CN109020992A - A kind of method that stereoselectivity prepares β type mono-/bis-sweet wormwood alkyl ether amine maleate - Google Patents
A kind of method that stereoselectivity prepares β type mono-/bis-sweet wormwood alkyl ether amine maleate Download PDFInfo
- Publication number
- CN109020992A CN109020992A CN201710433470.0A CN201710433470A CN109020992A CN 109020992 A CN109020992 A CN 109020992A CN 201710433470 A CN201710433470 A CN 201710433470A CN 109020992 A CN109020992 A CN 109020992A
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- CN
- China
- Prior art keywords
- group
- benzyl
- alkyl ether
- type
- sweet wormwood
- 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.)
- Granted
Links
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 30
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 26
- 240000001851 Artemisia dracunculus Species 0.000 title claims abstract description 22
- 235000009051 Ambrosia paniculata var. peruviana Nutrition 0.000 title claims abstract description 20
- 235000003097 Artemisia absinthium Nutrition 0.000 title claims abstract description 20
- 235000017731 Artemisia dracunculus ssp. dracunculus Nutrition 0.000 title claims abstract description 20
- 235000003261 Artemisia vulgaris Nutrition 0.000 title claims abstract description 20
- 239000001138 artemisia absinthium Substances 0.000 title claims abstract description 20
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 150000001412 amines Chemical class 0.000 title claims abstract description 18
- 150000005215 alkyl ethers Chemical class 0.000 title claims abstract description 14
- -1 acetyl dihydroartemisinine Chemical compound 0.000 claims abstract description 114
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 125000003368 amide group Chemical group 0.000 claims abstract description 20
- 229960002521 artenimol Drugs 0.000 claims abstract description 13
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 12
- 239000011976 maleic acid Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 230000000707 stereoselective effect Effects 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 35
- 240000000011 Artemisia annua Species 0.000 claims description 30
- 235000001405 Artemisia annua Nutrition 0.000 claims description 29
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 27
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 27
- 235000019441 ethanol Nutrition 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 210000000481 breast Anatomy 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
- 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 19
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 230000000903 blocking effect Effects 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052698 phosphorus Inorganic materials 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 9
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 229940031098 ethanolamine Drugs 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 5
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052772 Samarium Inorganic materials 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 229960001245 olaflur Drugs 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 150000004040 pyrrolidinones Chemical class 0.000 claims description 2
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- QSUJAUYJBJRLKV-UHFFFAOYSA-M tetraethylazanium;fluoride Chemical compound [F-].CC[N+](CC)(CC)CC QSUJAUYJBJRLKV-UHFFFAOYSA-M 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims 3
- 230000002378 acidificating effect Effects 0.000 claims 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims 1
- 229910015900 BF3 Inorganic materials 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- ZVVSSOQAYNYNPP-UHFFFAOYSA-N olaflur Chemical compound F.F.CCCCCCCCCCCCCCCCCCN(CCO)CCCN(CCO)CCO ZVVSSOQAYNYNPP-UHFFFAOYSA-N 0.000 claims 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000002841 Lewis acid Substances 0.000 abstract description 3
- 150000007517 lewis acids Chemical class 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- 150000003335 secondary amines Chemical class 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- 239000000243 solution Substances 0.000 description 35
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
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- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 10
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- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 8
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- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 description 6
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- 235000002639 sodium chloride Nutrition 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
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- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
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- 229960004991 artesunate Drugs 0.000 description 1
- FZIZEIAMIREUTN-UHFFFAOYSA-N azane;cerium(3+) Chemical compound N.[Ce+3] FZIZEIAMIREUTN-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 229940098333 coartem Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000010300 dimethyl dicarbonate Nutrition 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to organic synthesis and pharmaceutical intermediate fields, the method that specifically a kind of stereoselectivity prepares β type mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl ether amine maleate: using the straight chained alkyl alcamine compound and acetyl dihydroartemisinine of amido protecting under the catalysis of acid (including lewis acid) catalyst, Stereoselective generates the α that β type is primary product, mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl ether amine of β type mixing, it is recrystallized to give β type mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl ether amine of high diastereoisomer, after removing amido protection, obtained β type mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl ether primary amine or secondary amine and maleic acid is at salt, obtain the pure β type mono-/bis-sweet wormwood of respective optical (symmetrical and asymmetric) alkyl ether amine maleate, such as formula (1) and (2 ).Method high income and stereoselectivity of the invention is high.
Description
Technical field
The present invention relates to organic synthesis and pharmaceutical intermediate fields, specifically, being that a kind of stereoselectivity preparation β type is green
The method of wormwood artemisia mono-/bis-(symmetrical and asymmetric) alkyl ether amine maleate.
Background technique
Qinghaosu is anti-malaria medicaments isolated from medicinal plant artemisia annua the 1970s.To being at present
Only, it is one of the drug for effectively treating malaria in the world, clinically plays huge effect.So far there are five antimalarials
9 kinds of dosage forms of kind new medicine (qinghaosu, Artesunate, Artemether, dihydroartemisinine, Coartem), and sold in countries in the world.
It finds after study, it is its essential important set that plays a role that the dioxygen bridge in qinghaosu structure, which is crucial pharmacophore,
Point.It has been always the big hot spot of medical field one to the research of itself and its derivative antimalarial active, while section since being found from qinghaosu
Scholar, which is also desirable that, to be found new artemisinin derivative and probes into its activity.
Qinghaosu and its derivative also have immunosuppressive activity other than with anti-malarial activity.By to qinghaosu into
Row structure of modification, and find that its soluble derivative maleate has preferable immunosuppressive activity, it is expected to red as treating
The drug candidate of yabbi sore.Find have potential when carrying out further activity research to artemisine compounds simultaneously
Anti-tumor activity, such as the invasion transfer, inducing cell cycle arrest, the promotion that inhibit Tumor Angiongesis, block tumour cell
Apoptosis etc..
It was found that the double wormwood artemisia alkyl ether amine maleates of the novel water-soluble arteannuin derivant β type of another kind, activity grinds
Study carefully and shows can inhibit Leukemia Cell Proliferation, induces cell apoptosis；It is worth with preferable clinical development, for treating white blood
Disease, especially treatment acute leukemia.
The more demanding diastereoselectivity of spatial chemistry feature of these reactive compounds.Previous synthetic method is received
Rate is lower and stereoselectivity is not high.
