JP2009179562A - Glycine transporter inhibitor - Google Patents
Glycine transporter inhibitor Download PDFInfo
- Publication number
- JP2009179562A JP2009179562A JP2006220267A JP2006220267A JP2009179562A JP 2009179562 A JP2009179562 A JP 2009179562A JP 2006220267 A JP2006220267 A JP 2006220267A JP 2006220267 A JP2006220267 A JP 2006220267A JP 2009179562 A JP2009179562 A JP 2009179562A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- phenyl
- chloro
- trifluoromethyl
- pyridyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940088352 Glycine transporter inhibitor Drugs 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 169
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 86
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 51
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 13
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 7
- 206010010904 Convulsion Diseases 0.000 claims abstract description 7
- 206010012289 Dementia Diseases 0.000 claims abstract description 7
- 206010044565 Tremor Diseases 0.000 claims abstract description 7
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 7
- 230000036461 convulsion Effects 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 7
- 208000019116 sleep disease Diseases 0.000 claims abstract description 7
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 115
- 125000000217 alkyl group Chemical group 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 34
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 11
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000006413 ring segment Chemical group 0.000 claims description 8
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 206010013663 drug dependence Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 125000005252 haloacyl group Chemical group 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000005699 methyleneoxy group Chemical group [H]C([H])([*:1])O[*:2] 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 102000010726 Glycine Plasma Membrane Transport Proteins Human genes 0.000 abstract description 16
- 108010063380 Glycine Plasma Membrane Transport Proteins Proteins 0.000 abstract description 16
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 abstract description 5
- 206010041250 Social phobia Diseases 0.000 abstract description 5
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 abstract description 5
- 208000028173 post-traumatic stress disease Diseases 0.000 abstract description 5
- 206010034912 Phobia Diseases 0.000 abstract description 4
- 208000026345 acute stress disease Diseases 0.000 abstract description 4
- 208000019906 panic disease Diseases 0.000 abstract description 4
- 230000002265 prevention Effects 0.000 abstract description 4
- 208000011688 Generalised anxiety disease Diseases 0.000 abstract description 2
- 208000029364 generalized anxiety disease Diseases 0.000 abstract description 2
- 208000019899 phobic disease Diseases 0.000 abstract description 2
- 206010013654 Drug abuse Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 273
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 154
- -1 monofluoromethyl Chemical group 0.000 description 135
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 114
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 113
- 239000000243 solution Substances 0.000 description 95
- 238000005160 1H NMR spectroscopy Methods 0.000 description 84
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 84
- 238000004519 manufacturing process Methods 0.000 description 81
- 239000000203 mixture Substances 0.000 description 68
- 230000002829 reductive effect Effects 0.000 description 65
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 56
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 55
- 239000000741 silica gel Substances 0.000 description 53
- 229910002027 silica gel Inorganic materials 0.000 description 53
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 49
- 239000012044 organic layer Substances 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- 238000003786 synthesis reaction Methods 0.000 description 43
- 239000002274 desiccant Substances 0.000 description 39
- 238000004440 column chromatography Methods 0.000 description 38
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 35
- 239000007787 solid Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 31
- 230000015572 biosynthetic process Effects 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 30
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 28
- 235000017557 sodium bicarbonate Nutrition 0.000 description 28
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 238000001035 drying Methods 0.000 description 24
- 238000001816 cooling Methods 0.000 description 22
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 20
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 125000006239 protecting group Chemical group 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000003054 catalyst Substances 0.000 description 17
- 239000012442 inert solvent Substances 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000012299 nitrogen atmosphere Substances 0.000 description 15
- 239000004471 Glycine Substances 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 229910052763 palladium Inorganic materials 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
- 239000012046 mixed solvent Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 238000007112 amidation reaction Methods 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- GRJHONXDTNBDTC-UHFFFAOYSA-N phenyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC=CC=C1 GRJHONXDTNBDTC-UHFFFAOYSA-N 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 0 *c1ccc([C@]([C@]2NCCCC2)O)cc1 Chemical compound *c1ccc([C@]([C@]2NCCCC2)O)cc1 0.000 description 6
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 6
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
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- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
- PARVVALCOVPOBF-GMAHTHKFSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-(3-pyrazin-2-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)C=1N=CC=NC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl PARVVALCOVPOBF-GMAHTHKFSA-N 0.000 description 5
- WDORPWNWWOLVPN-UHFFFAOYSA-N 3-chloro-4-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC(C(F)(F)F)=C1Cl WDORPWNWWOLVPN-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 239000012264 purified product Substances 0.000 description 5
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 5
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- 239000000126 substance Substances 0.000 description 5
- 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 description 5
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 5
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- 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
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- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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- ZKBJKQHJQJRNOT-GOTSBHOMSA-N tert-butyl-dimethyl-[(s)-[(2s)-1-methylpiperidin-2-yl]-(4-pyridin-2-ylphenyl)methoxy]silane Chemical compound CN1CCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C1=CC=C(C=2N=CC=CC=2)C=C1 ZKBJKQHJQJRNOT-GOTSBHOMSA-N 0.000 description 1
- RNKJPFZCJJMCJP-VXKWHMMOSA-N tert-butyl-dimethyl-[(s)-[(2s)-1-methylpiperidin-2-yl]-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy]silane Chemical compound CN1CCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C1=CC=C(B2OC(C)(C)C(C)(C)O2)C=C1 RNKJPFZCJJMCJP-VXKWHMMOSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A47J—KITCHEN EQUIPMENT; COFFEE MILLS; SPICE MILLS; APPARATUS FOR MAKING BEVERAGES
- A47J27/00—Cooking-vessels
- A47J27/002—Construction of cooking-vessels; Methods or processes of manufacturing specially adapted for cooking-vessels
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- A—HUMAN NECESSITIES
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- A47J—KITCHEN EQUIPMENT; COFFEE MILLS; SPICE MILLS; APPARATUS FOR MAKING BEVERAGES
- A47J36/00—Parts, details or accessories of cooking-vessels
- A47J36/02—Selection of specific materials, e.g. heavy bottoms with copper inlay or with insulating inlay
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- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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Abstract
Description
本発明は、グリシントランスポーター阻害作用を有する化合物に関する。 The present invention relates to a compound having a glycine transporter inhibitory action.
グルタミン酸受容体の一つであるNMDA受容体は脳内の神経細胞膜上に存在しており、神経の可塑性、認知、注意、記憶など様々な神経生理学的な現象に関わっている。NMDA受容体には複数のアロステリック結合部位が存在し、グリシン結合部位もその1つである(NMDA受容体複合体グリシン結合部位)。NMDA受容体複合体グリシン結合部位はNMDA受容体の活性化に関与していることが報告されている(非特許文献1)。 The NMDA receptor, which is one of glutamate receptors, exists on the nerve cell membrane in the brain and is involved in various neurophysiological phenomena such as nerve plasticity, cognition, attention, and memory. The NMDA receptor has multiple allosteric binding sites, one of which is the glycine binding site (NMDA receptor complex glycine binding site). It has been reported that the NMDA receptor complex glycine binding site is involved in the activation of the NMDA receptor (Non-patent Document 1).
グリシン作動性神経のシナプス前終末に活動電位が到達するとシナプス間隙へのグリシンの放出が開始される。放出されたグリシンはシナプス後部の受容体等と結合した後、トランスポーターによりシナプス間隙から取り除かれる。このことよりグリシンのトランスポーターは細胞外液にあるグリシン量を調節することでNMDA受容体の機能を調節していると考えられている。 When the action potential reaches the presynaptic terminal of the glycinergic nerve, release of glycine into the synaptic cleft is started. The released glycine is removed from the synaptic cleft by the transporter after binding to a receptor or the like at the postsynaptic part. This suggests that the glycine transporter regulates the function of the NMDA receptor by regulating the amount of glycine in the extracellular fluid.
グリシントランスポーター(GlyT)は細胞外グリシンの細胞内への再取り込みに関わっているタンパクであり、現在までにGlyT1及びGlyT2の二つのサブタイプの存在が明らかとなっている。GlyT1は主に大脳皮質、海馬及び視床等に発現しており、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害(全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等)、うつ病、薬物依存、痙攣、振戦、及び睡眠障害等の疾患との関連が報告されている(非特許文献2〜4)。 Glycine transporter (GlyT) is a protein involved in the reuptake of extracellular glycine into cells, and the existence of two subtypes, GlyT1 and GlyT2, has been clarified so far. GlyT1 is mainly expressed in the cerebral cortex, hippocampus and thalamus, etc., and includes schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, Post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremors, and sleep disorders have been reported (Non-Patent Documents 2 to 4).
GlyT1阻害作用を有する化合物としてはピペリジン誘導体及びピロリジン誘導体が報告されている(特許文献1〜8)。
本発明は、グリシン取り込み阻害作用に基づいた統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害(全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等)、うつ病、薬物依存、痙攣、振戦、及び睡眠障害等の疾患の予防又は治療に有用な新規な化合物又はその塩を提供することを目的とする。 The present invention relates to schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific It is an object of the present invention to provide a novel compound or a salt thereof useful for the prevention or treatment of diseases such as phobias, acute stress disorders, etc.), depression, drug dependence, convulsions, tremors, and sleep disorders.
本発明者らはGlyT1に対し阻害作用を有する新規な骨格の化合物につき鋭意検討した結果、下記式[I]及び[I’]で表される化合物が優れたGlyT1阻害物質であることを見出し、本発明を完成するに至った。 As a result of intensive studies on a novel skeletal compound having an inhibitory action on GlyT1, the present inventors have found that the compounds represented by the following formulas [I] and [I ′] are excellent GlyT1 inhibitors, The present invention has been completed.
以下、本発明を詳細に説明する。
本発明の態様は以下に示すものである。
(1) 式[I]
Hereinafter, the present invention will be described in detail.
Embodiments of the present invention are as follows.
