Preparation method of hypodiol methyl ether

Abstract

The application discloses a method for preparing phellopterin methyl ether. In the application, the method comprises the following steps: coupling reaction of a compound of formula VII and (tri-n-butylstannyl)methyl alcohol in an organic medium to obtain phellopterin methyl ether. The method for preparing phellopterin methyl ether provided by the application avoids the use of a dimethyl methylene silyl ylide active intermediate with a short half-life, has no amplification effect, improves the yield, avoids the use of sulfur-containing materials, and has a high industrialization prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemistry, in particular to a preparation method of ingenol mehtylether. BACKGROUND

[0002] Triptolide, also known as triptolide and triptolide, is a kind of epoxy diterpene lactone compound extracted from the roots, leaves, flowers and fruits of Celastraceae plant Tripterygium wilfordii. Studies have shown that it has the effects of anti-oxidation, anti-rheumatoid, anti-alzheimer's disease, anticancer and the like, and has good antitumor activity on various cancers such as leukemia, breast cancer, pancreatic cancer and lung cancer.

[0003] New drugs developed from triptolide molecules have entered the clinical phase 2, such as letengshu, minnijiaosu, etc. The future market has high demand for triptolide molecules. At present, the supply of triptolide on the market depends entirely on natural extraction, and the source is extremely limited, and the price is extremely high, about 4000 yuan per gram. Neither the quantity nor the price can meet the demand and requirements of the future market. In the prior art, ingenol mehtylether is used as a biosynthetic precursor to synthesize triptolide, which is a relatively stable artificial synthesis method of triptolide. Triptolide can be obtained after 7 to 8 steps. The synthesis route is as follows:

[0004]

[0005] Ingenol mehtylether can be prepared by methylation of ingenol. Although ingenol has a higher content than triptolide in natural products, it also faces the problems of high cost of natural extraction and insufficient supply, resulting in a market price similar to that of triptolide. In 2010, Professor Li Yuanchao et al. developed a total synthesis method of ingenol mehtylether (Tetrahedron, 2010, vol. 66, p. 5396-5401). The method has relatively short steps, and the preparation scale reaches hundreds of grams, which has further industrial value.

[0006]

[0007] The inventors found in the research that at least the following problems exist in the prior art: first, the dimethyl methylene phosphorus ylide active intermediate needs to be used in the Corey-Chaykovsky reaction of the route N-2. The half-life of the intermediate is extremely short (Journal of the American Chemical Society, 1965, p1353-1364), resulting in a very obvious scale-up effect of the reaction, a significant decrease in yield with scale-up, and a great difference between batches, which makes it difficult to develop a further scale-up process. Secondly, thiol, sulfide and other sulfur-containing materials are used multiple times in the route, and all the sulfur-containing materials finally enter the three wastes, resulting in a great sulfur-containing odor in the entire synthesis process, poor environmental friendliness, and difficulty in personnel operation. SUMMARY

[0008] The purpose of the present application is to provide a preparation method of pseudoionindin methyl ether.

[0009] To solve the above technical problems, the first aspect of the present application provides a method for preparing pseudoionindin methyl ether, which comprises the following steps:

[0010]

[0011] In an organic medium, a coupling reaction of a compound of formula VII and tri-n-butylstannylmethanol is carried out to obtain pseudoionindin methyl ether.

[0012] In some preferred embodiments, the organic medium is hexamethylphosphoric triamide.

[0013] In some preferred embodiments, the coupling reaction is carried out in the presence of a palladium catalyst and a chloride.

[0014] In some preferred embodiments, the palladium catalyst is Pd2(dba)3-CHCl3 and / or Pd2(dba)3.

[0015] In some preferred embodiments, the chloride is lithium chloride and / or zinc chloride.

[0016] In some preferred embodiments, the coupling reaction comprises the following steps:

[0017] In an inert atmosphere, the organic medium containing the palladium catalyst and the chloride is heated to 65-75℃, then the compound of formula VII and tri-n-butylstannylmethanol are added, and the reaction is carried out at 65-75℃.

