CN101037411B - Splitting method of tetrahydroisoquinoline racemes - Google Patents
Splitting method of tetrahydroisoquinoline racemes Download PDFInfo
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- CN101037411B CN101037411B CN2007100205872A CN200710020587A CN101037411B CN 101037411 B CN101037411 B CN 101037411B CN 2007100205872 A CN2007100205872 A CN 2007100205872A CN 200710020587 A CN200710020587 A CN 200710020587A CN 101037411 B CN101037411 B CN 101037411B
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- 238000000034 method Methods 0.000 title claims abstract description 16
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 title 2
- -1 B:H Chemical group 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 10
- WXNXCEHXYPACJF-ZETCQYMHSA-M N-acetyl-L-leucinate Chemical compound CC(C)C[C@@H](C([O-])=O)NC(C)=O WXNXCEHXYPACJF-ZETCQYMHSA-M 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- WXNXCEHXYPACJF-SSDOTTSWSA-N N-acetyl-D-leucine Chemical compound CC(C)C[C@H](C(O)=O)NC(C)=O WXNXCEHXYPACJF-SSDOTTSWSA-N 0.000 claims description 5
- 239000012452 mother liquor Substances 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 230000004048 modification Effects 0.000 claims description 4
- 238000012986 modification Methods 0.000 claims description 4
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- MZHCENGPTKEIGP-RXMQYKEDSA-N (R)-dichlorprop Chemical compound OC(=O)[C@@H](C)OC1=CC=C(Cl)C=C1Cl MZHCENGPTKEIGP-RXMQYKEDSA-N 0.000 claims description 3
- YXWQTVWJNHKSCC-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCN1 YXWQTVWJNHKSCC-UHFFFAOYSA-N 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 4
- 230000003287 optical effect Effects 0.000 abstract description 7
- 239000007788 liquid Substances 0.000 abstract 2
- 230000001376 precipitating effect Effects 0.000 abstract 1
- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 125000000217 alkyl group Chemical group 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000005194 fractionation Methods 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- YXWQTVWJNHKSCC-MRXNPFEDSA-N (R)-tetrahydropapaverine Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H]1C2=CC(OC)=C(OC)C=C2CCN1 YXWQTVWJNHKSCC-MRXNPFEDSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
- VMPLLPIDRGXFTQ-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;hydrochloride Chemical compound [Cl-].C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CC[NH2+]1 VMPLLPIDRGXFTQ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- CEWCLHPMDWPDNQ-UHFFFAOYSA-N ethyl 2-(2-chloro-6-fluorophenyl)acetate Chemical compound CCOC(=O)CC1=C(F)C=CC=C1Cl CEWCLHPMDWPDNQ-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YXWQTVWJNHKSCC-INIZCTEOSA-N (1s)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Chemical compound C1=C(OC)C(OC)=CC=C1C[C@H]1C2=CC(OC)=C(OC)C=C2CCN1 YXWQTVWJNHKSCC-INIZCTEOSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a new method for resolution of a tetrahydroisoquinoline racemate, consisting of resolving the racemate by a resolving agent with an optical activity (formula II), precipitating diastereomers which S- takes most, getting diastereomer mother liquid which R- takes most, resolving with the resolving agent (formula III or IV) with another optical activity after dissociating themother liquid, getting a single R-stereoisomer. The invention solves the problem of applying single resolving agent and gets the enantiomer with a high yield and a high optical purity and improves the efficiency and benefit, which can be widely used in the racemate resolution field.
Description
Technical field
The present invention relates to the novel method that a kind of tetrahydrochysene isoquinoline racemate splits.
Background technology
The acquisition of single enantiomer, at present extensively the method that adopts is the fractionation of racemic modification, particularly forms and separates the diastereomer Split Method.Although the fractionation of a lot of racemic modifications is known, particularly resolving agent is known, only adopts a kind of resolving agent crystallization usually, obtains meeting the single corresponding isomer of optical purity requirement again by the method for recrystallization repeatedly.Simultaneously, the resolving agent that has is difficult to obtain, and is single too high with a kind of resolving agent cost, is unfavorable for industrialization.
Patent US5453510 report, split the tetrahydropapaverine raceme with N-acetyl-L-leucine, its process is: earlier isolate the S-tetrahydropapaverine with N-acetyl-L-leucine, and then concentrated mother liquor separates out R-tetrahydropapaverine crude product, obtain satisfactory R-tetrahydropapaverine by recrystallization.Though this method uses the N-acetyl-L-leucine that is easy to get to make resolving agent, but important disadvantages is required R enantiomorph and can only separates out from mother liquor, the speed of so not only separating out is slow, and purity is not high, needs recrystallization repeatedly just can obtain satisfactory R enantiomorph.
Patent CN200410091127.5 and patent CN96197238.6 report respectively and adopt N-acetyl-D-leucine and D-2,4-dichlorophenoxy propionic acid splits as resolving agent and directly obtains the R-tetrahydropapaverine, but these two kinds of resolving agents all are difficult to obtain, and about the amount that needs and mole numbers such as raceme to be split, therefore consumption is big, cost is also high, and industrialization has limitation.
Summary of the invention
The objective of the invention is to overcome the limitation of prior art, propose the novel method that a kind of tetrahydrochysene isoquinoline racemate splits, adopt two kinds of different resolving agents to split successively, high yield obtains meeting the R-isomer of the high-optical-purity of follow-up use.
The present invention is achieved in that
Formula I raceme joined with 1: 0.9 to 1: 1.5 mol ratio in the resolution solvent of 5 to 100 times of volume ratios with formula II compound earlier form diastereomer ,-20 ℃ to 30 ℃ crystallizatioies 12 hours to 5 days, the salt that mainly contains the S-enantiomorph is separated out from solution; Filter, mother liquor is concentrated into dried, and with the alkali lye neutralization, organic solvent extraction obtains the residuum that the R body occupies the majority; Again this residuum and formula III or formula IV compound are joined with 1: 0.9 to 1: 1.5 mol ratio in the resolution solvent of 5 to 100 times of volume ratios and form diastereomer,-20 ℃ to 30 ℃ crystallizatioies 12 hours to 5 days, the salt that is mainly contained the R-enantiomorph, recrystallization, with the alkali lye neutralization, obtain satisfactory R-enantiomorph again.
Its Chinese style I:
Substituting group has following implication in the formula:
A:H, Cl-4 alkoxyl group, halogen, Cl-4 alkyl,
B:H, Cl-4 alkoxyl group, halogen, Cl-4 alkyl,
E:H, Cl-4 alkoxyl group, halogen, Cl-4 alkyl,
F:H, Cl-4 alkoxyl group, halogen, Cl-4 alkyl,
What be particularly suitable for formula I is the tetrahydropapaverine raceme.
Formula II is N-acyl group-L-amino acid, and its structural formula is as follows:
Substituting group has following implication in the formula:
R
1: formyl radical, ethanoyl, propionyl, butyryl radicals, tertbutyloxycarbonyl, carbobenzoxy-(Cbz),
R
2: H, Cl-4 alkyl, phenyl,
What be particularly suitable for formula II is N-acetyl-L-leucine.
Formula III:
Substituting group has following implication in the formula:
R
3: H, Cl-4 alkoxyl group, Cl-4 alkyl,
R
4: H, Cl-4 alkoxyl group, halogen, Cl-4 alkyl, benzyl,
R
5: H, Cl-4 alkoxyl group, halogen, Cl-4 alkyl, benzyl
That be particularly suitable for formula III is D-2,4-dichlorophenoxy propionic acid.
Formula IV is N-acyl group-D-amino acid, and its structural formula is as follows:
Substituting group has following implication in the formula:
R
1: formyl radical, ethanoyl, propionyl, butyryl radicals, tertbutyloxycarbonyl, carbobenzoxy-(Cbz),
R
2: H, Cl-4 alkyl, phenyl,
What be particularly suitable for formula IV is N-acetyl-D-leucine.
The temperature range of twice fractionation is respectively at 0 ℃ of boiling point to used resolution solvent.
Fractionation is carried out in solvent commonly used, as lower alcohol, and acetone, toluene, methylene dichloride, chloroform, ethylene dichloride, ether, ethyl acetate and they press the mixed solvent that different ratios is formed.Preferred Virahol.
Characteristics of the present invention and technique effect are:
Present method has solved the deficiency of using single resolving agent, the enantiomorph productive rate height that obtains, and optical purity is also very high, has improved efficient and benefit, can be widely used in the mesotomy field.
Embodiment:
Embodiment 1:
38g tetrahydropapaverine hydrochloride is dissolved in the 500mL water, add ammoniacal liquor and be neutralized to neutrality, methylene dichloride 200ml * 3 extractions merges organic phase, the salt washing, drying is filtered the back and is concentrated organic phase to doing, with Virahol 500ml dissolving, add N-acetyl-L-leucine 19g, reflux, cooling, the room temperature crystallization spends the night.Filter, filtrate is concentrated into dried, adds ammoniacal liquor and is neutralized to neutrality, and methylene dichloride 150ml * 3 extractions merges organic phase, the salt washing, drying is filtered the back and is concentrated organic phase to doing, with Virahol 300ml dissolving, add N-acetyl-D-leucine 12g, reflux, cooling, the room temperature crystallization spends the night.Filter, the filter cake acetone recrystallization gets 22g.The ammoniacal liquor neutralization, toluene 300mL extraction adds acidic alcohol in the toluene layer, and to PH1-2, crystallization spends the night in the refrigerator, obtains 15g R-tetrahydropapaverine hydrochloride, yield 78.9%, optical purity 97%.
Embodiment 2:
76g tetrahydropapaverine hydrochloride is dissolved in the 800mL water, add 1N sodium hydroxide and be neutralized to neutrality, toluene 300ml * 3 extractions merges organic phase, the salt washing, dry, filter the back and concentrate organic phase,, add N-acetyl-L-leucine 38g with methyl alcohol 500ml dissolving to doing, ether 300ml, the freezing crystallization of refrigerator spends the night.Filter, filtrate is concentrated into dried, adds ammoniacal liquor and is neutralized to neutrality, and toluene 250ml * 3 extractions merges organic phase, the salt washing, and drying is filtered the back and is concentrated organic phase to doing, and with methyl alcohol 300ml dissolving, adds N-acetyl-D-leucine 26g, ether 100ml, crystallization spends the night.Filter, the filter cake acetone recrystallization gets 60g.The ammoniacal liquor neutralization, toluene 300mL extraction adds acidic alcohol in the toluene layer, and to PH1-2, crystallization spends the night in the refrigerator, obtains 35g R-tetrahydropapaverine hydrochloride, yield 82.1%, optical purity 97.5%.
Claims (4)
1. the method for the racemic modification of a split-type I compound, it is characterized in that earlier by a kind of optically active resolving agent formula II resolution of racemates, separate out the salt that mainly contains the S enantiomorph, obtain the mother liquor that the R enantiomorph occupies the majority, split the free single R-enantiomer that obtains high-optical-purity behind the free mother liquor again with another optically active resolving agent formula III or IV;
Its Chinese style I:
Substituting group has following implication in the formula:
A:H, C1-4 alkoxyl group, halogen or C1-4 alkyl,
B:H, C1-4 alkoxyl group, halogen or C1-4 alkyl,
E:H, C1-4 alkoxyl group, halogen or C1-4 alkyl,
F:H, C1-4 alkoxyl group, halogen or C1-4 alkyl,
Formula II is N-acyl group-L-amino acid, and its structural formula is as follows:
Substituting group has following implication in the formula:
R
1: formyl radical, ethanoyl, propionyl, butyryl radicals, tertbutyloxycarbonyl or carbobenzoxy-(Cbz),
R
2: H, C1-4 alkyl or phenyl,
The formula III compound is D-2,4-dichlorophenoxy propionic acid,
Formula IV is N-acyl group-D-amino acid, and its structural formula is as follows:
Substituting group has following implication in the formula:
R
1: formyl radical, ethanoyl, propionyl, butyryl radicals, tertbutyloxycarbonyl or carbobenzoxy-(Cbz),
R
2: H, C1-4 alkyl or phenyl.
2. the method for claim 1, formula I compound is the tetrahydropapaverine racemic modification.
3. the method for claim 1, formula II compound is N-acetyl-L-leucine.
4. the method for claim 1, formula IV compound is N-acetyl-D-leucine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100205872A CN101037411B (en) | 2007-03-13 | 2007-03-13 | Splitting method of tetrahydroisoquinoline racemes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100205872A CN101037411B (en) | 2007-03-13 | 2007-03-13 | Splitting method of tetrahydroisoquinoline racemes |
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| Publication Number | Publication Date |
|---|---|
| CN101037411A CN101037411A (en) | 2007-09-19 |
| CN101037411B true CN101037411B (en) | 2011-07-06 |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735229A (en) * | 2009-12-24 | 2010-06-16 | 沈阳药科大学 | Tetrahydroisoquinoline compounds and preparation method and application thereof |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5453510A (en) * | 1990-07-13 | 1995-09-26 | Burroughs Wellcome Co. | Neuromuscular blocking agents |
| US6015903A (en) * | 1995-09-26 | 2000-01-18 | Basf Aktiengesellschaft | Method of resolving racemic mixtures |
| 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 |
-
2007
- 2007-03-13 CN CN2007100205872A patent/CN101037411B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5453510A (en) * | 1990-07-13 | 1995-09-26 | Burroughs Wellcome Co. | Neuromuscular blocking agents |
| US6015903A (en) * | 1995-09-26 | 2000-01-18 | Basf Aktiengesellschaft | Method of resolving racemic mixtures |
| 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 |
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| CN101037411A (en) | 2007-09-19 |
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Application publication date: 20070919 Assignee: Sinobiopharma Inc. Assignor: Nanjing University Contract record no.: 2014320000207 Denomination of invention: Splitting method of tetrahydroisoquinoline racemes Granted publication date: 20110706 License type: Exclusive License Record date: 20140314 |
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