An intermediate for synthesizing dextromethorphan and its preparation method and application

Abstract

The present invention provides an intermediate for synthesizing dextromethorphan, as well as its preparation method and application. The chemical structure of the intermediate is shown in Formula 10: #imgabs0# This invention discloses compound 10 for the first time and uses it to prepare dextromethorphan, improving both yield and purity. This novel synthetic route avoids the use of expensive starting materials and operates under relatively mild reaction conditions, making it suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of synthesis of morphan ring compounds, and in particular to an intermediate for synthesizing dextromethorphan, a preparation method thereof, and an application thereof. Background Art

[0002] Dextromethorphan (also known as dextromethorphan) is widely used clinically to treat coughs due to its centrally acting antitussive effects and lack of narcotic or addictive properties. Dextromethorphan is primarily used in pharmaceuticals in the form of its hydrobromide salt. Common cold and cough suppressants on the market, such as Meco, Mexi-Pseudoephedrine tablets, Pulsilan tablets, Parker, and Jianer Infant Cough Syrup, all contain dextromethorphan hydrobromide.

[0003] Currently, the synthesis of dextromethorphan is mostly carried out using the Grewe cyclization method. For example, Chinese patent CN103044327A discloses a method for preparing dextromethorphan: (+)-N-methyl-1-(4-methoxy)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline a undergoes a cyclization reaction under acidic conditions at high temperature (130-140°C or reflux) to obtain (+)-3-hydroxy-N-methylmorphinan b. Finally, a methoxy group is introduced into the benzene ring to obtain dextromethorphan c. In this method, the cyclization reaction occurs under strong acid and high temperature conditions, which requires high equipment requirements. In addition, the cyclization produces many byproducts and has a low yield. The methoxy group is easily removed at high temperature, requiring further methylation, which is not conducive to environmental protection.

[0004] Summary of the Invention

[0005] In view of the deficiencies in the prior art, the present invention provides an intermediate for synthesizing dextromethorphan, a preparation method thereof, and an application thereof, which solve the problems of the prior art such as a large number of by-products, low yield, and being unfavorable to green environmental protection.

[0006] In one aspect of the present invention, an intermediate for synthesizing dextromethorphan is provided, and the chemical structure of the intermediate is shown in Formula 10:

[0007]

[0008] On the other hand, the present invention provides a preparation method for an intermediate for synthesizing dextromethorphan, comprising using cyclohexanedione 1 as a raw material, performing an acetonitrile substitution reaction to obtain compound 2; subjecting compound 2 to a Wieland-Michel ketone synthesis reaction to obtain compound 4; subjecting compound 4 to a monoketal protection reaction to obtain compound 5; subjecting compound 5 to a Robinson ring-enlargement reaction to obtain compound 6; subjecting compound 6 to an aromatization reaction and a methylation reaction to obtain compound 7; subjecting compound 7 to a keto group deprotection to obtain compound 8; subjecting compound 8 to a double bond isomerization reaction to obtain compound 9; and subjecting compound 9 to a reduction reaction to obtain compound 10. The reaction process is as follows:

[0009]

[0010] Further, the following steps are included:

[0011] S1: In the presence of a first base, cyclohexanedione and bromoacetonitrile undergo a nucleophilic substitution reaction in a first solvent to generate compound 2;

[0012] S2: Compound 2 reacts with butenone in the presence of the first catalyst to undergo Michael addition reaction to generate compound 3;

[0013] S3: Compound 3 undergoes an asymmetric Robinson cyclization reaction in the presence of a second catalyst and a first additive to produce compound 4;

[0014] S4: In a second solvent, compound 4 and ethylene glycol undergo a ketal reaction in the presence of a third catalyst and a second additive to produce compound 5;

[0015] S5: In a third solvent, compound 5 reacts with tetrahydropyrrole and butenone in sequence, and then undergoes a reflux cyclization reaction under acidic conditions to generate compound 6;

[0016] S6: In a fourth solvent, compound 6 undergoes an aromatization reaction in the presence of a fourth catalyst, and then undergoes a methylation reaction in the presence of a second base to produce compound 7;

[0017] S7: In the fifth solvent, compound 7 undergoes hydrolysis reaction under the action of acid to generate compound 8;

[0018] S8: In a sixth solvent, compound 8 undergoes an isomerization reaction with an alkali metal salt of tert-butoxide to generate compound 9;

[0019] S9: Compound 9 undergoes cyano group reduction, primary amine acylation, carbonyl reduction and acetyl removal under the action of the fifth catalyst, acylating agent and reducing agent to obtain compound 10.

