CN104761494B - A kind of preparation method of (S) or (R) 1 (4 methoxy-benzyl) 1,2,3,4,5,6,7,8 octahydro isoquinolin - Google Patents
A kind of preparation method of (S) or (R) 1 (4 methoxy-benzyl) 1,2,3,4,5,6,7,8 octahydro isoquinolin Download PDFInfo
- Publication number
- CN104761494B CN104761494B CN201410008353.6A CN201410008353A CN104761494B CN 104761494 B CN104761494 B CN 104761494B CN 201410008353 A CN201410008353 A CN 201410008353A CN 104761494 B CN104761494 B CN 104761494B
- Authority
- CN
- China
- Prior art keywords
- methoxy
- benzyls
- acetate
- solution
- isoquinolin
- 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
- 0 CO*1ccc(CC2NCCC3=C2CCCC3)cc1 Chemical compound CO*1ccc(CC2NCCC3=C2CCCC3)cc1 0.000 description 3
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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of (S) or (R) 1 (4 methoxy-benzyl) 1,2,3,4,5,6,7,8 octahydro isoquinolin acetate, methods described includes step：（1）The arene solution of compound containing structure as shown in formula III and acetic acid are mixed, obtain solution 1；（2）(S) 1 (4 methoxy-benzyl) 1,2,3,4,5,6 is added in solution 1,7,8 octahydro isoquinolin acetate crystal seeds or (R) 1 (4 methoxy-benzyl) 1,2,3,4,5,6,7,8 octahydro isoquinolin acetate crystal seeds, obtain solution 2；（3）Solution 2 is cooled to 05 DEG C, crystallization obtains (S) 1 (4 methoxy-benzyl) 1,2,3,4,5,6,7,8 octahydro isoquinolin acetate or (R) 1 (4 methoxy-benzyl) 1,2,3,4,5,6,7,8 octahydro isoquinolin acetate.
Description
Technical field
The present invention relates to chemical synthesis, more particularly to one kind (S) or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,
The preparation method of 7,8- octahydro isoquinolin.
Background technology
Dextromethorphan（Formula II compound）It is widely used oral antitussive.Prior art is by the left-handed mapping in formula I
The octahydro isoquinolin of isomers (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- changes into dextromethorphan, that is, passes through N-
It is acylated protection, Grewe is cyclized, slough N- acylation blocking groups and the reactions such as N- methylates synthesize dextromethorphan.Prior art will
Dextrorotatory enantiomers (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin in formula I changes into a left side
Dextromethorphan, levomethorphan are that one kind has addicted antalgesic.
(S) or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin typically passes through chiral resolution
Agent, which is split, to be prepared.Such as Helv.Chim.Acta39, using optically active mandelic acid as chiral resolving agent, fractionation obtains for 1376 (1956)
(S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin；Deutsche Bundespatent 2,003,486 is with (-)-bis--O-
Isopropylidene -2-keto-L-gulonic acid is chiral resolving agent, to raceme 1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,
8- octahydro isoquinolin is split, and obtains the octahydro isoquinolin of (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-.These
It is that the deficiency of preparation method is to need to use price and be not easy to the optical activity reagent of recovery, and these optical activities
Reagent can only split to obtain a kind of high enantiomter of purity, the cost control being unfavorable in production process.
United States Patent (USP) 4,727,147 describes one kind in water or alcohols, ketone polar solvent, passes through preferential crystallization
Method, the method for preparing (S) or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate.Although
This method avoids using optical activity reagent, but it is solvent that can be miscible with water that it, which uses solvent, in actual production process
In, existing defects.For example, in the preparation process for obtaining racemic free alkali, and product is split before subsequent reactions
Alkalize in extraction process, be required to the progress extract and separate operation of use immiscible with water solvent, and existing preferential crystallization method institute
Solvent is polar solvent miscible with water, and forward/backward operation process solvent is inconsistent, makes solvent recovery cumbersome, labor intensity
Increase, production cost increase, is unfavorable for industrialized production.
Therefore, there is an urgent need to provide a kind of easy, effective, economy and be advantageous to the fractionation of industrialized production for this area
Method prepares (S) or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin.
The content of the invention
The present invention is intended to provide one kind prepares (S) or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros
The method of isoquinolin.
