CN104557911B - A kind of preparation method of levo-praziquantel - Google Patents
A kind of preparation method of levo-praziquantel Download PDFInfo
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- CN104557911B CN104557911B CN201310487924.4A CN201310487924A CN104557911B CN 104557911 B CN104557911 B CN 104557911B CN 201310487924 A CN201310487924 A CN 201310487924A CN 104557911 B CN104557911 B CN 104557911B
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- CN
- China
- Prior art keywords
- praziquantel
- levo
- formula
- preparation
- tetrahydroisoquinoline
- Prior art date
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- 229960002957 praziquantel Drugs 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 29
- 102000004674 D-amino-acid oxidase Human genes 0.000 claims abstract description 21
- 108010003989 D-amino-acid oxidase Proteins 0.000 claims abstract description 21
- 102000016938 Catalase Human genes 0.000 claims abstract description 10
- 108010053835 Catalase Proteins 0.000 claims abstract description 10
- 229910000085 borane Inorganic materials 0.000 claims abstract description 10
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000000694 effects Effects 0.000 claims abstract description 7
- 238000006722 reduction reaction Methods 0.000 claims abstract description 4
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 49
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 42
- 239000007787 solid Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 19
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 14
- 102000004190 Enzymes Human genes 0.000 claims description 13
- 108090000790 Enzymes Proteins 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- -1 carboxylic acid ion Chemical class 0.000 claims description 9
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 5
- 230000004913 activation Effects 0.000 claims description 4
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 241000588724 Escherichia coli Species 0.000 claims description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 239000000411 inducer Substances 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 238000005215 recombination Methods 0.000 claims description 3
- 230000006798 recombination Effects 0.000 claims description 3
- 238000006479 redox reaction Methods 0.000 claims description 3
- 239000006228 supernatant Substances 0.000 claims description 3
- JBANFLSTOJPTFW-UHFFFAOYSA-N azane;boron Chemical compound [B].N JBANFLSTOJPTFW-UHFFFAOYSA-N 0.000 claims description 2
- RJTANRZEWTUVMA-UHFFFAOYSA-N boron;n-methylmethanamine Chemical compound [B].CNC RJTANRZEWTUVMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002091 cationic group Chemical group 0.000 claims description 2
- 230000000536 complexating effect Effects 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000005457 ice water Substances 0.000 claims description 2
- 238000011081 inoculation Methods 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- YRWWOAFMPXPHEJ-OFBPEYICSA-K sodium L-ascorbic acid 2-phosphate Chemical compound [Na+].[Na+].[Na+].OC[C@H](O)[C@H]1OC(=O)C(OP([O-])([O-])=O)=C1[O-] YRWWOAFMPXPHEJ-OFBPEYICSA-K 0.000 claims description 2
- 229940048058 sodium ascorbyl phosphate Drugs 0.000 claims description 2
- 238000002525 ultrasonication Methods 0.000 claims description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims 1
- 229960000723 ampicillin Drugs 0.000 claims 1
- 229910052796 boron Inorganic materials 0.000 claims 1
- 239000013049 sediment Substances 0.000 claims 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract description 47
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 abstract description 18
- 235000019253 formic acid Nutrition 0.000 abstract description 18
- 239000000047 product Substances 0.000 abstract description 9
- 150000003839 salts Chemical class 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- 230000007613 environmental effect Effects 0.000 abstract description 4
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 abstract 12
- 125000003368 amide group Chemical group 0.000 abstract 1
- 150000004675 formic acid derivatives Chemical class 0.000 abstract 1
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000001556 precipitation Methods 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 9
- 239000001103 potassium chloride Substances 0.000 description 9
- 235000011164 potassium chloride Nutrition 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 230000000813 microbial effect Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 230000006340 racemization Effects 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- PNLHOCUNLNUFIH-ZDUSSCGKSA-N tert-butyl (1r)-1-(hydroxymethyl)-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C1=CC=C2[C@H](CO)N(C(=O)OC(C)(C)C)CCC2=C1 PNLHOCUNLNUFIH-ZDUSSCGKSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000007836 KH2PO4 Substances 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- PVYPHUYXKVVURH-UHFFFAOYSA-N boron;2-methylpropan-2-amine Chemical compound [B].CC(C)(C)N PVYPHUYXKVVURH-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910001385 heavy metal Inorganic materials 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- OXFGRWIKQDSSLY-VIFPVBQESA-N (1s)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Chemical compound C1=CC=C2[C@@H](C(=O)O)NCCC2=C1 OXFGRWIKQDSSLY-VIFPVBQESA-N 0.000 description 2
- 0 CC1N(C[C@@]2N(*)CCc3ccccc23)C2(CC2)c2c1cccc2 Chemical compound CC1N(C[C@@]2N(*)CCc3ccccc23)C2(CC2)c2c1cccc2 0.000 description 2
- 150000008574 D-amino acids Chemical class 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- XAAKCCMYRKZRAK-UHFFFAOYSA-N isoquinoline-1-carboxylic acid Chemical class C1=CC=C2C(C(=O)O)=NC=CC2=C1 XAAKCCMYRKZRAK-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 2
- 235000019254 sodium formate Nutrition 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- FSVJFNAIGNNGKK-KRWDZBQOSA-N (11br)-2-(cyclohexanecarbonyl)-3,6,7,11b-tetrahydro-1h-pyrazino[2,1-a]isoquinolin-4-one Chemical compound N1([C@H](C2=CC=CC=C2CC1)C1)C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-KRWDZBQOSA-N 0.000 description 1
