WO2023086447A2

WO2023086447A2 - A method for the synthesis of cannabinol

Info

Publication number: WO2023086447A2
Application number: PCT/US2022/049504
Authority: WO
Inventors: Narender POTTABATHINI; Srivinas KOLA; Marc BENCIVENGA; Surendra Singh
Original assignee: Pureform Global, Inc.
Priority date: 2021-11-12
Filing date: 2022-11-10
Publication date: 2023-05-19
Also published as: WO2023086447A3

Abstract

Disclosed herein is a method for making cannabinol. Cannabinol. The method comprises coupling a protected 3,5-dihydroxy-1-pentylbenzene compound with a 4-methylbenzoate compound, cyclizing the coupled intermediate, and methylating the cyclized compound to form cannabinol.

Description

A METHOD FOR THE SYNTHESIS OF CANNABINOL

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of the earlier filing date of U.S. provisional patent application No. 63/278,619, filed November 12, 2021, which is incorporated herein by reference in its entirety.

FIELD

This disclosure concerns a novel synthesis for making cannabinol.

BACKGROUND

Cannabinol is a cannabinoid that can be isolated from the Cannabis plant, and is a metabolite of tetrahydrocannabinol (THC). Cannabinol may be useful as an appetite stimulant, sleep aid, and/or for reducing pain and affecting the immune system.

SUMMARY

Disclosed herein is a method for making cannabinol. The method may comprise providing a first compound of the formula

and exposing the first compound to conditions suitable to couple the first compound with a second compound having the formula

to form a product of the formula

With respect to these formulas, X is halo; each PG is independently a suitable protecting group; and each R is independently selected from a protecting group and hydrogen. In some embodiments, each R independently is selected from Ci-6alkyl and hydrogen.

The conditions suitable to couple the first compound with the second compound may comprise transition metal-catalyzed coupling conditions, such as conditions that facilitate a palladium-catalyzed coupling. In some embodiments, the palladium-catalyzed coupling conditions comprise Negishi conditions.

In some embodiments, the conditions suitable to couple the first compound with the second compound comprise contacting the first compound with a lithium base to form an organolithium reaction mixture. The method may further comprise contacting the organolithium reaction mixture with a zinc salt.

The method may further comprise exposing the product of formula t

. p g p y p exposing the product to a Lewis acid, such as AlCh.

And the method may further comprise contacting the compound of the formula f

. , , g p f the formula

And in any embodiments, the nucleophilic methylating agent may be a methyl Grignard reagent.

The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a NMR spectrum of compound 1-2 made according to the disclosed method.

FIG. 2 is a NMR spectrum of compound 1-4 made according to the disclosed method.

FIG. 3 is a NMR spectrum of compound 1-5 made according to the disclosed method.

FIG. 4 is a NMR spectrum of compound 1-6 made according to the disclosed method.

DETAILED DESCRIPTION

The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The singular forms “a,” “an,” and “the” refer to one or more than one, unless the context clearly dictates otherwise. The term “or” refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, “comprises” means “includes.” Thus, “comprising A or B,” means “including A, B, or A and B,” without excluding additional elements. All references, including patents and patent applications cited herein, are incorporated by reference.

Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, and so forth, as used in the specification or claims are to be understood as being modified by the term “about.” Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that may depend on the desired properties sought and/or limits of detection under standard test conditions/methods. When directly and explicitly distinguishing embodiments from discussed prior art, the embodiment numbers are not approximates unless the word “about” is recited.

Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.

“Alkyl” refers to a saturated aliphatic hydrocarbyl group having from 1 to 25 carbon atoms, typically 1 to 10 carbon atoms such as 1 to 6 carbon atoms (Ci-6alkyl). An alkyl moiety may be linear, branched or cyclic (i.e., cycloalkyl), unless otherwise specified. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec -butyl, and t-butyl, and cyclic hydrocarbyl groups such as cyclopropyl, cyclobutyl, and cyclohexyl.

“Halo,” “halide” or “halogen” refers to fluoro, chloro, bromo or iodo.

I. Synthesis

Disclosed herein is a novel synthesis for making cannabinol, also known as l-hydroxy-3-n- amyl-6,6,9-trimethyl-6H-dibenzo[b,d]pyran, or 6,6,9-trimethyl-3-pentylbenzo[c]chromen-l-ol. A first reaction step in the synthesis is provided below according to Scheme 1:

Scheme 1.

5-Pentylbenzene-l,3-diol (compound 1) is treated with a suitable protecting group reagent to add a suitable protecting group R¹ to the hydroxy moieties to form compound 2. Suitable protecting groups include any group that can protect the hydroxy moiety during subsequent reactions in the cannabinol synthesis, but can readily be removed at an appropriate time, such as when a hydroxy moiety is required. Suitable protecting groups for a hydroxy moiety include, but are not limited to, alkyl (for example, methyl, t-butyl, or cyclohexyl), methoxymethyl, 2- methoxyethoxymethyl, or a silyl groups (for example, t-butyldimethylsilyl). A person of ordinary skill in the art understands how to select a suitable protecting group, and methods for adding and removing such groups are known in the art. Additional information concerning adding and removing protecting groups, such as protecting groups for a hydroxy, can be found in Wuts, P. and Greene, T., Greene’s Protecting Groups in Organic Synthesis, Fourth Edition, April 2006, Published by Wiley. In some embodiments, each R¹ independently is alkyl, such as Ci-ealkyl, and may be methyl. In some embodiments, both R¹ moieties are the same. In certain embodiments, compound 1 is treated with a methylating agent, such as dimethyl sulfate, or methyl halide, such as methyl iodide, in the presence of a base to form compound 2. The base may be any suitable base to facilitate the reaction, such as a carbonate salt (for example, potassium carbonate, sodium carbonate, lithium carbonate), a hydroxide salt (for example sodium hydroxide, potassium hydroxide, lithium hydroxide), a hydride base, such as sodium hydride, or a combination thereof. The reaction proceeds in a suitable solvent, such as an aprotic solvent, for example, acetone, DMF, THF, acetonitrile, methyl ethyl ketone, or a combination thereof. The reaction is performed at a temperature suitable to facilitate the reaction proceeding to completion, such as from 0 °C to 100°C or more. In some embodiments, the reaction is heated to reflux.

After removal of any salts, such as by filtration and/or aqueous workup, compound 2 is isolated by chromatography and/or distillation.

A second step in the reaction synthesis proceeds according to Scheme 2:

Scheme 2.

Compound 2 is treated with compound 3 to form compound 4. With respect to compound 3, X is a suitable leaving group, such as a halide, for example, Cl, Br or I, typically, Br. And R² is a suitable carboxylate protecting group, such as Ci-ealkyl, for example, methyl, ethyl, propyl, isopropyl or y- butyl.

In some embodiments, compound 2 is treated with a suitable base, such as an organometallic base, typically a organolithium base (for example, n-butyllithium). A transition metal salt, such as a zinc salt, typically a zinc halide (for example, zinc chloride) may be added. The transition metal salt may be anhydrous. Compound 3 and a suitable catalyst are added to the reaction mixture. The catalyst may be any catalyst that facilitates the coupling reaction, such as a palladium catalyst. In some embodiments, Pd(PPh3)2C12 is used.

The reaction is performed in a suitable solvent, such as an aprotic solvent, for example, THF. And the reaction is performed at a temperature suitable to facilitate the reaction, such as from -10 °C to 100 °C or more. A person of ordinary skill in the art understands that different stages of the reaction may be performed at different temperatures. For example, the addition of the base may be performed at a low temperature, such as from -10 °C to 20 °C, whereas the after the addition of compound 3 and the catalyst, the reaction mixture may be maintained at room temperature or heated, such as from 25 °C to 100 °C, from 25 °C to 60 °C or from 25 °C to 40 °C. After an aqueous workup, compound 4 is isolated by chromatography.

In some embodiments, compound 4 may be formed by a Negishi coupling.

A third step in the reaction synthesis proceeds according to Scheme 3:

Scheme 3.

Compound 4 is treated with one or more reagents suitable to remove the hydroxy protecting groups and facilitate forming the pyran ring. A person of ordinary skill in the art understands that different R¹ protecting groups require different removal methods, and these methods are known in the art. One or more intermediate structures may be formed where one or both R¹ moieties is H. additionally, or alternatively, in an intermediate structure, R² may be H.

In some embodiments, the one or more reagents comprises a Lewis acid, such as AlCh, BF3, or FeCL. In some embodiments, such as certain embodiments where each R¹ is methyl, AICI3 may be used to remove the methyl groups and facilitate the cyclization reaction.