In the first aspect of the present invention, there is provided a kind of preparation method of the acetate of compound of structure as shown in formula I,
Methods described includes step：
（1）The arene solution of compound containing structure as shown in formula III and acetic acid are mixed, obtain solution 1；
（2）(S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate is added in solution 1
Crystal seed or the octahydro isoquinolin acetate crystal seeds of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-, obtain solution 2；
（3）Solution 2 is cooled to 0-5 DEG C, crystallization obtains (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- eight
Hydrogen isoquinoline acetate or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate；
In another preference, step（1）In compound containing structure as shown in formula III arene solution in formula III
Compound and the mol ratio of acetic acid 1: 0.8-1.2.
In another preference, step（1）Described in compound containing structure as shown in formula III arene solution be by
Compound and water mixing of the structure as described in formula IV, are obtained after alkalizing and dissociating with aromatic hydrocarbons extraction；
Wherein A represents HBr, HCl or HCOOH
In another preference, the aromatic hydrocarbons dosage should be 1-6 times of free base weight, more preferably 1-3 times.
In another preference, step（2）Carry out at subzero 10 to 10 DEG C, carried out at more preferably 0-5 DEG C.
In another preference, step（2）In in terms of the total amount of acetate in solution 1, the crystal seed of addition is its 0.05-5%
（w/w）, more preferably 0.1-5%（w/w）.
In another preference, step（3）In the crystallization time be 1-12 hours.
In another preference, step（1）Described in aromatic hydrocarbons be selected from following one or more kinds of mixing：Toluene,
Ethylbenzene and dimethylbenzene；More preferably toluene.
In the second aspect of the present invention, there is provided a kind of preparation method of compound of structure as described in formula II, the side
Method includes step：
（i）The arene solution of compound containing structure as shown in formula III and acetic acid are mixed, obtain solution 1；
（ii）(S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetic acid is added in solution 1
Salt crystal seed or the octahydro isoquinolin acetate crystal seeds of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-, obtain solution 2；
（iii）Solution 2 is cooled to 0-5 DEG C, crystallization obtains (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-
Octahydro isoquinolin acetate or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate；
（iv）(S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate is swum through alkalization
From obtaining the octahydro isoquinolin of (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-；
Or
The octahydro isoquinolin acetate of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- is free through alkalizing, obtain
To (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin；
（v）(S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros isoquinolin can be converted by prior art
Into dextromethorphan, i.e., protection is acylated by N-, Grewe is cyclized, slough N- acylation blocking groups and the reactions such as N- methylates synthesize
Dextromethorphan of the structure as shown in formula II；
Or by (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros isoquinolin by racemization be converted into (S) -
The octahydro isoquinolin of 1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-, then by N- be acylated protection, Grewe cyclisation, slough N-
The reaction such as methylate of acylated blocking group and N- synthesizes dextromethorphan as shown in formula II.
In the third aspect of the present invention, there is provided a kind of preparation method of compound of structure as described in formula V, the side
Method includes step：
（i）The arene solution of compound containing structure as shown in formula III and acetic acid are mixed, obtain solution 1；
（ii）(S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetic acid is added in solution 1
Salt crystal seed or the octahydro isoquinolin acetate crystal seeds of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-, obtain solution 2；
（iii）Solution 2 is cooled to 0-5 DEG C, crystallization obtains (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-
Octahydro isoquinolin acetate or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate；
（iv）(R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate is swum through alkalization
From obtaining the octahydro isoquinolin of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-；
（v）(R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros isoquinolin can be converted by prior art
Into levomethorphan, i.e., protection is acylated by N-, Grewe is cyclized, slough N- acylation blocking groups and the reactions such as N- methylates synthesize
Levomethorphan as shown in formula V；
Accordingly, the invention provides it is a kind of it is easy, effectively, it is economical and be advantageous to the method for splitting system of industrialized production
Standby (S) or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin.
Embodiment
Inventor is had found in 1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- eight by in-depth study extensively
During hydrogen isoquinoline separation, aromatic solvent can be used, both for free alkali extraction process, is used for preferential crystallization again
Method split process, so that front and rear during dextromethorphan is prepared used identical solvent system.On this basis,
Complete the present invention.
