CN104761494A - Preparation method of (S) or (R)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline - Google Patents
Preparation method of (S) or (R)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline Download PDFInfo
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- CN104761494A CN104761494A CN201410008353.6A CN201410008353A CN104761494A CN 104761494 A CN104761494 A CN 104761494A CN 201410008353 A CN201410008353 A CN 201410008353A CN 104761494 A CN104761494 A CN 104761494A
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- methoxy
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- octahydro isoquinoline
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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
- 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
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Abstract
The invention discloses a preparation method of (S) or (R)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline acetate, wherein the method includes the steps: (1) mixing an aromatic solution of a compound having a structure represented by the formula III with acetic acid, to obtain a solution 1; (2) adding a (S)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline acetate seed crystal or a (R)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline acetate seed crystal into the solution 1, to obtain a solution 2; and (3) cooling the solution 2 to 0-5 DEG C, crystallizing to obtain (S)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline acetate or (R)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline acetate.
Description
Technical field
The present invention relates to chemosynthesis, particularly relate to the preparation method of one (S) or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9.
Background technology
Dextromethorphane Hbr (formula II compound) is widely used oral antitussive.Prior art is by laevororotatory enantiomer (the S)-1-(4-methoxy-benzyl)-1 in formula I; 2; 3; 4; 5,6,7; 8-octahydro isoquinoline 99.9 changes into Dextromethorphane Hbr, namely by the protection of N-acidylate, Grewe cyclisation, slough N-acidylate blocking group and N-and the Reactive Synthesis Dextromethorphane Hbr such as to methylate.Dextrorotatory enantiomers (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 in formula I is changed into levomethorphan by prior art, and levomethorphan is that one has addicted anodyne.
(S) or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 generally by chiral resolving agent split preparation.As Helv.Chim.Acta
39, 1376 (1956) is chiral resolving agent with optically active mandelic acid, splits and obtains (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9; German Patent 2,003,486 with (-)-bis--O-isopropylidene-2-keto-L-gulonic acid for chiral resolving agent, to raceme 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 splits, and obtains (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9.That the deficiency of these preparation methods is to need to use price and be not easy to the optical activity reagent that reclaims, and these optical activity reagent can only split and obtain the high enantiomer of a kind of purity, are unfavorable for the cost control in production process.
United States Patent (USP) 4,727,147 describe a kind of in water or alcohols, ketone polar solvent, by preferential crystallization method, preparation (S) or (R)-1-(4-methoxy-benzyl)-1,2,3,4, the method of 5,6,7,8-octahydro isoquinoline 99.9 acetate.Although this method is avoided using optical activity reagent, its use solvent to be the solvent that can dissolve each other with water, in actual production process, existing defects.For example, in the preparation process obtaining racemic free alkali, and split in the alkalization extraction process of product before subsequent reactions, all need to use and carry out extracting and separating operation with the immiscible solvent of water, and existing preferential crystallization method solvent used is the polar solvent dissolved each other with water, forward/backward operation process solvent is inconsistent, make solvent recuperation loaded down with trivial details, labour intensity increases, and production cost increases, and is unfavorable for suitability for industrialized production.
Therefore, this area is in the urgent need to providing a kind of easy, effective, economical and be conducive to method for splitting preparation (S) or (R)-1-(4-methoxy-benzyl)-1,2 of suitability for industrialized production, 3,4,5,6,7,8-octahydro isoquinoline 99.9.
Summary of the invention
The present invention aims to provide the method that one prepares (S) or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9.
In a first aspect of the present invention, provide the preparation method of a kind of structure such as formula the acetate of the compound shown in I, described method comprises step:
(1) by containing structure such as formula the arene solution of the compound shown in III and acetic acid mixing, obtain solution 1;
(2) in solution 1, add (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed, obtains solution 2;
(3) solution 2 is cooled to 0-5 DEG C, crystallization obtains (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate;
In another preference, containing the mol ratio 1: 0.8-1.2 of structure such as formula formula III compound in the arene solution of the compound shown in III and acetic acid in step (1).