The reaction is performed in a suitable solvent, such as an aprotic solvent, for example, toluene, THF, acetonitrile, or a combination thereof, and may be performed in an inert atmosphere. The reaction proceeds at a temperature suitable to facilitate removal of the protecting groups and formation of the pyran. A suitable temperature may be from 60 °C or less to 120 °C or more, such as from 80 °C to 110 °C. In some embodiments, the reaction is heated to reflux. A person of ordinary skill in the art understands that the addition of the Lewis acid, such as AICI3, may proceed at a lower temperature that the reaction mixture, such as room temperature or lower, for example at about 0 °C. After the reaction is complete, compound 5 is isolated by an aqueous workup.

A fourth step in the reaction synthesis proceeds according to Scheme 4:

Scheme 4.

Compound 5 is treated with a nucleophilic methylating agent in a suitable solvent to form compound 6 (cannabinol). The nucleophilic methylating agent may be any agent suitable to di- methylate the carbonyl moiety on compound 5. In some embodiments, the nucleophilic methylating agent is a methyl Grignard reagent, such as MeMgBr. The solvent may be an aprotic solvent, for example, THF, an alkyl ether, toluene, or a combination thereof. Typically, the reaction is performed under an inert atmosphere, and the methylating agent is added to compound 5 slowly at a temperature of about 0 °C. After the addition, the reaction is maintained at a temperature below room temperature, such as about 0 °C until the reaction is complete.

Ammonium chloride solution then may be added to the reaction and the mixture is extracted with an organic solvent, such as ethyl acetate. After washing and drying the organic layer is concentrated and dissolved in a suitable organic solvent, such as a chlorinated solvent, for example, dichloromethane, chloroform, or dichloroethane, and trifluoroacetic acid may be added. After a suitable time, such as from 12 to 24 hours, the mixture is quenched with water and the crude product is extracted. Compound 6 is purified by a suitable technique, such as chromatography and/or recrystallization.

II. Examples

Example 1

K2CO3 (3 eq) was added to a solution of olivetol (compound 1-1) in acetone at 25 °C.

Dimethyl sulphate (3 eq) was added slowly to the mixture at 0 °C under a N2 atmosphere. The reaction was heated to reflux at about 55 °C for 6 hours. The reaction mixture then was cooled to 25 °C, filtered to remove potassium salts and the solid was rinsed with acetone. The filtrate and rinses were concentrated under vacuum to obtain a crude product as a brown colored oil. The crude product was poured onto a silica-gel plug column and eluted with hexanes to 2% EtOAc in hexanes solution to obtain compound 1-2 as colorless liquid. Yield 96.9%.

In a second run, compound 1-2 was purified by washing with 10% NaOH solution followed by high vacuum distillation. Yield 88%, and 99.1% purify.

FIG. 1 provides an exemplary NMR spectrum of compound 1-2. ^!H NMR (300 MHz; CDC1₃): 8 0.86 -0.91 (t, 3H), 8 1.26 - 1.38 (m, 4H), 8 1.55 - 1.65 (m, 2H), 8 2.54 (t, 2H), 8 3.77 (s, 6H), 8 6.28 -6.30 (t, 1H), 8 6.35 (d, 2H) ppm. ESI-MS (m/z): 209.2 [M+l]⁺.

Example 2

A solution of compound 1-2 (1.1 eq) in THF (5 v/w) was cooled to -5 °C. The cooled solution was treated with n-BuLi (2 M in cyclohexane, 1.2 eq) drop wise while maintaining the internal temperature at 0 °C. After the addition the reaction mixture was stirred for 2 hours at 20 °C. The reaction mixture was cooled to 0 °C and anhydrous ZnCb (1.3 eq) was added slowly while maintaining the internal temperature at 0 °C. After the addition, the reaction mixture was stirred for 2 hours at 20 °C. The reaction mixture was again cooled to 0 °C and methyl 2-bromo-4-methyl benzoate (compound 1-3) (1.0 eq) and Pd(PPh3)2Ch (0.01 eq) was added. THF (1.6 v/w) was then added and the reaction was allowed to stir at 25 °C for 10 minutes, followed by stirring at 40 °C for 16 hours. The reaction mixture was then cooled to 10 °C and quenched slowly with 10% aq. ammonium chloride. The aqueous layer was washed with EtOAc, and the combined organic layer was washed with 10% brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to produce the crude compound. The crude material was purified on a silica gel (230-400 mesh) column by using hexanes to 2 % EtOAc in hexanes as the eluent and compound 1-4 was obtained as pale yellow solid. Yield 16.7%.

