Synthesis method of harringtonine E ring functional group

Abstract

The application relates to a synthesis method of a harringtonine E ring functional group. The method takes enone M containing a pentacyclic skeleton as raw material, and obtains an intermediate T through carbonyl reduction, olefin epoxidation, oxidation and Meinwald rearrangement. Compared with a synthesis route in the literature taking Moriarty oxidation as a key step, the method has the advantages of cheap and easily available reagents, mild reaction conditions, simple operation and easy industrial compound production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for synthesizing the E-ring functional group of cephalotaxine. Background Technology

[0002] Homoharringtonine is a trace alkaloid extracted from plants of the genus Cephalotaxus. It has significant anti-leukemic effects and was officially recommended for clinical use in my country in 1978, mainly for the treatment of acute myeloid leukemia. In 2012, homoharringtonine was approved by the US FDA for marketing as a treatment for adult chronic myeloid leukemia.

[0003] Cephalotaxine is the main alkaloid in this genus, accounting for approximately 50% of the total alkaloids, and is the biosynthetic precursor of 18 known holotaxines. Only 0.39g of total alkaloids can be extracted from 100g of dried Cephalotaxus branches and leaves. Cephalotaxine itself has no biological activity, while the content of homoharringtonine, which has strong anticancer effects, is even lower. Extracting 1g of a mixture of homoharringtonine and holotaxine requires approximately 100 to 150 kg of dried branches and leaves. Furthermore, Cephalotaxus species grow slowly, their numbers have drastically decreased, and their resources are extremely limited, making them rare and protected plants. Therefore, developing safe and accessible synthetic methods is of great significance for solving the problem of homoharringtonine supply.

[0004] As the skeleton of homoharringtonine, cephalotaxine has three consecutive chiral carbon atoms in its E ring, one of which is a tertiary amine quaternary carbon. The E ring also contains dense functional groups. This makes previous cephalotaxine synthesis routes, especially those for synthesizing the E ring functional groups of cephalotaxine, suffer from drawbacks such as long routes, high costs, and low yields, and thus cannot be used for industrial synthesis. For example, compound I is one of the classic intermediates for the synthesis of cephalotaxine (Tetrahedron Lett. 1986, 27, 2023; Chem. Pharm. Bull. 1988, 36, 4229; Org. Lett. 2002, 4, 885; Org. Lett. 2018, 20, 1050; J. Am. Chem. Soc. 2023, 145, 9233.). The synthesis of cephalotaxine from compound I often requires the Moriarty oxidation reaction, which not only uses expensive high-valent iodine oxidant, but also yields only about 50% (J. Am. Chem. Soc. 2023, 145, 9233.). Moreover, the removal of regioselective byproducts can only rely on column chromatography separation.

[0005]

[0006] Therefore, there is an urgent need for a new method for constructing the E-ring functional group of cephalotaxine that is highly efficient, simple to operate, low in cost, environmentally friendly, and suitable for industrial production.

[0007] Based on the construction of the cephalotaxine skeleton (ZL 201410225442.6; ZL201410224701.3) and chiral construction (ZL 201711145937.8), this method aims to provide a new and efficient technique for synthesizing the E-ring functional group of cephalotaxine. Summary of the Invention

[0008] To address the aforementioned technical problems in the existing technology, this invention provides a method for synthesizing the E-ring functional group of cephalotaxine. This method is simple to operate, has a high conversion rate, stable process, low cost, and a total yield of up to 75% in four steps, making it suitable for large-scale preparation.

[0009] The synthesis method of the present invention may specifically include the following four reaction steps:

[0010]

[0011] Step 1), carbonyl reduction: Compound M is dissolved in organic solvent 1, a reducing agent is added, and the reaction is carried out at room temperature to obtain compound M-1;

[0012] Wherein, the organic solvent 1 is one, two or three of the following: methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethyl acetate, tetrahydrofuran, acetonitrile, formic acid, and acetic acid;

[0013] In some embodiments, the organic solvent 1 is one or two of methanol, ethanol, tert-butanol, and ethyl acetate.

[0014] The reducing agent is one, two, or three of the following: sodium borohydride / cerium chloride, lithium borohydride / cerium chloride, and potassium borohydride / cerium chloride.

[0015] In some implementations, the reducing agent is one of sodium borohydride / cerium chloride or lithium borohydride / cerium chloride.

