WO2023227996A1 - A deuterated amine compounds and process for synthesis thereof - Google Patents
A deuterated amine compounds and process for synthesis thereof Download PDFInfo
- Publication number
- WO2023227996A1 WO2023227996A1 PCT/IB2023/054922 IB2023054922W WO2023227996A1 WO 2023227996 A1 WO2023227996 A1 WO 2023227996A1 IB 2023054922 W IB2023054922 W IB 2023054922W WO 2023227996 A1 WO2023227996 A1 WO 2023227996A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- deuterated
- acid
- formula
- compound
- propyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 55
- -1 amine compounds Chemical class 0.000 title claims abstract description 50
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 46
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 14
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 150000007513 acids Chemical class 0.000 claims description 11
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 125000003944 tolyl group Chemical group 0.000 claims description 7
- 150000001298 alcohols Chemical class 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 claims description 2
- GWJSQKNYHPYZRN-UHFFFAOYSA-N 2-methylpropane-2-sulfonamide Chemical compound CC(C)(C)S(N)(=O)=O GWJSQKNYHPYZRN-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- YNJDSRPIGAUCEE-UHFFFAOYSA-N 4-methylbenzenesulfinamide Chemical compound CC1=CC=C(S(N)=O)C=C1 YNJDSRPIGAUCEE-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 claims description 2
- 238000000105 evaporative light scattering detection Methods 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical class [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 claims description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- INQOMBQAUSQDDS-FIBGUPNXSA-N trideuterio(iodo)methane Chemical compound [2H]C([2H])([2H])I INQOMBQAUSQDDS-FIBGUPNXSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 2
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 claims 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 claims 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims 1
- 239000001530 fumaric acid Substances 0.000 claims 1
- 239000000174 gluconic acid Substances 0.000 claims 1
- 235000012208 gluconic acid Nutrition 0.000 claims 1
- 239000004220 glutamic acid Substances 0.000 claims 1
- 239000004310 lactic acid Substances 0.000 claims 1
- 235000014655 lactic acid Nutrition 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- 239000011976 maleic acid Substances 0.000 claims 1
- 239000001630 malic acid Substances 0.000 claims 1
- 235000011090 malic acid Nutrition 0.000 claims 1
- 229960002510 mandelic acid Drugs 0.000 claims 1
- 239000011713 pantothenic acid Substances 0.000 claims 1
- 229940055726 pantothenic acid Drugs 0.000 claims 1
- 235000019161 pantothenic acid Nutrition 0.000 claims 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims 1
- 229960004889 salicylic acid Drugs 0.000 claims 1
- 239000011975 tartaric acid Substances 0.000 claims 1
- 235000002906 tartaric acid Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 9
- 229910052805 deuterium Inorganic materials 0.000 description 12
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 9
- 150000003956 methylamines Chemical class 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 7
- 150000001350 alkyl halides Chemical class 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- BAVYZALUXZFZLV-FIBGUPNXSA-N trideuteriomethanamine Chemical compound [2H]C([2H])([2H])N BAVYZALUXZFZLV-FIBGUPNXSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 3
- 239000012454 non-polar solvent Substances 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 229940124282 BMS-986165 Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000011941 photocatalyst Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- DPZHKLJPVMYFCU-UHFFFAOYSA-N 2-(5-bromopyridin-2-yl)acetonitrile Chemical compound BrC1=CC=C(CC#N)N=C1 DPZHKLJPVMYFCU-UHFFFAOYSA-N 0.000 description 1
- ZXLYYQUMYFHCLQ-FIBGUPNXSA-N 2-(trideuteriomethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(C([2H])([2H])[2H])C(=O)C2=C1 ZXLYYQUMYFHCLQ-FIBGUPNXSA-N 0.000 description 1
- OZDAOHVKBFBBMZ-UHFFFAOYSA-N 2-aminopentanedioic acid;hydrate Chemical compound O.OC(=O)C(N)CCC(O)=O OZDAOHVKBFBBMZ-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000004936 Sorafenib derivatives Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 150000001975 deuterium Chemical class 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical class FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical class IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- QPJSUIGXIBEQAC-UHFFFAOYSA-N n-(2,4-dichloro-5-propan-2-yloxyphenyl)acetamide Chemical compound CC(C)OC1=CC(NC(C)=O)=C(Cl)C=C1Cl QPJSUIGXIBEQAC-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-FIBGUPNXSA-N nitromethane-d3 Chemical compound [2H]C([2H])([2H])[N+]([O-])=O LYGJENNIWJXYER-FIBGUPNXSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229910021650 platinized titanium dioxide Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- NQMRYBIKMRVZLB-NIIDSAIPSA-N trideuteriomethanamine;hydrochloride Chemical compound Cl.[2H]C([2H])([2H])N NQMRYBIKMRVZLB-NIIDSAIPSA-N 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Definitions
- the present invention relates to a process for synthesis of a deuterated compound. Most particularly, it relates to synthesis of a deuterated amine compounds of formula (I) and salts thereof.
