CN108383786A - (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin the preparation methods - Google Patents
(S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin the preparation methods Download PDFInfo
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- CN108383786A CN108383786A CN201810407931.1A CN201810407931A CN108383786A CN 108383786 A CN108383786 A CN 108383786A CN 201810407931 A CN201810407931 A CN 201810407931A CN 108383786 A CN108383786 A CN 108383786A
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- Prior art keywords
- methoxy
- benzyls
- isoquinolin
- octahydro
- octahydro isoquinolin
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- 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
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- 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
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of preparation methods of 1,2,3,4,5,6,7,8 octahydro isoquinolin of dextromethorphan intermediate (S) 1 (4 methoxy-benzyl), with 1 (4 methoxy-benzyl) 3,4,5,6,7,8 hexahydro isoquinolin（II）For raw material, selection plus hydrogen obtain (S) 1 (4 methoxy-benzyl) 1,2 under the conditions of 2 sulfenamide of organic chiral ligand (R) N (5 fluorine, 2 hydroxybenzyl) 2 methylpropane and trichlorosilane, 3,4,5,6,7,8 octahydro isoquinolin（I）.The present invention uses organic chiral ligand, raw material cheap, safe, simple and easy to get；Reaction temperature is 20 ~ 15 DEG C, can be realized in the industrial production；Product ee values are up to 63%.
Description
Technical field
The present invention relates to a kind of field of pharmaceutical chemistry technology, and in particular to dextromethorphan key intermediate (S) -1- (4- first
Oxy-benzyl) -1,2,3,4,5,6,7,8- octahydro isoquinolin synthetic method.
Background technology
(S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros isoquinolin (I) is synthesis maincenter class antitussive
The key intermediate of dextromethorphan.This drug has the characteristics that efficient, safety, tolerance are good, additive relatively low, is a kind of be suitble to
The antibechic class drug that long-term use or high dose use.Therefore, (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-
The improvement of octahydro isoquinolin synthesis technology has very important significance to the production cost for reducing dextromethorphan.
The synthesis technology of tradition (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin is flat using R-
Peach acid carries out the method that chiral resolution obtains single optically-active product.This method the biggest problems are that yield can only close to 50%,
Cause a large amount of wastage of material.(S)-O- tertiary butyl valerian ammonia alcohol bases are introduced on the nitrogen-atoms of octahydro isoquinolin in addition, also having
Group carries out asymmetric Benzylation method, and carries out asymmetry using chiral ruthenium catalyst under then being acted on by butyl lithium
The method of hydrogenating reduction synthesizes -1,2,3,4,5,6,7,8- octahydro isoquinolin of (S) -1- (4- methoxy-benzyls), but due to anti-
It answers that condition is harsher or catalyst is more expensive, thus is limited to laboratory synthesis.
Invention content
The purpose of the present invention is to provide a kind of reaction condition is mild, easy to operate, high (S) -1- (the 4- first of product ee values
Oxy-benzyl) -1,2,3,4,5,6,7,8- octahydro isoquinolin preparation methods.
Technical solution of the invention is：
A kind of system of dextromethorphan intermediate (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin
Preparation Method, it is characterized in that：The specific steps are：It is original with 1- (4- methoxy-benzyls) -3,4,5,6,7,8- hexahydros isoquinolin (II)
Material, in organic chiral ligand (R)-N- (the fluoro- 2- hydroxybenzyls of 5-) -2- methylpropane -2- sulfenamides and trichlorosilane condition
Lower selection plus hydrogen obtain (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros isoquinolin (I).
Reaction temperature is -20 to -15 DEG C.Using dichloromethane as reaction dissolvent.
Its synthetic route is as follows：
Advantage of the present invention：
Using organic chiral ligand, raw material is cheap, safe, simple and easy to get；Reaction temperature is -20~-15 DEG C, can be in work
It is realized in industry production；Product ee values are up to 63%.
With reference to embodiment, the invention will be further described.
Specific implementation mode
Embodiment 1：1- (4- methoxy-benzyls) -3,4,5,6,7,8- hexahydro isoquinolin is added in 100mL three-necked flasks
(1.28g, 5mmol), (R)-N- (the fluoro- 2- hydroxybenzyls of 5-) -2- methylpropane -2- sulfenamides (0.13g, 0.5mmol) and
20mL steams dichloromethane again, is cooled to -20 DEG C of stirrings under nitrogen protection.Be slowly added dropwise later trichlorosilane (1.35g,
10mmol) enter reaction solution, maintains the temperature at -20 to -15 DEG C of ranges, drip off within 0.5 hour, maintain the temperature at -15 DEG C and continue to stir
Mix reaction.Saturated sodium bicarbonate solution is slowly added to after 12h until bubble-free generation, continues to filter after stirring 0.5h.Filtrate point
Water phase is extracted twice using 20mL dichloromethane after liquid, is merged organic phase, solvent is removed under reduced pressure after anhydrous sodium sulfate drying, slightly
Product obtains 1.15g yellow oils, yield 89.1%, ee values 4% after silica gel column chromatography.