Subsequent runs used 1.73 eq n-BuLi and 2.7 eq ZnCl? which resulted in a yield of 60% and a purity of 98.6%, and 2 eq n-BuLi and 2.3 eq ZnCE, which gave a yield of 58% and a purity of 98.3%.

FIG. 2 provides an exemplary NMR spectrum of compound 1-4. H NMR (300 MHz; CDCI3): 8 0.90 -0.94 (t, 3H), 8 1.34 - 1.39 (m, 4H), 8 1.62 - 1.72 (m, 2H), 8 2.38 (t, 2H), 82.6 - 2.65 (m, 2H), 8 3.60 (s, 3H), 8 3.68 (s, 3H), 8 6.44 (s, 2H), 8 7.14 -7.17 (m, 2H), 8 7.83 -7.85 (d, 1H) ppm. ESI-MS (m/z): 357.3 [M+l]⁺.

Example 3

To a solution of compound 1-4 (1.0 eq) in toluene, AlCh (3.5 eq) was slowly added at 0 °C under an N2 atmosphere. After the addition, the reaction mixture was refluxed for 3 hours. The reaction mixture then was cooled to 25 °C, poured into ice-cold water and extracted with EtOAc. The organic layer was washed with 10% brine solution, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude compound 1-5 as a brown-red color solid. The crude compound was slurried with hexanes, filtered, and washed with hexanes to give compound 1-4 as pale brown solid. Yield 90%.

FIG. 3 provides an exemplary NMR spectrum of compound 1-5.

(300 MHz; CDCI3): 6 0.80 -0.94 (t, 3H), 5 1.20 - 1.40 (m, 4H), 5 1.50 - 1.70 (m, 4H), 8 2.54 (s, 3H), 52.57 - 2.63 (m, 2H), 8 6.07 (s, 1H), 8 6.58 (d, 1H), 8 6.81 (d,lH), 8 7.30 -7.40 (m, 1H), 8 8.32 (d, 1H), 8 8.81 (t, 1H) ppm. ESI-MS (m/z): 297.2 [M+l]⁺.

Example 4

A solution of compound 1-5 (1 eq) in THF (26 v/w) was cooled to 0 °C under nitrogen and then was treated drop wise with MeMgBr (3.2 M in 2-MeTHF, 10.18 eq). After the addition, the reaction was stirred at 0 °C for 4 hours. The reaction mixture was quenched by adding 20% aq. NH4CI solution and water and the aqueous layer was extracted with EtOAc. The organic layer was washed with 10% brine solution, dried over anhydrous sodium sulfate, and concentrated. The residue was then dissolved in dichloromethane (DCM) (3 v/w), treated with trifluoroacetic acid ( 1 v/w) and the mixture was stirred for 16 hours at 25 °C. The mixture then was quenched by slowly pouring into ice water (3 v/w). The aqueous layer was extracted with DCM (3 v/w). The combined organic layer was washed with 10% brine solution, and the aqueous mixture was extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain crude compound 1-6. The crude material was purified on silica gel column chromatography by using hexanes to 2 % EtOAc in hexanes as gradient eluent. The pure fractions were combined, concentrated under vacuum to obtain purified I- 6 as a syrup. The product was confirmed by ¹ H-N MR and Mass analysis. Yield 65% and 99.8% purity.

In a second run of the method, the crude compound was purified with charcoal treatment followed by recrystallization from heptane. Yield 60%, 99.9% purity.

FIG. 4 provides an exemplary NMR spectrum of compound 1-6.

(300 MHz; CDCh): 5 0.86 -0.9(t, 3H), 5 1.31 - 1.33 (m, 4H), 5 1.60 (s, 6H), 5 1.61 - 1.64 (m, 2H), 52.38 (s, 3H), 5 2.50 (t, 2H), 5 5.14 (br, 1H), 5 6.28 (s, 1H), 8 6.43, 5 7.07 (d, 1H), 5 7.15 (d, 1H), 5 8.15 (s, 1H) ppm. ESI-MS (m/z): 311.61 [M+l]⁺.

III. Exemplary Embodiments

The following numbered paragraphs illustrate exemplary embodiments of the disclosed technology.

Paragraph 1. A method, comprising providing a first compound of the formula

,

X is halo; each PG is independently a suitable protecting group; and each R is independently selected from a protecting group and hydrogen.

Paragraph 2. The method of paragraph 1, wherein the conditions suitable to couple the first compound with the second compound comprise transition metal-catalyzed coupling conditions.

Paragraph 3. The method of paragraph 2, wherein the transition metal catalyzed coupling conditions comprise palladium-catalyzed coupling conditions.

Paragraph 4. The method of paragraph 2, wherein the palladium-catalyzed coupling conditions comprise Negishi conditions.

Paragraph 5. The method of any one of paragraphs 1-4, wherein the conditions suitable to couple the first compound with the second compound comprise contacting the first compound with a lithium base to form an organolithium reaction mixture.

Paragraph 6. The method of paragraph 5, further comprising contacting the organolithium reaction mixture with a zinc salt.

Paragraph 7. The method of any one of paragraphs 1-6, wherein each R independently is selected from CL ealky 1 and hydrogen.

Paragraph 8. The method of any one of paragraphs 1-7, further comprising exposing the product

Paragraph 9. The method of paragraph 8, wherein exposing the product to acidic conditions comprises exposing the product to a Lewis acid.

Paragraph 10. The method of paragraph 8 or paragraph 9, further comprising contacting the compound of the formula

Paragraph 11. The method of paragraph 10, wherein contacting the compound of the formula

Paragraph 12. The method of paragraph 10 or paragraph 11, wherein the nucleophilic methylating agent is methyl Grignard reagent.

Paragraph 13. The method of any one of paragraphs 1-12, wherein the method further comprises treating olivetol with a protecting group reagent to form

Paragraph 14. The method of paragraph 13, wherein PG is methyl.

Paragraph 15. The method of paragraph 1, comprising treating a compound having a formula 1-2

with an organolithium base followed by a zinc salt and methyl 2-bromo-4-methyl benzoate to form a compound having a formula 1-4

treating the compound having a formula 1-4 with a Lewis acid to form a compound having a

1-5; and treating the compound having a formula 1-5 with a methylating agent to form cannabinol.

Paragraph 16. The method of paragraph 15, wherein the organolithium base is n- butyllithium.

Paragraph 17. The method of paragraph 15 or paragraph 16, wherein the zinc salt is ZnCh.

Paragraph 18. The method of any one of paragraphs 15-17, wherein the Lewis acid is A1CL.

Paragraph 19. The method of any one of paragraphs 15-18, wherein the methylating agent is a methyl Grignard reagent.

Paragraph 20. The method of any one of paragraphs 15-19, further comprising forming the compound having a formula 1-2 by treating olivetol with a methylating agent.

In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

We claim:

1. A method, comprising providing a first compound of the formula

,

2. The method of claim 1, wherein the conditions suitable to couple the first compound with the second compound comprise transition metal-catalyzed coupling conditions.

3. The method of claim 2, wherein the transition metal catalyzed coupling conditions comprise palladium-catalyzed coupling conditions.

4. The method of claim 2, wherein the palladium-catalyzed coupling conditions comprise Negishi conditions.

5. The method of claim 1, wherein the conditions suitable to couple the first compound with the second compound comprise contacting the first compound with a lithium base to form an organolithium reaction mixture.

6. The method of claim 5, further comprising contacting the organohthium reaction mixture with a zinc salt.

7. The method of claim 1, wherein each R independently is selected from Ci ealkyl and hydrogen.

8. The method of claim 1, further comprising exposing the product

9. The method of any one of claims 1-8, wherein exposing the product to acidic conditions comprises exposing the product to a Lewis acid.

10. The method of claim 8, further comprising contacting the compound of the formula

11. The method of claim 10, wherein contacting the compound of the formula

12. The method of claim 10, wherein the nucleophilic methylating agent is methyl

Grignard reagent.

13. The method of claim 1, wherein the method further comprises treating olivetol with a protecting group reagent to form

14. The method of claim 13, wherein PG is methyl.

15. The method of claim 1, comprising treating a compound having a formula 1-2

with an organolithium base followed by a zinc salt and methyl 2-bromo-4-methyl benzoate to form

1-4; treating the compound having a formula 1-4 with a Lewis acid to form a compound having a formula 1-5

16. The method of claim 15, wherein the organolithium base is n-butyllithium.

17. The method of claim 15, wherein the zinc salt is ZnCh.

18. The method of claim 15, wherein the Lewis acid is AICI3.

19. The method of claim 15, wherein the methylating agent is a methyl Grignard reagent.

20. The method of claim 15, further comprising forming the compound having a formula 1-2 by treating olivetol with a methylating agent.