- the said compound is an important key intermediate in the synthesis of deuterated drugs and/or chemical compounds.
- Deuterium a stable isotope of hydrogen (H), also known as deuterium, is commonly denoted by the symbol D or 2H.
- the deuterium nucleus consists of one proton and one neutron, has twice the relative atomic weight of ordinary hydrogen, and has substantially the same shape and volume as hydrogen in a drug molecule. That is, hydrogen in the drug molecule is selectively replaced by deuterium, and the original biological activity and selectivity are generally retained.
- deuterated drugs due to deuterium has very low toxicity.
- deuterated drugs have entered clinical trials and have been approved for use.
- Deuterated methylamine and salt thereof as important key intermediates play significant roles in the preparation of deuterated drugs and pesticides.
- CD3NH2 deuterated methyl amine
- US8748666B2 and EP2548859 discloses preparation methods of methyl- d3-amine and salts thereof.
- the said method involves the following steps: (i) nitromethane is subjected to react with deuterium oxide in the present of bases and phase-transfer catalysts to form nitromethane-d3, which is subsequently subjected to reduction in an inert solvent to form methyl-d3- amine, and optionally, methyl-d3-amine reacts subsequently with acids to form salts of methyl-d3-amine; or (ii) N-(1,1,1-trideuteriomethyl) phthalimide is subjected to react with acids to form salts of methyl-d3- amine.
- CN111302951 describes N-deuterium methylamine compound and a preparation method thereof.
- the preparation method comprises the following steps: mixing an amine compound, a deuterium source and a photocatalyst, and carrying out a reaction in an inert gas atmosphere under a light source to obtain the N-deuterium methylamine compound.
- deuterium water and deuterated methanol are used as deuterium sources, the deuterated methanol is used as a deuterium methyl source.
- the photocatalyst is selected from Pd/PCN, Pt/PCN, Au/PCN, Pd/TiO 2 , Pt/TiO 2 , Au/TiO 2 , Pd/ZnCdS, Pt/ZnCdS or Au/ZnCdS.
- One of the objects of the present invention is to provide a process for synthesis of methyl amine compound, specially deuterated methyl amine compound.
- Another object of the present invention is to provide deuterated methylamine as a key starting material that can be used in the synthesis of deuterated drugs and chemicals.
- Anther embodiment of the present invention is to provide a process for synthesis deuterated methyl amine salts.
- Yet another embodiment of the present invention is to provide a process for synthesis of deuterated methyl amine, wherein the said process can be carried out in minimum steps with higher yield.
- Yet another embodiment of the present invention is to provide easy, high efficient, and low cost process for synthesis of deuterated methyl amine.
- One of the aspects of the present invention is to provide a deuterated amine compound represented by formula (I)
- R is selected from deuterated C1-C10 alkyl and C1-C20 aryl, wherein the alkyl and aryl optionally substituted with halo, -OH, aryl and alkyl.
- Another aspect of the present invention is to provide a process for synthesis of deuterated amine compounds of formula (I), the process comprising the steps of: a) reacting a compound of formula (A) or formula (B) with a compound of formula (b) (R-X) at desired reaction conditions in a solvent to obtain a compound of formula (C) or formula (D) respectively; and b) treating the compound of formula (C) or formula (D) obtained from step (a) with an acid at desired reaction conditions in a solvent to obtain a salt of the compound of formula (I).
- solvent refers to a substance that can dissolve another substance, or in which another substance is dissolved, forming a solution.
- the solvent used in the present invention can be polar or nonpolar solvent.
- the solvent includes such as but not limit to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
- reaction conditions refers to the conditions that may be applied to synthesis of product.
- the reaction conditions includes such as but not limited to temperature, pressure, time, concentration of reactants, the physical state of reactants and their dispersion, the solvent, and the presence of a catalyst.
