CN106632038B - A kind of method for splitting of octahydro isoquinolin - Google Patents
A kind of method for splitting of octahydro isoquinolin Download PDFInfo
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- CN106632038B CN106632038B CN201611089492.1A CN201611089492A CN106632038B CN 106632038 B CN106632038 B CN 106632038B CN 201611089492 A CN201611089492 A CN 201611089492A CN 106632038 B CN106632038 B CN 106632038B
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- 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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Abstract
The present invention provides a kind of method for splitting of octahydro isoquinolin, include the following steps, by 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin (mixed body) are dissolved in reaction dissolvent；Benzaldehyde is added in S1 and chiral acid resolution reagent is heated to reflux and obtains clarified solution, then cools down and solid is precipitated, suction filtration obtains (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6, the mandelate of 7,8- octahydro isoquinolin (d-isomer) is simultaneously dissolved in water, and saturated aqueous sodium carbonate is added dropwise and adjusts pH to alkalinity, then it is extracted with organic solvent, extract liquor is obtained, concentration, vacuum distillation obtain (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin (d-isomer).Method of the invention is not required to high pressure, and route is easy to operate, and the product ee value of acquisition is greater than 99%, and yield significantly reduces production cost close to 90%.
Description
Technical field
The present invention relates to a kind of method for splitting of antibechic class drug octahydro isoquinolin, more particularly to a kind of right U.S. of hydrobromic acid are husky
Fragrant key intermediate (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin (d-isomer) and its fractionation side
Method belongs to technical field of organic synthesis.
Background technique
Dextromethorphan hydrobromide also known as Dextromethorphan Hvdrobromide, chemistry entitled -9 α of 3- methoxyl group -17- methyl, 13 α, 14 α
Morphinan hydrobromide hydrate is a kind of central antitussive that may replace codeine, the main coughing centre for inhibiting medulla oblongata
And it plays a role.It is widely used because its central antitussive effect is with non-narcotic and without additive in clinical treatment cough
Cough, and show unique superiority, treat flu, acute/chronic bronchitis, sphagitis, bronchial asthma, pulmonary tuberculosis and its
Few productive cough caused by its infection of the upper respiratory tract is coughed.
Currently, contain dextromethorphan in more than 100 kinds of non-prescribed medicine ingredients of United States sale, dextromethorphan mainly with
The form of hydrobromate is applied in drug.In addition, in the market common flu antitussive such as beauty can, Dextromethorphan Hydrobromide Compound Tablets, Bai Jia
Black common cold tablet (the pseudo- numb piece of U.S. breath), pusiran tablet, beautiful pearl quarter pleasure, Paar gram, Fair Baby Cough Syrup etc. are also right containing hydrobromic acid
Dextromethorphan.Therefore research dextromethorphan hydrobromide key intermediate 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro
The efficient separating method of isoquinolin (mixed body) is realized with simple process route, low cost, high production capacity, the method for high yield
Industrialized production has important researching value and application value.
Obtaining (S) -1- different quinoline of (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro (d-isomer) at present mainly has
Two lines:
First route is dissymmetric synthesis, main to be urged by introducing larger sterically hindered group or metal complex
The enantioselective hydrogenation of change realizes that wherein the increase of the steric hindrance of aryl substituent results in product ee value in catalyst
Significantly improve.Document (the Tetrahedron:Asymmetry 9 (1998) 4043-that Emil A.Broger etc. is delivered
4054) synthetic method, 1- (4- methoxyl group) benzyl -1,2, the fluorine of 3,4,5,6,7,8- octahydro isoquinolin (mixed body) are reported
Borate is in the methanol of 1:1 and the in the mixed solvent of toluene, in iridium catalyst (S)-(3,5-tBu, 4-MeO)-tLANOP effect
Lower hydrogenation (Hydrogen Vapor Pressure 100bar, room temperature 44h) obtains (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydros
The borofluoride ee value of different quinoline (d-isomer) is 78%, chemo-selective 55%.And its sulfate is in the tetrahydro furan of 40:1
The in the mixed solvent muttered with water is obtained in the lower hydrogenation (hydrogenation conditions are same as above) of iridium catalyst (S)-(3,5-tBu)-tLANOP effect
Product ee value is up to 86%, chemo-selective 46%.Such method needs high-pressure hydrogenation, the high requirements on the equipment, the product ee of acquisition
Value and chemo-selective are relatively low, and the catalyst of the catalytic enantioselective hydrogenation used is expensive, increases production cost,
The synthetic method is as shown in following formulas:
Route second is that first synthesize 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin (mixed body), then
Different quinoline (the dextrorotation of (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro required for obtaining is split with chiral acid
Body).The route raw material is simple and easy to get, and reaction condition is mild, simple production process, but the disadvantage is that fractionation theoretical yield is only
50%, by-product (R) -1- (4- methoxyl group) benzyl -1,2 of generation, the different quinoline of 3,4,5,6,7,8- octahydros (levo form) is house
Go to part, cause very big waste, which results in dextromethorphan key intermediate this step utilization rate it is generally relatively low, cost compared with
It is high.The raceme chiral acid L- mandelic acid of the synthesis as described in the patent of India 2014 (2014CH03933,21Nov2014)
Resolution yield is only 31%.
Summary of the invention
It is an object of the invention to solve above-mentioned technical problem, a kind of method for splitting of octahydro isoquinolin is provided, specifically
For dextromethorphan hydrobromide intermediate (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin (d-isomer)
Efficient separating method.
The purpose of the present invention is achieved through the following technical solutions:
The present invention provides a kind of method for splitting of octahydro isoquinolin, include the following steps,
S1, dissolution of raw material: 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin (mixed body) is dissolved in
Reaction dissolvent；
S2, fractionation: benzaldehyde and chiral acid resolution reagent are added in S1；
The formation of S3, intermediate salt: S2 solution is heated to reflux and obtains clarified solution, then cools down and solid is precipitated, is filtered
To the mandelate of (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin (d-isomer)；
S4, product are formed: by (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinoline obtained in S3
The mandelate of quinoline (d-isomer) is dissolved in water, and saturated aqueous sodium carbonate is added dropwise and adjusts pH to alkalinity, is then extracted with organic solvent
It takes, obtains extract liquor, concentration, vacuum distillation obtain (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolines
Quinoline (d-isomer).
Reaction equation is as follows:
Preferably, the reaction dissolvent in the S1 be one of methanol, ethyl alcohol, tetrahydrofuran, acetone or more than one
Combination,
Preferably, the mixed solvent of the reaction dissolvent methanol in the S1 and tetrahydrofuran, and the methanol: tetrahydrofuran
For 5:1 (v/v).
Preferably, chiral acid resolution reagent is L- mandelic acid ,-two pairs of D- tartaric acid, D- (+) toluyls in the S2
Tartaric acid, preferred L- mandelic acid in the present invention.
Preferably, the chiral acid resolution reagent dosage is 0.9~1.5 equivalent of substrate, preferably 1.3 is worked as in the present invention
Amount.
Preferably, the benzaldehyde dosage is 0.05~5.0 equivalent of substrate, preferably 0.2 equivalent.
Preferably, the extraction can be any solvent immiscible with water and stable under alkaline condition with organic solvent
Solution, including one of methylene chloride, methyl tertiary butyl ether(MTBE), toluene or more than one combination.
The beneficial effects of the present invention are embodied in: catalytic amount economical and easily available benzaldehyde is added when fractionation, is not required to high pressure, route
Easy to operate, the product ee value of acquisition is greater than 99%, and yield significantly reduces production cost close to 90%, this is but also this hair
Bright method has good prospects for commercial application.It is innovatively added to benzaldehyde, promotes left-handed optical isomer can scene
Racemization improves and splits yield, improves production capacity, is suitble to industrialized production.
Specific embodiment
Method of the invention is illustrated below by specific embodiment, so that technical solution of the present invention is easier to manage
Solution is grasped, but the present invention is not limited thereto.Experimental method described in following embodiments is unless otherwise specified conventional side
Method；The reagent and material commercially obtain unless otherwise specified.And some reagents can also carry out
Conventional replacement, since these are without special, therefore only with preferred embodiment in embodiment.It should be noted that in the application
The clarification referred to refers to that reactant is completely dissolved.
Embodiment one
It is (right to present embodiments provide one kind (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin
Revolve body) efficient separating method comprising following steps:
In 250ml there-necked flask, 5.0g 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin are added
(mixed body) is dissolved in 50ml methanol and 10ml tetrahydrofuran mixed liquor, is added with stirring 0.4g benzaldehyde, adds 3.8g D-
Tartaric acid.Reaction solution is heated to 58~60 DEG C and is back to reaction solution clarification, then is cooled to room temperature and solid is gradually precipitated, is filtered,
Filter cake is washed with a small amount of ethyl acetate.
Filter cake is dissolved in 50ml water, and saturated aqueous sodium carbonate is added dropwise and adjusts pH to 8.5~9.0, methylene chloride (50ml is added
× 3) it extracting, organic phase adds sodium sulphate dry again, it is evaporated under reduced pressure after concentration to get (S) -1- (4- methoxyl group) benzyl -1,2 is arrived,
It is 99.1% that 3,4,5,6,7,8- octahydro isoquinolin (d-isomer) 4.3g, GC, which detect ee value,.
Embodiment two
It is (right to present embodiments provide one kind (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin
Revolve body) efficient separating method comprising following steps:
In 500ml there-necked flask, 11.0g 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin are added
(mixed body) is dissolved in 110ml methanol and 22ml tetrahydrofuran mixed liquor, is added with stirring 0.9g benzaldehyde, is added 11.8g
L- mandelic acid.Reaction solution is heated to 58~60 DEG C and is back to reaction solution clarification, then is cooled to room temperature and solid is gradually precipitated, is taken out
Filter, filter cake are washed with a small amount of ethyl acetate.Filter cake is dissolved in 110ml water, be added dropwise saturated aqueous sodium carbonate adjust pH to 8.5~
9.0, methylene chloride (110ml × 3) extraction is added, organic phase adds sodium sulphate dry again, is evaporated under reduced pressure after concentration to get (S)-is arrived
1- (4- methoxyl group) benzyl -1,2, it is 99.4% that 3,4,5,6,7,8- octahydro isoquinolin (d-isomer) 9.5g, GC, which detect ee value,.
Embodiment three
It is (right to present embodiments provide one kind (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin
Revolve body) efficient separating method comprising following steps:
In 250ml there-necked flask, 15.0g 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin are added
(mixed body) is dissolved in 150ml methanol and 30ml tetrahydrofuran mixed liquor, is added with stirring 1.2g benzaldehyde, is added 16.0g
L- mandelic acid.Reaction solution is heated to 58~60 DEG C and is back to reaction solution clarification, then is cooled to room temperature and solid is gradually precipitated, is taken out
Filter, filter cake are washed with a small amount of ethyl acetate.Filter cake is dissolved in 150ml water, be added dropwise saturated aqueous sodium carbonate adjust pH to 8.5~
9.0, methylene chloride (150ml × 3) extraction is added, organic phase adds sodium sulphate dry again, is evaporated under reduced pressure after concentration to get (S)-is arrived
1- (4- methoxyl group) benzyl -1,2, it is 99.6% that 3,4,5,6,7,8- octahydro isoquinolin (d-isomer) 13.8g, GC, which detect ee value,.
Example IV
In 250ml there-necked flask, 15.0g 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin are added
(mixed body) is dissolved in 150ml methanol and 30ml tetrahydrofuran mixed liquor, is added with stirring 1.2g benzaldehyde, is added 16.0g
L- mandelic acid.Reaction solution is heated to 58~60 DEG C and is back to reaction solution clarification, then is cooled to room temperature and solid is gradually precipitated, is taken out
Filter, filter cake are washed with a small amount of ethyl acetate.Filter cake is dissolved in 150ml water, be added dropwise saturated aqueous sodium carbonate adjust pH to 8.5~
9.0, methylene chloride (150ml × 3) extraction is added, organic phase adds sodium sulphate dry again, is evaporated under reduced pressure after concentration to get (S)-is arrived
1- (4- methoxyl group) benzyl -1,2, it is 99.4% that 3,4,5,6,7,8- octahydro isoquinolin (d-isomer) 13.2g, GC, which detect ee value,.
Embodiment five
In 50L there-necked flask, 1.2Kg 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin are added
(mixed body) is dissolved in 12L methanol and 2.4L tetrahydrofuran mixed liquor, is added with stirring 99g benzaldehyde, adds 1.3Kg L-
Mandelic acid.Reaction solution is heated to 58~60 DEG C and is back to reaction solution clarification, then is cooled to room temperature and solid is gradually precipitated, is filtered,
Filter cake is washed with a small amount of ethyl acetate.Filter cake is dissolved in 12L water, and saturated aqueous sodium carbonate is added dropwise and adjusts pH to 8.5~9.0, adds
Enter methylene chloride (12L × 3) extraction, organic phase adds sodium sulphate dry again, is evaporated under reduced pressure after concentration to get (S) -1- (4- first is arrived
Oxygroup) benzyl -1,2, it is 99.6% that 3,4,5,6,7,8- octahydro isoquinolin (d-isomer) 1.07Kg, GC, which detect ee value,.