Summary of the invention
To solve the above-mentioned problems, it is (symmetrical and not right to provide a kind of stereoselectivity preparation β type mono-/bis-sweet wormwood by the present invention
Claim) method of alkyl ether amine maleate: use the straight chained alkyl alcamine compound and acetyl dihydroartemisinine of amido protecting
Under the catalysis of acid (including lewis acid) catalyst, Stereoselective generates what α, β type that β type is primary product mixed
Mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl ether amine, the β type mono-/bis-sweet wormwood for being recrystallized to give high diastereoisomer are (symmetrical
And it is asymmetric) alkyl ether amine, after removing amido protection, obtained β type mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl ether primary amine or
Secondary amine and maleic acid obtain the pure β type mono-/bis-sweet wormwood of respective optical (symmetrical and asymmetric) alkyl ether amine maleate, such as at salt
Following formula (1) and (2).
The first aspect of the present invention provides a kind of stereoselectivity preparation β type mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl
The method of ether amines maleate, comprising the following steps:
(i) amido protecting of β type mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl alcoholamine: different blocking groups is selected
(Protective groups, P) protects alcamine compound, obtains the amido alcohol containing blocking group, such as following formula
(3) and shown in (4):
Work as P1When=H, P2For benzyl (Bn), tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), trifluoroacetyl group (Tfa),
Tablet held before the breast by officials methoxycarbonyl group (Fmoc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, 2,4- dimethoxy-benzyl (DMB)
And it is suitable for methoxy-benzyl (PMB) etc. the amido protecting group of the reaction；
Work as P1、P2When ≠ H, P1、P2For benzyl (Bn), tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), trifluoroacetyl group
(Tfa), tablet held before the breast by officials methoxycarbonyl group (Fmoc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, 2,4- dimethoxy-benzyl
(DMB) and to methoxy-benzyl (PMB) etc. it is suitable for combination or the P of any two of the amido protecting group of the reaction1-P2For
Wherein R is H ,-NO2、-Cl、-F、-Br、-CF3,-CN and-NHCOCH3The combination of equal groups include one of them or
The different combination in the position of person's two or more and substituent group；
Wherein, P3For benzyl (Bn), tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), trifluoroacetyl group (Tfa), tablet held before the breast by officials first
Oxygen carbonyl (Fmoc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, 2,4- dimethoxy-benzyl (DMB) and right
Methoxy-benzyl (PMB) etc. is suitable for the amido protecting group of the reaction；
(ii) condensation reaction:
1) with amine alcohol compound containing blocking group obtained by (i) and acetyl dihydroartemisinine in acid (including Louis
This acid) under the action of catalyst, Stereoselective generates single sweet wormwood alkyl ether amine that α, β type that β type is primary product mix,
As shown in following formula (5):
Work as P1When=H, P2For benzyl (Bn), tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), trifluoroacetyl group (Tfa),
Tablet held before the breast by officials methoxycarbonyl group (Fmoc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, 2,4- dimethoxy-benzyl (DMB)
And it is suitable for methoxy-benzyl (PMB) etc. the amido protecting group of the reaction；
Work as P1、P2When ≠ H, P1、P2For benzyl (Bn), tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), trifluoroacetyl group
(Tfa), tablet held before the breast by officials methoxycarbonyl group (Fmoc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, 2,4- dimethoxy-benzyl
(DMB) and to methoxy-benzyl (PMB) etc. it is suitable for combination or the P of any two of the amido protecting group of the reaction1-P2For
Wherein R is H ,-NO2、-Cl、-F、-Br、-CF3,-CN and-NHCOCH3The combination of equal groups include one of them or
The different combination in the position of person's two or more and substituent group；
2) with amine alcohol compound containing blocking group obtained by (i) and acetyl dihydroartemisinine in acid (including Louis
This acid) under the action of catalyst, Stereoselective generates double sweet wormwoods that α, β type that β type is primary product mix (symmetrically and not
Symmetrically) alkyl ether amine, as shown in following formula (6):
Wherein, P3For benzyl (Bn), tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), trifluoroacetyl group (Tfa), tablet held before the breast by officials first
Oxygen carbonyl (Fmoc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, 2,4- dimethoxy-benzyl (DMB) and right
Methoxy-benzyl (PMB) etc. is suitable for the amido protecting group of the reaction；
The sweet wormwood alkyl ether amine of α, β type mixing is recrystallized to give optically pure β type sweet wormwood alkyl ether amine；
(iii) deprotection reaction:
1) deprotection reaction is carried out to optically pure β type list sweet wormwood alkyl ether amine obtained by (ii), obtains optically pure β type list
Sweet wormwood alkyl ether amine, as shown in following formula (7):
Work as P1When=H, P2For benzyl (Bn), tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), trifluoroacetyl group (Tfa),
Tablet held before the breast by officials methoxycarbonyl group (Fmoc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, 2,4- dimethoxy-benzyl (DMB)
And it is suitable for methoxy-benzyl (PMB) etc. the amido protecting group of the reaction；
Work as P1、P2When ≠ H, P1、P2For benzyl (Bn), tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), trifluoroacetyl group
(Tfa), tablet held before the breast by officials methoxycarbonyl group (Fmoc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, 2,4- dimethoxy-benzyl
(DMB) and to methoxy-benzyl (PMB) etc. it is suitable for combination or the P of any two of the amido protecting group of the reaction1-P2For
Wherein R is H ,-NO2、-Cl、-F、-Br、-CF3,-CN and-NHCOCH3The combination of equal groups include one of them or
The different combination in the position of person's two or more and substituent group；
2) deprotection reaction is carried out to the double sweet wormwoods of optically pure β type obtained by (ii) (symmetrical and asymmetric) alkyl ether amine, obtained
To the double sweet wormwoods of optically pure β type (symmetrical and asymmetric) alkyl ether amine, as shown in following formula (8):
Wherein, P3For benzyl (Bn), tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), trifluoroacetyl group (Tfa), tablet held before the breast by officials first
Oxygen carbonyl (Fmoc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, 2,4- dimethoxy-benzyl (DMB) and right
Methoxy-benzyl (PMB) etc. is suitable for the amido protecting group of the reaction；
(iv) salt-forming reaction:
1) optically pure single β type list sweet wormwood alkyl ether amine and maleic acid without blocking group obtained by (vi) is obtained at salt
To optically pure β type list sweet wormwood alkyl ether amine maleate, as shown in following formula (9):
2) to the double sweet wormwoods of the optically pure β type without blocking group obtained by (vi) (symmetrical and asymmetric) alkyl ether amine and horse
It is sour to obtain the double sweet wormwoods of optically pure β type (symmetrical and asymmetric) alkyl ether amine maleate at salt, as shown in following formula (10):
The β type sweet wormwood alkyl ether amine maleate is by being recrystallized to give pure compounds.