[0020] Furthermore, the first base is a quaternary ammonium base, preferably, the first base is benzyltrimethylammonium hydroxide, and the second base is potassium carbonate.

[0021] Furthermore, the first solvent is methanol and water, the second solvent is dichloromethane, the third solvent is toluene, the fourth solvent is acetonitrile, the fifth solvent is a mixed solution of dichloromethane and water, and the sixth solvent is tert-butanol.

[0022] Furthermore, the first catalyst is triethylamine; the second catalyst is (S)-N1,N1-diethyl-3,3-dimethyl-1,2-butanediamine and trifluoromethanesulfonic acid; the third catalyst is trimethylsilyl trifluoromethanesulfonate, the fourth catalyst is ketone bromide, and the fifth catalyst is Raney-Ni.

[0023] Furthermore, the first additive is m-nitrobenzoic acid; and the second additive is triethyl orthoformate.

[0024] Furthermore, the acid is oxalic acid, the alkali metal tert-butoxide is potassium tert-butoxide, the acylating agent is acetic anhydride, and the reducing agent is hydrazine hydrate.

[0025] Furthermore, the molar ratio of cyclohexanedione: bromoacetonitrile: first base is 1:1:0.4; the molar ratio of compound 2: butenone: first catalyst is 1:1:0.01; in step S3, the molar ratio of compound 3: second catalyst: first additive is 1:0.1:0.05; the molar ratio of compound 4: ethylene glycol: third catalyst: second additive is 1:5.5:0.02:1.1; the molar ratio of compound 5: butenone: tetrahydropyrrole is 1:1.05:1.2; the molar ratio of compound 6: fourth catalyst is 1:0.05; the molar ratio of compound 7: acid is 1:3.2; the molar ratio of compound 8: alkali metal salt of tert-butoxide is 1:1; the molar ratio of compound 9: fifth catalyst: acylating agent: reducing agent is 1:0.1:1.05:1.1.

[0026] Preferably, in step S1, the reaction temperature is room temperature, and the reaction time is 20-24 h; in step S2, the reaction temperature is room temperature, and the reaction time is 2-3 h; in step S3, the reaction temperature is room temperature, and the reaction time is 2-3 h; in step S4, the reaction temperature is -15 to -10 ° C, and the reaction time is 5-7 h; in step S5, the reaction temperature is 110-115 ° C, and the reaction time is 16-20 h; in step S6, the reaction temperature is room temperature, and the reaction time is 16-20 h; in step S7, the reaction temperature is room temperature, and the reaction time is 2-5 h; in step S8, the reaction temperature is 20-25 ° C, and the reaction time is 2-4 h; in step S9, the acylation temperature is room temperature, and the acylation time is 6-8 h; the reduction temperature is 160-180 ° C, and the reduction reaction time is 6-8 h.

[0027] In another aspect, the present invention provides use of an intermediate for synthesizing dextromethorphan in the preparation of a morphan ring drug. Preferably, the morphan ring drug is dextromethorphan.

[0028] In one embodiment of the present invention, the method for synthesizing dextromethorphan using compound 10 comprises the following steps:

[0029] S10: Compound 10 undergoes a cyclization reaction in the presence of bromine in the seventh solvent, and then undergoes a dehydrohalogenation reaction in the presence of a third base to obtain compound 11;

[0030] S11: In the eighth solvent, compound 11 undergoes stereoselective hydrogenation reaction with a hydrogen donor in the presence of a sixth catalyst to obtain compound 12;

[0031] S12: Compound 12 undergoes Eschweiler–Clarke methylation reaction in the presence of formic acid and formaldehyde to give dextromethorphan;

[0032] In one embodiment of the present invention, the seventh solvent is dichloromethane, the eighth solvent is methanol, the third base is sodium carbonate, the sixth catalyst is palladium hydroxide, and the hydrogen donor is ammonium formate.

[0033] In one embodiment of the present invention, in step S10, the molar ratio of compound 10: bromine: the third base is 1:1:2, the cyclization reaction temperature is 0-5°C, and the cyclization reaction time is 0.5-1h; the dehydrohalogenation reaction temperature is 135-150°C, and the reaction time is 1-1.5h;

[0034] In one embodiment of the present invention, in step S11, the molar ratio of compound 11: sixth catalyst: hydrogen donor is 1:0.1:5, the reaction temperature is 135-145° C., and the reaction time is 5-7 h;

[0035] In one embodiment of the present invention, in step S12, the molar ratio of compound 12:formaldehyde is 1:2; the usage ratio of compound 12:formic acid is 0.3:4 in g / ml; the reaction temperature is 70-100° C., and the reaction time is 2-4 h.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] (1) The present invention discloses compound 10 for the first time and uses the compound to prepare dextromethorphan, which not only improves the yield but also improves the purity.

[0038] (2) The novel 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.

[0039] (3) The present invention avoids harsh process conditions, greatly reduces the three wastes, and is environmentally friendly. DETAILED DESCRIPTION

[0040] The technical solution of the present invention is further described below with reference to the embodiments.

[0041] Example 1 Preparation of (3-(2,6-dioxocyclohexyl)acetonitrile) (Compound 2)

[0042]

[0043] In a standard glass bottle, cyclohexanedione (900 mg, 8.03 mmol), bromoacetonitrile (8.03 mmol, 1.0 eq.), and benzyltrimethylammonium hydroxide (3.21 mmol, 0.4 eq.) were dissolved in 10 ml of a 20:1 volume ratio methanol and water mixture and reacted at room temperature for 24 h. The methanol was concentrated, and isopropyl acetate was added to the residue, which was washed with water, dried, and concentrated to give compound 2 (840 mg) in a 70% yield.

[0044] Example 2 Preparation of Compound 3

[0045]

[0046] Compound 2 (5 g, 33.08 mmol), methyl vinyl ketone (33.08 mmol, 1.0 eq.), and 1% triethylamine (TEA, 335 mg) were added to a standard glass bottle and reacted at 25° C. without solvent for 2 h to obtain compound 3 (7.32 g) with a yield of 100%.

[0047] Example 3 Preparation of Compound 4

[0048]

[0049] To compound 3 (2.0 g, 9.04 mmol) were added the catalyst (S)-N1,N1-diethyl-3,3-dimethyl-1,2-butanediamine trifluoromethanesulfonic acid (0.9 mmol, 0.1 eq.) and m-NO2C6H4CO2H (0.45 mmol, 0.05 eq.) at room temperature in the absence of solvent for 2 h. The reaction mixture was separated by chromatography to afford compound 4 (1.66 g) in a 90% yield and 96% enantioselectivity.

[0050] Example 4 Preparation of Compound 5

[0051]

[0052] Compound 4 (2.0 g, 9.84 mmol), 1,2-ethylene glycol (54.12 mmol, 5.5 eq.), and 20 ml of dichloromethane were added to a reaction flask. Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 0.2 mmol, 0.02 eq.) and triethyl orthoformate (10.82 mmol, 1.1 eq.) were also added. The mixture was reacted at -10°C for 5 h to obtain compound 5 (2.16 g) with a yield of 89%.

[0053] Example 5 Preparation of Compound 6

[0054]

[0055] Tetrahydropyrrole (4.37 mmol, 1.2 eq.) and 20 ml of toluene were added dropwise to compound 5 (900 mg, 3.64 mmol). The mixture was refluxed at 110-115°C for 6 h to separate the water. Methyl vinyl ketone (4.37 mmol, 1.05 eq.) was then added and the mixture was refluxed at 110-115°C for 5 h. The organic phase was separated and concentrated. 8 ml of a 2:1 volume ratio mixture of acetic acid and water was added to the concentrate, and the mixture was refluxed at 100°C for 5 h. The mixture was separated and distilled under reduced pressure to afford compound 6 (0.71 g) in a 65% yield.

[0056] Example 6 Preparation of Compound 7

[0057]

[0058] Compound 6 (800 mg, 2.67 mmol) and copper bromide (0.14 mmol, 0.05 eq.) were dissolved in 10 ml of acetonitrile in a standard glass bottle and aromatized at room temperature for 13 h. Then, iodomethane (3.47 mmol, 1.3 eq.) and potassium carbonate (3.47 mmol, 1.3 eq.) were added and reacted at room temperature for 3 h to obtain compound 7 (0.774 g) with a yield of 93%.

[0059] Example 7 Preparation of (R)-2-(6-methoxy-2-carbonyl-2,3,4,4a,9,10-hexahydrophenanthren-4a-yl)acetonitrile (Compound 8)

[0060]

[0061] To a standard glass bottle, 10 ml of a mixed solvent of water and dichloromethane (DCM) in a volume ratio of 1:1 was added, followed by compound 7 (1.0 g, 3.21 mmol) and oxalic acid (10.28 mmol, 3.2 eq.). The mixture was reacted at room temperature for 2 h. Compound 8 (729 mg) was obtained by column chromatography in a yield of 85%.

[0062] Example 8 Preparation of (S)-2-(6-methoxy-2-carbonyl-1,2,3,4,4a,9-hexahydrophenanthren-4a-yl)acetonitrile (Compound 9)

[0063]

[0064] 8 ml of tert-butanol was added to a standard glass bottle, followed by compound 8 (850 mg, 3.18 mmol) and potassium tert-butoxide (3.18 mmol, 1 eq.). The isomerization reaction was carried out at room temperature for 2 h to produce compound 9 (638 mg) with a yield of 75%.

[0065] Example 9 Preparation of (S)-2-(6-methoxy-1,2,3,4,4a,9-hexahydrophenanthren-4a-yl)ethylamine (Compound 10)

[0066]

[0067] Compound 9 (1.0 g, 3.74 mmol), 10 mL of THF, Raney-Ni (0.37 mmol, 0.1 eq.), and acetic anhydride (3.93 mmol, 1.05 eq.) were added to a standard glass bottle. The hydrogen atmosphere was replaced, and the reaction was carried out at 25°C for 6 h. The mixture was then filtered and the filtrate was concentrated to obtain a concentrate. 10 mL of diethylene glycol diethyl ether and hydrazine hydrate (4.11 mmol, 1.1 eq.) were added, and the reaction was continued at 180°C for 6 h to obtain compound 10. The yield was 86%.

[0068] Example 10 Preparation of Compound 11

[0069]

[0070] Compound 10 (2.0 g, 7.77 mmol) and bromine (7.77 mmol, 1.0 eq.) were added to 20 ml of dichloromethane solution. The intramolecular cyclization reaction was carried out at 0-5°C for 0.5 h. The dichloromethane was then washed twice with water, dried, and concentrated. N,N-dimethylformamide (DMF, 20 ml) and sodium bicarbonate (15.54 mmol, 2.0 eq.) were added, and the reaction was carried out at 135°C for 1.0 h to obtain compound 11. The yield was 73%.

[0071] Example 11 Preparation of Compound 12

[0072]

[0073] Compound 11 (500 mg, 1.96 mmol), palladium hydroxide (0.2 mmol, 0.1 eq.), and ammonium formate (9.79 mmol, 5 eq.) were added to 10 ml of methanol, and stereoselective hydrogenation was carried out at 135° C. for 5 h to obtain compound 12 in a yield of 90%.

[0074] Example 12 Preparation of Dextromethorphan

[0075]

[0076] Compound 12 (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 h to produce dextromethorphan in a yield of 95%.

[0077] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not limiting. 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 solutions of the present invention may be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. An intermediate for synthesizing dextromethorphan, characterized in that: The chemical structure of the intermediate is shown in Formula 10:

2. The method for preparing an intermediate for synthesizing dextromethorphan according to claim 1, wherein: The method comprises taking cyclohexanedione 1 as a raw material, performing an acetonitrile substitution reaction to obtain compound 2; subjecting compound 2 to a Wieland-Michel ketone synthesis reaction to obtain compound 4; subjecting compound 4 to a monoketal protection reaction to obtain compound 5; subjecting compound 5 to a Robinson ring-increasing reaction to obtain compound 6; subjecting compound 6 to an aromatization reaction and a methylation reaction to obtain compound 7; subjecting compound 7 to a keto group deprotection reaction to obtain compound 8; subjecting compound 8 to a double bond isomerization reaction to obtain compound 9; and subjecting compound 9 to a reduction reaction to obtain compound 10. The reaction process is as follows:

3. A method for preparing an intermediate for synthesizing dextromethorphan as claimed in claim 2, characterized in that: The following steps are involved: S1: In the presence of a first base, cyclohexanedione and bromoacetonitrile undergo a nucleophilic substitution reaction in a first solvent to generate compound 2; S2: Compound 2 reacts with butenone in the presence of the first catalyst to undergo Michael addition reaction to generate compound 3; S3: Compound 3 undergoes an asymmetric Robinson cyclization reaction in the presence of a second catalyst and a first additive to produce compound 4; S4: In a second solvent, compound 4 and ethylene glycol undergo a ketal reaction in the presence of a third catalyst and a second additive to produce compound 5; S5: In a third solvent, compound 5 reacts with tetrahydropyrrole and butenone in sequence, and then undergoes a reflux cyclization reaction under acidic conditions to generate compound 6; S6: In a fourth solvent, compound 6 undergoes an aromatization reaction in the presence of a fourth catalyst, and then undergoes a methylation reaction in the presence of a second base to produce compound 7; S7: In the fifth solvent, compound 7 undergoes hydrolysis reaction under the action of acid to generate compound 8; S8: In a sixth solvent, compound 8 undergoes an isomerization reaction with an alkali metal salt of tert-butoxide to generate compound 9; S9: Compound 9 undergoes cyano reduction, primary amine acetylation, carbonyl reduction and acetyl removal under the action of the fifth catalyst, acylating agent and reducing agent to obtain compound 10.

4. The method for preparing an intermediate for synthesizing dextromethorphan according to claim 3, wherein: The first base is a quaternary ammonium base, and the second base is potassium carbonate.

5. The method for preparing an intermediate for synthesizing dextromethorphan according to claim 3, wherein: The first solvent is methanol and water, the second solvent is dichloromethane, the third solvent is toluene, the fourth solvent is acetonitrile, the fifth solvent is a mixed solution of dichloromethane and water, and the sixth solvent is tert-butanol.

6. The method for preparing an intermediate for synthesizing dextromethorphan according to claim 3, wherein: The first catalyst is triethylamine; the second catalyst is (S)-N1,N1-diethyl-3,3-dimethyl-1,2-butanediamine and trifluoromethanesulfonic acid; the third catalyst is trimethylsilyl trifluoromethanesulfonate, the fourth catalyst is ketone bromide, and the fifth catalyst is Raney-Ni.

7. The method for preparing an intermediate for synthesizing dextromethorphan according to claim 3, wherein: The first additive is m-nitrobenzoic acid; the second additive is triethyl orthoformate.

8. The method for preparing an intermediate for synthesizing dextromethorphan according to claim 3, wherein: The acid is oxalic acid, the alkali metal tert-butoxide is potassium tert-butoxide, the acylating agent is acetic anhydride, and the reducing agent is hydrazine hydrate.

9. The method for preparing an intermediate for synthesizing dextromethorphan according to claim 3, wherein: The molar ratio of cyclohexanedione: bromoacetonitrile: the first base is 1:1:0.4; the molar ratio of compound 2: butenone: the first catalyst is 1:1:0.01; in step S3, the molar ratio of compound 3: the second catalyst: the first additive is 1:0.1:0.05; the molar ratio of compound 4: ethylene glycol: the third catalyst: the second additive is 1:5.5:0.02:1.1; the molar ratio of compound 5: butenone: tetrahydropyrrole is 1:1.05:1.2; the molar ratio of compound 6: the fourth catalyst is 1:0.05; the molar ratio of compound 7: the acid is 1:3.2; the molar ratio of compound 8: the alkali metal salt of tert-butoxide is 1:1; and the molar ratio of compound 9: the fifth catalyst: the acylating agent: the reducing agent is 1:0.1:1.05:1.

1.

10. Use of the intermediate for synthesizing dextromethorphan according to claim 1 in the preparation of a morphan ring drug, wherein the morphan ring drug is dextromethorphan.

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