SK12452002A3 - Azetidínové deriváty, ich príprava a farmaceutické prostriedky, ktoré ich obsahujú - Google Patents
Azetidínové deriváty, ich príprava a farmaceutické prostriedky, ktoré ich obsahujú Download PDFInfo
- Publication number
- SK12452002A3 SK12452002A3 SK1245-2002A SK12452002A SK12452002A3 SK 12452002 A3 SK12452002 A3 SK 12452002A3 SK 12452002 A SK12452002 A SK 12452002A SK 12452002 A3 SK12452002 A3 SK 12452002A3
- Authority
- SK
- Slovakia
- Prior art keywords
- methyl
- chlorophenyl
- formula
- alk
- bis
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 5
- 150000001539 azetidines Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 117
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 472
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 205
- -1 NH-R 15 Chemical group 0.000 claims description 199
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 183
- 238000000034 method Methods 0.000 claims description 156
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 153
- 125000000217 alkyl group Chemical group 0.000 claims description 140
- 239000001257 hydrogen Substances 0.000 claims description 101
- 229910052739 hydrogen Inorganic materials 0.000 claims description 101
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 85
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 78
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 77
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 62
- 229910052757 nitrogen Inorganic materials 0.000 claims description 62
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 57
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 55
- 230000008569 process Effects 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 53
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 51
- 150000007522 mineralic acids Chemical class 0.000 claims description 45
- 150000007524 organic acids Chemical class 0.000 claims description 44
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 43
- 229920006395 saturated elastomer Polymers 0.000 claims description 37
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 36
- SVSARCCKBMZNMR-UHFFFAOYSA-N [1-[2-[methyl-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethyl]amino]ethyl]pyridin-4-ylidene]methyl-oxoazanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(=C[NH+]=O)C=CN1CCN(C)CCN1C=CC(=C[NH+]=O)C=C1 SVSARCCKBMZNMR-UHFFFAOYSA-N 0.000 claims description 33
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 32
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims description 29
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 239000011593 sulfur Chemical group 0.000 claims description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 22
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 22
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000002393 azetidinyl group Chemical group 0.000 claims description 19
- 125000003386 piperidinyl group Chemical group 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 16
- 125000002757 morpholinyl group Chemical group 0.000 claims description 16
- 125000004193 piperazinyl group Chemical group 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 14
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 12
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 10
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical group FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 10
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 9
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 claims description 5
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 230000003287 optical effect Effects 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000005493 quinolyl group Chemical group 0.000 claims description 5
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000004069 aziridinyl group Chemical group 0.000 claims description 4
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- TWVVWQMEVZOYBV-UHFFFAOYSA-N 3-(benzenesulfonylmethyl)-1-[bis(4-chlorophenyl)methyl]azetidine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(CS(=O)(=O)C=2C=CC=CC=2)C1 TWVVWQMEVZOYBV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 125000004686 alkyl sulfanyl alkyl group Chemical group 0.000 claims description 3
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- TYCYYNMXAWMHEA-SANMLTNESA-N (2r)-2-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-2-(3,5-difluorophenyl)-n-(2-methylpropyl)acetamide Chemical compound C1C([C@@H](C(=O)NCC(C)C)C=2C=C(F)C=C(F)C=2)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 TYCYYNMXAWMHEA-SANMLTNESA-N 0.000 claims description 2
- UHMHGGXIBPOJIS-SANMLTNESA-N (2r)-2-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-n-(cyclopropylmethyl)-2-(3,5-difluorophenyl)acetamide Chemical compound FC1=CC(F)=CC([C@@H](C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)NCC2CC2)=C1 UHMHGGXIBPOJIS-SANMLTNESA-N 0.000 claims description 2
- ACXVVMBUFIJKPS-UHFFFAOYSA-N 1-[bis(4-chlorophenyl)methyl]-3-[1-(3,5-difluorophenyl)-1-methylsulfonylethyl]azetidine Chemical compound C=1C(F)=CC(F)=CC=1C(S(C)(=O)=O)(C)C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 ACXVVMBUFIJKPS-UHFFFAOYSA-N 0.000 claims description 2
- TYCYYNMXAWMHEA-UHFFFAOYSA-N 2-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-2-(3,5-difluorophenyl)-n-(2-methylpropyl)acetamide Chemical compound C=1C(F)=CC(F)=CC=1C(C(=O)NCC(C)C)C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 TYCYYNMXAWMHEA-UHFFFAOYSA-N 0.000 claims description 2
- CCOOAROJUCENFX-UHFFFAOYSA-N 2-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-2-(3,5-difluorophenyl)-n-propan-2-ylacetamide Chemical compound C=1C(F)=CC(F)=CC=1C(C(=O)NC(C)C)C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 CCOOAROJUCENFX-UHFFFAOYSA-N 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
- CDQPJCIBUYGOGO-UHFFFAOYSA-N 5-[(4-chlorophenyl)-[3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-1-yl]methyl]pyrimidine Chemical compound FC1=CC(F)=CC(CS(=O)(=O)CC2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=NC=NC=2)=C1 CDQPJCIBUYGOGO-UHFFFAOYSA-N 0.000 claims 2
- CCOOAROJUCENFX-RUZDIDTESA-N (2s)-2-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-2-(3,5-difluorophenyl)-n-propan-2-ylacetamide Chemical compound C1C([C@H](C(=O)NC(C)C)C=2C=C(F)C=C(F)C=2)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 CCOOAROJUCENFX-RUZDIDTESA-N 0.000 claims 1
- HVPPNCDSPWPNCQ-MUUNZHRXSA-N (2s)-2-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-n-cyclohexyl-2-(3,5-difluorophenyl)acetamide Chemical compound FC1=CC(F)=CC([C@H](C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(=O)NC2CCCCC2)=C1 HVPPNCDSPWPNCQ-MUUNZHRXSA-N 0.000 claims 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 1
- FWVOLXNAXIIUAJ-UHFFFAOYSA-N 1-[bis(4-chlorophenyl)methyl]azetidine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CCC1 FWVOLXNAXIIUAJ-UHFFFAOYSA-N 0.000 claims 1
- RRSPXUIYOGUPIM-UHFFFAOYSA-N 3-[(4-chlorophenyl)-[3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-1-yl]methyl]pyridine Chemical compound FC1=CC(F)=CC(CS(=O)(=O)CC2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=NC=CC=2)=C1 RRSPXUIYOGUPIM-UHFFFAOYSA-N 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- CJYKKXXTLLKFMO-UHFFFAOYSA-N N-(cyclopropylmethyl)-2-(3,5-difluorophenyl)acetamide Chemical compound FC=1C=C(C=C(C=1)F)CC(=O)NCC1CC1 CJYKKXXTLLKFMO-UHFFFAOYSA-N 0.000 claims 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 1
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims 1
- 125000001207 fluorophenyl group Chemical group 0.000 claims 1
- 125000001041 indolyl group Chemical group 0.000 claims 1
- 229910017053 inorganic salt Inorganic materials 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical group CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 claims 1
- 125000000565 sulfonamide group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 285
- 239000000203 mixture Substances 0.000 description 260
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 201
- 239000000243 solution Substances 0.000 description 181
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 176
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 160
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 135
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 133
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 114
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 88
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 87
- 229910052786 argon Inorganic materials 0.000 description 80
- 239000000741 silica gel Substances 0.000 description 80
- 229910002027 silica gel Inorganic materials 0.000 description 80
- 239000007787 solid Substances 0.000 description 74
- 239000002245 particle Substances 0.000 description 72
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 67
- 235000019341 magnesium sulphate Nutrition 0.000 description 67
- 239000011541 reaction mixture Substances 0.000 description 63
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- 239000012442 inert solvent Substances 0.000 description 54
- 239000012074 organic phase Substances 0.000 description 54
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 description 52
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 51
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- 239000006260 foam Substances 0.000 description 42
- 238000009835 boiling Methods 0.000 description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 33
- 239000002904 solvent Substances 0.000 description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000013078 crystal Substances 0.000 description 30
- 239000012429 reaction media Substances 0.000 description 30
- 239000000725 suspension Substances 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- 239000003921 oil Substances 0.000 description 27
- 235000019198 oils Nutrition 0.000 description 27
- 239000012279 sodium borohydride Substances 0.000 description 26
- 229910000033 sodium borohydride Inorganic materials 0.000 description 26
- 239000012043 crude product Substances 0.000 description 25
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- YNCSKKKEHOJSKK-UHFFFAOYSA-N 2-chloro-5-[(4-chlorophenyl)-[3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-1-yl]methyl]pyridine Chemical compound FC1=CC(F)=CC(CS(=O)(=O)CC2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=NC(Cl)=CC=2)=C1 YNCSKKKEHOJSKK-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 23
- 238000010992 reflux Methods 0.000 description 22
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 21
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 20
- 239000000843 powder Substances 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
- 239000002585 base Substances 0.000 description 18
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 12
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- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 11
- URQORJRWDYDXFF-UHFFFAOYSA-N 1-[bis(4-chlorophenyl)methyl]azetidin-3-one Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(=O)C1 URQORJRWDYDXFF-UHFFFAOYSA-N 0.000 description 11
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
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Classifications
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0002775A FR2805818B1 (fr) | 2000-03-03 | 2000-03-03 | Derives d'azetidine, leur preparation et les compositions pharmaceutiques les contenant |
| PCT/FR2001/000600 WO2001064632A1 (fr) | 2000-03-03 | 2001-03-01 | Derives d'azetidine, leur preparation et les compositions pharmaceutiques les contenant |
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| Publication Number | Publication Date |
|---|---|
| SK12452002A3 true SK12452002A3 (sk) | 2003-05-02 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK1245-2002A SK12452002A3 (sk) | 2000-03-03 | 2001-03-01 | Azetidínové deriváty, ich príprava a farmaceutické prostriedky, ktoré ich obsahujú |
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| FR (1) | FR2805818B1 (da) |
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| US11072602B2 (en) | 2016-12-06 | 2021-07-27 | Merck Sharp & Dohme Corp. | Antidiabetic heterocyclic compounds |
| US20200140383A1 (en) * | 2017-07-03 | 2020-05-07 | Glaxosmithkline Intellectual Property Development Limited | 2-(4-chlorophenoxy)-n-((1 -(2-(4-chlorophenoxy)ethynazetidin-3-yl)methyl)acetamide derivatives and related compounds as atf4 inhibitors for treating cancer and other diseases |
| WO2019201255A1 (zh) * | 2018-04-17 | 2019-10-24 | 天津合美医药科技有限公司 | 异吲哚衍生物 |
| CN108794389B (zh) * | 2018-08-20 | 2021-03-23 | 利尔化学股份有限公司 | 2,3,5,6-四氯-4-甲磺酰基吡啶的制备方法 |
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| EP3924058A1 (en) | 2019-02-13 | 2021-12-22 | Merck Sharp & Dohme Corp. | 5-alkyl pyrrolidine orexin receptor agonists |
| CN110551133A (zh) * | 2019-07-23 | 2019-12-10 | 上海合全药业股份有限公司 | 叔丁基-5-(羟甲基)-7-氧杂-2-氮杂螺[3.5]壬烷-2-甲酸基酯的制法 |
| WO2021026047A1 (en) | 2019-08-08 | 2021-02-11 | Merck Sharp & Dohme Corp. | Heteroaryl pyrrolidine and piperidine orexin receptor agonists |
| GEAP202416395A (en) | 2020-08-18 | 2024-02-12 | Merck Sharp & Dohme Llc | Bicycloheptane pyrrolidine orexin receptor agonists |
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| US4242261A (en) * | 1979-07-19 | 1980-12-30 | A. H. Robins Company, Inc. | Production of methylene-cycloamines |
| FR2649100B1 (fr) * | 1989-06-29 | 1994-03-04 | Laboratorios Dr Esteve Sa | Nouvelles azetidines, leur preparation et leur application comme intermediaires pour la preparation de composes avec activite antimicrobienne |
| US5198449A (en) * | 1990-04-27 | 1993-03-30 | A. H. Robins Company Incorporated | N-substituted alpha-arylazacycloalkylmethanamines and their use as cardiovascular agents |
| GB2285977B (en) * | 1994-01-24 | 1998-05-27 | Du Pont Merck Pharma | Novel azetidine antipsychotic drugs |
| EP0842172A1 (en) * | 1995-06-29 | 1998-05-20 | Novo Nordisk A/S | Novel substituted azacyclic or azabicyclic compounds |
| HN1998000118A (es) * | 1997-08-27 | 1999-02-09 | Pfizer Prod Inc | 2 - aminopiridinas que contienen sustituyentes de anillos condensados. |
| GB9719187D0 (en) * | 1997-09-09 | 1997-11-12 | Glaxo Group Ltd | Compounds |
| GB9815880D0 (en) * | 1998-07-21 | 1998-09-16 | Pfizer Ltd | Heterocycles |
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