- One of the embodiments of the present invention provides a deuterated amine compound represented by formula (I)
- R is selected from deuterated C1-C10 alkyl and C1-C20 aryl, wherein the alkyl and aryl optionally substituted with halo, -OH, aryl and alkyl;
- X is OMs, OTf, OTs, ONs or halogen selected from fluorine, chlorine, bromine, and iodine.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), the process comprises the steps of: a) reacting a compound of formula (A) or formula (B) with a compound of formula (b) (R-X) at desired reaction conditions in a solvent to obtain a compound of formula (C) or formula (D); and b) treating the compound of formula (C) or (D) obtained from step (a) with an acid at desired reaction conditions in a solvent to obtain a salt of the compound of formula (I).
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (A) is represented by: wherein R in the compound of formula (I) is alkyl, tolyl or aryl group.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the alkyl group (R) in the compound of formula (A) may be selected from methyl, ethyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-propyl, iso-propyl, pentyl, isopentyl, neopentyl group.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (B) is represented by: wherein R is alkyl, tolyl or aryl group.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the alkyl group (R) in the compound of formula (B) may be selected from methyl, ethyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-propyl, iso-propyl, pentyl, isopentyl, neopentyl group.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (b) is represented by R-X, wherein R is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated pentyl, deuterated isopentyl, deuterated neopentyl group; and X is any leaving group.
- R-X wherein R is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated pentyl, deuterated isopentyl, deuterated
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein X group in the compound of formula (b) (R-X) including but not limited to OMs, OTf, OTs, ONs or halogen.
- Yet another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the halogen in the compound of formula (b) (R-X) is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (C) is represented by formula wherein R in the compound of formula (C) is alkyl, tolyl or aryl group; wherein the alkyl group (R) in the compound of formula (C) is selected from methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl; and deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated pentyl, deuterated isopentyl, deuterated neopentyl group.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (D) is represented by formula wherein R in the compound of formula (C) is alkyl, tolyl or aryl group; and wherein R group in the compound of formula (D) is selected from methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, secondary butyl, tertiary butyl, n- pentyl, isopentyl, neopentyl; and deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated n-pentyl, deuterated isopentyl, deuterated neopentyl group.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the deuterated amine compounds of formula (I) are deuterated aliphatic amines and/or aromatic amines, preferably deuterated methyl amine (D3C-NH2.HX).
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the acid can be organic and/or inorganic acid.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulphuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulphonic acids (for example, methanesulphonic, trifluoromethanesulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, benzenesulphonic, tolu
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the alkyl halide (R-X) is deuterated alkyl halide.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the deuterated alkyl halide (R-X) is selected from deuterated methyl iodide, deuterated methyl chloride, deuterated methyl bromide and deuterated methyl fluoride.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (A) or formula (B) including but not limited to t-butylsulfinamide, t-butylsulfonamide, p-toluenesulfinamide and p-toluenesulfonamide.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (b) (R-X) including but not limited to methyliodide-D3 methanol-d4 containing leaving groups like methylbromide-d3, methylchloride-d3, CD3OTs, CD3OMs, CD3OTf, CD3ONs.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein methanol-d4 can also be directly coupled with t-butylsulfinamide using Mitsunobu reaction (PPh3, DEAD or PPh3, DIAD).
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the base including such as but not limited to organic and inorganic bases.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the base may be selected from inorganic base including but not limited to sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide; and wherein the base is selected from organic base including such as but not limited to pyridine, triethyl amine, dimethyl amino pyridine, diethyl amine.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the solvent used in the present invention can be polar or nonpolar solvent and/or deuterated polar or non-polar solvents.
- the solvent including but not limited to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein salt of deuterated amine compound of formula (I) may be prepared by adding HCI gas in an organic solvent.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the solvent used in the present invention can be deuterated solvents.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compound of formula (I), wherein the deuterated amine compound of formula (I) can be further purified or recrystallized by known conventional methods.
- Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the said amine compounds can be used as intermediate in the synthesis of drug compounds and/or chemical compounds.
- step-1 To a 25 mL RB flask was added 2.1g of compound of example I (step-1), 5 mL of IPA and 3 mL of 6M-IPA.HCI at room temperature, stirred the reaction mass at room temperature for 1h, filtered the solid and recrystallized using chloroform and Ethanol to obtain 0.5g of pure Methyl- D3 Amine Hydrochloride, 43% overall yield after two steps (Chemical purity: 100% by ELSD, D%:99.89% by Q-NMR) 13C NMR: 23.412 (septet, 21.58Hz).