- SHNMAZJVVFUXAQ-UHFFFAOYSA-N 2h-quinoline-1-carboxylic acid Chemical class C1=CC=C2N(C(=O)O)CC=CC2=C1 SHNMAZJVVFUXAQ-UHFFFAOYSA-N 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WFAQUYZCXCZOAU-UHFFFAOYSA-N CC(C)(C)OC(N1C(CNC(C2CCCCC2)=N)c2ccccc2CC1)=O Chemical compound CC(C)(C)OC(N1C(CNC(C2CCCCC2)=N)c2ccccc2CC1)=O WFAQUYZCXCZOAU-UHFFFAOYSA-N 0.000 description 1
- 241000242722 Cestoda Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 206010009344 Clonorchiasis Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 206010014096 Echinococciasis Diseases 0.000 description 1
- 208000009366 Echinococcosis Diseases 0.000 description 1
- 241000244160 Echinococcus Species 0.000 description 1
- 241001126309 Fasciolopsis Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N O=C(C1CCCCC1)Cl Chemical compound O=C(C1CCCCC1)Cl RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 241000242683 Schistosoma haematobium Species 0.000 description 1
- 241000242680 Schistosoma mansoni Species 0.000 description 1
- 241001442514 Schistosomatidae Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- FGFSNEVQGWVKAU-UHFFFAOYSA-N [NH4+].C1(=NC=CC2=CC=CC=C12)C(=O)[O-] Chemical compound [NH4+].C1(=NC=CC2=CC=CC=C12)C(=O)[O-] FGFSNEVQGWVKAU-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007678 heart toxicity Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- GPBRIMOJKVDGLP-UHFFFAOYSA-N isoquinoline;pyrazine Chemical class C1=CN=CC=N1.C1=NC=CC2=CC=CC=C21 GPBRIMOJKVDGLP-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 206010033794 paragonimiasis Diseases 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
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Abstract
The present invention relates to the preparation method of levo-praziquantel, it includes with (R, S) tetrahydroisoquinoline 1 formic acid or its salt, or 1 (S) tetrahydroisoquinoline 1 formic acid or its salt are that raw material prepares the step of 1 (R) tetrahydroisoquinoline 1 formates and by this salt to prepare the step of levo-praziquantel, the method of preparation 1 (R) tetrahydroisoquinoline 1 formic acid or its salt is as follows: first make described raw material and oxygen that oxidation reaction occurs in the presence of restructuring D amino acid oxidase and catalase, then oxidation reaction products therefrom is made to issue raw reduction reaction in the effect of borine amido complex compound, realize 1 (S) tetrahydroisoquinoline 1 formic acid or its salt is continuously converted to 1 (R) tetrahydroisoquinoline 1 formic acid or its salt isomers.The present invention is possible not only to obtain the levo-praziquantel product of more high-optical-purity, and cost is lower, produces more environmental protection.
Description
Technical field
The present invention relates to the preparation method of a kind of levo-praziquantel ((R)-praziquantel).
Background technology
Praziquantel is the pyrazine isoquinoline derivative of Prof. Du Yucang, has another name called ring praziquantel, white or off-white color
Crystalline powder, bitter, is universally acknowledged high-efficiency broad spectrum anti-parasite medicine, is widely used in treatment Japan
Blood fluke, Schistosoma haematobium, Schistosoma mansoni, clonorchiasis, paragonimiasis, Meng Shi pleroceroid,
The diseases such as fasciolopsis, Echinococcus hydatid cyst, tapeworm and cysticercus.It has, and pest-resistant spectrum is wide, curative effect is high, toxicity is low, treatment
The advantages such as journey is short and easy to use.In addition to for human body, it is also widely used in the anti-of animal, poultry etc. and posts
Infested treatment.The appearance of praziquantel is an important breakthrough in parasitic disease chemotherapy history, and praziquantel is current
It it is the choice drug treating multiple parasitic disease on market.
Praziquantel is the racemic compound collectively constituted by left-handed and dextrorotation praziquantel, and scientific research personnel is from conjunction
Become praziquantel splits and obtain levo-praziquantel and dextrorotation praziquantel optical isomer, and by before clinical and
Initial clinical experience finds: levo-praziquantel is effective insecticidal constituent of praziquantel, and dextrorotation praziquantel is
Invalid even harmful components；Under same dose, levo-praziquantel clinical efficacy is more preferable than praziquantel, dextrorotation
Praziquantel is then almost without curative effect, bitter, and is the main generation source of drug side-effect.To heart
Toxicity levo form is lower than d-isomer, and therefore exploitation levo-praziquantel replaces praziquantel, will have curative effect higher,
Toxic and side effect is less, the more preferable clinical value of medical science compliance.Although World Health Organization's expectation is used
Levo-praziquantel replacement praziquantel, but the process difficulties one that the yield of levo-praziquantel chemical synthesis for many years is low
Directly hang and do not solve.
First praziquantel was synthesized by Seubere et al. in 1975, Germany Merck and Bayer two
This kind of medicine is successfully developed in pharmaceutical factory.1980, on Merck company takes the lead in trade name Cesol
City, the most extensively applies.Praziquantel to use that some are poisonous in process of production, have
The chemical substance of evil, such as potassium cyanide, heavy metal etc., and its process route is longer, and reaction condition is also
Relatively harsh (high temperature, high pressure).And this kind of course of reaction to control difficulty relatively big, seriously polluted.
The synthesis of levo-praziquantel currently mainly has three kinds of methods:
1, chemical resolution method: using racemization intermediate or racemization praziquantel is raw material, passes through chemical resolution
Synthesis levo-praziquantel (Resolution of Praziquantel, Matthew H.Todd1,
Australia,PLOS,Neglected Troplcal Diseases,September2011,
Volume5, Issue9, e1260), synthetic route is as follows:
The method complex operation, yield is low, needs to use severe toxicity raw material and heavy metal and HTHP bar
Part, environmental pollution is serious.
2, method of enzymatic resolution: needing dextrorotation racemization, process is loaded down with trivial details, and total recovery has much room for improvement.(CN
102911979A, a kind of method preparing levo-praziquantel).
3, enzymatic Dynamic Kinetic conversion method: crucial chiral intermediate is by lipase-catalyzed dynamic
Prepared by kinetic transformation.But enzyme catalyst consumption is big, enzyme catalyst and raw material dosage reach 1:1, after
Processing complexity, labour intensity is big, and product optical purity needs to meet pharmacy needs by recrystallization,
Relatively costly.
Summary of the invention
The technical problem to be solved is to overcome the deficiencies in the prior art, it is provided that a kind of new left-handed
The preparation method of praziquantel.
For solving above technical problem, the present invention adopts the following technical scheme that:
A kind of preparation method of levo-praziquantel, it compound including representing with formula 2a (such as (R, S)-
Tetrahydroisoquinoline-1-formic acid or its salt) or compound (such as 1-(S)-tetrahydroisoquinoline of representing of formula 2b
-1-formic acid or its salt) come the step of intermediate that formula 1 represents and the intermediate represented by formula 1
(1-(R)-tetrahydroisoquinoline-1-formates) prepares the step of levo-praziquantel:
In formula 1,2a and 2b, X+Identical, and represent the cationic moiety contended with carboxylic acid ion；
The method of the intermediate that formula 1 represents is as follows: the compound first making formula 2a or 2b represent and oxygen
There is oxidation reaction in gas in the presence of recommbined D-amino acid oxidase and catalase, then makes oxidation
Reaction products therefrom issues, in the effect of borine-amido complex compound, the centre that raw reduction reaction production 1 represents
Body.
Preferably, in formula 1,2a and 2b, X+Represent H+, K+、Na+Or NH4 +.Now, formula 1
The intermediate represented is specially 1-(R)-tetrahydroisoquinoline-1-formic acid sylvite, 1-(R)-tetrahydroisoquinoline-1-first
Acid sodium-salt, 1-(R)-tetrahydroisoquinoline-1-formic acid ammonium salt or 1-(R)-tetrahydroisoquinoline-1-formic acid.
According to the present invention, the preparation method of described recommbined D-amino acid oxidase is: will be containing D-amino acid
The recombination bacillus coli list colony inoculation of oxidase gene is cultivated to the liquid LB containing amicillin resistance
In base, activated overnight 12～16 hours at 37 ± 1 DEG C, the culture that will obtain after activation is inoculated into containing ammonia
In the LB liquid medium of parasiticin resistance, shaken cultivation at 37 ± 1 DEG C, to OD600Value reaches
When 0.6～0.8, add inducer isopropylthio-β-D-thiogalactoside to final concentration of
0.8mmol/L～1.0mmol/L, continues to cultivate 8～10 hours at 30 ± 1 DEG C, centrifugal, collects precipitation
Thing, the phosphate buffer adding pH7～9 obtains suspension, suspension is placed in ultrasonication in ice-water bath,
It is centrifuged again, supernatant pre-freeze to temperature is down to-20 DEG C～-30 DEG C, then freeze-drying 34～40 hours,
Obtain lyophilized powdery recommbined D-amino acid oxidase.
According to the present invention, described borine-amido complex compound can be to be selected from as ammonia borane complex compound, borine two
Methylamine complex compound, borine-triethylamine complex, borine tert-butylamine complex compound, borine diethylamine complex compound with
And borine N, the combination of one or more in N-amine complex.
The compound represented according to the present invention, formula 2a or 2b and the molar ratio of borine-amido complex compound
It is preferably 1:1.1～5.The inventory of recommbined D-amino acid oxidase and hydrogen peroxide account for substrate formula 2a or
The mass percent of the compound that 2b represents is respectively preferably 4%～6%(such as 5%) and 0.5%～1.5%
(such as 1%).
Further, make oxidation reaction and reduction reaction in the aqueous phase cushioning liquid of pH7.5～9.0, temperature
Carry out at spending 15 DEG C～40 DEG C.Preferably pH scope is 8.0～8.5.Preferably temperature range is 20 DEG C
～40 DEG C.
Further, the one during aqueous phase cushioning liquid is preferably selected from sodium ascorbyl phosphate, potassium phosphate, ammoniacal liquor
Or multiple combination.
Preferably, the detailed process of the intermediate that formula 1 represents is as follows: change formula 2a or 2b represented
Compound is dissolved in cushioning liquid, adds borine-amido complex compound, is passed through oxygen or air, adds restructuring D-
Amino acid oxidase and catalase, under stirring, start reaction at described temperature, and HPLC monitors
Reaction process, when the content of the compound represented to formula 2a or 2b is less than 1wt%, stops reaction.
Further: after stopping reaction, heating (50 DEG C～60 DEG C) makes the enzyme generation sex change in system, mistake
Filtering enzyme (diatomite can be used to filter), add acetone in filtrate, the crude product that precipitation is collected by filtration is solid
Body, then recrystallize with the mixed solvent of water and acetone, i.e. obtain the intermediate that formula 1 represents.Wherein,
In the mixed solvent of described water and acetone, water is preferably 1:1～3 with the volume ratio of acetone.
According to a preferred aspect of the present invention, the intermediate represented from Formulas I prepares the route of levo-praziquantel
As follows:
In above-mentioned formula 3 to formula 7, R is identical, and represents amino protecting group.
More specifically, R can be tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group, fluorenes methoxy carbonyl acyl group, alkene
Third oxygen carbonyl or trichloro-ethoxycarbonyl etc..
In above-mentioned route, each step reaction comprised all can by the routine techniques in organic synthesis field or
Means realize, and are not particularly limited.Such as, routine can be used from formula 1 compound to formula 3 compound
Amido protecting method.The method of reducing of routine can be used, such as from formula 3 compound to formula 4 compound
Reducing agent BH can be used3。
Due to the enforcement of above technical scheme, the present invention compared with prior art has the advantage that
The invention provides a kind of is a key intermediate synthesis left side with 1-(R)-tetrahydroisoquinoline-1-formates
The variation route of rotation praziquantel, wherein the preparation of 1-(R)-tetrahydroisoquinoline-1-formates uses chemo-enzymatic process phase
In conjunction with technology, make full use of the High level of stereoselectivity selectivity of recommbined D-amino acid oxidase, make 1-(S)-four
Hydrogen isoquinoline-1-formates changes into 1-tetrahydroisoquinoline imines formates, utilizes water miscible borine simultaneously
It is different that-amido complex compound the most efficiently reduction 1-tetrahydroisoquinoline imines formates generates racemization 1-(R, S)-tetrahydrochysene
Quinoline-1-formates, it is achieved that 1-(S)-tetrahydroisoquinoline-1-formates is efficiently, quickly, the most thoroughly
Deracemization generates enantiomter 1-(R)-tetrahydroisoquinoline-1-formates, with the pick-up rate more than 90%
Obtain optical purity 1-(R)-tetrahydroisoquinoline-1-formates more than 99.0%.Additionally, 1-(R)-tetrahydrochysene
The preparation of isoquinolin-1-formates also has the advantages such as process is simple, post processing is easy.
After efficiently obtaining 1-(R)-tetrahydroisoquinoline-1-formates, from 1-(R)-tetrahydroisoquinoline-1-first
Hydrochlorate then can use the conventional and ripe chemistry in organic synthesis field to the preparation of final levo-praziquantel
Synthetic reaction realizes.
Compared with prior art, the preparation method of levo-praziquantel of the present invention is possible not only to obtain higher optics
The levo-praziquantel product of purity, and cost is lower, produces more environmental protection, for facing further
Before bed and clinical druggability evaluation, large-scale industrialized production levo-praziquantel also enters international market and paves
Road.
Detailed description of the invention
The present invention essentially consists in and carries to overcome the defect existing for the preparation of prior art levo-praziquantel
For a kind of new enzyme Catalytic processes technology, improve the weak point of traditional chemical routes safety and environmental protection,
Reduce existing enzyme catalyst consumption big, the difficult problem that post processing is complicated. solve chemical method by the present invention and produce
In praziquantel and intermediate thereof, the dangerous and problem of pollution, relative to conventional chemical methods, it is advantageous that and keep away
Exempt from hypertoxic raw material Cymag and heavy metal has used, it is to avoid the hazardous reactions such as HTHP, reduced organic molten
Agent consumption, reduces praziquantel and intermediate produces the pollution for environment；By this invention also solves
Traditional biological method produces praziquantel and intermediate enzyme dosage is big, concentration of substrate is low, post processing is complicated, energy
The problems such as consumption is big, efficiency is low, be difficult to control to.
The present invention provides one to utilize recommbined D-amino acid oxidase and water miscible borine-amido complex compound
The method that the most efficiently deracemization prepares 1-(R)-tetrahydroisoquinoline-1-formates.Material used by reaction
In addition to recommbined D-amino acid oxidase, all can be by commercially available.
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the present invention is not limited to
Following example.
The preparation of embodiment 1 recommbined D-amino acid oxidase
From glycerine pipe or convert flat board by the recombination bacillus coli list bacterium containing daao gene
Fall to being inoculated in the 4mL LB liquid medium containing (100ug/mL) amicillin resistance, in 37 DEG C
Lower activation overnight 12～16 hours, contains the culture obtained after activation with 2% inoculum concentration switching
(100ug/mL) the 100mL LB liquid medium of amicillin resistance, in 37 DEG C, 220rpm
Shaken cultivation is to OD600Value reaches about 0.6, adds inducer isopropylthio-β-D-thiogalactoside extremely
Final concentration 0.8mmol/L, continues overnight incubation in 30 DEG C.Centrifugal (4 DEG C, 5000rpm, 15min) are collected
Cell, with 10mL phosphate buffer (100mM, pH7.0) suspension cell.Cell suspending liquid is put
Ultrasonic disruption 10 minutes in ice bath, more centrifugal (4 DEG C, 12000rpm, 15min), supernatant in
-20 DEG C of pre-freezes overnight, then freeze-drying 34～40 hours, obtain lyophilized powdery recommbined D-amino acid
Oxidizing ferment.
The preparation of embodiment 2 intermediate 1-(R)-tetrahydroisoquinoline formic acid ammonium salt
1.77g (0.01mol) DL-tetrahydroisoquinoline-1-formic acid is dissolved in 5ml ammoniacal liquor and (regulates pH extremely
8.0), add 1.5g (0.05mol) borane-ammonia complex, be at the uniform velocity passed through oxygen, add 88.5mg
Recommbined D-amino acid oxidase and 18mg catalase, under stirring, start reaction, HPLC in 28 DEG C
Detection reaction process.About 28 hours HPLC testing result display 1-(S)-tetrahydroisoquinoline-1-ammonium formates
Salt is less than 1%.Stopping reaction, be heated to 50-60 DEG C, half an hour, above anaenzyme albumen, heated
Reaction through diatomite filter dezymotize, in filtrate add 2 times of volumes of reactant liquor acetone dilution, filter receive
The crude solid that collection separates out, then it is recrystallized to give pure white solid 1.8g through water/acetone (volume ratio 1/2),
It is intermediate 1-(R)-tetrahydroisoquinoline formic acid ammonium salt, microbial recovery rate 92.5%, e.e. value 99.3%.
This example products therefrom nuclear magnetic data is as follows:1H-NMR(400MHz,D2O, δ ppm):
3.07–3.10(m,2H,H-4),3.45–3.66(m,2H,H-3),4.95(s,1H,H-1),
7.29 7.54 (m, 4H, Ph), confirm as 1-(R)-tetrahydroisoquinoline formic acid ammonium salt.
The preparation of embodiment 3 intermediate 1-(R)-tetrahydroisoquinoline formic acid sylvite
1.77g (0.01mol) DL-tetrahydroisoquinoline-1-formic acid is dissolved in 5ml K2HPO4-KH2PO4Slow
In dissolved liquid (regulation pH to 8.2), add 2.61g (0.03mol) borane-t-butylamine complex compound, even
Speed is passed through oxygen, adds 35.5mg recommbined D-amino acid oxidase, 9mg catalase, stirring
Under, starting reaction in 35 DEG C, HPLC detects reaction process.About 30 hours HPLC testing results
Display 1-(S)-tetrahydroisoquinoline-1-formic acid sylvite is less than 1%.Stop reaction, be heated to 50-60 DEG C,
Half an hour above anaenzyme albumen, heated reaction through diatomite filter dezymotize, filtrate is through toluene
(3x5ml) extraction, toluene reclaims tert-butylamine (2.1g) mutually.Aqueous phase after extraction adds reactant liquor 2
The acetone dilution of times volume, is collected by filtration the crude solid of precipitation, then through water/acetone (volume ratio 1/2)
It is recrystallized to give pure white solid 1.98g, is intermediate 1-(R)-tetrahydroisoquinoline formic acid sylvite, point
From pick-up rate 91.8%, e.e. value 99.2%.
The preparation of embodiment 4 intermediate 1-(R)-tetrahydroisoquinoline formic acid sodium salt
1.77g (0.01mol) DL-tetrahydroisoquinoline-1-formic acid is dissolved in 5ml Na2HPO4-NaH2PO4
In cushioning liquid (regulation pH to 8.0), add 1.77g (0.03mol) borane-dimethyl amine complex,
At the uniform velocity it is passed through air, adds 53.5mg recommbined D-amino acid oxidase and 9mg catalase, stir
Mixing down, start reaction in 37 DEG C, HPLC detects reaction process.About 32 hours HPLC detection knots
Fruit display 1-(S)-tetrahydroisoquinoline-1-formic acid sodium salt is less than 1%.Stop reaction, be heated to 50-60 DEG C,
Half an hour above anaenzyme albumen, heated reaction through diatomite filter dezymotize, in filtrate add reaction
The acetone dilution of 2 times of volumes of liquid, is collected by filtration the crude solid of precipitation, then through water/acetone (volume ratio
1/2) it is recrystallized to give pure white solid 1.86g, is compound 1-(R)-tetrahydroisoquinoline formic acid sodium salt,
Microbial recovery rate 93.1%, e.e. value 99.3%.
The preparation of embodiment 5 intermediate 1-(R)-tetrahydroisoquinoline formic acid ammonium salt
1.77g (0.01mol) DL-tetrahydroisoquinoline-1-formic acid is dissolved in 5ml ammonia spirit (regulation
PH to 8.5), add 3.45g (0.03mol) borine-triethylamine complex compound, be slowly introducing air,
Adding 70.8mg recommbined D-amino acid oxidase, 12mg catalase, under stirring, in 40 DEG C
Starting reaction, HPLC detects reaction process.Within about 28 hours, HPLC testing result shows 1-(S)-four
Hydrogen isoquinoline-1-formic acid ammonium salt is less than 1%.Stop reaction, be heated to 50-60 DEG C, more than half an hour become
Property zymoprotein, heated reaction is filtered through diatomite and is dezymotized, and adds reactant liquor 2 times of volumes in filtrate
Acetone dilutes, and the crude solid of precipitation is collected by filtration, then recrystallizes through water/acetone (volume ratio 1/2)
To pure white solid 1.81g, it is compound 1-(R)-tetrahydroisoquinoline formic acid ammonia salt, microbial recovery rate
93.3%, e.e. value 99.3%.
The preparation of embodiment 6 intermediate 1-(R)-tetrahydroisoquinoline formic acid sylvite
1.77g (0.01mol) (S)-tetrahydroisoquinoline-1-formic acid is dissolved in 5ml K2HPO4-KH2PO4Slow
In dissolved liquid (regulation pH to 8.2), add 3.48g (0.04mol) borane-t-butylamine complex compound, even
Speed is passed through oxygen, adds 47.5mg recommbined D-amino acid oxidase, 12mg catalase, stirs
Mixing down, start reaction in 35 DEG C, HPLC detects reaction process.About 35 hours HPLC detection knots
Fruit display 1-(S)-tetrahydroisoquinoline-1-formic acid sylvite is less than 1%.Stop reaction, be heated to 50-60 DEG C,
Half an hour above anaenzyme albumen, heated reaction through diatomite filter dezymotize, filtrate add reactant liquor
The acetone dilution of 2 times of volumes, is collected by filtration the crude solid of precipitation, then through water/acetone (volume ratio 1/2)
It is recrystallized to give white solid 1.99g, is compound 1-(R)-tetrahydroisoquinoline formic acid sylvite, separate
Pick-up rate 92.3%, e.e. value 99.1%.
The preparation of embodiment 71-(R)-tetrahydroisoquinoline formic acid
1-(the R)-tetrahydroisoquinoline formates that can prepare with embodiment 1～6 respectively is prepared by raw material
1-(R)-tetrahydroisoquinoline formic acid.One concrete example is as follows:
Embodiment 6 gained intermediate 1-(R)-tetrahydroisoquinoline formic acid sylvite white solid 1.99g is dissolved in
In 5mL pure water, it is passed through hydrogen chloride gas to pH value 2-3, adds 10mL acetone, analysis is collected by filtration
The solid gone out, drying obtains 1-(R)-tetrahydroisoquinoline formic acid 1.59g, yield 97%, e.e. value 99.1%.
The nuclear magnetic data of this example products therefrom is as follows:1H NMR (DMSO-d6,400MHz, δ ppm):
2.87-3.11(m,2H,CH2CH2N),3.35-3.76(m,2H,CH2CH2N),5.3(d,1H,
CHCOOH), 7.24-7.35 (m, 4H, ArH), 9.45 (s, 1H, COOH), confirmation product is
1-(R)-tetrahydroisoquinoline formic acid.
The preparation of embodiment 8 intermediate 1-(R)-tetrahydroisoquinoline formic acid
1.77g (0.01mol) (S)-tetrahydroisoquinoline-1-formic acid is dissolved in 5ml Na2HPO4-NaH2PO4
In cushioning liquid (regulation pH to 8.5), add 5.72g (0.04mol) borine-diisopropylethylamine complexing
Thing, is at the uniform velocity passed through air, adds 70.8mg recommbined D-amino acid oxidase and 12mg hydrogen peroxide
Enzyme, under stirring, starts reaction in 37 DEG C, and HPLC detects reaction process.About 36 hours HPLC
Testing result display 1-(S)-tetrahydroisoquinoline-1-formic acid sodium salt is less than 1%.Stop reaction, be heated to
50-60 DEG C, half an hour above anaenzyme albumen, heated reaction through diatomite filter dezymotize, filtrate
It is cooled to 3-5 DEG C, is slowly added dropwise concentrated hydrochloric acid regulation pH value to about 6.8, has a large amount of precipitation to wash out, mistake
Precipitation is collected in filter, adds the acetone dilution of dropping 2-3 times of volume of filtrate, refilter in the filtrate after filtration
Collect the precipitation separated out, merge the precipitation collected, then obtain white solid 1.66g through water/acetone recrystallization,
It is intermediate 1-(R)-tetrahydroisoquinoline formic acid, microbial recovery rate 93.5%, e.e. value 99.3%.
The preparation of embodiment 9 intermediate 1-(R)-tetrahydroisoquinoline formic acid
5.31g (0.03mol) (R, S)-tetrahydroisoquinoline-1-formic acid is dissolved in 15ml K2HPO4-
KH2PO4In cushioning liquid (regulation pH to 8.3), add 5.22g (0.06mol) borane-t-butylamine
Complex compound, is at the uniform velocity passed through air, adds 106.5mg recommbined D-amino acid oxidase, 27mg peroxide
Changing hydrogen enzyme, under stirring, start reaction in 35 DEG C, HPLC detects reaction process.About 30 hours HPLC
Testing result display 1-(S)-tetrahydroisoquinoline-1-formic acid sylvite is less than 1%.Stop reaction, be heated to
50-60 DEG C, half an hour above anaenzyme albumen, heated reaction through diatomite filter dezymotize, filtrate
Extracting through toluene (3x10ml), toluene reclaims tert-butylamine (4.0g) mutually.Aqueous phase after extraction is cooled to
3-5 DEG C, it is slowly added dropwise concentrated hydrochloric acid regulation pH value to about 6.8, has a large amount of precipitation to wash out, be collected by filtration
Precipitation, adds the acetone dilution of dropping 2-3 times of volume of filtrate, refilters collection analysis in the filtrate after filtration
The precipitation gone out, merges the precipitation collected, then obtains white solid 5g, being through water/acetone recrystallization
Compound 1-(R)-tetrahydroisoquinoline formic acid, microbial recovery rate 93.7%, e.e. value 99.3%.
Embodiment 10 (1R)-1-'s carboxyphenyl-2-tertbutyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline (compound 4A)
Preparation
The 1-(R) being dissolved in 845ml oxolane-tetrahydroisoquinoline formic acid (80g, 0.45mol)
After sodium carbonate liquor (191.5g, the 1.8mol) mixing being dissolved in 845ml water, it is cooled to 0
DEG C, then will be dissolved in (Boc) of 280ml oxolane2O (108g, 0.5mol) at 0 DEG C by
It is added drop-wise in this solution, is stirred overnight.After reaction terminates, being extracted with ethyl acetate, extract has
Machine layer is washed with saturated common salt after merging, and anhydrous sodium sulfate is dried, evaporated in vacuo.Residual after being evaporated
The eluant, eluent of excess PE/EA=1:1 carries out silica gel column chromatography, obtains being of white solid after concentration
Compound 4A (106g, productivity 85%).
Embodiment 11 (1R)-1-methylol-2-tertbutyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline (compound 4B)
Preparation
At N2Under protection, toward the 975ml of be dissolved with compound 4A (70.2g, 0.25mol) 0 DEG C
The BH being dissolved in oxolane it is added dropwise in oxolane3Solution (2.0M, 377mL, 754
mmol).After dropping, it is stirred for 3 hours, then drips NaHCO3Solution.Reaction terminates
After, it being extracted with ethyl acetate, the organic phase of merging saturated aqueous common salt cleans, and anhydrous sodium sulfate is dried,
Then evaporated in vacuo.The eluant, eluent of residue PE/EA=10:1～5:1 after being evaporated carries out silicagel column
Chromatography, obtains the product of faint yellow oily, is compound 4B (53.3g, productivity 80%) after concentration.
Embodiment 12 (1R)-1-(N-phthalyl aminomethyl)-2-tertbutyloxycarbonyl-1,2,3,4-tetrahydrochysene is different
The preparation of quinoline (4C)
DIAD is added in the dichloromethane of the 1L being dissolved with compound 4B (85g, 0.32mol)
(131g, 0.65mol) and triphenylphosphine (170g, 0.65mol), after 30min is stirred at room temperature,
This mixture is down to 0 DEG C.Then phthalimide (52.6g, 0.36mol) it is dividedly in some parts,
It is stirred overnight after being warmed to room temperature.After reaction terminates, add the water of 1L, be extracted with ethyl acetate, merge
Organic phase through washing, saturated common salt washing, anhydrous sodium sulfate be dried, then evaporated in vacuo.It is evaporated
After the eluant, eluent of residue PE/EA=200:1～20:1 carry out silica gel column chromatography, obtain after concentration
White solid, is compound 4C (90.0g, productivity 71%).
Embodiment 13 (1R)-1-(N-cyclohexyl formamido methyl)-2-tertbutyloxycarbonyl-1,2,3,4-tetrahydrochysene is different
The preparation of quinoline (compound 4F)
Toward being dissolved with the water dripping 60ml in the 360ml ethanol of compound 4C (61g, 0.15mol)
Close hydrazine, be cooled to room temperature after backflow 40min, after concentration, add the ethyl acetate of 360ml, stir 30
Min, filters out the solid of generation, filtrate is concentrated to give yellow oily compounds 4D (41.4g) straight
Connect and react for next step.
Compound 4D (41.4g, 0.15mol) is dissolved in the oxolane of 450ml, by 2mol/L
NaOH solution (300mL, 600mmol) add and be cooled to 0 DEG C.Then it is added dropwise over dissolving
Compound 4E (27g, 0.18mol) in 150mlTHF, is heated to room temperature after stirring 2 hours,
It is stirred overnight.After reaction terminates, add the water of 600ml, be extracted with ethyl acetate.Merge is organic
Through washing, saturated common salt washing, then anhydrous sodium sulfate is dried, is vacuum dried.Use PE/EA=after drying
The eluant, eluent of 20:1～10:1 carries out silica gel column chromatography, obtains white solid after concentration, is compound 4F
(40.5g, two step gross production rates 70%).
The preparation of embodiment 14 levo-praziquantel
The solution of compound 4F (90g, 0.24mol) and HCl/EA (1.9L) is stirred at room temperature 2
Hour, and detect with LC-MS.After reaction terminates, boil off solvent.Residue after steaming is dissolved into two
In chloromethanes, with saturated sodium bicarbonate cleaning, saturated common salt washing, after concentration, obtain white solid 4G
(66.9g).This white solid 4G (66.9g, 0.24mol) is dissolved into the dichloromethane of 250ml
And add the chloroacetic chloride (30.3g, 0.26mol) being dissolved in 130ml dichloromethane, it is subsequently added 50%
NaOH solution (77mL).After stirring 30 minutes, add benzyltriethylammoinium chloride
(TEBAC, 5.5g, 0.024mol) is also heated to reflux 2 hours.After reaction terminates, add 380ml
Water, and extract with dichloromethane.The organic phases washed with water merged twice, the hydrochloric acid solution of 5% clean,
Then washing with saturated common salt, anhydrous sodium sulfate is dried.After boiling off solvent, residue PE/EA=20:1
～the eluant, eluent of 5:1 carries out silica gel column chromatography, the product after concentration carries out recrystallizing in ethyl acetate
To white solid (54.3g, three step gross production rates 72%), it is levo-praziquantel.
Product nuclear magnetic data is as follows:1HNMR(300MHz,DMSO-d6):δ1.26-1.30(m,
3H),1.46-1.63(m,3H),1.72-1.88(m,5H),2.43-2.56(m,1H),2.77-2.87
(m,2H),2.90-3.25(m,2H),3.84-4.10(m,1H),4.35-4.49(m,1H),
4.79-4.87(m,2H),5.15-5.18(d,1H),7.17-7.19(d,2H),7.24-7.28(d,
2H)。
To sum up, the present invention has lot of advantages by the route of synthesis of biological enzyme, is more suitable for extensive
Industrialized production.By the High level of stereoselectivity selectivity of recommbined D-amino acid oxidase, catalytic chemistry synthesis
A certain enantiomer in racemic modification is oxidized to imine intermediate and reduces through borane amine complex in-situ chemical
Become raceme, realize the method that raceme is continuously converted to single chiral isomers.The present invention uses new enzyme
Means of catalysis, reduces enzyme dosage, safety and environmental protection.Compared with prior art, present invention improves over tradition side
The weak point of method, and it is simple to have enzymatic process, post-processes the advantages such as easy, and reacts bar
Part is relatively mild, and each operation is easy, it is easy to controls, and can apply mechanically existing process equipment,
Reduce equipment investment, reduce energy consumption and organic solvent amount, decrease environmental pollution, it is achieved green production.Solve
The industrial problem that the high-purity levo-praziquantel hanged over nearly 30 years and do not solve of having determined is isolated and purified, for further
International city is also entered with clinical druggability evaluation, large-scale industrialized production levo-praziquantel before carrying out clinic
Road has been paved in field.
Above-described embodiment only for technology design and the feature of the present invention are described, its object is to allow and is familiar with this
The personage of technology will appreciate that present disclosure and implements according to this, can not limit the guarantor of the present invention with this
Protect scope.All equivalence changes made according to spirit of the invention or modification, all should contain in the present invention
Protection domain within.
Claims (9)
1. the preparation method of a levo-praziquantel, it is characterised in that: described preparation method includes with formula 2a
Or the compound that represents of the 2b step of carrying out the intermediate that formula 1 represents and the intermediate that represented by formula 1
Prepare the step of levo-praziquantel:
In formula 1,2a and 2b, X+Identical, and represent the cationic moiety contended with carboxylic acid ion；
The method of the intermediate that formula 1 represents is as follows: the compound first making formula 2a or 2b represent and oxygen
There is oxidation reaction in gas or air in the presence of recommbined D-amino acid oxidase and catalase, then
Described oxidation reaction products therefrom is made to issue described in the generation of raw reduction reaction in the effect of borine-amido complex compound
The intermediate that formula 1 represents,
The preparation method of described recommbined D-amino acid oxidase is: by containing daao gene
Recombination bacillus coli list colony inoculation in the LB liquid medium containing amicillin resistance, in
Activated overnight 12～16 hours at 37 ± 1 DEG C, the culture that will obtain after activation is inoculated into containing ampicillin
In the LB liquid medium of resistance, shaken cultivation at 37 ± 1 DEG C, to OD600Value reaches 0.6～0.8
Time, add inducer isopropylthio-β-D-thiogalactoside extremely final concentration of 0.8mmol/L～1.0
Mmol/L, continues to cultivate 8～10 hours at 30 ± 1 DEG C, centrifugal, collects sediment, adds pH
The phosphate buffer of 7～9 obtains suspension, suspension is placed in ultrasonication in ice-water bath, then is centrifuged,
Supernatant pre-freeze to temperature is down to-20 DEG C～-30 DEG C, then freeze-drying 34～40 hours, obtains lyophilized
Powdery recommbined D-amino acid oxidase.
The preparation method of levo-praziquantel the most according to claim 1, it is characterised in that: formula 1,
In 2a and 2b, X+Represent H+, K+、Na+Or NH4 +。
The preparation method of levo-praziquantel the most according to claim 1, it is characterised in that: described boron
Alkane-amido complex compound is selected from ammonia borane complex compound, borane dimethylamine complex compound, borine-triethylamine complexing
Thing, borine tert-butylamine complex compound, borine diethylamine complex compound and borine N, N-diisopropylethylamine is complexed
The combination of one or more in thing.
The preparation method of levo-praziquantel the most according to claim 1, it is characterised in that: make described
Oxidation reaction and reduction reaction are in the aqueous phase cushioning liquid of pH 7.5～9.0, enter at temperature 15 DEG C～40 DEG C
OK.
The preparation method of levo-praziquantel the most according to claim 4, it is characterised in that: described water
Phase cushioning liquid is the combination of one or more in sodium ascorbyl phosphate, potassium phosphate, ammoniacal liquor.
The preparation method of levo-praziquantel the most according to claim 4, it is characterised in that: make described
Oxidation reaction and reduction reaction are carried out at temperature 20 DEG C～40 DEG C.
7., according to the preparation method of the levo-praziquantel described in claim 4 or 5 or 6, its feature exists
In: the detailed process of the intermediate that formula 1 represents is as follows: compound formula 2a or 2b represented is molten
In described aqueous phase cushioning liquid, add borine-amido complex compound, be passed through oxygen or air, add restructuring
D-AAO and catalase, under stirring, start reaction at described temperature, and HPLC supervises
Measured reaction process, when the content of the compound represented to formula 2a or 2b is less than 1wt%, stops reaction.
The preparation method of levo-praziquantel the most according to claim 7, it is characterised in that: stop anti-
Ying Hou, heating makes the enzyme generation sex change in system, and filtration is dezymotized, and adds acetone, be collected by filtration in filtrate
The crude solid separated out, then recrystallize with the mixed solvent of water and acetone, i.e. obtain described formula 1 table
The intermediate shown.
The preparation method of levo-praziquantel the most according to claim 1, it is characterised in that: from formula 1
The route that the intermediate represented prepares levo-praziquantel is as follows:
In above-mentioned formula 3 to formula 7, R is identical, and represents amino protecting group.
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| PCT/CN2014/088713 WO2015055127A1 (en) | 2013-10-17 | 2014-10-16 | (r)-praziquantel preparation method |
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| CN110317849B (en) * | 2018-03-30 | 2020-12-08 | 浙江大学 | A method for preparing (S)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and derivatives thereof |
| CN108358916B (en) * | 2018-04-19 | 2019-09-10 | 浙江工业大学 | The preparation method of one kind (R)-praziquantel intermediate and (R)-praziquantel |
| CN110835639B (en) * | 2018-08-16 | 2021-08-10 | 苏州同力生物医药有限公司 | Method for preparing (S) -1,2,3, 4-tetrahydroisoquinoline-1-formic acid and derivatives thereof |
| CN111254181B (en) * | 2018-11-30 | 2023-06-06 | 苏州同力生物医药有限公司 | Method for preparing (S) -1,2,3, 4-tetrahydroisoquinoline-3-formic acid by chemical enzyme method |
| CN111254170B (en) * | 2018-11-30 | 2023-04-28 | 浙江大学 | Method for preparing (S) -1,2,3, 4-tetrahydroisoquinoline-3-formic acid by multienzyme coupling |
| CN111254180B (en) * | 2018-11-30 | 2023-04-28 | 浙江大学 | Method for preparing (S) -1,2,3, 4-tetrahydroisoquinoline-3-formic acid by enzymatic resolution |
| CN112480001A (en) * | 2019-09-11 | 2021-03-12 | 苏州同力生物医药有限公司 | Method and composition for preparing levo-praziquantel chiral intermediate |
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| CN1922328A (en) * | 2004-02-19 | 2007-02-28 | 德古萨股份公司 | Method for producing L-amino acids from D-amino acids |
| CN101194020A (en) * | 2005-06-09 | 2008-06-04 | 大赛璐化学工业株式会社 | The production method of L-amino acid |
| CN102925528A (en) * | 2011-10-26 | 2013-02-13 | 苏州同力生物医药有限公司 | Method for producing intermediate of levo-praziquantel and levo-praziquantel |
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| CN1922328A (en) * | 2004-02-19 | 2007-02-28 | 德古萨股份公司 | Method for producing L-amino acids from D-amino acids |
| CN101194020A (en) * | 2005-06-09 | 2008-06-04 | 大赛璐化学工业株式会社 | The production method of L-amino acid |
| CN102925528A (en) * | 2011-10-26 | 2013-02-13 | 苏州同力生物医药有限公司 | Method for producing intermediate of levo-praziquantel and levo-praziquantel |
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