In another preference, be by structure such as formula the compound described in IV and water mixing containing structure such as formula the arene solution of the compound shown in III described in step (1), through alkalize free after obtain with aromatic hydrocarbons extraction;
Wherein A represents HBr, HCl or HCOOH
。
In another preference, described aromatic hydrocarbons consumption should be the 1-6 of free base weight doubly, and more preferably 1-3 doubly.
In another preference, step (2) is carried out at subzero 10 to 10 DEG C, carries out at being more preferably 0-5 DEG C.
In another preference, with the total amount of acetate in solution 1 in step (2), the crystal seed added is its 0.05-5%(w/w), be more preferably 0.1-5%(w/w).
In another preference, the crystallization time in step (3) is 1-12 hour.
In another preference, described in step (1), aromatic hydrocarbons is selected from one or more following mixing: toluene, ethylbenzene and dimethylbenzene; Be more preferably toluene.
In a second aspect of the present invention, provide the preparation method of a kind of structure such as formula the compound described in II, described method comprises step:
By containing structure such as formula the arene solution of the compound shown in III and acetic acid mixing, obtain solution 1;
(ii) in solution 1, add (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed, obtains solution 2;
(iii) solution 2 is cooled to 0-5 DEG C, crystallization obtains (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate;
(iv) by (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate is free through alkalizing, and obtains (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9;
Or
By free through alkalizing for (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate, obtain (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9;
(v) by (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 can change into Dextromethorphane Hbr by prior art, namely by the protection of N-acidylate, Grewe cyclisation, slough N-acidylate blocking group and N-and the Reactive Synthesis structure such as to methylate such as formula the Dextromethorphane Hbr shown in II;
Or by (R)-1-(4-methoxy-benzyl)-1,2,3; 4,5,6; 7,8-octahydro isoquinoline 99.9 is converted into (S)-1-(4-methoxy-benzyl)-1,2 by racemization; 3,4,5; 6; 7,8-octahydro isoquinoline 99.9, then by the protection of N-acidylate, Grewe cyclisation, slough N-acidylate blocking group and N-and the Reactive Synthesis such as to methylate such as formula the Dextromethorphane Hbr shown in II.
In a third aspect of the present invention, provide the preparation method of a kind of structure such as formula the compound described in V, described method comprises step:
By containing structure such as formula the arene solution of the compound shown in III and acetic acid mixing, obtain solution 1;
(ii) in solution 1, add (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed, obtains solution 2;
(iii) solution 2 is cooled to 0-5 DEG C, crystallization obtains (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate;
(iv) by (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate is free through alkalizing, and obtains (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9;
(v) by (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 can change into levomethorphan by prior art, namely by the protection of N-acidylate, Grewe cyclisation, slough N-acidylate blocking group and N-and the Reactive Synthesis such as to methylate such as formula the levomethorphan shown in V;
Accordingly, the invention provides a kind of easy, effective, economical and be conducive to method for splitting preparation (S) or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 of suitability for industrialized production.
Embodiment
Contriver, through extensive and deep research, finds at 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7, in 8-octahydro isoquinoline 99.9 separation process, aromatic solvent can be used, both for free alkali extraction process, again for preferential crystallization method split process, thus make to employ identical solvent systems before and after in the process preparing Dextromethorphane Hbr.On this basis, the present invention is completed.
The structural formula of the compound that the present invention relates to is:
Wherein A represents HBr, HCl or HCOOH
The method for splitting of 1-provided by the invention (4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 optical isomer comprises step:
The first step, by 1-(4-methoxy-benzyl)-1,2,3,4,5,6, after the mixing of the salt of 7,8-octahydro isoquinoline 99.9, water and aromatic solvent, carry out alkalization free, get aromatic solvent layer, obtain containing 1-(4-methoxy-benzyl)-1,2,3,4,5, the arene solution of 6,7,8-octahydro isoquinoline 99.9;
Second step, by the arene solution containing 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 and acetic acid mixing, obtains solution 1;
3rd step, adds the 1-(4-methoxy-benzyl)-1,2 having optically-active in the solution 1 of subzero 10-10 DEG C, 3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed, subzero 10-5 DEG C crystallization again, obtains the 1-(4-methoxy-benzyl)-1,2 of corresponding opticity, 3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate.