The structural formula of compound of the present invention is：
Wherein A represents HBr, HCl or HCOOH
1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin optical isomers provided by the invention are torn open
Method is divided to include step：
The first step, by salt, water and the aromatic solvent of the octahydro isoquinolin of 1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-
After mixing, carry out alkalization and dissociate, take aromatic solvent layer, obtain containing 1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- eight
The arene solution of hydrogen isoquinoline；
Second step, will contain the octahydro isoquinolin of 1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- arene solution and
Acetic acid mixes, and obtains solution 1；
3rd step, being added in subzero 10-10 DEG C of solution 1 has the 1- (4- methoxy-benzyls) -1 of optically-active, and 2,3,4,5,
6,7,8- octahydro isoquinolin acetate crystal seeds, then subzero 10-5 DEG C of crystallization, obtain 1- (the 4- methoxybenzyls of corresponding optical activity
Base) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate.
In the above-mentioned first step, the salt of the octahydro isoquinolin of 1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- includes
Hydrobromate, formates, hydrochloride etc..
In the above-mentioned first step, the dosage of aromatic solvent is 1-6 times, preferably 1-3 times.Alkalization trip described in the above-mentioned first step
From being exactly that the alkali as described in formula III in the salt of 1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin dissociates
Process out, the conventional method in this area can be used to carry out, such as, but not limited to, by 1- (4- methoxy-benzyls) -1,2,
After salt, water and the aromatic solvent of 3,4,5,6,7,8- octahydro isoquinolin mix, alkaline solution is added, makes the chemical combination as described in formula III
Thing separate out, and enter aromatic solvent layer.Described alkaline solution is selected from sodium hydroxide, potassium hydroxide, sodium carbonate etc., preferably
Sodium hydroxide or potassium hydroxide.Described aromatic solvent is selected from following one or more kinds of mixing：Toluene, ethylbenzene and two
Toluene, preferably toluene.
In above-mentioned second step, mole of the octahydro isoquinolin of 1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- and acetic acid
Than 1: 0.8-1.2, preferably 1: 0.9-1.1.
Preferred 5-10 DEG C of the temperature of solution 1 in above-mentioned 3rd step, preferred 0-5 DEG C of recrystallization temperature.
The crystal seed used in above-mentioned 3rd step can by optically pure (S) or (R) -1- (4- methoxy-benzyls) -1,2,3,4,
5,6,7,8- octahydro isoquinolin, it is prepared with proper amount of acetic acid in methyl tertiary butyl ether(MTBE).With the total amount of acetate in solution 1
Meter, the crystal seed of addition is its 0.05-5%（w/w）, preferably 0.1-5%（w/w）.
In 3rd step, if what is added is the octahydro isoquinolin of (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-
Acetate crystal seed, what is obtained is the octahydro isoquinolin acetate of (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-；Such as
What fruit added is the octahydro isoquinolin acetate crystal seeds of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-, is obtained just
It is (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate.
It is possible to further the octahydro isoquinolin of (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- that will be obtained
Acetate or the octahydro isoquinolin acetate of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- carry out alkalization and dissociated, from
And obtain compound of the structure as described in formula I.Described alkalization is free be by (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,
6,7,8- octahydro isoquinolin acetate or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate
In (S) -1- (4- the methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros isoquinolin or (R) -1- (4- methoxies as shown in formula I
Base benzyl) -1,2,3,4,5,6,7,8- octahydro isoquinolin separate outs, the conventional method in this area can be used to carry out, such as
But it is not limited to, by the octahydro isoquinolin acetate of (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- or (R) -1- (4- first
Oxy-benzyl) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate, water and aromatic solvent mixing after, add alkaline solution, make
Compound separate out as described in formula I, and enter aromatic solvent layer.Described alkaline solution is selected from sodium hydroxide, hydroxide
Potassium, sodium carbonate etc., preferably sodium hydroxide or potassium hydroxide.Described aromatic solvent is selected from following one or more kinds of mixed
Close：Toluene, ethylbenzene and dimethylbenzene, preferably toluene.
Yet further, (the S) -1- (4- methoxy-benzyls) -1 obtained using the above method of the present invention, 2,3,4,5,
6,7,8- octahydro isoquinolin, dextromethorphan is obtained by the conventional method in this area, such as, but not limited to, is acylated and protected by N-
Shield, Grewe cyclisation, slough N- and be acylated blocking group and N- and the reaction such as methylate.
On (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6 obtained by the method that is provided by the invention described above,
7,8- octahydro isoquinolin, the conventional method of this area can be used to be converted into racemic 1- (4- methoxy-benzyls) -1,2,3,
4,5,6,7,8- octahydro isoquinolin, re-use the production process into dextromethorphan.
The features described above that the present invention mentions, or the feature that embodiment is mentioned can be in any combination.Disclosed in this case specification
All features can be used in combination with any combinations thing form, each feature disclosed in specification, can with it is any provide it is identical,
The alternative characteristics substitution of impartial or similar purpose.Therefore except there is special instruction, disclosed feature is only impartial or similar spy
The general example of sign.
Main advantages of the present invention are：
1st, in accordance with the above content is visible, and the present invention utilizes aromatic solvent extraction of free base in alkalinization, so
Preferential crystallization method fractionation is directly carried out in aromatic solvent system afterwards, makes front and rear technical process solvent for use consistent.
2nd, method provided by the invention is easy to operate, and the amount of labour is greatly decreased, and convenient solvent reclaiming, production cost substantially drops
It is low, be advantageous to industrialized production.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise all percentage, ratio, ratio or number is pressed
Weight meter.
The unit in percent weight in volume in the present invention is well-known to those skilled in the art, such as is referred to
The weight of solute in 100 milliliters of solution.
Unless otherwise defined, anticipated known to all specialties used in text and scientific words and one skilled in the art
Justice is identical.In addition, any method similar or impartial to described content and material all can be applied in the inventive method.Wen Zhong
Described preferable implementation only presents a demonstration with material to be used.
Embodiment 1
1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin hydrobromates 150.0g（0.443mol）,
Stirred in water 400ml and toluene 170ml input reaction bulbs, add sodium hydroxide 19.0g（0.475mol）Alkalization is free, stands and divides
Layer, takes toluene layer, obtains 230.0g toluene solutions.
Embodiment 2
Into embodiment 1 in the 230.0g toluene solutions of gained, 26.6g glacial acetic acid is added（0.443mol）, it is stirred at room temperature
After 10 minutes, 10 DEG C are cooled to, adds (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate
Crystal seed 1.6g（0.005mol）, 2h is stirred, is cooled to 5 DEG C of crystallization 2h.Filtering, obtain 21.3g (S) -1- (4- methoxy-benzyls) -
1,2,3,4,5,6,7,8- octahydro isoquinolin acetate（Yield：30.3%）[HPLC：(S)∶(R)=98.9∶1.0].MS（+ ve from
Sub- electron spray）m/z258[M1+H]+;m/z59[M2-H]-。
Embodiment 3
Into embodiment 1 in the 230.0g toluene solutions of gained, 26.6g glacial acetic acid is added（0.443mol）, it is stirred at room temperature
After 10 minutes, 5 DEG C are cooled to, adds (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate
Crystal seed 0.7g（0.002mol）, 2h is stirred, is cooled to 0 DEG C of crystallization 8h.Filtering, obtain 21.7g (R) -1- (4- methoxy-benzyls) -
1,2,3,4,5,6,7,8- octahydro isoquinolin acetate（Yield：31.5%）[HPLC：(S)∶(R)=0.9∶99.0].MS（+ ve from
Sub- electron spray）m/z258[M1+H]+;m/z59[M2-H]-。
Embodiment 4
Mother liquor in embodiment 2 is cooled to 10 DEG C, adds (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-
Octahydro isoquinolin acetate crystal seed 1.0g（0.003mol）, 2h is stirred, is cooled to 5 DEG C of crystallization 2h.Filtering, obtain 22.8g (R)-
1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate（Yield：32.4%）[HPLC：(S)∶(R)=
1.2∶98.7]。
Embodiment 5
Mother liquor in embodiment 3 is cooled to 10 DEG C, adds (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-
Octahydro isoquinolin acetate crystal seed 5.0g（0.015mol）, 2h is stirred, is cooled to 0-5 DEG C of crystallization 2h.Filtering, obtains 28.0g
(S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate（Disregard crystal seed amount, yield：32.7%）
[HPLC：(S)∶(R)=98.8∶1.0].
Embodiment 6
1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin hydrobromates 150.0g（0.443mol）,
Stirred in water 400ml and toluene 400ml input reaction bulbs, add sodium hydroxide 19.0g（0.475mol）Alkalization is free, stands and divides
Layer, takes toluene layer.Water layer again with toluene（300ml×2）Extraction, after merging organic phase.Be concentrated under reduced pressure organic phase, and recovery is about
500ml toluene, obtain 547.0g toluene solutions.
Embodiment 7
Into embodiment 6 in the 547.0g toluene solutions of gained, 26.6g glacial acetic acid is added（0.443mol）, it is stirred at room temperature
After 10 minutes, subzero 10 DEG C are cooled to, adds (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin vinegar
Hydrochlorate crystal seed 7.0g（0.022mol）, stir 2h, then subzero 10 DEG C of crystallization 8h.Filtering, obtains 26.7g (S) -1- (4- methoxybenzyls
Base) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate（Disregard crystal seed amount, yield：28.1%）[HPLC：(S)∶(R)=98.9
∶1.0]。
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not limited to the substantial technological content model of the present invention
Enclose, substantial technological content of the invention is broadly to be defined in the right of application, any technology that other people complete
Entity or method, if with the right of application defined in it is identical, also or a kind of equivalent change, will
It is considered as being covered by among the right.
Claims (12)
1. the preparation method of the acetate of compound of a kind of structure as shown in formula I, it is characterised in that methods described includes step
Suddenly：
(1) arene solution of the compound containing structure as shown in formula III and acetic acid are mixed, obtains solution 1；It is described to contain knot
The arene solution of compound of the structure as shown in formula III is to mix compound of the structure as described in formula IV and water, through alkalize it is free after
Obtained with aromatic hydrocarbons extraction；The aromatic hydrocarbons is selected from following one or more kinds of mixing：Toluene, ethylbenzene and dimethylbenzene；
(2) (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate crystal seeds are added in solution 1
Or the octahydro isoquinolin acetate crystal seeds of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-, obtain solution 2；
(3) solution 2 is cooled to 0-5 DEG C, crystallization obtains (S) -1- (4- methoxy-benzyls) -1, and 2,3,4,5,6,7,8- octahydros are different
Quinoline acetate or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate；
Wherein A represents HBr, HCl or HCOOH.
2. preparation method as claimed in claim 1, it is characterised in that the chemical combination in step (1) containing structure as shown in formula III
The mol ratio 1: 0.8-1.2 of the compound of formula III and acetic acid in the arene solution of thing.
3. preparation method as claimed in claim 1, it is characterised in that the aromatic hydrocarbons dosage should be 1-6 times of free base weight.
4. preparation method as claimed in claim 3, it is characterised in that the aromatic hydrocarbons dosage should be 1-3 times of free base weight.
5. preparation method as claimed in claim 1, it is characterised in that step (2) is carried out at subzero 10 to 10 DEG C.
6. preparation method as claimed in claim 5, it is characterised in that step (2) is carried out at 0-5 DEG C.
7. preparation method as claimed in claim 1, it is characterised in that in step (2) in terms of the total amount of acetate in solution 1,
The crystal seed of addition is its 0.05-5% (w/w).
8. preparation method as claimed in claim 7, it is characterised in that in step (2) in terms of the total amount of acetate in solution 1,
The crystal seed of addition is its 0.1-5% (w/w).
9. preparation method as claimed in claim 1, it is characterised in that the crystallization time in step (3) is 1-12 hours.
10. preparation method as claimed in claim 1, it is characterised in that the aromatic hydrocarbons is toluene.
11. the preparation method of compound of a kind of structure as described in formula II, it is characterised in that methods described includes step：
(i) arene solution of the compound containing structure as shown in formula III and acetic acid are mixed, obtains solution 1；It is described to contain knot
The arene solution of compound of the structure as shown in formula III is to mix compound of the structure as described in formula IV and water, through alkalize it is free after
Obtained with aromatic hydrocarbons extraction；The aromatic hydrocarbons is selected from following one or more kinds of mixing：Toluene, ethylbenzene and dimethylbenzene；
(ii) it is brilliant that (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate is added in solution 1
Kind or the octahydro isoquinolin acetate crystal seeds of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-, obtain solution 2；
(iii) solution 2 is cooled to 0-5 DEG C, crystallization obtains (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros
Isoquinolin acetate or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate；
(iv) it is the octahydro isoquinolin acetate of (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- is free through alkalizing, obtain
To (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin；
Or
The octahydro isoquinolin acetate of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- is free through alkalizing, obtain
(R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin；
(v) (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros isoquinolin is acylated protection, Grewe by N-
It is cyclized, sloughs the dextromethorphan of N- acylation blocking group and N- methylation reactions composite structure as shown in formula II；
Or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros isoquinolin is converted into (S) -1- by racemization
(4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin, then by N- be acylated protection, Grewe cyclisation, slough N- acyls
Change the dextromethorphan of blocking group and the synthesis of N- methylation reactions as shown in formula II；
Wherein A represents HBr, HCl or HCOOH.
12. the preparation method of compound of a kind of structure as described in formula V, it is characterised in that methods described includes step：
(i) arene solution of the compound containing structure as shown in formula III and acetic acid are mixed, obtains solution 1；It is described to contain knot
The arene solution of compound of the structure as shown in formula III is to mix compound of the structure as described in formula IV and water, through alkalize it is free after
Obtained with aromatic hydrocarbons extraction；The aromatic hydrocarbons is selected from following one or more kinds of mixing：Toluene, ethylbenzene and dimethylbenzene；
(ii) it is brilliant that (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate is added in solution 1
Kind or the octahydro isoquinolin acetate crystal seeds of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8-, obtain solution 2；
(iii) solution 2 is cooled to 0-5 DEG C, crystallization obtains (S) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros
Isoquinolin acetate or (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin acetate；
(iv) it is the octahydro isoquinolin acetate of (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- is free through alkalizing, obtain
To (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydro isoquinolin；
(v) (R) -1- (4- methoxy-benzyls) -1,2,3,4,5,6,7,8- octahydros isoquinolin is acylated protection, Grewe by N-
It is cyclized, sloughs the levomethorphan of N- acylation blocking groups and the synthesis of N- methylation reactions as shown in formula V；
Wherein A represents HBr, HCl or HCOOH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410008353.6A CN104761494B (en) | 2014-01-08 | 2014-01-08 | A kind of preparation method of (S) or (R) 1 (4 methoxy-benzyl) 1,2,3,4,5,6,7,8 octahydro isoquinolin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410008353.6A CN104761494B (en) | 2014-01-08 | 2014-01-08 | A kind of preparation method of (S) or (R) 1 (4 methoxy-benzyl) 1,2,3,4,5,6,7,8 octahydro isoquinolin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104761494A CN104761494A (en) | 2015-07-08 |
| CN104761494B true CN104761494B (en) | 2018-01-19 |
Family
ID=53643643
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410008353.6A Active CN104761494B (en) | 2014-01-08 | 2014-01-08 | A kind of preparation method of (S) or (R) 1 (4 methoxy-benzyl) 1,2,3,4,5,6,7,8 octahydro isoquinolin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104761494B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632038B (en) * | 2016-12-01 | 2019-10-29 | 暨明医药科技（苏州）有限公司 | A kind of method for splitting of octahydro isoquinolin |
