CN116444433A - Preparation method of dextromethorphan - Google Patents

Preparation method of dextromethorphan Download PDF

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CN116444433A
CN116444433A CN202310334062.5A CN202310334062A CN116444433A CN 116444433 A CN116444433 A CN 116444433A CN 202310334062 A CN202310334062 A CN 202310334062A CN 116444433 A CN116444433 A CN 116444433A
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陈忠湖
于帅
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/28—Morphinans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention provides a preparation method of dextromethorphan, which comprises the steps of taking cyclohexanedione 1 as a raw material, and carrying out acetonitrile substitution reaction to obtain a compound 2; carrying out a Wilde-Michelson synthesis reaction on the compound 2 to obtain a compound 4; ketal protection of compound 4 to give compound 5; carrying out Robinson cyclization reaction on the compound 5 to obtain a compound 6; carrying out aromatization reaction and methylation reaction on the compound 6 to obtain a compound 7; deprotection of compound 7 over a ketone group to afford compound 8; carrying out double bond isomerization reaction on the compound 8 to obtain a compound 9; carrying out acetonitrile-based reduction reaction on the compound 9 to obtain a compound 10; subjecting compound 10 to lactam cyclisation to give compound 11; compound 11 was subjected to asymmetric hydrogenation to give dextromethorphan. The invention develops a new asymmetric synthetic route for preparing dextromethorphan, avoids intermediate resolution and improves the yield.

Description

Preparation method of dextromethorphan
Technical Field
The invention relates to the technical field of morphinan ring synthesis, in particular to a preparation method of dextromethorphan.
Background
Dextromethorphan (3-methoxy-N-methyl morphinan) is abbreviated as DXM, is an antitussive drug, and is the dextrorotatory body of morphine levorphanol methyl ether. Available in 140 more over-the-counter cough and colds formulations. Due to their availability, efficacy and safety of targeted doses, codeine has become the most widely used antitussive agent.
Currently, the synthesis method of dextromethorphan is mostly carried out by adopting resolution and Grewe cyclization methods. Such as: taking 2- (1-cyclohexenyl) ethylamine III and p-methoxyphenylacetic acid II as raw materials, dehydrating and condensing to form an amide intermediate IV, and performing POCl (push-to-talk) reaction on the amide intermediate IV 3 Under the action ofAfter Bishler-Napierdsky cyclization, hexahydroisoquinoline intermediate V is generated, the compound is unstable, 1-p-methoxybenzyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline V-1 is directly obtained by Raney-Ni catalytic hydrogenation, N-methyl compound V-2 is obtained after methylation, the product has a chiral center, and (S) -1- (p-methoxybenzyl) -1,2,3,4,5,6,7, 8-octahydroisoquinoline VII is obtained by resolution, and then the product is obtained in H 3 PO 4 The intermediate VII-1 is obtained through Grewe cyclization under catalysis, and the dextromethorphan is obtained through further methylation. The synthetic route of the method is as follows:
this method has the following disadvantages:
(1) During the Grewe cyclization reaction, intermediate VII is affected by steric hindrance, accompanied by the formation of the by-product 3-methoxy-17 acetyl- (9α,13α,14β) -morphinan; and the Grewe cyclization reaction yield is lower; the reaction is carried out at 130-140 ℃, methoxy on benzene ring can be converted into corresponding hydroxyl after cyclization, further methylation treatment is needed, and other side reactions are more at high temperature.
(2) The resolution of the intermediate V-2 not only greatly reduces the yield, but also is complex and tedious in operation, and generates a large amount of waste residues and waste liquid.
(3) The process route uses reagents such as phosphorus oxychloride, concentrated phosphoric acid and the like, has more three wastes and is not friendly to the environment.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method of dextromethorphan, which solves the problem of low yield caused by intermediate resolution existing in the prior art.
The invention aims to provide a preparation method of dextromethorphan, which comprises the steps of taking cyclohexanedione 1 as a raw material, and carrying out acetonitrile substitution reaction to obtain a compound 2; carrying out a Wilde-Michelson synthesis reaction on the compound 2 to obtain a compound 4; ketal protection of compound 4 to give compound 5; carrying out Robinson cyclization reaction on the compound 5 to obtain a compound 6; carrying out aromatization reaction and methylation reaction on the compound 6 to obtain a compound 7; deprotection of compound 7 over a ketone group to afford compound 8; carrying out double bond isomerization reaction on the compound 8 to obtain a compound 9; carrying out acetonitrile-based reduction reaction on the compound 9 to obtain a compound 10; subjecting compound 10 to lactam cyclisation to give compound 11; subjecting compound 11 to asymmetric hydrogenation to obtain compound 12; the compound 12 is subjected to N-methylation reaction to obtain dextromethorphan, and the reaction process is as follows:
further, the method comprises the following steps:
s1: in the presence of a first base, carrying out nucleophilic substitution reaction on cyclohexanedione and bromoacetonitrile in a first solvent to generate a compound 2;
s2: the compound 2 and butenone undergo Michael addition reaction under the action of a first catalyst to generate a compound 3;
s3: carrying out asymmetric Robinson cyclization reaction on the compound 3 under the action of a second catalyst and a first additive to generate a compound 4;
s4: in a second solvent, carrying out ketalization reaction on the compound 4 and ethylene glycol under the action of a third catalyst and a second additive to generate a compound 5;
s5: in a third solvent, the compound 5 is reacted with tetrahydropyrrole and butenone in sequence, and then reflux cyclization reaction is carried out under an acidic condition to generate a compound 6;
s6: in a fourth solvent, carrying out aromatization reaction on the compound 6 under the action of a fourth catalyst, and then carrying out methylation reaction in the presence of a second base to generate a compound 7;
s7: in a fifth solvent, the compound 7 undergoes hydrolysis reaction under the action of acid to generate a compound 8;
s8: in a sixth solvent, carrying out isomerization reaction on the compound 8 and the tert-butyl alcohol alkali metal salt to generate a compound 9;
s9: under the action of a fifth catalyst, an acylating agent and a reducing agent, the compound 9 undergoes cyano reduction, primary amine acetylation, carbonyl reduction and acetyl removal to obtain a compound 10;
s10: in a seventh solvent, cyclizing the compound 10 under the action of bromine, and then dehydrohalogenating the compound in the presence of a third base to obtain a compound 11;
s11: in an eighth solvent, the compound 11 and a hydrogen donor undergo stereoselective hydrogenation reaction under a sixth catalyst to obtain a compound 12;
s12: under the action of formic acid and formaldehyde, the compound 12 undergoes Eschweiler-Clarke methylation reaction to obtain dextromethorphan.
Further, the first base is a quaternary ammonium base, preferably, the first base is benzyltrimethylammonium hydroxide, the second base is potassium carbonate, and the third base is sodium carbonate.
Further, 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, the sixth solvent is tert-butanol, the seventh solvent is dichloromethane, and the eighth solvent is methanol.
Further, 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 trimethyl silicone triflate, the fourth catalyst is ketone bromide, the fifth catalyst is Raney Ni, and the sixth catalyst is palladium hydroxide.
Further, the first additive is m-nitrobenzoic acid; the second additive is triethyl orthoformate.
Further, the acid is oxalic acid.
Further, the alkali metal tert-butoxide is potassium tert-butoxide, the acylating agent is acetic anhydride, and the hydrogen donor is ammonium formate.
Further, the reducing agent is hydrazine hydrate.
Further, the molar ratio of cyclohexanedione to bromoacetonitrile to the first base is 1:1:0.4; the molar ratio of the compound 2 to the butenone to the first catalyst is 1:1:0.01; in the step S3, the mol ratio of the compound 3 to the second catalyst to the first additive is 1:0.1:0.05; the mol ratio of the compound 4 to the glycol to the third catalyst to the second additive is 1:5.5:0.02:1.1; the molar ratio of the butenone to the tetrahydropyrrole is 1:1.05:1.2; the molar ratio of the compound 6 to the fourth catalyst is 1:0.05; the molar ratio of the compound 7 to the acid is 1:3.2; the molar ratio of the compound 8 to the alkali metal tert-butoxide is 1:1; the molar ratio of the compound 9 to the fifth catalyst to the acylating agent to the reducing agent is 1:0.1:1.05:1.1; the molar ratio of the bromine to the third base is 1:1:2; the mol ratio of the compound 11 to the sixth catalyst to the hydrogen donor is 1:0.1:5; the molar ratio of the compound 12 to formaldehyde is 1:2; the dosage ratio of compound 12 to formic acid was 0.3:4 in g/ml.
In one embodiment of the present invention, in step S1, the reaction temperature is room temperature and the reaction time is 20-24 hours.
In one embodiment of the present invention, in step S2, the reaction temperature is room temperature and the reaction time is 2-3 hours.