In the above-mentioned the first step, the salt of described 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 comprises hydrobromate, formate, hydrochloride etc.
In the above-mentioned the first step, the consumption of aromatic solvent is 1-6 times, and preferred 1-3 doubly.Alkalization described in the above-mentioned the first step is free is exactly by 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7, the process of dissociating out such as formula the alkali described in III in the salt of 8-octahydro isoquinoline 99.9, the method of this area routine can be used to carry out, such as but not limited to, by 1-(4-methoxy-benzyl)-1,2,3,4,5,6, after the mixing of the salt of 7,8-octahydro isoquinoline 99.9, water and aromatic solvent, add basic solution, make such as formula the compound described in III free out, and enter aromatic solvent layer.Described basic solution is selected from sodium hydroxide, potassium hydroxide, sodium carbonate etc., preferred sodium hydroxide or potassium hydroxide.Described aromatic solvent is selected from one or more following mixing: toluene, ethylbenzene and dimethylbenzene, preferred toluene.
In above-mentioned second step, the mol ratio 1: 0.8-1.2 of 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 and acetic acid, is preferably 1: 0.9-1.1.
The preferred 5-10 DEG C of temperature of solution 1, the preferred 0-5 DEG C of recrystallization temperature in above-mentioned 3rd step.
The crystal seed used in above-mentioned 3rd step by optically pure (S) or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9, can prepare in methyl tertiary butyl ether with proper amount of acetic acid.With the total amount of acetate in solution 1, the crystal seed added is its 0.05-5%(w/w), be preferably 0.1-5%(w/w).
In 3rd step, if that add is (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed, that obtain is (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate; If that add is (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed, that obtain is (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate.
Further, (the S)-1-(4-methoxy-benzyl)-1,2 that can will obtain, 3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate carries out alkalization and dissociates, thus obtains structure such as formula the compound described in I.Described alkalization is free is by (S)-1-(4-methoxy-benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline 99.9 acetate or (R)-1-(4-methoxy-benzyl)-1, 2, 3, 4, 5, 6, 7, in 8-octahydro isoquinoline 99.9 acetate such as formula (the S)-1-(4-methoxy-benzyl)-1 shown in I, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline 99.9 or (R)-1-(4-methoxy-benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline 99.9 is free out, the method of this area routine can be used to carry out, such as but not limited to, by (S)-1-(4-methoxy-benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline 99.9 acetate or (R)-1-(4-methoxy-benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline 99.9 acetate, after water and aromatic solvent mix, add basic solution, make such as formula the compound described in I free out, and enter aromatic solvent layer.Described basic solution is selected from sodium hydroxide, potassium hydroxide, sodium carbonate etc., preferred sodium hydroxide or potassium hydroxide.Described aromatic solvent is selected from one or more following mixing: toluene, ethylbenzene and dimethylbenzene, preferred toluene.
Again further; (the S)-1-(4-methoxy-benzyl)-1,2,3 using aforesaid method of the present invention to obtain; 4; 5,6,7; 8-octahydro isoquinoline 99.9; Dextromethorphane Hbr is obtained by the method for this area routine, such as but not limited to, by the protection of N-acidylate, Grewe cyclisation, slough N-acidylate blocking group and N-and the reaction such as to methylate.
About (R)-1-(4-methoxy-benzyl)-1,2,3 that the method provided by the invention described above is obtained, 4,5,6,7,8-octahydro isoquinoline 99.9, can use the ordinary method of this area to be converted into racemic 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9, re-uses the production process entering Dextromethorphane Hbr.
The above-mentioned feature that the present invention mentions, or the feature that embodiment is mentioned can arbitrary combination.All features that this case specification sheets discloses can with any composition forms and use, each feature disclosed in specification sheets, anyly can provide identical, alternative characteristics that is impartial or similar object replaces.Therefore apart from special instruction, the feature disclosed is only general example that is impartial or similar features.
