A preparation method for an intermediate for synthesizing dextromethorphan

Abstract

The invention provides a preparation method of an intermediate for synthesizing dextromethorphan, which is characterized by: taking 2-(2-oxocyclohexyl)acetonitrile as a raw material, undergoing a Robinson annulation reaction to generate a compound 2; undergoing an aromatization reaction to generate a compound 3; undergoing a ketocarbonyl reduction reaction to generate a compound 4; and undergoing a cyano reduction to generate an intermediate 5; the reaction process is as follows: The invention discloses a new intermediate 5 and a new preparation method thereof for the first time, avoiding low yield caused by splitting the intermediate, and not only improving the yield but also improving the purity.

Description

Technical Field

[0001] The invention relates to the technical field of synthesis of phenanthrene compounds, and in particular to a method for preparing an intermediate for synthesizing dextromethorphan. Background Art

[0002] Dextromethorphan (DM), also known as dextromethorphan, is a centrally acting antitussive drug that works mainly by inhibiting the cough center in the brainstem medulla oblongata and blocking the excitement of the vagus nerve. Its antitussive effect is comparable to that of codeine. It is widely used in clinical antitussive because of its non-narcotic and non-addictive properties.

[0003] Due to its similar structure to morphine, people mainly use 6,7,8,9-tetrahydroisoquinoline, 2-(1-cyclohexenyl)acetonitrile or octahydrophenanthrene derivatives as starting materials to synthesize racemic N-methylmorphinan or 3-hydroxy-N-methylmorphinan, and then obtain a single optically active product through chemical resolution; at the same time, dextromethorphan can also be synthesized through asymmetric synthesis. Among them, in the construction of the morphinan ring, the process of constructing the tetracyclic ring through the Grewe cyclization reaction is the key step in the synthesis of dextromethorphan. However, the cyclization reaction in this method occurs under strong acid and high temperature conditions, which has high requirements on equipment, and there are many by-products after cyclization, and the yield is low.

[0004] CN102977021A discloses a method for preparing dextromethorphan hydrobromide, which comprises reacting p-methoxyphenylacetic acid with cyclohexeneethylamine to generate p-methoxyphenylacetic acid-(cyclohexeneethylamineethyl)-amide, then undergoing Bischler-Napieralski cyclization under the action of phosphorus oxychloride, reducing to obtain octahydroisoquinoline, splitting the octahydroisoquinoline, hydrogenating at normal pressure under Raney-Ni catalysis to obtain N-methyloctahydroisoquinoline, and undergoing cyclization under the action of Lewis acid and acidifying with hydrobromic acid to obtain dextromethorphan hydrobromide. In addition to the need to split the intermediate resulting in a low yield, the patent also uses reagents such as phosphorus oxychloride and hydrobromic acid in the process route, and the process conditions are relatively harsh, the three wastes are relatively large, 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 preparing an intermediate for synthesizing dextromethorphan, which solves the problem of low yield in the prior art.

[0006] The invention provides a preparation method of an intermediate for synthesizing dextromethorphan. 2-(2-oxocyclohexyl)acetonitrile is used as a raw material, and a compound 2 is generated through a ring-forming reaction; the compound 2 is subjected to a dehydrogenation reaction to generate a compound 3; the compound 3 is subjected to a keto reduction reaction to generate a compound 4; the compound 4 is subjected to a cyano reduction reaction to generate an intermediate 5. The reaction process is as follows:

[0007]

[0008] Further, the following steps are included:

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

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

[0011] S3: In a third solvent, compound 3 undergoes ketocarbonyl reduction reaction under the action of a reducing agent to generate compound 4;

[0012] S4: In the fourth solvent, compound 4 undergoes cyano reduction reaction with hydrogen in the presence of a third catalyst and an additive to generate intermediate 5.

[0013] Furthermore, the first solvent is toluene, the second solvent is acetonitrile, the third solvent is dioxane, and the fourth solvent is ethanol.

[0014] Furthermore, the first catalyst is p-toluenesulfonic acid, the second catalyst is copper bromide, and the third catalyst is Raney-Ni.

[0015] Furthermore, the reducing agent is zinc.

[0016] Furthermore, the additive is aqueous ammonia.

[0017] Furthermore, in step S1, the molar ratio of 2-(2-oxocyclohexyl)acetonitrile:S-1-phenylethylamine:p-toluenesulfonic acid:1-(4-methoxy-1,4-cyclohexadiene)ethanone is 1:1:0.1:1.05; the reaction temperature is 70-110°C, and the reaction time is 2-3h.

[0018] Furthermore, in step S2, the molar ratio of compound 2:copper bromide is 1:0.05; the reaction temperature is 25° C., and the reaction time is 16-18 h.

[0019] Furthermore, in step S3, the molar ratio of compound 3: reducing agent is 1:2; the reaction temperature is room temperature, and the reaction time is 2-3h.

[0020] Furthermore, in step S4, the molar ratio of compound 4: third catalyst is 1:0.1; in terms of g / ml, the dosage ratio of compound 4: additive is 3:1; the reaction temperature is 70-80°C, and the reaction time is 1-2h.

[0021] In one embodiment of the present invention, the steps of using intermediate 5 to synthesize dextromethorphan include:

[0022] S5: In a fifth solvent, intermediate 5 undergoes a cyclization reaction under the action of bromine, and then undergoes a dehydrohalogenation reaction in a sixth solvent in the presence of a first base to obtain compound 6;

[0023] S6: Compound 6 undergoes an asymmetric catalytic hydrogenation reaction in the seventh solvent under the action of a fourth catalyst and a hydrogen donor to obtain compound 7;

[0024] S7: Compound 7 undergoes Eschweiler–Clarke methylation reaction in the presence of formic acid and formaldehyde to generate dextromethorphan.

[0025] In one embodiment of the present invention, the fifth solvent is dichloromethane, the sixth solvent is N,N-dimethylformamide, and the seventh solvent is methanol.

[0026] In one embodiment of the present invention, the fourth catalyst is palladium hydroxide.

[0027] In one embodiment of the present invention, the first base is NaHCO3, and the hydrogen donor is ammonium formate.

[0028] In one embodiment of the present invention, in step S5, the molar ratio of compound 5: bromine: first base is 1:1:2;

[0029] In one embodiment of the present invention, in step S6, the molar ratio of compound 6: fourth catalyst: hydrogen donor is 1:0.1:5.

[0030] In one embodiment of the present invention, in step S7, the molar ratio of compound 7:formaldehyde is 1:2; and in terms of g / ml, the usage ratio of compound 7:formic acid is 0.3:4.

[0031] In one embodiment of the present invention, in step S5, the reaction temperature of the cyclization is 0-5°C, and the reaction time is 0.5-1h; the reaction temperature of the dehydrohalogenation reaction is 135-150°C, and the reaction time is 1.0-1.5h.

[0032] In one embodiment of the present invention, in step S6, the reaction temperature is 135-145° C., and the reaction time is 5-7 h.

[0033] In one embodiment of the present invention, in step S7, the reaction temperature is 70-100° C., and the reaction time is 2-4 hours.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] (1) The present invention discloses for the first time a novel intermediate 5 and a novel preparation method thereof, thereby avoiding the low yield caused by the separation of the intermediate, and not only improving the yield but also improving the purity.

[0036] (2) The new synthetic route of the present invention does not use expensive starting materials, and the reaction conditions are relatively mild, which is conducive to industrial production.

[0037] (3) The present invention avoids harsh process conditions, greatly reduces the three wastes, and is environmentally friendly. DETAILED DESCRIPTION

[0038] The technical solution of the present invention is further described below in conjunction with embodiments.

[0039] Example 1 Preparation of 2-((4aR)-6-methoxy-9-carbonyl-1,2,3,4,4a,4b,5,8,8a,9-decahydrophenanthrene-4a-yl)acetonitrile (Compound 2)

[0040]

[0041] 20 ml of toluene, 2-(2-oxocyclohexyl)acetonitrile (2.0 g, 14.58 mmol), S-1-phenylethylamine (14.58 mmol, 1.0 eq.), toluenesulfonic acid (1.46 mmol, 0.1 eq.) were added to a reaction glass bottle, and the mixture was refluxed for 1 h to generate an enamine compound; then 1-(4-methoxy-1,4-cyclohexadiene)ethanone (15.31 mmol, 1.05 eq.) was added, and the mixture was reacted at 70° C. for 2 h to obtain 2-((4aR)-6-methoxy-9-carbonyl-1,2,3,4,4a,4b,5,8,8a,9-decahydrophenanthren-4a-yl)acetonitrile (Compound 2) with a yield of 65%.

[0042] Example 2 Preparation of Compound 3

[0043]

[0044] Add 20 ml of acetonitrile, compound 2 (2.0 g, 7.37 mmol) and copper bromide (0.37 mmol, 0.05 eq.) into a reaction glass bottle, and react at room temperature for 16 h to generate compound 3 with a yield of 96%.

[0045] Example 3 Preparation of Compound 4

[0046]

[0047] Add 10 ml of dioxane, compound 3 (1.0 g, 3.69 mmol), zinc (7.38 mmol, 2 eq.), and 1 ml of concentrated hydrochloric acid (diluted with water to 3 mL before use) to a reaction glass bottle, and react at room temperature for 2 h to generate compound 4 with a yield of 82%.

