CN1634892A - Method for resolution of isoquinolines - Google Patents
Method for resolution of isoquinolines Download PDFInfo
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- CN1634892A CN1634892A CN 200410091127 CN200410091127A CN1634892A CN 1634892 A CN1634892 A CN 1634892A CN 200410091127 CN200410091127 CN 200410091127 CN 200410091127 A CN200410091127 A CN 200410091127A CN 1634892 A CN1634892 A CN 1634892A
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- ethanoyl
- benzyl
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Abstract
The invention relates to a method for resolution of isoquinolines compound, which belongs to the field of the medicine preparation technology. The preparation process comprises: isoquinolines compound and said resolving agent in the mol ratio between 1:1 and 1:1.5 are added into 10-30 times volume solvent to form two diastereoisomer with different dissolvability, said solution is cooled to -5DEG C~-20DEG C, and stirred and allowed to stand for 24 hours to 5 days, and R-diastereoisomer with lower dissolubility and high optical purity is liberated from said solution directly. The operation step is reduced and resolution product with high optical purity is prepared by the method.
Description
Technical field
The invention belongs to field of medicine preparing technology, particularly from compound, split out the method for splitting of the high individual isomer of optical purity.
Background technology
Chiral drug is that the single enantiomer medicine more and more comes into one's own in recent years, correspondingly how to obtain the high individual isomer of optical purity and also receives much concern.The method of the most extensive employing at present is still the fractionation of racemic modification, particularly by forming the salt of diastereomer, utilizes the difference of its physical properties (as solvability, molten boiling point etc.) to split then.The difficult problem that this method for splitting faces remains the selection of resolving agent.Suitable resolving agent should be able to form stable crystalline salt with raceme, and the physical properties difference of two diastereomers should be enough big, so just is convenient to separate, and guarantees the optical purity of product.
Patent US6015903 has reported and can utilize L-2 that 4-dichlorophenoxy propionic acid splits out the synthetic R-tetrahydropapaverine that needs of medicine as resolving agent, but does not have concrete experimental data; And 2,4 dichloro benzene oxygen base propionic acid is a kind of agricultural chemicals, limited its application aspect the medicine fractionation.
Patent US5453510 has reported with N-ethanoyl-L-leucine and has made resolving agent that its method for splitting is: at first isolate the S-tetrahydropapaverine from solution, reclaim needed R-tetrahydropapaverine then from mother liquor.This split process is not only loaded down with trivial details, and is difficult to obtain to meet the synthetic single enantiomer that requires of medicine.
Summary of the invention
The objective of the invention is to propose a kind of method of resolution of isoquinolines, adopt N-acyl group-D-amino acid to make resolving agent can directly be separated out high-optical-purity from system R-type diastereomer for overcoming the weak point of prior art.Split process of the present invention is simple, can be widely used in medicine and split the field.
The method that the present invention adopts is: two kinds of diastereomers that isoquinoline compound and N-acyl group-D-amino acid resolving agent joined 10 to 30 times of volume of solvent dissolving formation different solubilities with 1: 1 to 1: 1.5 mol ratio, this solution is reduced temperature to-5 ℃～-20 ℃, stir or left standstill 24 hours to 5 days, directly from this solution, separate out the high R-type diastereomer of the less optical purity of solubleness; The chemical formula of above-mentioned isoquinoline compound is:
Substituent A, B, D, E, F have following implication in the formula:
A:H, C1-6 alkyl, C1-6 alkoxyl group, C1-6 acyl group, phenyl, benzyl, halogen, nitro
B:H, C1-6 alkyl, C1-6 alkoxyl group, C1-6 acyl group, halogen, nitro, phenyl, benzyl
D:H, C1-6 alkyl, C1-6 alkoxyl group, C1-6 acyl group, halogen, nitro, phenyl, benzyl
E:H, hydroxyl, C1-3 alkyl, C1-6 alkoxyl group, formyl radical, ethanoyl, benzoyl
F:H, C1-3 alkyl, C1-6 alkoxyl group, formyl radical, ethanoyl
Above-mentioned N-acyl group-D-amino acid resolving agent, its chemical formula is:
Wherein R1 nail base, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, phenyl, phenmethyl, R2 nail acyl group, ethanoyl, propionyl, benzoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), fluorenylmethyloxycarbonyl.
Above-mentioned R-type diastereomer is through transforming into R-isoquinoline compound hydrochloride, and it is synthetic to can be used for medicine.
Characteristics of the present invention and technique effect: the present invention has simplified operation steps, and the resolved product optical purity height that obtains can satisfy the synthetic needs of chiral drug.
Embodiment
Embodiment 1
Get 17.0g tetrahydropapaverine racemic modification, add 200ml methyl alcohol, stirring and dissolving.Add 10.9g N-ethanoyl-D-phenylalanine again, stir on the limit, and it is freezing that the limit changes refrigerator-freezer over to.Filter ， Lv Bing methanol wash, drying obtains R-tetrahydropapaverine-N-ethanoyl-D-phenylalanine salt 12.9g.
Products obtained therefrom is dissolved in 60ml hot water, and the ammonification scaleization with the tetrahydropapaverine that the toluene extracting dissociates and, is told toluene, washes clean residual ammonia with water, and the ethanolic soln of dropping hydrogenchloride in the toluene is to PH2.Filter out throw out, use washing with alcohol, dry, obtain the R-tetrahydropapaverine hydrochloride 8.0g of optical purity 98.1%, yield 83.5%.
Embodiment 2
In 100ml ethanol, add 8.0g 6; 7-dimethoxy-1-(3; the 4-dimethoxy-benzyl)-the 4-methyl isophthalic acid; 2; 3; 4-tetrahydrochysene isoquinoline racemate and 5.3g N-benzoyl-D-leucine are placed under-10 ℃ of temperature after the heated and stirred dissolving and stirred 24 hours, use cold washing with alcohol behind the solid filtering of separating out; recrystallization in ethanol; vacuum-drying obtains R-6,7-dimethoxy-1-(3; the 4-dimethoxy-benzyl)-the 4-methyl isophthalic acid; 2,3,4-tetrahydroisoquinoline-N benzoyl-D-leucine salt 6.4g.The salt that obtains is converted into R-6,7-dimethoxy-1-(3, the 4-dimethoxy-benzyl)-4-methyl isophthalic acid, 2,3,4-four hydrogen isoquinoline hydrochloric acid salt.Obtain optical purity and be 98.5% R-6,7-dimethoxy-1-(3, the 4-dimethoxy-benzyl)-4-methyl isophthalic acid, 2,3,4-four hydrogen isoquinoline hydrochloric acid salt 3.7g.Yield 82.7%.
Embodiment 3
In the single neck bottle of 500ml, add 300ml Virahol, 6.0g tetrahydropapaverine and 3.1g N-ethanoyl-D-leucine successively, single neck bottle is transferred under-10 ℃ of temperature stirred 24 hours, leach precipitation, use ethyl alcohol recrystallization, vacuum-drying.Obtain R-tetrahydropapaverine-N-ethanoyl-D-leucine salt 2.9g.The salt that obtains is converted into R-tetrahydropapaverine hydrochloride.Obtain optical purity and be 99.0% R-tetrahydropapaverine hydrochloride 2.4g.Yield 71.6%.
Embodiment 4
With 20.0g6,7,8-trimethoxy-1-(3,4,5-trimethoxy benzyl)-1,2,3,4-tetrahydroisoquinoline, 7.9g N-ethanoyl-D-leucine add in the 350ml acetonitrile successively, after the stirring and dissolving, change over to continue under-15 ℃ of temperature to stir 24 hours.Sedimentation and filtration is come out, use ethyl alcohol recrystallization.The product that obtains is converted into R-6,7,8-trimethoxy-1-(3,4,5-trimethoxy benzyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt.Obtain optical purity and be 96.8% R-6,7,8-trimethoxy-1-(3,4,5-trimethoxy benzyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt 8.4g, yield 74.6%.
Embodiment 5
With 20.0g6,7,8-trimethoxy-1-(4-methoxybenzyl)-1,2,3, the 4-tetrahydroisoquinoline, 10.0g N-tertbutyloxycarbonyl-D-L-Ala is dissolved in 300ml methyl alcohol, changes low temperature over to and stirs a few days.The filter thing that filtration obtains is converted into R-6, and 7,8-trimethoxy-1-(4-methoxybenzyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt.Obtain optical purity and be 96.4% R-6,7,8-trimethoxy-1-(4-methoxybenzyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt 6.9g, yield 60.1%.
Embodiment 6
Add 18.0g 6 successively, 7-dimethoxy-1-(4-luorobenzyl)-1,2,3,4-tetrahydroisoquinoline, 10.0g N-ethanoyl-D-phenylalanine and 300ml ethanol, stirring and dissolving in the bottle at the bottom of the garden of 500ml.Change under the low temperature and stir a few days, filter, be converted into hydrochloride.Obtain optical purity greater than 95% R-6,7-dimethoxy-1-(4-luorobenzyl)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt 7.0g, yield 58.4%.
Claims (4)
1. the method for a resolution of isoquinolines, it is characterized in that, acyl group-D-amino acid is resolving agent to adopt N-, isoquinoline compound and described resolving agent are joined two kinds of diastereomers that 10 to 30 times of volume of solvent dissolvings form different solubilities with 1: 1 to 1: 1.5 mol ratio, this solution is reduced temperature to-5 ℃～-20 ℃, stir or left standstill 24 hours to 5 days, directly from this solution, separate out the high R-type diastereomer of the less optical purity of solubleness; The chemical formula of this isoquinoline compound is:
Substituent A, B, D, E, F have following implication in the formula:
A:H, C1-6 alkyl, C1-6 alkoxyl group, C1-6 acyl group, phenyl, benzyl, halogen, nitro
B:H, C1-6 alkyl, C1-6 alkoxyl group, C1-6 acyl group, halogen, nitro, phenyl, benzyl
D:H, C1-6 alkyl, C1-6 alkoxyl group, C1-6 acyl group, halogen, nitro, phenyl, benzyl
E:H, hydroxyl, C1-3 alkyl, C1-6 alkoxyl group, formyl radical, ethanoyl, benzoyl
F:H, C1-3 alkyl, C1-6 alkoxyl group, formyl radical, ethanoyl
Acyl group-D-amino acid is resolving agent to adopt N-, and its chemical formula is:
Wherein R1 nail base, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, phenyl, phenmethyl, R2 nail acyl group, ethanoyl, propionyl, benzoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), fluorenylmethyloxycarbonyl.
2. the method for claim 1 is characterized in that, described isoquinoline compound comprises tetrahydropapaverine, 6,7-dimethoxy-1-(3, the 4-dimethoxy-benzyl)-and the 4-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline, 6,7,8-trimethoxy-1-(3,4,5-trimethoxy benzyl)-1,2,3,4-tetrahydroisoquinoline, 6,7,8-trimethoxy-1-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline, 6,7-dimethoxy-1-(4-luorobenzyl)-1,2,3, the 4-tetrahydroisoquinoline.
3. the method for claim 1 is characterized in that, described resolving agent comprises N-benzoyl-D-leucine, N-ethanoyl-D-phenylalanine, N-ethanoyl-D-leucine, N-tertbutyloxycarbonyl-D-L-Ala.
4. as claim 1,2 or 3 described methods, wherein employed solvent is chosen any among methyl alcohol, ethanol, Virahol, second eyeball, acetone, toluene, dimethylbenzene, ether, dioxane, tetrahydrofuran (THF) or the ethyl acetate.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410091127 CN1634892A (en) | 2004-11-19 | 2004-11-19 | Method for resolution of isoquinolines |
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| CN 200410091127 CN1634892A (en) | 2004-11-19 | 2004-11-19 | Method for resolution of isoquinolines |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007091753A1 (en) * | 2006-02-06 | 2007-08-16 | Chong Kun Dang Pharmaceutical Corp. | Method for resolving enantiomers from racemic mixture having chiral carbon in alpha position of nitrogen |
| CN101037411B (en) * | 2007-03-13 | 2011-07-06 | 南京大学 | Splitting method of tetrahydroisoquinoline racemes |
| CN107056700A (en) * | 2017-04-18 | 2017-08-18 | 哈尔滨医科大学 | A kind of Resolution method of tetrahydroisoquinolicompounds compounds racemic modification |
-
2004
- 2004-11-19 CN CN 200410091127 patent/CN1634892A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007091753A1 (en) * | 2006-02-06 | 2007-08-16 | Chong Kun Dang Pharmaceutical Corp. | Method for resolving enantiomers from racemic mixture having chiral carbon in alpha position of nitrogen |
| CN101037411B (en) * | 2007-03-13 | 2011-07-06 | 南京大学 | Splitting method of tetrahydroisoquinoline racemes |
| CN107056700A (en) * | 2017-04-18 | 2017-08-18 | 哈尔滨医科大学 | A kind of Resolution method of tetrahydroisoquinolicompounds compounds racemic modification |
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