In preferred embodiment method, in step (i), under the conditions of existing for the solvent and alkali to alcamine compound into
Row amido protecting obtains mono-/bis-(symmetrical and asymmetric) alkylamine containing blocking group.
In preferred embodiment method, in step (i), protection reagent used has cylite (BnBr), two dimethyl dicarbonates
Butyl ester ((Boc)2O), benzyl chloroformate (CbzCl), trifluoroacetic anhydride (TFAA), to mehtoxybenzyl chlorine (PMBCl), chloromethane
Acid -9- fluorenyl methyl ester (FmocCl), trimethyl silicon substrate carbethoxyl group chlorine (TeocCl), 2,4- dimethoxy-benzyl chlorine (DMBCl),
First (or second) oxygen carbonyl chlorine and phthalic anhydride etc. are applicable in the protection reagent of the reaction.
In preferred embodiment method, in step (i), alkali used includes: sodium hydroxide, sodium carbonate, potassium carbonate, carbonic acid
Hydrogen sodium, triethylamine, bis- (trimethyl silicon substrate) Sodamides and bis- (trimethyl silicon substrate) potassamides etc. be suitable for the reaction organic or
Person's inorganic base.
In preferred embodiment method, in step (i), three component of alcamine compound, alkali and amido protecting agent
Molar ratio is 1:2.0~10:2~5, and reaction temperature is -10 DEG C~50 DEG C.
In preferred embodiment method, in step (i), anti-solvent-applied is tetrahydrofuran, chloroform, methylene chloride, second
Alcohol, ether, 1,4- dioxane, methanol, N,N-dimethylformamide, ethyl acetate, toluene and acetonitrile etc. are suitable for the reaction
Organic solvent.
In preferred embodiment method, acidity (including lewis acid) catalyst used in step (ii) includes but is not limited to
Boron trifluoride etherate and trifluoracetic acid；Acetyl dihydroartemisinine, the hydramine containing blocking group and acidity are urged in reaction
The molar ratio of three component of agent is 1.0:1.0~5.0:0.4~1, and reaction temperature is -10 DEG C~30 DEG C；And anti-solvent-applied is
Tetrahydrofuran, chloroform, methylene chloride, 1,2- dichloroethanes or ether etc. are suitable for the organic solvent of the reaction, recrystallize with molten
Agent is that n-hexane, petroleum ether, hexamethylene, normal heptane, ether, methylene chloride, ethyl acetate, ethyl alcohol and methanol etc. are suitable for the step
The solvent of recrystallization, and β type product usually accounts for 90% or more in α, β mixture.
In preferred embodiment method, in step (iii), the reagent of removing amido protection includes: the fluorination of (1) tetraalkyl
Amine: such as tetramethyl amine fluoride, tetraethyl ammonium fluoride, tetrabutyl ammonium fluoride can be used for removing tablet held before the breast by officials methoxycarbonyl group and trimethyl silicane
The groups such as carbethoxyl group；(2) organic amine: such as piperidines, ethanol amine, cyclohexylamine, morpholine, pyrrolidones, DBU and triethylamine
It can be used for removing tablet held before the breast by officials methoxycarbonyl group and trifluoroacetyl group；(3) alkyl silicon alkanes, such as Iodotrimethylsilane can be used for removing first
(second) oxygen carbonyl, tablet held before the breast by officials methoxycarbonyl group, trimethylsilyl ethoxycarbonyl and tertbutyloxycarbonyl；(4) acid reagent: as p-methyl benzenesulfonic acid,
Methanesulfonic acid etc. can be used for removing the groups such as 2,4- dimethoxy-benzyl and trimethylsilyl ethoxycarbonyl；(5) oxidative reagent: such as nitre
The reagents such as sour cerium ammonium (CAN), DDQ and samarium diodide can be used for removing to methoxy-benzyl, 2,4- dimethoxy-benzyl and benzyl
Equal groups；(6) other deprotecting regents, hydrazine hydrate, methylamine alcohol solution and sodium borohydride etc. can be used for removing adjacent aryl benzoyl
Base.
In preferred embodiment method, in step (iii), β type mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl ether amine with
The molar ratio of deprotecting regent is 1.0:1.0~10.0, and reaction temperature is 0 DEG C~30 DEG C, and anti-solvent-applied is Isosorbide-5-Nitrae-dioxy six
Ring, chloroform, acetonitrile, methylene chloride, ethyl alcohol, methylene chloride, tetrahydrofuran, ether, isopropanol etc. are suitable for the organic of the reaction
Solvent.
In preferred embodiment method, in step (iv), acid used is maleic acid, and β type mono-/bis-sweet wormwood is (symmetrically and not
Symmetrically) molar ratio of alkyl ether amine and maleic acid is 1.0:1.0~10.0, and reaction temperature is -10 DEG C~15 DEG C, and used in reaction
Solvent includes but is not limited to the solvent that ethyl acetate, ether etc. are suitable for the reaction；Recrystallize solvent for use are as follows: ethyl alcohol/just oneself
Alkane, ethyl alcohol/normal heptane, ethanol/cyclohexane, ethyl alcohol/petroleum ether etc. are suitable for the solvent of step recrystallization.
The invention has the advantages that:
The present invention provides a kind of highly-solid selectively preparation β type mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl ether amine horses
Carry out the method for hydrochlorate, compared with prior art, method high income of the invention and stereoselectivity height.
Detailed description of the invention
Fig. 1 is double double maleate nuclear magnetic resonance spectroscopies of arteether amine.
Specific embodiment
It elaborates below with reference to embodiment to specific embodiment provided by the invention.
Embodiment 1: amido protecting reaction
(1) reaction equation:
Experimental implementation: it takes ethanol amine (5.0mL, 82.8mmol) in 100mL round-bottomed flask, and 50mL methylene chloride is added
It is dissolved into homogeneous and triethylamine (23mL, 165.7mmol) is added.Ice bath is cooled to 0 DEG C, and two carbon are slowly added dropwise into the solution
Sour di tert butyl carbonate (28.5mL, 124.2mmol).It finishes, reaction is warmed to room temperature, continue to stir.TLC tracking reaction, to raw material
After consumption completely, deionized water (30mL) quenching reaction, stratification is added.Organic phase washs two with saturated salt solution (30mL)
It is secondary and dry with anhydrous sodium sulfate.Solvent is evaporated off under reduced pressure after being filtered to remove desiccant, gained residue passes through silica gel column layer
Analysis purifying obtains pure compounds 12.7g, yield 95%.
1H NMR(400MHz,CDCl3):δ1.37(s,9H),3.18-3.6(m,4H),3.93(s,1H),5.42(s,1H)
.13C NMR(100MHz,CDCl3):δ28.6,48.7,79.5,116.3,134.0,155.4.
(2) reaction equation:
Experimental implementation: it takes diethanol amine (3.1mL, 0.05mol) in 100mL round-bottomed flask, and 50mL dichloromethane is added
Alkane is dissolved into homogeneous and N, N- diisopropylethylamine (16.5mL, 0.1mol) is added.Ice bath is cooled to 0 DEG C, and into the solution
The dichloromethane solution (20mL) of p-methoxybenzyl chloride (10.2mL, 0.075mol) is slowly added dropwise.It finishes, reaction is risen into room
Temperature continues to stir.Deionized water (20mL) quenching reaction, stratification is added after consumption of raw materials is complete in TLC tracking reaction.
Organic phase is washed twice with saturated salt solution (30mL), and dry with anhydrous sodium sulfate.It is filtered to remove after desiccant under reduced pressure
Solvent is evaporated off, gained residue purifies to obtain pure compounds 8.3g, yield 92% by silica gel column chromatography.
1H NMR(400MHz,CDCl3):δ2.73-2.76(m,4H),3.62-3.65(m,2H),3.70(s,2H),3.78
(s,3H),6.86-6.84(m,2H),7.21-7.20(m,2H).
(3) reaction equation:
Experimental implementation: it takes ethanol amine (2.5mL, 41.4mmol) in 100mL round-bottomed flask, and 50mL methylene chloride is added
It is dissolved into homogeneous and sodium bicarbonate (13.8g, 0.17mol) is added.Ice bath is cooled to 0 DEG C, and chlorine is slowly added dropwise into the solution
Formic acid -9- fluorenyl methyl ester (9.6g, 37.3mmol).It finishes, reaction is warmed to room temperature, continue to stir.TLC tracking reaction, to original
After material consumption completely, deionized water (30mL) quenching reaction, stratification is added.Organic phase is washed with saturated salt solution (30mL)
Twice, and it is dry with anhydrous sodium sulfate.Solvent is evaporated off under reduced pressure after being filtered to remove desiccant, gained residue passes through silicagel column
Chromatographic purifying obtains pure compounds 9.5g, yield 90%.
1H NMR(400MHz,CDCl3): δ 2.06 (t, J=4.8Hz, 1H), 3.40-3.30 (m, 2H), 3.77-3.67 (m,
2H), 4.22 (t, J=6.5Hz, 1H), 4.43 (d, J=6.7Hz, 2H), 5.15 (s, 1H), 7.32 (t, J=7.4Hz, 2H),
7.41 (t, J=7.4Hz, 2H), 7.59 (d, J=7.5Hz, 2H), 7.77 (d, J=7.5Hz, 2H)13C NMR(100MHz,
CDCl3,):δ43.45,47.24,62.36,66.76,125.00,1127.05,127.70,141.33,143.86,157.14,
19.98.
(4) reaction equation:
Experimental implementation: it takes ethanol amine (5.0mL, 82.8mmol) in 100mL round-bottomed flask, and 50mL methylene chloride is added
It is dissolved into homogeneous and triethylamine (23mL, 165.7mmol) is added.Ice bath is cooled to 0 DEG C, and chloromethane is slowly added dropwise into the solution
Acetoacetic ester (17.3mL, 124.2mmol).It finishes, reaction is warmed to room temperature, continue to stir.TLC tracking reaction, to consumption of raw materials
After completely, deionized water (30mL) quenching reaction, stratification is added.Organic phase is washed twice with saturated salt solution (30mL),
And it is dry with anhydrous sodium sulfate.Solvent is evaporated off under reduced pressure after being filtered to remove desiccant, gained residue passes through silica gel column chromatography
Purifying obtains pure compounds 10.1g, yield 92%.
1H NMR(400MHz,CDCl3): δ 1.24 (t, J=7.1Hz, 3H), 3.49 (t, J=6.6Hz, 2H), 3.48 (t, J
=6.6,2H), 4.23 (q, J=7.1Hz, 2H)
Experimental implementation: weigh ethanolamine derivant (5.0g, 37.6mmol) and sodium carbonate (5.18g, 48.9mmol) in
In 250mL round-bottomed flask, Isosorbide-5-Nitrae-dioxane/water (90mL, 1:1) is added, stirring forms suspension at room temperature.Separately take chloromethane
Acid -9- fluorenyl methyl ester (8.7g, 33.8mmol) is dissolved in 30ml toluene, and is slowly dropped to above-mentioned reaction solution with dropping funel
In (during dropwise addition control in temperature be no more than 25 DEG C), all be added after, continue to be stirred overnight.TLC tracking reaction, raw material disappear
After consumption is complete, concentrated hydrochloric acid adjusts pH and is extracted twice to 3, and with ethyl acetate (50mL), separates organic phase, is washed with saturated common salt
Wash (50mL) twice, anhydrous sodium sulfate is dry (20g), is concentrated to give crude product 10.8g, yield 90%.
(5) reaction equation:
Experimental implementation: diethanol amine (5.0g, 47.56mmol) and sodium carbonate (6.55g, 61.83mmol) are weighed in 250mL
In round-bottomed flask, Isosorbide-5-Nitrae-dioxane/water (90mL, 1:1) is added, stirring forms suspension at room temperature.Separately take chloro-carbonic acid -9- fluorenes
Base methyl esters (11.07g, 42.80mmol) is dissolved in 30ml toluene, and is slowly dropped in above-mentioned reaction solution with dropping funel
(temperature is no more than 25 DEG C in controlling during dropwise addition), after being all added, continue to be stirred overnight.TLC tracking reaction, consumption of raw materials
After completely, concentrated hydrochloric acid adjusts pH and is extracted twice to 3, and with ethyl acetate (50mL), organic phase is separated, with saturated common salt water washing
(50mL) twice, anhydrous sodium sulfate is dry (20g), is concentrated to give crude product 12g, yield 95.5%.
