CN102477057A - Thioinamide adenine dinucleotide, intermediate thereof and preparation methods thereof - Google Patents
Thioinamide adenine dinucleotide, intermediate thereof and preparation methods thereof Download PDFInfo
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- CN102477057A CN102477057A CN2010105704794A CN201010570479A CN102477057A CN 102477057 A CN102477057 A CN 102477057A CN 2010105704794 A CN2010105704794 A CN 2010105704794A CN 201010570479 A CN201010570479 A CN 201010570479A CN 102477057 A CN102477057 A CN 102477057A
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- Prior art keywords
- thionicotinamide
- nucleosides
- ribose
- trityl group
- add
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Links
- 229960000643 adenine Drugs 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 229930024421 Adenine Natural products 0.000 title description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 title description 2
- 239000002777 nucleoside Substances 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 27
- CXONXVMMINSQBV-NNYOXOHSSA-N (2r,3r,4s,5r)-5-[[[[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxymethyl]-2-(3-carbamothioylpyridin-1-ium-1-yl)-4-hydroxyoxolan-3-olate Chemical compound NC(=S)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)[O-])=C1 CXONXVMMINSQBV-NNYOXOHSSA-N 0.000 claims abstract description 25
- -1 thio-nicotinamide adenine dinucleotide monophosphate Chemical class 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 105
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 60
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 44
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 35
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 30
- 229960005181 morphine Drugs 0.000 claims description 30
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 30
- 239000000047 product Substances 0.000 claims description 27
- 239000011347 resin Substances 0.000 claims description 26
- 229920005989 resin Polymers 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 25
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 21
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 claims description 20
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 20
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 claims description 20
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 20
- 229950006790 adenosine phosphate Drugs 0.000 claims description 19
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 19
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 239000000843 powder Substances 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 17
- 229930003776 Vitamin B4 Natural products 0.000 claims description 17
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 17
- 235000008979 vitamin B4 Nutrition 0.000 claims description 17
- 239000011579 vitamin B4 Substances 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- 229910019213 POCl3 Inorganic materials 0.000 claims description 15
- XQWBMZWDJAZPPX-UHFFFAOYSA-N pyridine-3-carbothioamide Chemical compound NC(=S)C1=CC=CN=C1 XQWBMZWDJAZPPX-UHFFFAOYSA-N 0.000 claims description 14
- 238000001291 vacuum drying Methods 0.000 claims description 14
- 238000004821 distillation Methods 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 10
- 229960005305 adenosine Drugs 0.000 claims description 10
- 150000002500 ions Chemical class 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000010828 elution Methods 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 230000008021 deposition Effects 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 238000002386 leaching Methods 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 5
- 230000006837 decompression Effects 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 239000006188 syrup Substances 0.000 claims description 5
- 235000020357 syrup Nutrition 0.000 claims description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 3
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 3
- 229920005654 Sephadex Polymers 0.000 claims description 3
- 239000012507 Sephadex™ Substances 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 3
- 239000001099 ammonium carbonate Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000011521 glass Substances 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 235000002867 manganese chloride Nutrition 0.000 claims description 3
- 239000011565 manganese chloride Substances 0.000 claims description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- 238000005267 amalgamation Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 239000012265 solid product Substances 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 abstract description 12
- 108090000790 Enzymes Proteins 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 238000005285 chemical preparation method Methods 0.000 abstract 3
- IOEVSSJBWYUXPZ-MCDZGGTQSA-N [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate morpholine Chemical compound P(=O)(O)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C=NC=2C(N)=NC=NC12)O)O.N1CCOCC1 IOEVSSJBWYUXPZ-MCDZGGTQSA-N 0.000 abstract 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 239000002994 raw material Substances 0.000 description 8
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 6
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 206010013786 Dry skin Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 229950006238 nadide Drugs 0.000 description 3
- 229940101270 nicotinamide adenine dinucleotide (nad) Drugs 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- IHADVZPGQYQGLH-QXRNQMCJSA-N (4r,5r,6r)-4,5,6,7-tetrahydroxyheptane-2,3-dione Chemical compound CC(=O)C(=O)[C@H](O)[C@H](O)[C@H](O)CO IHADVZPGQYQGLH-QXRNQMCJSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 230000001851 biosynthetic effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229930182478 glucoside Natural products 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000005477 standard model Effects 0.000 description 2
- 239000011708 vitamin B3 Substances 0.000 description 2
- 235000019160 vitamin B3 Nutrition 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- 101710172561 3alpha-hydroxysteroid dehydrogenase Proteins 0.000 description 1
- 102100024089 Aldo-keto reductase family 1 member C2 Human genes 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 0 O[C@@](C[C@](COP(O)(O)=O)O*1)C1*(*1)(*1C1)C=*1*=S Chemical compound O[C@@](C[C@](COP(O)(O)=O)O*1)C1*(*1)(*1C1)C=*1*=S 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 230000003570 biosynthesizing effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- 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
- Saccharide Compounds (AREA)
Abstract
The invention provides a full-chemical preparation method of thio-nicotinamide adenine dinucleotide, and provides two stable intermediates formed by the preparation method, namely thio-nicotinamide-D-nucleoside monophosphate (a compound shown in a structural formula (1)) and morpholine adenosine monophosphate, and preparation methods of the thio-nicotinamide adenine dinucleotide monophosphate, the thio-nicotinamide-a-D-nucleoside monophosphate and the morpholine adenosine monophosphate. The all-chemical preparation method of the thionicotinamide adenine dinucleotide provided by the invention does not need any biosynthesisThe steps and the method avoid the problems of using biological enzyme and the product enzymolysis caused by the biological enzyme, thereby having the advantage of low cost; the all-chemical preparation method of the thio-nicotinamide adenine dinucleotide can be used for simultaneously and respectively synthesizing the stable intermediates, so that the method has the advantages of low cost and high synthesis efficiency.
Description
Technical field
The present invention relates to the preparation method of Thionicotinamide adenine dinucleotide, also relate to its midbody list phosphoric acid Thionicotinamide-α-D-nucleosides, morphine quinoline list adenosine phosphate and preparation method thereof.
Background technology
Thionicotinamide adenine dinucleotide (Thio-NAD) is a kind of Thionicotinamide-NAD, and this compound is widely used in the external diagnosis reagent as a kind of auxiliary material.For example, in the tolal bile acid determination reagent box, Thio-NAD is with 3alpha-Hydroxysteroid dehydrogenase (3 α-HSD), with the bile acide reaction, generate Thionicotinamide adenine dinucleotide reduced form (Thio-NADH).Through measuring the absorbancy velocity of variation of resultant Thio-NADH, can determine the concentration of bile acide at 405nm.