[0016] The molar ratio of compound M to reducing agent is 1:1 to 2;

[0017] In some embodiments, the molar ratio of compound M to reducing agent is 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

[0018] Step 2), olefin epoxidation: Compound M-1 is dissolved in organic solvent 2, an epoxidizing agent is added, and the mixture is reacted at a certain temperature to obtain compound M-2;

[0019] Wherein, the organic solvent 2 is one, two or three of the following: dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, formic acid, and acetic acid;

[0020] In some embodiments, the organic solvent 2 is one or two of dichloromethane, chloroform, and 1,2-dichloroethane.

[0021] The epoxidizing agent is one, two, or three of the following: peroxytert-butanol, hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, peroxyformic acid, p-nitroperbenzoic acid, and trifluoroperacetic acid.

[0022] In some embodiments, the epoxidizing agent is one of m-chloroperoxybenzoic acid, peroxybenzoic acid, and peracetic acid.

[0023] The specified temperature is 0–25°C;

[0024] In some implementations, the specified temperature is 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C.

[0025] The olefin oxidation reaction time is 1 to 2 hours.

[0026] The molar ratio of compound M-1 to the epoxidizing agent is 1:2 to 5;

[0027] In some embodiments, the molar ratio of compound M-1 to the epoxidizing agent is 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4, 1:4.2, 1:4.4, 1:4.6, 1:4.8, or 1:5.

[0028] Step 3), Oxidation reaction: Compound M-2 is dissolved in organic solvent 3, an oxidizing agent is added, and the reaction is carried out at a certain temperature to obtain epoxy ketone M-3;

[0029] Wherein, the organic solvent 3 is one, two or three of the following: dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, and acetonitrile;

[0030] In some embodiments, the organic solvent 3 is one of dichloromethane or chloroform.

[0031] The oxidizing agent is a combination of DMSO and an activating agent;

[0032] The activating agent is one or two of oxalyl chloride, acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, and N,N-dicyclohexylcarbodiimide;

[0033] In some embodiments, the activating agent is one or two of oxalyl chloride, acetic anhydride, and N,N-dicyclohexylcarbodiimide.

[0034] The molar ratio of compound M-2 to DMSO is 1:2.4 to 3, or the molar ratio of compound M-2 to activating reagent is 1:1.2 to 1.5.

[0035] In some embodiments, the molar ratio of compound M-2 to DMSO is 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, or 1:3;

[0036] Alternatively, the molar ratio of compound M-2 to the activating reagent may be 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0037] The specific temperature mentioned in the oxidation reaction is -78℃ to 30℃;

[0038] In some embodiments, the specific temperature mentioned in the oxidation reaction is -78°C, -70°C, -65°C, -60°C, -55°C, -50°C, -45°C, -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, or 30°C.

[0039] Step 4), Meinwald rearrangement: Compound M-3 is dissolved in organic solvent 4, an acidic catalyst is added, and the mixture is reacted at room temperature to give enol compound T.

[0040] Wherein, the organic solvent 4 is one, two or three of the following: dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, and acetonitrile;

[0041] In some embodiments, the organic solvent 4 is one or both of dichloromethane and chloroform.

[0042] The acid catalyst is one, two, or three of the following: boron trifluoride diethyl ether complex, tin tetrachloride, titanium tetrachloride, ferric chloride, aluminum trichloride, methanesulfonic acid, p-toluenesulfonic acid, hydrogen chloride, and sulfuric acid.

[0043] In some embodiments, the Lewis acid is one of boron trifluoride diethyl ether complex and p-toluenesulfonic acid.

[0044] The molar ratio of compound M-3 to Lewis acid is 1:1.2 to 1.5.

[0045] In some embodiments, the molar ratio of compound M-3 to Lewis acid is 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0046] The Meinwald rearrangement reaction takes about 12 hours. Detailed Implementation

[0047] The following embodiments are provided to aid in understanding the present invention. However, it should be understood that these embodiments are for illustrative purposes only and do not constitute any limitation. The actual scope of protection of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention.

[0048] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention in any way. Furthermore, descriptions of well-known structures and techniques are omitted in the following description to avoid unnecessarily obscuring the concept of the invention. Such structures and techniques have also been described in many publications.

[0049] Unless the context clearly indicates otherwise, the terms “a” and “an” as used herein include plural references. For example, reference to “a cell” includes multiple such cells and equivalents known to those skilled in the art, etc.

[0050] As used herein, the term "about" indicates a range of ±20% of the following value. In some embodiments, the term "about" indicates a range of ±10% of the following value. In some embodiments, the term "about" indicates a range of ±5% of the following value.

[0051] The solvents used in this article are commercially available. The following abbreviations are used in this article:

[0052] TLC: Thin-layer chromatography

[0053] THF: Tetrahydrofuran

[0054] DCM: Dichloromethane

[0055] DMF: Dimethylformamide

[0056] DIPEA: Diisopropylethylamine

[0057] DMSO: Dimethyl sulfoxide

[0058] eq: equivalent

[0059] Concentration N: g / L

[0060] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0061] Example

[0062] The synthetic route is as follows:

[0063]

[0064] Example 1

[0065] Carbonyl reduction: The organic solvent is methanol solution, and the reducing agent is sodium borohydride / cerium chloride;

[0066] Carbonyl reduction: Cerium chloride (97 mg, 0.396 mmol) was dissolved in anhydrous methanol (1 mL). Compound M (178 mg, 0.6 mmol) was added to the above reaction solution, and the mixture was stirred at room temperature for 5 min. Sodium borohydride (45.6 mg, 1.2 mmol) was slowly added, and the mixture was stirred at room temperature for 30 min. The reaction was then quenched with saturated NH4Cl solution (1 mL), concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 1:4) to give the reduced product M-1 (220 mg), with a yield of 98%. The relevant data for the product are as follows: 1 H NMR(500MHz,CDCl3)δppm 6.64(s,1H),6.59(s,1H),5.94-5.92(d,J=10Hz,2H),4.33-4.3(m,1H),4.14-4.05(m,1H),3.99(s,1H),3.72-3.66(m,1H ),3.36-3.24(m,1H),3.2-3.15(m,1H),2.48-2.41(m,1H),2.16-2.11(m,1H),2.08-2.03(m,2H),1.78-1.65(m,3H).[M+H] + m / z = 300.12. Other instance conditions are shown in the table below:

[0067] methanol Lithium borohydride / cerium chloride 93％ tert-Butanol solution Sodium borohydride / cerium chloride 94％

[0068] Example 2

[0069] Olefin epoxidation: The organic solvent is dichloromethane solution, and the epoxidizing agent is m-chloroperoxybenzoic acid;

[0070] m-chloroperoxybenzoic acid (146 mg, 0.85 mmol) was dissolved in dichloromethane (0.5 mL), and Na₂CO₃ (86.3 mg, 0.814 mmol) was slowly added. The mixture was stirred at 0 °C for 30 min. Then, the reduction product M-1 (50 mg, 0.17 mmol) dissolved in dichloromethane (0.5 mL) was added. The mixture was heated to room temperature and stirred for 3 h. After the reaction was complete, saturated Na₂SO₃ was added to quench the reaction. The mixture was then extracted with dichloromethane (30 mL × 3), dried, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the epoxidized product M-2 (51 mg), with a yield of 96%. The relevant data for the product are as follows: 1 H NMR(500MHz,CDCl3)δppm 6.64(s,1H),6.59(s,1H),5.94-5.92(d,J=10Hz,2H),4.33-4.3(m,1H),4.14-4.05(m,1H),3.99(s,1H),3.72-3.66(m,1H ),3.36-3.24(m,1H),3.2-3.15(m,1H),2.48-2.41(m,1H),2.16-2.11(m,1H),2.08-2.03(m,2H),1.78-1.65(m,3H).[M+H] + :m / z=316.12.

[0071] Other instance conditions are shown in the table below:

[0072] dichloromethane peroxybenzoic acid 89％ chloroform m-chloroperoxybenzoic acid 92％

[0073] Example 3

[0074] Oxidation reaction: The organic solvent is dichloromethane, and the activating agent is oxalyl chloride;

[0075] Oxaloyl chloride (30 mg, 0.24 mmol) was dissolved in anhydrous dichloromethane. The solution was cooled to -60 °C, and DMSO (34.4 mg, 2.2 mmol) was dissolved in anhydrous dichloromethane (0.3 mL) and slowly added under low-temperature stirring. After 5 min, compound M-2 (62.6 mg, 0.2 mmol) was dissolved in anhydrous dichloromethane (1 mL) and added. After 15 min, DIPEA (0.1 mL, 0.6 mmol) was added. The solution was heated to room temperature. After the reaction of the starting material was complete, the mixture was quenched with saturated NaHCO3, and dichloromethane (15 mL) was added. The mixture was washed with water and saturated brine, dried, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow oily compound M-3 (56 mg) in 89% yield. The relevant data for the product are as follows: 1H NMR(500MHz,CDCl3)δppm 6.7(s,1H),6.58(s,1H),5.98-5.96(d,J=10Hz,2H),4.22-4.17(m,1H),3.89(m,1H),3.78-3.68(m,1H),3.38-3.31(m,1H) ,3.28-3.23(m,1H),2.87-2.84(d,J=15Hz,1H),2.50-2.44(m,1H),2.25-2.17(m,2H),1.9-1.84(m,1H),1.69-1.65(m,1H).

[0076] Other instance conditions are shown in the table below:

[0077] dichloromethane Acetic anhydride 72％ dichloromethane Trifluoroacetic anhydride 70％

[0078] Example 4

[0079] Meinwald rearrangement: The organic solvent is dichloromethane, and the acidic catalyst is a boron trifluoride diethyl ether complex.

[0080] Compound M-3 (31 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (0.5 mL), and boron trifluoride diethyl ether (1.5 mg, 0.01 mmol) was added. The mixture was stirred at room temperature for 12 h, quenched with saturated NaHCO3, extracted with dichloromethane, washed with water, washed with saturated brine, dried and concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 1:2) to give a white solid T (28 mg), with a yield of 90%. The relevant data for the product are as follows: 1 H NMR(500MHz,CDCl3)δppm 6.82(s,1H),6.78(s,1H),6.03-6.0(d,J=15Hz,2H),3.76-3.71(m,1H),3.16-3.10(m,1H),3.06-2.99(m,1H),2.93-2.88 (m,1H),2.78-2.75(d,J=15Hz,1H),2.62-2.59(d,J=15Hz,1H),2.50-2.42(m,1H),2.07-1.99(m,1H),1.90-1.80(m,2H).

[0081] Other instance conditions are shown in the table below:

[0082] dichloromethane p-Toluenesulfonic acid 67％ chloroform Boron trifluoride diethyl ether complex 70％

[0083] The above description is merely a specific embodiment of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing an enol compound T having a cephalotaxine skeleton, comprising the following steps: Step 1), carbonyl reduction: Compound M is dissolved in an organic solvent, a reducing agent is added, and the mixture is reacted at room temperature to obtain compound M-1; Step 2), olefin epoxidation: Compound M-1 is dissolved in an organic solvent, an epoxidizing agent is added, and the mixture is reacted at a certain temperature to obtain compound M-2; Step 3), Oxidation reaction: Compound M-2 is dissolved in an organic solvent, an oxidizing agent is added, and the reaction is carried out at a certain temperature to obtain epoxy ketone M-3; Step 4); Meinwald rearrangement: Compound M-3 is dissolved in an organic solvent, an acidic catalyst is added, and the mixture is reacted at room temperature to give enol compound T.

2. The synthesis method according to claim 1, characterized in that, The organic solvent mentioned in step 1) is one, two, or three of the following: methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethyl acetate, tetrahydrofuran, acetonitrile, formic acid, and acetic acid; The reducing agent is one, two, or three of the following: sodium borohydride / cerium chloride, lithium borohydride / cerium chloride, and potassium borohydride / cerium chloride.

3. The synthesis method according to claim 2, characterized in that, The molar ratio of compound M to reducing agent is 1:1~2.

4. The synthesis method according to claim 1, characterized in that, The organic solvent mentioned in step 2) is one, two, or three of the following: dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, formic acid, and acetic acid. The epoxidizing agent is one, two, or three of the following: peroxytert-butanol, hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, peroxyformic acid, p-nitroperbenzoic acid, and trifluoroperacetic acid. The specified temperature is -30 ℃ to 30 ℃.

5. The synthesis method according to claim 4, wherein, The molar ratio of compound M-1 to the epoxidizing agent is 1:2~5.

6. The synthesis method according to claim 1, characterized in that, The organic solvent mentioned in step 3) is one, two or three of the following: dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, and acetonitrile. The oxidizing agent is a combination of DMSO and an activating agent; The activating agent is one or two of oxalyl chloride, acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, and N,N-dicyclohexylcarbodiimide; The oxidation reaction occurs at a temperature of -78 ℃ to 30 ℃.

7. The synthesis method according to claim 6, wherein, The molar ratio of compound M-2 to DMSO is 1:2.4~3, or the molar ratio of compound M-2 to activating reagent is 1:1.2~1.

5.

8. The method for synthesizing the enol compound T with a cephalotaxine skeleton according to claim 1, characterized in that, The organic solvent mentioned in step 4) is one, two or three of the following: dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, and acetonitrile. The acidic catalyst is one, two, or three of the following: boron trifluoride diethyl ether complex, tin tetrachloride, titanium tetrachloride, ferric chloride, aluminum trichloride, methanesulfonic acid, p-toluenesulfonic acid, hydrogen chloride, and sulfuric acid. The molar ratio of compound M-3 to the acidic catalyst is 1:1.2~1.5.

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