1H NMR(400MHz,CDCl3): 3.19 (d, J=3.6Hz, 2H), 3.40 (m, J=4.0Hz, 4H), 3.77 (d, J
=8.0Hz, 2H), 4.23 (t, J=5.2Hz, 1H), 4.56-4.58 (m, 1H), 7.30-7.34 (m, 2H), 7.36-7.41 (m,
2H), 7.56 (d, J=7.6Hz, 2H), 7.76 (d, J=7.6Hz, 2H)
Embodiment 2: condensation reaction
(1) reaction equation:
Experimental implementation: Weigh Compound acetyl dihydroartemisinine (3.3g, 10.0mmol) is dissolved in 20mL methylene chloride,
Add alcamine compound (1.6g, 10.0mmol) into the solution.Ice bath is cooled to 0-5 DEG C, and BF is added dropwise under stiring3.Et2O
The dichloromethane solution (2mL) of (0.5mL, 4.0mmol), is then slowly ramped to 20-25 DEG C, TLC tracks reaction in time, about
Reaction reaches balance after 4 hours.Reaction solution is successively used to water (pH value for paying attention to measurement washing water), saturated sodium bicarbonate aqueous solution
It washes, then is washed to neutrality, finally washed with saturated common salt aqueous solution, organic phase is dry with anhydrous sodium sulfate.Filtering, concentration, column
Chromatograph to obtain pure product 2.2g, yield 51%.
1H NMR(400MHz,CDCl3):δ0.93-0.97(m,7H),1.25-1.36(m,2H),1.38(s,9H),1.43
(s,3H),1.48-1.56(m,2H),1.62-1.67(m,1H),1.73-1.79(m,2H),1.81-1.92(m,1H),2.03-
2.07(m,1H),2.21-2.24(m,1H),2.34-2.42(m,1H),2.67-2.69(m,1H),3.63-3.91(m,4H),
4.85 (d, J=3.2Hz, 1H), 5.44 (s, 1H)
(2) reaction equation:
Experimental implementation: Weigh Compound acetyl dihydroartemisinine (1.6g, 5.0mmol) is dissolved in 20mL methylene chloride,
Add alcamine compound (0.9g, 5.0mmol) into the solution.Ice bath is cooled to 0-5 DEG C, and BF is added dropwise under stiring3.Et2O
(0.25mL, 2.0mmol) is then slowly ramped to 20-25 DEG C, and TLC tracks reaction in time, and reaction reaches flat after about 4 hours
Weighing apparatus.Reaction solution is successively used to water (pH value for paying attention to measurement washing water), saturated sodium bicarbonate aqueous solution is washed, then is washed to neutrality,
It is finally washed with saturated common salt aqueous solution, organic phase is dry with anhydrous sodium sulfate.Filtering, concentration, column chromatograph to obtain product 940mg,
Yield is 42%.
1H NMR(400MHz,CDCl3):δ0.89-0.95(m,7H),1.22-1.31(m,2H),1.43(s,3H),1.45-
1.52(m,2H),1.58-1.63(m,1H),1.69-1.75(m,2H),1.79-2.05(m,2H),2.13-2.20(m,1H),
2.30-2.65(m,2H),3.62-3.65(m,1H),3.69-3.72(m,2H),3.76-3.79(m,2H),3.83(s,3H),
3.85-3.91 (m, 1H), 4.82 (d, J=3.2Hz, 1H), 5.50 (s, 1H), 6.84-6.86 (m, 2H), 7.20-7.24 (m,
2H).
(3) reaction equation:
Experimental implementation: Weigh Compound acetyl dihydroartemisinine (1.6g, 5.0mmol) is dissolved in 20mL methylene chloride,
Add alcamine compound (0.9g, 5.0mmol) into the solution.Ice bath is cooled to 0-5 DEG C, and trifluoroacetic acid is added dropwise under stiring
The dichloromethane solution (2mL) of (0.15mL, 2.0mmol), is then slowly ramped to 20-25 DEG C, TLC tracks reaction in time, greatly
Reaction reaches balance after about 4 hours.Reaction solution is successively used to water (pH value for paying attention to measurement washing water), saturated sodium bicarbonate water is molten
Liquid is washed, then is washed to neutrality, is finally washed with saturated common salt aqueous solution, and organic phase is dry with anhydrous sodium sulfate.Filtering, concentration,
Column chromatographs to obtain product 890mg, yield 40%.
The same experimental implementation of nuclear magnetic data (3).
(4) reaction equation:
Experimental implementation: Weigh Compound acetyl dihydroartemisinine (3.3g, 10.0mmol) is dissolved in 20mL methylene chloride,
Add alcamine compound (2.8g, 10.0mmol) into the solution.Ice bath is cooled to 0-5 DEG C, and BF is added dropwise under stiring3.Et2O
The dichloromethane solution (2mL) of (0.5mL, 4.0mmol), is then slowly ramped to 20-25 DEG C, TLC tracks reaction in time, about
Reaction reaches balance after 4 hours.Reaction solution is successively used to water (pH value for paying attention to measurement washing water), saturated sodium bicarbonate aqueous solution
It washes, then is washed to neutrality, finally washed with saturated common salt aqueous solution, organic phase is dry with anhydrous sodium sulfate.Filtering, concentration, column
Chromatograph to obtain pure product 2.75g, yield 50%.
1H NMR(400MHz,CDCl3):δ0.85-0.90(m,7H),1.21-1.31(m,2H),1.38(s,3H),1.42-
1.50(m,2H),1.56-1.62(m,1H),1.67-1.73(m,2H),1.75-2.01(m,2H),2.10-2.21(m,1H),
2.32-2.63 (m, 2H), 3.60-3.62 (m, 1H), 3.68-3.70 (m, 2H), 3.84-3.90 (m, 1H), 4.22 (t, J=
6.5Hz, 1H), 4.43 (d, J=6.7Hz, 2H), 4.85 (d, J=3.2Hz, 1H), 5.52 (s, 1H), 7.30 (t, J=7.4Hz,
2H), 7.36 (t, J=7.4Hz, 2H), 7.59 (d, J=7.5Hz, 2H), 7.75 (d, J=7.5Hz, 2H)
(5) reaction equation:
Experimental implementation: Weigh Compound acetyl dihydroartemisinine (3.2g, 10.0mmol) is dissolved in 20mL methylene chloride,
Add alcamine compound (3.6g, 10.0mmol) into the solution.Ice bath is cooled to 0-5 DEG C, and BF is added dropwise under stiring3.Et2O
The dichloromethane solution (2mL) of (0.5mL, 2.0mmol), is then slowly ramped to 20-25 DEG C, TLC tracks reaction in time, about
Reaction reaches balance after 4 hours.Reaction solution is successively used to water (pH value for paying attention to measurement washing water), saturated sodium bicarbonate aqueous solution
It washes, then is washed to neutrality, finally washed with saturated common salt aqueous solution, organic phase is dry with anhydrous sodium sulfate.Filtering, concentration, column
Chromatograph to obtain pure product 2.7g, yield 44%.