(1) Formula [I]
[式中、
環Aは、N及びOから選択される1又は2個のヘテロ原子を環内原子として有する5員又は6員の芳香環であり(ここで、該芳香環は無置換又は1〜3個のC1−6アルキルで置換されている);
Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルは無置換、或いはハロゲン、C1−6アルキル、C1−6ハロアルキル、シアノ、C1−6アルコキシ、C1−6アシル、C1−6ハロアシル及びC1−6ハロアルコキシからなる群から選ばれる1から3個の基で置換されているか、又はメチレンオキシで置換されている);
R1は水素原子、C1−6アルキル、C3−6アルケニル、又はC3−8シクロアルキルであり(ここで、該C1−6アルキルは無置換又はシアノで置換されている)、
nは1又は2である]で表される化合物又はその医薬上許容される塩、
(2) 式[I’]
[Where
Ring A is a 5- or 6-membered aromatic ring having 1 or 2 heteroatoms selected from N and O as ring atoms (wherein the aromatic ring is unsubstituted or 1 to 3 Substituted with C 1-6 alkyl);
Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are unsubstituted or halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 1-6 alkoxy, C 1-6 acyl, C 1 Substituted with 1 to 3 groups selected from the group consisting of 1-6 haloacyl and C 1-6 haloalkoxy, or substituted with methyleneoxy);
R 1 is a hydrogen atom, C 1-6 alkyl, C 3-6 alkenyl, or C 3-8 cycloalkyl (wherein the C 1-6 alkyl is unsubstituted or substituted with cyano);
n is 1 or 2, or a pharmaceutically acceptable salt thereof,
(2) Formula [I ′]
[式中、
Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルは無置換、或いはハロゲン、C1−6アルキル、C1−6ハロアルキル、シアノ、C1−6アルコキシ、C1−6アシル、C1−6ハロアシル及びC1−6ハロアルコキシからなる群から選ばれる1から3個の基で置換されているか、又はメチレンオキシで置換されている)、
R1は水素原子、C1−6アルキル、C3−6アルケニル、又はC3−8シクロアルキルであり(ここで、該C1−6アルキルは無置換又はシアノで置換されている)、
nは1又は2である]で表される化合物又はその医薬上許容される塩、
(3) 式[I]において、環Aが、ピリジル、ピリミジニル、ピラジニル、ピラゾリル、イミダゾリル、フリル又はイソオキサゾリルである(ここで、該ピリジル、ピリミジニル、ピラジニル、ピラゾリル、イミダゾリル又はイソオキサゾリルは無置換又は1〜3個のC1−6アルキルで置換されている)上記(1)記載の化合物又はその医薬上許容される塩、
(4)式[II]
[Where
Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are unsubstituted or halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 1-6 alkoxy, C 1-6 acyl, C 1 Substituted with 1 to 3 groups selected from the group consisting of 1-6 haloacyl and C 1-6 haloalkoxy, or substituted with methyleneoxy),
R 1 is a hydrogen atom, C 1-6 alkyl, C 3-6 alkenyl, or C 3-8 cycloalkyl (wherein the C 1-6 alkyl is unsubstituted or substituted with cyano);
n is 1 or 2, or a pharmaceutically acceptable salt thereof,
(3) In the formula [I], ring A is pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, furyl or isoxazolyl (wherein the pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl or isoxazolyl is unsubstituted or 1- A compound or a pharmaceutically acceptable salt thereof described in (1) above, which is substituted with three C 1-6 alkyls;
(4) Formula [II]
(式中、
環Aは1又は2個の窒素原子を環内原子として有する5員又は6員の芳香環であり(ここで、該芳香環は無置換又は1個のC1−6アルキルで置換されている)、
Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ及びC1−6ハロアルコキシからなる群から選ばれる1個から3個の基で置換されている。)、
nは1又は2である。)で表される上記(1)記載の化合物又はその医薬上許容される塩、
(5)式[III]
(Where
Ring A is a 5-membered or 6-membered aromatic ring having 1 or 2 nitrogen atoms as ring atoms (wherein the aromatic ring is unsubstituted or substituted by 1 C 1-6 alkyl) ),
Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy) Substituted with from 1 to 3 groups),
n is 1 or 2. ) Or a pharmaceutically acceptable salt thereof described in (1) above,
(5) Formula [III]
(式中、Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル及びC1−6ハロアルキルからなる群から選ばれる2又は3個の基で置換されている。)、
R2は水素原子又はC1−6アルキルであり、
nは1又は2であり、
ベンゼン環上におけるピラゾリルの置換位置は3位又は4位である。)で表される上記(1)記載の化合物又はその医薬上許容される塩、
(6)式[IV]
Wherein Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are substituted with 2 or 3 groups selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl. ),
R 2 is a hydrogen atom or C 1-6 alkyl,
n is 1 or 2,
The substitution position of pyrazolyl on the benzene ring is the 3- or 4-position. ) Or a pharmaceutically acceptable salt thereof described in (1) above,
(6) Formula [IV]
(式中、Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル及びC1−6ハロアルキルからなる群から選ばれる2又は3個の基で置換されている。)、
nは1又は2であり、
ベンゼン環上におけるピリジルの置換位置は3位又は4位である。)で表される上記(1)記載の化合物又はその医薬上許容される塩、
(7)式[V]
Wherein Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are substituted with 2 or 3 groups selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl. ),
n is 1 or 2,
The substitution position of pyridyl on the benzene ring is the 3rd or 4th position. ) Or a pharmaceutically acceptable salt thereof described in (1) above,
(7) Formula [V]
(式中、Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル及びC1−6ハロアルキルからなる群から選ばれる2又は3個の基で置換されている。)、
nは1又は2であり、
ベンゼン環上におけるピリミジニルの置換位置は3位又は4位である。)で表される上記(1)記載の化合物又はその医薬上許容される塩、
(8) 式[VI]
Wherein Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are substituted with 2 or 3 groups selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl. ),
n is 1 or 2,
The substitution position of pyrimidinyl on the benzene ring is the 3rd or 4th position. ) Or a pharmaceutically acceptable salt thereof described in (1) above,
(8) Formula [VI]
(式中、Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル及びC1−6ハロアルキルからなる群から選ばれる2又は3個の基で置換されている。)、
nは1又は2であり、
ベンゼン環上におけるピラジニルの置換位置は3位又は4位である。)で表される上記(1)記載の化合物又はその医薬上許容される塩、
(9)nが2である上記(1)及び(3)〜(8)のいずれか1つに記載の化合物又はその医薬上許容される塩、
(10)nが2である上記(2)に記載の化合物又はその医薬上許容される塩、
(11)ピロリジン環又はピペリジン環の2位の不斉炭素原子の立体配置がSであり、アミドの窒素原子が結合している不斉炭素原子の立体配置もSである上記(1)及び(3)〜(9)のいずれかに記載の化合物又はその医薬上許容される塩、
(12)ピロリジン環又はピペリジン環の2位の不斉炭素原子の立体配置がSであり、アミドの窒素原子が結合している不斉炭素原子の立体配置もSである上記(2)又は(10)に記載の化合物又はその医薬上許容される塩、
(13) Ar1がフェニルである(ここで、該フェニルは、2位にクロロ、フルオロ又はメチルを有し、かつ3位、5位又は6位にトリフルオロメチル及び/又は3位若しくは6位にクロロを有する)上記(1)、(3)〜(9)及び(11)のいずれかに記載の化合物又はその医薬上許容される塩、
(14) Ar1がフェニルである(ここで、該フェニルは2位にクロロ又はメチルを有し、3位又は5位にトリフルオロメチルを有し、さらに6位にクロロを有してもよい)上記(1)、(3)〜(9)及び(11)のいずれかに記載の化合物又はその医薬上許容される塩、
(15) Ar1が3位にクロロ及び4位にトリフルオロメチルを有するピリジン−2−イル又は3位にクロロ及び2位にトリフルオロメチルを有するピリジン−4−イルである上記(1)、(3)〜(9)及び(11)のいずれかに記載の化合物又はその医薬上許容される塩、
(16) Ar1が3位にクロロ及び4位にトリフルオロメチルを有するピリジン−2−イル又は3位にクロロ及び2位にトリフルオロメチルを有するピリジン−4−イルである上記(2)、(10)又は(12)に記載の化合物又はその医薬上許容される塩、
(17) 上記(1)〜(16)のいずれかに記載の化合物又はその医薬上許容される塩を有効成分として含有する医薬組成物、
(18) グリシントランスポーター阻害剤である、上記(17)に記載の医薬組成物、及び
(19) 上記(1)〜(16)のいずれかに記載の化合物又はその医薬上許容される塩を有効成分として含有する統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害、うつ病、薬物依存、痙攣、振戦及び睡眠障害からなる群から選択される疾患の予防又は治療用医薬組成物。
Wherein Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are substituted with 2 or 3 groups selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl. ),
n is 1 or 2,
The substitution position of pyrazinyl on the benzene ring is the 3rd or 4th position. ) Or a pharmaceutically acceptable salt thereof described in (1) above,
(9) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) and (3) to (8) above, wherein n is 2.
(10) The compound according to the above (2) or a pharmaceutically acceptable salt thereof, wherein n is 2.
(11) The configuration of the asymmetric carbon atom at the 2-position of the pyrrolidine ring or piperidine ring is S, and the configuration of the asymmetric carbon atom to which the nitrogen atom of the amide is bonded is also S (1) and ( 3) to the compound according to any one of (9) or a pharmaceutically acceptable salt thereof,
(12) The configuration of the asymmetric carbon atom at the 2-position of the pyrrolidine ring or piperidine ring is S, and the configuration of the asymmetric carbon atom to which the nitrogen atom of the amide is bonded is also S (2) or ( 10) or a pharmaceutically acceptable salt thereof,
(13) Ar 1 is phenyl (wherein the phenyl has chloro, fluoro or methyl at the 2-position, and trifluoromethyl at the 3-position, 5-position or 6-position and / or 3-position or 6-position) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1), (3) to (9) and (11),
(14) Ar 1 is phenyl (wherein the phenyl may have chloro or methyl at the 2-position, trifluoromethyl at the 3-position or 5-position, and further chloro at the 6-position) ) The compound according to any one of (1), (3) to (9) and (11) above, or a pharmaceutically acceptable salt thereof,
(15) The above (1), wherein Ar 1 is pyridin-2-yl having chloro at the 3-position and trifluoromethyl at the 4-position, or pyridin-4-yl having chloro at the 3-position and trifluoromethyl at the 2-position, (3) to (9) and the compound according to any one of (11) or a pharmaceutically acceptable salt thereof,
(16) The above (2), wherein Ar 1 is pyridin-2-yl having chloro at the 3-position and trifluoromethyl at the 4-position, or pyridin-4-yl having chloro at the 3-position and trifluoromethyl at the 2-position, (10) or the compound according to (12) or a pharmaceutically acceptable salt thereof,
(17) A pharmaceutical composition comprising the compound according to any one of (1) to (16) above or a pharmaceutically acceptable salt thereof as an active ingredient,
(18) The pharmaceutical composition according to (17) above, which is a glycine transporter inhibitor, and (19) the compound according to any one of (1) to (16) above or a pharmaceutically acceptable salt thereof. Pharmaceutical composition for prevention or treatment of a disease selected from the group consisting of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, drug dependence, convulsions, tremors and sleep disorders contained as an active ingredient object.
本発明化合物はグリシントランスポーター1(GlyT1)阻害活性を有しており、従ってグリシン取り込み阻害作用に基づいた統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害(全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等)、うつ病、薬物依存、痙攣、振戦、及び睡眠障害等の予防及び治療に有効である。 The compound of the present invention has glycine transporter 1 (GlyT1) inhibitory activity. Therefore, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder, panic) Disorder, obsessive-compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremors, and sleep disorders are effective in the prevention and treatment.
本明細書において用いる「N及びOから選択される1又は2個のヘテロ原子を環内原子として有する5員又は6員の芳香環」とは、窒素及び酸素から選択される同一又は異なる1〜2個の原子を環内に有する複素環芳香族基(但し、2個の酸素原子を環内原子として有することはない)を意味し、例えばピリジル、ピリミジニル、ピラジニル、ピラゾリル、イミダゾリル、フリル、イソオキサゾリルを挙げることができる。 As used herein, “5-membered or 6-membered aromatic ring having 1 or 2 heteroatoms selected from N and O as ring atoms” is the same or different 1 to 2 selected from nitrogen and oxygen Heterocyclic aromatic group having two atoms in the ring (but not having two oxygen atoms as ring atoms), for example pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, furyl, isoxazolyl Can be mentioned.
本明細書において用いる「1又は2個の窒素原子を環内原子として有する5員又は6員の芳香環」とは、例えば、ピリジル、ピリミジニル、ピラジニル、ピラゾリル又はイミダゾリルを挙げることができる。 Examples of the “5-membered or 6-membered aromatic ring having 1 or 2 nitrogen atoms as ring atoms” used herein include pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl and imidazolyl.
本明細書において用いる「C1−6アルキル」とは直鎖状又は分岐鎖状の炭素数1〜6個のアルキル基を意味し、例えばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、t−ブチル、ペンチル、イソペンチル、ヘキシルを挙げることができる。 As used herein, “C 1-6 alkyl” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- Examples include butyl, pentyl, isopentyl, and hexyl.
本明細書において用いる「ハロゲン(ハロ)」とは、フッ素原子、塩素原子、臭素原子及びヨウ素原子を意味する。
本明細書において用いる「C1−6ハロアルキル」とはハロゲン原子で置換された直鎖状又は分岐鎖状の炭素数1〜6個のアルキル基を示し、置換されるハロゲン原子の好ましい数は1〜3個であり、例えばモノフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリクロロメチルを挙げることができる。
As used herein, “halogen” means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
As used herein, “C 1-6 haloalkyl” refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, and the preferred number of substituted halogen atoms is 1. ~ 3, and examples thereof include monofluoromethyl, difluoromethyl, trifluoromethyl, and trichloromethyl.
本明細書において用いる「C1−6アルコキシ」とは直鎖状又は分岐鎖状の炭素数1〜6個のアルコキシ基を意味し、例えばメトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブチルオキシ、ペンチルオキシ、イソペンチルオキシ、ヘキシルオキシを挙げることができる。 As used herein, “C 1-6 alkoxy” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, Mention may be made of pentyloxy, isopentyloxy, hexyloxy.
本明細書において用いる「C3−8シクロアルキル」とは、炭素数3〜8個の飽和の炭素環式環基を意味し、例えばシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル又はシクロオクチルを挙げることができる。 As used herein, “C 3-8 cycloalkyl” means a saturated carbocyclic ring group having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Can be mentioned.
本明細書において用いる「C1−6アシル」とはカルボニル基と水素原子又は直鎖状、分岐鎖状若しくは環状のC1−5アルキルとが結合した基を意味し、例えばホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、シクロプロピルカルボニル、シクロブチルカルボニルを挙げることができる。 As used herein, “C 1-6 acyl” means a group in which a carbonyl group is bonded to a hydrogen atom or a linear, branched or cyclic C 1-5 alkyl, such as formyl, acetyl, propionyl. , Butyryl, isobutyryl, cyclopropylcarbonyl, cyclobutylcarbonyl.
本明細書において用いる「C1−6ハロアシル」とはハロゲン原子で置換された直鎖状又は分岐鎖状の炭素数1〜6個のアシル基を意味し、置換されるハロゲン原子の好ましい数は1〜3個であり、例えばフルオロアセチル、ジフルオロアセチル、トリフルオロアセチル、トリクロロアセチルを挙げることができる。 As used herein, “C 1-6 haloacyl” means a linear or branched acyl group having 1 to 6 carbon atoms substituted with a halogen atom, and the preferred number of halogen atoms to be substituted is 1 to 3, for example, fluoroacetyl, difluoroacetyl, trifluoroacetyl, and trichloroacetyl.
本明細書において用いる「C1−6ハロアルコキシ」とはハロゲン原子で置換された直鎖状又は分岐鎖状の炭素数1〜6個のアルコキシ基を意味し、好ましくは1〜3個のハロゲン原子を有する直鎖状又は分岐鎖状の炭素数1〜6個のアルコキシ基を意味する。例えばフルオロメトキシ、ジフルオロメトキシ、トリフルオロメトキシを挙げることができる。 As used herein, “C 1-6 haloalkoxy” means a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with a halogen atom, preferably 1 to 3 halogen atoms. It means a linear or branched alkoxy group having 1 to 6 carbon atoms having an atom. For example, fluoromethoxy, difluoromethoxy and trifluoromethoxy can be mentioned.
本明細書において用いる「C3−6アルケニル」とは二重結合を中にひとつ含む直鎖状又は分岐鎖状のC3−6アルキルを意味し、例えばアリル、ブタ−2−エニルを挙げることができる。 As used herein, “C 3-6 alkenyl” means linear or branched C 3-6 alkyl containing one double bond, and includes, for example, allyl and but-2-enyl. Can do.
本明細書中における「医薬上許容される塩」とは、薬剤的に許容することのできる酸付加塩を意味し、用いられる酸としては、硫酸、塩酸、臭化水素酸、硝酸及び燐酸等の無機酸、或いは、酢酸、シュウ酸、乳酸、クエン酸、リンゴ酸、グルコン酸、酒石酸、フマール酸、マレイン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸及びp−トルエンスルホン酸等の有機酸を挙げることができる。 As used herein, “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt, and examples of the acid used include sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid. Or inorganic acids such as acetic acid, oxalic acid, lactic acid, citric acid, malic acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid Mention may be made of acids.
本発明化合物の好ましい形態は以下の通りである。
すなわち、式[I]において好ましい環Aはピリジル、ピリミジニル、ピラジニル、ピラゾリル、及びイミダゾリルである(ここで該ピラゾリル及びイミダゾリルは無置換又は1個のC1−6アルキルで置換されている。)。より好ましい環Aは無置換又はC1−6アルキルで置換されたピラゾリル(例えば、1H−ピラゾール−4−イル、1−メチル−1H−ピラゾール−4−イル、1−エチル−1H−ピラゾール−4−イル、1−イソプロピル−1H−ピラゾール−4−イル、1−プロピル−1H−ピラゾール−4−イル)、ピリミジニル(例えば、ピリミジン−5−イル)、ピラジニル(例えば、ピラジン−2−イル)及びC1−6アルキルで置換されたイミダゾリル(例えば、3−メチル−3H−イミダゾール−4−イル)である。
環Aが置換しているベンゼン環上の好ましい置換位置は3位又は4位であり、さらに好ましい置換位置は3位である。
Preferred forms of the compound of the present invention are as follows.
That is, in Formula [I], preferred ring A is pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, and imidazolyl (wherein the pyrazolyl and imidazolyl are unsubstituted or substituted with one C 1-6 alkyl). More preferred ring A is an unsubstituted or C 1-6 alkyl substituted pyrazolyl (eg, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazole-4 -Yl, 1-isopropyl-1H-pyrazol-4-yl, 1-propyl-1H-pyrazol-4-yl), pyrimidinyl (eg pyrimidin-5-yl), pyrazinyl (eg pyrazin-2-yl) and Imidazolyl substituted with C 1-6 alkyl (eg 3-methyl-3H-imidazol-4-yl).
A preferred substitution position on the benzene ring substituted by ring A is the 3-position or 4-position, and a more preferred substitution position is the 3-position.
式[I]において好ましいR1は水素原子及びC1−6アルキルである。さらに好ましいR1は水素原子及びメチルである。本発明化合物の肝代謝安定性の点で好ましいR1は水素原子である。 Preferred R 1 in the formula [I] is a hydrogen atom and C 1-6 alkyl. More desirable R 1 is a hydrogen atom and methyl. R 1 is preferably a hydrogen atom from the viewpoint of liver metabolic stability of the compound of the present invention.
なお、肝代謝安定性は下記試験により確認された:肝代謝安定性試験は、ヒト肝ミクロソーム(XENOTECH LLC (Kansas City, KS, USA)より入手)(1 mg タンパク質/mL)と化合物(5μM)をpH7.4の0.25Mリン酸緩衝液に加え、37℃で5分間のプレインキュベーション後、NADPH産生系を添加することにより反応を開始し、15分後に反応停止液を加え、LC−MSにより残存する化合物を測定した。 The liver metabolic stability was confirmed by the following test: The liver metabolic stability test was obtained from human liver microsome (available from XENOTECH LLC (Kansas City, KS, USA)) (1 mg protein / mL) and compound (5 μM). Is added to a 0.25 M phosphate buffer having a pH of 7.4, and after 5 minutes of preincubation at 37 ° C., the reaction is started by adding a NADPH production system, and after 15 minutes, a reaction stop solution is added and LC-MS is added. The remaining compound was measured.
式[I]において、Ar1がフェニルの場合、該フェニルは好ましくは、2位にクロロ、フルオロ又はメチルを有し、かつ3位、5位又は6位にトリフルオロメチル及び/又は3位若しくは6位にクロロを有する、より好ましくは、2位にクロロ又はメチルを有し、3位又は5位にトリフルオロメチルを有し、さらに6位にクロロを有してもよい。 In the formula [I], when Ar 1 is phenyl, the phenyl preferably has chloro, fluoro or methyl at the 2-position, and trifluoromethyl and / or 3-position at the 3-position, 5-position or 6-position or It may have chloro at the 6-position, more preferably chloro or methyl at the 2-position, trifluoromethyl at the 3- or 5-position, and further chloro at the 6-position.
式[I]において、Ar1がピリジルの場合の好ましい基は、3位にクロロ及び4位にトリフルオロメチルを有するピリジン−2−イル又は3位にクロロ及び2位にトリフルオロメチルを有するピリジン−4−イルである。 In Formula [I], when Ar 1 is pyridyl, a preferred group is pyridin-2-yl having chloro at the 3-position and trifluoromethyl at the 4-position, or pyridine having chloro at the 3-position and trifluoromethyl at the 2-position It is -4-yl.
式[I]において好ましい具体的なAr1は2−クロロ−3−トリフルオロメチルフェニル、3−クロロ−2−メチルフェニル、2,3−ジクロロフェニル、2−メチル−3−トリフルオロメチルフェニル、2−クロロ−3−メチルフェニル、2−クロロ−5−トリフルオロメチルフェニル、2−メチル−5−トリフルオロメチルフェニル、2,5−ジクロロフェニル、2,6−ジクロロフェニル、2,6−ジクロロ−3−トリフルオロメチルフェニル、3−クロロ−2−フルオロ−6−トリフルオロメチルフェニル、2,6−ジメチルフェニル、2,4,6−トリクロロフェニル、2−クロロ−6−メチルフェニル、3−クロロ−4−トリフルオロメチル−ピリジン−2−イル及び3−クロロ−2−トリフルオロメチル−ピリジン−4−イルである。さらに好ましいAr1は2−クロロ−3−トリフルオロメチルフェニル、2,6−ジクロロ−3−トリフルオロメチルフェニル、2−クロロ−5−トリフルオロメチルフェニル、2−メチル−3−トリフルオロメチルフェニル、3−クロロ−4−トリフルオロメチル−ピリジン−2−イル及び3−クロロ−2−トリフルオロメチル−ピリジン−4−イルである。 Specific preferred Ar 1 in the formula [I] is 2-chloro-3-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2-methyl-3-trifluoromethylphenyl, 2 -Chloro-3-methylphenyl, 2-chloro-5-trifluoromethylphenyl, 2-methyl-5-trifluoromethylphenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dichloro-3- Trifluoromethylphenyl, 3-chloro-2-fluoro-6-trifluoromethylphenyl, 2,6-dimethylphenyl, 2,4,6-trichlorophenyl, 2-chloro-6-methylphenyl, 3-chloro-4 -Trifluoromethyl-pyridin-2-yl and 3-chloro-2-trifluoromethyl-pyridin-4-y It is le. Further preferred Ar 1 is 2-chloro-3-trifluoromethylphenyl, 2,6-dichloro-3-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 2-methyl-3-trifluoromethylphenyl 3-chloro-4-trifluoromethyl-pyridin-2-yl and 3-chloro-2-trifluoromethyl-pyridin-4-yl.
式[I’]において好ましいAr1は、3位にクロロ及び4位にトリフルオロメチルを有するピリジン−2−イル又は3位にクロロ及び2位にトリフルオロメチルを有するピリジン−4−イルである。 Preferred Ar 1 in the formula [I '] is a pyridin-4-yl having a trifluoromethyl to chloro and 2-position 2-yl or 3-position with a trifluoromethyl in the chloro and 4-positions in the 3-position .
本発明における好ましい化合物群は以下の通りである。
すなわち、好ましい化合物は式[II]
Preferred compound groups in the present invention are as follows.
That is, preferred compounds are those of formula [II]
(式中、環Aは1又は2個の窒素原子を環内原子として有する5員又は6員の芳香環であり(ここで、該芳香環は無置換又は1個のC1−6アルキルで置換されている)、
Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ及びトリフルオロメトキシからなる群から選ばれる1個から3個の基で置換されている。)、
nは1又は2である。)で表される化合物である。
Wherein ring A is a 5- or 6-membered aromatic ring having 1 or 2 nitrogen atoms as ring atoms (wherein the aromatic ring is unsubstituted or 1 C 1-6 alkyl Replaced),
Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are 1 to 3 selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and trifluoromethoxy) Substituted with 1 group).
n is 1 or 2. ).
他の好ましい化合物は式[III] Other preferred compounds are those of formula [III]
(式中、Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル及びC1−6ハロアルキルからなる群から選ばれる2又は3個の基で置換されている。)、
nは1又は2であり、
R2は水素原子又はC1−6アルキルであり、
ベンゼン環上におけるピラゾリルの置換位置は3位又は4位である。)で表される化合物である。
Wherein Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are substituted with 2 or 3 groups selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl. ),
n is 1 or 2,
R 2 is a hydrogen atom or C 1-6 alkyl;
The substitution position of pyrazolyl on the benzene ring is the 3- or 4-position. ).
他の好ましい化合物は式[IV] Other preferred compounds are of the formula [IV]
(式中、Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル及びC1−6ハロアルキルからなる群から選ばれる2又は3個の基で置換されている。)、
nは1又は2であり、
ベンゼン環上におけるピリジル基の置換位置は3位又は4位である。)で表される化合物である。
Wherein Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are substituted with 2 or 3 groups selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl. ),
n is 1 or 2,
The substitution position of the pyridyl group on the benzene ring is the 3rd or 4th position. ).
他の好ましい化合物は式[V] Other preferred compounds are of the formula [V]
(式中、Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル及びC1−6ハロアルキルからなる群から選ばれる2又は3個の基で置換されている。)、
nは1又は2であり、
ベンゼン環上におけるピリミジニル基の置換位置は3位又は4位である。)で表される化合物である。
Wherein Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are substituted with 2 or 3 groups selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl. ),
n is 1 or 2,
The substitution position of the pyrimidinyl group on the benzene ring is the 3rd or 4th position. ).
他の好ましい化合物は式[VI] Other preferred compounds are those of formula [VI]
(式中、Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル及びC1−6ハロアルキルからなる群から選ばれる2又は3個の基で置換されている。)、
nは1又は2であり、
ベンゼン環上におけるピラジニル基の置換位置は3位又は4位である。)で表される化合物である。
Wherein Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are substituted with 2 or 3 groups selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl. ),
n is 1 or 2,
The substitution position of the pyrazinyl group on the benzene ring is the 3rd or 4th position. ).
好ましい具体的な化合物は下記に挙げられる:
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(4-ピリジン-3-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(4-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリジン-3-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリジン-4-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリジン-2-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(4-ピリジン-2-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリミジン-5-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(2-フリル)フェニル)((2S)-1-メチルピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピラジン-2-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
N-((S)-ビフェニル-3-イル((2S)-ピペリジン-2-イル)メチル)-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-((S)-(2S)-ピペリジン-2-イル(4-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピリジン-3-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピリミジン-5-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(4-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2,6-ジクロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2,3-ジクロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-(1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-イソブチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-エチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-(1-プロピル-1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-イソプロピル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-メチル-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピラジン-2-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピロリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-ピリミジン-5-イルフェニル)((2S)-ピロリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-ピリジン-3-イルフェニル)((2S)-ピロリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2,6-ジクロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-5-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-イソプロピル-1H-ピラゾール-4-イル)フェニル)((2S)-ピロリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
2-メチル-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-5-(トリフルオロメチル)ベンズアミド、
3-クロロ-2-フルオロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-6-(トリフルオロメチル)ベンズアミド、
2,4,6-トリクロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)ベンズアミド、
2-クロロ-6-メチル-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)ベンズアミド、
2,6-ジクロロ-N-((S)-(4-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-2-(トリフルオロメチル)イソニコチンアミド、
2-クロロ-N-{(S)-[3-(1-メチル-1H-イミダゾール-5-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-3-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピラジン-2-イルフェニル)メチル]-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3,6-ジクロロ-2-メトキシ-N-{(S)-[3-(1-メチル-1H-ピラゾール-4-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}ベンズアミド、
3-クロロ-N-{(S)-(2S)-ピペリジン-2-イル[3-(1-プロピル-1H-ピラゾール-4-イル)フェニル]メチル}-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-{(S)-[3-(1-イソプロピル-1H-ピラゾール-4-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピリミジン-5-イルフェニル)メチル]-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-{(S)-[3-(1-エチル-1H-ピラゾール-4-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-4-(トリフルオロメチル)ピリジン-2-カルボキサミド
3-クロロ-N-((S)-((2S)-1-(シアノメチル)ピペリジン-2-イル)(3-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
2-クロロ-N-((S)-((2S)-1-シクロプロピルピペリジン-2-イル)(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-{(S)-[(2S)-1-イソプロピルピペリジン-2-イル][3-(1-メチル-1H-ピラゾール-4-イル)フェニル]メチル}-3-(トリフルオロメチル)ベンズアミド及び
N-((S)-((2S)-1-アリルピペリジン-2-イル)(3-ピリミジン-5-イルフェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド。
Preferred specific compounds are listed below:
2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (4-pyridin-3-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
3-Chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (4-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2-carboxamide ,
2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyridin-3-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyridin-4-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyridin-2-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (4-pyridin-2-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyrimidin-5-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3- (1-methyl-1H-pyrazol-4-yl) phenyl) methyl) -3- (tri Fluoromethyl) benzamide,
2-chloro-N-((S)-(3- (2-furyl) phenyl) ((2S) -1-methylpiperidin-2-yl) methyl) -3- (trifluoromethyl) benzamide,
2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyrazin-2-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
N-((S) -biphenyl-3-yl ((2S) -piperidin-2-yl) methyl) -3-chloro-4- (trifluoromethyl) pyridine-2-carboxamide,
3-chloro-N-((S)-(2S) -piperidin-2-yl (4-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2-carboxamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3-pyridin-3-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
3-chloro-N-((S)-(2S) -piperidin-2-yl (3-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2-carboxamide,
2-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3-pyrimidin-5-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-(4- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2,6-dichloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoro Methyl) benzamide,
2,3-dichloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3- (1H-pyrazol-4-yl) phenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-(3- (1-isobutyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-Chloro-N-((S)-(3- (1-ethyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3- (1-propyl-1H-pyrazol-4-yl) phenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-(3- (1-isopropyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-Methyl-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3-pyrazin-2-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -pyrrolidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-chloro-N-((S)-(3-pyrimidin-5-ylphenyl) ((2S) -pyrrolidin-2-yl) methyl) -3- (trifluoromethyl) benzamide,
2-chloro-N-((S)-(3-pyridin-3-ylphenyl) ((2S) -pyrrolidin-2-yl) methyl) -3- (trifluoromethyl) benzamide,
2,6-dichloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) benzamide,
2-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -5- (trifluoromethyl) Benzamide,
2-Chloro-N-((S)-(3- (1-isopropyl-1H-pyrazol-4-yl) phenyl) ((2S) -pyrrolidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
3-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -4- (trifluoromethyl) Pyridine-2-carboxamide,
2-Methyl-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -5- (trifluoromethyl) Benzamide,
3-Chloro-2-fluoro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -6- ( (Trifluoromethyl) benzamide,
2,4,6-trichloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) benzamide,
2-chloro-6-methyl-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) benzamide,
2,6-dichloro-N-((S)-(4- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoro Methyl) benzamide,
3-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -2- (trifluoromethyl) Isonicotinamide,
2-Chloro-N-{(S)-[3- (1-methyl-1H-imidazol-5-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -3- (trifluoromethyl) Benzamide,
3-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyrazin-2-ylphenyl) methyl] -4- (trifluoromethyl) pyridine-2-carboxamide,
3,6-dichloro-2-methoxy-N-{(S)-[3- (1-methyl-1H-pyrazol-4-yl) phenyl] [(2S) -piperidin-2-yl] methyl} benzamide,
3-chloro-N-{(S)-(2S) -piperidin-2-yl [3- (1-propyl-1H-pyrazol-4-yl) phenyl] methyl} -4- (trifluoromethyl) pyridine- 2-carboxamide,
3-chloro-N-{(S)-[3- (1-isopropyl-1H-pyrazol-4-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -4- (trifluoromethyl) Pyridine-2-carboxamide,
3-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyrimidin-5-ylphenyl) methyl] -4- (trifluoromethyl) pyridine-2-carboxamide,
3-Chloro-N-{(S)-[3- (1-ethyl-1H-pyrazol-4-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -4- (trifluoromethyl) Pyridine-2-carboxamide
3-Chloro-N-((S)-((2S) -1- (cyanomethyl) piperidin-2-yl) (3-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2 -Carboxamide,
2-Chloro-N-((S)-((2S) -1-cyclopropylpiperidin-2-yl) (3- (1-methyl-1H-pyrazol-4-yl) phenyl) methyl) -3- ( (Trifluoromethyl) benzamide,
2-chloro-N-{(S)-[(2S) -1-isopropylpiperidin-2-yl] [3- (1-methyl-1H-pyrazol-4-yl) phenyl] methyl} -3- (tri Fluoromethyl) benzamide and
N-((S)-((2S) -1-allylpiperidin-2-yl) (3-pyrimidin-5-ylphenyl) methyl) -2-chloro-3- (trifluoromethyl) benzamide.
より好ましい具体的な化合物は下記に挙げられる:
3-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(4-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリジン-3-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリミジン-5-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピラジン-2-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピリミジン-5-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2,6-ジクロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-(1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-エチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-(1-プロピル-1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-イソプロピル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピラジン-2-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピロリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-ピリミジン-5-イルフェニル)((2S)-ピロリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-5-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-2-フルオロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-6-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-2-(トリフルオロメチル)イソニコチンアミド、
2-クロロ-N-{(S)-[3-(1-メチル-1H-イミダゾール-5-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-3-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピラジン-2-イルフェニル)メチル]-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-{(S)-(2S)-ピペリジン-2-イル[3-(1-プロピル-1H-ピラゾール-4-イル)フェニル]メチル}-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-{(S)-[3-(1-イソプロピル-1H-ピラゾール-4-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピリミジン-5-イルフェニル)メチル]-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-{(S)-[3-(1-エチル-1H-ピラゾール-4-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-((S)-((2S)-1-(シアノメチル)ピペリジン-2-イル)(3-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
2-クロロ-N-{(S)-[(2S)-1-イソプロピルピペリジン-2-イル][3-(1-メチル-1H-ピラゾール-4-イル)フェニル]メチル}-3-(トリフルオロメチル)ベンズアミド及び
N-((S)-((2S)-1-アリルピペリジン-2-イル)(3-ピリミジン-5-イルフェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド。
More preferred specific compounds are listed below:
3-Chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (4-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2-carboxamide ,
2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyridin-3-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyrimidin-5-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3- (1-methyl-1H-pyrazol-4-yl) phenyl) methyl) -3- (tri Fluoromethyl) benzamide,
2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyrazin-2-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
3-chloro-N-((S)-(2S) -piperidin-2-yl (3-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2-carboxamide,
2-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3-pyrimidin-5-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2,6-dichloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoro Methyl) benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3- (1H-pyrazol-4-yl) phenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-(3- (1-ethyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3- (1-propyl-1H-pyrazol-4-yl) phenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-(3- (1-isopropyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3-pyrazin-2-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -pyrrolidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-chloro-N-((S)-(3-pyrimidin-5-ylphenyl) ((2S) -pyrrolidin-2-yl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -5- (trifluoromethyl) Benzamide,
3-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -4- (trifluoromethyl) Pyridine-2-carboxamide,
3-Chloro-2-fluoro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -6- ( (Trifluoromethyl) benzamide,
3-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -2- (trifluoromethyl) Isonicotinamide,
2-Chloro-N-{(S)-[3- (1-methyl-1H-imidazol-5-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -3- (trifluoromethyl) Benzamide,
3-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyrazin-2-ylphenyl) methyl] -4- (trifluoromethyl) pyridine-2-carboxamide,
3-chloro-N-{(S)-(2S) -piperidin-2-yl [3- (1-propyl-1H-pyrazol-4-yl) phenyl] methyl} -4- (trifluoromethyl) pyridine- 2-carboxamide,
3-chloro-N-{(S)-[3- (1-isopropyl-1H-pyrazol-4-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -4- (trifluoromethyl) Pyridine-2-carboxamide,
3-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyrimidin-5-ylphenyl) methyl] -4- (trifluoromethyl) pyridine-2-carboxamide,
3-chloro-N-{(S)-[3- (1-ethyl-1H-pyrazol-4-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -4- (trifluoromethyl) Pyridine-2-carboxamide,
3-Chloro-N-((S)-((2S) -1- (cyanomethyl) piperidin-2-yl) (3-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2 -Carboxamide,
2-chloro-N-{(S)-[(2S) -1-isopropylpiperidin-2-yl] [3- (1-methyl-1H-pyrazol-4-yl) phenyl] methyl} -3- (tri Fluoromethyl) benzamide and
N-((S)-((2S) -1-allylpiperidin-2-yl) (3-pyrimidin-5-ylphenyl) methyl) -2-chloro-3- (trifluoromethyl) benzamide.
最も好ましい具体的な化合物は下記に挙げられる:
3-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピリミジン-5-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2,6-ジクロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-(1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-エチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-(1-プロピル-1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-イソプロピル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド、
2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-5-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-2-(トリフルオロメチル)イソニコチンアミド、
2-クロロ-N-{(S)-[3-(1-メチル-1H-イミダゾール-5-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-3-(トリフルオロメチル)ベンズアミド、
3-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピラジン-2-イルフェニル)メチル]-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-{(S)-(2S)-ピペリジン-2-イル[3-(1-プロピル-1H-ピラゾール-4-イル)フェニル]メチル}-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-{(S)-[3-(1-イソプロピル-1H-ピラゾール-4-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-4-(トリフルオロメチル)ピリジン-2-カルボキサミド、
3-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピリミジン-5-イルフェニル)メチル]-4-(トリフルオロメチル)ピリジン-2-カルボキサミド及び
3-クロロ-N-{(S)-[3-(1-エチル-1H-ピラゾール-4-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-4-(トリフルオロメチル)ピリジン-2-カルボキサミド。
The most preferred specific compounds are listed below:
3-chloro-N-((S)-(2S) -piperidin-2-yl (3-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2-carboxamide,
2-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3-pyrimidin-5-ylphenyl) methyl) -3- (trifluoromethyl) benzamide,
2,6-dichloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoro Methyl) benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3- (1H-pyrazol-4-yl) phenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-(3- (1-ethyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-chloro-N-((S)-(2S) -piperidin-2-yl (3- (1-propyl-1H-pyrazol-4-yl) phenyl) methyl) -3- (trifluoromethyl) benzamide,
2-Chloro-N-((S)-(3- (1-isopropyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Benzamide,
2-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -5- (trifluoromethyl) Benzamide,
3-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -4- (trifluoromethyl) Pyridine-2-carboxamide,
3-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -2- (trifluoromethyl) Isonicotinamide,
2-Chloro-N-{(S)-[3- (1-methyl-1H-imidazol-5-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -3- (trifluoromethyl) Benzamide,
3-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyrazin-2-ylphenyl) methyl] -4- (trifluoromethyl) pyridine-2-carboxamide,
3-chloro-N-{(S)-(2S) -piperidin-2-yl [3- (1-propyl-1H-pyrazol-4-yl) phenyl] methyl} -4- (trifluoromethyl) pyridine- 2-carboxamide,
3-chloro-N-{(S)-[3- (1-isopropyl-1H-pyrazol-4-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -4- (trifluoromethyl) Pyridine-2-carboxamide,
3-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyrimidin-5-ylphenyl) methyl] -4- (trifluoromethyl) pyridine-2-carboxamide and
3-chloro-N-{(S)-[3- (1-ethyl-1H-pyrazol-4-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -4- (trifluoromethyl) Pyridine-2-carboxamide.
式[I]及び[I’]の化合物は種々の合成方法によって製造することができる。以下では、便宜上、式[I]の化合物の一般的製造法として示すが、式[I’]の化合物
の場合は、環Aがフェニル基に置き換わる以外は、全く同様に製造される。なお、以下の方法は、本発明化合物の製造法の例示であり、これに限定されるものではない。一般的製造法中、P1はメトキシカルボニル基、エトキシカルボニル基、t−ブトキシカルボニル基、又はベンジルオキシカルボニル基等のカルバメートを形成する窒素原子の保護基(Theodora W.Greene and Peter G.M.Wuts「有機合成における保護基(Protective Groups in Organic Synthesis Third Edition)」;Wiley−Interscience参照)であり、P2はメチル基、ベンジル基、又はt−ブチルジメチルシリル基等のフェノール水酸基の保護基(同上資料参照)であり、P3はメチル基、或いは、ベンジル基又はアリル基等の3級アミノ基を形成するアミノ基の保護基(同上資料参照)であり、P4はピバロイル基等の水酸基の保護基であり(同上資料参照)、X1は塩素原子、臭素原子又はヨウ素原子であり、RaはC1−6アルキルであり(ここで、該C1−6アルキルは無置換又はシアノ基で置換されている。)、X2は塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、トルエンスルホニルオキシ基、又はトリフルオロメタンスルホニルオキシ基である。その他の記号は全て既に定義した通りである。「不活性溶媒」とは例えばメタノール、エタノール、イソプロパノール、n−ブタノール、エチレングリコール等のアルコール類、ジエチルエーテル、テトラヒドロフラン、1,4−ジオキサン、1,2−ジメトキシエタン等のエーテル類、トルエン、ベンゼン、キシレン等の炭化水素類、酢酸エチル、ギ酸エチル等のエステル類、アセトン、メチルエチルケトン等のケトン類、クロロホルム、ジクロロメタン等のハロゲン化炭素系溶媒、ジメチルホルムアミド、N-メチルピロリドン等のアミド類、アセトニトリル、ジメチルスルホキシド、水又はこれらの混合溶媒等であり、「塩基」とは、例えば、トリエチルアミン、N,N−ジイソプロピルエチルアミン、ピリジン、1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エン、N,N−ジメチルアニリン、N,N−ジエチルアニリン、4−ジメチルアミノピリジンなどのアミン;炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、水酸化ナトリウム、水酸化カリウム、水酸化バリウム、水素化ナトリウムなどの無機塩基;ナトリウムメトキシド、ナトリウムエトキシド、カリウムtert−ブトキシドなどの金属アルコラート;ナトリウムアミド、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラザニド、ナトリウムヘキサメチルジシラザニド、カリウムヘキサメチルジシラザニドなどの金属アミド;n−ブチルリチウム、sec-ブチルリチウム、tert−ブチルリチウム、メチルリチウムなどのアルキルリチウム;及び臭化メチルマグネシウムなどのグリニャール試薬であり、「酸」とは、例えば塩酸、臭化水素酸、硫酸、硝酸及び燐酸等の無機酸類、p−トルエンスルホン酸、メタンスルホン酸、トリフルオロ酢酸、蟻酸、酢酸等の有機酸類である。
[一般的製造法1]
Compounds of formula [I] and [I ′] can be prepared by various synthetic methods. Hereinafter, for convenience, it will be shown as a general production method of the compound of the formula [I]. However, the compound of the formula [I ′] is produced in the same manner except that the ring A is replaced with a phenyl group. In addition, the following method is an illustration of the manufacturing method of this invention compound, and is not limited to this. In a general production method, P 1 represents a protecting group for a nitrogen atom forming a carbamate such as a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, or a benzyloxycarbonyl group (Theodora W. Greene and Peter GM Wuts “Protective group in organic synthesis (see Protective Groups in Organic Synthesis Edition)”; see Wiley-Interscience), P 2 is a protecting group of a phenolic hydroxyl group such as a methyl group, a benzyl group, or a t-butyldimethylsilyl group ( P 3 is a protective group for an amino group forming a tertiary amino group such as a methyl group or a benzyl group or an allyl group (see the same document), and P 4 is a hydroxyl group such as a pivaloyl group. of A Mamorumoto (see ibid article), X 1 is a chlorine atom, a bromine atom or an iodine atom, R a is C 1-6 alkyl (wherein said C 1-6 alkyl is unsubstituted or cyano group in is substituted.), X 2 is chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group. All other symbols are as previously defined. Examples of the “inert solvent” include alcohols such as methanol, ethanol, isopropanol, n-butanol and ethylene glycol, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, toluene, benzene , Hydrocarbons such as xylene, esters such as ethyl acetate and ethyl formate, ketones such as acetone and methyl ethyl ketone, halogenated carbon solvents such as chloroform and dichloromethane, amides such as dimethylformamide and N-methylpyrrolidone, acetonitrile , Dimethyl sulfoxide, water or a mixed solvent thereof, and the “base” means, for example, triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene. , N, N Amines such as dimethylaniline, N, N-diethylaniline, 4-dimethylaminopyridine; sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, etc. Inorganic bases; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide; metals such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide Amido; alkyllithium such as n-butyllithium, sec-butyllithium, tert-butyllithium, and methyllithium; and Grignard reagents such as methylmagnesium bromide. Inorganic acids such as acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid and acetic acid.
[General production method 1]
工程1:不活性溶媒中塩基の存在下又は非存在下化合物(1)に対してN,O−ジメチルヒドロキシアミンを用いてアミド化反応を行うことにより化合物(2)を得ることができる。ここでアミド化反応とは当業者に公知である多くの標準的な手順により実施することができ、例えばクロロ炭酸エチル、クロロ炭酸イソブチル、又はピバロイルクロリド等を用いた混合酸無水物経由のアミド化、或いは1−(3,3−ジメチルアミノプロピル)−3−エチルカルボジイミド、1,3−ジシクロヘキシルカルボジイミド、ジフェニルホスホリルアジド、シアノリン酸ジエチル、カルボニルジイミダゾール、又はベンゾトリアゾール−1−イルオキシトリス(ジメチルアミノ)ホスホニウム ヘキサフルオロホスフェート(BOP試薬)等の縮合剤を用いたアミド化を挙げることができる。このアミド化の際、必要に応じて1−ヒドロキシベンゾトリアゾール(HOBt)等の添加剤を使用することもできる。
工程2:化合物(3)を金属又はアルキルリチウム試薬を用いてアルキル金属試薬に変換した後、不活性溶媒中化合物(2)と反応させることにより化合物(4)を得ることができる。ここで金属とは例えばマグネシウム又は亜鉛を挙げることができ、アルキルリチウム試薬とは例えばn−ブチルリチウム、sec―ブチルリチウム、t−ブチルリチウム、フェニルリチウム試薬を挙げることができる。
工程3:不活性溶媒中化合物(4)に対して還元剤を反応させることにより化合物(5)を得ることができる。ここで、還元剤とはカルボニル基を還元して水酸基に変換することができる試薬であり、例えば、水素化ホウ素リチウム、水素化ホウ素ナトリウム、水素化ホウ素カルシウム、トリエチル水素化ホウ素リチウム、トリ−sec-ブチル水素化ホウ素リチウム、トリ−sec-ブチル水素化ホウ素カリウム、水素化ホウ素亜鉛、ボラン、トリメトキシ水素化ホウ素リチウム、トリアセトキシ水素化ホウ素リチウム、ホウ素水素化テトラメチルアンモニウム、水素化アルミニウムリチウム、水素化アルミニウムナトリウム、水素化ビス(2−メトキシエトキシ)アルミニウムナトリウム、水素化ジイソブチルアルミニウム、トリクロロシラン等を挙げることができる。
工程4:不活性溶媒中化合物(5)に対して酸又は塩基による加水分解、或いは、Theodora W.Greene and Peter G.M.Wuts「有機合成における保護基(Protective Groups in Organic Synthesis Third Edition)」に記載の脱保護の反応により化合物(6)を得ることができる。
工程5:不活性溶媒中塩基の存在下又は非存在下化合物(6)に対してアリルクロリド、アリルブロミド等のアリル化剤、ベンジルクロリド、ベンジルブロミド等のベンジル化剤を反応させることにより化合物(7)を得ることができる。
工程6:P3がメチル基の場合、不活性溶媒中化合物(5)に対して還元剤を反応させることにより化合物(7)を得ることができる。ここで還元剤とはカルバメートを還元してメチル基に変換することができる試薬であり、例えば、ボラン、水素化アルミニウムリチウム、水素化アルミニウムナトリウム、水素化ビス(2−メトキシエトキシ)アルミニウムナトリウム、水素化ジイソブチルアルミニウムを挙げることができる。
工程7:不活性溶媒中塩基の存在下又は非存在下化合物(7)に対してスルホニル化剤を反応させた後、アンモニアを反応させることにより化合物(8)を得ることができる。スルホニル化剤とは水酸基をスルホニル化することができる試薬であり、例えば塩化p−トルエンスルホニル、塩化メタンスルホニル、p−トルエンスルホン酸無水物、メタンスルホン酸無水物、トリフルオロメタンスルホン酸無水物、N−フェニルビス(トリフルオロメタンスルホンイミド)を挙げることができる。
工程8:不活性溶媒中塩基の存在下又は非存在下化合物(8)に対して化合物(9)とアミド化反応を行うことにより化合物(10)を得ることができる。ここでアミド化とは工程1で記載した方法と同様の方法である。
工程9:化合物(10)に対して(1)P2がメチル基の場合は、例えば不活性溶媒中三臭化ホウ素、臭化アルミニウム(III)、塩化アルミニウム(III)を反応させ、(2)P2がベンジル基の場合は、不活性溶媒中例えば三臭化ホウ素、臭化アルミニウム(III)、塩化アルミニウム(III)を反応させるか或いはパラジウム触媒又は白金触媒を使用した水素添加反応を実施することにより化合物(11)を得ることができる。ここでパラジウム触媒とは例えばパラジウムブラック、パラジウム炭素、水酸化パラジウムを挙げることができ、白金触媒とは酸化白金を挙げることができる。P2が上記保護基以外の場合はTheodora W.Greene and Peter G.M.Wuts「有機合成における保護基(Protective Groups in Organic Synthesis Third Edition)」に記載の脱保護の反応によりP2を除去することで化合物(11)を得ることができる。
工程10:不活性溶媒中塩基の存在下又は非存在下化合物(11)に対してトリフレート化剤を反応させることにより化合物(12)を得ることができる。ここでトリフレート化剤とは例えばトリフルオロメタンスルホン酸無水物、N−フェニルビス(トリフルオロメタンスルホンイミド)を挙げることができる。
工程11:不活性溶媒中塩基の存在下又は非存在下パラジウム触媒及び必要に応じてパラジウム触媒の配位子を使用することにより化合物(12)に対してホウ酸又はホウ酸エステルが置換した環Aを反応させることにより本発明化合物(13)を得ることができる。ここで、パラジウム触媒とは例えばPd(OAc)2、Pd2(dba)3、Pd(PPh3)4を挙げることができ、配位子とは例えばトリフェニルホスフィン、2,2−ビス(ジフェニルホルフィノ)−1,1−ビナフチル(BINAP)、2−(ジ−t−ブチルホスフィノ)ビフェニル、9,9−ジメチル−4,5−ビス(ジフェニルホスフィノ)キサンテン(Xantphos)等を挙げることができる。
工程12:化合物(13)に対して(1)P3がアリル基の場合はN,N−ジメチルバルビツール酸及びパラジウム触媒を使用して脱保護反応を実施することにより(ここで、パラジウム触媒とは例えばPd(OAc)2、Pd2(dba)3、Pd(PPh3)4を挙げることができる。)、(2)ベンジル基の場合はパラジウム触媒又は白金触媒を使用した水素添加反応により脱保護反応を実施することにより(ここでパラジウム触媒とは例えばパラジウムブラック、パラジウム炭素、水酸化パラジウムを挙げることができ、白金触媒とは酸化白金を挙げることができる。)本発明化合物(14)を得ることができる。P3が上記保護基以外の場合はTheodora W.Greene and Peter G.M.Wuts「有機合成における保護基(Protective Groups in Organic Synthesis Third Edition)」に記載の脱保護の反応によりP3を除去することで本発明化合物(14)を得ることができる。
[一般的製造法2]
Step 1: Compound (2) can be obtained by subjecting compound (1) to an amidation reaction using N, O-dimethylhydroxyamine in the presence or absence of a base in an inert solvent. The amidation reaction here can be carried out by a number of standard procedures known to those skilled in the art, for example via a mixed acid anhydride using ethyl chlorocarbonate, isobutyl chlorocarbonate or pivaloyl chloride. Amidation or 1- (3,3-dimethylaminopropyl) -3-ethylcarbodiimide, 1,3-dicyclohexylcarbodiimide, diphenylphosphoryl azide, diethyl cyanophosphate, carbonyldiimidazole, or benzotriazol-1-yloxytris ( And amidation using a condensing agent such as (dimethylamino) phosphonium hexafluorophosphate (BOP reagent). In this amidation, an additive such as 1-hydroxybenzotriazole (HOBt) can be used as necessary.
Step 2: Compound (4) can be obtained by converting compound (3) to an alkyl metal reagent using a metal or alkyllithium reagent and then reacting with compound (2) in an inert solvent. Here, examples of the metal include magnesium or zinc, and examples of the alkyl lithium reagent include n-butyl lithium, sec-butyl lithium, t-butyl lithium, and phenyl lithium reagent.
Step 3: Compound (5) can be obtained by reacting compound (4) in an inert solvent with a reducing agent. Here, the reducing agent is a reagent that can reduce a carbonyl group and convert it into a hydroxyl group. For example, lithium borohydride, sodium borohydride, calcium borohydride, lithium triethylborohydride, tri-sec. -Butyl lithium borohydride, tri-sec-butyl potassium borohydride, zinc borohydride, borane, lithium trimethoxyborohydride, lithium triacetoxyborohydride, tetramethylammonium borohydride, lithium aluminum hydride, hydrogen Examples include sodium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride, and trichlorosilane.
Step 4: Hydrolysis of compound (5) in an inert solvent with acid or base, or Theodora W. Greene and Peter G. M.M. Compound (6) can be obtained by the deprotection reaction described in Wuts “Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis Third Edition)”.
Step 5: Compound (6) is reacted with an allylating agent such as allyl chloride and allyl bromide and a benzylating agent such as benzyl chloride and benzyl bromide with compound (6) in the presence or absence of a base in an inert solvent. 7) can be obtained.
Step 6: P 3 can be obtained when the methyl group, the compound by reacting a reducing agent to an inert solvent in the compound (5) to (7). Here, the reducing agent is a reagent that can reduce the carbamate and convert it into a methyl group. For example, borane, lithium aluminum hydride, sodium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, hydrogen And diisobutylaluminum chloride.
Step 7: Compound (8) can be obtained by reacting compound (7) with an sulfonylating agent in the presence or absence of a base in an inert solvent and then reacting with ammonia. A sulfonylating agent is a reagent capable of sulfonylating a hydroxyl group. For example, p-toluenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonic acid anhydride, methanesulfonic acid anhydride, trifluoromethanesulfonic acid anhydride, N -Phenylbis (trifluoromethanesulfonimide) can be mentioned.
Step 8: Compound (10) can be obtained by subjecting compound (8) to an amidation reaction with compound (8) in the presence or absence of a base in an inert solvent. Here, amidation is a method similar to the method described in Step 1.
Step 9: When the compound (10) with respect to (1) P 2 is a methyl group, for example an inert solvent boron tribromide, aluminum bromide (III), is reacted with aluminum chloride (III), (2 ) When P 2 is a benzyl group, for example, boron tribromide, aluminum bromide (III), aluminum chloride (III) is reacted in an inert solvent, or a hydrogenation reaction using a palladium catalyst or a platinum catalyst is performed. Thus, the compound (11) can be obtained. Here, examples of the palladium catalyst include palladium black, palladium carbon, and palladium hydroxide, and examples of the platinum catalyst include platinum oxide. When P 2 is other than the above protecting group, Theodora W. Greene and Peter G. M.M. Compound (11) can be obtained by removing P 2 by the deprotection reaction described in Wuts “Protective Group in Organic Synthesis (Protective Groups in Organic Synthesis Third Edition)”.
Step 10: Compound (12) can be obtained by reacting compound (11) with a triflator in the presence or absence of a base in an inert solvent. Examples of the triflating agent include trifluoromethanesulfonic anhydride and N-phenylbis (trifluoromethanesulfonimide).
Step 11: Ring in which boric acid or boric acid ester is substituted for compound (12) by using a palladium catalyst in the presence or absence of a base in an inert solvent and optionally using a ligand of a palladium catalyst The compound (13) of the present invention can be obtained by reacting A. Here, examples of the palladium catalyst include Pd (OAc) 2 , Pd 2 (dba) 3 , and Pd (PPh 3 ) 4 , and examples of the ligand include triphenylphosphine and 2,2-bis (diphenyl). Forfino) -1,1-binaphthyl (BINAP), 2- (di-t-butylphosphino) biphenyl, 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos), etc. Can do.
Step 12: (1) When P 3 is an allyl group with respect to the compound (13), a deprotection reaction is performed using N, N-dimethylbarbituric acid and a palladium catalyst (wherein the palladium catalyst Examples thereof include Pd (OAc) 2 , Pd 2 (dba) 3 , and Pd (PPh 3 ) 4. ) (2) In the case of a benzyl group, a hydrogenation reaction using a palladium catalyst or a platinum catalyst. By carrying out a deprotection reaction (here, examples of the palladium catalyst include palladium black, palladium carbon, and palladium hydroxide, and examples of the platinum catalyst include platinum oxide). Compound (14) of the present invention Can be obtained. When P 3 is other than the above protecting group, Theodora W. Greene and Peter G. M.M. The present compound (14) can be obtained by removing P 3 by the deprotection reaction described in Wuts “Protective Group in Organic Synthesis (Protective Groups in Organic Synthesis Third Edition)”.
[General production method 2]
工程13:一般的製造法1中の工程9と同様の手法により化合物(4)を化合物(15)に変換することができる。
工程14:一般的製造法1中の工程10と同様の手法により化合物(15)を化合物(16)に変換することができる。
工程15:一般的製造法1中の工程3と同様の手法により化合物(16)を化合物(17)に変換することができる。
工程16:一般的製造法1中の工程11と同様の手法により化合物(17)を化合物(18)に変換することができる。
工程17:一般的製造法1中の工程4と同様の手法により化合物(18)を化合物(19)に変換することができる。
工程18:一般的製造法1中の工程5と同様の手法により化合物(19)を化合物(20)に変換することができる。
工程19:P3がメチル基の場合、一般的製造法1中の工程6と同様の手法により化合物(18)を化合物(20)に変換することができる。
工程20:一般的製造法1中の工程7と同様の手法により化合物(20)を化合物(21)に変換することができる。
工程21:一般的製造法1中の工程8と同様の手法により化合物(21)を本発明化合物(13)に変換することができる。
工程22:一般的製造法1中の工程12と同様の手法により化合物(13)を本発明化合物(14)に変換することができる。
[一般的製造法3]
Step 13: Compound (4) can be converted to Compound (15) by the same method as in Step 9 in General Production Method 1.
Step 14: Compound (15) can be converted to compound (16) by the same method as in Step 10 in General Production Method 1.
Step 15: Compound (16) can be converted to compound (17) by the same method as in Step 3 in General Production Method 1.
Step 16: Compound (17) can be converted to compound (18) by the same method as in Step 11 in General Production Method 1.
Step 17: Compound (18) can be converted to compound (19) by the same method as in Step 4 in General Production Method 1.
Step 18: Compound (19) can be converted to compound (20) by the same method as in Step 5 in General Production Method 1.
Step 19: When P 3 is a methyl group, compound (18) can be converted to compound (20) by the same method as in step 6 in general production method 1.
Step 20: Compound (20) can be converted to compound (21) by the same method as in Step 7 in General Production Method 1.
Step 21: Compound (21) can be converted to compound (13) of the present invention by the same method as in Step 8 in General Production Method 1.
Step 22: Compound (13) can be converted to compound (14) of the present invention by the same method as in Step 12 in General Production Method 1.
[General production method 3]
工程23:不活性溶媒中塩基の存在下又は非存在下本発明化合物(14)に対して化合物(22)を反応させることにより化合物(23)を得ることができる。
前述の中間体(18)は以下の一般的製造法4に従っても製造することができる。
[一般的製造法4]
Step 23: Compound (23) can be obtained by reacting Compound (22) with Compound (14) of the present invention in the presence or absence of a base in an inert solvent.
The intermediate (18) can also be produced according to the following general production method 4.
[General production method 4]
工程24:化合物(17)を不活性溶媒中塩基の存在下又は非存在下、パラジウム触媒及び必要に応じてパラジウム触媒の配位子を使用することによりビスピナコールボランを反応させ、化合物(24)を得ることができる。ここで、パラジウム触媒とは例えばPd(OAc)2、Pd2(dba)3、Pd(PPh3)4、Pd(dppf)Cl2を挙げることができ、配位子とは例えばトリフェニルホスフィン、2,2−ビス(ジフェニルホスフィノ)−1,1−ビナフチル(BINAP)、2−(ジ−t−ブチルホスフィノ)ビフェニル、9,9−ジメチル−4,5−ビス(ジフェニルホスフィノ)キサンテン(Xantphos)、1,1’−ビスジフェニルホスフィノフェロセン(dppf)等を挙げることができる。
工程25:化合物(24)及びハロゲンが置換した環Aを一般的製造法1の工程11と同様にして反応させ、化合物(18)を得ることができる。
前述の中間体(7)は以下の一般的製造法5に従っても製造することができる。
[一般的製造法5]
Step 24: Compound (17) is reacted with bispinacolborane by using a palladium catalyst and, if necessary, a ligand of a palladium catalyst, in the presence or absence of a base in an inert solvent, to give compound (24) Can be obtained. Here, examples of the palladium catalyst include Pd (OAc) 2 , Pd 2 (dba) 3 , Pd (PPh 3 ) 4 , and Pd (dppf) Cl 2. Examples of the ligand include triphenylphosphine, 2,2-bis (diphenylphosphino) -1,1-binaphthyl (BINAP), 2- (di-t-butylphosphino) biphenyl, 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos), 1,1′-bisdiphenylphosphinoferrocene (dppf) and the like.
Step 25: Compound (18) can be obtained by reacting Compound (24) and halogen-substituted ring A in the same manner as in Step 11 of General Production Method 1.
The intermediate (7) can also be produced according to the following general production method 5.
[General production method 5]
工程26:P4がピバロイル基の場合、不活性溶媒中塩基の存在下又は非存在下化合物(5)に対してピバロイルクロリドを反応させることにより化合物(25)を得ることができる。P4がその他の保護基の場合はTheodora W.Greene and Peter G.M.Wuts「有機合成における保護基(Protective Groups in Organic Synthesis Third Edition)」に記載の手法により化合物(25)を得ることができる。
工程27:一般的製造法1中の工程4と同様の手法により化合物(25)を化合物(26)に変換することができる。
工程28:一般的製造法1中の工程5と同様の手法により化合物(26)を化合物(27)に変換することができる。
工程29:P4がピバロイル基の場合は不活性溶媒中水素化アルミニウムリチウム、水素化ビス(2−メトキシエトキシ)アルミニウムナトリウム、又は水素化ジイソブチルアルミニウム等の還元剤による脱保護を行うか、或いは、Theodora W.Greene and Peter G.M.Wuts「有機合成における保護基(Protective Groups in Organic Synthesis Third Edition)」に記載の手法により脱保護を行い、化合物(7)を得ることができる。P4がそれ以外の保護基の場合は同著に記載の手法にて化合物(7)を得ることができる。
前述の中間体(18)は以下の一般的製造法6に従っても製造することができる。
[一般的製造法6]
Step 26: When P 4 is a pivaloyl group, compound (25) can be obtained by reacting pivaloyl chloride with compound (5) in the presence or absence of a base in an inert solvent. P 4 is the case of the other protecting group Theodora W. Greene and Peter G. M.M. The compound (25) can be obtained by the method described in Wuts “Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis Third Edition)”.
Step 27: Compound (25) can be converted to compound (26) by the same method as in Step 4 in General Production Method 1.
Step 28: Compound (26) can be converted to compound (27) by the same method as in Step 5 in General Production Method 1.
Step 29: When P 4 is a pivaloyl group, deprotection with a reducing agent such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride in an inert solvent, or Theodora W. Greene and Peter G. M.M. Deprotection can be carried out by the method described in Wuts “Protective Group in Organic Synthesis (Protective Groups in Organic Synthesis Third Edition)” to give compound (7). When P 4 is other protecting group, the compound (7) can be obtained by the method described in the same book.
The aforementioned intermediate (18) can also be produced according to the following general production method 6.
[General production method 6]
工程30:化合物(28)を一般的製造法1中工程2で示した手法で金属塩とした後化合物(2)と反応させることにより化合物(29)を得ることができる。
工程31:一般的製造法1中の工程3と同様の手法により化合物(18)を得ることができる。
Step 30: Compound (29) can be obtained by making compound (28) a metal salt by the method shown in Step 2 in General Production Method 1 and then reacting with Compound (2).
Step 31: Compound (18) can be obtained by the same method as in Step 3 in General Production Method 1.
本発明化合物は複数の不斉中心を含むことができる。従って前記化合物は光学活性体で存在するとともにそのラセミ体でも存在することができ、さらに複数のジアステレオマーも存在することができる。前記の全ての形態は本発明の範囲内に含まれる。個々の異性体は公知の方法、例えば光学活性な出発物質若しくは中間体の使用、中間体若しくは最終生成物の製造における光学選択的な反応又はジアステレオ選択的な反応、或いは中間体又は最終生成物の製造におけるクロマトグラフを用いた分離等により得ることが可能である。さらに、本発明化合物が水和物又は溶媒和物を形成する場合、それらも本発明の範囲内に含まれる。 The compound of the present invention may contain a plurality of asymmetric centers. Therefore, the compound can exist in an optically active form and also in a racemic form thereof, and a plurality of diastereomers can also exist. All of the above forms are included within the scope of the present invention. The individual isomers are known methods, for example the use of optically active starting materials or intermediates, optically selective or diastereoselective reactions in the production of intermediates or final products, or intermediates or final products. It can be obtained by separation using a chromatograph in the production of Further, when the compounds of the present invention form hydrates or solvates, they are also included within the scope of the present invention.
本発明に係る化合物は、経口又は非経口的に投与することができる。その投与剤型は錠剤、カプセル剤、顆粒剤、散剤、粉剤、トローチ剤、軟膏剤、クリーム剤、乳剤、懸濁剤、坐剤、注射剤等であり、いずれも慣用の製剤技術(例えば、第14改正日本薬局方に規定する方法等)によって製造することができる。これらの投与剤型は、患者の症状、年齢及び治療の目的に応じて適宜選択することができる。 The compound according to the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulation techniques (for example, Etc.) according to the 14th revision Japanese Pharmacopoeia. These dosage forms can be appropriately selected according to the patient's symptoms, age and purpose of treatment.
これらの製剤は、本発明の化合物を含有する組成物に薬理学的に許容されるキャリヤー、すなわち、賦形剤(例えば、結晶セルロース、デンプン、乳糖、マンニトール)、結合剤(例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン)、滑沢剤(例えば、ステアリン酸マグネシウム、タルク)、崩壊剤(例えば、カルボキシメチルセルロースカルシウム)、その他薬理学的に許容される各種添加剤を配合し、製造することができる。 These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
本発明に係る化合物の投与量は、成人を治療する場合で1日1〜2000mgであり、これを1日1回又は数回に分けて投与する。この投与量は、患者の年齢、体重及び症状によって適宜増減することができる。 The dose of the compound according to the present invention is 1 to 2000 mg per day when treating an adult, and this is administered once or divided into several times per day. This dosage can be appropriately increased or decreased depending on the age, weight and symptoms of the patient.
次に、製造例、実施例及び試験例により本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。
カラムクロマトグラフィーを使用して精製した際の「シリカゲル」にはシリカゲル60N(関東化学)、「NHシリカゲル」にはChromatorex NH(Fuji Silysia)を使用した。TLCを使用して精製した際のTLC(シリカゲル)にはSilica gel 60F254(メルク)、TLC(NHシリカゲル)にはTLCプレートNH(Fuji Silysia)を使用した。
Next, the present invention will be described in more detail with reference to production examples, examples and test examples, but the present invention is not limited to these examples.
Silica gel 60N (Kanto Chemical) was used as the “silica gel” when purified using column chromatography, and Chromatorex NH (Fuji Silysia) was used as the “NH silica gel”. Silica gel 60F254 (Merck) was used for TLC (silica gel) when purified using TLC, and TLC plate NH (Fuji Silysia) was used for TLC (NH silica gel).
製造例及び実施例中記載の各機器データは以下の測定機器にて測定された。
MSスペクトル:島津LCMS−2010EV又はmicromass Platform LC
NMRスペクトル:[1H-NMR]600MHz:JNM−ECA600(日本電子)、500MHz:JNM−ECA500(日本電子)、300MHz:UNITYNOVA300(Varian Inc.)、200MHz:GEMINI2000/200(Varian Inc.)
比旋光度:AUTOPOL V(Rudolph Research Analytical)
Each instrument data described in the production examples and the examples was measured by the following measuring instruments.
MS spectrum: Shimadzu LCMS-2010EV or micromass Platform LC
NMR spectrum: [ 1 H-NMR] 600 MHz: JNM-ECA600 (JEOL), 500 MHz: JNM-ECA500 (JEOL), 300 MHz: UNITYNOVA300 (Varian Inc.), 200 MHz: GEMINI 2000/200 (Varian Inc.)
Specific rotation: AUTOPOL V (Rudolph Research Analytical)
実施例中の化合物名はACD/Name (ACD/Labs 8.00, Advanced Chemistry Development Inc.)により命名した。
製造例、実施例、及び試験例中で使用した略語を以下に示す。
ALX5407:N−[(3R)−3−([1,1’−ビフェニル]−4−イルオキシ)−3−(4−フルオロフェニル)プロピル]−N−メチルグリシンHCl塩
Boc:t−ブトキシカルボニル
BOP試薬:ベンゾトリアゾール−1−イルオキシトリス(ジメチルアミノ)ホスフォニウム ヘキサフルオロホスフェート
Bn:ベンジル
DMAP:4−ジメチルアミノピリジン
DMF:N,N−ジメチルホルムアミド
dppf:ビスジフェニルホスフィノフェロセン
EDC:1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド
HEPES:N−2−ヒドロキシエチルピペラジン−N’−2−エタンスルホン酸
HOBT:1−ヒドロキシベンゾトリアゾール
Me:メチル
MeOH:メタノール
Piv:ピバロイル
TBAF:n−テトラブチルアンモニウムフルオリド
TBS:t−ブチルジメチルシリル
Tf:トリフルオロメタンスルホニル
THF:テトラヒドロフラン
TLC:薄層クロマトグラフィー
The compound names in the Examples were named by ACD / Name (ACD / Labs 8.00, Advanced Chemistry Development Inc.).
Abbreviations used in Production Examples, Examples, and Test Examples are shown below.
ALX5407: N-[(3R) -3-([1,1′-biphenyl] -4-yloxy) -3- (4-fluorophenyl) propyl] -N-methylglycine HCl salt Boc: t-butoxycarbonyl BOP Reagent: Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate Bn: benzyl DMAP: 4-dimethylaminopyridine DMF: N, N-dimethylformamide dppf: bisdiphenylphosphinoferrocene EDC: 1-ethyl-3 -(3-Dimethylaminopropyl) carbodiimide HEPES: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid HOBT: 1-hydroxybenzotriazole Me: methyl MeOH: methanol Piv: pivaloyl TBAF: n-te Tetrabutylammonium fluoride TBS: t-butyldimethylsilyl Tf: trifluoromethanesulfonyl THF: Tetrahydrofuran TLC: Thin layer chromatography
製造例1 tert-ブチル (2S)-2-((メトキシ(メチル)アミノ)カルボニル)ピペリジン-1-カルボキシラートの合成 Production Example 1 Synthesis of tert-butyl (2S) -2-((methoxy (methyl) amino) carbonyl) piperidine-1-carboxylate
(S)−1−(t−ブトキシカルボニル)ピペリジン−2−カルボン酸(165g)のクロロホルム(1200ml)の溶液にトリエチルアミン(218g)及びN,O−ジメチルヒドロキシアミン塩酸塩(84g)を加え、氷冷後BOP試薬(334g)をゆっくり加えた。室温で一晩攪拌後、反応混合物を減圧下濃縮し、酢酸エチルにて希釈後、0.5M塩酸、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、ヘキサン/酢酸エチル=5:1)で精製し、表題化合物(178g)を無色油状物質として得た。
MS (ESI pos.) m/z : 273([M+H]+), (ESI pos.) m/z : 295([M+Na]+)
1H NMR (200 MHz, CDCl3) δ ppm 1.32 - 1.81 (m, 14 H), 1.93 - 2.06 (m, 1 H), 3.18 (s, 3 H), 3.30 - 3.61 (m, 1 H), 3.70 - 4.06 (m, 4 H), 4.82 - 5.18 (m, 1 H)
同様の方法にて以下の化合物を得た。
tert-ブチル (2S)-2-((メトキシ(メチル)アミノ)カルボニル)ピロリジン-1-カルボキシラート
MS (ESI pos.) m/z : 259([M+H]+), (ESI pos.) m/z : 281([M+Na]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.39 - 1.48 (m, 9 H), 1.79 - 2.03 (m, 3 H), 2.13 - 2.27 (m, 1 H), 3.20 (s, 3 H), 3.37 - 3.51 (m, 1 H), 3.53 - 3.63 (m, 1 H), 3.70 - 3.81 (m, 3 H), 4.57 - 4.74 (m, 1 H)
Triethylamine (218 g) and N, O-dimethylhydroxyamine hydrochloride (84 g) were added to a solution of (S) -1- (t-butoxycarbonyl) piperidine-2-carboxylic acid (165 g) in chloroform (1200 ml) and iced. After cooling, BOP reagent (334 g) was slowly added. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed successively with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 5: 1) to give the title compound (178 g) as a colorless product. Obtained as an oil.
MS (ESI pos.) M / z: 273 ([M + H] +), (ESI pos.) M / z: 295 ([M + Na] +)
1H NMR (200 MHz, CDCl3) δ ppm 1.32-1.81 (m, 14 H), 1.93-2.06 (m, 1 H), 3.18 (s, 3 H), 3.30-3.61 (m, 1 H), 3.70- 4.06 (m, 4 H), 4.82-5.18 (m, 1 H)
The following compounds were obtained by the same method.
