A method for synthesizing dextromethorphan

Abstract

The present invention provides a method for synthesizing dextromethorphan. Using 2-(2-oxocyclohexyl)acetonitrile as a raw material, through a Robinson annulation reaction, compound 2 is generated; compound 2 undergoes an aromatization reaction to generate compound 3; compound 3 undergoes a ketone carbonyl reduction reaction to generate compound 4; compound 4 undergoes a cyano reduction to generate compound 5; compound 5 undergoes a cyclization reaction to obtain compound 6; compound 6 undergoes an asymmetric catalytic hydrogenation to obtain compound 7; compound 7 undergoes an N-methylation reaction to obtain dextromethorphan. The present invention develops a new asymmetric synthesis route for preparing dextromethorphan, avoiding the splitting of intermediates, improving the yield, enhancing the atom economy, and reducing waste.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of morphinan compounds, and particularly to a method for synthesizing dextromethorphan. Background Art

[0002] Dextromethorphan (DM), also known as dextromethorphan, is a central cough suppressant. It mainly exerts its effect by inhibiting the cough center in the medulla oblongata of the brainstem and blocking the excitation of the vagus nerve. Its antitussive effect can be compared with that of codeine, and it is widely used in clinical antitussive due to its non-narcotic and non-addictive properties.

[0003] Due to its structure similar to morphine, people mainly synthesize racemic N-methylmorphinan or 3-hydroxy-N-methylmorphinan starting from 6,7,8,9-tetrahydroisoquinoline, 2-(1-cyclohexenyl)acetonitrile or octahydrophenanthrene derivatives, and then obtain a single optically active product through chemical resolution; at the same time, dextromethorphan can also be synthesized by an asymmetric synthesis method. Among them, in the process of constructing the morphinan ring, the process of constructing a four-ring through the Grewe cyclization reaction is the key step in the synthesis of dextromethorphan.

[0004] CN102977021A discloses a method for preparing dextromethorphan hydrobromide. The method includes reacting p-methoxyphenylacetic acid with cyclohexeneethylamine to form p-methoxyphenylacetic acid-(cyclohexeneethylamineethyl)-amide, and then under the action of phosphorus oxychloride, a Bischler-Napieralski cyclization reaction occurs, followed by reduction to obtain octahydroisoquinoline. The octahydroisoquinoline is resolved, and then catalytic hydrogenation under normal pressure with Raney-Ni is carried out to obtain N-methyloctahydroisoquinoline. Under the action of a Lewis acid, a cyclization reaction occurs and acidification with hydrobromic acid is carried out to obtain dextromethorphan hydrobromide. In addition to the need to resolve intermediates resulting in a low yield in this patent, reagents such as phosphorus oxychloride and hydrobromic acid are also used in the process route, the process conditions are relatively harsh, there is more three-waste, and it is not environmentally friendly. Summary of the Invention

[0005] In view of the deficiencies in the prior art, the present invention provides a method for synthesizing dextromethorphan, which solves the problems of low yield and high pollution existing in the prior art.

[0006] On the one hand, the present invention provides a method for synthesizing dextromethorphan. Using 2-(2-oxocyclohexyl)acetonitrile as a raw material, through a ring-forming reaction, compound 2 is generated; compound 2 undergoes a dehydrogenation reaction to generate compound 3; compound 3 undergoes a ketone reduction reaction to generate compound 4; compound 4 undergoes a cyano reduction to generate compound 5; compound 5 undergoes a cyclization reaction to obtain compound 6; compound 6 undergoes asymmetric catalytic hydrogenation to obtain compound 7; compound 7 undergoes an N-methylation reaction to obtain dextromethorphan, and its reaction process is as follows:

[0007]

[0008] Further, it includes the following steps:

[0009] S1: In a first solvent, 2-(2-oxocyclohexyl)acetonitrile and S-1-phenylethylamine undergo a Michael addition reaction under the action of a first catalyst, and then 1-(4-methoxy-1,4-cyclohexadien-1-yl)ethanone is added to undergo an Aldol condensation reaction to form Compound 2;

[0010] S2: In a second solvent, Compound 2 undergoes an aromatization reaction under the action of a second catalyst to form Compound 3;

[0011] S3: In a third solvent, Compound 3 undergoes a ketone carbonyl reduction reaction under the action of a reducing agent to form Compound 4;

[0012] S4: In a fourth solvent, Compound 4 undergoes a cyano reduction reaction with hydrogen under the action of a third catalyst and an additive to form Compound 5;

[0013] S5: In a fifth solvent, Compound 5 undergoes a cyclization reaction under the action of bromine, and then in a sixth solvent, a dehydrohalogenation reaction occurs in the presence of a first base to obtain Compound 6;

[0014] S6: In a seventh solvent, Compound 6 undergoes an asymmetric catalytic hydrogenation reaction under the action of a fourth catalyst and a hydrogen donor to obtain Compound 7;

[0015] S7: Compound 7 undergoes an Eschweiler–Clarke methylation reaction under the action of formic acid and formaldehyde to form dextromethorphan.

[0016] Further, the first solvent is toluene, the second solvent is acetonitrile, the third solvent is dioxane, the fourth solvent is ethanol, the fifth solvent is dichloromethane, the sixth solvent is N,N-dimethylformamide, and the seventh solvent is methanol.

[0017] Further, the first catalyst is p-toluenesulfonic acid, the second catalyst is copper bromide, the third catalyst is Raney-Ni, and the fourth catalyst is palladium hydroxide.

[0018] Further, the reducing agent is zinc.

[0019] Further, the additive is ammonia water, the first base is NaHCO3, and the hydrogen donor is ammonium formate.

[0020] Further, the molar ratio of 2-(2-oxocyclohexyl)acetonitrile:S-1-phenylethylamine:p-toluenesulfonic acid:1-(4-methoxy-1,4-cyclohexadien-1-yl)ethanone is 1:1:0.1:1.05; the molar ratio of Compound 2:copper bromide is 1:0.05; the molar ratio of Compound 3:reducing agent is 1:2; the molar ratio of Compound 4:third catalyst is 1:0.1; calculated by g / ml, the dosage ratio of Compound 4:additive is 3:1; the molar ratio of Compound 5:bromine:first base is 1:1:2; the molar ratio of Compound 6:fourth catalyst:hydrogen donor is 1:0.1:5; the molar ratio of Compound 7:formaldehyde is 1:2; calculated by g / ml, the dosage ratio of Compound 7:formic acid is 0.3:4.

[0021] Further, in Step S1, the reaction temperature is 70-110°C and the reaction time is 2-3 h; in Step S2, the reaction temperature is 25°C and the reaction time is 16-18 h; in Step S3, the reaction temperature is room temperature and the reaction time is 2-3 h.

[0022] Further, in Step S4, the reaction temperature is 70-80°C and the reaction time is 1-2 h; in Step S5, the reaction temperature for cyclization is 0-5°C and the reaction time is 0.5-1 h; the reaction temperature for dehydrohalogenation reaction is 135-150°C and the reaction time is 1.0-1.5 h.

[0023] Further, in Step S6, the reaction temperature is 135-145°C and the reaction time is 5-7 h; in Step S7, the reaction temperature is 70-100°C and the reaction time is 2-4 h.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] (1) The present invention develops a new asymmetric synthesis route for preparing dextromethorphan, avoiding intermediate resolution, improving the yield, enhancing the atom economy, and reducing waste.

[0026] (2) The new synthesis route of the present invention does not use expensive starting materials and has relatively mild reaction conditions, which is conducive to industrial production.

[0027] (3) The present invention avoids harsh process conditions, greatly reduces the three wastes, and is environmentally friendly. Specific Embodiments

[0028] The technical solutions in the present invention are further described below in conjunction with embodiments.

[0029] Example 1 Preparation of 2-((4aR)-6-methoxy-9-oxo-1,2,3,4,4a,4b,5,8,8a,9-decahydrophenanthren-4a-yl)acetonitrile (Compound 2)

[0030]

[0031] Add 20 ml of toluene to a reaction glass bottle, add 2-(2-oxocyclohexyl)acetonitrile (2.0 g, 14.58 mmol), S-1-phenylethylamine (14.58 mmol, 1.0 eq.), and toluenesulfonic acid (1.46 mmol, 0.1 eq.), and reflux for 1 h to form an enamine compound; then add 1-(4-methoxy-1,4-cyclohexadienyl)ethanone (15.31 mmol, 1.05 eq.), and react at 70 °C for 2 h to obtain 2-((4aR)-6-methoxy-9-oxo-1,2,3,4,4a,4b,5,8,8a,9-decahydrophenanthren-4a-yl)acetonitrile (Compound 2) with a yield of 65%.

[0032] Preparation of Compound 3 in Example 2

[0033]

[0034] Add 20 ml of acetonitrile to a reaction glass bottle, add Compound 2 (2.0 g, 7.37 mmol), copper(II) bromide (0.37 mmol, 0.05 eq.), and react at room temperature for 16 h to form Compound 3 with a yield of 96%.

[0035] Preparation of Compound 4 in Example 3

[0036]

[0037] Add 10 ml of dioxane to a reaction glass bottle, add Compound 3 (1.0 g, 3.69 mmol), zinc (7.38 mmol, 2 eq.), dilute 1 ml of concentrated hydrochloric acid with water to 3 mL before use, and react at room temperature for 2 h to form Compound 4 with a yield of 82%.

[0038] Preparation of Compound 5 in Example 4

[0039]

[0040] Add 20 ml of ethanol to a reaction glass bottle, add Compound 4 (1.5 g, 5.83 mmol), Raney-Ni (0.6 mmol, 0.1 eq.), 0.5 mL of ammonia water, and reflux at 70 °C under hydrogen (0.1 MPa) for 2 h to form Compound 5 with a yield of 94%.

[0041] Preparation of Compound 6 in Example 5

[0042]

[0043] Add 20 ml of dichloromethane to a reaction glass bottle, add compound 5 (2.0 g, 7.77 mmol), bromine (7.77 mmol, 1.0 eq.), and carry out an intramolecular cyclization reaction at 0 - 5 °C for 0.5 h. Then wash with water twice with dichloromethane, dry, concentrate, add N,N-dimethylformamide (DMF, 30 ml), sodium bicarbonate (15.54 mmol, 2.0 eq.), and react at 135 °C for 1.0 h to obtain compound 6 with a yield of 65%.

[0044] Preparation of Compound 7 in Example 6

[0045]

[0046] Add 10 ml of methanol to a reaction glass bottle, add compound 6 (500 mg, 1.96 mmol), palladium hydroxide (0.2 mmol, 0.1 eq.), ammonium formate (9.79 mmol, 5.0 eq.), and react at 135 °C for 5 h to obtain compound 7. The yield is 86%.

[0047] Preparation of Dextromethorphan in Example 7

[0048]

[0049] Add compound 7 (1.5 g, 5.83 mmol), 20 ml of formic acid and formaldehyde (11.66 mmol, 2.0 eq.) to a reaction glass bottle, and reflux at 100 °C for 2.0 h to generate dextromethorphan. The yield is 95%.

[0050] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and are not intended to limit. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered by the scope of the claims of the present invention.

Claims

1. A method for synthesizing dextromethorphan, characterized in that: Using 2-(2-oxocyclohexyl)acetonitrile as a raw material, through a Robinson annulation reaction, compound 2 is formed; compound 2 undergoes an aromatization reaction to form compound 3; Compound 3 undergoes a ketone carbonyl reduction reaction to form compound 4; Compound 4 undergoes a cyano reduction to form compound 5; compound 5 undergoes a cyclization reaction to obtain compound 6; compound 6 undergoes an asymmetric catalytic hydrogenation to obtain compound 7; compound 7 undergoes an N-methylation reaction to obtain dextromethorphan, and its reaction process is as follows: ； It includes the following steps: S1: In a first solvent, 2-(2-oxocyclohexyl)acetonitrile and S-1-phenylethylamine undergo a Michael addition reaction under the action of a first catalyst, and then 1-(4-methoxy-1,4-cyclohexadienyl)ethanone is added to undergo an Aldol condensation reaction to form compound 2; S2: In a second solvent, compound 2 undergoes an aromatization reaction under the action of a second catalyst to form compound 3; S3: In a third solvent, compound 3 undergoes a ketone carbonyl reduction reaction under the action of a reducing agent to form compound 4; S4: In a fourth solvent, compound 4 undergoes a cyano reduction reaction with hydrogen under the action of a third catalyst and an additive to form compound 5; S5: In a fifth solvent, compound 5 undergoes a cyclization reaction under the action of bromine, and then in a sixth solvent, a dehydrohalogenation reaction occurs in the presence of a first base to obtain compound 6; S6: In a seventh solvent, compound 6 undergoes an asymmetric catalytic hydrogenation reaction under the action of a fourth catalyst and a hydrogen donor to obtain compound 7; S7: Compound 7 undergoes an Eschweiler–Clarke methylation reaction under the action of formic acid and formaldehyde to form dextromethorphan; The first solvent is toluene, the second solvent is acetonitrile, the third solvent is dioxane, the fourth solvent is ethanol, the fifth solvent is dichloromethane, the sixth solvent is N,N-dimethylformamide, and the seventh solvent is methanol; The first catalyst is p-toluenesulfonic acid, the second catalyst is copper bromide, the third catalyst is Raney-Ni, and the fourth catalyst is palladium hydroxide; The reducing agent is zinc; The additive is ammonia water, the first base is NaHCO3, and the hydrogen donor is ammonium formate.

2. The synthetic method of dextromethorphan according to claim 1, characterized in that: The molar ratio of 2-(2-oxocyclohexyl)acetonitrile:S-1-phenylethylamine:p-toluenesulfonic acid:1-(4-methoxy-1,4-cyclohexadienyl)ethanone is 1:1:0.1:1.05; the molar ratio of compound 2:copper bromide is 1:0.05; the molar ratio of compound 3:reducing agent is 1:2; the molar ratio of compound 4:third catalyst is 1:0.1; calculated by g / ml, the dosage ratio of compound 4:additive is 3:1; the molar ratio of compound 5:bromine:first base is 1:1:2; the molar ratio of compound 6:fourth catalyst:hydrogen donor is 1:0.1:5; the molar ratio of compound 7:formaldehyde is 1:2; calculated by g / ml, the dosage ratio of compound 7:formic acid is 0.3:

4.

3. The synthetic method of dextromethorphan according to claim 1, wherein: In step S1, the reaction temperature is 70 - 110 °C and the reaction time is 2 - 3 h; in step S2, the reaction temperature is 25 °C and the reaction time is 16 - 18 h; in step S3, the reaction temperature is room temperature and the reaction time is 2 - 3 h.

4. The synthetic method of dextromethorphan according to claim 1, characterized in that: In step S4, the reaction temperature is 70 - 80 °C and the reaction time is 1 - 2 h; in step S5, the reaction temperature for cyclization is 0 - 5 °C and the reaction time is 0.5 - 1 h; the reaction temperature for dehydrohalogenation is 135 - 150 °C and the reaction time is 1.0 - 1.5 h.

5. The synthetic method of dextromethorphan according to claim 1, characterized in that: In step S6, the reaction temperature is 135 - 145 °C and the reaction time is 5 - 7 h; in step S7, the reaction temperature is 70 - 100 °C and the reaction time is 2 - 4 h.

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