1H NMR(400MHz,CDCl3): δ 0.79-0.85 (m, 7H), 1.15-1.27 (m, 2H), 1.30 (t, J=3.8Hz,
3H),1.39(s,3H),1.39-1.47(m,2H),1.53-1.60(m,1H),1.65-1.71(m,2H),1.73-1.98(m,
2H),2.08-2.17(m,1H),2.31-2.60(m,2H),3.58-3.60(m,1H),3.65-3.69(m,2H),3.85-3.92
(m, 1H), 4.12-4.15 (m, 2H), 4.20 (t, J=6.5Hz, 1H), 4.39 (d, J=6.7Hz, 2H), 4.82 (d, J=
3.2Hz, 1H), 5.50 (s, 1H), 7.31 (t, J=7.4Hz, 2H), 7.39 (t, J=7.4Hz, 2H), 7.61 (d, J=7.5Hz,
2H), 7.79 (d, J=7.5Hz, 2H)
(6) reaction equation:
Experimental implementation: Weigh Compound 105 (8.2g, 25.0mmol) is dissolved in 20mL methylene chloride, into the solution
Add alcamine compound (1.6g, 5.0mmol).Ice bath is cooled to 0-5 DEG C, and BF is added dropwise under stiring3.Et2O(0.5mL,
4.0mmol), it is then slowly ramped to 20-25 DEG C, TLC tracks reaction in time, and reaction reaches balance after about 4 hours.It will reaction
Liquid successively uses water (pH value for paying attention to measurement washing water), and saturated sodium bicarbonate aqueous solution is washed, then is washed to neutrality, finally with saturation
Common salt aqueous solution washing, organic phase are dry with anhydrous sodium sulfate.Filtering, concentration, column chromatograph to obtain product 2.1g, yield 50%.
1H NMR(400MHz,CD2Cl2):0.80-0.97(m,14H),1.16-1.28(m,5H),1.42-1.58(m,
9H),1.49-1.59(m,2H),1.65-1.70(m,4H),1.83-2.03(m,3H),2.31-2.39(m,2H),2.60-2.63
(m,1H),3.29-3.94(m,5H),3.84-3.94(m,1H),4.21-4.25(m,1H),4.40-4.48(m,2H),4.68-
4.77(m,1H),5.31-5.37(m,2H),7.29-7.33(m,2H),7.38-7.41(m,2H),7.56-7.58(m,2H),
7.75-7.70(m,2H).
Embodiment 3: deprotection reaction
(1) reaction equation:
Experimental implementation: Weigh Compound (1.7g, 4mmol) is placed in 50mL round-bottomed flask, and 15mL acetonitrile is added.Backward
Trimethyl iodate alkane (5.1mL, 36mmol) is added in the solution and is stirred at room temperature overnight.After consumption of raw materials is complete, add
Enter methanol and evaporating solvent under reduced pressure.1mol/LNaOH solution (20mL) is added into residue to dilute and be extracted with ethyl acetate
(30mL, TLC detection, confirm water phase in no longer contain product), combined organic phase with saturated common salt water washing (30mL) twice,
Anhydrous sodium sulfate is dry (10g), and after filtering out desiccant, evaporating solvent under reduced pressure obtains yellow oil, yield 85%.
(2) reaction equation:
Experimental implementation: Weigh Compound (890mg, 2mmol) is placed in 50mL round-bottomed flask, and be added 15mL acetonitrile and
3mL deionized water.Then ammonium ceric nitrate (3.3g, 6mmol) is added into the solution.TLC tracking reaction, it is complete to consumption of raw materials
Afterwards, evaporating solvent under reduced pressure.Deionized water (20mL) is added into residue to dilute and (30mL, TLC inspection is extracted with ethyl acetate
Survey, confirm water phase in no longer contain product), combined organic phase with saturated common salt water washing (30mL) twice, anhydrous sodium sulfate
Dry (10g), after filtering out desiccant, evaporating solvent under reduced pressure obtains yellow oil, yield 87%.
(3) reaction equation:
Experimental implementation: Weigh Compound (1.2g, 3.33mmol) is placed in 100mL round-bottomed flask, and 25mL THF is added
Dissolve it all.Then tetrabutyl ammonium fluoride (1.4mL, 0.5mol) is added into the solution, continues to stir at 25 DEG C.
TLC tracking reaction is added deionized water (20mL) and dilutes and (30mL, TLC is extracted with ethyl acetate after consumption of raw materials is complete
Detection, confirm water phase in no longer contain product), combined organic phase with saturated common salt water washing (30mL) twice, anhydrous slufuric acid
Sodium is dry (10g), and after filtering out desiccant, evaporating solvent under reduced pressure obtains yellow oil, yield 90%
(4) reaction equation:
Experimental implementation: Weigh Compound (1.83g, 3.33mmol) is placed in 50mL round-bottomed flask and 30mL dichloromethane is added
Alkane stirs at room temperature dissolves it all, and DBU (1.5mL, 10mmol) is added into the solution and continues to stir at room temperature
Overnight.It is complete to consumption of raw materials, it is added deionized water (20mL), stratification.Organic phase is washed with saturated salt solution (20mL),
Anhydrous sodium sulfate filtering.Evaporating solvent under reduced pressure after desiccant is filtered out, yellow oil, yield 92% are obtained.
(5) reaction equation:
Experimental implementation: Weigh Compound (3.1g, 5mmol) is placed in 50mL round-bottomed flask, and 15mL acetonitrile is added.Backward
Trimethyl iodate alkane (5.7mL, 40mmol) is added in the solution and is stirred at room temperature overnight.After consumption of raw materials is complete, add
Enter methanol and evaporating solvent under reduced pressure.1mol/LNaOH solution (20mL) is added into residue to dilute and be extracted with ethyl acetate
(30mL, TLC detection, confirm water phase in no longer contain product), combined organic phase with saturated common salt water washing (30mL) twice,
Anhydrous sodium sulfate is dry (10g), and after filtering out desiccant, evaporating solvent under reduced pressure obtains yellow oil, yield 85%.
(6) reaction equation:
Experimental implementation: Weigh Compound (800mg, 0.94mmol) is placed in 50mL round-bottomed flask, and 8mL THF is added makes
It is all dissolved.Then tetrabutyl ammonium fluoride (0.64mL, 1.34mmol) is added into the solution, continues to stir at 25 DEG C.
TLC tracking reaction is added deionized water (20mL) and dilutes and (30mL, TLC is extracted with ethyl acetate after consumption of raw materials is complete
Detection, confirm water phase in no longer contain product), combined organic phase with saturated common salt water washing (30mL) twice, anhydrous slufuric acid
Sodium is dry (10g), and after filtering out desiccant, evaporating solvent under reduced pressure obtains yellow oil, yield 88%.
