NZ716277B2 - Methods of preparing nicotinamide riboside and derivatives thereof - Google Patents
Methods of preparing nicotinamide riboside and derivatives thereof Download PDFInfo
- Publication number
- NZ716277B2 NZ716277B2 NZ716277A NZ71627714A NZ716277B2 NZ 716277 B2 NZ716277 B2 NZ 716277B2 NZ 716277 A NZ716277 A NZ 716277A NZ 71627714 A NZ71627714 A NZ 71627714A NZ 716277 B2 NZ716277 B2 NZ 716277B2
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- NZ
- New Zealand
- Prior art keywords
- unsubstituted
- substituted
- optionally
- formula
- compound
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- 235000020956 nicotinamide riboside Nutrition 0.000 title claims abstract description 49
- 239000011618 nicotinamide riboside Substances 0.000 title claims abstract description 49
- JLEBZPBDRKPWTD-TURQNECASA-O N-ribosylnicotinamide Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 JLEBZPBDRKPWTD-TURQNECASA-O 0.000 title claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- 125000003118 aryl group Chemical group 0.000 claims abstract description 47
- 150000001450 anions Chemical class 0.000 claims abstract description 41
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 10
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 9
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 8
- 150000004820 halides Chemical class 0.000 claims abstract description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 6
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims abstract description 5
- 239000010452 phosphate Substances 0.000 claims abstract description 5
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims abstract description 5
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims abstract description 4
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 claims abstract 3
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims abstract 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 39
- -1 isopropionyl Chemical group 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 11
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 claims description 9
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 9
- 235000010323 ascorbic acid Nutrition 0.000 claims description 9
- 239000011668 ascorbic acid Substances 0.000 claims description 9
- 239000000376 reactant Substances 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 235000019270 ammonium chloride Nutrition 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 claims description 8
- 229940072107 Ascorbate Drugs 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- 239000012351 deprotecting agent Substances 0.000 claims description 7
- 229940009098 Aspartate Drugs 0.000 claims description 6
- CKLJMWTZIZZHCS-UHFFFAOYSA-N DL-aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 6
- 238000000498 ball milling Methods 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 235000019260 propionic acid Nutrition 0.000 claims description 6
- 239000003638 reducing agent Substances 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000005695 Ammonium acetate Substances 0.000 claims description 5
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 5
- JVBXVOWTABLYPX-UHFFFAOYSA-L Sodium dithionite Chemical group [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- 235000019257 ammonium acetate Nutrition 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- 150000003863 ammonium salts Chemical class 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- YCNIBOIOWCTRCL-UHFFFAOYSA-N azane;2,2,2-trifluoroacetic acid Chemical compound [NH4+].[O-]C(=O)C(F)(F)F YCNIBOIOWCTRCL-UHFFFAOYSA-N 0.000 claims description 5
- 150000001768 cations Chemical class 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- JOUIQRNQJGXQDC-ZYUZMQFOSA-O nicotinic acid D-ribonucleotide Chemical compound O1[C@H](COP(O)(O)=O)[C@@H](O)[C@@H](O)[C@@H]1[N+]1=CC=CC(C(O)=O)=C1 JOUIQRNQJGXQDC-ZYUZMQFOSA-O 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- 229960001701 Chloroform Drugs 0.000 claims description 4
- PUEDDPCUCPRQNY-ZYUZMQFOSA-N D-ribosylnicotinate Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1[N+]1=CC=CC(C([O-])=O)=C1 PUEDDPCUCPRQNY-ZYUZMQFOSA-N 0.000 claims description 4
- 229940049906 Glutamate Drugs 0.000 claims description 4
- 229940001447 Lactate Drugs 0.000 claims description 4
- 229940035295 Ting Drugs 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 claims description 4
- 150000004672 propanoic acids Chemical class 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- VZTDIZULWFCMLS-UHFFFAOYSA-N Ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-O Pyridinium Chemical class C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 238000000227 grinding Methods 0.000 claims description 3
- 150000002739 metals Chemical class 0.000 claims description 3
- 239000003586 protic polar solvent Substances 0.000 claims description 3
- 229960002415 trichloroethylene Drugs 0.000 claims description 3
- XSTXAVWGXDQKEL-UHFFFAOYSA-N triclene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-Trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- QIONYIKHPASLHO-UHFFFAOYSA-M 2,2,2-tribromoacetate Chemical compound [O-]C(=O)C(Br)(Br)Br QIONYIKHPASLHO-UHFFFAOYSA-M 0.000 claims description 2
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-Methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- NKDDWNXOKDWJAK-UHFFFAOYSA-N Dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 claims description 2
- 229960002989 Glutamic Acid Drugs 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N Methyl isopropyl ketone Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N Propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- 229940066528 Trichloroacetate Drugs 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229960003750 ethyl chloride Drugs 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 239000008079 hexane Substances 0.000 claims description 2
- 150000004693 imidazolium salts Chemical class 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 229910000069 nitrogen hydride Inorganic materials 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-M trichloroacetate Chemical compound [O-]C(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-M 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 229950005499 carbon tetrachloride Drugs 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 claims 1
- RZOBLYBZQXQGFY-UHFFFAOYSA-N Ammonium lactate Chemical compound [NH4+].CC(O)C([O-])=O RZOBLYBZQXQGFY-UHFFFAOYSA-N 0.000 claims 1
- 239000004251 Ammonium lactate Substances 0.000 claims 1
- 229960005261 Aspartic Acid Drugs 0.000 claims 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N Di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims 1
- 229940059265 ammonium lactate Drugs 0.000 claims 1
- 235000019286 ammonium lactate Nutrition 0.000 claims 1
- 239000000010 aprotic solvent Substances 0.000 claims 1
- 235000003704 aspartic acid Nutrition 0.000 claims 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 claims 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbamate Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 abstract 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 16
- 125000004432 carbon atoms Chemical group C* 0.000 description 15
- 150000008223 ribosides Chemical class 0.000 description 15
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 150000002500 ions Chemical class 0.000 description 10
- 239000011570 nicotinamide Substances 0.000 description 10
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 9
- 229910000831 Steel Inorganic materials 0.000 description 8
- 235000005152 nicotinamide Nutrition 0.000 description 8
- 229960003966 nicotinamide Drugs 0.000 description 8
- 239000010959 steel Substances 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 7
- MAKBMGXNXXXBFE-TURQNECASA-N 1-(β-D-ribofuranosyl)-1,4-dihydronicotinamide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 MAKBMGXNXXXBFE-TURQNECASA-N 0.000 description 6
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 6
- 150000003841 chloride salts Chemical class 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000001264 neutralization Effects 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 6
- YNGDWRXWKFWCJY-UHFFFAOYSA-N dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000012429 reaction media Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 235000015872 dietary supplement Nutrition 0.000 description 4
- 229940064982 ethylnicotinate Drugs 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000001603 reducing Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- BLMPQMFVWMYDKT-NZTKNTHTSA-N Carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BAWFJGJZGIEFAR-NNYOXOHSSA-N Nicotinamide adenine dinucleotide Chemical class 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 2
- GFNANZIMVAIWHM-OBYCQNJPSA-N Triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 2
- 159000000021 acetate salts Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 150000001805 chlorine compounds Chemical group 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000004675 formic acid derivatives Chemical class 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000000707 stereoselective Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- KGUMNRYFUFLBGA-UHFFFAOYSA-N 1,4-dihydropyridine-3-carboxamide Chemical compound NC(=O)C1=CNC=CC1 KGUMNRYFUFLBGA-UHFFFAOYSA-N 0.000 description 1
- LCFVNOPFCICOIS-UHFFFAOYSA-N 1-methyl-2-(3-phenylprop-1-ynyl)benzene Chemical compound CC1=CC=CC=C1C#CCC1=CC=CC=C1 LCFVNOPFCICOIS-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229940022663 Acetate Drugs 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N Bis(trimethylsilyl)amine Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 241000272165 Charadriidae Species 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N Disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- NUMQCACRALPSHD-UHFFFAOYSA-N Ethyl tert-butyl ether Chemical compound CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- PHKGGXPMPXXISP-UHFFFAOYSA-N Monoammonium glutamate Chemical compound [NH4+].OC(=O)C(N)CCC([O-])=O PHKGGXPMPXXISP-UHFFFAOYSA-N 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) 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-O 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 102100012174 PIWIL2 Human genes 0.000 description 1
- 101710043199 PIWIL2 Proteins 0.000 description 1
- 239000005092 Ruthenium Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N Trimethylsilyl chloride Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- BSXZJWHTFAEYDT-UHFFFAOYSA-N [NH4+].[NH4+].[O-]C=O.[O-]C=O Chemical compound [NH4+].[NH4+].[O-]C=O.[O-]C=O BSXZJWHTFAEYDT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 125000004947 alkyl aryl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 150000001356 alkyl thiols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 150000008378 aryl ethers Chemical group 0.000 description 1
- 150000001504 aryl thiols Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002051 biphasic Effects 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000004986 diarylamino group Chemical group 0.000 description 1
- YEOCBTKAGVNPMO-JIZZDEOASA-N diazanium;(2S)-2-aminobutanedioate Chemical compound [NH4+].[NH4+].[O-]C(=O)[C@@H](N)CC([O-])=O YEOCBTKAGVNPMO-JIZZDEOASA-N 0.000 description 1
- 239000002037 dichloromethane fraction Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000005111 flow chemistry technique Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 238000011031 large scale production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 235000013917 monoammonium glutamate Nutrition 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229950006238 nadide Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 230000004783 oxidative metabolism Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-O pyrrolidinium Chemical class C1CC[NH2+]C1 RWRDLPDLKQPQOW-UHFFFAOYSA-O 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VYGSFTVYZHNGBU-UHFFFAOYSA-M trichloromethanesulfonate Chemical compound [O-]S(=O)(=O)C(Cl)(Cl)Cl VYGSFTVYZHNGBU-UHFFFAOYSA-M 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical group CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
-
- 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
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Abstract
The invention relates to methods of preparing nicotinamide riboside and derivatives thereof. In an aspect, the invention relates to a method of preparing a compound of formula (I), wherein n is 0 or 1; m is 0 or 1; Y is O or S; R1 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted primary or secondary amino, and substituted or unsubstituted azido; R2- R5, which may be the same or different, are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl; and X- is an anion, selected from an anion of a substituted or unsubstituted carboxylic acid, a halide, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted carbamate. r unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted primary or secondary amino, and substituted or unsubstituted azido; R2- R5, which may be the same or different, are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl; and X- is an anion, selected from an anion of a substituted or unsubstituted carboxylic acid, a halide, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted carbamate.