In one embodiment of the present invention, in step S3, the reaction temperature is room temperature and the reaction time is 2-3 hours.
In one embodiment of the present invention, in step S4, the reaction temperature is-15 to-10 ℃ and the reaction time is 5 to 7 hours.
In one embodiment of the present invention, in step S5, the reaction temperature is 110-115℃and the reaction time is 16-20 hours.
In one embodiment of the present invention, in step S6, the reaction temperature is room temperature and the reaction time is 16-20 hours.
In one embodiment of the present invention, in step S7, the reaction temperature is room temperature and the reaction time is 2-5 hours.
In one embodiment of the present invention, in step S8, the reaction temperature is 20-25℃and the reaction time is 2-4 hours.
In one embodiment of the present invention, in step S9, the cyano reduction and primary amine acetylation temperatures are room temperature, and the reaction time is 6-8 hours; the carbonyl reduction temperature is 160-180 ℃ and the reaction time is 6-8h.
In one embodiment of the present invention, in step S10, the cyclization reaction temperature is 0-5 ℃, and the cyclization reaction time is 0.5-1h; the dehydrohalogenation reaction temperature is 135-150 ℃ and the reaction time is 1-1.5h.
In one embodiment of the present invention, in step S11, the reaction temperature is 135-145℃and the reaction time is 5-7 hours.
In one embodiment of the present invention, in step S12, the reaction temperature is 70-100deg.C and the reaction time is 2-4 hours.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention develops a new asymmetric synthetic route for preparing dextromethorphan, avoids intermediate resolution, improves the yield, improves the atom economy and reduces the waste.
(2) The new synthetic route of the invention does not use expensive starting materials, and the reaction condition is mild, thereby being beneficial to industrial production.
(3) The invention avoids harsh process conditions, greatly reduces three wastes and is environment-friendly.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Example 13 preparation of (2, 6-Dioxocyclohexyl) acetonitrile (Compound 2)
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 10ml of a mixed solution of methanol and water in a volume ratio of 20:1 and reacted at room temperature for 24h; methanol was concentrated, isopropyl acetate was added to the residue, which was washed with water, dried, and concentrated to give compound 2 (840 mg) in 70% yield.
Example 2 preparation of Compound 3
In a standard glass bottle, compound 2 (5 g,33.08 mmol), methyl vinyl ketone (33.08 mmol,1.0 eq.) and 1% triethylamine (TEA, 335 mg) were added and reacted at 25℃for 2h without solvent. Compound 3 (7.32 g) was obtained in 100% yield.
EXAMPLE 3 preparation of Compound 4
To compound 3 (2.0 g,9.04 mmol) was added the catalyst (S) -N1, N1-diethyl-3, 3-dimethyl-1, 2-butanediamine triflic acid (0.9 mmol,0.1 eq.) m-NO at room temperature without solvent 2 C 6 H 4 CO 2 H (0.45 mmol,0.05 eq.) for 2H. The reaction mixture was chromatographed to give compound 4 (1.66 g), 90% yield, 96% enantioselectivity.
Example 4 preparation of Compound 5
Compound 4 (2.0 g,9.84 mmol), 1, 2-ethanediol (54.12 mmol,5.5 eq.) and dichloromethane (20 ml) were added to the reaction flask, and trimethylsilicone triflate (TMSOTF, 0.2mmol,0.02 eq.) and triethylorthoformate (10.82 mmol,1.1 eq.) were added simultaneously, and reacted at-10℃for 5h to give compound 5 (2.16 g) in 89% yield.
EXAMPLE 5 preparation of Compound 6
Into a standard glass bottle were charged tetrahydropyrrole (4.37 mmol,1.2 eq.) and toluene 20ml, compound 5 (900 mg,3.64 mmol) was added dropwise, reflux water splitting reaction was performed at 110-115℃for 6h, then methylketene (4.37 mmol,1.05 eq.) was added, and reflux reaction was performed at 110-115℃for 5h. The organic phase was separated and concentrated. The concentrate was added to 8ml of a mixture of acetic acid and water in a volume ratio of 2:1, and the mixture was refluxed at 100℃for 5 hours, separated, and distilled under reduced pressure to give Compound 6 (0.71 g) in 65% yield.
EXAMPLE 6 preparation of Compound 7
Compound 6 (800 mg,2.67 mmol) and copper bromide (0.14 mmol,0.05 eq.) were dissolved in acetonitrile 10ml in a standard glass bottle, aromatization was performed at room temperature for 13h, then methyl iodide (3.47 mmol,1.3 eq.) and potassium carbonate (3.47 mmol,1.3 eq.) were added and reacted at room temperature for 3h to give compound 7 (0.774 g) in 93% yield.