Embodiment 4: salt-forming reaction
(1) reaction equation:
Experimental implementation: weighing sweet wormwood alkhyl ethers amine (1.09g, 3.3mmol), weighs maleic acid (306mg, 2.64mmol)
And it is dissolved with ethyl acetate (10.0mL), and be slowly added dropwise in the ethyl acetate solution of above-mentioned gained compound.It is added dropwise
Afterwards, 15min is stood at 0 DEG C, is then filtered, and with ethyl alcohol/n-hexane recrystallization after filtration cakes torrefaction, obtains pure compounds, yield
It is 30%.
1H NMR(400MHz,CD2Cl2):δ0.87-0.94(m,7H),1.21-1.38(m,2H),1.42(s,3H),
1.45-1.48(m,2H),1.59-1.69(m,2H),1.71-1.77(m,1H),1.85-1.90(m,1H),2.00-2.05(m,
1H),2.32-2.40(m,1H),2.65-2.67(m,1H),3.30-3.32(m,2H),3.73-3.78(m,1H),4.08-4.14
(m, 1H), 4.86 (d, J=3.2Hz, 1H), 5.45 (s, 1H), 6.23 (s, 2H), 8.14-8.16 (m, 2H)
13C NMR(100MHz,CDCl3):δ12.83,20.31,24.49,24.67,26.09,30.75,34.54,
36.33,37.23,39.92,44.15,52.41,65.03,80.96,88.03,102.69,104.26,135.90,170.06.
(2) reaction equation:
Experimental implementation: sweet wormwood alkhyl ethers amine (1.09g, 3.3mmol) is weighed, is cooled to room temperature hereinafter, weighing maleic acid
It (770mg, 6.6mmol) and is dissolved with ethyl acetate (20.0mL), and the ethyl acetate into above-mentioned gained compound is slowly added dropwise
In solution.After being added dropwise, 15min is stood at 0 DEG C, is then filtered, with ethyl alcohol/n-hexane recrystallization after filtration cakes torrefaction, obtain
Pure compounds, yield 25%.
1H NMR(400MHz,CD2Cl2):δ0.92-0.96(m,7H),1.21-1.38(m,2H),1.42(s,3H),
1.45-1.48(m,2H),1.59-1.69(m,2H),1.71-1.77(m,1H),1.85-1.90(m,1H),2.00-2.05(m,
1H),2.32-2.40(m,1H),2.65-2.67(m,1H),3.30-3.32(m,2H),3.73-3.78(m,1H),4.08-4.14
(m, 1H), 4.86 (d, J=3.2Hz, 1H), 5.45 (s, 1H), 6.23 (s, 4H), 8.14-8.16 (m, 4H)
(3) reaction equation:
Experimental implementation: double sweet wormwood alkhyl ethers amine (640mg, 1mmol) are weighed, are cooled to room temperature hereinafter, weighing maleic acid
It (90mg, 0.8mmol) and is dissolved with ethyl acetate (5mL), and the ethyl acetate solution into above-mentioned gained compound is slowly added dropwise
In.After being added dropwise, 15min is stood at 0 DEG C, is then filtered, with ethyl alcohol/n-hexane recrystallization after filtration cakes torrefaction, obtain chemical combination
Object sterling 300mg, yield 40%.
1H NMR(400MHz,CD2Cl2):0.92-0.96(m,14H),1.24-1.37(m,11H),1.43-1.51(m,
4H),1.60-1.64(m,4H),1.74-1.79(m,2H),1.87-1.92(m,2H),2.01-2.07(m,2H),2.29-1.37
(m, 2H), 2.62-2.65 (m, 2H), 3.40 (s, 4H), 3.83-3.86 (m, 2H), 4.10-4.15 (m, 2H), 4.82 (d, J=
3.2Hz,2H),5.14(s,2H),6.37(s,4H).
(4) reaction equation:
Experimental implementation: double sweet wormwood alkhyl ethers amine (640mg, 1mmol) are weighed, are cooled to room temperature hereinafter, weighing maleic acid
It (90mg, 0.75mmol) and is dissolved with ethyl acetate (5mL), and the ethyl acetate solution into above-mentioned gained compound is slowly added dropwise
In.After being added dropwise, 15min is stood at 0 DEG C, is then filtered, with ethyl alcohol/n-hexane recrystallization after filtration cakes torrefaction, obtain chemical combination
Object sterling 260mg, yield 35%.The double maleate nuclear magnetic resonance spectroscopies of double arteether amine are shown in Fig. 1.
1H NMR(400MHz,CD2Cl2):0.89-0.96(m,14H),1.21-1.4(m,12H),1.42-1.58(m,
3H),1.69-1.79(m,4H),1.86-1.91(m,2H),1.99-2.05(m,2H),2.32-2.41(m,4H),3.22-3.34
(m, 4H), 4.05-4.07 (m, 4H), 4.53 (d, J=9.2Hz, 2H), 5.42 (s, 2H), 6.26 (s, 4H)
The preferred embodiment of the present invention has been described in detail above, but the invention be not limited to it is described
Embodiment, those skilled in the art can also make various equivalent on the premise of not violating the inventive spirit of the present invention
Variation or replacement, these equivalent variation or replacement are all included in the scope defined by the claims of the present application.
