阅读说明：本技术 戴斯马丁试剂在合成Ocotillol型皂苷衍生物关键中间体中的应用 (Application of descimidine reagent in synthesis of Ocotillol type saponin derivative key intermediate ) 是由 杨刚强 高萌 王聪慧 任瑞银 邹宗吉 乔鑫 于 2020-04-30 设计创作，主要内容包括：本发明提供戴斯马丁试剂在合成Ocotillol型皂苷衍生物关键中间体中的应用,所述应用的方法为：(一)式(1-R)或式(1-S)所示的(20S,24R/24S)-环氧达玛烷-3β,12β,25-三醇与戴斯马丁试剂按照物质的量之比为1:1～1.2反应制备得到相应的式(2-R)或式(2-S)所示的(20S,24R/24S)-环氧-25-羟基-3β-羟基-达玛烷-3-酮；(二)式(1-R)或式(1-S)所示的(20S,24R/24S)-环氧达玛烷-3β,12β,25-三醇与戴斯马丁试剂按照物质的量之比为1:2～3反应制备得到相应的式(3-R)或式(3-S)所示的(20S,24R/24S)-环氧-25-羟基-达玛烷-3,12-二酮。本发明采用DMP为氧化剂,后处理方便,选择性高,收率好,在低用量情况下单氧化产物收率高达96％,在高用量情况下双氧化产物收率达90％以上。(The invention provides an application of a descimycin reagent in synthesizing an Ocotillol saponin derivative key intermediate, which comprises the following steps: (I), (20S,24R/24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-R) or formula (1-S) and a dessimutan reagent react according to the mass ratio of 1: 1-1.2 to prepare corresponding (20S,24R/24S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula (2-R) or formula (2-S); (II) (20S,24R/24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-R) or formula (1-S) and a dessimutan reagent react according to the mass ratio of 1: 2-3 to prepare the corresponding (20S,24R/24S) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in formula (3-R) or formula (3-S). The invention adopts DMP as an oxidant, has convenient post-treatment, high selectivity and good yield, the yield of the mono-oxidation product reaches up to 96% under the condition of low dosage, and the yield of the di-oxidation product reaches up to more than 90% under the condition of high dosage.)

1. The application of descimidine reagent in the synthesis of key intermediates of Ocotillol type saponin derivatives is one of the following two methods:

(I) carrying out oxidation reaction on (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in the formula (1-S) and a desselatin reagent according to the mass ratio of 1: 1-1.2 to prepare corresponding (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in the formula (2-R) or (20S,24S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in the formula (2-S); the reaction formula is shown as follows:

(II) carrying out oxidation reaction on (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in the formula (1-S) and a dessimutan reagent according to the mass ratio of 1: 2-3 to prepare corresponding (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-R) or (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-S); the reaction formula is shown as follows:

2. the use according to claim 1, wherein in the method (one), the ratio of the amounts of the (20S,24R) -epoxydammarane-3 β,12 β, 25-triol represented by the formula (1-R) or the (20S,24S) -epoxydammarane-3 β,12 β, 25-triol represented by the formula (1-S) and the dessimutan reagent is 1:1 to 1.1.

3. The use according to claim 1, wherein in the first application method (I) or the second application method (II), the reaction temperature is initially from-5 ℃ to 0 ℃, the reaction is carried out at from-5 ℃ to 0 ℃ for 1 to 2 hours, and then the reaction is carried out at room temperature for 3 to 5 hours.

4. The use according to claim 1, characterized in that said application method (one) operates according to the following steps:

feeding (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-S) and an oxidant desimadine reagent according to the mass ratio of 1: 1-1.2, reacting for 1-2 hours at the ice bath temperature of-5-0 ℃ by using dichloromethane as a solvent under the action of sodium bicarbonate and tert-butyl alcohol at normal temperature for 3-5 hours, and after the TLC detection reaction is completed, carrying out post-treatment on the reaction liquid to correspondingly prepare (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula (2-R) or (20S,24S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula (2-S) -3-ketones.

5. The use according to claim 1, characterized in that the application method (two) operates according to the following steps:

feeding (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-S) and an oxidant desimadine reagent according to the mass ratio of 1: 2-3, reacting at normal temperature for 3-5 hours at-5-0 ℃ in an ice bath by taking dichloromethane as a solvent under the action of sodium bicarbonate and tert-butyl alcohol, carrying out TLC detection reaction for completely, carrying out post-treatment on reaction liquid to correspondingly prepare (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in a formula (3-R) or (20S,24S) -epoxy-25-hydroxy-dammarane-3 shown in a formula (3-S), 12-diketones.

6. The use according to claim 4 or 5, wherein the ratio of the mass of dessimutant reagent to sodium bicarbonate is 1:1.2 to 3.

7. The use according to claim 4 or 5, wherein the tert-butanol is used in a volume of 0.2 to 1mL/mmol, based on the amount of substance of the dessimutant reagent.

8. The use according to claim 4 or 5, characterized in that the reaction solution post-treatment step is: adding saturated sodium bicarbonate and sodium sulfite aqueous solution into the reaction solution to adjust the pH, extracting with ethyl acetate, washing the organic phase with sodium bicarbonate and saturated saline solution respectively, drying with anhydrous sodium sulfate, filtering, concentrating, separating by silica gel column chromatography, and eluting to obtain the target product.

Technical Field

The invention relates to an application of a dessamidine reagent in synthesizing an Ocotillol saponin derivative key intermediate.

Background

In tumor treatment, multidrug resistance is a problem to be solved urgently, and one of promising strategies is to find a novel P-glycoprotein inhibitor, wherein the main metabolic component of the natural product ginsenoside in the body is Ocotillol type ginsenoside. Patent CN109021058A introduces a synthesis method of an Ocotillol ginsenoside amide derivative, and in vitro cytotoxicity experiments and research on anti-drug resistance reversion capability, verapamil is used as a positive control, and the research shows that the Ocotillol ginsenoside amide derivative is a potential P-glycoprotein inhibitor and has good drug resistance reversion activity.

The latest synthetic route for the Ocotillol type saponin amide derivatives is as follows

In the above route, (24R/24S) Ocotillol ginsenoside shown in formula 1 is reacted under the oxidation of PPC to obtain (24R/24S) C-3 mono-oxidized Ocotillol ginsenoside shown in formula 2, then the obtained product is reacted with hydroxylamine hydrochloride to obtain C-3 oximinolated Ocotillol ginsenoside, and then the obtained product is reacted with ammonium acetate and sodium cyanoborohydride to obtain C-3 aminated Ocotillol ginsenoside, a series of linear alkyl compounds and aromatic compounds, and finally the obtained product is subjected to peptide-forming condensation reaction to obtain the Ocotillol ginsenoside amide derivative.

Wherein (24R/24S) Ocotillol ginsenoside shown in formula 1 is reacted under the oxidation of PPC to obtain (20S,24R/S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula 2, PCC is used as an oxidant in the reaction, the selectivity of the oxidant is poor, the highest yield of the reaction is 85% as described in patent CN109021058A, and the yield of byproducts (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone is high and low. The catalyst is easy to form sticky with a product after reaction, is difficult to separate, can extract the product by using a solvent after being subjected to suction filtration and adsorption by using kieselguhr, and can influence the yield of the product.

Disclosure of Invention

In view of the poor selectivity of the oxidant selected for selective oxidation, the easy formation of sticky and difficult separation with the product after reaction, and the need of suction filtration and adsorption with diatomite, the invention provides a new method, which selects DMP oxidant, and the like, and has good selective oxidation, safety and high efficiency, and better solubility with the product of oxidation of ocotilol type ginsenoside in a series of organic solvents. The catalyst has high selectivity and no influence on subsequent reaction, and has no influence on the activity of the final product, namely the Ocotillol type ginsenoside derivative.

The invention mainly solves the technical problem of providing an oxidation method which is simple to operate, mild in reaction conditions and high in selectivity and is used for preparing key intermediates of the Ocotillol type ginsenoside derivatives.

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

the application of descimidine reagent in the synthesis of key intermediates of Ocotillol type saponin derivatives is one of the following two methods:

(20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-S) and a deshimaladine reagent (DMP reagent) are subjected to oxidation reaction according to the mass ratio of 1: 1-1.2 to prepare corresponding (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula (2-R) or (20S,24S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula (2-S).

The reaction formula is shown as follows:

(II) carrying out oxidation reaction on (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in the formula (1-S) and a dessimutan reagent (DMP reagent) according to the mass ratio of 1: 2-3 to prepare corresponding (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-R) or (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-S).

The reaction formula is shown as follows

Because chiral isomers exist, R or S configuration raw materials respectively correspondingly prepare R or S configuration products, and the preparation methods of the two isomers are written together in an OR mode for convenience of description.

Specifically, in the method (I), the (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in the formula (1-R) reacts with DMP according to the mass ratio of 1: 1-1.2 to prepare (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in the formula (2-R);

reacting (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-S) with DMP according to the mass ratio of 1: 1-1.2 to prepare (20S,24S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in formula (2-S).

Specifically, in the second method, the (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in the formula (1-R) reacts with DMP according to the mass ratio of 1: 2-3 to prepare (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-R); reacting (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in formula (1-S) with DMP according to the mass ratio of 1: 2-3 to obtain (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in formula (3-S).

The reaction principle of DMP is: the first step is that hydroxyl at C-3 position of the Ocotillol type ginsenoside is replaced with one acetoxyl group of DMP, and the second step is that when the other acetoxyl group is separated, the proton of the carbon atom linked with the alcoholic hydroxyl group is transferred to the acetoxyl group, and simultaneously the hydroxyl group is oxidized into corresponding ketone, and the reaction process not only completely avoids the occurrence of transition reaction, but also has quite high chemical selectivity.

The inventor finds through a large number of experiments that the selectivity of the mono-oxidation product and the di-oxidation product can be controlled by adjusting the dosage ratio of DMP, when the dosage ratio of DMP to the raw material is 1-1.2: 1, the mono-oxidation product is generated with high selectivity, the yield is over 90%, and when the dosage ratio of DMP to the raw material is 2-3: 1, the di-oxidation product is generated with high selectivity, the yield is over 93%.

Further, it is preferable that the ratio of the amounts of the (20S,24R) -epoxy dammarane-3 β,12 β, 25-triol represented by the formula (1-R) or the (20S,24S) -epoxy dammarane-3 β,12 β, 25-triol represented by the formula (1-S) to the DMP is 1:1 to 1.1, the compound represented by the formula (2-R) is (20S,24R) -epoxy-25-hydroxy-3 β -hydroxy-dammarane-3-one or the compound represented by the formula (2-S) is (20S,24S) -epoxy-25-hydroxy-3 β -hydroxy-dammarane-3-one, and the yield is 94% or more.

The initial reaction temperature of the invention is controlled below 0 ℃, generally between-5 ℃ and 0 ℃, preferably between-5 ℃ and 0 ℃ for 1 to 2 hours, and then the temperature is raised to room temperature for 3 to 5 hours.

In the reaction of the invention, sodium bicarbonate is added to adjust the pH, and the mass ratio of the DMP reagent to the sodium bicarbonate is 1: 1.2-3.

In the reaction of the invention, a proper amount of tertiary butanol is added to promote the oxidation reaction and is used as a cosolvent of an oxidant. The volume of the tert-butyl alcohol is generally 0.2-1 mL/mmol based on the amount of the substance of the dessimutan reagent (DMP).

The reaction of the invention adopts dichloromethane as solvent. The volume usage amount of the dichloromethane is generally 8-15 mL/mmol, preferably 10-15 mL/mmol, based on the amount of (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol represented by formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol represented by formula (1-S).

Specifically, the method of the present invention is preferably operated by the following steps:

the application method (I): feeding (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-S) and an oxidant desimadine reagent (DMP reagent) according to the mass ratio of 1: 1-1.2, reacting for 1 hour in an ice bath at-5-0 ℃ by taking dichloromethane as a solvent under the action of sodium bicarbonate and tert-butyl alcohol at normal temperature for 3-5 hours, and after the TLC detection reaction is completed, carrying out post-treatment on the reaction solution to correspondingly prepare (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-3-ketone shown in a formula (2-R) or (20S shown in a formula (2-S), 24S) -epoxy-25-hydroxy-3 β -hydroxy-dammaran-3-one.

The application method (II): feeding (20S,24R) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-R) or (20S,24S) -epoxy dammarane-3 beta, 12 beta, 25-triol shown in a formula (1-S) and an oxidant desimadine reagent (DMP reagent) according to the mass ratio of 1: 2-3, reacting for 1 hour at the temperature of-5-0 ℃ in an ice bath by using dichloromethane as a solvent under the action of sodium bicarbonate and tert-butyl alcohol, reacting for 3-5 hours at normal temperature, performing TLC detection reaction completely, and performing post-treatment on a reaction solution to correspondingly prepare (20S,24R) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in a formula (3-R) or (20S,24S) -epoxy-25-hydroxy-dammarane-3 shown in a formula (3-S), 12-diketones.

The reaction solution post-treatment steps of the invention are as follows: adding saturated sodium bicarbonate and sodium sulfite aqueous solution into the reaction solution to adjust the pH, extracting with ethyl acetate, washing the organic phase with sodium bicarbonate and saturated saline solution respectively, drying with anhydrous sodium sulfate, filtering, concentrating, separating by silica gel column chromatography, and eluting to obtain the target product.

The objective product was washed with an aqueous sodium sulfite solution in order to remove acetic acid and iodine as by-products.

The (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-dione shown in formula (3-R) or (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-dione shown in formula (3-S) prepared by the invention is a new compound, and can be used for continuously synthesizing a new Ocotillol type esterified derivative in the following process, and has anti-inflammatory activity. The method comprises the following specific steps: selectively reducing the (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-R) or the (20S,24S) -epoxy-25-hydroxy-dammarane-3, 12-diketone shown in the formula (3-S) with sodium borohydride to selectively reduce the carbonyl at the 3-position into hydroxy, and respectively and correspondingly preparing (20S,24R) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-12-ketone shown in the formula (4-R) or (20S,24S) -epoxy-25-hydroxy-3 beta-hydroxy-dammarane-12-ketone shown in the formula (4-S); then carrying out esterification reaction with amino acid derivatives shown in formula (7) to respectively and correspondingly prepare the protection group-containing Ocotillol type esterified derivatives shown in formula (5-R) or formula (5-S). The protection group-containing Ocotillol esterified derivative represented by the formula (5-R) or (5-S) is subjected to deprotection reaction to obtain the Ocotillol esterified derivative represented by the formula (6-R) or (6-S). The protection group-containing Ocotillol esterified derivative shown in the formula (5-R) or the formula (5-S) and the Ocotillol esterified derivative shown in the formula (6-R) or the formula (6-S) have anti-inflammatory activity, can be used for preparing anti-inflammatory drugs or anti-inflammatory drug compositions, and further can be used for preparing drugs or drug compositions for treating and preventing diseases related to acute lung injury, sepsis and the like.

Wherein R is₁Is hydrogen, C1-C4 alkyl, phenyl, benzyl, p-hydroxybenzyl, -R_aCOOR_b、-R_aOR_b、-R_aNHR_cor-R_aSR_d；R₂Is tert-butyloxycarbonyl (Boc), fluorenyl-methoxycarbonyl (Fmoc) or benzyl (Bn); r₃Is H or C1-C4 alkyl; or R₁、R₃Connecting with N to form a ring to form N-tetrahydropyrrole;

R₁in, R_aIs C1-C4 alkylene; r_bH, Bn or tBu; r_cH, Boc or Fmoc; r_dIs H or methyl;

preferably R₁Is hydrogen, isopropyl, benzyl, - (CH)₂)₂-COOH、-CH₂-COOH、-(CH₂)₂-COO-tBu or-CH₂-COO-tBu；

Preferably R₂Is Boc; preferably R₃Is H.

The invention has the beneficial effects that:

DMP is adopted as an oxidant, so that the selectivity is high, the yield is good, the mono-oxidation product can be prepared with high selectivity under the condition of low dosage, the yield is up to 96%, and the di-oxidation product can be prepared with high selectivity under the condition of high dosage, and the yield is up to more than 90%.

And the oxidant and the product after the reaction do not produce sticky substances, the post-treatment operation is simple, acid by-products generated by oxidation can be removed through washing and the like, the separation is easier, and the product loss is reduced.

Detailed Description

The technical solution of the present invention is further described with specific examples, but the scope of the present invention is not limited thereto.