Example 7 preparation of (R) -2- (6-methoxy-2-carbonyl-2, 3, 4a,9, 10-hexahydrophenanthren-4 a-yl) acetylnitrile (Compound 8)
In a standard glass bottle 10ml of a mixed solvent of water and Dichloromethane (DCM) in a volume ratio of 1:1 was added, and compound 7 (1.0 g,3.21 mmol), oxalic acid (10.28 mmol,3.2 eq.) were added and reacted at room temperature for 2 hours to give compound 8 (729 mg) by column chromatography in 85% yield.
Example 8 preparation of (S) -2- (6-methoxy-2-carbonyl-1, 2,3, 4a, 9-hexahydrophenanthren-4 a-yl) acetylnitrile (Compound 9)
In a standard glass bottle, 8ml of t-butanol, and compound 8 (850 mg,3.18 mmol) and potassium t-butoxide (3.18 mmol,1 eq.) were added, and the isomerization reaction was carried out at room temperature for 2 hours to give compound 9 (638 mg) in 75% yield.
Example 9 preparation of (S) -2- (6-methoxy-1, 2,3, 4a, 9-hexahydrophenanthren-4 a-yl) ethylamine (Compound 10)
In a standard glass bottle, compound 9 (1.0 g,3.74 mmol), THF 10mL, raney Ni (0.37 mmol,0.1 eq.) and acetic anhydride (3.93 mmol,1.05 eq.) were added, hydrogen was replaced, and the reaction was carried out at 25 ℃ for 6h. After that, filtration was carried out, and the filtrate was concentrated to obtain a concentrate, 10mL of diethylene glycol diethyl ether and hydrazine hydrate (4.11 mmol,1.1 eq.) were added, and the reaction was carried out at 180℃for 6 hours to obtain compound 10. The yield thereof was found to be 86%.
EXAMPLE 10 preparation of Compound 11
To 20ml of a methylene chloride solution were added compound 10 (2.0 g,7.77 mmol), bromine (7.77 mmol,1.0 eq.) and intramolecular cyclization reaction was carried out at 0-5℃for 0.5 hours, followed by washing with water twice, drying, concentrating, adding N, N-dimethylformamide (DMF, 20 ml), sodium hydrogencarbonate (15.54 mmol,2.0 eq.) and reaction at 135℃for 1.0 hour to give compound 11. The yield thereof was found to be 73%.
EXAMPLE 11 preparation of Compound 12
To 10ml of methanol was added 11 (500 mg,1.96 mmol), palladium hydroxide (0.2 mmol,0.1 eq.) and ammonium formate (9.79 mmol,5 eq.) and the mixture was subjected to stereoselective hydrogenation at 135℃for 5 hours to give 12. The yield thereof was found to be 90%.
EXAMPLE 12 preparation of dextromethorphan
In a reaction glass flask was charged compound 12 (1.5 g,5.83 mmol), formic acid 20ml and formaldehyde (11.66 mmol,2.0 eq.) and reacted at 100℃under reflux for 2h to give dextromethorphan. The yield thereof was found to be 95%.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.