Claims (7)
1. a kind of method that stereoselectivity prepares β type mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl ether amine maleate, special
Sign is, comprising the following steps:
(i) amido protecting of β type mono-/bis-sweet wormwood (symmetrical and asymmetric) alkyl alcoholamine: select different blocking group P to hydramine
Class compound is protected, and the amido alcohol containing blocking group is obtained, as shown in following formula (3) and (4):
Work as P1When=H, P2For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, tablet held before the breast by officials methoxycarbonyl group, trimethyl silicane ethoxy
Carbonyl, methoxycarbonyl group, carbethoxyl group, 2,4- dimethoxy-benzyl or to methoxy-benzyl；
Work as P1、P2When ≠ H, P1、P2For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, tablet held before the breast by officials methoxycarbonyl group, trimethyl silicane
The combination of carbethoxyl group, methoxycarbonyl group, carbethoxyl group, 2,4- dimethoxy-benzyl or any two to methoxy-benzyl, or
P1-P2For
Wherein R is H ,-NO2、-Cl、-F、-Br、-CF3,-CN and-NHCOCH3Combination, including more than one or both of them
And the different combination in position of substituent group；
Wherein, P3For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, tablet held before the breast by officials methoxycarbonyl group, trimethylsilyl ethoxycarbonyl,
Methoxycarbonyl group, carbethoxyl group, 2,4- dimethoxy-benzyl or to methoxy-benzyl；
(ii) condensation reaction:
1) use amido alcohol compound containing blocking group obtained by (i) and acetyl dihydroartemisinine in the effect of acidic catalyst
Under, Stereoselective generates single sweet wormwood alkyl ether amine that α, β type that β type is primary product mix, as shown in following formula (5):
Work as P1When=H, P2For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, tablet held before the breast by officials methoxycarbonyl group, trimethyl silicane ethoxy
Carbonyl, methoxycarbonyl group, carbethoxyl group, 2,4- dimethoxy-benzyl or to methoxy-benzyl；
Work as P1、P2When ≠ H, P1、P2For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, tablet held before the breast by officials methoxycarbonyl group, trimethyl silicane
The combination of carbethoxyl group, methoxycarbonyl group, carbethoxyl group, 2,4- dimethoxy-benzyl or any two to methoxy-benzyl, or
P1-P2For
Wherein R is H ,-NO2、-Cl、-F、-Br、-CF3,-CN and-NHCOCH3Combination include one or both of them or more
And the different combination in position of substituent group；
2) use amido alcohol compound containing blocking group obtained by (i) and acetyl dihydroartemisinine in the effect of acidic catalyst
Under, Stereoselective generates double sweet wormwoods (symmetrical and asymmetric) alkyl ether amine that α, β type that β type is primary product mix, such as
Shown in following formula (6):
Wherein, P3For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, tablet held before the breast by officials methoxycarbonyl group, trimethylsilyl ethoxycarbonyl,
Methoxycarbonyl group, carbethoxyl group, 2,4- dimethoxy-benzyl or to methoxy-benzyl；
The sweet wormwood alkyl ether amine of α, β type mixing is recrystallized to give optically pure β type sweet wormwood alkyl ether amine；
(iii) deprotection reaction:
1) deprotection reaction is carried out to optically pure β type list sweet wormwood alkyl ether amine obtained by (ii), obtains optically pure β type list sweet wormwood
Alkyl ether amine, as shown in following formula (7):
Work as P1When=H, P2For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, tablet held before the breast by officials methoxycarbonyl group, trimethyl silicane ethoxy
Carbonyl, methoxycarbonyl group, carbethoxyl group, 2,4- dimethoxy-benzyl or to methoxy-benzyl；
Work as P1、P2When ≠ H, P1、P2For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, tablet held before the breast by officials methoxycarbonyl group, trimethyl silicane
The combination of carbethoxyl group, methoxycarbonyl group, carbethoxyl group, 2,4- dimethoxy-benzyl or any two to methoxy-benzyl, or
P1-P2For
Wherein R is H ,-NO2、-Cl、-F、-Br、-CF3,-CN and-NHCOCH3Combination include one or both of them or more
And the different combination in position of substituent group；
2) deprotection reaction is carried out to the double sweet wormwoods of optically pure β type obtained by (ii) (symmetrical and asymmetric) alkyl ether amine, obtains light
The double sweet wormwoods of pure β type (symmetrical and asymmetric) alkyl ether amine is learned, as shown in following formula (8):
Wherein, P3For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, tablet held before the breast by officials methoxycarbonyl group, trimethylsilyl ethoxycarbonyl,
Methoxycarbonyl group, carbethoxyl group, 2,4- dimethoxy-benzyl or to methoxy-benzyl；
(iv) salt-forming reaction:
1) light is obtained at salt to optically pure single β type list sweet wormwood alkyl ether amine and maleic acid without blocking group obtained by (vi)
Pure β type list sweet wormwood alkyl ether amine maleate is learned, as shown in following formula (9):
2) to the double sweet wormwoods of the optically pure β type without blocking group obtained by (vi) (symmetrical and asymmetric) alkyl ether amine and maleic acid
At salt, the double sweet wormwoods of optically pure β type (symmetrical and asymmetric) alkyl ether amine maleate is obtained, as shown in following formula (10):
β type mono-/bis-sweet wormwood (symmetrical and asymmetric) the alkyl ether amine maleate is by being recrystallized to give pure compounds.
It is right under the conditions of existing for the solvent and alkali 2. the method according to claim 1, wherein in step (i)
Alcamine compound carries out amido protecting, obtains mono-/bis-(symmetrical and asymmetric) alkylamine containing blocking group.
3. according to the method described in claim 2, it is characterized in that, alkali used includes: sodium hydroxide, carbonic acid in step (i)
Sodium, potassium carbonate, sodium bicarbonate, triethylamine, bis- (trimethyl silicon substrate) Sodamides or bis- (trimethyl silicon substrate) potassamides；It reacts with molten
Agent is tetrahydrofuran, chloroform, methylene chloride, ethyl alcohol, ether, 1,4- dioxane, methanol, N,N-dimethylformamide, acetic acid
Ethyl ester, toluene or acetonitrile.
4. the method according to claim 1, wherein acidic catalyst used is borontrifluoride in step (ii)
Diethyl etherate or trifluoracetic acid；Anti- solvent-applied is tetrahydrofuran, chloroform, methylene chloride, 1,2- dichloroethanes or ether；
Recrystallization is n-hexane, petroleum ether, hexamethylene, normal heptane, ether, methylene chloride, ethyl acetate, ethyl alcohol or methanol with solvent.
5. the method according to claim 1, wherein the reagent of deprotection includes tetramethyl in step (iii)
Amine fluoride, tetraethyl ammonium fluoride, tetrabutyl ammonium fluoride, piperidines, ethanol amine, cyclohexylamine, morpholine, pyrrolidones, DBU and three second
Amine, Iodotrimethylsilane, p-methyl benzenesulfonic acid, methanesulfonic acid, CAN, DDQ, samarium diodide, hydrazine hydrate or sodium borohydride.
6. the method according to claim 1, wherein deprotection reaction is Isosorbide-5-Nitrae-with solvent in step (iii)
Dioxane, chloroform, acetonitrile, methylene chloride, ethyl alcohol, methylene chloride, tetrahydrofuran, ether or isopropanol.
7. the method according to claim 1, wherein acid used is maleic acid, and reacts institute in step (iv)
It is ethyl acetate or ether with solvent；Recrystallize solvent for use are as follows: ethyl alcohol/n-hexane, ethyl alcohol/normal heptane, ethanol/cyclohexane,
Or ethyl alcohol/petroleum ether.
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