CN111233763B - Preparation method of 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline - Google Patents
Preparation method of 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline Download PDFInfo
- Publication number
- CN111233763B CN111233763B CN202010277725.0A CN202010277725A CN111233763B CN 111233763 B CN111233763 B CN 111233763B CN 202010277725 A CN202010277725 A CN 202010277725A CN 111233763 B CN111233763 B CN 111233763B
- Authority
- CN
- China
- Prior art keywords
- methyl
- methoxy
- benzyl
- octahydro
- isoquinoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of 1- (4-methoxy-benzyl) -2-methyl-octahydro isoquinoline, which comprises the steps of dissolving 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methyl isoquinoline in a solvent, adding a formaldehyde solution, stirring, adding a catalyst, introducing hydrogen, carrying out catalytic hydrogenation reaction, filtering the catalyst after the reaction is finished, and carrying out desolventizing, distilling and separating to obtain the 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydro isoquinoline. The method has the characteristics of mild and safe reaction conditions, environmental protection, reduction of side reactions, high yield, good purity, simple and convenient operation and the like, so that the preparation industry achieves the environmental protection, safety and high efficiency, and the production cost is reduced.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline.
Background
1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline, of the formula: c18H25NO, CAS No.: 31414-58-1.
1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline is a key intermediate for synthesizing dextromethorphan. Dextromethorphan (Dextromethorphan), also known as Dextromethorphan hydrobromide, abbreviated as DM or DXM in English, is an antitussive drug, has a chemical name of (+) -cis-1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4 a-iminoethanonthrene, is a central antitussive drug and is mainly used for dry cough. It is suitable for treating common cold, acute or chronic bronchitis, bronchial asthma, pharyngolaryngitis, pulmonary tuberculosis, and other cough due to upper respiratory infection.
1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline is an intermediate for synthesizing dextromethorphan, which is currently synthesized by the following general formula:
1. the product is obtained by cyclization, reduction, methylation, resolution and the like of N-cyclohexene ethyl p-methoxy phenylacetamide.
2. The product is obtained by Grignard reaction, hydrogenation reduction, methylation, resolution and the like of brominated N-methyl tetrahydroisoquinoline and halogenated p-methoxybenzyl chloride.
The above route has the disadvantages of difficult raw material acquisition, complex synthesis and yield lower than 30%. In view of the above disadvantages, the present invention provides a key intermediate 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline for preparing dextromethorphan.
Disclosure of Invention
The invention aims to provide a preparation method of 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydro isoquinoline, which has the characteristics of mild and safe reaction conditions, environmental protection, reduction of side reactions, high yield, good purity, simple and convenient operation and the like, so that the preparation industry achieves the aims of environmental protection, safety and high efficiency, and the production cost is reduced.
In order to achieve the above object, the technical scheme of the present invention is to design a preparation method of 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline, firstly dissolving 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline in a solvent, then adding a formaldehyde solution, stirring, then adding a catalyst, introducing hydrogen, carrying out a catalytic hydrogenation reaction, filtering the catalyst after the reaction is finished, and obtaining 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydro-isoquinoline through desolventizing, distilling and separating.
Preferably, the solvent is methanol, ethanol or isopropanol.
Preferably, the formaldehyde solution contains 30% wt of formaldehyde.
Preferably, the catalyst is Raney nickel or palladium on carbon.
Preferably, the mass ratio of the 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline to the solvent is 1: 8-15.
Preferably, the molar ratio of the 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline to the formaldehyde is 1: 3.2-1: 3.8.
Preferably, the mass ratio of the catalyst to the 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline is 0.15-0.2: 1.
Preferably, the stirring time is 2-8 hours.
Preferably, the temperature of the catalytic hydrogenation reaction is controlled to be 25-60 ℃, and the hydrogen pressure is controlled to be 1.2-2.5 MPa.
The invention has the advantages and beneficial effects that: the preparation method of the 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline has the characteristics of mild and safe reaction conditions, environmental friendliness, reduction of side reactions, high yield, good purity, simplicity and convenience in operation and the like, so that the preparation industry is environment-friendly, safe and efficient, and the production cost is reduced.
Detailed Description
The following further describes embodiments of the present invention with reference to examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
The invention provides a preparation method of 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methyl isoquinoline, which comprises the steps of dissolving 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methyl isoquinoline in a solvent, adding a formaldehyde solution, stirring, adding a catalyst, introducing hydrogen, carrying out catalytic hydrogenation reaction, filtering the catalyst after the reaction is finished, and carrying out desolventizing, distilling and separating to obtain the 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydro isoquinoline.
Specifically, the method comprises the following steps:
the solvent is methanol, ethanol or isopropanol.
The formaldehyde solution contained 30% wt of formaldehyde.
The catalyst is Raney nickel or palladium carbon.
The mass ratio of the 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline to the solvent is 1: 8-15.
The mol ratio of the 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline to the formaldehyde is 1: 3.2-1: 3.8.
The mass ratio of the catalyst to 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline is 0.15-0.2: 1.
The stirring time is 2-8 hours.
The temperature of the catalytic hydrogenation reaction is controlled to be 25-60 ℃, and the hydrogen pressure is controlled to be 1.2-2.5 MPa.
The specific embodiment of the invention is as follows:
example 1
Adding 300g of ethanol into a hydrogenation kettle, adding 40g (0.16 mol) of 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline, adding 22g (0.22 mol) of 30% formaldehyde solution under mechanical stirring, continuously stirring at 25 ℃ for 4 hours, adding 6g of Raney nickel catalyst, stirring at room temperature for 8 hours under the hydrogen pressure of 1.8MPa, filtering to remove the catalyst, concentrating the filtrate, and carrying out vacuum distillation and separation to obtain the 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline, wherein the yield is 90%.
Example 2
Adding 800g of ethanol into a hydrogenation kettle, adding 80g (0.32 mol) of 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline, adding 44g (0.44 mol) of 30% formaldehyde solution under mechanical stirring, continuously stirring at 30 ℃ for 6 hours, adding 12g of Raney nickel catalyst, stirring at room temperature for 8 hours under the hydrogen pressure of 1.5MPa, filtering to remove the catalyst, concentrating the filtrate, and carrying out vacuum distillation and separation to obtain the 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline, wherein the yield is 90.5%.
Example 3
Adding 300g of ethanol into a hydrogenation kettle, adding 40g (0.16 mol) of 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline, adding 22g (0.22 mol) of 30% formaldehyde solution under mechanical stirring, continuously stirring at 25 ℃ for 4 hours, adding 6g of 5% palladium-carbon catalyst, stirring at room temperature for 8 hours under the hydrogen pressure of 1.8MPa, filtering to remove the catalyst, concentrating the filtrate, and carrying out vacuum distillation and separation to obtain the 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline, wherein the yield is 95%.
Example 4
Adding 300g of ethanol into a hydrogenation kettle, adding 40g (0.16 mol) of 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline, adding 22g (0.22 mol) of 30% formaldehyde solution under mechanical stirring, continuously stirring at 25 ℃ for 4 hours, adding 6g of Raney nickel catalyst, stirring at room temperature for 8 hours under the hydrogen pressure of 2.5MPa, filtering to remove the catalyst, concentrating the filtrate, and carrying out vacuum distillation and separation to obtain the 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline, wherein the yield is 91%.
Example 5
According to the synthesis method of example 1, catalytic hydrogenation temperature is increased to 50 ℃, the rest is not changed, 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline yield is 88%.
Example 6
According to the embodiment 1 synthesis method, Raney nickel catalyst input to 8 grams, the rest is unchanged, 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-eight hydrogen isoquinoline yield is 89%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A preparation method of 1- (4-methoxy-benzyl) -2-methyl-octahydro-isoquinoline is characterized in that 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methyl isoquinoline is dissolved in a solvent, then a formaldehyde solution is added, after stirring, a catalyst is added, hydrogen is introduced, catalytic hydrogenation reaction is carried out, after the reaction is finished, the catalyst is filtered out, and desolventizing and distillation separation are carried out, so that 1- (4-methoxy-benzyl) -2-methyl-1, 2,3,4,5,6,7, 8-octahydro-isoquinoline is obtained.
2. The method for producing 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline according to claim 1, characterized in that the solvent is methanol, ethanol or isopropanol.