Claims (10)

1. A preparation method of dextromethorphan is characterized by comprising the following steps: comprises the steps of taking cyclohexanedione 1 as a raw material, and carrying out acetonitrile substitution reaction to obtain a compound 2; carrying out a Wilde-Michelson synthesis reaction on the compound 2 to obtain a compound 4; performing mono ketal protection on the compound 4 to obtain a compound 5; carrying out Robinson cyclization reaction on the compound 5 to obtain a compound 6; carrying out aromatization reaction and methylation reaction on the compound 6 to obtain a compound 7; deprotection of compound 7 over a ketone group to afford compound 8; carrying out double bond isomerization reaction on the compound 8 to obtain a compound 9; carrying out reduction reaction on the compound 9 to obtain a compound 10; cyclizing the compound 10 to obtain a compound 11; subjecting compound 11 to asymmetric hydrogenation to obtain compound 12; the compound 12 is subjected to N-methylation reaction to obtain dextromethorphan, and the reaction process is as follows:
2. a process for the preparation of dextromethorphan as set forth in claim 1 wherein: the method comprises the following steps:
s1: in the presence of a first base, carrying out nucleophilic substitution reaction on cyclohexanedione and bromoacetonitrile in a first solvent to generate a compound 2;
s2: the compound 2 and butenone undergo Michael addition reaction under the action of a first catalyst to generate a compound 3;
s3: carrying out asymmetric Robinson cyclization reaction on the compound 3 under the action of a second catalyst and a first additive to generate a compound 4;
s4: in a second solvent, carrying out ketalization reaction on the compound 4 and ethylene glycol under the action of a third catalyst and a second additive to generate a compound 5;
s5: in a third solvent, the compound 5 is reacted with tetrahydropyrrole and butenone in sequence, and then reflux cyclization reaction is carried out under an acidic condition to generate a compound 6;
s6: in a fourth solvent, carrying out aromatization reaction on the compound 6 under the action of a fourth catalyst, and then carrying out methylation reaction in the presence of a second base to generate a compound 7;
s7: in a fifth solvent, the compound 7 undergoes hydrolysis reaction under the action of acid to generate a compound 8;
s8: in a sixth solvent, carrying out isomerization reaction on the compound 8 and the tert-butyl alcohol alkali metal salt to generate a compound 9;
s9: under the action of a fifth catalyst, an acylating agent and a reducing agent, the compound 9 undergoes cyano reduction, primary amine acetylation, carbonyl reduction and acetyl removal to obtain a compound 10;
s10: in a seventh solvent, cyclizing the compound 10 under the action of bromine, and then dehydrohalogenating the compound in the presence of a third base to obtain a compound 11;
s11: in an eighth solvent, the compound 11 and a hydrogen donor undergo stereoselective hydrogenation reaction under a sixth catalyst to obtain a compound 12;
s12: under the action of formic acid and formaldehyde, the compound 12 undergoes Eschweiler-Clarke methylation reaction to obtain dextromethorphan.
3. A process for the preparation of dextromethorphan as set forth in claim 2 wherein: the first base is a quaternary ammonium base, preferably the first base is benzyltrimethylammonium hydroxide, the second base is potassium carbonate, and the third base is sodium carbonate.
4. A process for the preparation of dextromethorphan as set forth in claim 2 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, the sixth solvent is tertiary butanol, the seventh solvent is dichloromethane, and the eighth solvent is methanol.
5. A process for the preparation of dextromethorphan as set forth in claim 2 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 trimethyl silicone triflate, the fourth catalyst is ketone bromide, the fifth catalyst is Raney-Ni, and the sixth catalyst is palladium hydroxide.
6. A process for the preparation of dextromethorphan as set forth in claim 2 wherein: the first additive is m-nitrobenzoic acid; the second additive is triethyl orthoformate.
7. A process for the preparation of dextromethorphan as set forth in claim 2 wherein: the acid is oxalic acid.
8. A process for the preparation of dextromethorphan as set forth in claim 2 wherein: the alkali metal tert-butoxide is potassium tert-butoxide, the acylating agent is acetic anhydride, and the hydrogen donor is ammonium formate.
9. A process for the preparation of dextromethorphan as set forth in claim 2 wherein: the reducing agent is hydrazine hydrate.
10. A process for the preparation of dextromethorphan as set forth in claim 2 wherein: the molar ratio of cyclohexanedione to bromoacetonitrile to the first base is 1:1:0.4; the molar ratio of the compound 2 to the butenone to the first catalyst is 1:1:0.01; in the step S3, the mol ratio of the compound 3 to the second catalyst to the first additive is 1:0.1:0.05; the mol ratio of the compound 4 to the glycol to the third catalyst to the second additive is 1:5.5:0.02:1.1; the molar ratio of the butenone to the tetrahydropyrrole is 1:1.05:1.2; the molar ratio of the compound 6 to the fourth catalyst is 1:0.05; the molar ratio of the compound 7 to the acid is 1:3.2; the molar ratio of the compound 8 to the alkali metal tert-butoxide is 1:1; the molar ratio of the compound 9 to the fifth catalyst to the acylating agent to the reducing agent is 1:0.1:1.05:1.1; the molar ratio of the bromine to the third base is 1:1:2; the mol ratio of the compound 11 to the sixth catalyst to the hydrogen donor is 1:0.1:5; the molar ratio of the compound 12 to formaldehyde is 1:2; the dosage ratio of compound 12 to formic acid was 0.3:4 in g/ml.
CN202310334062.5A 2023-03-31 2023-03-31 Preparation method of dextromethorphan Pending CN116444433A (en)

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