Major advantage of the present invention is:
1, visible according to above-described content, the present invention utilizes aromatic solvent extraction of free base in alkalinization, then in aromatic solvent system, directly carries out the fractionation of preferential crystallization method, makes front and back technological process solvent for use consistent.
2, method provided by the invention is easy and simple to handle, and labor capacity significantly reduces, convenient solvent reclaiming, and production cost obviously reduces, and is conducive to suitability for industrialized production.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or number by weight.
Unit in percent weight in volume in the present invention is well-known to those skilled in the art, such as, refer to the weight of solute in the solution of 100 milliliters.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
Embodiment 1
1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 hydrobromate 150.0g(0.443mol), water 400ml and toluene 170ml drops in reaction flask and stirs, and adds sodium hydroxide 19.0g(0.475mol) alkalize and dissociate, stratification, get toluene layer, obtain 230.0g toluene solution.
Embodiment 2
In embodiment 1 gained 230.0g toluene solution in, add 26.6g Glacial acetic acid (0.443mol), stirring at room temperature is after 10 minutes, be cooled to 10 DEG C, add (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed 1.6g(0.005mol), stir 2h, then be cooled to 5 DEG C of crystallization 2h.Filter, obtain 21.3g (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate (yield: 30.3%) [HPLC:(S): (R)=98.9: 1.0].MS(+ve ion electrospray) m/z258 [M
1+ H]
+; M/z59 [M
2-H]
-.
Embodiment 3
In embodiment 1 gained 230.0g toluene solution in, add 26.6g Glacial acetic acid (0.443mol), stirring at room temperature is after 10 minutes, be cooled to 5 DEG C, add (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed 0.7g(0.002mol), stir 2h, then be cooled to 0 DEG C of crystallization 8h.Filter, obtain 21.7g (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate (yield: 31.5%) [HPLC:(S): (R)=0.9: 99.0].MS(+ve ion electrospray) m/z258 [M
1+ H]
+; M/z59 [M
2-H]
-.
Embodiment 4
Mother liquor in embodiment 2 is cooled to 10 DEG C, adds (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed 1.0g(0.003mol), stir 2h, then be cooled to 5 DEG C of crystallization 2h.Filter, obtain 22.8g (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 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-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed 5.0g(0.015mol), stir 2h, then be cooled to 0-5 DEG C of crystallization 2h.Filter, obtain 28.0g (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate (disregard crystal seed amount, yield: 32.7%) [HPLC:(S): (R)=98.8: 1.0].
Embodiment 6
1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 hydrobromate 150.0g(0.443mol), water 400ml and toluene 400ml drops in reaction flask and stirs, and adds sodium hydroxide 19.0g(0.475mol) alkalize and dissociate, stratification, gets toluene layer.Water layer uses toluene (300ml × 2) to extract again, after merging organic phase.Concentrating under reduced pressure organic phase, reclaims about 500ml toluene, obtains 547.0g toluene solution.
Embodiment 7
In embodiment 6 gained 547.0g toluene solution in, add 26.6g Glacial acetic acid (0.443mol), stirring at room temperature is after 10 minutes, be cooled to subzero 10 DEG C, add (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed 7.0g(0.022mol), stir 2h, more subzero 10 DEG C of crystallization 8h.Filter, obtain 26.7g (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate (disregard crystal seed amount, yield: 28.1%) [HPLC:(S): (R)=98.9: 1.0].
The foregoing is only preferred embodiment of the present invention, and be not used to limit substantial technological context of the present invention, substantial technological content of the present invention is broadly defined in the right of application, any technology entities that other people complete or method, if with application right define identical, also or a kind of change of equivalence, be all covered by being regarded as among this right.
Claims (11)
1. structure is such as formula a preparation method for the acetate of the compound shown in I, it is characterized in that, described method comprises step:
(1) by containing structure such as formula the arene solution of the compound shown in III and acetic acid mixing, obtain solution 1;
(2) in solution 1, add (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed, obtains solution 2;
(3) solution 2 is cooled to 0-5 DEG C, crystallization obtains (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate;
2. preparation method as claimed in claim 1, is characterized in that, containing the mol ratio 1: 0.8-1.2 of structure such as formula formula III compound in the arene solution of the compound shown in III and acetic acid in step (1).
3. preparation method as claimed in claim 1, is characterized in that, is by structure such as formula the compound described in IV and water mixing containing structure such as formula the arene solution of the compound shown in III described in step (1), through alkalize free after obtain with aromatic hydrocarbons extraction;
Wherein A represents HBr, HCl or HCOOH
。
4. preparation method as claimed in claim 3, is characterized in that, described aromatic hydrocarbons consumption should be the 1-6 of free base weight doubly, and preferred 1-3 doubly.
5. preparation method as claimed in claim 1, it is characterized in that, step (2) is carried out at subzero 10 to 10 DEG C, carries out at being preferably 0-5 DEG C.
6. preparation method as claimed in claim 1, it is characterized in that, with the total amount of acetate in solution 1 in step (2), the crystal seed added is its 0.05-5%(w/w), be preferably 0.1-5%(w/w).
7. preparation method as claimed in claim 1, it is characterized in that, the crystallization time in step (3) is 1-12 hour.
8. the preparation method as described in any one of claim 1-7, is characterized in that, described in step (1), aromatic hydrocarbons is selected from one or more following mixing: toluene, ethylbenzene and dimethylbenzene.
9. preparation method as claimed in claim 8, it is characterized in that, described aromatic hydrocarbons is toluene.
10. structure is such as formula a preparation method for the compound described in II, it is characterized in that, described method comprises step:
By containing structure such as formula the arene solution of the compound shown in III and acetic acid mixing, obtain solution 1;
(ii) in solution 1, add (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed, obtains solution 2;
(iii) solution 2 is cooled to 0-5 DEG C, crystallization obtains (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate;
(iv) by (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate is free through alkalizing, and obtains (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9;
Or
By free through alkalizing for (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate, obtain (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9;
(v) by (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 by the protection of N-acidylate, Grewe cyclisation, slough N-acidylate blocking group and N-and the Reactive Synthesis structure such as to methylate such as formula the Dextromethorphane Hbr shown in II;
Or by (R)-1-(4-methoxy-benzyl)-1,2,3; 4,5,6; 7,8-octahydro isoquinoline 99.9 is converted into (S)-1-(4-methoxy-benzyl)-1,2 by racemization; 3,4,5; 6; 7,8-octahydro isoquinoline 99.9, then by the protection of N-acidylate, Grewe cyclisation, slough N-acidylate blocking group and N-and the Reactive Synthesis such as to methylate such as formula the Dextromethorphane Hbr shown in II.
11. 1 kinds of structures, such as formula the preparation method of the compound described in V, is characterized in that, described method comprises step:
By containing structure such as formula the arene solution of the compound shown in III and acetic acid mixing, obtain solution 1;
(ii) in solution 1, add (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate crystal seed, obtains solution 2;
(iii) solution 2 is cooled to 0-5 DEG C, crystallization obtains (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate or (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate;
(iv) by (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 acetate is free through alkalizing, and obtains (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9;
By (R)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9 by the protection of N-acidylate, Grewe cyclisation, slough N-acidylate blocking group and N-and the Reactive Synthesis such as to methylate such as formula the levomethorphan shown in V;
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| CN106632038A (en) * | 2016-12-01 | 2017-05-10 | 暨明医药科技（苏州）有限公司 | Resolution method of octahydro isoquinoline |
| CN110007028A (en) * | 2019-04-26 | 2019-07-12 | 上海葆隆生物科技有限公司 | (S) detection method of -1- (4- methoxybenzyl) -1,2,3,4,5,6,7,8- octahydro isoquinolin isomers |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106632038A (en) * | 2016-12-01 | 2017-05-10 | 暨明医药科技（苏州）有限公司 | Resolution method of octahydro isoquinoline |
| 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 |
| CN110007028A (en) * | 2019-04-26 | 2019-07-12 | 上海葆隆生物科技有限公司 | (S) detection method of -1- (4- methoxybenzyl) -1,2,3,4,5,6,7,8- octahydro isoquinolin isomers |
| 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 |
| 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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