Therefore the method for the present invention is in 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin (mixed
Body) with benzaldehyde that catalytic amount is added in the system of resolution reagent, promote left-handed optical isomer scene racemization, can continue
It splitting to increase target product d-isomer, the product ee value finally obtained is greater than 99%, while yield increases to about 90%, this
But also the method for the present invention has good prospects for commercial application.
The process of left-handed optical isomer scene racemization is promoted to follow Kinetic Resolution principle in the present invention:
Resolution reagent is configured to ammonium salt with the half S in raw material raceme first, and thermodynamics easily precipitates crystal, remaining R
Configuration and catalyst benzaldehyde form imine structure, which forms conjugated alkene intermediate state, which generates racemization again
Body, then resolution reagent is re-formed with the S configuration in newly generated raceme again and is salted out, and so circulation is in dynamic process.
Therefore the benzaldehyde being added can promote the racemization of optical isomer scene
Method of the invention needs high-pressure hydrogenation, the high requirements on the equipment, the product ee value and chemistry of acquisition compared to original technique
Selectivity is relatively low, and the catalyst of the catalytic enantioselective hydrogenation used is expensive, increases production cost, side of the present invention
The economical and easily available benzaldehyde of addition catalytic amount, is not required to high pressure, route is easy to operate, and the product ee value of acquisition is big when method passes through fractionation
In 99%, yield significantly reduces production cost close to 90%, this but also the method for the present invention have good industrial application before
Scape.
And it is low compared to the generally existing yield of original resolution process, production capacity is small, and problem at high cost, the method for the present invention innovatively adds
Added benzaldehyde, promote left-handed optical isomer can live racemization, improve and split yield, improve production capacity, be suitble to industry
Metaplasia produces.
Still there are many specific embodiments by the present invention.All all skills formed using equivalent replacement or equivalent transformation
Art scheme, all falls within the scope of protection of present invention.
Claims (9)
1. a kind of method for splitting of octahydro isoquinolin, it is characterised in that: reaction equation is as follows:
Include the following steps:
S1, dissolution of raw material: it is molten that 1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin mixed body is dissolved in reaction
Agent；
S2, fractionation: benzaldehyde and chiral acid resolution reagent are added in S1；
The formation of S3, intermediate salt: S2 solution is heated to reflux and obtains clarified solution, then cools down and solid is precipitated, is obtained after suction filtration
(S) mandelate of -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin d-isomer；
S4, product are formed: (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin obtained in S3 is right
The mandelate of rotation body is dissolved in water, and adjusts pH to alkalinity, is then extracted with organic solvent, obtains extract liquor, concentration, decompression are steamed
It evaporates to obtain (S) -1- (4- methoxyl group) benzyl -1,2,3,4,5,6,7,8- octahydro isoquinolin d-isomer.
2. a kind of method for splitting of octahydro isoquinolin according to claim 1, it is characterised in that: the reaction in the S1 is molten
Agent is one of methanol, ethyl alcohol, tetrahydrofuran, acetone or more than one combination.
3. a kind of method for splitting of octahydro isoquinolin according to claim 1, it is characterised in that: the reaction in the S1 is molten
Agent is the mixed solvent of methanol and tetrahydrofuran, and the methanol and tetrahydrofuran volume ratio are 5:1.
4. a kind of method for splitting of octahydro isoquinolin according to claim 1, it is characterised in that: chiral acid is torn open in the S2
Dividing reagent is L- mandelic acid.
5. a kind of method for splitting of octahydro isoquinolin according to claim 1, it is characterised in that: chiral acid is torn open in the S2
Dividing reagent dosage is 0.9~1.5 equivalent of substrate.
6. a kind of method for splitting of octahydro isoquinolin according to claim 1, it is characterised in that: benzaldehyde is used in the S2
Amount is 0.05~5.0 equivalent of substrate dosage.
7. a kind of method for splitting of octahydro isoquinolin according to claim 1, it is characterised in that: pass through dropwise addition in the S3
Saturated aqueous sodium carbonate carries out the adjusting of pH, and pH is adjusted to 8.5~9.0.
8. a kind of method for splitting of octahydro isoquinolin according to claim 1, it is characterised in that: be heated to reflux in the S3
Temperature is 58~60 DEG C.
9. a kind of method for splitting of octahydro isoquinolin according to claim 1, it is characterised in that: the S4 is extracted with organic
Solvent is one of methylene chloride, methyl tertiary butyl ether(MTBE), toluene or more than one combination.
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