The Thionicotinamide adenine dinucleotide adopts synthesizing of biosynthetic means the earliest; For example from Reduced nicotinamide-adenine dinucleotide (NAD) preparation Thionicotinamide adenine dinucleotide; With NAD is raw material; Utilize of the glucosides transferance of pig brain NPD enzyme, vitamin PP is partly changed into Thionicotinamide pyridine glucosides class substrate.And remove remaining raw material with arteries and veins born of the same parents bacterium DPN enzyme, obtain the Thionicotinamide adenine dinucleotide of purity more than 90%.The chemical synthesis process of used raw material Reduced nicotinamide-adenine dinucleotide (NAD) generally is to be the semisynthesis of raw material from single adenosine phosphate and single phosphoric acid vitamin PP nucleosides.
At present, preparation Thionicotinamide adenine dinucleotide, the method that generally adopts chemosynthesis and biosynthesizing to combine.For example, non-patent literature 1 and 2 reported method of non-patent literature.Biosynthetic means needs special-purpose place and equipment, and needed specificity enzyme can only be in prepared in laboratory, and not having business-like enzyme can buy; Aftertreatment is easy to cause the product enzymolysis if processing is bad; The cost of raw material NAD and various enzymes is all very high.
Non-patent literature 1:Synthesis of Nicotinamide Adenine Dinucleotide (NAD) fromAdenosine Monophosphate (AMP), David R.Wait, etc, J.Am.Chem.Soc., 1980 (102): 7805-7806;
Non-patent literature 2:An Efficient Chemical and Enzymatic Synthesis ofNicotinamide Adenine Dinucleotide (NAD
+), David R.Wait, etc, J.Am.Chem.Soc., 1984 (106): 234-239.
Summary of the invention
The purpose of this invention is to provide a kind of full chemical synthesis process of cost acceptable Thionicotinamide adenine dinucleotide, described method may further comprise the steps:
1) with triphenylmethyl chloride and/or three p-methoxyphenyl methyl chloride as the protection base of D-ribose 5-position, make 5-trityl group-D-ribose and/or 5-three p-methoxyphenyl methyl D-ribose;
2) the 5-trityl group-D-ribose that step 1) is made and/or 5-three p-methoxyphenyl methyl D-ribose and saturated methanolic ammonia solution make 5-trityl group-1-amido-D-ribose and/or 5-three p-methoxyphenyl methyl isophthalic acid-amidos-D-ribose 0-4 ℃ of reaction;
3) with step 2) 5-trityl group-1-amido-D-ribose of making and/or 5-three p-methoxyphenyl methyl isophthalic acid-amidos-D-ribose and Thionicotinamide reaction; The column chromatography for separation isomer makes Thionicotinamide-5-trityl group-α-D-nucleosides and/or Thionicotinamide-5-three p-methoxyphenyl methyl-α-D-nucleosides;
4) Thionicotinamide that step 3) is made-5-trityl group-α-D-nucleosides and/or Thionicotinamide-5-three p-methoxyphenyl methyl-α-D-nucleosides stir in methyl alcohol-Hydrogen chloride; Take off basic trityl group of protection and/or three p-methoxyphenyl methyl, make Thionicotinamide-α-D-nucleosides;
5) Thionicotinamide-α that step 4) is made-D-nucleosides makes single phosphoric acid Thionicotinamide-α-D-nucleosides under the effect of POCl3 and trimethyl phosphite 99.
6) with adenosine under the effect of POCl3 and trimethyl phosphite 99, make single Vitamin B4 nucleosides;
7) the single Vitamin B4 nucleosides that step 6) is made makes morphine quinoline list adenosine phosphate under DCC (NSC 57182), the effect of morphine quinoline;
8) the single phosphoric acid Thionicotinamide-α-D-nucleosides that step 5) is made and with the morphine quinoline list adenosine phosphate reaction that step 7) makes makes the Thionicotinamide adenine dinucleotide.
Another object of the present invention provides two kinds of stable intermediates---the single phosphoric acid Thionicotinamide-α-D-nucleosides (compound shown in structural formula (1)) and the morphine quinoline list adenosine phosphate (compound shown in structural formula (2)) of the method that is used for preparing the Thionicotinamide adenine dinucleotide.
Further object of the present invention provides the preparation method of described two kinds of stable intermediates.
The preparation method of single phosphoric acid Thionicotinamide-α-D-nucleosides comprises the steps:
1) with triphenylmethyl chloride and/or three p-methoxyphenyl methyl chloride as the protection base of D-ribose 5-position, make 5-trityl group-D-ribose and/or 5-three p-methoxyphenyl methyl D-ribose;
2) the 5-trityl group-D-ribose that step 1) is made and/or 5-three p-methoxyphenyl methyl D-ribose and saturated methanolic ammonia solution make 5-trityl group-1-amido-D-ribose and/or 5-three p-methoxyphenyl methyl isophthalic acid-amidos-D-ribose 0-4 ℃ of reaction;
3) with step 2) 5-trityl group-1-amido-D-ribose of making and/or 5-three p-methoxyphenyl methyl isophthalic acid-amidos-D-ribose and Thionicotinamide reaction; The column chromatography for separation isomer makes Thionicotinamide-5-trityl group-α-D-nucleosides and/or Thionicotinamide-5-three p-methoxyphenyl methyl-α-D-nucleosides;
4) Thionicotinamide that step 3) is made-5-trityl group-α-D-nucleosides and/or Thionicotinamide-5-three p-methoxyphenyl methyl-α-D-nucleosides stir in methyl alcohol-Hydrogen chloride; Take off basic trityl group of protection and/or three p-methoxyphenyl methyl, make Thionicotinamide-α-D-nucleosides;
5) Thionicotinamide-α that step 4) is made-D-nucleosides makes single phosphoric acid Thionicotinamide-α-D-nucleosides under the effect of POCl3 and trimethyl phosphite 99.
The preparation method of morphine quinoline list adenosine phosphate comprises the steps:
1) with adenosine under the effect of POCl3 and trimethyl phosphite 99, make single Vitamin B4 nucleosides.
2) the single Vitamin B4 nucleosides that step 1) is made makes morphine quinoline list adenosine phosphate under DCC, the effect of morphine quinoline.
Description of drawings
Fig. 1 is the HNMR collection of illustrative plates of Thionicotinamide adenine dinucleotide.
Embodiment
The compound method of Thionicotinamide adenine dinucleotide of the present invention exemplary is expressed as following synthetic route chart, but not as limitation of the present invention:
Wherein, Tr represents trityl group.
According to full chemical synthesis process of the present invention, it comprises the steps:
With single phosphoric acid Thionicotinamide-α-D-nucleosides and the reaction of morphine quinoline list adenosine phosphate, make the Thionicotinamide adenine dinucleotide.
According to full chemical synthesis process of the present invention, it preferably includes following steps:
Mix 20-25ml methane amide, 187mg manganous chloride and 240mg anhydrous magnesium sulfate, add the morphine quinoline list Vitamin B4 nucleosides of 416mg again, stirred 15-30 minute; The single phosphoric acid Thionicotinamide-α-D-nucleosides that adds 384mg again, 20-30 ℃ is stirred after 12-18 hour down; Add acetonitrile and separate out thick product; With said thick product with resin Sephadex QAE A-25 purifying, with the ammonium bicarbonate soln wash-out of 0.25M.Use Amberite XAD-16 resin purification again, with water-methanol gradient elution (volume ratio 2: 1 to 1: 1.)。Afterwards, lyophilize.Obtain yellow powder 394mg.
The preparation method of single phosphoric acid Thionicotinamide-α-D-nucleosides comprises the steps:
1) with triphenylmethyl chloride and/or three p-methoxyphenyl methyl chloride as the protection base of D-ribose 5-position, make 5-trityl group-D-ribose and/or 5-three p-methoxyphenyl methyl D-ribose;
2) the 5-trityl group-D-ribose that step 1) is made and/or 5-three p-methoxyphenyl methyl D-ribose and saturated methanolic ammonia solution make 5-trityl group-1-amido-D-ribose and/or 5-three p-methoxyphenyl methyl isophthalic acid-amidos-D-ribose 0-4 ℃ of reaction;
3) with step 2) 5-trityl group-1-amido-D-ribose of making and/or 5-three p-methoxyphenyl methyl isophthalic acid-amidos-D-ribose and Thionicotinamide reaction; The column chromatography for separation isomer makes Thionicotinamide-5-trityl group-α-D-nucleosides and/or Thionicotinamide-5-three p-methoxyphenyl methyl-α-D-nucleosides;
4) Thionicotinamide that step 3) is made-5-trityl group-α-D-nucleosides and/or Thionicotinamide-5-three p-methoxyphenyl methyl-α-D-nucleosides stir in methyl alcohol-Hydrogen chloride; Take off basic trityl group of protection and/or three p-methoxyphenyl methyl, make Thionicotinamide-α-D-nucleosides;
5) Thionicotinamide-α that step 4) is made-D-nucleosides makes single phosphoric acid Thionicotinamide-α-D-nucleosides under the effect of POCl3 and trimethyl phosphite 99.
Wherein, employed D-ribose: triphenylmethyl chloride and/or three p-methoxyphenyl methyl chloride: Thionicotinamide: the molar ratio range of trimethyl phosphite 99 is 1: (1-1.2): (1-1.2): (1-1.2).
The preparation method of single phosphoric acid Thionicotinamide-α-D-nucleosides further preferably includes following steps:
1) 5-trityl group-D-ribose is synthetic:
15.0g D-ribose with after the anhydrous pyridine of 90-110ml mixes, is begun to stir, add 27.8g to 30.58g triphenylmethyl chloride, be heated to 70-80 ℃, stirring reaction 4-6 hour; Under 40-50 ℃, underpressure distillation goes out the 75-85ml pyridine then; In the gained residue, add 20-30ml methylbenzene azeotropic, 2-4 time repeatedly again; Evaporate to dryness gets brown syrup shape product; Use 180-220ml dissolved in chloroform gained brown syrup shape product afterwards,, use saturated common salt water washing 2-4 time then with frozen water washing 2-4 time; Collect organic phase, dry with siccative, remove by filter siccative, extremely dry 40-50 ℃ of following underpressure distillation organic phase, anhydrous alcohol solution, recrystallization promptly obtains product 5-trityl group-D-ribose;
2) 5-trityl group-1-amido-D-ribose is synthetic:
39.4g 5-trityl group-D-ribose is dissolved in the 180-220ml anhydrous methanol; Place the water-bath of 0-4 ℃ of constant temperature low temperature, under the agitation condition, constantly feed the exsiccant ammonia; Disappear until detecting 5-trityl group-D-ribose, be transformed into 5-trityl group-1-amido-D-ribose; After 40-50 ℃ of following drying, get yellow solid product.
3) Thionicotinamide-5-trityl group-α-D-nucleosides is synthetic:
Under 20-30 ℃, add the 6.9-7.5g Thionicotinamide to the 40-60ml anhydrous methanol under the agitation condition, with slow dropping 11.6-12.5g trifluoromethanesulfonic acid trimethylsilyl group; After 25-35 minute, the methanol solution of slow Dropwise 5-trityl group-1-amido-D-ribose; Wherein, the methanol solution of said 5-trityl group-1-amido-D-ribose is dissolved in the 50-60ml methyl alcohol and makes through 19.6-20.5 being restrained 5-trityl group-1-amido-D-ribose;
The methanol solution of all said 5-trityl group-1-amido-D-ribose is dropwised, and 20-30 ℃ was stirred 5-6 hour down, went out solvent methanol to dry 40-50 ℃ of following underpressure distillation; With the dry thing of the dissolve with methanol of 10-22ml, slowly add the 50-80ml anhydrous diethyl ether, filter and collect the solid of separating out, get thick product behind the gained solid drying; The thick product of gained is used purification by silica gel column chromatography, with 50: 1 methylene dichloride and methanol system eluent wash-out, obtains the Thionicotinamide-5-trityl group-α-D-nucleosides of purifying;
4) Thionicotinamide-α-D-nucleosides is synthetic:
Under 20-30 ℃, 10.0g Thionicotinamide-5-trityl group-α-D-nucleosides is dissolved in the 50-60ml anhydrous methanol, begins to stir, slowly be added dropwise to 1% the Hydrogen chloride of 20-30ml; Stirred 13-17 minute, and removed by filter deposition, collect filtrate decompression and steam solvent to dry; With the dry thing of the water dissolution of 10-22ml, the gained mixture carries out column chromatography with 70-230 purpose C-2 reversed-phase column; The gained chromatographic solution to dry, obtains Thionicotinamide-α-D-nucleosides 40-50 ℃ of following underpressure distillation; 40-50 ℃ of following vacuum-drying to constant weight;
5) single phosphoric acid Thionicotinamide-α-D-nucleosides is synthetic:
Under 0-3 ℃, mix 0.06ml POCl3 and 0.36ml trimethyl phosphite 99; Begin to stir, add 100mg Thionicotinamide-α-D-nucleosides; Reactant keeps 0-3 ℃, reacts 4-6 hour; Add 3-5 and drip, add HCO again
3-type 20-50 purpose Dao Aikesi resin 1 * 8 is regulated pH to 5; Said resin washes with 180-220ml water; The gained water merges, and is concentrated into 10ml 40-50 ℃ of following underpressure distillation, and last appearance is to ion column, and the filler of wherein said ion column is CH
3The Dao Aikesi resin 1 * 2 of COO-type 200-400 order 8 * 1cm is used water elution; The chromatographic solution of gained is merged, at 30-40 ℃ of following evaporated under reduced pressure water; In the dry thing of gained, add 40-50ml acetone, filter and collect the solid of separating out, obtain amorphous powder, 40-50 ℃ of following vacuum-drying of this powder.
Wherein, in described step 1), 2) and 4) in, because described reaction is quantitative reaction (productive rate 100%) basically, thus after reaction finishes, can be without purifying, and directly drop into next step reaction.If product directly drops into next step reaction without purifying, the amount that then drops into next step is converted into the amount of bullion according to the amount of the pure article that should add.
The preparation method of morphine quinoline list adenosine phosphate comprises the steps:
1) with adenosine under the effect of POCl3 and trimethyl phosphite 99, make single Vitamin B4 nucleosides.
2) the single Vitamin B4 nucleosides that step 1) is made makes morphine quinoline list adenosine phosphate under DCC, the effect of morphine quinoline.
Wherein, employed adenosine: NSC 57182: the molar ratio range of morphine quinoline is 1: (4-4.8): (4-4.8).
The preparation method of morphine quinoline list adenosine phosphate further preferably includes following steps:
1) single Vitamin B4 nucleosides is synthetic:
Under 0-3 ℃, mix 0.6ml POCl3 and 3.6ml trimethyl phosphite 99; Begin to stir, add the 801mg adenosine; Reactant keeps 0-3 ℃, reacts 5-6 hour; Add 1.5-3ml water, add HCO again
3-type 20-50 purpose Dao Aikesi resin 1 * 8 is regulated pH to 5; Said resin washes with 900-1100ml water; The gained water merges, and is concentrated into 50ml 30-40 ℃ of following underpressure distillation, and last appearance is to ion column, and the filler of wherein said ion column is CH
3The Dao Aikesi resin 1 * 2 of COO-type 200-400 order 8 * 1cm is used water elution; The chromatographic solution of gained is merged, at 30-40 ℃ of following evaporated under reduced pressure water; In the dry thing of gained, add 60-70ml acetone, filter and collect the solid of separating out, obtain amorphous powder, 40-50 ℃ of following vacuum-drying of this powder;
2) morphine quinoline list Vitamin B4 nucleosides is synthetic:
Mix the single adenosine phosphate of 347mg, 10-12ml water, the 10-12ml trimethyl carbinol and 4-4.8mmol morphine quinoline; The gained mixture heating up is to refluxing; Drip the t-butanol solution of NSC 57182 with the speed of 3.75-5ml per hour; The t-butanol solution of wherein said NSC 57182 makes through the 4-4.8mmol NSC 57182 is dissolved in the 14-16ml trimethyl carbinol; Reaction solution continues to stir when on HPLC, showing a principal point, and reaction solution is cooled to room temperature, removes by filter the solid of separating out, and uses trimethyl carbinol washing leaching cake, collects filtrating and washings and merges; The organic phase of gained amalgamation liquid is all removed until the trimethyl carbinol 40-50 ℃ of following evaporated in vacuo; Remaining water is with ether extraction 2-4 time, and consumption 45-55ml removes by filter the solid that produces in the leaching process at every turn; The ether that merges is 40 ℃ of following evaporated under reduced pressure, and the middle mutually remainder water of ether is drained with oil pump, obtains glass residue; With the said residue of the dissolve with methanol of 10-20ml, transfer in the single port bottle; Under 40-50 ℃, steam 1/3rd to 1/2nd methyl alcohol, add the anhydrous diethyl ether deposition then, collecting precipitation gets the white solid powder; With 40-50 ℃ of following vacuum-drying of this powder.
In synthesis step of the present invention, according to the common understanding in this area, for example PM 5-10 drips term " slowly dropping ".Wherein, described term " drips ", and those skilled in the art can confirm that for example 0.05ml/ drips according to the scale of reaction.About " slowly adding " solvent, for disposable adding solvent, those skilled in the art confirm according to specific circumstances that in actually operating for example gradation adds.
In the synthesis step of the present invention, those skilled in the art carry out various distortion and change to the present invention under prerequisite without departing from the spirit and scope of the present invention, all within protection scope of the present invention.For example, the solvent of dissolving ammonia except anhydrous methanol, can also be absolute ethyl alcohol, anhydrous isopropyl alcohol etc.; The used eluent system of column chromatography also can replace with the mixed solvent that other can be used for the inventive method; Described siccative can be present technique field siccative commonly used, for example anhydrous magnesium sulfate, SODIUM SULPHATE ANHYDROUS 99PCT etc.; Azeotropic solvent can also be other solvent that can form azeotropic system with pyridine except toluene.
Compared with prior art, the present invention has obtained following beneficial effect:
The first, the present invention adopts chemical process synthetic fully, and is of no use to any biological method, avoided comparatively expensive enzyme catalyst.All there is sale in each big reagent company of the chemical feedstocks of being selected for use, is easy to buy, and cheap, greatly reduce production cost of products, be fit to suitability for industrialized production in the future.
The second, on synthetic route, the present invention adopts the synthetic route of convergence type, has designed two key intermediates: single phosphoric acid Thionicotinamide-α-D-nucleosides and morphine quinoline list adenosine phosphate synthesize a key intermediate respectively, and then dock.Effective like this risk of avoiding linear synthetic route.Raising to yield also has bigger help.This operational path has 8 step reactions, and total recovery generally can reach about 4.62%, and according to the compound method of non-patent literature 1, calculates from full acetyl-D-ribose, and total recovery is merely 2.01%.
Three, the invention provides two stable midbodys, promptly single phosphoric acid Thionicotinamide-α-D-nucleosides and morphine quinoline list adenosine phosphate are for extensive full chemosynthesis Thionicotinamide adenine dinucleotide has in the future been opened up new approach.
Embodiment
Below through embodiment the present invention is further described, but not as limitation of the present invention.
Instrument and reagent
D-ribose, Dakang Chemical Co Ltd, Hangzhou;
Pyridine, Chemical Reagent Co., Ltd., Sinopharm Group;
Toluene, the Beijing Chemical Plant;
Chloroform, Chemical Reagent Co., Ltd., Sinopharm Group;
Anhydrous methanol, Beijing Yili Fine Chemicals Co., Ltd.;
Strong aqua, Beijing Yili Fine Chemicals Co., Ltd.;
Thionicotinamide, sigma;
The trifluoromethanesulfonic acid trimethyl, sigma;
POCl3, Chemical Reagent Co., Ltd., Sinopharm Group;
Trimethyl phosphite 99, Chemical Reagent Co., Ltd., Sinopharm Group;
Adenosine, sigma;
The trimethyl carbinol, Beijing Yili Fine Chemicals Co., Ltd.;
The morphine quinoline, Chemical Reagent Co., Ltd., Sinopharm Group;
Ether, Chemical Reagent Co., Ltd., Sinopharm Group.
Rotary Evaporators, the Shanghai prompt experimental installation ltd of shaking, model: RE-52AA;
The LC-MS appearance, Agilent, model: 6110;
NMR, Bruker, model: AM400MHz.
Related purity adopts high-efficient liquid phase technique to measure.
Performance liquid model (with the LC-MS appearance): Agilent, model: 6110;
Synthesizing of embodiment 1:5-Tr-D-ribose.
15.0g D-ribose is joined in the 250ml there-necked flask, add the 100ml anhydrous pyridine, open and stir.Add the 27.8g triphenylmethyl chloride.Be heated to 75 ℃, stirring reaction 4 hours.40 ℃ down steam major part (about 80ml) pyridine under the decompression, with toluene band three times, add 20ml toluene more at every turn, and evaporate to dryness gets brown syrup shape product.Use 200ml left and right sides dissolved in chloroform again, it is inferior to give a baby a bath on the third day after its birth with frozen water and saturated aqueous common salt successively.Organic phase is used anhydrous magnesium sulfate drying, filters, and revolves driedly, and ethyl alcohol recrystallization obtains the 39.4g product.Be 5-Tr-D-ribose.
LC-MS：【M+Na】
+＝415。
HNMR(MeOH-d4)：δ：7.605-7.104(m，15H)；6.260(d，1H)；5.832(d，1H)；5.201(d，1H)；5.006(d，1H)ppm.
Synthesizing of embodiment 2:5-Tr-1-amido-D-ribose.
39.4g 5-Tr-D-ribose is dissolved in the 200ml anhydrous methanol, places the water-bath of constant temperature low temperature, keep 0 ℃.Stir down, constantly feed the exsiccant ammonia, detect raw material after 20 hours and disappear the almost quantitative 5-Tr-1-amido-D-ribose that is transformed into.After 45 ℃ of dryings of vacuum drying oven, get the 39.2g yellow solid, be product.
LC-MS：【M+H】
+＝392。
HNMR(MeOH-d4)：δ：7.523-7.078(m，15H)；5.891(d，1H)；5.755(d，1H)；4.568(d，1H)；4.306(d，1H)ppm.
Embodiment 3: Thionicotinamide-5-Tr-α-D-nucleosides synthetic.
Under the room temperature (25 ℃), add the 50ml anhydrous methanol in the 250ml there-necked flask, stir adding 6.9g Thionicotinamide down.Slowly drip 11.6g trifluoromethanesulfonic acid trimethylsilyl group (TMSOTf).After half a hour, add the methanol solution (19.6 gram 5-Tr-1-amido-D-ribose are dissolved in the 50ml methyl alcohol) of 5-Tr-1-amido-D-ribose.Dropwise stirring at room 5 hours.Decompression steams solvent under 45 ℃.Dissolve with methanol 20ml with lack volume as far as possible slowly adds anhydrous diethyl ether 60ml, has solid to separate out.Filter,, get thick product with 35 ℃ of dryings of vacuum drying oven.Column chromatography with methylene dichloride and methanol system wash-out (eluent volume ratio 50: 1), gets Thionicotinamide-5-Tr-α-D-nucleosides 10.5g.Yield about 32%.
LC-MS: [M]
+=512 (after the deduction trifluoromethanesulfonic acid roots).
HNMR(DMSO-d6)：δ：9.472(s，1H)；9.387(s，1H)；9.165(d，1H)；9.076(d，1H)；8.245-8.134(m，1H)；7.412-7.305(m，15H)；6.784(d，1H)；6.523(d，1H)；4.851-4.764(m，1H)；4.562-4.012(m，2H)；3.623-3.268(m，2H)ppm.
Embodiment 4: Thionicotinamide-α-D-nucleosides synthetic.
Under the room temperature, 10.0g Thionicotinamide-5-Tr-α-D-nucleosides is dissolved in the 50ml anhydrous methanol, opens and stir, slowly add the Hydrogen chloride of 25ml 1%.Stirred about 15 minutes, and deposition in a large number occurred.Filter, filtrate decompression steams solvent.With the water dissolution of lacking volume as far as possible, do column chromatography with C-2 reversed-phase column (Merck, 70-230 order).Chromatographic solution is done at 40-50 ℃ of underspin, obtains almost quantitative Thionicotinamide-α-D-nucleosides.40 ℃ of dryings of vacuum drying oven are weighed: 6.33g.
LC-MS: [M]
+=270 (after the deduction trifluoromethanesulfonic acid roots).
HNMR(DMSO-d6)：δ：10.512(s，1H)；9.772(s，1H)；9.310(d，2H)；8.642(s，1H)；8.163(t，1H)；7.220(d，1H)；5.985(t，1H)；5.532(t，1H)；5.218(d，1H)；4.495(dd，1H)；4.348(dd，1H)ppm.
Embodiment 5: single phosphoric acid Thionicotinamide-α-D-nucleosides synthetic.
Under 0 ℃, in reaction flask, add 0.06ml POCl3 and 0.36ml trimethyl phosphite 99.Open and stir, add 100mg Thionicotinamide-α-D-nucleosides.Reactant keeps 0 ℃, reacts 4 hours.Add several dripping (3-5 drips), add Dowex resin (Dowex resin 1 * 8, HCO again
3-type, the 20-50 order) adjusting pH to 5.Resin washes with 200ml water.Water merges, and is concentrated into 10ml, and last appearance is to ion column.Filler is Dowex resin 1 * 2, CH
3The COO-type, the 200-400 order, 8 * 1cm uses water elution.Through comparing with standard model, confirm the chromatographic solution at product place, merge, 30-40 ℃ down with vacuum oil pump evaporate to dryness water.Add about 40-50ml acetone and separate out solid, filter and obtain amorphous powder, 40 ℃ of dry down 61mg products that get of vacuum drying oven.Yield 65%.
LC-MS：【M-1】
-＝348。
HNMR(D
2O)：δ：9.987(s，1H)；9.896(d，1H)；9.654(d，1H)；8.956(t，1H)；5.218(d，1H)；4.895(t，2H)；4.256(d，1H)；3.958(d，1H)；3.632(t，1H)ppm.
Embodiment 6: single Vitamin B4 nucleosides synthetic.
Under 0 ℃, in reaction flask, add 0.6ml POCl3 and 3.6ml trimethyl phosphite 99.Open and stir, add the 801mg adenosine.Reactant keeps 0 ℃, reacts 5 hours.Add 2ml water, add Dowex resin (Dowex resin 1 * 8, HCO again
3-type, the 20-50 order) adjusting pH to 5.Resin washes with 1000ml water.Water merges, and under 30-40 ℃, is concentrated into 50ml with the vacuum oil pump, and last kind is arrived ion column.Filler is Dowex resin 1 * 2, CH
3The COO-type, the 200-400 order, 8 * 1cm uses water elution.Through comparing with standard model, confirm the chromatographic solution at product place, merge, 30-40 ℃ down with vacuum oil pump evaporate to dryness water.Add about 60-70ml acetone and separate out solid, filter and obtain amorphous powder, 40 ℃ of dry down 0.56g products that get of vacuum drying oven.Yield 54%.
LC-MS：【M-1】
-＝346。
HNMR(D
2O)：δ：8.956(s，1H)；8.458(s，1H)；6.054(d，1H)；5.147(t，1H)；4.763(t，2H)；4.261(d，1H)；4.013(d，1H)；3.657(d，1H)ppm.
Embodiment 7: morphine quinoline list Vitamin B4 nucleosides synthetic.
Add single adenosine phosphate of 347mg and 10ml water in the reaction flask, the 10ml trimethyl carbinol, the morphine quinoline that 0.34ml (4mmol) purifying is crossed.Be heated to backflow.Slowly drip the t-butanol solution (824mg, 4mmolDCC are dissolved in the 15ml trimethyl carbinol) of DCC, whole dropping process about 3-4 hour.Reaction solution continues to stir 2-3 hour, until on HPLC, showing a principal point.At this moment, reaction solution is cooled to room temperature, and the solid of separating out is removed with filtering method, and uses trimethyl carbinol washing leaching cake.Filtrating is evaporate to dryness under vacuum, all removes until the trimethyl carbinol.Remaining water is with ether extraction three times (each about 50ml of consumption).If needed can solids removed by filtration in the leaching process.Ether is 40 ℃ of following evaporated under reduced pressure, and last more remaining water is drained with oil pump, obtains glass residue.With the dissolve with methanol of 10-20ml, transfer in the single port bottle.Slowly steam methyl alcohol, add dry ether, deposition gets the white solid powder.40 ℃ of vacuum drying ovens are dry down, weigh: 295mg, yield: 71%.
LC-MS：【M-1】
-＝415。
HNMR(D
2O)：δ：9.235(s，1H)；8.391(s，1H)；5.964(d，1H)；4.648(t，1H)；4.542(t，2H)；4.139(d，1H)；4.007(d，1H)；3.912(d，1H)；3.689(m，4H)；3.457(m，4H)ppm.
Embodiment 8: Thionicotinamide adenine dinucleotide synthetic.
Add the 20ml methane amide in the reaction flask, add 187mg manganous chloride and 240mg anhydrous magnesium sulfate.Add the morphine quinoline list Vitamin B4 nucleosides of 416mg again, stirred 15 minutes.The single phosphoric acid Thionicotinamide-α-D-nucleosides that adds 384mg again.Stirring at room 16 hours.Reaction finishes, and reaction solution adds acetonitrile, and thick product is separated out.Use resin (Sephadex QAE A-25) purifying again, with the ammonium bicarbonate soln wash-out of 0.25M.Use Amberite XAD-16 resin purification again, with water-methanol gradient elution (volume ratio 2: 1 to 1: 1.)。Afterwards, lyophilize.Obtain yellow powder 394mg.Yield 58%.Purity 98%.
LC-MS：【M+1】
+＝680。
HNMR(D
2O)：δ：9.263(s，1H)；9.063(d，1H)；8.782(d，1H)；8.498(s，1H)；8.271(s，1H)；8.062(t，1H)；6.004(t，2H)；4.598(t，1H)；4.455-4.051(9H)ppm.
This operational path has the reaction of 8 steps, and total recovery generally can reach about 4.62%.The yield that each step provides at the back is the molar yield of this step.Total recovery is to multiply each other according to each step yield to obtain: 100% * 100% * 32% * 100% * 65% * 54% * 71% * 58%=4.62%.If only calculate the main road line, ignore the synthetic of morphine quinoline list adenosine phosphate, total recovery is: 100% * 100% * 32% * 100% * 65% * 58%=12.1%.
The method of non-patent literature 1 has just been synthesized Reduced nicotinamide-adenine dinucleotide, and its synthetic route begins from single adenosine phosphate, and raw materials cost is expensive.Enzyme catalysis is used in final step, the difficult preparation of used enzyme, and cost is also high.Synthetic route of the present invention begins from the D-ribose of cheapness, and does not use enzyme.
The design synthetic route of non-patent literature 1 is totally 4 steps, and total recovery is between 10.4%-11.3%, and yield is very high.But what be synthesized is not the Thionicotinamide adenine dinucleotide, has just synthesized Reduced nicotinamide-adenine dinucleotide.Test about 10 days of total time.Raw materials used costliness, used enzyme need be made by oneself, and total cost is too high.About 8 days of the total experimental period of compound method of the present invention.
According to the compound method of non-patent literature 1, to calculate from full acetyl-D-ribose, total recovery is merely 2.01%.
Claims (10)
1. the compound shown in structural formula (1):
2. method that is used to prepare the said compound of claim 1, it may further comprise the steps:
1) with triphenylmethyl chloride and/or three p-methoxyphenyl methyl chloride as the protection base of D-ribose 5-position, make 5-trityl group-D-ribose and/or 5-three p-methoxyphenyl methyl D-ribose;
2) the 5-trityl group-D-ribose that step 1) is made and/or 5-three p-methoxyphenyl methyl D-ribose and saturated methanolic ammonia solution make 5-trityl group-1-amido-D-ribose and/or 5-three p-methoxyphenyl methyl isophthalic acid-amidos-D-ribose 0-4 ℃ of reaction;
3) with step 2) 5-trityl group-1-amido-D-ribose of making and/or 5-three p-methoxyphenyl methyl isophthalic acid-amidos-D-ribose and Thionicotinamide reaction; The column chromatography for separation isomer makes Thionicotinamide-5-trityl group-α-D-nucleosides and/or Thionicotinamide-5-three p-methoxyphenyl methyl-α-D-nucleosides;
4) Thionicotinamide that step 3) is made-5-trityl group-α-D-nucleosides and/or Thionicotinamide-5-three p-methoxyphenyl methyl-α-D-nucleosides stir in methyl alcohol-Hydrogen chloride; Take off basic trityl group of protection and/or three p-methoxyphenyl methyl, make Thionicotinamide-α-D-nucleosides;
5) Thionicotinamide-α that step 4) is made-D-nucleosides makes single phosphoric acid Thionicotinamide-α-D-nucleosides under the effect of POCl3 and trimethyl phosphite 99.
3. method according to claim 2, wherein, employed D-ribose: triphenylmethyl chloride and/or three p-methoxyphenyl methyl chloride: Thionicotinamide: the molar ratio range of trimethyl phosphite 99 is 1: (1-1.2): (1-1.2): (1-1.2).
4. method that is used to prepare the said compound of claim 1, it may further comprise the steps:
1) 5-trityl group-D-ribose is synthetic:
15.0g D-ribose with after the anhydrous pyridine of 90-110ml mixes, is begun to stir, add 27.8g to 30.58g triphenylmethyl chloride, be heated to 70-80 ℃, stirring reaction 4-6 hour; Under 40-50 ℃, underpressure distillation goes out the 75-85ml pyridine then; In the gained residue, add 20-30ml methylbenzene azeotropic, 2-4 time repeatedly again; Evaporate to dryness gets brown syrup shape product; Use 180-220ml dissolved in chloroform gained brown syrup shape product afterwards,, use saturated common salt water washing 2-4 time then with frozen water washing 2-4 time; Collect organic phase, dry with siccative, remove by filter siccative, to dry, directly drop into next step reaction 40-50 ℃ of following underpressure distillation organic phase; Perhaps the distillatory product is used anhydrous alcohol solution, recrystallization obtains product 5-trityl group-D-ribose;
2) 5-trityl group-1-amido-D-ribose is synthetic:
39.4g 5-trityl group-D-ribose is dissolved in the 180-220ml anhydrous methanol; Place the water-bath of 0-4 ℃ of constant temperature low temperature, under the agitation condition, constantly feed the exsiccant ammonia; Disappear until detecting 5-trityl group-D-ribose, be transformed into 5-trityl group-1-amido-D-ribose; After 40-50 ℃ of following drying, get yellow solid product;
3) Thionicotinamide-5-trityl group-α-D-nucleosides is synthetic:
Under 20-30 ℃, add the 6.9-7.5g Thionicotinamide to the 40-60ml anhydrous methanol under the agitation condition, slowly drip 11.6-12.5g trifluoromethanesulfonic acid trimethylsilyl group; After 25-35 minute, the methanol solution of slow Dropwise 5-trityl group-1-amido-D-ribose; Wherein, the methanol solution of said 5-trityl group-1-amido-D-ribose is dissolved in the 50-60ml methyl alcohol and makes through 19.6-20.5 being restrained 5-trityl group-1-amido-D-ribose;
The methanol solution of all said 5-trityl group-1-amido-D-ribose is dropwised, and 20-30 ℃ was stirred 5-6 hour down, went out solvent methanol to dry 40-50 ℃ of following underpressure distillation; With the dry thing of the dissolve with methanol of 10-22ml, slowly add the 50-80ml anhydrous diethyl ether, filter and collect the solid of separating out, get thick product behind the gained solid drying; The thick product of gained is used purification by silica gel column chromatography, and the use volume ratio is 50: 1 methylene dichloride and a methanol system eluent wash-out, obtains the Thionicotinamide-5-trityl group-α-D-nucleosides of purifying;
4) Thionicotinamide-α-D-nucleosides is synthetic:
Under 20-30 ℃, 10.0g Thionicotinamide-5-trityl group-α-D-nucleosides is dissolved in the 50-60ml anhydrous methanol, begins to stir, slowly be added dropwise to 1% the Hydrogen chloride of 20-30ml; Stirred 13-17 minute, and removed by filter deposition, collect filtrate decompression and steam solvent, directly drop into next step reaction to dry; Perhaps use the dry thing of water dissolution of 10-22ml, the gained mixture carries out column chromatography with 70-230 purpose C-2 reversed-phase column, and the gained chromatographic solution to drying, obtains Thionicotinamide-α-D-nucleosides 40-50 ℃ of following underpressure distillation, 40-50 ℃ of following vacuum-drying to constant weight;
5) single phosphoric acid Thionicotinamide-α-D-nucleosides is synthetic:
Under 0-3 ℃, mix 0.06ml POCl3 and 0.36ml trimethyl phosphite 99; Begin to stir, add 100mg Thionicotinamide-α-D-nucleosides; Reactant keeps 0-3 ℃, reacts 4-6 hour; Add 3-5 and drip, add HCO again
3-type 20-50 purpose Dao Aikesi resin 1 * 8 is regulated pH to 5; Said resin washes with 180-220ml water; The gained water merges, and is concentrated into 10ml 40-50 ℃ of following underpressure distillation, and last appearance is to ion column, and the filler of wherein said ion column is CH
3The Dao Aikesi resin 1 * 2 of COO-type 200-400 order 8 * 1cm is used water elution; The chromatographic solution of gained is merged, at 30-40 ℃ of following evaporated under reduced pressure water; In the dry thing of gained, add 40-50ml acetone, filter and collect the solid of separating out, obtain amorphous powder, 40-50 ℃ of following vacuum-drying of this powder.
5. the compound shown in structural formula (2):
6. method that is used to prepare the said compound of claim 5, it may further comprise the steps:
1) with adenosine under the effect of POCl3 and trimethyl phosphite 99, make single Vitamin B4 nucleosides.
2) the single Vitamin B4 nucleosides that step 1) is made makes morphine quinoline list adenosine phosphate under NSC 57182, the effect of morphine quinoline.
7. method according to claim 6, wherein, employed adenosine: NSC 57182: the molar ratio range of morphine quinoline is 1: (4-4.8): (4-4.8).
8. method that is used to prepare the said compound of claim 5, it may further comprise the steps:
1) single Vitamin B4 nucleosides is synthetic:
Under 0-3 ℃, mix 0.6ml POCl3 and 3.6ml trimethyl phosphite 99; Begin to stir, add the 801mg adenosine; Reactant keeps 0-3 ℃, reacts 5-6 hour; Add 1.5-3ml water, add HCO again
3-type 20-50 purpose Dao Aikesi resin 1 * 8 is regulated pH to 5; Said resin washes with 900-1100ml water; The gained water merges, and is concentrated into 50ml 30-40 ℃ of following underpressure distillation, and last appearance is to ion column, and the filler of wherein said ion column is CH
3The Dao Aikesi resin 1 * 2 of COO-type 200-400 order 8 * 1cm is used water elution; The chromatographic solution of gained is merged, at 30-40 ℃ of following evaporated under reduced pressure water; In the dry thing of gained, add 60-70ml acetone, filter and collect the solid of separating out, obtain amorphous powder, 40-50 ℃ of following vacuum-drying of this powder;
2) morphine quinoline list Vitamin B4 nucleosides is synthetic:
Mix the single adenosine phosphate of 347mg, 10-12ml water, the 10-12ml trimethyl carbinol and 4-4.8mmol morphine quinoline; The gained mixture heating up is to refluxing; Drip the t-butanol solution of NSC 57182 with the speed of 3.75-5ml per hour; The t-butanol solution of wherein said NSC 57182 makes through the 4-4.8mmol NSC 57182 is dissolved in the 14-16ml trimethyl carbinol; Reaction solution continues to stir when on HPLC, showing a principal point, and reaction solution is cooled to room temperature, removes by filter the solid of separating out, and uses trimethyl carbinol washing leaching cake, collects filtrating and washings and merges; The organic phase of gained amalgamation liquid is all removed until the trimethyl carbinol 40-50 ℃ of following evaporated in vacuo; Remaining water is with ether extraction 2-4 time, and consumption 45-55ml removes by filter the solid that produces in the leaching process at every turn; The ether that merges is 40 ℃ of following evaporated under reduced pressure, and the middle mutually remainder water of ether is drained with oil pump, obtains glass residue; With the said residue of the dissolve with methanol of 10-20ml, transfer in the single port bottle; Under 40-50 ℃, steam the methyl alcohol of 1/3-1/2, add the anhydrous diethyl ether deposition then, collecting precipitation gets the white solid powder; With 40-50 ℃ of following vacuum-drying of this powder.
9. method that is used to prepare the Thionicotinamide adenine dinucleotide, it may further comprise the steps:
With the reaction of the compound shown in compound shown in the structural formula (1) and the structural formula (2), make the Thionicotinamide adenine dinucleotide.
10. method according to claim 9, it may further comprise the steps:
Mix 20-25ml methane amide, 187mg manganous chloride and 240mg anhydrous magnesium sulfate, add the morphine quinoline list Vitamin B4 nucleosides of 416mg again, stirred 15-30 minute; The single phosphoric acid Thionicotinamide-α-D-nucleosides that adds 384mg again, 20-30 ℃ is stirred after 12-18 hour down; Add acetonitrile and separate out thick product; With said thick product with resin Sephadex QAE A-25 purifying, with the ammonium bicarbonate soln wash-out of 0.25M; Use Amberite XAD-16 resin purification again, with 2: 1 to 1: 1 water-methanol gradient elution of volume ratio, afterwards, lyophilize obtains yellow powder 394mg.
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| CN103233051A (en) * | 2012-12-19 | 2013-08-07 | 浙江嘉华化工有限公司 | Chemical and biological synthesis method for large-scale preparation of nicotinamide adenine dinucleotide |
| CN103601780A (en) * | 2013-10-29 | 2014-02-26 | 北京利德曼生化股份有限公司 | Synthetic method of 3-acetylpyridine adenine dinucleotide |
| CN104231008A (en) * | 2013-06-07 | 2014-12-24 | 沈阳药科大学 | Regional selective synthesis method of nucleoside drug 5'-site amino-acid ester |
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| E. I. HYDE，ET AL.: "Proton Nuclear Magnetic Resonance Saturation Transfer Studies of Coenzyme Binding to Lactobacillus casei Dihydrofolate Reductase", 《BIOCHEMISTRY》 * |
| JAEMOON LEE,ET AL.: "A chemical synthesis of nicotinamide adenine dinucleotide (NAD+)", 《CHEM.COMMUN.》 * |
| MARTINA TYLICHOVÁ，ET AL.: "Structural and Functional Characterization of Plant Aminoaldehyde Dehydrogenase from Pisum sativum with a Broad Specificity for Natural and Synthetic Aminoaldehydes", 《J.MOL.BIOL.》 * |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103233051A (en) * | 2012-12-19 | 2013-08-07 | 浙江嘉华化工有限公司 | Chemical and biological synthesis method for large-scale preparation of nicotinamide adenine dinucleotide |
| CN103233051B (en) * | 2012-12-19 | 2016-01-27 | 浙江嘉华化工有限公司 | The method of nicotinamide adenine dinucleotide is prepared in the mass-producing of a kind of chemical-biological synthesis method |
| CN104231008A (en) * | 2013-06-07 | 2014-12-24 | 沈阳药科大学 | Regional selective synthesis method of nucleoside drug 5'-site amino-acid ester |
| CN104231008B (en) * | 2013-06-07 | 2017-03-01 | 沈阳药科大学 | The Regioselective synthesis of nucleoside medicine 5 ' bit amino acid esters |
| CN103601780A (en) * | 2013-10-29 | 2014-02-26 | 北京利德曼生化股份有限公司 | Synthetic method of 3-acetylpyridine adenine dinucleotide |
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