3. The method for preparing 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline, according to claim 1, characterized in that the formaldehyde solution contains 30% wt of formaldehyde.
4. The method for preparing 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline according to claim 1, characterized in that the catalyst is Raney nickel or palladium on carbon.
5. The method for producing 1- (4-methoxy-benzyl) -2-methyl-octahydro-isoquinoline according to claim 1, characterized in that the mass ratio of the 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline to the solvent is 1:8 to 15.
6. The method for preparing 1- (4-methoxy-benzyl) -2-methyl-octahydro-isoquinoline, according to claim 1, characterized in that the molar ratio of 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline to formaldehyde is 1:3.2 to 1: 3.8.
7. The method for producing 1- (4-methoxy-benzyl) -2-methyl-octahydro-isoquinoline according to claim 1, characterized in that the mass ratio of the catalyst to 1,2,3,4,5,6,7, 8-octahydro-1- (methoxyphenyl) methylisoquinoline is 0.15 to 0.2: 1.
8. The method for producing 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline according to claim 1, wherein the stirring is carried out for 2 to 8 hours.
9. The method for preparing 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline according to claim 1, wherein the temperature of the catalytic hydrogenation reaction is controlled to be 25 to 60 ℃ and the hydrogen pressure is controlled to be 1.2 to 2.5 MPa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010277725.0A CN111233763B (en) | 2020-04-10 | 2020-04-10 | Preparation method of 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010277725.0A CN111233763B (en) | 2020-04-10 | 2020-04-10 | Preparation method of 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111233763A CN111233763A (en) | 2020-06-05 |
| CN111233763B true CN111233763B (en) | 2022-03-18 |
Family
ID=70869909
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010277725.0A Active CN111233763B (en) | 2020-04-10 | 2020-04-10 | Preparation method of 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111233763B (en) |
-
2020
- 2020-04-10 CN CN202010277725.0A patent/CN111233763B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111233763A (en) | 2020-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO1993008189A1 (en) | Chemical reactions on camptothecin or analogs | |
| WO2023137874A1 (en) | Method for preparing deuterated pharmaceutical intermediate | |
| CN101575321B (en) | Production method of trimetazidine and its hydrochloride | |
| CN111233763B (en) | Preparation method of 1- (4-methoxy-benzyl) -2-methyl-octahydroisoquinoline | |
| WO2005044805A1 (en) | A novel process for preparing donepezil and its derivatives | |
| CN110845443B (en) | Method for preparing high-purity tolperisone hydrochloride | |
| WO2024031838A1 (en) | Method for industrially producing deuterated pharmaceutical intermediate by means of catalysis of solid-supported nickel | |
| CN112010730A (en) | Green preparation method of diphenylmethane | |
| WO2024045292A1 (en) | Method for catalytic industrial production of deuterated pharmaceutical intermediate by means of combination of immobilized nickel and organic alkali | |
| CN113896728B (en) | Synthesis and preparation method of rotundine | |
| CN112573996B (en) | Preparation method of optically active menthol | |
| CN111217690B (en) | Preparation method of propafenone hydrochloride and intermediate 2' -hydroxy dihydrochalcone thereof | |
| CN112939849B (en) | (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof | |
| CN112679512B (en) | Trabectedin intermediate and preparation method thereof | |
| CN109824520B (en) | Preparation method of cis-4-methylcyclohexylamine | |
| CN109053563B (en) | Method for preparing flupirtine hydrochloride | |
| CN116239529B (en) | Preparation method of N-methyltetrahydroquinoline alkaloid with participation of carbon dioxide | |
| CN110590786B (en) | Improved method of 9-deazaguanine synthesis process | |
| CN110627672B (en) | Preparation method of dimemorfan phosphate and intermediate thereof | |
| CN115160280B (en) | Synthesis method of flavonoid compound | |
| CN114349635B (en) | Synthesis method of dolutegravir core intermediate | |
| CN110041207B (en) | Method for catalytically synthesizing enamine by using nickel imine complex containing pyridine ligand | |
| CN112661687A (en) | Synthesis method of (R) -3-hydroxypyrrolidine | |
| CN115557891A (en) | Preparation method of dextromethorphan | |
| CN113264867A (en) | Preparation method of cis-2, 6-dimethylpiperidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |