s2, adding organic alkali and a certain amount of oxidant and pro-oxidant into S1, oxidizing the hydroxyl at the 23 position into carbonyl, adding alkali to remove excessive oxidant, washing with water to remove salt generated by the reaction, and layering to obtain an organic phase;

and S3, adding a certain amount of acid into the organic phase, removing the protective agent, washing with water for layering, and evaporating the solvent from the organic phase to obtain the target product shown in the formula I.

The technical scheme of the invention is further improved as follows: the protective agent in the step S1 is alkoxy chlorosilane, the molar ratio of the protective agent to the raw material formula II is 1.0-3.0: 1.0, and the reaction temperature is-20-10 ℃.

The technical scheme of the invention is further improved as follows: the protective agent in the step S1 is trimethylchlorosilane or triethylchlorosilane.

The technical scheme of the invention is further improved as follows: the inert solvent in the step S1 is dichloromethane, dichloroethane, toluene, sec-butyl acetate or isopropyl acetate, and the weight ratio of the inert solvent to the raw material formula II is 2-5: 1.

The technical scheme of the invention is further improved as follows: the organic base in the steps S1 and S2 is triethylamine, tetramethyl ethylene diamine or diisopropylamine, and the molar ratio of the organic base to the protective agent is 1-1.5: 1.

The technical scheme of the invention is further improved as follows: the oxidant in step S2 is dimethyl sulfoxide; the pro-oxidant is solid phosgene or phenyl phosphate diacid chloride, the molar ratio of the oxidant to the pro-oxidant to the raw material formula II is 1.0-5.0: 0.5-4.0: 1.0, and the reaction temperature is as follows: -20 ℃ to 30 ℃.

The technical scheme of the invention is further improved as follows: the pro-oxidant is phenyl phosphate diacid chloride.

The technical scheme of the invention is further improved as follows: the acid in the step S3 is organic strong acid and inorganic strong acid, and the molar ratio of the acid to the raw material formula II is 0.1-2.0: 1.0, the reaction temperature is: 0 to 30 ℃.

The technical scheme of the invention is further improved as follows: the acid is trifluoroacetic acid.

The invention is suitable for preparing compounds containing a plurality of hydroxyl groups with different activities and needing to oxidize the hydroxyl group at the position with lower activity into carbonyl.

Starting from R in formula II²And R³And when the hydroxyl is simultaneously the abamectin B2a/B2B, the reaction equation is as follows:

starting from R in formula II²And R³When only one is hydroxyl, abamectin B2a/B2B is used as a raw material, and a non-hydroxyl substituent is subjected to a series of reactions to prepare the abamectin compound.

Due to the adoption of the technical scheme, the invention has the technical progress that:

1. the use of the protective agent of alkyl chlorosilane well protects the hydroxyl outside the 23-position, so that the hydroxyl at the 23-position can be completely oxidized;

2. the alkyl chlorosilane is easy to strip off under the action of trifluoroacetic acid, is changed into hydroxyl in situ, has no influence on a macrocyclic structure and a carbonyl group at the 23 th site, and can obtain a target product with higher content and yield.

3. In the traditional allyl protection method, a protected 23-carbonyl abamectin B2a/B2B derivative can be obtained after oxidation, but during deprotection, a catalyst and sodium borohydride are used to reduce a 23-carbonyl group back to a hydroxyl group, so that a target product, namely the 23-keto abamectin B2a/B2B derivative cannot be obtained.

Detailed Description

The present invention will be described in further detail with reference to the following examples:

the invention is suitable for preparing compounds containing a plurality of hydroxyl groups with different activities and needing to oxidize the hydroxyl group at the position with lower activity into carbonyl.

R²And R³Meanwhile, the preparation process of the hydroxyl group comprises the following steps:

example 123 Synthesis of ketoavermectin B2a/B2B

10g (0.01mol) of 95% avermectin B2a/B2B, 50g of dichloromethane, cooling to-20 ℃, adding 2.4g (0.022mol) of trimethylchlorosilane, slowly adding 2.6g (0.022mol) of tetramethylethylenediamine, keeping the temperature of-10-0 ℃ for 0.5h after finishing adding, adding 2.4g (0.02mol) of tetramethylethylenediamine, 1.6g (0.02mol) of dimethyl sulfoxide, adding 4.2g (0.02mol) of phenyl phosphate diacid chloride, slowly raising the temperature to 0-10 ℃, keeping the temperature for 2h, adding 1% of sodium hydroxide aqueous solution to adjust the pH value to 7-8, layering, adding 1.2g (0.01mol) of trifluoroacetic acid into the organic phase, stirring for 2h at room temperature, washing with water, separating out the water phase, distilling off the dichloromethane to obtain 9.0g of white-like solid, 23-keto avermectin B2 a/B2B% content, and yield of 90.7%.

Hydrogen nuclear magnetic resonance spectroscopy:

^lH NMR(400.13MHz):5.55(m,3H),5.42(t,J＝5.0,1H),5.28(t,J＝5.0,1H),5.00(m,lH),4.87(brd,lH),4.70(m,2H),4.40(br d,J＝6.0,lH),4.20(br q,J＝7.7,lH),4.00(d,J＝6.6,lH),3.90(br s,lH),3.86(m,2H),3.80(dq,J＝8.8,6.8,lH),3.84(ddd,J＝12.5,5.8,4.6,lH),3.70(s,lH),3.68(m,lH),3.55(dd,J＝10.8,2.0,lH),3.40(s,3H),3.35(m,lH),3.30(q,J＝2.2,lH),3.23(dd,J＝9.1,8.7,lH),2.80(s,1H),2.67(s,3H),2.52(m,lH),2.41-2.17(m,3H),2.10-1.90(m,2H),1.80(br s,3H),1.76(m,lH),1.70(d,J＝4.5,2H),1.65-1.50(m,6H),1.44(brs,3H),1.34(d,J＝6.7,3H),1.20(d,J＝6.2,3H),1.19(d,J＝7.0,3H),1.13(d,J＝7.6,3H),0.93-0.88(m,9H),0.80(m,1H).

LC-MS [ M + Na ] liquid mass analysis]⁺911.48, 23-ketoavermectin B2a [ M + Na [ ]]⁺Calculated values: 911.48.

the nuclear magnetic resonance and liquid-state results show that the obtained white-like solid is the compound shown in the formula I.

Example 223 Synthesis of ketoavermectin B2a/B2B

10g (0.01mol) of 95 percent abamectin B2a/B2B, 50g of dichloromethane, cooling to-10 ℃, adding 4.5g (0.03mol) of triethylchlorosilane, dropwise adding 3.5g (0.03mol) of tetramethylethylenediamine, keeping the temperature of 0-10 ℃ for 2h after the dropwise adding is finished, then adding 2.4g (0.02mol) of tetramethylethylenediamine, 2.4g (0.03mol) of dimethyl sulfoxide, dropwise adding 4.2g (0.02mol) of phenyl phosphate diacid chloride, keeping the temperature slowly to 20 ℃, keeping the temperature for 1h, adding 1 percent sodium hydroxide aqueous solution to adjust the pH value to 7-8, demixing, adding 0.6g (0.005mol) of trifluoroacetic acid into the organic phase, stirring for 2h at room temperature, washing, separating out the aqueous phase, evaporating the organic phase to remove dichloromethane, obtaining 8.7g of white-like solid, 23-keto abamectin B2a/B2B percent, and the yield is 86.2 percent.

The results of hydrogen nuclear magnetic resonance and mass spectrometry are the same as in example 1.

The results of nuclear magnetic resonance and liquid mass analysis show that the obtained white-like solid is the compound shown in the formula I.

R²Is hydroxy, R³Is acetylThe preparation process of the amino group comprises the following steps:

example 34 Synthesis of "-acetamido-23-ketoavermectin B2a/B2B

10g (0.01mol) of 96.0 percent 4 '-acetamido abamectin B2a/B2B, 50g of dichloroethane, cooling to-20 ℃, adding 1.1g (0.01mol) of trimethylchlorosilane, slowly adding 1.2g (0.01mol) of tetramethylethylenediamine, keeping the temperature for 2h at-10 to 0 ℃, adding 2.4g (0.02mol) of tetramethylethylenediamine, 1.6g (0.02mol) of dimethyl sulfoxide, adding 3.2g (0.015mol) of phenyl phosphate diacid chloride, slowly raising the temperature to 10 ℃, keeping the temperature for 2h, adding 1 percent sodium hydroxide aqueous solution to adjust the pH value to 7-8, demixing, adding 0.6g (0.005mol) of trifluoroacetic acid in the organic phase, stirring for 2h at room temperature, washing with water, separating out the water phase, evaporating dichloromethane to obtain light yellow solid with the content of 8.5g, 4' -acetamido-23-keto abamectin B2a/B2B percent, the yield thereof was found to be 83.3%.

Hydrogen nuclear magnetic resonance spectrum and mass spectrum analysis results:

^lH NMR(400.0MHz):5.90(m,lH),5.75(dd,J＝9.8,2.6,lH),5.53(m,3H),5.20(m,lH),4.90(br d,J＝5.0,lH),4.75(m,2H),4.52(br d,J＝4.5,lH),4.33(br q,J＝7.7,lH),4.18(br s,lH),4.08(m,2H),3.99(dq,J＝9.9,6.5,lH),3.85(ddd,J＝12.4,5.0,6.8,lH),3.70(s,lH),3.62(s,3H),3.54(s,3H),3.48(m,lH),3.40(q,J＝3.5,lH),3.33(dd,J＝7.8,7.6,lH),2.97(s,3H),2.64(m,lH),2.50(s,3H),2.41-2.35(m,3H),2.20(s,lH),2.15-2.00(m,2H),1.90(brs,3H),1.88(m,lH),1.82(d,J＝4.4,2H),1.78-1.49(m,5H),1.42(brs,3H),1.30(d,J＝5.8,3H),1.35(d,J＝6.8,3H),1.20(d,J＝7.0,3H),1.16(d,J＝7.6,3H),0.99-0.89(m,9H),0.88(m,1H),.