| CN110007028B (en) * | 2019-04-26 | 2021-12-10 | 上海葆隆生物科技有限公司 | Method for detecting (S) -1- (4-methoxybenzyl) -1,2,3,4,5,6,7, 8-octahydroisoquinoline isomer |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4727147A (en) * | 1984-10-03 | 1988-02-23 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Optically active 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinium acetates |
| US5892044A (en) * | 1995-07-11 | 1999-04-06 | Lonza Ltd. | Process for preparing optically active 1-(p-methoxybenzyl)-1,2,3,4,5,3,7,8-octahydroisoquinoline |
| CN103073494A (en) * | 2013-02-04 | 2013-05-01 | 苏州立新制药有限公司 | Preparation method of ent-3-methoxymorphinan |
| EP2628728A1 (en) * | 2011-01-18 | 2013-08-21 | Divi's Laboratories Limited | Process for the optical resolution of 1-(4-methoxybenzyl)-octahydro-isoquinoline |
-
2014
- 2014-01-08 CN CN201410008353.6A patent/CN104761494B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4727147A (en) * | 1984-10-03 | 1988-02-23 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Optically active 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinium acetates |
| US5892044A (en) * | 1995-07-11 | 1999-04-06 | Lonza Ltd. | Process for preparing optically active 1-(p-methoxybenzyl)-1,2,3,4,5,3,7,8-octahydroisoquinoline |
| EP2628728A1 (en) * | 2011-01-18 | 2013-08-21 | Divi's Laboratories Limited | Process for the optical resolution of 1-(4-methoxybenzyl)-octahydro-isoquinoline |
| CN103073494A (en) * | 2013-02-04 | 2013-05-01 | 苏州立新制药有限公司 | Preparation method of ent-3-methoxymorphinan |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104761494A (en) | 2015-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103360348B (en) | Carfilzomib intermediate and preparation method thereof, and preparation method of Carfilzomib | |
| JPH07309834A (en) | Production of diarylprolinol enantiomerically pure | |
| CN104761494B (en) | A kind of preparation method of (S) or (R) 1 (4 methoxy-benzyl) 1,2,3,4,5,6,7,8 octahydro isoquinolin | |
| WO2020052545A1 (en) | Method for preparing brivaracetam and intermediates thereof | |
| CN109563023A (en) | The method for preparing substituted biphenyl | |
| CN104761495A (en) | New compound and preparation method and application thereof | |
| Szakonyi et al. | Regio-and stereoselective synthesis of the enantiomers of monoterpene-based β-amino acid derivatives | |
| CN106008316B (en) | A kind of method of synthesis Lei Dipawei chiral intermediates | |
| EP2891647B1 (en) | Method for producing (r)-1,1,3-trimethyl-4-aminoindane | |
| CN102964307B (en) | Dabigatran etexilate related substance and preparation method thereof | |
| CN105272966A (en) | Preparation method of ALK inhibitor crizotinib and analogue or salt thereof | |
| CN102887826B (en) | Synthesis method of (-)-chicoric acid | |
| US20080214837A1 (en) | Synthetic Method of Optically Pure (S)-3-Hydroxypyrrolidine | |
| CN105294828B (en) | The preparation method of Ao Beitawei | |
| CN109810059A (en) | A kind of preparation method of left-handed hydrochloric acid demethyl benzene ring pelargonate | |
| CN104628584A (en) | High-purity dapoxetine preparation method suitable for industrialization | |
| KR101460694B1 (en) | New synthetic method of glycopyrrolate and pharmaceutical formulations containing this active ingredient | |
| WO2011131027A1 (en) | Preparation methods of l-phenylephrine hydrochloride | |
| CN106432059A (en) | Preparation method of 3-hydroxypiperidine, preparation method of derivative of 3-hydroxypiperidine, and intermediate of 3-hydroxypiperidine | |
| CN106632038B (en) | A kind of method for splitting of octahydro isoquinolin | |
| CN104829513B (en) | A kind of preparation method of 2- carboxyl -4- methoxymethylpyrrolidine derivative | |
| CN112812054A (en) | Preparation method of high-purity benidipine hydrochloride | |
| EP3447044A1 (en) | Method for preparing d-4,4'-biphenylalanine alkyl ester or l-4,4'-biphenylalanine alkyl ester from dl-4,4'-biphenylalanine alkyl ester | |
| EP3067344A1 (en) | Method for preparing lacosamide | |
| CN110078657A (en) | A kind of synthetic method of chirality 3- amino piperidine and its derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200630 Address after: No.399, Jiangnan Road, Hengdian Town, Dongyang City, Jinhua City, Zhejiang Province Co-patentee after: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY Patentee after: APELOA PHARMACEUTICAL Co.,Ltd. Co-patentee after: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd. Address before: 200040 No. 1320 West Beijing Road, Shanghai, Jingan District Co-patentee before: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd. Patentee before: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY |