Synthesis method and application of azaspirocycloally alcohol

Abstract

The application provides a new method for synthesizing azaspiro cycloalkenyl alcohol F and application thereof. The method comprises five steps of carbonyl reduction, olefin epoxidation, oxidation, Wharton reaction and Boc removal. Compared with previous synthesis methods, the reagent used in the method is cheap and easy to obtain, the reaction condition is mild, the operation is simple, the key intermediate F is synthesized in five steps, and the method is easy to produce in an industrialized manner.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a new method for synthesizing spiro allyl alcohol. BACKGROUND

[0002] Harringtonine and its ester derivatives are alkaloids extracted from plants of the genus Cephalotaxus, and are a class of alkaloids with special structure and biological activity. Harringtonine is composed of five ring fusions, and its E ring contains three consecutive chiral centers as well as an enol methyl ether and a secondary alcohol functional group.

[0003] Homoharringtonine is a chiral compound. The parent skeleton of harringtonine contains three consecutive chiral carbon atoms, one of which is a tertiary amine quaternary carbon, and the C2 position of the ester side chain is a tertiary alcohol quaternary carbon with an absolute configuration of R configuration. In 2012, homoharringtonine was approved by the US FDA for the treatment of adult chronic myeloid leukemia. Like other drugs for treating hematological diseases, homoharringtonine also has side effects, but the side effects of homoharringtonine are milder and more reversible than other drugs for treating leukemia.

[0004] Harringtonine is an alkaloid extracted from Cephalotaxus hainanensis. Over time, the population of Cephalotaxus hainanensis is still shrinking year by year, and now it is almost endangered, but the existing chemical synthesis method has the disadvantages of long route, high cost and low yield, which cannot be used for industrial synthesis. For example, compound F is an intermediate for synthesizing harringtonine (J. Org. Chem. 1995, 60, 115-119), and a noble metal catalyst is used when the five-membered ring is synthesized, which is relatively high in cost, and the synthesis route is long and not conducive to industrial production.

[0005]

[0006] Therefore, there is an urgent need for a new method for constructing nitrogen spiro allyl alcohol F with high conversion rate, simple operation, low cost and green environmental protection, which is suitable for industrial production. SUMMARY

[0007] In order to solve the problems existing in the prior art, the present application provides a synthesis method of nitrogen spiro allyl alcohol F, which is simple in operation, high in conversion rate, stable in process and low in cost.

[0008] The synthesis method of the present application can specifically include the following five reaction steps:

[0009]

[0010] Among them, PG is an amino protecting group, and the amino protecting group is selected from: C 1-6 alkylcarbonyl, C 1-6alkylcarbonyloxy, C 1-6 alkenylcarbonyloxy, benzylcarbonyloxy (Cbz), fluorenylcarbonyloxy (Fmoc), tosyl (Tos), p-methoxybenzyl (PMB), or benzyl (Bn).

[0011] In some embodiments, the amino protecting group is selected from one of tert-butyloxycarbonyl (Boc), benzylcarbonyloxy (Cbz), fluorenylcarbonyloxy (Fmoc), allyloxycarbonyl (Alloc), ethoxycarbonyl (Teoc), tosyl (Tos), p-methoxybenzyl (PMB), or benzyl (Bn).

[0012] Step 1) carbonyl reduction: compound A is dissolved in an organic solvent 1, a reducing reagent is added, and the reaction is carried out at room temperature to obtain compound B;

[0013] wherein the organic solvent 1 is one, two, or three of methanol, ethanol, n-propanol, isopropanol, t-butanol, ethyl acetate, tetrahydrofuran, acetonitrile, formic acid, acetic acid.

[0014] In some embodiments, the organic solvent 1 is one or two of methanol, ethanol, t-butanol, ethyl acetate.

[0015] wherein the reducing reagent is one, two, or three of sodium borohydride / cerium chloride, lithium borohydride / cerium chloride, potassium borohydride / cerium chloride.

[0016] In some embodiments, the reducing reagent is one of sodium borohydride / cerium chloride, lithium borohydride / cerium chloride.

[0017] wherein the molar ratio of compound A to reducing reagent is 1:1~2.

[0018] In some embodiments, the molar ratio of compound A to reducing reagent is 1:1, 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.

[0019] Step 2) olefin epoxidation reaction: compound B is dissolved in an organic solvent 2, an epoxidation reagent is added, and the reaction is carried out at a certain temperature to obtain compound C;

[0020] wherein the organic solvent 2 is one, two, or three of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, methanol, ethanol, n-propanol, isopropanol, t-butanol, formic acid, acetic acid.

[0021] In some embodiments, the organic solvent 2 is one or two of dichloromethane, chloroform, 1,2-dichloroethane.

[0022] The epoxidation reagent is one, two or three of tert-butyl hydroperoxide, hydrogen peroxide, peroxyacetic acid, peroxybenzoic acid, meta-chloro peroxybenzoic acid, peroxyformic acid, p-nitro peroxybenzoic acid, trifluoro peroxyacetic acid.

[0023] In some embodiments, the epoxidation reagent is one of meta-chloro peroxybenzoic acid, peroxybenzoic acid, peroxyacetic acid.

[0024] The molar ratio of compound B to epoxidation reagent is 1:2-5.

[0025] In some embodiments, the molar ratio of compound B to epoxidation reagent is 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:4.2, 1:4.5, 1:4.8 or 1:5.

[0026] The temperature in the epoxidation reaction is 0-25°C.

[0027] In some embodiments, the temperature in the epoxidation reaction is 0°C, 1°C, 2°C, 3°C, 5°C, 6°C, 8°C, 9°C, 10°C, 12°C, 15°C, 18°C, 20°C, 21°C, 22°C, 23°C, 24°C or 25°C.

[0028] The epoxidation reaction time is 2.5-3h.

[0029] Step 3) Oxidation reaction: compound C is dissolved in organic solvent 3, an oxidation reagent is added, and the reaction is carried out at a certain temperature to obtain compound D.

[0030] The organic solvent 3 is one, two or three of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, acetonitrile.

[0031] In some embodiments, the organic solvent 3 is one or two of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane.

[0032] The oxidation reagent is a combination of DMSO and an activating reagent.

[0033] In some embodiments, the activating reagent is one or more of oxalyl chloride, acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, N,N-dicyclohexylcarbodiimide.

[0034] In some other embodiments, the activating reagent is one of oxalyl chloride, acetic anhydride, N,N-dicyclohexylcarbodiimide.

[0035] In some embodiments, the molar ratio of compound C to DMSO is 1:2.4-3.

[0036] In some embodiments, the molar ratio of compound C to DMSO is 1 : 1.2, 1 : 1.5, 1 : 1.8, 1 : 2, 1 : 2.2, 1 : 2.4, 1 : 2.5, 1 : 2.6, 1 : 2.7, 1 : 2.8, 1 : 2.9, or 1 : 3.

[0037] In some embodiments, the molar ratio of compound C to activating agent is 1 : 1.2-1.5;

[0038] In some embodiments, the molar ratio of compound C to activating agent is 1 : 1.2-1.5;

[0039] In some embodiments, the temperature in the oxidation reaction is -78 °C to 30 °C.

[0040] In some embodiments, the temperature 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.

[0041] Step 4) Wharton reaction: compound D is dissolved in organic solvent 4, hydrazine reagent is added, and the reaction is carried out in the presence of a base at a certain temperature to obtain compound E.

[0042] In some embodiments, the organic solvent 4 is one of methanol, ethanol, n-propanol, isopropanol, t-butanol, ethyl acetate, tetrahydrofuran.

[0043] In some embodiments, the organic solvent 4 is one of methanol, ethanol, isopropanol.

[0044] The base is one, two, or three of triethylamine, diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate.

[0045] The hydrazine is hydrazine hydrate or its hydrochloride. In some embodiments, the base is one of triethylamine, potassium tert-butoxide, potassium carbonate.

[0046] In some embodiments, the molar ratio of compound D to hydrazine reagent is 1 : 1-2.

[0047] In some embodiments, the molar ratio of compound D to hydrazine reagent is 1 : 1.2-1.5.

[0048] In some embodiments, the molar ratio of compound D to hydrazine reagent is 1 : 1.2-1.5. In some embodiments, the molar ratio of compound D to hydrazine reagent is 1 : 1.2-1.5.

[0049] The temperature in the Wharton reaction is 0°C;

[0050] Step 5) PG removal reaction: compound E is dissolved in organic solvent 5, and an acidic reagent is added, and reacted at a certain temperature to obtain compound F;

[0051] The organic solvent 5 is one, two or three of dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, diethyl ether, 1,2-dichloroethane, and 1,4-dioxane.

[0052] In some embodiments, the organic solvent 5 is one of dichloromethane, chloroform, and 1,2-dioxane.

[0053] The acid is one or both of trifluoroacetic acid and hydrochloric acid.

[0054] In some embodiments, the acid is trifluoroacetic acid or hydrochloric acid.

[0055] The molar ratio of compound E to acidic reagent is 1:5-13.5.

[0056] In some embodiments, the molar ratio of compound E to acidic reagent is 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10, 1:10.5, 1:11, 1:11.5, 1:12, 1:12.5, 1:13, or 1:13.5.

[0057] The temperature in the PG removal reaction is 0°C. DETAILED DESCRIPTION

[0058] The following examples are provided to assist in understanding the present application. It is understood, however, that these examples are intended to be illustrative only and are not intended to limit the present application in any way. The true scope of the present application is set forth in the appended claims. It is understood that any modification and alteration to the examples are possible without departing from the spirit of the present application.

[0059] In order to make the objectives, technical solutions, and advantages of the present application clearer, the following further describes the present application in conjunction with examples. The specific examples described herein are only used to explain the present application and do not constitute any limitation on the present application. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessarily confusing the concept of the present application. Such structures and technologies are also described in many publications.

[0060] The expressions "one" and "a" as used herein, include plural referents unless the context clearly dictates otherwise. For example, reference to "a cell" includes a plurality of such cells, as well as equivalents thereof known to those skilled in the art, and so forth.

[0061] As used herein, the term "about" refers to a range of ±20% of the value that follows. In some embodiments, the term "about" refers to a range of ±10% of the value that follows. In some embodiments, the term "about" refers to a range of ±5% of the value that follows.

[0062] The solvents used herein are commercially available. The following abbreviations are used herein:

[0063] TLC: Thin layer chromatography

[0064] THF: Tetrahydrofuran

[0065] DCM: dichloromethane

[0066] DMF: dimethylformamide

[0067] DIPEA: diisopropylethylamine

[0068] DMSO: dimethyl sulfoxide

[0069] eq: equivalent

[0070] Concentration N: g / L

[0071] Compounds are manually or The software named the commercially available compounds using the supplier's catalog name.

[0072] Example

[0073] The synthetic route is as follows

[0074]

[0075] Example 1

[0076] Carbonyl reduction reaction: organic solvent 1 is methanol solution, and reducing reagent is sodium borohydride / cerium chloride.

[0077] Cerium chloride (165 mg, 0.67 mmol) was dissolved in anhydrous methanol (10 mL). Spirocyclopentane A (237 mg, 1 mmol) was added to the reaction mixture and stirred at room temperature for 5 minutes. Sodium borohydride (76 mg, 2 mmol) was slowly added and stirred at room temperature for 30 minutes. The reaction was quenched by adding saturated NH4Cl solution (1 mL). The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the reduction product B (232 mg) in a 97% yield. Product data are as follows: 1H NMR (500 MHz, CDC13) δ ppm 5.95 (dd, J=5.5, 2.4 Hz, 1 H), 5.62 (d, J=5.5 Hz, 1 H), 4.58 (dd, J=6.2, 2.3 Hz, 1 H), 3.47-3.37 (m, 2 H), 2.30 (dd, J=14.9, 7.5 Hz, 1 H), 2.16 (d, J=14.8 Hz, 1 H), 1.95-1.76 (m, 4 H), 1.44-1.39 (m, 1 H). [M+H] + : m / z = 240.16.

[0078] Other example conditions are shown in the table below:

[0079] organic solvent reducing agent yield methanol lithium borohydride / cerium chloride 92％ tert-butanol sodium borohydride / cerium chloride 90％

[0080] Example 2

[0081] Oxidation reaction: organic solvent 3 was dichloromethane, and the activating reagent was oxalyl chloride.

[0082] MCPBA (1.15 g, 5 mmol) was dissolved in dichloromethane (10 mL), Na2CO3(530 mg, 5 mmol) was added slowly, stirred at 0 °C for 30 min, then the reduced product B (232 mg, 1 mmol) dissolved in dichloromethane (10 mL) was added, stirred at room temperature for 3 h, after the reaction was completed, saturated Na2SO3was added to quench, extracted with dichloromethane (30 mL x 3), dried, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the epoxidation product C (214 mg) with a yield of 91%.

[0083] Other example conditions are shown in the table below:

[0084] organic solvent epoxidation agent yield dichloromethane benzeneperozoic acid 89％ chloroform m-chloroperbenzoic acid 78％

[0085] Example 3

[0086] Oxidation reaction: organic solvent 3 was dichloromethane, and the activating reagent was oxalyl chloride.

[0087] Oxalyl chloride (150 mg, 4.2 mmol) was dissolved in anhydrous dichloromethane, and cooled to -60 °C. DMSO (172 mg, 11 mmol) was dissolved in anhydrous dichloromethane (1.5 mL) and added slowly under stirring at low temperature. After 5 min, compound C (233 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL) and added. After 15 min, DIPEA (0.5 mL, 3 mmol) was added, and the temperature was raised to room temperature. After the reaction was completed, saturated NaHCO3was added for quenching, dichloromethane (25 mL) was added, and the mixture was washed with water and saturated brine. The mixture was dried and concentrated, and the product was separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the oxidation product D (212 mg) with a yield of 92%. The relevant data of the product are as follows: 1 H NMR (500 MHz, CDC13) δ ppm 3.69 (d, J = 2.6 Hz, 1H), 3.62-3.54 (m, 1H), 3.52-3.45 (m, 1H), 3.34 (d, J = 2.3 Hz, 1H), 2.03-1.95 (m, 1H), 1.92-1.75 (m, 3H), 1.73-1.59 (m, 1H), 1.48 (s, 5H). [M+H] + m / z = 254.14.

[0088] Other example conditions are shown in the following table:

[0089] organic solvent activating agent yield dichloromethane trifluoroacetic anhydride 78％ dichloromethane acetic anhydride 73％

[0090] Example 4

[0091] Wharton reaction: organic solvent 4 is methanol solution, and the base is triethylamine.

[0092] The monohydrazine hydrochloride (103 mg, 1.5 mmol) was dissolved in a methanol solution (3 mL), and triethylamine (0.21 mL) was added thereto. The mixture was stirred at 0 °C for 30 min, and then the above reaction solution was added dropwise to a methanol solution (3 mL) of the oxidation product D (253 mg, 1 mmol). The mixture was stirred at 0 °C for 2 h, and then concentrated under reduced pressure. The product was separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the spirocyclic enol E (194 mg) with a yield of 81%. The relevant data of the product are as follows: 1H NMR (500 MHz, CDC13) δ ppm 5.99 - 5.91 (m, 1 H), 5.84 (s, 1 H), 4.10 (d, J=10.3 Hz, 1 H), 3.93 (d, J=11.7 Hz, 1 H), 3.59 - 3.52 (m, 1 H), 3.47 (dd, J=14.6, 8.5 Hz, 1 H), 2.14 (d, J=17.3 Hz, 1 H), 2.02 - 1.95 (m, 1 H), 1.94 - 1.76 (m, 3 H), 1.47 - 1.42 (m, 1 H). [M+H] + : m / z = 240.16.

[0093] Other example conditions are shown in the table below:

[0094] organic solvent base yield ethanol potassium carbonate 43％ isopropanol potassium carbonate 44％

[0095] Example 5

[0096] Boc removal reaction: organic solvent 5 is dichloromethane solution, acid is trifluoroacetic acid.

[0097] Spirane enol E (239 mg, 1 mmol) was dissolved in anhydrous dichloromethane (10 mL), stirred at 0 °C for 2 h, after the reaction was complete, add trifluoroacetic acid (1 mL) and concentrate under reduced pressure, column chromatography separation (dichloromethane:methanol = 20:1) to obtain the Boc removal product F (134 mg), the yield was 96%. The product related data are as follows: 1 H NMR (500 MHz, CDC13) δ ppm 5.99 - 5.91 (m, 1 H), 5.84 (s, 1 H), 4.10 (d, J=10.3 Hz, 1 H), 3.93 (d, J=11.7 Hz, 1 H), 3.59 - 3.52 (m, 1 H), 3.47 (dd, J=14.6, 8.5 Hz, 1 H), 2.14 (d, J=17.3 Hz, 1 H), 2.02 - 1.95 (m, 1 H), 1.94 - 1.76 (m, 3 H), 1.47 - 1.42 (m, 1 H). [M+H] + : m / z = 140.11.

[0098] Other example conditions are shown in the table below:

[0099] organic solvent acid yield chloroform trifluoroacetic acid 73％ 1,4-dioxane hydrochloric acid 71％

[0100] The above description is only a specific implementation of the present application, and cannot limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for synthesizing an azaspirocyclic allyl alcohol F, wherein the reaction process comprises the following steps: Step 1), carbonyl reduction: Compound A is dissolved in an organic solvent 1, a reducing agent is added, and the mixture is reacted at room temperature to obtain Compound B; the reducing agent is one, two, or three of sodium borohydride / cerium chloride, lithium borohydride / cerium chloride, and potassium borohydride / cerium chloride; Step 2), olefin epoxidation: Compound B is dissolved in an organic solvent 2, an epoxidation reagent is added, and the mixture is reacted at a certain temperature to obtain Compound C; the epoxidation reagent is one, two or three of tert-butyl peroxide, hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, performic acid, p-nitroperbenzoic acid, and trifluoroperacetic acid; Step 3), oxidation reaction: Compound C is dissolved in organic solvent 3, an oxidizing agent is added, and the mixture is reacted at a certain temperature to obtain Compound D; the oxidizing agent is a combination of DMSO and an activating agent; the activating agent is oxalyl chloride, acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, or N,N-dicyclohexylcarbodiimide; Step 4), Wharton reaction: Compound D is dissolved in an organic solvent 4, a hydrazine reagent and a base are added, and the mixture is reacted at a certain temperature to obtain Compound E; the base is one, two or three of triethylamine, diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, and sodium carbonate; Step 5), PG removal reaction: Compound E is dissolved in an organic solvent 5, an acidic reagent is added, and the reaction is carried out at a certain temperature to obtain compound F; wherein PG is an amino protecting group, and the amino protecting group is selected from: C 1-6 Alkylcarbonyl, C 1-6 One of an alkyloxycarbonyl group, a benzyloxycarbonyl group (Cbz) and a tosylsulfonyl group (Tos).

2. The synthesis method according to claim 1, wherein The organic solvent 1 in step 1) is one, two or three of methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethyl acetate, tetrahydrofuran, acetonitrile, formic acid and acetic acid.

3. The synthesis method according to claim 1, wherein the organic solvent 2 in step 2) is one, two or three of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, formic acid and acetic acid.

4. The synthesis method according to claim 1, wherein The molar ratio of compound B to the epoxidation reagent is 1:2-5.

5. The synthesis method according to claim 1, wherein the organic solvent 3 in step 3) is one, two or three of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, and acetonitrile; The temperature of the oxidation reaction is minus 78 degrees to 30 degrees.

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

5.

7. The synthesis method according to claim 1, wherein the organic solvent 4 used in step 4) is one, two or three of methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethyl acetate and tetrahydrofuran; The hydrazine is hydrazine hydrate or its hydrochloride.

8. The synthesis method according to claim 1, wherein the molar ratio of compound D to hydrazine reagent is 1:1-2.

9. The method for synthesizing an azaspirocyclic allyl alcohol F according to claim 1, characterized in that In step 5), the organic solvent 5 is one, two or three selected from the group consisting of dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, diethyl ether and 1,2-dichloroethane; The acid is one or both of trifluoroacetic acid and hydrochloric acid; The molar ratio of compound E to the acidic reagent is 1:5 to 13.5.

Images