1H NMR(400MHz,CDCl3,ppm)δ:7.07 (d, 2H), 6.78 (d, 2H), 3.72 (s, 3H), 3.18 (d, 1H),
2.93(m,2H),2.64(m,1H),2.40(m,1H),2.10(m,1H),1.99-1.38(m,10H)
Embodiment 2：1- (4- methoxy-benzyls) -3,4,5,6,7,8- hexahydro isoquinolin is added in 100mL three-necked flasks
(1.28g, 5mmol), (R)-N- (the fluoro- 2- hydroxybenzyls of 5-) -2- methylpropane -2- sulfenamides (0.25g, 1mmol) and
20mL steams dichloromethane again, is cooled to -20 DEG C of stirrings under nitrogen protection.Be slowly added dropwise later trichlorosilane (1.35g,
10mmol) enter reaction solution, maintains the temperature at -20 to -15 DEG C of ranges, drip off within 0.5 hour, maintain the temperature at -15 DEG C and continue to stir
Mix reaction.Saturated sodium bicarbonate solution is slowly added to after 12h until bubble-free generation, continues to filter after stirring 0.5h.Filtrate point
Water phase is extracted twice with 20mL dichloromethane again after liquid, merges organic phase, solvent is removed under reduced pressure after anhydrous sodium sulfate drying.Make
1.12g yellow oils, yield 86.8%, ee values 31% are obtained after crossing column with silica gel.
1H NMR(400MHz,CDCl3,ppm)δ:7.07 (d, 2H), 6.78 (d, 2H), 3.72 (s, 3H), 3.18 (d, 1H),
2.93(m,2H),2.64(m,1H),2.40(m,1H),2.10(m,1H),1.99-1.38(m,10H)。
Embodiment 3：1- (4- methoxy-benzyls) -3,4,5,6,7,8- hexahydro isoquinolin is added in 100mL three-necked flasks
(1.28g, 5mmol), (R)-N- (the fluoro- 2- hydroxybenzyls of 5-) -2- methylpropane -2- sulfenamides (0.50g, 2mmol) and
20mL steams dichloromethane again, is cooled to -20 DEG C of stirrings under nitrogen protection.Be slowly added dropwise later trichlorosilane (1.35g,
10mmol) enter reaction solution, maintains the temperature at -20 to -15 DEG C of ranges, drip off within 0.5 hour, maintain the temperature at -15 DEG C and continue to stir
Mix reaction.Saturated sodium bicarbonate solution is slowly added to after 12h until bubble-free generation, continues to filter after stirring 0.5h.Filtrate point
Water phase is extracted twice using 20mL dichloromethane after liquid, is merged organic phase, solvent is removed under reduced pressure after anhydrous sodium sulfate drying, slightly
Product obtains 1.14g yellow oils, yield 88.4%, ee values 63% after silica gel column chromatography.
1H NMR(400MHz,CDCl3,ppm)δ:7.07 (d, 2H), 6.78 (d, 2H), 3.72 (s, 3H), 3.18 (d, 1H),
2.93(m,2H),2.64(m,1H),2.40(m,1H),2.10(m,1H),1.99-1.38(m,10H)。
Claims (3)
1. a kind of preparation of dextromethorphan intermediate (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin
Method, it is characterized in that：The specific steps are：With 1- (4- methoxy-benzyls) -3,4,5,6,7,8- hexahydro isoquinolin（II）For raw material,
It is selected under the conditions of organic chiral ligand (R)-N- (the fluoro- 2- hydroxybenzyls of 5-) -2- methylpropane -2- sulfenamides and trichlorosilane
It selects plus hydrogen obtains (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin（I）.
2. dextromethorphan intermediate (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- according to claim 1
The preparation method of octahydro isoquinolin, it is characterized in that：Reaction temperature is -20 to -15 DEG C.
3. dextromethorphan intermediate (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7 according to claim 1 or 2,
The preparation method of 8- octahydro isoquinolin, it is characterized in that：Using dichloromethane as reaction dissolvent.
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| CN201810407931.1A CN108383786A (en) | 2018-05-02 | 2018-05-02 | (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin the preparation methods |
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| CN201810407931.1A CN108383786A (en) | 2018-05-02 | 2018-05-02 | (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin the preparation methods |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110643650A (en) * | 2019-09-20 | 2020-01-03 | 复旦大学 | Preparation method of (S) -1-benzyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927830A (en) * | 2006-10-24 | 2007-03-14 | 中国科学院成都生物研究所 | Compound of optically pure sulfenamides and application thereof |
| CN104119273A (en) * | 2014-04-24 | 2014-10-29 | 上海天慈生物谷生物工程有限公司 | Novel method for preparing dextromethorphan |
-
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- 2018-05-02 CN CN201810407931.1A patent/CN108383786A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927830A (en) * | 2006-10-24 | 2007-03-14 | 中国科学院成都生物研究所 | Compound of optically pure sulfenamides and application thereof |
| CN104119273A (en) * | 2014-04-24 | 2014-10-29 | 上海天慈生物谷生物工程有限公司 | Novel method for preparing dextromethorphan |
Non-Patent Citations (2)
| Title |
|---|
| DONG PEI ET AL.: "S-Chiral Sulfinmides as highly enantioselectives organocatalysts", 《ORG. LETT.》 * |
| GAKU HATTORI ET AL.: "Copper-catalyzed Asymmetric propargylic substitution reactions of propargylic acetates with amines", 《ANGEW. CHEM. INT. ED.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110643650A (en) * | 2019-09-20 | 2020-01-03 | 复旦大学 | Preparation method of (S) -1-benzyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline compound |
| CN110643650B (en) * | 2019-09-20 | 2023-03-07 | 复旦大学 | Preparation method of (S) -1-benzyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline compound |
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