CN107056700A - A kind of Resolution method of tetrahydroisoquinolicompounds compounds racemic modification - Google Patents
A kind of Resolution method of tetrahydroisoquinolicompounds compounds racemic modification Download PDFInfo
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- CN107056700A CN107056700A CN201710253474.0A CN201710253474A CN107056700A CN 107056700 A CN107056700 A CN 107056700A CN 201710253474 A CN201710253474 A CN 201710253474A CN 107056700 A CN107056700 A CN 107056700A
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- resolution
- racemic modification
- resolution method
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- 0 Cc(cc1)ccc1C(OC(*)[C@@](C(O)=O)OC(c1ccc(C)cc1)=O)=O Chemical compound Cc(cc1)ccc1C(OC(*)[C@@](C(O)=O)OC(c1ccc(C)cc1)=O)=O 0.000 description 1
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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- 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
Abstract
The invention discloses a kind of Resolution method of tetrahydroisoquinolicompounds compounds racemic modification, step is as follows：The hydrochloride of tetrahydroisoquinolicompounds compounds is dissolved in water, alkalization in the basic conditions is racemic modification；Racemic modification is dissolved in polar solvent; in a heated condition; salt is reacted into single Resolution agent N acyl group D amino acid or D diphenyl acyl group tartaric acids; or first with after resolving agent N acyl group D amino acid reaction certain times, adding another resolving agent N acyl groups D amino acid reaction into salt；Reaction is crystallized and last handling process after terminating through slow cooling, you can directly obtain the salt of the high R configuration tetrahydroisoquinolicompounds compounds of optical purity.The present invention is using half amount mixing or partly measures single resolving agent, saves resolving agent consumption, it is not necessary to recrystallize, and reasonable in design, preparation method is easy, and practical, the total recovery of R anomeric products reaches as high as 83.25%, and purity reaches as high as more than 97%.
Description
Technical field
The present invention relates to a kind of Resolution method of tetrahydroisoquinolicompounds compounds racemic modification, belong to medical science neck
Domain.
Background technology
R- tetrahydroisoquinolicompounds compounds are the important source materials for synthesizing other derivatives, can with very high pharmacological activity
Suppress dopamine biosynthesis, for treating cerebrovascular sclerosis, surgical operation anesthesia and angiocardiopathy.Wherein R- tetrahydrochysenes
Papaverine is important intermediate of the anesthetic benzene sulphur along atracurium, is widely used.
Patent US5453510, CN10147529A are that resolving agent is split outside tetrahydroisoquinoline using N- acetyl-L-Leu
Raceme, all needs repeated recrystallize to obtain the higher product of purity, expends the time, and complex operation is unfavorable for industrial production.Patent
CN200710020587 attempts to carry out double resolution using N- acetyl-L-Leu and N- acetyl-two kinds of D-Leu resolving agent,
But complex operation, lose larger, expend raw material.Patent CN200410091127 uses N- acyl group-D- amino acid as fractionation
Agent and tetrahydroisoquinoline reaction generation diastereoisomer, but it uses full dose Split Method, and resolving agent consumption is more, is unfavorable for work
The cost calculation of industry production.Patent US6015903 is resolving agent using half amount (-) 2- (2,4- dichlorophenoxy) propionic acid, is obtained
The higher R configuration tetrahydroisoquinolines of purity, but resolving agent (-) 2- (2,4- dichlorophenoxy) propionic acid is a kind of agricultural chemicals, harm
It is larger, it is not suitable for substantial amounts of industrial production.
It is an object of the invention to provide a kind of method for splitting of tetrahydrochysene isoquinoline racemate, using Resolution method, tear open
It is divided to agent for single or in ratio two kinds of N- acyl group-D- amino acid, or single D- diphenyl acyl group tartaric acid, purity can be obtained
Higher R configuration tetrahydroisoquinolicompounds compounds, and need not recrystallizing, effectively save making for fractionation time and resolving agent
With cost is low, simple to operate, it is easy to implement, it is adaptable to industrial production.
The content of the invention
It is an object of the invention to provide a kind of method for splitting of tetrahydroisoquinolicompounds compounds racemic modification, torn open using half amount
Point method, resolving agent is single or in ratio two kinds of N- acyl group-D- amino acid, or single D- diphenyl acyl group tartaric acid,
The higher R configuration tetrahydroisoquinolicompounds compounds of purity can be obtained, and need not be recrystallized, effectively save the fractionation time and
The use of resolving agent, cost is low, simple to operate, it is easy to implement, it is adaptable to industrial production.
For up to above-mentioned purpose, the invention provides a kind of Resolution side of tetrahydroisoquinolicompounds compounds racemic modification
Method, is comprised the steps of：
(1) pre-treatment：The hydrochloride of tetrahydroisoquinolicompounds compounds shown in formula I is soluble in water, in alkaline environment
It is lower to be alkalized as the racemic modification of tetrahydroisoquinolicompounds compounds, extraction, drying；
Wherein, R1~R4It is respectively and independently selected from-H ,-CH3、-C2-4Alkyl or methoxyl group；
(2) resolution reaction：The racemic modification of tetrahydroisoquinolicompounds compounds obtained by step (1) is dissolved in polar solvent,
In a heated condition, salt is reacted into the single Resolution agent as shown in Formula II or formula III, or first with a kind of such as Formula II
After shown Resolution agent reaction certain time, add another Resolution agent as shown in Formula II and reacted；
Wherein, R5Selected from formoxyl, acetyl group, propiono, bytyry, tertbutyloxycarbonyl or benzyloxycarbonyl group, R6Selected from-H ,-
C1-4Alkyl or benzyl, R7And R8It is respectively and independently selected from toluyl groups, toluene acetyl group, Methoxyphenyl acetyl base；
(3) crystallize：Resolution reaction terminates rear slow cooling crystallization；
(4) post-process：After solid is separated out, filter, wash, drying obtains the high single R configurations Tetrahydroisoquinoli- of optical purity
The salt of quinoline class compound.
Experimental principle is as follows：
It is preferred that, alkaline environment described in step (1) is ammoniacal liquor, sodium hydroxide solution, sodium carbonate liquor or sodium acid carbonate
Solution environmental；More preferably ammoniacal liquor.
It is preferred that, polar solvent described in step (2) is methanol, ethanol, isopropanol, acetonitrile or its mixing；More preferably
Acetonitrile.
It is preferred that, the ratio of polar solvent and the racemic modification described in step (2) is 10~30 (mL)：1(g)；More
It is preferred that, it is 10 (mL)：1(g).
It is preferred that, the temperature of heating condition described in step (2) is 50~80 DEG C；More preferably 70 DEG C.
It is preferred that, resolving agent described in step (2) is single or in ratio two kinds of N- acyl group-D- amino acid, Huo Zhedan
One D- diphenyl acyl group tartaric acids；More preferably mol ratio is 9：1 N- acetyl-D-Leu and N- acetyl-D-phenylalanine,
Or single D- bis- is to toluoyl tartaric acid；D- bis- is to the structural formula of toluoyl tartaric acid as shown in formula IV：
It is preferred that, the mol ratio of the racemic modification of the total amount of resolving agent and tetrahydroisoquinoline described in step (2) is 0.5:
1。
It is preferred that, the total reaction time of resolution reaction described in step (2) is 45~90min.
It is preferred that, the temperature crystallized described in step (3) is -20~25 DEG C；More preferably 4 DEG C.
It is preferred that, the time crystallized described in step (3) is 12~72h；More preferably 24h.
It is preferred that, the tetrahydroisoquinolicompounds compounds are tetrahydropapaverine, and its structural formula is shown as a formula V：
Relative to prior art, beneficial effects of the present invention are：
It is contemplated that developing a kind of Resolution method of tetrahydrochysene isoquinoline racemate.Achievement in research can effectively drop
The synthesis cost of low Cisatracurium besylate, and produce extensive social benefit, and it is contemplated that its economic benefit is huge,
Have a extensive future.
The present invention is with two kinds of N- acyl group-D- amino acid single or in ratio, or single D- diphenyl acyl group tartaric acid
For resolving agent, the racemic modification of tetrahydroisoquinolicompounds compounds is split using Resolution method.Do not recrystallized, obtain R-
Tetrahydroisoquinolicompounds compounds salt total recovery reaches as high as 83.25%, and purity reaches as high as more than 97%.The method work of the present invention
Skill is reasonable in design, practical, shortens the reaction time, reduces resolving agent consumption, has saved reaction cost, it is adaptable to a large amount of
Industrial production.
Brief description of the drawings
Fig. 1 is the chromatogram of the products therefrom of embodiment 1；
Fig. 2 is the chromatogram of the products therefrom of embodiment 2；
Fig. 3 is the chromatogram of the products therefrom of embodiment 3；
Fig. 4 is the chromatogram of the products therefrom of embodiment 4；
Fig. 5 is the chromatogram of the products therefrom of embodiment 5；
Fig. 6 is the chromatogram of the products therefrom of embodiment 6.
Specific implementation method
The invention will now be further described with reference to specific embodiments, advantages of the present invention and feature will be with description and
It is apparent.But these embodiments are only exemplary, do not constitute any limitation to the scope of the present invention.People in the art
Member to the details and form of technical solution of the present invention it should be understood that can enter without departing from the spirit and scope of the invention
Row modifications or substitutions, but these are changed and replacement is each fallen within protection scope of the present invention.
Embodiment 1
20g tetrahydropapaverine hydrochlorides are dissolved in 400mL distilled water, stirring adds ammoniacal liquor and dissociated, extremely to being completely dissolved
Separated out without white oil thing, add 400mL toluene and be sufficiently stirred for, to water layer without tetrahydropapaverine, use anhydrous sodium sulfate drying first
Benzene layer, is spin-dried for, and obtains tetrahydropapaverine racemic modification 17.3g.
Tetrahydropapaverine racemic modification is dissolved in 173mL acetonitriles, 70 DEG C are heated to, be slowly added to resolving agent N- acetyl-
D-Leu 3.93g, stirring reaction 20min, add resolving agent N- acetyl-D-phenylalanine 0.522g, stirring reaction 35min,
Room temperature is slowly dropped to, is placed 24 hours after 4 DEG C of refrigerators, waits to be crystallized.
After solid is separated out, filtering adds hydrochloric acid and product is changed into hydrochloride, dries, obtain R- tetrahydropapaverine hydrochloric acid
Salt 8.325g.Total recovery 83.25%, purity 97.6%.The chromatogram of product is as shown in Figure 1.
Embodiment 2
30g tetrahydropapaverine hydrochlorides are dissolved in 600mL distilled water, stirring adds ammoniacal liquor and dissociated, extremely to being completely dissolved
Separated out without white oil thing, add 600mL toluene and be sufficiently stirred for, to water layer without tetrahydropapaverine, use anhydrous sodium sulfate drying first
Benzene layer, is spin-dried for, and obtains tetrahydropapaverine racemic modification 26.1g.
Tetrahydropapaverine racemic modification is dissolved in 261mL acetonitriles, 70 DEG C are heated to, resolving agent D- bis- is slowly added to first
Benzoyl tartaric acids 12.56g, reacts 45min, is slowly dropped to room temperature, is placed 24 hours after 4 DEG C of refrigerators, waits to be crystallized.
After solid is separated out, filter, drying obtains the salt of R- tetrahydropapaverines and resolving agent.Obtained salt is converted into R-
Tetrahydropapaverine hydrochloride, after drying, weighs, 12.3g, total recovery 82%, purity 97.8%.The chromatogram of product such as Fig. 2 institutes
Show.
Embodiment 3
1.5g tetrahydropapaverine hydrochlorides are dissolved in 30mL distilled water, stirring adds ammoniacal liquor and dissociated, extremely to being completely dissolved
Separated out without white oil thing, add 30mL toluene and be sufficiently stirred for, to water layer without tetrahydropapaverine, use anhydrous sodium sulfate drying toluene
Layer, is spin-dried for, obtains tetrahydropapaverine racemic modification 1.32g.
Tetrahydropapaverine racemic modification is dissolved in 13.2mL acetonitriles, 70 DEG C are heated to, be slowly added to resolving agent N- acetyl-
D-phenylalanine 0.379g, reacts 45min, is slowly dropped to room temperature, is placed 24 hours after 4 DEG C of refrigerators, waits to be crystallized.
After solid is separated out, filter, drying obtains R- tetrahydropapaverines N- acetyl-D-phenylalanine salt, and obtained salt is turned
R- tetrahydropapaverine hydrochlorides are turned to, add up to 0.60g.Total recovery 80.1%, purity 91.9%.The chromatogram of product such as Fig. 3 institutes
Show.
Embodiment 4
2g tetrahydropapaverine hydrochlorides are dissolved in 40mL distilled water, stirring adds ammoniacal liquor and dissociated, to nothing to being completely dissolved
White oil thing is separated out, and is added 30mL toluene and is sufficiently stirred for, to water layer without tetrahydropapaverine, uses anhydrous sodium sulfate drying toluene
Layer, is spin-dried for, obtains tetrahydropapaverine racemic modification 1.75g.
Tetrahydropapaverine racemic modification is dissolved in 17.5mL acetonitriles, 70 DEG C are heated to, be slowly added to resolving agent N- acetyl-
D-Leu 0.44g, reacts 45min, is slowly dropped to room temperature, is placed 24 hours after 4 DEG C of refrigerators, waits to be crystallized.
After solid is separated out, filter, drying obtains the salt of R- tetrahydropapaverines and resolving agent, obtained salt is converted into R-
Tetrahydropapaverine hydrochloride, 0.7034g.Total recovery 70.34%, purity 95.7%.The chromatogram of product is as shown in Figure 4.
Embodiment 5
2g tetrahydropapaverine hydrochlorides are dissolved in 40mL distilled water, stirring adds ammoniacal liquor and dissociated, to nothing to being completely dissolved
White oil thing is separated out, and is added 30mL toluene and is sufficiently stirred for, to water layer without tetrahydropapaverine, uses anhydrous sodium sulfate drying toluene
Layer, is spin-dried for, obtains tetrahydropapaverine racemic modification 1.75g.
Tetrahydropapaverine racemic modification is dissolved in 35mL acetonitriles, 70 DEG C are heated to, resolving agent N- formyls-D- is slowly added to
Phenylalanine 0.49g, reacts 45min, is slowly dropped to room temperature, is placed 24 hours after -4 DEG C of refrigerators, waits to be crystallized.
After solid is separated out, filter, drying obtains the salt of R- tetrahydropapaverines and resolving agent, obtained salt is converted into R-
Tetrahydropapaverine hydrochloride, 0.3267g.Total recovery 65.34%, purity 91.7%.The chromatogram of product is as shown in Figure 5.
Embodiment 6
By 1.5g 6,7- dimethoxy -1- benzyls -1,2,3,4- four hydrogen isoquinoline hydrochloric acid salts are dissolved in 30mL distilled water,
Stirring adds ammoniacal liquor and dissociated, separated out to without white oil thing to being completely dissolved, and adds 30mL toluene and is sufficiently stirred for, to water layer without
6,7- dimethoxy -1- benzyls -1,2,3,4- tetrahydroisoquinoline alkali are used anhydrous sodium sulfate drying toluene layer, are spin-dried for, obtain 6,7- bis-
Methoxyl group -1- benzyl -1,2,3,4- tetrahydrochysene isoquinoline racemates 1.32g.
By 6,7- dimethoxy -1- benzyls -1,2,3,4- tetrahydrochysene isoquinoline racemates are dissolved in 13.2mL acetonitriles, heating
To 70 DEG C, resolving agent N- acetyl-D-Leu 0.363g, stirring reaction 20min are slowly added to, resolving agent N- acetyl-D- is added
Phenylalanine 0.0482g, stirring reaction 35min, is slowly dropped to room temperature, is placed 24 hours after -4 DEG C of refrigerators, waits to be crystallized.
After solid is separated out, filter, drying, conversion obtains R-6,7- dimethoxy -1- benzyls -1,2,3,4- tetrahydroisoquinolines
Hydrochloride 0.59g.Total recovery 78.7%, purity 92.2%.The chromatogram of product is as shown in Figure 6.
Claims (10)
1. a kind of Resolution method of tetrahydroisoquinolicompounds compounds racemic modification, it is characterised in that comprise the steps of：
(1) pre-treatment：The hydrochloride of tetrahydroisoquinolicompounds compounds shown in formula I is soluble in water, will under alkaline environment
Its alkalization is the racemic modification of tetrahydroisoquinolicompounds compounds, is extracted, and is dried；
Wherein, R1~R4It is respectively and independently selected from-H ,-CH3、-C2-4Alkyl or methoxyl group；
(2) resolution reaction：The racemic modification of tetrahydroisoquinolicompounds compounds obtained by step (1) is dissolved in polar solvent, added
Under heat condition, salt is reacted into the single Resolution agent as shown in Formula II or formula III, or first with one kind as shown in Formula II
Resolution agent reaction certain time after, add another Resolution agent as shown in Formula II and reacted；
Wherein, R5Selected from formoxyl, acetyl group, propiono, bytyry, tertbutyloxycarbonyl or benzyloxycarbonyl group, R6Selected from-H ,-C1-4
Alkyl or benzyl, R7And R8It is respectively and independently selected from toluyl groups, toluene acetyl group, Methoxyphenyl acetyl base；
(3) crystallize：Resolution reaction terminates rear slow cooling crystallization；
(4) post-process：After solid is separated out, filter, wash, drying obtains the tetrahydroisoquinoline of the high single R configurations of optical purity
The salt of class compound.
2. Resolution method according to claim 1, it is characterised in that alkaline environment described in step (1) be ammoniacal liquor,
Sodium hydroxide solution, sodium carbonate liquor or sodium bicarbonate solution environment；Preferably ammoniacal liquor.
3. Resolution method according to claim 1, it is characterised in that polar solvent described in step (2) be methanol,
Ethanol, isopropanol, acetonitrile or its mixing；Preferably acetonitrile.
4. Resolution method according to claim 1, it is characterised in that polar solvent described in step (2) with it is described
The ratio of racemic modification is 10~30 (mL)：1(g)；Preferably 10 (mL)：1(g).
5. Resolution method according to claim 1, it is characterised in that the temperature of heating condition described in step (2)
For 50~80 DEG C；Preferably 70 DEG C.
6. Resolution method according to claim 1, it is characterised in that resolving agent described in step (2) to be single or
In two kinds of N- acyl group-D- amino acid of ratio, or single D- diphenyl acyl group tartaric acid；Preferably mol ratio is 9：1 N-
Acetyl-D-Leu and N- acetyl-D-phenylalanine, or single D- bis- is to toluoyl tartaric acid；D- bis- is to toluene first
The structural formula of acyl group tartaric acid is as shown in formula IV：
7. Resolution method according to claim 1, it is characterised in that the total amount of resolving agent described in step (2) with
The mol ratio of the racemic modification of tetrahydroisoquinolicompounds compounds is 0.5:1.
8. Resolution method according to claim 1, it is characterised in that resolution reaction described in step (2) it is total anti-
It is 45~90min between seasonable.
9. Resolution method according to claim 1, it is characterised in that the temperature crystallized described in step (3) is -20
~25 DEG C, preferably 4 DEG C；The time of the crystallization is 12~72h；Preferably 24h.
10. Resolution method according to claim 1, it is characterised in that the tetrahydroisoquinolicompounds compounds are four
Hydrogen papaverine, its structural formula is shown as a formula V：
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111440121A (en) * | 2020-03-26 | 2020-07-24 | 浙江金华康恩贝生物制药有限公司 | Method for splitting two key intermediates in total synthesis process of optical pure tetrandrine |
| US11345941B2 (en) | 2019-09-20 | 2022-05-31 | Fudan University | Method for preparing (S)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound |
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| WO1992000965A1 (en) * | 1990-07-13 | 1992-01-23 | The Wellcome Foundation Limited | Neuromuscular blocking agents |
| CN1634892A (en) * | 2004-11-19 | 2005-07-06 | 徐州恩华药业集团有限责任公司 | Method for resolution of isoquinolines |
| CN1680330A (en) * | 2005-01-25 | 2005-10-12 | 华东理工大学 | Preparation of (R)-(-)-apomorphine |
| CN101037411A (en) * | 2007-03-13 | 2007-09-19 | 南京大学 | Splitting method of tetrahydroisoquinoline racemes |
| CN106083717A (en) * | 2016-06-07 | 2016-11-09 | 浙江永太药业有限公司 | The racemization recovery method of by-product in the fractionation mother solution of a kind of dextromethorphan hydrobromide intermediate |
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2017
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992000965A1 (en) * | 1990-07-13 | 1992-01-23 | The Wellcome Foundation Limited | Neuromuscular blocking agents |
| CN1634892A (en) * | 2004-11-19 | 2005-07-06 | 徐州恩华药业集团有限责任公司 | Method for resolution of isoquinolines |
| CN1680330A (en) * | 2005-01-25 | 2005-10-12 | 华东理工大学 | Preparation of (R)-(-)-apomorphine |
| CN101037411A (en) * | 2007-03-13 | 2007-09-19 | 南京大学 | Splitting method of tetrahydroisoquinoline racemes |
| CN106083717A (en) * | 2016-06-07 | 2016-11-09 | 浙江永太药业有限公司 | The racemization recovery method of by-product in the fractionation mother solution of a kind of dextromethorphan hydrobromide intermediate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11345941B2 (en) | 2019-09-20 | 2022-05-31 | Fudan University | Method for preparing (S)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound |
| CN111440121A (en) * | 2020-03-26 | 2020-07-24 | 浙江金华康恩贝生物制药有限公司 | Method for splitting two key intermediates in total synthesis process of optical pure tetrandrine |
| CN111440121B (en) * | 2020-03-26 | 2023-03-24 | 浙江金华康恩贝生物制药有限公司 | Method for splitting two key intermediates in total synthesis process of optical pure tetrandrine |
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Application publication date: 20170818 |