[0048] Example 4 Preparation of Compound 5

[0049]

[0050] Add 20 ml of ethanol, compound 4 (1.5 g, 5.83 mmol), Raney-Ni (0.6 mmol, 0.1 eq.), and 0.5 mL of aqueous ammonia to a reaction glass bottle, and reflux at 70° C. for 2 h under hydrogen (0.1 MPa) to generate compound 5 with a yield of 94%.

[0051] Example 5 Preparation of Compound 6

[0052]

[0053] Add 20 ml of dichloromethane to a reaction glass bottle, add compound 5 (2.0 g, 7.77 mmol) and bromine (7.77 mmol, 1.0 eq.), and carry out intramolecular cyclization reaction at 0-5°C for 0.5 h. Then wash the dichloromethane twice with water, dry and concentrate, add N,N-dimethylformamide (DMF, 30 ml) and 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%.

[0054] Example 6 Preparation of Compound 7

[0055]

[0056] 10 ml of methanol was added to a reaction glass bottle, and compound 6 (500 mg, 1.96 mmol), palladium hydroxide (0.2 mmol, 0.1 eq.), and ammonium formate (9.79 mmol, 5.0 eq.) were added, and the mixture was reacted at 135° C. for 5 h to obtain compound 7 with a yield of 86%.

[0057] Example 7 Preparation of Dextromethorphan

[0058]

[0059] Compound 7 (1.5 g, 5.83 mmol), 20 ml of formic acid and formaldehyde (11.66 mmol, 2.0 eq.) were added to a reaction glass bottle and refluxed at 100° C. for 2.0 h to generate dextromethorphan with a yield of 95%.

[0060] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be included in the scope of the claims of the present invention.

Claims

1. A method for preparing an intermediate for synthesizing dextromethorphan, characterized in that: Using 2-(2-oxocyclohexyl)acetonitrile as the raw material, compound 2 is generated through Robinson annulation reaction; compound 2 is subjected to aromatization reaction to generate compound 3; compound 3 is subjected to keto reduction reaction to generate compound 4; compound 4 is subjected to cyano reduction to generate intermediate 5; The reaction process is as follows: 。 2. A method for preparing an intermediate for synthesizing dextromethorphan as claimed in claim 1, characterized in that: The following steps are involved: S1: In the first solvent, 2-(2-oxocyclohexyl)acetonitrile and S-1-phenylethylamine undergo Michael addition reaction under the action of the first catalyst, and then 1-(4-methoxy-1,4-cyclohexadiene)ethanone is added to undergo Aldol condensation reaction to generate compound 2; S2: In the second solvent, compound 2 undergoes an aromatization reaction under the action of a second catalyst to generate compound 3; S3: In a third solvent, compound 3 undergoes ketocarbonyl reduction reaction under the action of a reducing agent to generate compound 4; S4: In the fourth solvent, compound 4 undergoes cyano reduction reaction with hydrogen in the presence of a third catalyst and an additive to generate intermediate 5.

3. A method for preparing an intermediate for synthesizing dextromethorphan as claimed in claim 2, characterized in that: The first solvent is toluene, the second solvent is acetonitrile, the third solvent is dioxane, and the fourth solvent is ethanol.

4. A method for preparing an intermediate for synthesizing dextromethorphan as claimed in claim 2, characterized in that: The first catalyst is p-toluenesulfonic acid, the second catalyst is copper bromide, and the third catalyst is Raney-Ni.

5. A method for preparing an intermediate for synthesizing dextromethorphan as claimed in claim 2, characterized in that: The reducing agent is zinc.

6. A method for preparing an intermediate for synthesizing dextromethorphan as claimed in claim 2, characterized in that: The additive is ammonia water.

7. A method for preparing an intermediate for synthesizing dextromethorphan as claimed in claim 4, characterized in that: In step S1, the molar ratio of 2-(2-oxocyclohexyl)acetonitrile:S-1-phenylethylamine:p-toluenesulfonic acid:1-(4-methoxy-1,4-cyclohexadiene)ethanone is 1:1:0.1:1.05; the reaction temperature is 70-110°C, and the reaction time is 2-3h.

8. A method for preparing an intermediate for synthesizing dextromethorphan as claimed in claim 4, characterized in that: In step S2, the molar ratio of compound 2: copper bromide is 1:0.05; the reaction temperature is 25° C., and the reaction time is 16-18 h.

9. A method for preparing an intermediate for synthesizing dextromethorphan as claimed in claim 2, characterized in that: In step S3, the molar ratio of compound 3: reducing agent is 1:2; the reaction temperature is room temperature, and the reaction time is 2-3 h.

10. A method for preparing an intermediate for synthesizing dextromethorphan as claimed in claim 2, characterized in that: In step S4, the molar ratio of compound 4: third catalyst is 1:0.1; in terms of g / ml, the dosage ratio of compound 4: additive is 3:1; the reaction temperature is 70-80° C., and the reaction time is 1-2 h.

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