Description
Methods of ing namide riboside and derivatives thereof
Field of the invention
The invention relates to methods of ing nicotinamide riboside and derivatives thereof.
Background to the invention
Nicotinamide riboside and derivatives thereof, including nicotinate riboside, nicotinamide
mononucieotide and nicotinate mononucleotide, are metabolites of nicotinamide adenine
dinucleotide (NAD*). The B-anomer forms of nicotinamide riboside, nicotinate riboside, namide
mononucleotide and nicotinate mononucleotide are shown, without counter ions, in Figure 1. As a
NAD+ precursor, nicotinamide riboside has been shown in mice to enhance oxidative metabolism
and protect against at diet induced obesity, which has resulted in cant interest in
namide de and its derivatives. Since nicotinamide riboside is a naturally occurring
compound, nicotinamide riboside and its derivatives have great potential as natural, ional
supplements, which may provide health benefits t causing side effects. One limitation in the
commercial exploitation of nicotinamide riboside and derivatives thereof, as nutritional supplements,
or otherwise, is that known synthetic protocols for preparing nicotinamide riboside and derivatives
thereof have disadvantages, rendering them unsuitable for scaling up for commercial or industrial
use.
describes a method for the preparation of nicotinamide riboside and derivatives
f. However, the disclosed method has a number of disadvantages. For example, trimethylsilyl
trifluoromethanesuifonate (TMSOTf) is used as the st in the disclosed method, and results in
the prepared compounds inevitably being in the form of their triflate (‘OTf) salts. The triflate salt form
of nicotinamide riboside, or derivatives thereof, is not suitable for use as a nutritional supplement,
because of its associated toxicity. Thus, the compounds produced by the disclosed method are not
le for use as they are prepared, and require an additional step to ge the triflate anion for
an anion that would be pharmaceutically acceptable and therefore suitable for cialisation,
utilizing for example, reverse phase liquid tography as sed. Additionally, nicotinamide
riboside is chemically labile, in particular under the chromatographic conditions used in the disclosed
method. it is therefore proposed that the chromatographic conditions used could result in s of
less than optimum purity and, within the batches, great variability in terms of the side products
produced. Another disadvantage is that careful control of the temperature of the reaction is
necessary to minimise decomposition in the final stages of the synthesis of nicotinamide riboside, yet
the disclosed method is exothermic and is therefore prone to nvironment thermal fluctuation,
especially in the event of large scale production set up.
Tanimori at al (8. Tanimori, T. Ohta and M. Kirihata, Bioorganic & Medicinal try Letters, 2002,
12, 1135—1137) and etti et 8/ (P. Franchetti, M. Pasqualini, R. Petrelli, M. Ricciutelli, P. Vita
and L. lacci, Bioorganic & Medicinal Chemistry Letters, 2004, 14, 658) also describe
methods for the preparation of nicotinamide riboside. r, these methods also have the
disadvantage of inevitably resulting in the preparation of the triflate salt by virtue of using TMSOTf as
catalyst.
in summary, the disclosed methods have disadvantages which present obstacles to the scaling up of
the method for commercial or industrial use, and which, ore, greatly limit the commercial
opportunities for the methods and the resultant compounds.
it is therefore an object of the invention to avoid or mitigate the disadvantages of the prior art.
It is also an object of the invention to provide a novel, useful and efficient method for the preparation
of nicotinamide riboside and derivatives f.
it is also an object of the invention to provide a method for the ation of nicotinamide riboside
and derivatives thereof, whereby the method may be used to introduce a counter ion of choice to the
prepared compounds, thereby producing compounds suitable for use as nutritional supplements or
otherwise.
Summary of the invention
According to the present invention, there is provided a method of preparing a compound of formula
(3)
wherein
nisOort;
misOorl;
YisOorS;
R1 is selected from H, substituted or unsubstituted alkyi, substituted or unsubstituted i,
substituted or unsubstituted alkynyi, substituted or unsubstituted aryl, substituted or unsubstituted
primary or secondary amino, and substituted or unsubstituted azido;
R2— R5, which may be the same or different, are each independently selected from H, substituted or
unsubstituted alkyi, substituted or tituted aikenyi, substituted or unsubstituted aikynyl, and
substituted or unsubstituted aryl; and
X‘ is an anion, ed from an anion of a substituted or unsubstituted carboxyiic acid, a halide, a
substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or
tituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted
carbamate;
sing reacting a compound of formula (it)
wherein n, m, Y and R1— R5 are as defined above;
with a compound of the formuia Z+X‘,
n X' is as defined above, and
wherein Z+ is a N-containing cation;
in the presence of an aqueous solution and a carbon—containing catalyst;
to form the compound of formula (l).
Optionally, Z is selected from a substituted or unsubstituted ammonium, a substituted or
unsubstituted pyridinium, a substituted or unsubstituted pyrrolidinium, a substituted or unsubstituted
imidazolium and a substituted or tituted triazolium.
Optionally, Z+ is a substituted or unsubstituted um of the formula N+HR'R"R'“, wherein R‘, R"
and R”, which may be the same or different, are each independently selected from H, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyt, and
substituted or unsubstituted aryl.
ally, Z+ is an unsubstituted ammonium of the formula NHJ.
Optionally, X‘ is an anion of a substituted or tituted carboxylic acid selected from an anion of a
tuted or unsubstituted monocarboxylic acid and an anion of a substituted or unsubstituted
dicarboxylic acid.
ally, X‘ is an anion of a tuted monocarboxylic acid, further optionally an anion of a
substituted propanoic acid or an anion of a substituted acetic acid. Optionally, X‘ is an anion of
substituted propanoic acid, further optionally an anion of a hydroxy propanoic acid, still r
optionally an anion of 2—hydroxypropanoic acid, being tactic acid, the anion of lactic acid being
lactate. Optionally, X“ is an anion of a substituted acetic acid, being a substituted acetate, further
optionally a trihaloacetate selected from trichloroacetate, tribromoacetate and trifluoroacetate. Still
further optionally, the trihaloacetate is triftuoroacetate.
Optionally, X' is an anion of an unsubstituted monocarboxyiic acid ed from formic acid, acetic
acid, propionic acid and butyric acid, being formate, acetate, propionate and butyrate, respectively.
Optionally, X' is an anion of a substituted or tituted amino~monocarboxyiic acid or an anion of
a substituted or unsubstituted amino-dicarboxylic acid. Further optionally, X’ is an anion of an
amino-dicarboxylic acid, optionally selected from glutamic acid and ic acid, being giutamate
and aspartate, respectively.
Optionally, X' is an anion of ascorbic acid, being ascorbate.
Optionally, X‘ is a halide selected from de, bromide, fluoride and iodide, further optionally
chloride or bromide,
2014/065971
Optionally, X‘ is a substituted or unsubstituted suifonate. Further optionally, X‘ is a
trihalomethanesulfonate ed from trifluoromethanesulfonate, tribromomethanesuifonate and
trichloromethanesulfonate. Still further optionally, the trihalomethanesulfonate is
trifluoromethanesulfonate.
Optionally, X‘ is a tuted or unsubstituted carbonate, further optionally hydrogen ate.
Optionally, X’ is selected from chloride, acetate, formate, trifluoroacetate, ascorbate, aspartate,
glutamate and lactate. Further optionally, X‘ is selected from chloride, acetate, formate and
1O trifluoroacetate.
Optionally, the compound of the formula Z*X' is selected from ammonium chloride, ammonium
acetate, ammonium formate, ammonium trifluoroacetate, ammonium ascorbate, ammonium
aspartate, ammonium glutamate and ammonium e. Further optionally, the compound of the
formula [X is seiected from ammonium chloride, ammonium acetate, ammonium formate and
ammonium trifluoroacetate.
Optionally, the compound of formula (ll) and the carbon—containing catalystare present in a
tive molar ratio of from about 10:1 to about 1:10, optionally from about 5:1 to about 1:5, further
optionally from about 4:1 to about 1:4, still further optionally about 1:1 or 1:2 or 1:3 or 1:4.
ie -containing catalysts include, but are not limited to, activated charcoal or graphite.
As used herein, the term "activated charcoal" is intended to mean a carbon containing material
processed to be highly porous y increasing the surface area of the material. The term
"activated charcoal” is intended to be synonymous with the term “activated carbon". The activated
charcoal may be in the form of powders and/or fibres and/or granules and/or pellets. ally, the
activated al may act as a support for a metal. Suitable metals include, but are not limited to,
transition metals. Suitable transition metals include, but are not limited to the platinum group metals,
optionally selected from ruthenium, rhodium, palladium, osmium, m, and platinum, or a
combination thereof.
Optionally, the aqueous solution consists essentially of water.
Optionally, the aqueous solution comprises, in addition to water, an organic solvent.
Suitable organic solvents include, but are not limited to, substituted or unsubstituted ethers,
substituted or tituted esters, substituted or tituted s, substituted or unsubstituted
aiiphatic or aromatic hydrocarbons, and combinations thereof.
Optionally, the organic solvent, when present, ses an ether selected from diethyi ether, methyl
tert-butyl ether, ethyl tert—butyl ether, di-tert-butyi ether, diisopropyl ether, dimethoxymethane,
4O ydrofuran, 2-methyltetrahydrofuran, and tetrahydropyran, or a combination thereof.
Optionally, the organic solvent, when present, comprises an ester selected from methyl acetate,
ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate and n—butyl acetate, or a
combination thereof.
Optionally, the organic solvent, when present, comprises a ketone selected from methyl isobutyl
ketone and methyl isopropyl ketone, or a combination thereof.
Optionally, the c solvent, when present, comprises an unsubstituted tic hydrocarbon
solvent ed from pentane, hexane, cyclohexane and e, or a combination thereof.
Optionally, the organic t, when present, comprises a substituted aliphatic hydrocarbon solvent,
optionally a halogenated aliphatic hydrocarbon t, further optionally a chlorinated aliphatic
1O hydrocarbon sotvent selected from dichloromethane, trichloromethane, tetrachtoromethane, 1,2—
chloroethane, 1, 1, 1-trichloroethane and trichloroethylene, or a combination thereof.
Optionally the c soivent, when present, comprises an aromatic hydrocarbon solvent selected
from benzene, e, enzene and xylene, or a combination thereof.
ally, the aqueous solution comprises water and organic solvent in a respective ratio by volume
of from about 1:5 to about 5:1, optionally from about 1:3 to about 3:1, further optionally from about
1:2 to about 2:1, still further optionally about 1:1.
Optionally, the reaction is carried out in a pH range of from about 6 to about 8, optionaliy from about
6.5 to about 7.5.
Optionally, the reaction is carried out at a temperature of from about 10°C to about 40°C, optionally
from about 15°C to about 35°C, further optionally from about 15°C to about 30°C, still further
optionally from about 15°C to about 20°C, even further optionally from about 20°C to about 25°C,
even r optionally at a ature of about 20°C or 21°C or 22°C or 23°C or 24°C or 25°C.
Optionally, the reaction is carried out for a period of time of from about 1 minute to about 180
minutes, optionally, from about 2 minutes to about 120 s, further optionally from about 5
minutes to about 120 minutes, stiil further optionally from about 10 minutes to about 120 minutes,
even further optionally from about 20 minutes to about 120 s, even further optionally from
about 30 s to about 120 minutes, stilt further optionally from about 60 minutes to about 120
minutes, even further optionaliy from about 60 minutes to about 90 minutes, stili further optionally
about 60 minutes or 70 s or 80 s.
Optionally, the method further comprises a filtration step to remove the carbon-containing catalyst
from the prepared compound of formula (I). le filtration means for use in the filtration step
include, but are not limited to, syringe filters and/or paper filters, and/or any inert, insoluble
substance capable of acting as a filter, e.g, alumina and/or silica and/or diatomaceous earth. it will
be appreciated any other suitable filtration means may be used.
As used herein, the term “substituted” is intended to mean that any one or more hydrogen atoms is
replaced with any suitable substituent, provided that the normal valency is not exceeded and the
replacement results in a stable compound. Suitable substituents include, but are not limited to, alkyl,
alkylaryl, aryl, heteroaryl, halide, hydroxyl, carboxylate, carbonyl (including alkylcarbonyl and
arylcarbonyl), phosphate, amino (including alkylamino, dialkylamino, hydroxylamino,
dihydroxylamino, alkyl hydroxylamino, arylamino, diarylamino and alkylarylamino), thiol (including
alkylthiol, arylthiol and thiocarboxylate), sulfate, nitro, cyano and azido.
As used herein, the term “alkyl” is intended to mean a substituted or tituted, saturated or
unsaturated, optionally saturated, linear, branched or cyclic, aliphatic hydrocarbon, having from 1 to
12 carbon atoms, optionally from 1 to 10 carbon atoms, r optionally from 1 to 8 carbon atoms,
still further optionally from 1 to 6 carbon atoms, even still further optionally 1 or 2 or 3 or4 or 5
carbon atoms. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, opyl, n-
butyl, iso-butyl, tert-butyl, yl, iso-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl
and cyclohexyl. Optionally, when Y is O, n is 1, and m is 1, ethyl is preferred.
As used herein, the term “alkenyl" is intended to mean a tuted or unsubstituted, linear,
branched or cyclic, aliphatic hydrocarbon, having at least one -carbon double bond, and
having from 2 to 12 carbon atoms, optionally from 2 to 10 carbon atoms, further optionally from 2 to 8
carbon atoms, still further ally from 2 to 6 carbon atoms, even still further ally 2 or 3 or 4
or 5 carbon atoms. Suitable alkenyl groups include, but are not limited to, ethenyi, propenyl and
l,
As used herein, the term “alkynyl” is ed to mean a substituted or unsubstituted, linear,
branched or cyclic, aliphatic hydrocarbon, having at least one carbon-carbon triple bond, and having
from 2 to 12 carbon atoms, optionally from 2 to 10 carbon atoms, further optionally from 2 to 8
carbon atoms, still further optionally from 2 to 6 carbon atoms, even still further optionally 2 or 3 or 4
or 5 carbon atoms. Suitable alkynyl groups e, but are not limited to, ethynyl, propynyl, butynyl,
and the like.
As used herein, the term “aryl” is intended to mean a tuted, tituted, monocyclic or
3O polycyclic, aromatic hydrocarbon. le aryls include, but are not limited to, substituted or
unsubstituted phenyl, and substituted or unsubstituted heteroaryl.
Optionally, the substituted or unsubstituted primary or secondary amino is ed from substituted
or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted
hydroxylamino, substituted or unsubstituted dihydroxylamino, and substituted or unsubstituted alkyl
hydroxylamino.
Optionally, the substituted or unsubstituted azido is selected from substituted or unsubstituted alkyl
azido and substituted or unsubstituted aryi azido.
it will be appreciated that, when n is 0 and m is 0, R1 is directly attached to the pyridine ring or to the
pyridinium ring, as appropriate.
Optionally, in an embodiment of formula (l), n is O, m is 1, R1 is NHZ, R2 ~ R5 are each H, and X' is
selected from chloride, acetate, formate and trifluoroacetate.
Optionally, in an embodiment of formula (ll), n is 0, m is 1, R1 is NH?” and R2 — R5 are each H.
Optionally, the compound of formula (II) and the compound of the formula Z+X‘ are present in a
respective molar ratio of from about 1:5 to about 5:1, optionally from about 1:3 to about 3:1, further
optionally from about 1:2 to about 2:1, still r optionally about 1:1.
ally, the method comprises ng the reactants, optionally using a magnetic or ical
stirrer, further optionally an overhead mechanical stirrer.
ln an ment, the carbon-containing catalyst used in the preparation of a compound of a
(l) may be provided in the form of an activated charcoal column, for example an activated charcoal
material such as those supplied by Sigma Aldrich under the trade names NORlT (Trade Mark) or
DARCO (Trade Mark), or from CarboChem, W Lancaster Ave, e, PA 19003, USA, or a
carbon supported catalyst in a CatCart Packer (Trade Mark) column from ThalesNano, soft
Park, Zéhony u. 7‘ H1031 Budapest, Hungary. in this embodiment, the activated charcoal column
may be used as part of any suitable liquid chromatography , including, but not limited to, a
fast protein liquid chromatography (FPLC) or a high performance liquid chromatography (HPLC)
system, or a flow chemistry system, such as the ThalesNano (Trade Mark) H-cube systems and
related flow reactors, available from ThalesNano, details provided above, in this case, the nts
would be recirculated onto the column in a continuous manner until the compound of formula (ll) is
no longer detected by UV at 340nm.
Optionally, the compound of formula (It) is prepared by reacting a compound of formula (lll)
(ill)
wherein
n, m. Y and R1—- R5 are as defined above; and
R5, R7 and R8, which may be the same or different, are each independently a hydroxyl—protecting
group;
with a deprotecting agent;
to form the compound of formula (II)
le R6, R7 and R8 moieties include, but are not limited to, ester-type protecting groups, ether-
type protecting groups, and silyl—type protecting groups.
As used , the term “ester-type protecting group” is ed to mean a protecting group that
forms an ester bond for the e of yl protection and which may be substituted or
unsubstituted. Suitable ester—type ting groups include, but are not limited to, acetyl, propionyl,
isopropionyl, benzoyl, and trihaloacetyl, optionally trifluoroacetyl or trichloroacetyl.
As used herein, the term “ether-type protecting group" is intended to mean a protecting group that
forms an ether bond for the purpose of hydroxyl tion and which may be tuted or
unsubstituted. Suitable type ting groups include, but are not limited to, benzyl, p-
methoxybenzyl, methoxymethyl and allyl ethers.
As used herein, the term “silyl—type protecting group” refers to a protecting group that forms a silyloxy
bond for the purpose of hydroxyl protection. Examples thereof from trimethylsiiyl, triethylsilyl,
triisopropylsilyl, 2—(trimethylsilyl)eth0)Q/methyl, tyldimethylsilyl, tert—butyldiphenylsilyl and
tetraisopropyldisilyl.
Optionally, the R5, R7 and R8 moieties are selected from substituted and unsubstituted acetyl, and
substituted and unsubstituted benzoyl.
Optionally, at least two of R6, R7 and R5 are selected from unsubstituted acetyl or unsubstituted
benzoyl.
Optionally the deprotecting agent is an acid or a base. Deprotection can also be achieved by
catalytic hydrogenation (Pd/C; Hz) for the aromatic ether protecting groups and by fluoride-catalysed
chemistry (at. TBAF in THF) for all the silyl ethers. Optionally, when R5, R7 and R3 each comprise
unsubstituted acetyl or unsubstituted benzoyl, the deprotecting agent is a base, optionally selected
from NH3, Nazcog and NaOH. it will be appreciated by a skilled person that any other tional
deprotecting agent may be used.
Optionally, the on is carried out in the presence of a protic or c solvent or a combination
thereof.
Suitable protic solvents include, but are not limited to, water, substituted or unsubstituted alcohol, or
a combination thereof. Suitable substituted alcohols include substituted or unsubstituted fluorinated
alcohols. Suitable unsubstituted alcohols include methanol, ethanol and propanol, optionally
methanol.
le aprotic organic solvents include, but are not limited to, substituted or unsubstituted ,
substituted or unsubstituted esters, substituted or unsubstituted ketones, substituted or unsubstituted
aliphatic or ic hydrocarbons, and combinations thereof, as defined above.
Optionally, the reactants are subjected to mechanical grinding, further ally using a ball milling
or planetary ball g machine.
Optionally, in an embodiment of formula (lll), n is O, m is 1, R1 is NHZ, R2 — R5 are each H, and R6 ~
R8 are each acetyl.
Further optionally, in another embodiment of formula (Ill), n is 1, Y is O, m is 1, R1 is ethyl, R2 —— R5
are each H, and R6 — R8 are each acetyl.
Still further optionally, in another embodiment of formula (Ill), n is O, m is 1, R1 is NH2, R2 —- R5 are
each H, and R6 -— R8 are each benzoyl.
Optionally, the nd of formula (ill) is prepared by reacting a compound of formula (W)
wherein
n, m, Y, R1- R8 and X' are as defined above;
with a reducing agent,
an aqueous solution
and an organic solvent
to form a nd of formula (lll).
Optionally, X- is selected from ascorbate, glutamate, aspartate, lactate and acetate.
Suitable organic ts are as defined above in respect of the preparation of a compound of
formula (I) from formula (ll).
Optionally, when at least two of R6, R7 and R8 comprise tituted acetyl, the organic solvent is
selected from dichloromethane, 1,2—chloroethane, n—butyl acetate, chloroform and ethyl acetate, or a
combination thereof, further optionally ethyl acetate.
Optionally, when at least two of R2, R3 and R4 comprise unsubstituted benzoyl, the organic solvent is
selected from oroethylene, carbon tetrachloride, diisopropyl ether, toluene, methyl tert—butyl
ether, e and diethyl ether, or a combination thereof, r optionally diethyl ether.
Optionally, the reducing agent is selected from sodium dithionite or sodium borohydride.
Optionally, the method may comprise the simultaneous addition of the reducing agent, aqueous
solution and organic solvent; or the sequential addition of the reducing agent, aqueous solution and
organic t, in any order; or a combination thereof.
Optionally, the aqueous solution consists essentially of water.
It will be appreciated that, ally, the aqueous solution and the organic solvent form a bi-phasic
solution sing an aqueous phase and an organic phase.
Optionally, the method comprises the additional steps of
separating the organic phase from the aqueous phase; and
extracting the compound of a (ill) from the c solvent
4o it will be appreciated by a skilled person that the hydroxyl protecting groups R5, R7 and R8, are
required to be lipophilic to the extent that the reduced compound of formula (Ill), once prepared,
migrates into the organic phase of the bi-phasic reaction medium formed by the aqueous solution
(aqueous phase) and organic t (organic phase).
Optionally, the reactants are ted to mechanical grinding, further optionally using a ball mill or
planetary ball milling machine.
Optionally, in an ment of formula (W), n is O, m is 1, R1 is NHZ, R2 —— R5 are each H, R6 — R8
are each acetyl, and X‘ is ‘OTf.
Further optionally, in another embodiment of formula (ill), n is 1, Y is O, m is 1, R1 is ethyl, R2 —— R5
are each H, R5 -— R3 are each acetyl, and X‘ is 'OTf.
Still further optionally, in another ment of a (Ill), n is 0, m is 1, R1 is NHZ, R2 —— R5 are
each H, and R6 - R8 are each benzoyl, and X" is ‘OTf.
According to the invention, there are also provided compounds derivable from the methods disclosed
herein.
ingly to the invention, there is further provided a compound of formula (l)
wherein
n, m, Y, R1— R5 and X‘ are as defined above.
Optionally, X' is selected from acetate, formate and trifluoroacetate.
Optionally, the compound of formula (i) has the formula (LA), is is the B-anomer,
\“c 3”;
HOS ’40
(1A)
wherein
n, m, Y, R1~ R5 and X‘are as defined above.
Optionally, the compound of formula (II) has the formula (HA), le. is the B~anomer,
\\\\\\
(llA)
wherein
n, m, Y and R1-R5 are as defined above.
Optionally, the compound of formula (lll) has the formula , Le. is the B-anomer,
R70\
(lllA)
wherein
n, m, Y and R1~ R8 are as defined above.
ally, the compound of formula (W) has the formula (lVA), i.e. is the B-anomer,
YnR1
R70‘
(NA)
wherein
n, m, Y, R1~R8 and X' are as defined above
Advantages of the invention include, but are not limited to the following:
(1) The preparation of compounds of formula (1) from compounds of formula (ll) provides an
efficient method of ucing a counter ion of choice for namide riboside and its
derivatives Starting from a compound of formula (ii), e.g. reduced NRH, a desired counter
ion may be introduced. Furthermore, even if the method starts by using compounds of
formula (IV) in the form of the te salt, the methods of the invention enable the triflate
anion to be exchanged during the method in a simple and efficient manner, to a counter ion
of choice. Thus, the disclosed methods conveniently enable the preparation of compounds
having potential use as nutritional supplements or otherwise.
(2) The invention provides stereoselective methods for the preparation of nicotinamide riboside
and derivatives thereof, producing the desired B-anomer. This is in contrast, for example, to
Tanimori et al, which is not stereoselective and produces significant s of the Cl—
anomer, which is undesirable. onally, the methods of the invention are useful, efficient,
and can be easily scaled up for industry and cialisation, and provide for the
minimisation of solvent use, purification and reaction time. For example, the methods of the
invention for preparing compounds of formula (i) from compounds of formula (it), are
conveniently completed in less than 2 hours with quantitative yields. The methods for the
preparation of compounds of formula (l) starting from compounds of formula (W) are also
very efficient and e very good yields. The methods may iently be carried out at
room temperature.
(3) The s described herein are capable of preparing not just nicotinamide riboside but
also a whole range of derivatives, which is not disclosed in either ri et a/ or Franchetti
et al. The derivatives include not just derivatives of namide riboside but also the
reduced form of nicotinamide riboside and derivatives thereof. Furthermore, although not
described herein, a skilled person will appreciate that, starting from compounds of formula
(ll), it is possible to easily access the phosphorylated parents of nicotinamide riboside and
derivatives thereof, for example nicotinamide cleotide and nicotinate
mononucleotide.
(4) The protecting groups used in the preparation of compounds of a (ill) from compounds
of formula (W) may advantageously be chosen to be sufficiently lipophilic so that they
facilitate the migration of the compounds of formula (lll) into the organic phase of the
reaction medium, for ease of extraction.
(5) The methods described herein conveniently use nts which enable the compounds of
formula (l) to be prepared in a neutral pH range of from about 6 to about 8. For example, in
the preparation of the compounds of formula (l) from the compounds of formula (ll), this
neutral pH range enables both the starting materials (compounds of formula (ll)), which are
acid labile, and the final products (compounds of formula (l)), which are base labile, to be
stable during the reaction.
(6) The inventors have surprisingly found that, the use of a aining cation as Z+ (the proton
source), conveniently s the ent preparation of compounds of formula (i) from
compounds of formula (ii) in quantitative yield, and, as mentioned in point (5), in a neutral pH
range. Without wishing to be bound by theory, it is proposed that Z, the proton source, must
be a conjugated acid of an organic base which is protonated in an equilibrated manner within
the neutral pH range. The inventors propose that, by using a aining cation as the
proton source Z", the N atom of the proton source has a pKa greater than the pKa of the N
atom of the dihydropyridine of the nd of a (ll). Therefore, in simple terms, due
40 to the relative pKa values, the N atom of the proton source Z+ (i.e. N-Hi) holds onto the
proton H+ until after the N atom of the dihydropyridine has been oxidised (which oxidation,
the inventors propose, is facilitated by the carbon—containing catalyst). It is only after the N
atom of the dihydropyridine has been oxidised that it will be protonated by the proton source
Z“. The inventors propose that if a proton source other than one containing a N atom is
used, for example a phosphonium cation containing P-H+ or a sulfonium cation containing S-
H, it is proposed that such proton sources would cause the pH of the reaction medium to fall
below the neutral pH range, and the proton sources would release their protons in this lower
pH range. it is proposed that this change would cause the N atom of the dihydropyridine to
be protonated before oxidation, y resulting in the undesirable hydrolysis of a C-N bond
of the dihydropyridine, it is also proposed that this resultant instability of the opyridine
due to the undesirable ng of a C-N bond, would also occur using a weak acid (eg.
carboxylic acid) or a strong acid (e.g. hydrochloric acid, phosphoric acid or sulphuric acid).
Thus, it is ed that only a N-containing cation as proposed, is capable of releasing a
proton in a pH range (neutral) which allows the reaction to proceed as desired to form the
compounds of formula (l) from the compounds of formula (ll).
Examples
Embodiments of the present invention will now be described, with reference to the accompanying,
non-limiting es and drawings, in which:
Figure 1 shows the B-anomer forms of nicotinamide de, nicotinate riboside, namide
mononucleotide and nicotinate mononucleotide, without counter ions;
Figure 2 depicts Scheme A, which is a scheme illustrating, in l terms, that compounds of
a (W) may be used to prepare compounds of formula (III), as described in Example 1; that
compounds of formula (ll!) may be used to prepare compounds of formula (ll), as described in
Example 2; and that compounds of formula (ll) may be used to prepare nds of formula (l), as
described in Example 3; wherein n, m, Y, R1 — R3 and X' are as defined above;
Figure 3 depicts Scheme B, which is a scheme illustrating, in general terms, that triacetyl
namide riboside, trifiate salt may be used to prepare triacetyl~1,4—dihydronicotinamide de,
as described in Example 1(A), and that triacetyl-1 ,4-dihydronicotinamide riboside may be used to
prepare 1-(beta—D-ribofuranosyi)—1,4—dihydronicotinamide, as described in Example 2, and that 1-
(beta-D-ribofuranosyl)—’l ,4-dihydronicotinamide may be used to prepare namide riboside,
chloride salt, as described in Examples 3(A), 3(E) and 3(F). The B-anomers of all of the mentioned
compounds are shown. It will be appreciated that Scheme B is merely exemplary and is not to be
construed as limiting the invention o;
4o Figure 4 shows the B—anomer forms oftriacetyl-1,4—dihydronicotinamide riboside (Example 1(A)),
tyl O-ethyl-1, dronicotinate riboside, (Example 1(8)), tribenzoyl—1,4—dihydronicotlnamide
riboside le 1(0)), and 1—(beta-D—ribofuranosyl)—1,4-dihydronicotinamide (Example 2); and
Figure 5 shows the B-anomer forms of nicotinamide riboside, chloride salt (Examples 3(A), 3(E) and
3(F)), nicotinamide riboside, acetate salt (Example 3(8)), nicotinamide riboside, formate salt
(Example 3(C)), and nicotinamide riboside, trifluoroacetate salt (Example 3(D)).
Example 1
1O Compounds of formula (Ill) were prepared in accordance with the ion as follows. The pH of the
on media described in the following examples was in the region of about 6—8.
Exam Ie 1 A : Pre aration of reduced triacet l nicotinamide riboside. namel triacet l-1.4-
dihydronicotinamide riboside a compound of formula (ill) (the g-anomer form of which is shown in
Figure 4).
Reduction: All solvents were degassed prior to use by sonication and argon ng. Sodium
dithionite (0.6569, 3.76 mmol, 2 eq) and sodium hydrogencarbonate (0.799, 9.40 mmol, 5 eq) were
added to a clean, dry round bottom flask with a magnetic stirrer and placed under inert atmosphere.
A compound of formula (lW, namely triacetyl nicotinamide riboside, triflate (CF3803’, also known as
—OTf) salt (19, 1.88 mmol, 1 eq) was then dissolved in a minimum amount of water (<10 ml) and
slowly added to the reaction vessel. Once the reaction d, further water was added to the
reaction until ail of the reactants had dissolved (<10 ml) and was left to stir for 20 minutes. The
aqueous solution was then extracted with three half portions of dichloromethane (DCM). The DCM
fractions were ted and concentrated under reduced pressure, ing the triacetyl~1, 4-
dihydronlcotinamide riboside derivative (triacetyl-NRH) with residual amounts of starting material
(<5%). The aqueous layer was subjected to the above conditions a second time to increase yields
which ed 65%. Ethyl acetate was also an excellent alternative extraction solvent in place of
DCM, yielding a 75% yield.
lR (MeOD, 400MHz) — 57.15 (s, 1H, H-5), 5.95 (d, 1H, J: 7.21Hz, H—6), 5.25 (d, 1H, J=2.84Hz)
& 5.17 (d, 1H, J=1.80Hz) (H-8 & H-7), 4.96 (d, 1H, J=7.09Hz, H~4), 4.87 (ABX, 1H, Jaa=8.18Hz,
Jab=3.60Hz, H—9), 4.26 (d, 2H, J=3.20Hz, H—10 & H-10’) 4.19 (m, 1H, J=3.00Hz, H—3), 3.13 (m, 2H,
J=1.18Hz, H—2), 2.13 (s, 3H), 2.11 (s, 3H), 2.10 (s, 3H) (H-13, H—15, H-17). 130—NMR (MeOD,
125MHz) — 5172.80 (0—11), 170.40 (C-12, C~14, 0—16), 137.90 (C-5), 125.20 (04), 105.12 (C-6),
95.24 (C-3), 83.49 (C—9), 71.18 (C~8), 70.26 (C—7), 61.55 (C-10), 22.16 (C—2), 21.52 (C-13, C-15, C»
17). HMRS m/z: 45; Calc. Mass: 383.1454.
The compound of formula (W), namely trlacetyl nicotinamide de, triflate (-OTf) salt was
prepared as follows. Nicotinamide (10g, 81.89 mmol, 1eq) was silylated using TMSCl (15.6 ml,
40 122.85 mmol, 1.5 eq) in HMDS (100 ml) at 130°C in tative yield, in order to force the B-
, selectivity via the following VorerQgen reaction. Ribose tetraacetate (also known as tetraacetate
riboside) was reacted with the resultant silyiated nicotinamide in the presence of 5 equivalents of
TMSOTf. The reactants were shaken in a 1.5 mi steel vessei with a 5 mm diameter steel bail bearing
in a Retsch MM400 mixer mili at 25 Hz for 0.5 h. At this point the formed triacetylated nicotinamide
riboside (compound of formula (iV)) could be isolated. it will be appreciated that the tyl
nicotinamide riboside is not limited to being produced by this exact method, and could, for example,
be produced using a conventional Vorbriiggen reaction as described, for example, in ational
PCT patent publication no. or in T. Yang, N. Y. K. Chan and A. A. Sauve, Journal
of Medicinal Chemistry, 2007, 50, 6458—6461.
1H—NMR (MeOD, 400MHz) — 5 9.61 (s, 1H, aromatic), 9.30 (dt, 1H, J=6.3, 1.4 Hz, aromatic), 9.10 (dt,
1H, J=8.2, 1.4 Hz, aromatic), 8.37 (dd, 1H, J=8.2, 6.3 Hz, aromatic), 6.60 (d, 1H, J=3.9 Hz, H—1
(anomeric)), 5.60 (dd, 1H, J=5.6, 3.9Hz, H-2), 5.46 (t, 1H, J=5.6 Hz, H-3), 4.81-4.84 (m, 1H, H-4),
4.61 (ABX, 1H, Ja,a:=13.1 Hz, Ja|b=3.5 Hz, H-5), 4.51 (ABX, 1H, Ja,a!=13.0 Hz, Ja,b=2.8 Hz, H-5'), 2.20
(s, 3H, OAc), 2.17 (s, 3H, OAc), 2.16 (s, 3H, OAc).
13C-NMR (MeOD, 125MHz) - 6 172.1, 171.6, 171.2 (3x Q=OCH3), 164.9 (Q=ONH2) 147.0, 144.3,
142.3, 136.2, 129.6, tic), 121.6 (q, J: 3202 Hz, CF3), 99.4 (C-1 (anomeric)), 84.4 (0—4), 77.6
(C-2), 70.7 (C-3), 63.5 (C—5), 20.7 (OAc), 20.3 (OAc), 20.2 (OAc).
1QF-NlVlR (MeOD, ) — 6 —79.9 (triflate counterion)
e 1(B): ation of reduced mi nicotinate ester riboside, namely triacetyi O-ethyl-1,
4-dihydronicotinate riboside. a compound of formula (lll) (the g-anomer form of which is shown in
Figure 4).
Reduction: A compound of formula (IV), namely triacetyi i nate riboside, triflate (—OTf)
sait (2.309, 4.2mmol, 1eq) was dissolved in 20mL H20 and a solution of a solution of NaHCO3
(1.779, oi, Seq) and sodium dithionite (1.479, 8.22mmol, 2eq) in 30mL H20 was added and
stirred for 2hrs. The yellow solution obtained was then washed with 2 x ethyl acetate (EtOAc, 40mL),
the organic layer dried over M9804, filtered and concentrated to provide 900mg (39% yield) of 2,3,5—
triacetyi O-ethyl-i, 4- dihydronicotinate riboside (a yellow 05!) without further purification. 80% purity
based on 1H—NMR.
1H-NMR-o 7.27 (1H, s, H—6), 6.05 (1H, dd, J: 8.2, 1.5Hz, H-7), 5.26 (1H, dd, J: 5.8, 2.8Hz, H-3),
.23 (1H, dd, J: 6.9, 5.8Hz, H-2), 5.08 (1H, d, J: 6.9Hz, H-1), 4.91 (1 H, dt, J: 8.3, 3.5Hz, H—8), 4.24-
4.30 (3H, m, H—4, H-5, H-5’), 4.11 (2H, 9, J: 7.2Hz, H—11), 3.04-3.06 (2H, m, H—9), 2.16 (3H, 5, OAc),
2.12 (3H, 5, OAc), 2.09 (3H, s, OAc), 1.25 (3H, t, J: 7.2Hz, H—12).
R— 6 172.2, 171.5, 171.3, 169.8, (3x Q=O-CH3 and Q=O-0Et), 139.9 (C—6), 126.3 (C-7), 106.4
(C—8), 101.5 (C-10), 94.2 (C—1), 80.4 (0-4), 72.3 (0—2), 72.1 (0-3), 64.8 (0—5), 61.0 (C-11), 23.4 (C-
9), 20.7, 20.5, 20.3 (3x C=O-_(;H3), 14.8 (0-12).
The compound of formula (W), namely tyi O~ethyl nicotinate riboside, triflate (—OTf) salt was
40 prepared as follows. Ribose tetraacetate (also known as tetraacetate riboside) was reacted with ethyl
nicotinate (Sigma Aldrich) using the genera! bail milling Vorbrtiggen ure described in Exampie
2014/065971
1(A) above. The reactants, namely 1eq tetraacetate riboside, 1eq TMSOTf, 1eq ethyl nicotinate,
were d for 30mins in a 1.5 ml steel vessel with a 1.5cm diameter steel ball bearing in a Retsch
MM400 mixer mill at 25 Hz. The crude reaction mixture ining some unreacted ethyl nicotinate
and starting sugar, <10%) was used for the reduction step (described above) without further
purification. It will be appreciated that the triacetyl O—ethyl nicotinate riboside, triflate (-OTf) salt is not
limited to being produced by this exact method, and could, for example, be produced using a
conventional ‘iggen reaction as described for example, in international PCT patent publication
no. or in T. Yang, N. Y. K. Chan and A. A. Sauve, Journal of Medicinal Chemistry,
2007, 50, 6458—6461.
1O lR (D20, 400MHz) — 5 9.45 (s, 1H, aromatic), 9.14 (d, 1H, J=6.1 Hz, aromatic), 9.02 (d, 1H,
J=7.8 Hz, aromatic), 8.18 (t, 1H, J=6.7 Hz, aromatic), 6.51 (d, 1H, J=4.1 Hz, H-1 (anomeric)), 5.47 (t,
1H, J=4.4 Hz, H-2), 5.36 (t, 1H, J=4.7 Hz, H-3), 4.81-4.84 (m, 1H, H-4), 4.45—4.48 (m, 2H, H~5), 4.36
(q, 2H, J=7.0 Hz, C=OCfi2CH3), 2.04 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.98 (s, 3H, OAc), 1.25 (t, 3H,
J=7.0 Hz, CH3).
‘gF-NMR (ozo, 376MHz) — 6 -790 (triflate counterion)
Example 1(C): Preparation of reduced tribenzoyl nicotinamide riboside, namely tribenzoyl—1, 4-
dihydronicotinamide riboside, a compound of formula (ill) (the fi-anomer form of which is shown in
Figure 4).
ion imised): A compound of formula (IV), namely tribenzoyl nicotinamide riboside,
triflate (—OTf) salt was dissolved in minimal methanol and transferred to a round bottomed flask,
10mL of H20 was added to the on and most of the methanol removed via rotary evaporation.
The starting al crashed out of solution and 20mL of diethyl ether (EtZO) was added until the
solids solubilized into a biphasic system. A solution of NaHC03 (420mg, 5mmol, Seq) and sodium
dithionite (348mg, 2mmol, 2eq) in 10mL H20 was added and stirred for 2hrs. The layers were
separated and the ether layer was dried over MgSO4 and concentrated to provide 428mg (76% yield)
of zoyl-1, 4-dihydronicotinamide riboside (yellow solid) t further purification. 80% purity
based on 1H-NMR. Pure material is obtained by Biotage purification.
3O 1H-NMR- 5 8.01-8.04 (2H, m, 0B2), 7.81—7.86 (4H, m, 082), 7.25-7.55 (9H, m, 082), 7.13 (1H, s, H—
6), 6.01 (1H, dd, J: 8.2, 1.5Hz, H-7), 5.68 (1H, dd, J: 6.2, 3.5Hz, H—3), 5.57 (1H, dd, J: 6.7, 6.2Hz,
H-2), 5.29 (1H, cl, J: 6.7Hz, H-1), 4.61-4.68 (2H, m, H—8, H—5), 4.50-4.55 (2H, m, H-4, H-5’), 3.93—
3.94 (2H, m, H-9).
13C-NMR- 6 172.7, 167.6, 166.7, 166.6 (3x CGH5, Q=ONH2), 138.1 ((3-6), 134.9, 134.8, 134.6,
130.9, 130.8, 130.7, 130.3, 130.0, 129.8, 129.7 (3x 032), 125.7 (C-7), 105.9 ((3-8), 94.9 (0-1), 80.3
(C—4), 72.9 (0-2), 72.7 (C-3), 65.4 (C-5), 23.6 ((3-9).
The compound of formula (W), namely tribenzoyl nicotinamide riboside, triflate (-OTf) salt was
prepared as follows. Ribose tetraacetate (also known as tetraacetate riboside) was reacted with
40 TMS—nicotinamide (trimethylsilyl N-trimethylsilylpyridine-B-Carboximidate, available from Sigma-
h) using the l ball milling VorbriJggen procedure described in Example 1(A) above. The
WO 14722
reactants, namely 1eq 1-acetate-tribenzoate riboside, 1eq TMSOTf and 1eq TMS—nicotinamide, were
reacted for 30mins in a 1.5 ml steel vessel with a 1.5cm diameter steel ball bearing in a Retsch
MM4OO mixer mill at 25 Hz. 1eq of DCE (dichloroethylene) was required and the crude reaction
mixture (containing some unreacted nicotinamide and starting benzoate sugar, <10%) was used for
the reduction step (described above) without further purification. It will be appreciated that the
tribenzoyl nicotinamide riboside, triflate (—OTf) salt is not limited to being produced by this exact
, and could, for example, be produced using a conventional Vorbrtrggen reaction as
described, for example, in international PCT patent publication no. or in T. Yang,
N. Y. K. Chan and A. A. Sauve, Journal of Medicinal try, 2007, 50, 6458—6461.
1O 1H—NMR (MeOD, ) — 6 9.59 (s, 1H, aromatic), 9.31 (cl, 1H, J=6.4 Hz, ic), 8.94 (d, 1H,
J=8.1 Hz, aromatic), 8.15 (dd, 1H, J=8.1, 6.4 Hz, aromatic), 7.90-7.94 (m, 6H, OBz), 7.50-7.54 (m,
SH, 082), .38 (m, 6H, 08.2), 6.79 (d, 1H, J=3.9 Hz, H-1 (anomeric)), 5.97 (dd, 1H, J=5,6,
3.9Hz, H~2), 5.87 (t, 1H, J=5.6 Hz, H—3), 5.13-5.16 (m, 1H, H-4), 4.83—4.91 (m, 2H, H—5).
19F-NMR (MeOD, 376MHz) ~ 5 -791 (triflate counterion)
A compound of formula (ll), nameiy NRH ed nicotinamide riboside, also known as 1-(beta—D-
ribofuranosyl)-1,4—dihydronicotinamide (the B-anomer form of which is shown in Figure 4)
was prepared as follows. The pH of the reaction medium described in the following example was in
the region of about 6—8.
d triacetyl nicotinamide riboside, namely triacetyl—1, 4—dihydronicotinamide riboside, a
compound of formula (Ill), prepared in Example 1(A) above, was deprotected using
mechanochemical (MeOH, NaOH) processes to remove the acetyl moiety afforded NRH
quantitatively. 100mgs of (ill) was dissolved in 0.5mL of MeOH containing 0.05g of NaOH. The
nds were reacted for 30mins in a 1.5 ml steel vessel with a 1.5cm diameter steel ball bearing
in a Retsch MM400 mixer mill at 25 Hz.
1H—NMR (MeOD, 400MHz) — 57.18 (s, 1H, H-5), 6.14 (d, 1H, J: 8.28Hz, H-6), 4.85 (m, 1H, H-3),
4.76 (d, 1H, J: 5.77Hz, H-4), 4.04 (m, 2H, H~7&H-8), 3.93 (m, 1H, J=2.76, H-9), 3.72 (ABX, 1H,
Jaa=12.55Hz, Jab=3.51Hz, H—10), 3.65 (ABX, 1H, Jaa=12.55Hz, Jab=4.02Hz, H—10’), 3.10 (q, 2H,
Hz H-2). 13C—NMR (MeOD, 125MHz) — 6172.88 ((3-11), 137.83 (0-5), 125.29 (0-4), 105.19
(C—B), 95.00 (C-3), 83.54 (C-9), 71.10 ((3-8), 70.20 (C-7), 61.61 (0—10), 22.09 (C-2); HRMS m/z:
257.1130; Calc. Mass: 257.1137.
it will be appreciated that the deprotection step as described above may be used to deprotect any
other compound of formula (lll), including, but not limited to, reduced triacetyl nicotinate ester
riboside, namely 2,3,5-triacetyl l-1, 4—dihydronicotinate riboside, ed in Example 1(8),
and reduced tribenzoyl nicotinamide riboside, namely tribenzoyl-1, dronicotinamide riboside,
40 prepared in Example 1(0). The deprotection step may also be modified to suit particular
requirements.
Example 3
Compounds of formula (I) were prepared in accordance with the ion as follows. The pH of the
reaction media described in the following es was in the region of about 6-8.
Exam le 3 A : Pre aration of nicotinamide de chloride salt the —anomer form of which is
1O shown in Figure 5).
A compound of formula (ll), namely NRH (reduced nicotinamide riboside, shown in Figure 2; 50mg,
0.20mmol, 1eq), was dissolved in 5mL H20 and then 1eq (i.e. 0.20mmol) of ammonium chloride was
added in one portion. Activated charcoal , i.e. 0.80mmol) was then added and the mixture
stirred at RT for ~1hr and then filtered and freeze—dried to give the chloride salt of nicotinamide
riboside, quantitatively, i.e. 100% conversion and pure product.
1H-NMR (D20, ) ~ 6 9.46 (s, 1H, aromatic), 9.12 (dt, 1H, J=6.3, 1.4 Hz, aromatic), 8.83 (dt,
1H, J=8.2, 1.4 Hz, aromatic), 8.13 (dd, 1H, J=8.2, 6.3 Hz, aromatic), 6.13 (d, 1H, J=4.3 Hz, H—1
(anomeric)), 4.37 (t, 1H, J=4.7Hz, H-2), 4.31-4.34 (m, 1H, H-4), 4.21 (t, 1H, J=4.7Hz, H—3), 3.90
(ABX, ‘lH, Ja,a-=13.0 Hz, Ja,b=3.5 Hz, H—5), 3.75 (ABX, 1H, JaIa-=13.O Hz, Ja'_b=2.8 Hz, H-5’).
lt will be appreciated that the NRH may be that ed in Example 2, or may be obtained
commercially from eg. Diverchim, 100, rue Louis Blane, 60 765 Montataire Cedex, France — (CAS
Registry Number:19132—12~8) either as a pure product or as a mixture of anomers.
Exam le 3 B : Pre aration of nicotinamide riboside acetate salt the —anomer form of which is
shown in Figure 5).
The method described in Example 3(A) was carried out, except that 1eq (i.e. 0.20mmol) of
ammonium acetate was added. The acetate salt of nicotinamide riboside was obtained,
quantitatively.
1H—NMR (D20, ) ~ 6 9.46 (s, 1H, aromatic), 9.12 (d, 1H, J=6.3 Hz, aromatic), 8.83 (d, 1H,
J=8.2 Hz, aromatic), 8.12 (m, 1H, ic), 6.09 (d, 1H, J=4.4 Hz, H—1 (anomeric)), 4.36 (t, 1H,
J=4.7Hz, H-2), 4.32-4.35 (m, 1H, H—4), 4.21 (t, 1H, J:4.7Hz, H-3), 3.91 (ABX, 1H, 13.1 Hz,
Ja,b=2.8 Hz, H—5), 3.75 (ABX, 1H, Javay=13.0 Hz, 3.5 Hz, H-5'), 1.79 (s, 3H, OAc).
Exam le 3 C : Pre aration of nicotinamide riboside formate salt the -anomer form of which is
shown in Figure 5).
The method described in Example 3(A) was carried out, except that 1eq (i.e. 0.20mmol) of
ammonium formate (methanoate) was added. The formate salt of nicotinamide riboside was
obtained, quantitatively.
1H-NMR (D20, 400MHz) - 6 9.46 (s, 1H, aromatic), 9.12 (d, 1H, J=6.3 Hz, aromatic), 8.83 (d, 1H,
J=8.2 Hz, aromatic), 8.29 (s, 1H, formate), 8.12 (m, 1H, aromatic), 6.09 (d, 1H, J=4.4 Hz, H~1
(anomeric)), 4.36 (t, 1H, J=4.7Hz, H-2), 4.31-4.34 (m, 1H, H—4), 4.21 (t, 1H, J=4.7Hz, H—3). 3.91
(ABX, 1H, 13-1 Hz, Ja,b=3.5 Hz, H-5), 3.79 (ABX, 1H, Ja‘a:=13.0 Hz, 2.8 Hz, H-5').
Exam le 3 D : Pre aration of nicotinamide riboside oroacetate salt the -anomer form of which
1O is shown in Figure 5).
The method described in Example 3(A) was carried out, except that 1eq (i.e. ol) of
ammonium trifluoroacetate was added. The trifluoroacetate salt of nicontinamide riboside was
obtained, quantitatively.
1H-NMR (D20, ) - 6 9.46 (s, 1H, aromatic), 9.12 (d, 1H, J=6.3Hz, aromatic), 8.83 (d, 1H,
J=8.2, aromatic), 8.13 (dd, 1H, J=8.2. 6.3 Hz, aromatic), 6.13 (d, 1H, J=4.3 Hz, H-1 (anomeric)), 4.35
(t, 1H, J=4.7Hz, H-2), 4.31-4.34 (m, 1H, H—4), 4.20 (t, 1H, J=4.7Hz, H-3), 3.89 (ABX, 1H, Jalai=130
Hz, Ja'b=3.6 Hz, H-5), 3.74 (ABX, 1H, Ja,a.=13.o Hz, Jagb=2.9 Hz, H-5'). 19F-NMR (ozo, 376MHz)— 5 -
75.7 COO').
Exam le 3 E : Pre aration of nicotinamide riboside chloride salt the -anomer form of which is
shown in Figure 5).
An alternative method to that described in Example 3(A) was carried out as s. NRH (reduced
nicotinamide riboside, shown in Figure 4; 50mg, 0.20mmol, teq) was dissolved in 5mL H20:EtOAc
(1:1) and then 1eq. (i.e. 0.20mmol) of ammonium de was added in one portion. Upon work-up
after 1 hr, no oxidation had taken place and the starting materials were fully recovered. The
recovered NRH and ammonium chloride were re—suspended in the same solvent system with
addition of activated charcoal (~10mg. i.e. l) and stirred at RT for 1 hr. Subsequent filtration
3O and freeze-drying afforded the chloride salt of nicotinamide riboside in quantitative yield. Thus it was
ded that a carbon-containing catalyst, e.g. activated al, was essential to the method.
1H—NMR (020, 400MHz) — 6 9.46 (s, 1H, aromatic), 9.12 (dt, 1H, J=6.3, 1.4 Hz, aromatic), 8.83 (dt,
1H, J=8.2, 1.4 Hz, aromatic), 8.13 (dd, 1H, J=8.2, 6.3 Hz, aromatic), 6.13 (d, 1H, J=4.3 Hz, H—1
(anomeric)), 4.37 (t, 1H, J=4.7Hz, H-2), 4.31—4.34 (m, 1H, H—4), 4.21 (t, 1H, J=4.7Hz, H~3), 3.90
(ABX, 1H, Ja,a’=13.0 Hz, Ja,b=3.5 Hz, H—5), 3.75 (ABX, 1H, Ja,a'=13.0 Hz, Ja',b=2.8 Hz, H—5‘).
Exam le 3 F : Pre aration of namide riboside chloride salt the -anomer form of which is
shown in Figure 5).
4O The method described in e 3(E) was carried out, except that NRH (reduced nicotinamide
riboside, shown in Figure 4; 50mg, 0.20mmol, 1eq) was dissolved in 5mL H20:THF (1:1),
instead of H201EtOAc (1:1), and then 1eq (i.e. 0.20mmol) of ammonium chloride was added in one
portion. Upon work-up after 1 hr, no ion had taken place and the starting materials were fully
red. The recovered NRH and ammonium chloride were resuspended in the same solvent
system with addition of ted charcoal (~10mg, i.e. 0.8mmol) and stirred at RT for 1 hr.
uent filtration and freeze-drying afforded the chloride salt of nicotinamide riboside in
quantitative yield. Thus it was concluded that a carbon-containing catalyst, e.g. activated charcoal,
was essential to the method.
1H—NMR (D20, 400MHz) — 6 9.46 (s, 1H, aromatic), 9.12 (dt, 1H, J=6.3, 1.4 Hz, aromatic), 8.83 (dt,
1H, J=8.2, 1.4 Hz, aromatic), 8.13 (dd, 1H, J=8.2, 6.3 Hz, aromatic), 6.13 (d, 1H, J=4.3 Hz, H-1
(anomeric)), 4.37 (t, 1H, J=4.7Hz, H—2), 4.31-4.34 (m, 1H, H—4), 4.21 (t, 1H, J=4.7Hz, H-3), 3.90
(ABX, 1H, Ja‘a>=13.0 Hz, Ja,b=3.5 Hz, H-5), 3.75 (ABX, 1H, Ja,ai=13.0 Hz, Jajb=2.8 Hz, H—5').
Claims (58)
1. A method of preparing a compound of formula (I) wherein 10 n is 0 or 1; m is 0 or 1; Y is O or S; R1 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, tuted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted primary or secondary amino, and substituted or unsubstituted azido; 20 R2 – R5, which may be the same or different, are each independently ed from H, substituted or unsubstituted alkyl, tuted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and tuted or unsubstituted aryl; and X- is an anion, selected from an anion of a substituted or tituted carboxylic acid, a halide, a 25 substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted carbamate; comprising reacting a compound of formula (II) (II) 5 wherein n, m, Y and R1 – R5 are as defined above; with a compound of the formula Z+X-, wherein X- is as defined above, and wherein Z+ is a N-containing cation; in the ce of an aqueous solution and a carbon-containing catalyst, wherein the carboncontaining catalyst is activated charcoal; to form the compound of formula (I).
2. A method according to claim 1, wherein Z+ is selected from a substituted or unsubstituted ammonium, a tuted or unsubstituted pyridinium, a substituted or unsubstituted idinium, a 20 substituted or unsubstituted imidazolium and a substituted or unsubstituted triazolium.
3. A method according to claim 1 or claim 2, wherein Z+ is a substituted or unsubstituted ammonium of the formula ˡˡRˡˡˡ, wherein Rˡ, Rˡˡ and Rˡˡˡ, which may be the same or different, are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted 25 alkenyl, tuted or unsubstituted alkynyl, and substituted or unsubstituted aryl.
4. A method according to any one of claims 1 to 3, wherein Z+ is an unsubstituted ammonium of the formula NH4+. 30
5. A method according to any ing claim, wherein the aqueous solution comprises, in addition to water, an organic solvent.
6. A method according to claim 5, wherein the aqueous solution ses water and organic solvent in a respective ratio by volume of from 1:5 to 5:1, optionally from 1:3 to 3:1, r optionally from 1:2 to 2:1, still further optionally 1:1. 5
7. A method according to claim 5 or claim 6, wherein the organic solvent is selected from a substituted or unsubstituted ether, a substituted or unsubstituted ester, a substituted or unsubstituted ketone, a substituted or unsubstituted aliphatic or aromatic hydrocarbon, or a combination thereof.
8. A method according to any one of claims 5 to 7, wherein the organic solvent comprises an 10 ether selected from diethyl ether, methyl tert-butyl ether, ethyl utyl ether, di-tert-butyl ether, diisopropyl ether, dimethoxymethane, tetrahydrofuran, 2-methyltetrahydrofuran, and tetrahydropyran, or a combination thereof.
9. A method according to any one of claims 5 to 8, wherein the organic t comprises an ester selected from methyl acetate, ethyl acetate, isopropyl e, n-propyl acetate, isobutyl 15 acetate and n-butyl acetate, or a ation thereof.
10. A method according to any one of claims 5 to 9, wherein the organic solvent comprises a ketone selected from methyl isobutyl ketone and methyl isopropyl ketone, or a ation thereof.
11. A method ing to any one of claims 5 to 10, wherein the organic t comprises an 20 unsubstituted aliphatic arbon solvent ed from pentane, hexane, cyclohexane and heptane, or a ation thereof.
12. A method according to any one of claims 5 to 11, wherein the organic solvent comprises a substituted aliphatic hydrocarbon solvent, optionally a halogenated aliphatic hydrocarbon solvent, 25 further optionally a chlorinated aliphatic hydrocarbon solvent selected from romethane, trichloromethane, tetrachloromethane, 1,2-chloroethane, 1, 1, 1-trichloroethane and trichloroethylene, or a combination thereof.
13. A method according to any one of claims 5 to 12, wherein the organic solvent comprises an 30 aromatic hydrocarbon solvent selected from benzene, toluene, ethylbenzene and xylene, or a combination f.
14. A method according to any preceding claim, wherein the compound of formula (II) and the compound of the formula Z+X- are present in a respective molar ratio of from 1:5 to 5:1, optionally 35 from 1:3 to 3:1, further optionally from 1:2 to 2:1, still further optionally 1:1.
15. A method according to any preceding claim, wherein the compound of formula (II) and the carbon-containing catalyst are t in a respective molar ratio of from 10:1 to 1:10, ally from 5:1 to 1:5, further optionally from 4:1 to 1:4, still further optionally 1:1 or 1:2 or 1:3 or 1:4.
16. A method ing to any ing claim, wherein the reaction is carried out in a pH range of from 6 to 8, optionally from 6.5 to 7.5.
17. A method according to any preceding claim, wherein the on is carried out at a 5 temperature of from 10°C to 40°C, optionally from 15°C to 35°C, further optionally from 15°C to 30°C, still further optionally from 15°C to 20°C, even further optionally from 20°C to 25°C, even r optionally at a temperature of 20°C or 21°C or 22°C or 23°C or 24°C or 25°C.
18. A method according to any preceding claim, wherein the on is d out for a period 10 of time of from 1 minute to 180 minutes, optionally from 2 minutes to 120 minutes, further optionally from 5 s to 120 minutes, still further optionally from 10 s to 120 minutes, even further ally from 20 minutes to 120 minutes, even further optionally from 30 minutes to 120 minutes, still further optionally from 60 minutes to 120 minutes, even further optionally from 60 minutes to 90 minutes, still r ally 60 minutes or 70 minutes or 80 minutes.
19. A method according to any preceding claim, wherein X- is an anion of a substituted or unsubstituted carboxylic acid selected from an anion of a substituted or unsubstituted monocarboxylic acid and an anion of a substituted or unsubstituted dicarboxylic acid.
20 20. A method according to claim 19, wherein X- is an anion of a substituted monocarboxylic acid, optionally an anion of a substituted propanoic acid or an anion of a substituted acetic acid.
21. A method according to claim 20, wherein X- is an anion of a substituted propanoic acid, optionally an anion of a hydroxy propanoic acid, further optionally an anion of 2-hydroxypropanoic 25 acid, being e.
22. A method according to claim 20, n X- is an anion of a substituted acetic acid, being a substituted acetate, optionally a trihaloacetate selected from trichloroacetate, tribromoacetate and trifluoroacetate, further optionally trifluoroacetate.
23. A method according to claim 19, wherein X- is an anion of an unsubstituted rboxylic acid selected from formic acid, acetic acid, propionic acid and butyric acid, being formate, acetate, propionate and butyrate, respectively. 35
24. A method according to claim 19, wherein X- is an anion of a substituted or unsubstituted amino-monocarboxylic acid or an anion of a substituted or unsubstituted amino-dicarboxylic acid, wherein, optionally, X- is an anion of an amino-dicarboxylic acid, further optionally selected from glutamic acid and aspartic acid, being glutamate and aspartate, respectively. 40
25. A method according to claim 19, wherein X- is an anion of ascorbic acid, being ascorbate.
26. A method according to any one of claims 1 to 18, n X- is a halide ed from chloride, bromide, fluoride and iodide, optionally chloride or bromide. 5
27. A method according to any one of claims 1 to 18, wherein X- is selected from chloride, acetate, formate, trifluoroacetate, ascorbate, aspartate, glutamate and lactate, optionally selected from chloride, acetate, formate and trifluoroacetate.
28. A method according to any one of claims 1 to 18, wherein the compound of the formula Z+X- 10 is selected from ammonium chloride, ammonium acetate, ammonium e, ammonium trifluoroacetate, ammonium ascorbate, um aspartate, ammonium ate and ammonium lactate, optionally selected from ammonium chloride, ammonium acetate, ammonium formate and ammonium trifluoroacetate. 15
29. A method according to any preceding claim, wherein the method further comprises a tion step to remove the carbon-containing stfrom the compound of formula (I).
30. A method according to any one of claims 1 to 18, wherein, in the compound of formula (I), n is 0, m is 1, R1 is NH2, R2 – R5 are each H, and X- is selected from chloride, acetate, formate and 20 trifluoroacetate.
31. A method according to any preceding claim, wherein the compound of a (II) is prepared by reacting a nd of formula (III) (III) wherein 30 n, m, Y and R1 – R5 are as defined in the preceding claims; and R6, R7 and R8, which may be the same or different, are each independently a hydroxyl-protecting group; with a deprotecting agent; to form the compound of formula (II).
32. A method according to claim 31, n R6, R7 and R8 are each independently an ester-type protecting group, an ether-type ting group, or a silyl-type protecting group.
33. A method according to claim 32, wherein an ester-type ting group is a protecting group 10 ed from acetyl, propionyl, isopropionyl, benzoyl, and trihaloacetyl, optionally trifluoroacetyl or trichloroacetyl.
34. A method according to claim 32, n an ether-type protecting group is a protecting group selected from benzyl, p-methoxybenzyl, methoxymethyl and allyl ethers.
35. A method according to claim 32, wherein a silyl-type protecting group is a protecting group selected from trimethylsilyl, ylsilyl, triisopropylsilyl, 2-(trimethylsilyl)ethoxymethyl, tertbutyldimethylsilyl , tert-butyldiphenylsilyl and tetraisopropyldisilyl. 20
36. A method according to any one of claims 31 to 33, wherein the R6, R7 and R8 moieties are selected from tuted and unsubstituted acetyl, and substituted and unsubstituted benzoyl.
37. A method according to claim 36, wherein least two of R6, R7 and R8 are ed from unsubstituted acetyl or unsubstituted benzoyl.
38. A method according to any one of claims 31 to 37, wherein the deprotecting agent is an acid or a base.
39. A method according to claim 37, wherein R6, R7 and R8 each comprise unsubstituted acetyl 30 or unsubstituted benzoyl and the deprotecting agent is a base, ally selected from NH3, Na2CO3 and NaOH.
40. A method according to any one of claims 31 to 39, wherein the reaction is carried out in the presence of a protic or aprotic solvent or a combination thereof.
41. A method according to claim 41, wherein the reaction is carried out in the presence of a protic solvent selected from water, substituted or unsubstituted alcohol, or a combination thereof.
42. A method according to claim 42, wherein the reaction is d out in the presence of 40 methanol.
43. A method according to any one of claims 31 to 42, wherein the reactants are subjected to mechanical ng, optionally using a ball milling or planetary ball milling machine.
44. A method according to any one of claims 31 to 43, wherein, in the compound of formula (III), 5 n is 0, m is 1, R1 is NH2, R2 – R5 are each H, and R6 – R8 are each acetyl.
45. A method according to any one of claims 31 to 43, wherein, in the compound of formula (III), n is 1, Y is O, m is 1, R1 is ethyl, R2 – R5 are each H, and R6 – R8 are each acetyl. 10
46. A method according to any one of claims 31 to 43, wherein, in the compound of formula (III), n is 0, m is 1, R1 is NH2, R2 – R5 are each H, and R6 – R8 are each benzoyl.
47. A method according to any one of claims 31 to 46, wherein the nd of formula (III) is prepared by reacting a nd of formula (IV) (IV) wherein n, m, Y, R1 – R8 and X- are as defined in the preceding claims; with a reducing agent, 25 an aqueous solution, and an organic solvent, to form a compound of a (III).
48. A method according to claim 47, n the organic solvent is as defined in any one of claims 7 to 13.
49. A method according to claim 47 or claim 48, wherein when at least two of R6, R7 and R8 comprise unsubstituted acetyl, the organic solvent is selected from dichloromethane, 1,2- chloroethane, n-butyl acetate, chloroform and ethyl e, or a combination thereof, r optionally ethyl acetate.
50. A method according to claim 47 or claim 48, n when at least two of R2, R3 and R4 comprise unsubstituted l, the organic solvent is selected from trichloroethylene, carbon tetrachloride, diisopropyl ether, toluene, methyl tert-butyl ether, benzene and diethyl ether, or a ation thereof, further optionally diethyl ether.
51. A method according to any one of claims 47 to 50, wherein the reducing agent is selected from sodium dithionite or sodium borohydride.
52. A method according to any one of claims 47 to 51, wherein the method comprises the 15 additional steps of separating the c phase from the aqueous phase; and extracting the compound of formula (III) from the organic solvent.
53. A method according to any one of claims 47 to 52, wherein the reactants are subjected to 20 mechanical grinding, optionally using a ball mill or planetary ball milling machine.
54. A method according to any one of claims 47 to 53, wherein, in the compound of formula (IV), n is 0, m is 1, R1 is NH2, R2 – R5 are each H, R6 – R8 are each acetyl, and X- is -OTf. 25
55. A method according to any one of claims 47 to 53, wherein, in the compound of formula (IV), n is 1, Y is O, m is 1, R1 is ethyl, R2 – R5 are each H, R6 – R8 are each acetyl, and X- is -OTf.
56. A method ing to any one of claims 47 to 53, wherein, in the compound of formula (IV), n is 0, m is 1, R1 is NH2, R2 – R5 are each H, and R6 – R8 are each benzoyl, and X- is -OTf. 30
57. A method according to any one of claims 1 to 56, wherein the activated charcoal acts as a support for a metal, the metal optionally including tion metals.
58. A method according to claim 57, wherein the metal includes tion metals. WO 14722 HowN+ / NH2 \o ,, O \\ ’4 Nicotinamide riboside HowN+ / OH @‘° ”2 O HO 6/ Nicotinate riboside N+ / NH2 \P/O / c , N / OH \P/O 0 HO Nicotinate mononucleotide
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GBGB1313465.5A GB201313465D0 (en) | 2013-07-29 | 2013-07-29 | Methods of preparing nicotinamide riboside and derivatives thereof |
GB1313465.5 | 2013-07-29 | ||
PCT/EP2014/065971 WO2015014722A1 (en) | 2013-07-29 | 2014-07-24 | Methods of preparing nicotinamide riboside and derivatives thereof |
Publications (2)
Publication Number | Publication Date |
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NZ716277A NZ716277A (en) | 2021-03-26 |
NZ716277B2 true NZ716277B2 (en) | 2021-06-29 |
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