[0018] In some preferred embodiments, the equivalent ratio of the compound of formula VII to the (tri-n-butylstannyl)methanol is 1:(1.5-2.5). For example: 1:2.

[0019] In some preferred embodiments, the preparation of the compound of formula VII comprises the steps of:

[0020]

[0021] In an organic medium, the compound of formula VI is subjected to a reduction reaction with triflic anhydride to obtain the compound of formula VII.

[0022] In some preferred embodiments, the reduction reaction is carried out in the presence of an organic base.

[0023] In some preferred embodiments, the organic base is triethylamine and / or diisopropylethylamine; more preferably, it is triethylamine.

[0024] In some preferred embodiments, the organic medium is dichloromethane.

[0025] In some preferred embodiments, the reduction reaction comprises the steps of:

[0026] At 0 to 4°C, triflic anhydride is added to an organic medium in which the compound of formula VI and the organic base are dissolved, and the reaction is carried out at room temperature.

[0027] In some preferred embodiments, the triflic anhydride is added dropwise.

[0028] In some preferred embodiments, the equivalent ratio of the compound of formula VI to the triflic anhydride is 1 : (1 to 2). For example, 1 : 1.5.

[0029] In some preferred embodiments, the preparation of the compound of formula VI comprises the steps of:

[0030]

[0031] In an organic medium, the compound of formula III is subjected to a nucleophilic addition reaction with dimethyl carbonate to obtain the compound of formula VI.

[0032] In some preferred embodiments, the nucleophilic addition reaction comprises the steps of:

[0033] At 0 to 4°C, sodium hydride is added to an organic medium containing the compound of formula III and dimethyl carbonate, and the reaction is carried out at elevated temperature.

[0034] In some preferred embodiments, the organic medium is dimethyl carbonate and / or tetrahydrofuran.

[0035] In some preferred embodiments, the elevated temperature is an elevated temperature of 85 to 95°C.

[0036] In some preferred embodiments, 9-11 g of the compound of formula III are mixed in every 45-60 mL of the dimethyl carbonate.

[0037] In some preferred embodiments, the equivalent ratio of the compound of formula III and the sodium hydride is 1:(3-6). For example: 1:5.

[0038] The present application has at least the following advantages over the prior art:

[0039] (1) The preparation method of phellopterin methyl ether provided by the present application avoids the use of dimethyl methylene phosphorus ylide active intermediate with short half-life, has no amplification effect, and improves the yield.

[0040] (2) The preparation method of phellopterin methyl ether provided by the present application avoids the use of sulfur-containing materials, and has high industrialization prospects.

[0041] It should be understood that, within the scope of the present application, each of the above technical features of the present application and each of the technical features specifically described below (such as the examples) can be combined with each other to form a new or preferred technical scheme. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0042] One or more embodiments are exemplified by the pictures in the corresponding drawings, which do not constitute a limitation on the embodiments.

[0043] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of the product compound VII obtained in Example 4 of the present application;

[0044] Figure 2 is the nuclear magnetic resonance hydrogen spectrum of phellopterin methyl ether obtained in Example 6 of the present application. DETAILED DESCRIPTION

[0045] In the present application, a preparation method of phellopterin methyl ether is provided, which avoids the use of dimethyl methylene phosphorus ylide active intermediate. The method specifically comprises the following steps:

[0046] The compound of formula III is subjected to nucleophilic addition reaction with dimethyl carbonate to obtain a compound of formula VI;

[0047] The compound of formula VI is subjected to reduction reaction with trifluoromethanesulfonic anhydride to obtain a compound of formula VII.

[0048] The compound of formula VII is subjected to coupling reaction with tri-n-butyltin methanol to obtain phellopterin methyl ether.

[0049] Preparation of phellopterin methyl ether

[0050] In the embodiments of the present application, phellopterin methyl ether is prepared by the following method, which comprises the following steps:

[0051]

[0052] In an organic medium, the compound of formula VII is coupled with tri-n-butyltin methanol to obtain physcion methyl ether.

[0053] In the present application, the term "coupling reaction" refers to a process in which two organic chemical molecules are chemically reacted to form one organic molecule.

[0054] In the present application, the term "organic medium" refers to any organic solvent that can dissolve the reactants and does not react with the reactants. In the present application, the organic medium itself can also participate in the reaction as a reactant while serving as an organic solvent. In a specific embodiment of the present application for preparing physcion methyl ether from the compound of formula VII, the organic medium is an aprotic dipolar solvent, such as hexamethylphosphoramide.

[0055] In a preferred embodiment of the present application, the coupling reaction is carried out in the presence of a palladium catalyst and a chloride.

[0056] In the present application, the term "palladium catalyst" refers to various catalysts that use palladium black or a palladium salt to load palladium on a carrier such as alumina or zeolite, and use a salt such as sodium, cadmium, or lead as a cocatalyst. In a preferred embodiment of the present application, the palladium catalyst is Pd2(dba)3-CHCl3and / or Pd2(dba)3.

[0057] In a preferred embodiment of the present application, the chloride is preferably a metal chloride, such as at least one of lithium chloride and zinc chloride.

[0058] In a preferred embodiment of the present application, the coupling reaction comprises the steps of:

[0059] In an inert atmosphere, the organic medium containing the palladium catalyst and the chloride is heated to 65 to 75°C, and then the compound of formula VII and tri-n-butyltin methanol are added and the reaction is carried out at 65 to 75°C.

[0060] In a preferred embodiment of the present application, the equivalent ratio of the compound of formula VII to the (tri-n-butyltin) methanol is 1:(1.5 to 2.5). For example, 1:2.

[0061] In the present application, the term "inert atmosphere" refers to an atmosphere that is extremely unreactive and generally does not react with other substances.

[0062] In the present application, the term "equivalent ratio" refers to the ratio of the theoretical amount of a reactant required to the actual amount of the reactant in the reaction system.

[0063] Preparation of the compound of formula VII

[0064] In an embodiment of the present application, the compound of formula VII is prepared by a process comprising the steps of:

[0065]

[0066] In an organic medium, the compound of formula VI is subjected to a reduction reaction with triflic anhydride to obtain the compound of formula VII.

[0067] In a preferred embodiment of the present application, the reduction reaction is carried out in the presence of an organic base.

[0068] In the present application, the term "organic base" refers to a basic compound containing an organic group, more preferably the organic base is an amine compound and a nitrogen-containing heterocyclic compound. In a particular embodiment of the present application for the preparation of the compound of formula VII from the compound of formula VI, the organic base is triethylamine and / or diisopropylethylamine; more preferably, it is triethylamine.

[0069] In a particular embodiment of the present application for the preparation of the compound of formula VII from the compound of formula VI, the organic medium is dichloromethane.

[0070] In a preferred embodiment of the present application, the reduction reaction comprises the steps of:

[0071] At 0 to 4°C, triflic anhydride is added to an organic medium containing the compound of formula VI and an organic base, and the reaction is carried out at room temperature.

[0072] In a preferred embodiment of the present application, the triflic anhydride is added dropwise.

[0073] In a preferred embodiment of the present application, the equivalent ratio of the compound of formula VI to the triflic anhydride is 1 : (1 to 2). For example, 1 : 1.5.

[0074] Preparation of the compound of formula VI

[0075] In an embodiment of the present application, the compound of formula VII is prepared by a process comprising the steps of:

[0076]

[0077] In an organic medium, the compound of formula III is subjected to a nucleophilic addition reaction with dimethyl carbonate to obtain the compound of formula VI.

[0078] In a preferred embodiment of the present application, the nucleophilic addition reaction comprises the steps of:

[0079] At 0 to 4°C, sodium hydride is added to an organic medium containing the compound of formula III and dimethyl carbonate, and the reaction is carried out at room temperature.

[0080] In one embodiment of the present application for preparing compound VI from compound III, the organic medium is dimethyl carbonate and / or tetrahydrofuran.

[0081] In a preferred embodiment of the present application, the temperature is raised to 85 to 95°C.

[0082] In a preferred embodiment of the present application, 9-11 g of compound III is mixed in 45-60 mL of dimethyl carbonate.

[0083] In a preferred embodiment of the present application, the equivalent ratio of compound III to sodium hydride is 1:(3-6). For example: 1:5.

[0084] In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the present application will be further described below with specific examples. It should be understood that these examples are only used to illustrate the present application and not intended to limit the scope of the present application. The experimental methods in the following examples, if no specific conditions are noted, are usually carried out under conventional conditions or under the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are weight percentages and weight parts. The experimental materials and reagents used in the following examples, if no special instructions are given, can be obtained from commercial channels.

[0085] Unless otherwise indicated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It should be further understood that the terms used herein are not intended to limit the exemplary embodiments of the present application.

[0086] Example 1, synthesis of compound III

[0087] Compound III was synthesized according to the method in the literature Tetrahedron, 2010, vol. 66, p. 5396-5401

[0088] A three-necked flask was prepared, anhydrous tetrahydrofuran (2000 ml) and N,N- dimethylformamide (3.4 g) were added, and stirring was started. Compound I (683.0 g) was added and mixed well. At 0-10 degrees, oxalyl chloride (367.3 g, 1.4 eq.) was added dropwise. After the reaction was completed, it was concentrated to dryness and dissolved in toluene. At 0-10 degrees, this solution was slowly added dropwise to a reaction flask containing sodium pyrithione (400 g, 1.3 eq.), toluene (1 L), and dimethylaminopyridine (25.6 g, 0.1 eq.). After the dropwise addition was completed, reflux stirring was carried out until the reaction was complete. After the reaction was cooled to room temperature, it was washed with water and concentrated to give about 820 g of the intermediate, which was used directly in the next step.

[0089] The intermediate was dissolved in dichloromethane (1.6 L) and cooled to -55 to -65 °C. A solution of meta-chloroperoxybenzoic acid (420 g, 1 eq.) in dichloromethane (3 L) was added dropwise. After the addition was complete, toluene was added and the reaction was stirred at reflux until complete. The reaction was cooled to room temperature and washed with aqueous base to remove the by-products. The organic phase was concentrated to dryness and chromatographed on silica gel (petroleum ether) to give compound II, about 450 g. The yield was about 75%.

[0090] Compound II (450 g) was dissolved in dichloromethane (3 L) and methanol (3 L) and cooled to -55 to -65 °C. Ozone was bubbled through the solution until the reaction was complete. Dimethyl sulfide was added to quench the reaction and the solution was warmed to room temperature. The organic phase was concentrated to give compound III, about 450 g, in 100% yield.

[0091] Example 2, Synthesis of compound VI

[0092] A three-necked flask was charged with compound III (10 g, 1 eq), tetrahydrofuran (100 mL), and dimethyl carbonate (10 mL). After cooling to 0 °C, sodium hydride (2.8 g, 2 eq) was added. The reaction was stirred at reflux until complete. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was concentrated to dryness and used directly in the next step.

[0093] Example 3, Synthesis of compound VI

[0094] A three-necked flask was charged with compound III (10 g, 1 eq), tetrahydrofuran (100 mL), and dimethyl carbonate (10 mL). After cooling to 0 °C, sodium hydride (2.8 g, 2 eq) was added. The reaction was stirred at reflux until complete. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was concentrated to dryness and used directly in the next step.

[0095] Example 4, Synthesis of compound VII

[0096] A three-necked flask was charged with compound VI from Example 3. Dichloromethane (50 mL) and diisopropylethylamine (9 g, 2 eq) were added. At 0 °C, triflic anhydride (14.8 g, 1.5 eq) was added dropwise. The reaction was stirred at room temperature until complete. The reaction was quenched with water and concentrated to dryness. Chromatography on silica gel (petroleum ether) gave 8 g of oil in about 50% yield. The proton nuclear magnetic resonance spectrum of the product is shown in Figure 2. Figure 1 .

[0097] 1H NMR (CDC13, 400 MHz): δ = 7.10 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.29 (sept, J = 6.9 Hz, 1H), 2.95-2.82 (m, 1H), 2.75-2.62 (m, 1H), 2.60-2.42 (m, 2H), 2.35-2.25 (m, 1H), 2.22-2.12 (m, 1H), 2.00-1.90 (m, 1H), 1.87-1.68 (m, 2H), 1.36 (s, 3H), 1.22 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H) ppm

[0098] Example 5, synthesis of compound VII

[0099] A three-necked flask was prepared and charged with compound VI from Example 2. Dichloromethane (50 mL) and triethylamine (10.5 g, 3 eq) were added. At 0 °C, triflic anhydride (14.8 g, 1.5 eq) was added dropwise. The reaction was stirred at room temperature until completion. The reaction was washed with water and filtered through a pad of silica gel. The filter cake was washed with n-hexane / ethyl acetate. The filtrate was concentrated to dryness to give an oil, about 16 g, in about 96% yield, which was used directly in the next step.

[0100] Example 6, synthesis of psorospermin methyl ether

[0101] A three-necked flask was prepared and charged with HMPA (50 mL), Pd2(dba)3-CHCl3(3.2 g, 0.1 eq), and zinc chloride (12.8 g, 3 eq). Under nitrogen protection, the temperature was raised to 70 °C, and a solution of compound VII (15 g) and tri-n-butyltin methoxide (20 g, 2 eq) in HMPA (20 mL) was added dropwise. The reaction was stirred at room temperature until completion. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to dryness, and the residue was separated by column chromatography on silica gel (petroleum ether / ethyl acetate = 20:1) to give psorospermin methyl ether 5.1 g in about 50% yield. The1H NMR spectrum of the product is shown in Figure 2. Figure 2 .

[0102] 1H NMR (CDCI3, 400 MHz): δ = 7.11 (s, 2H), 4.85-4.65 (m, 2H), 3.74 (s, 3H), 3.30 (sept, J = 6.9 Hz, 1H), 3.06 (ddd, J = 18.1, 7.5, 2 Hz, 1H), 3.01-2.88 (m, 1H), 2.75-2.65 (m, 1H), 2.57-2.45 (m, 2H), 2.45-2.30 (m, 1H), 2.02-1.92 (m, 1H), 1.92-1.82 (m, 1H), 177-1.65 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H), 1.03 (s, 3H) ppm

[0103] Those skilled in the art will understand that the above described embodiments are merely illustrative of the application and that modifications can be made in form and detail thereof without departing from the spirit and scope of the application.

Claims

1. A process for the preparation of phlomisoside A methylether, characterized in that, The method comprises step 1: In an organic medium, a coupling reaction of a compound of formula VII and tri-n-butylstannylmethanol is carried out to obtain phellopterin methyl ether; the coupling reaction is carried out in the presence of a palladium catalyst and a chloride; the palladium catalyst is Pd2(dba)3-CHCl3 and / or Pd2(dba)3, and the organic medium is hexamethylphosphoric triamide; Preparation of the compound of formula VII comprises step 2: In an organic medium, a reduction reaction of a compound of formula VI and triflic anhydride is carried out to obtain a compound of formula VII; and Preparation of the compound of formula VI comprises step 3: A nucleophilic addition reaction of a compound of formula III and dimethyl carbonate is carried out to obtain a compound of formula VI, and the chloride is zinc chloride.

2. The method of claim 1, wherein, The coupling reaction comprises the following steps: After the organic medium containing the palladium catalyst and the chloride is warmed to 65 to 75 DEG C in an inert atmosphere, the compound of formula VII and tri-n-butylstannylmethanol are added, and the reaction is carried out at 65 to 75 DEG C.

3. The method of claim 1, wherein, In step 2, the organic medium is dichloromethane.

4. The method of claim 1, wherein, The reduction reaction is carried out in the presence of an organic base.

5. The method of claim 4, wherein, The organic base is triethylamine and / or diisopropylethylamine.

6. The method of claim 1, wherein, The reduction reaction comprises the following steps: At 0 to 4 DEG C, triflic anhydride is added to an organic medium in which the compound of formula VI and the organic base are dissolved, and the reaction is carried out at room temperature.

7. The method of claim 1, wherein, In step 3, the organic medium is dimethyl carbonate and / or tetrahydrofuran.

8. The method of claim 1, wherein, The nucleophilic addition reaction is carried out in the presence of sodium hydride.

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