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Abstract
The present invention relates to a process for synthesis of a deuterated compound. Most particularly, it relates to synthesis of a deuterated amine compounds of formula (l) and salts thereof. The said compound is an important key intermediate in the synthesis of deuterated drugs and/or chemical compounds.
Description
A DEUTERATED AMINE COMPOUNDS AND PROCESS FOR SYNTHESIS THEREOF
PRIORITY:
This application claims the benefit of Indian complete application number 202221029766 dated 24/05/2022 and bearing title “A DEUTERATED AMINE COMPOUNDS AND PROCESS FOR SYNTHESIS THEREOF” the contents of which are incorporated herein by reference.
FIELD OF INVENTION:
The present invention relates to a process for synthesis of a deuterated compound. Most particularly, it relates to synthesis of a deuterated amine compounds of formula (I) and salts thereof. The said compound is an important key intermediate in the synthesis of deuterated drugs and/or chemical compounds.
BACKGROUND OF INVENTION:
Deuterium (deuterium), a stable isotope of hydrogen (H), also known as deuterium, is commonly denoted by the symbol D or 2H. The deuterium nucleus consists of one proton and one neutron, has twice the relative atomic weight of ordinary hydrogen, and has substantially the same shape and volume as hydrogen in a drug molecule. That is, hydrogen in the drug molecule is selectively replaced by deuterium, and the original biological activity and selectivity are generally retained.
Moreover, due to deuterium has very low toxicity. In recent years, several deuterated drugs have entered clinical trials and have been approved for use. Currently, there are two main routes for introducing deuterium into a compound: one is by proton exchange with hydrogen; and secondly, the synthesis is carried out by using deuterated raw materials.
Deuterated methylamine and salt thereof as important key intermediates play significant roles in the preparation of deuterated drugs and pesticides.
Several deuterated methyl amine (CD3NH2) containing drugs have been undergoing Phase III clinical studies (Deucravacitinib- BMS-986165; Enzalutamide-d3- HC 1119; Donafenib- CM-4307). Recently FDA has approved Deucravacitinib- BMS-986165 to treat plaque psoriasis.
(Methyl-d3) amine is used during the preparation of sorafenib derivatives. However, the synthetic steps or the current preparation processes are relatively complex, or the cost is high.
US8748666B2 and EP2548859 discloses preparation methods of methyl- d3-amine and salts thereof. The said method involves the following steps: (i) nitromethane is subjected to react with deuterium oxide in the present of bases and phase-transfer catalysts to form nitromethane-d3, which is subsequently subjected to reduction in an inert solvent to form methyl-d3- amine, and optionally, methyl-d3-amine reacts subsequently with acids to form salts of methyl-d3-amine; or (ii) N-(1,1,1-trideuteriomethyl) phthalimide is subjected to react with acids to form salts of methyl-d3- amine.
CN111302951 describes N-deuterium methylamine compound and a preparation method thereof. The preparation method comprises the following steps: mixing an amine compound, a deuterium source and a photocatalyst, and carrying out a reaction in an inert gas atmosphere under a light source to obtain the N-deuterium methylamine compound. In the said preparation method, deuterium water and deuterated methanol are used as deuterium sources, the deuterated methanol is used as a deuterium methyl source. The photocatalyst is selected from Pd/PCN,
Pt/PCN, Au/PCN, Pd/TiO2, Pt/TiO2, Au/TiO2, Pd/ZnCdS, Pt/ZnCdS or Au/ZnCdS.
Current manufacturing process of deuterated methylamine HCI has the following issues (a) Isotopic enrichment; (b) workup and isolation; and (c) not cost effective
Therefore, it is urgently needed to develop a simple, efficient and inexpensive method for preparing deuterated methylamine salt.
OBJECTS OF INVENTION
One of the objects of the present invention is to provide a process for synthesis of methyl amine compound, specially deuterated methyl amine compound.
Another object of the present invention is to provide deuterated methylamine as a key starting material that can be used in the synthesis of deuterated drugs and chemicals.
Anther embodiment of the present invention is to provide a process for synthesis deuterated methyl amine salts.
Yet another embodiment of the present invention is to provide a process for synthesis of deuterated methyl amine, wherein the said process can be carried out in minimum steps with higher yield.
Yet another embodiment of the present invention is to provide easy, high efficient, and low cost process for synthesis of deuterated methyl amine.
SUMMARY OF INVENTION
One of the aspects of the present invention is to provide a deuterated amine compound represented by formula (I)
Wherein R is selected from deuterated C1-C10 alkyl and C1-C20 aryl, wherein the alkyl and aryl optionally substituted with halo, -OH, aryl and alkyl.
Another aspect of the present invention is to provide a process for synthesis of deuterated amine compounds of formula (I), the process comprising the steps of: a) reacting a compound of formula (A) or formula (B) with a compound of formula (b) (R-X) at desired reaction conditions in a solvent to obtain a compound of formula (C) or formula (D) respectively; and
b) treating the compound of formula (C) or formula (D) obtained from step (a) with an acid at desired reaction conditions in a solvent to obtain a salt of the compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art.
The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
It must also be noted that as used herein, the singular forms "a", "an," and "the" include plural references unless the context clearly dictates otherwise. Although any systems and methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred, systems are now described.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. Throughout this specification, unless the context requires otherwise the word “comprise”, and variations, such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. The terms “Including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill
in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described.
Detailed embodiments of the present invention are disclosed herein, however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific functional and structural details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure.
The term “compound” used herein, is also intended to include any salts, solvates, or hydrates thereof. Thus, it is to be understood that when any compound is referred to herein by name and structure, salts, solvates, and hydrates thereof are included.
The term “solvent” used herein refers to a substance that can dissolve another substance, or in which another substance is dissolved, forming a solution. The solvent used in the present invention can be polar or nonpolar solvent. The solvent includes such as but not limit to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
The term ‘desired reaction conditions’ used herein refers to the conditions that may be applied to synthesis of product. The reaction conditions includes such as but not limited to temperature, pressure, time,
concentration of reactants, the physical state of reactants and their dispersion, the solvent, and the presence of a catalyst.
One of the embodiments of the present invention provides a deuterated amine compound represented by formula (I)
Wherein R is selected from deuterated C1-C10 alkyl and C1-C20 aryl, wherein the alkyl and aryl optionally substituted with halo, -OH, aryl and alkyl; and
X is OMs, OTf, OTs, ONs or halogen selected from fluorine, chlorine, bromine, and iodine.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), the process comprises the steps of: a) reacting a compound of formula (A) or formula (B) with a compound of formula (b) (R-X) at desired reaction conditions in a solvent to obtain a compound of formula (C) or formula (D); and
b) treating the compound of formula (C) or (D) obtained from step (a) with an acid at desired reaction conditions in a solvent to obtain a salt of the compound of formula (I).
Another embodiment of the present invention provides a process for
synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (A) is represented by: wherein R in the compound of formula (I) is alkyl, tolyl or aryl group.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the alkyl group (R) in the compound of formula (A) may be selected from methyl, ethyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-propyl, iso-propyl, pentyl, isopentyl, neopentyl group.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (B) is represented by:
wherein R is alkyl, tolyl or aryl group.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the alkyl group (R) in the compound of formula (B) may be selected from methyl, ethyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-propyl, iso-propyl, pentyl, isopentyl, neopentyl group.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (b) is represented by R-X, wherein R is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated pentyl, deuterated isopentyl, deuterated neopentyl group; and X is any leaving group.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein X group in the compound of formula (b) (R-X) including but not limited to OMs, OTf, OTs, ONs or halogen.
Yet another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the halogen in the compound of formula (b) (R-X) is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the
compound of formula (C) is represented by formula wherein R in the compound of formula (C) is alkyl, tolyl or aryl group; wherein the alkyl group (R) in the compound of formula (C) is selected from methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl; and deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated pentyl, deuterated isopentyl, deuterated neopentyl group.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (D) is represented by formula
wherein R in the compound of formula (C) is alkyl, tolyl or aryl group; and wherein R group in the compound of formula (D) is selected from methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, secondary butyl, tertiary butyl, n- pentyl, isopentyl, neopentyl; and deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated n-pentyl, deuterated isopentyl, deuterated neopentyl group.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the deuterated amine compounds of formula (I) are deuterated aliphatic amines and/or aromatic amines, preferably deuterated methyl amine (D3C-NH2.HX).
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the acid can be organic and/or inorganic acid.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulphuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulphonic acids (for example, methanesulphonic, trifluoromethanesulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, benzenesulphonic, toluene-p-sulphonic, naphthalene-2-sulphonic or camphorsulphonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid).
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the alkyl halide (R-X) is deuterated alkyl halide.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the deuterated alkyl halide (R-X) is selected from deuterated methyl iodide, deuterated methyl chloride, deuterated methyl bromide and deuterated methyl fluoride.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the
compound of formula (A) or formula (B) including but not limited to t-butylsulfinamide, t-butylsulfonamide, p-toluenesulfinamide and p-toluenesulfonamide.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (b) (R-X) including but not limited to methyliodide-D3 methanol-d4 containing leaving groups like methylbromide-d3, methylchloride-d3, CD3OTs, CD3OMs, CD3OTf, CD3ONs.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein methanol-d4 can also be directly coupled with t-butylsulfinamide using Mitsunobu reaction (PPh3, DEAD or PPh3, DIAD).
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the base including such as but not limited to organic and inorganic bases.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the base may be selected from inorganic base including but not limited to sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide; and wherein the base is selected from organic base including such as but not limited to pyridine, triethyl amine, dimethyl amino pyridine, diethyl amine.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the solvent used in the present invention can be polar or nonpolar solvent and/or deuterated polar or non-polar solvents.
The solvent including but not limited to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein salt of deuterated amine compound of formula (I) may be prepared by adding HCI gas in an organic solvent.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the solvent used in the present invention can be deuterated solvents.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compound of formula (I), wherein the deuterated amine compound of formula (I) can be further purified or recrystallized by known conventional methods.
Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the said amine compounds can be used as intermediate in the synthesis of drug compounds and/or chemical compounds.
The details of the present invention are provided in the examples given below to illustrate the invention only and therefore they should not be construed to limit the scope of invention.
EXAMPLES
I. Synthesis of compound of formula (C) or formula (D):
To a 100 mL three neck RB flask were added 2 g of t-butylsulfinamide, 10 mL of THF and 2.78g of powdered KOH, cooled the reaction mass to - 10°C using ice salt and stirred for 15 min, then added 3.12g of CD3I drop wise, and stirred at same temperature for 2h, quench the reaction with 10 ml of water and extracted with chloroform for three times, the combined organic layer dried over sodium sulphate, and evaporated under reduced pressure, the crude reaction mass directly used for the next step without further purification 2.1g Mass: 139 (M+1).
II. Synthesis of deuterated methyl amine hydrochloride (compound of formula I):
To a 25 mL RB flask was added 2.1g of compound of example I (step-1), 5 mL of IPA and 3 mL of 6M-IPA.HCI at room temperature, stirred the reaction mass at room temperature for 1h, filtered the solid and recrystallized using chloroform and Ethanol to obtain 0.5g of pure Methyl- D3 Amine Hydrochloride, 43% overall yield after two steps (Chemical purity: 100% by ELSD, D%:99.89% by Q-NMR) 13C NMR: 23.412 (septet, 21.58Hz).
Claims
1. A process for synthesis of deuterated amine compounds of formula
Wherein R in the formula (I) is selected from deuterated C1-C10 alkyl and C1-C20 aryl, wherein the alkyl and aryl optionally substituted with halo, -OH, aryl and alkyl; and
X in the formula (I) is OMs, OTf, OTs, ONs or halogen selected from fluorine, chlorine, bromine, and iodine; the process comprising: a) reacting a compound of formula (A) or formula (B) with a compound of formula (b) (R-X) in presence of potassium hydroxide (KOH) at desired reaction conditions in a solvent to obtain a compound of formula (C) or formula (D); and
b) treating the compound of formula (C) or (D) obtained from step (a) with an acid at desired reaction conditions in a solvent to obtain a salt of the compound of formula (I).
} c) recrystallizing the compound of formula (I) obtained from step (b) by using solvent or combinations of solvents to obtain a pure compound of formula (I) with overall yield 43% and having Chemical purity 100% by ELSD, deuterated percentage (D%) 99.89%. The process as claimed in claim 1, wherein R in the compound of formula (I) is alkyl, tolyl or aryl group; wherein alkyl group is selected from methyl, ethyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-propyl, iso-propyl, pentyl, isopentyl, neopentyl group. The process as claimed in claim 1, wherein the R group in the compound of formula (B) is alkyl, tolyl or aryl group; wherein alkyl group is selected from methyl, ethyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-propyl, iso-propyl, pentyl, isopentyl, neopentyl group. The process as claimed in claim 1, wherein the compound of formula (b) is represented by R-X, wherein R is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated pentyl, deuterated isopentyl, deuterated neopentyl group; and X is any leaving group selected from to OMs, OTf, OTs, ONs or halogen.
The process as claimed in claim 1, wherein R group in the compound of formula (C) is alkyl, tolyl or aryl group; wherein the alkyl group (R) in the compound of formula (C) is selected from methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl; and deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated pentyl, deuterated isopentyl, deuterated neopentyl group. The process as claimed in claim 1, wherein R group in the compound of formula (D) is selected from methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl; and deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated n-pentyl, deuterated isopentyl, deuterated neopentyl group. The process as claimed in claim 1, wherein the acid is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, hydrochloric acid in isopropanol, nitric, perchloric, sulphuric acid, phosphoric acid, propionic acid, butyric acid, glycolic acid, lactic acid, mandelic acid, citric acid, acetic acid, benzoic acid, salicylic acid, succinic acid, malic acid, hydroxysuccinic acid, tartaric acid, fumaric acid, maleic acid, hydroxymaleic acid, mucic acid, galactaric acid, gluconic acid, pantothenic acid, pamoic acid, methanesulphonic acid, trifluoromethanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, benzenesulphonic acid, toluene-p-sulphonic acid, naphthalene-2- sulphonic acid, camphorsulphonic acid, ornithinic acid, glutamic acid, aspartic acid.
The process as claimed in claim 1, wherein the compound of formula (A) or formula (B) is selected from t-butylsulfinamide, t- butylsulfonamide, p-toluenesulfinamide and p-toluenesulfonamide. The process as claimed in claim 1, wherein the compound of formula (b) (R-X) is selected from a group consisting of methyliodide-D3, methanol-d4, methylbromide-d3, methylchloride- d3, CD3OTS, CD3OMS, CD3OTf, CD3ONs. The process as claimed in claim 1, wherein the solvent is selected from water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s). The process as claimed in claim 1 , wherein the deuterated amine compound of formula (I) is deuterated methyl amine hydrochloride (D3C-NH2.HCI).
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| CN108047055B (en) * | 2017-11-29 | 2020-07-17 | 成都海创药业有限公司 | Method for synthesizing deuterated methylamine salt by using halogenated deuterated methane |
| US20220127206A1 (en) * | 2019-03-13 | 2022-04-28 | Otsuka Pharmaceutical Co., Ltd. | Method for introducing deuterated lower alkyl into amine moiety of compound containing secondary amine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108047055B (en) * | 2017-11-29 | 2020-07-17 | 成都海创药业有限公司 | Method for synthesizing deuterated methylamine salt by using halogenated deuterated methane |
| US20220127206A1 (en) * | 2019-03-13 | 2022-04-28 | Otsuka Pharmaceutical Co., Ltd. | Method for introducing deuterated lower alkyl into amine moiety of compound containing secondary amine |
Non-Patent Citations (2)
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| LIU PENG, CHEN XIAOZHONG, XU XIANGCHAO, YANG LINLIN, ZENG GUIXIANG, YE CHUANG, SHI QIXUN, YANG JIAZHI, LI FENG: "From hydrogen autotransfer process to deuterium autotransfer process: The N-trideuteromethylation of amines with deuterated methanol to trideuteromethylated amines catalyzed by a Cp*Ir complex bearing a flexible bridging and functional ligand", JOURNAL OF CATALYSIS, ACADEMIC PRESS, DULUTH, MN., US, vol. 410, 1 June 2022 (2022-06-01), US , pages 333 - 338, XP093115088, ISSN: 0021-9517, DOI: 10.1016/j.jcat.2022.04.022 * |
| LIU ZHAOGANG, REN XIANGYU, WANG PENG: "A practical synthesis of deuterated methylamine and dimethylamine", JOURNAL OF CHEMICAL RESEARCH, SCIENCE REVIEWS LTD., GB, vol. 45, no. 3-4, 1 March 2021 (2021-03-01), GB , pages 265 - 268, XP093115085, ISSN: 1747-5198, DOI: 10.1177/1747519820969636 * |
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