LC-MS [ M + Na ] liquid mass analysis]⁺952.50, 4' -acetamido-23-one avermectin B2a [ M + Na]⁺Calculated values: 952.50.

the results of nuclear magnetic resonance and liquid mass analysis show that the obtained light yellow solid is the compound shown in the formula I.

The 4 ' -acetamido-5-avermectin B2a/B2B is prepared by using avermectin B2a/B2B as a raw material, protecting 5-hydroxy with allyl chloroformate in dichloromethane, oxidizing 4 ' -hydroxy, performing ammoniation and acylation to obtain 4 ' -acetamido-5-protected avermectin B2a/B2B, and removing 5-protection.

R²Is hydroxy, R³The preparation process of methylsulfonylmethylamine comprises the following steps:

example 44 Synthesis of "-Methylsulfonylmethylamino-23-one Avermectin B2a/B2B

10g (0.01mol) of 96.0 percent 4 '-methylsulfonylmethylaminoacetin B2a/B2B is added into 50g sec-butyl acetate, the temperature is reduced to 0 ℃, 1.1g (0.01mol) of trimethylchlorosilane is added, 1.5g (0.015mol) of triethylamine is slowly dripped, after the dripping is finished, the temperature is kept for 2h at the temperature of 10 ℃ to 0 ℃, 2.0g (0.02mol) of triethylamine, 2.0g (0.025mol) of dimethyl sulfoxide is added, 3.2g (0.015mol) of phenyl phosphate diacid chloride is dripped, the temperature is slowly raised to 10 ℃, the temperature is kept for 2h, 1 percent sodium hydroxide aqueous solution is added to adjust the pH value to be 7-8, the mixture is layered, 1.1g (0.01mol) of trifluoroacetic acid is added into the organic phase, the mixture is stirred for 2h at room temperature, the water is washed, the aqueous phase is separated out, the sec-butyl acetate is distilled out from the organic phase, and light yellow solid with the content of 9.0g, 4' -methylsulfonylmethylamido-23-keto-abamectin B2a/B2B is obtained, the yield thereof was found to be 89.2%.

Hydrogen nuclear magnetic resonance spectrum and mass spectrum analysis results:

^lH NMR(400.0MHz):5.53(m,3H),5.40(m,lH),4.76(br d,J＝2.0,lH),4.70(m,2H),4.50(br d,J＝4.8,lH),4.42(br q,J＝6.6,lH),4.30(d,J＝6.6,lH),4.00(br s,lH),3.88(m,2H),3.85(s,1H),3.82(dq,J＝11.5,6.2,lH),3.74(ddd,J＝11.5,5.0,3.8,lH),3.68(s,lH),3.42(s,3H),3.40(s,3H),3.38(m,lH),3.32(s,1H),3.30(q,J＝3.2,lH),3.23(dd,J＝10.8,8.4,lH),3.00(s,3H),2.87(br d,J＝5.8,lH),2.67(s,3H),2.52(m,lH),2.31-2.25(m,3H),2.21(dd,J＝10.8,5.0,lH),2.05-1.90(m,2H),1.87(br s,3H),1.78(m,lH),1.72(d,J＝5.7,2H),1.70(d,J＝5.6,2H),1.63-1.46(m,6H),1.49(brs,3H),1.34(d,J＝7.5,3H),1.23(d,J＝8.8,3H),1.16(d,J＝8.4,3H),1.11(d,J＝9.7,3H),0.96-0.91(m,9H),0.89(m,1H).

LC-MS [ M + Na ] liquid mass analysis]⁺1002.49, 4' -methylsulfonylmethylamino-23-one avermectin B2a [ M + Na]⁺Calculated values: 1002.49.

the results of nuclear magnetic resonance and liquid mass analysis show that the obtained light yellow solid is the compound shown in the formula I.

The 4 ' -methylsulfonylmethylamine abamectin B2a/B2B is prepared by using abamectin B2a/B2B as a raw material, protecting 5-hydroxy with allyl chloroformate in dichloromethane, oxidizing 4 ' -hydroxy, performing methylamination and sulfonylation to obtain 4 ' -methylsulfonylmethylamine-5-protected abamectin B2a/B2B, and removing 5-protection.