tert-Butyl (2S) -2-((methoxy (methyl) amino) carbonyl) pyrrolidine-1-carboxylate
MS (ESI pos.) M / z: 259 ([M + H] +), (ESI pos.) M / z: 281 ([M + Na] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.39-1.48 (m, 9 H), 1.79-2.03 (m, 3 H), 2.13-2.27 (m, 1 H), 3.20 (s, 3 H), 3.37- 3.51 (m, 1 H), 3.53-3.63 (m, 1 H), 3.70-3.81 (m, 3 H), 4.57-4.74 (m, 1 H)
製造例2 tert-ブチル(2S)-2-((S)-ヒドロキシ(3-メトキシフェニル)メチル)ピペリジン-1-カルボキシラートの合成 Production Example 2 Synthesis of tert-butyl (2S) -2-((S) -hydroxy (3-methoxyphenyl) methyl) piperidine-1-carboxylate
(1)窒素雰囲気下マグネシウム(7.1g)をテトラヒドロフラン(270ml)に懸濁させ、少量のヨウ素を加えた後3−ブロモアニソール(35ml)をゆっくり加えた。室温で1時間攪拌後、この反応溶液を氷冷下tert-ブチル (2S)-2-((メトキシ(メチル)アミノ)カルボニル)ピペリジン-1-カルボキシラート(50g)のテトラヒドロフラン溶液(300ml)に滴下した。室温で2時間攪拌後、10%塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、ヘキサン/酢酸エチル=8:1)で精製し、tert-ブチル (2S)-2-(3-メトキシベンゾイル)ピペリジン-1-カルボキシラート(33g)を淡黄色油状物質として得た。
MS (ESI pos.) m/z : 342([M+Na]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.29 - 1.53 (m, 11 H), 1.53 - 1.88 (m, 3 H), 1.99 - 2.22 (m, 1 H), 3.07 - 3.29 (m, 1 H), 3.81 - 4.05 (m, 4 H), 5.41 - 5.69 (m, 1 H), 7.05 - 7.15 (m, 1 H), 7.30 - 7.57 (m, 3 H)
(2)窒素雰囲気下、tert-ブチル (2S)-2-(3-メトキシベンゾイル)ピペリジン-1-カルボキシラート(33g)のテトラヒドロフラン溶液(300ml)を−78℃に冷却し、L−Selectride(商標)(1Mテトラヒドロフラン溶液、200ml)を40分間かけて滴下した。同温にて3時間攪拌後、15%過酸化水素水溶液(200ml)を15分間かけて滴下し、室温で30分間攪拌後、有機溶媒を減圧下留去し、酢酸エチル及び水を加え、分液後、水層を酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮した。析出した固体をヘキサン/酢酸エチル(=9:1)で洗浄し、表題化合物(22g)を無色固体として得た。
MS (ESI pos.) m/z : 344([M+Na]+)
NMR 1H NMR (600 MHz, CDCl3) δ ppm 1.26 - 1.34 (m, 1 H), 1.35 - 1.75 (m, 14 H), 2.84 - 3.15 (m, 1 H), 3.82 (s, 3 H), 3.95 - 4.46 (m, 2 H), 4.83 - 4.88 (m, 1 H), 6.81 - 6.87 (m, 1 H), 6.90 - 7.00 (m, 2 H), 7.22 - 7.31 (m, 1 H)
同様にして以下の化合物を得た。
tert-ブチル(2S)-2-((S)-(3-(ベンジルオキシ)フェニル)(ヒドロキシ)メチル)ピペリジン-1-カルボキシラート
MS (ESI pos.) m/z : 398([M+H]+), (ESI pos.) m/z : 420([M+Na]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.24 - 1.32 (m, 1 H), 1.34 - 1.42 (m, 1 H), 1.42 - 1.62 (m, 12 H), 1.63 - 1.73 (m, 1 H), 2.86 - 3.11 (m, 1 H), 3.96 - 4.47 (m, 2 H), 4.82 - 4.87 (m, 1 H), 5.07 (s, 2 H), 6.90 - 6.93 (m, 1 H), 6.95 - 7.06 (m, 2 H), 7.26 - 7.30 (m, 1 H), 7.30 - 7.35 (m, 1 H), 7.36 - 7.41 (m, 2 H), 7.42 - 7.45 (m, 2 H)
tert-ブチル(2S)-2-((S)-ヒドロキシ(3-メトキシフェニル)メチル)ピロリジン-1-カルボキシラート
MS (ESI pos.) m/z : 308([M+H]+)
1H NMR (600 MHz, CDCl3) δ (ppm) ; 1.19 - 4.98 (m, 20 H), 6.73 - 6.85 (m, 1 H), 6.84 - 7.01 (m, 2 H), 7.16 - 7.28 (m, 1 H)
tert-ブチル(2S)-2-((S)-ビフェニル-3-イル(ヒドロキシ)メチル)ピペリジン-1-カルボキシラート
MS (ESI pos.) m/z : 368([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.30 - 1.37 (m, 1 H), 1.37 - 1.65 (m, 13 H), 1.65 - 1.74 (m, 1 H), 2.87 - 3.18 (m, 1 H), 3.97 - 4.54 (m, 2 H), 4.95 (d, J=10.1 Hz, 1 H), 7.31 - 7.40 (m, 2 H), 7.39 - 7.49 (m, 3 H), 7.50 - 7.65 (m, 4 H)
tert-ブチル(2S)-2-((S)-ビフェニル-4-イル(ヒドロキシ)メチル)ピペリジン-1-カルボキシラート
MS (ESI pos.) m/z : 390([M+Na]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.32 - 1.38 (m, 1 H), 1.38 - 1.65 (m, 13 H), 1.66 - 1.74 (m, 1 H), 2.89 - 3.17 (m, 1 H), 3.98 - 4.55 (m, 2 H), 4.93 (d, J=10.5 Hz, 1 H), 7.32 - 7.37 (m, 1 H), 7.40 - 7.49 (m, 4 H), 7.54 - 7.64 (m, 4 H)
tert-ブチル(2S)-2-((S)-(4-((tert-ブチル(ジメチル)シリル)オキシ)フェニル)(ヒドロキシ)メチル)ピペリジン-1-カルボキシラート
MS (ESI pos.) m/z : 422([M+H]+), (ESI pos.) m/z : 444([M+Na]+)
1H NMR (600 MHz, DMSO-d6) δ ppm 0.17 (s, 6 H), 0.94 (s, 9 H), 1.11 - 1.19 (m, 1 H), 1.22 - 1.33 (m, 2 H), 1.35 - 1.47 (m, 10 H), 1.54 - 1.72 (m, 2 H), 2.79 - 3.01 (m, 1 H), 3.82 - 3.92 (m, 1 H), 4.02 - 4.20 (m, 1 H), 4.71 - 4.77 (m, 1 H), 6.77 - 6.86 (m, 2 H), 7.17 - 7.25 (m, 2 H)
(1) Magnesium (7.1 g) was suspended in tetrahydrofuran (270 ml) under a nitrogen atmosphere, a small amount of iodine was added, and then 3-bromoanisole (35 ml) was slowly added. After stirring at room temperature for 1 hour, the reaction solution was added dropwise to a tetrahydrofuran solution (300 ml) of tert-butyl (2S) -2-((methoxy (methyl) amino) carbonyl) piperidine-1-carboxylate (50 g) under ice cooling. did. After stirring at room temperature for 2 hours, 10% aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 8: 1), and tert-butyl (2S)- 2- (3-Methoxybenzoyl) piperidine-1-carboxylate (33 g) was obtained as a pale yellow oil.
MS (ESI pos.) M / z: 342 ([M + Na] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.29-1.53 (m, 11 H), 1.53-1.88 (m, 3 H), 1.99-2.22 (m, 1 H), 3.07-3.29 (m, 1 H), 3.81-4.05 (m, 4 H), 5.41-5.69 (m, 1 H), 7.05-7.15 (m, 1 H), 7.30-7.57 (m, 3 H)
(2) Under a nitrogen atmosphere, a tetrahydrofuran solution (300 ml) of tert-butyl (2S) -2- (3-methoxybenzoyl) piperidine-1-carboxylate (33 g) was cooled to −78 ° C., and L-Selectride (trademark) ) (1M tetrahydrofuran solution, 200 ml) was added dropwise over 40 minutes. After stirring at the same temperature for 3 hours, 15% aqueous hydrogen peroxide (200 ml) was added dropwise over 15 minutes. After stirring at room temperature for 30 minutes, the organic solvent was distilled off under reduced pressure, and ethyl acetate and water were added. After the liquid, the aqueous layer was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The precipitated solid was washed with hexane / ethyl acetate (= 9: 1) to obtain the title compound (22 g) as a colorless solid.
MS (ESI pos.) M / z: 344 ([M + Na] +)
NMR 1H NMR (600 MHz, CDCl3) δ ppm 1.26-1.34 (m, 1 H), 1.35-1.75 (m, 14 H), 2.84-3.15 (m, 1 H), 3.82 (s, 3 H), 3.95 -4.46 (m, 2 H), 4.83-4.88 (m, 1 H), 6.81-6.87 (m, 1 H), 6.90-7.00 (m, 2 H), 7.22-7.31 (m, 1 H)
Similarly, the following compounds were obtained.
tert-Butyl (2S) -2-((S)-(3- (benzyloxy) phenyl) (hydroxy) methyl) piperidine-1-carboxylate
MS (ESI pos.) M / z: 398 ([M + H] +), (ESI pos.) M / z: 420 ([M + Na] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.24-1.32 (m, 1 H), 1.34-1.42 (m, 1 H), 1.42-1.62 (m, 12 H), 1.63-1.73 (m, 1 H), 2.86-3.11 (m, 1 H), 3.96-4.47 (m, 2 H), 4.82-4.87 (m, 1 H), 5.07 (s, 2 H), 6.90-6.93 (m, 1 H), 6.95- 7.06 (m, 2 H), 7.26-7.30 (m, 1 H), 7.30-7.35 (m, 1 H), 7.36-7.41 (m, 2 H), 7.42-7.45 (m, 2 H)
tert-butyl (2S) -2-((S) -hydroxy (3-methoxyphenyl) methyl) pyrrolidine-1-carboxylate
MS (ESI pos.) M / z: 308 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ (ppm); 1.19-4.98 (m, 20 H), 6.73-6.85 (m, 1 H), 6.84-7.01 (m, 2 H), 7.16-7.28 (m, 1 H)
tert-Butyl (2S) -2-((S) -biphenyl-3-yl (hydroxy) methyl) piperidine-1-carboxylate
MS (ESI pos.) M / z: 368 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.30-1.37 (m, 1 H), 1.37-1.65 (m, 13 H), 1.65-1.74 (m, 1 H), 2.87-3.18 (m, 1 H), 3.97-4.54 (m, 2 H), 4.95 (d, J = 10.1 Hz, 1 H), 7.31-7.40 (m, 2 H), 7.39-7.49 (m, 3 H), 7.50-7.65 (m, 4 H)
tert-Butyl (2S) -2-((S) -biphenyl-4-yl (hydroxy) methyl) piperidine-1-carboxylate
MS (ESI pos.) M / z: 390 ([M + Na] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.32-1.38 (m, 1 H), 1.38-1.65 (m, 13 H), 1.66-1.74 (m, 1 H), 2.89-3.17 (m, 1 H), 3.98-4.55 (m, 2 H), 4.93 (d, J = 10.5 Hz, 1 H), 7.32-7.37 (m, 1 H), 7.40-7.49 (m, 4 H), 7.54-7.64 (m, 4 H)
tert-butyl (2S) -2-((S)-(4-((tert-butyl (dimethyl) silyl) oxy) phenyl) (hydroxy) methyl) piperidine-1-carboxylate
MS (ESI pos.) M / z: 422 ([M + H] +), (ESI pos.) M / z: 444 ([M + Na] +)
1H NMR (600 MHz, DMSO-d6) δ ppm 0.17 (s, 6 H), 0.94 (s, 9 H), 1.11-1.19 (m, 1 H), 1.22-1.33 (m, 2 H), 1.35- 1.47 (m, 10 H), 1.54-1.72 (m, 2 H), 2.79-3.01 (m, 1 H), 3.82-3.92 (m, 1 H), 4.02-4.20 (m, 1 H), 4.71- 4.77 (m, 1 H), 6.77-6.86 (m, 2 H), 7.17-7.25 (m, 2 H)
製造例3 (S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-メトキシフェニル)メタンアミンの合成 Production Example 3 Synthesis of (S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3-methoxyphenyl) methanamine
(1)tert-ブチル(2S)-2-((S)-ヒドロキシ(3-メトキシフェニル)メチル)ピペリジン-1-カルボキシラート(22g)のメタノール溶液(400ml)に水酸化カリウム(39g)の水溶液(350ml)を加え、100℃で16時間攪拌した。室温まで冷却後有機溶媒を留去し、水を加えた後クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、固体を得た。得られた固体をヘキサン/酢酸エチル=19:1の混合溶媒で洗浄し、(S)-(3-メトキシフェニル)((2S)-ピペリジン-2-イル)メタノール(19g)を無色固体として得た。
MS (ESI pos.) m/z : 222([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.20 - 1.32 (m, 2 H), 1.34 - 1.44 (m, 2 H), 1.54 - 1.61 (m, 1 H), 1.73 - 1.79 (m, 1 H), 2.56 - 2.63 (m, 1 H), 2.63 - 2.68 (m, 1 H), 3.06 - 3.11 (m, 1 H), 3.82 (s, 3 H), 4.37 (d, J=6.9 Hz, 1 H), 6.79 - 6.85 (m, 1 H), 6.88 - 6.94 (m, 2 H), 7.23 - 7.28 (m, 1 H)
(2)窒素雰囲気下(S)-(3-メトキシフェニル)((2S)-ピペリジン-2-イル)メタノール(17g)のDMF溶液(200ml)に炭酸カリウム(16g)及びアリルブロミド(7.3ml)を加え、50℃で2時間攪拌した。反応混合物を氷冷後、水及び酢酸エチルを加え、分液後、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮した。残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=19:1)で精製し、(S)-((2S)-1-アリルピペリジン-2-イル)(3-メトキシフェニル)メタノール(17g)を無色油状物質として得た。
MS (ESI pos.) m/z : 262([M+H]+)
1H NMR (200 MHz, CDCl3) δ ppm 1.12 - 1.77 (m, 6 H), 2.56 - 2.81 (m, 2 H), 2.93 - 3.11 (m, 1 H), 3.27 - 3.51 (m, 2 H), 3.81 (s, 3 H), 4.72 (d, J=9.7 Hz, 1 H), 5.11 - 5.26 (m, 2 H), 5.76 - 5.99 (m, 1 H), 6.76 - 6.85 (m, 1 H), 6.89 - 6.97 (m, 2 H), 7.18 - 7.28 (m, 1 H)
(3)窒素雰囲気下(S)-((2S)-1-アリルピペリジン-2-イル)(3-メトキシフェニル)メタノール(17g)及びトリエチルアミン(15ml)のクロロホルム溶液(160ml)を氷冷後、メタンスルホニルクロリド(6.9ml)を滴下した。氷冷下で1.5時間さらに室温で30分間攪拌後、反応液を減圧下濃縮し、8Mアンモニア/メタノール溶液(150ml)を加え40℃で1時間攪拌した。反応液を減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール/28%アンモニア水=50:1:0.5)で精製し、表題化合物(13g)を黄色油状物質として得た。
MS (ESI pos.) m/z : 261([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.01 - 1.07 (m, 1 H), 1.29 - 1.54 (m, 4 H), 1.59 - 1.69 (m, 1 H), 2.62 - 2.71 (m, 2 H), 3.01 - 3.08 (m, 1 H), 3.32 - 3.42 (m, 2 H), 3.81 (s, 3 H), 4.17 (d, J=9.6 Hz, 1 H), 5.10 - 5.15 (m, 1 H), 5.18 - 5.24 (m, 1 H), 5.84 - 5.93 (m, 1 H), 6.76 - 6.80 (m, 1 H), 6.91 - 6.96 (m, 2 H), 7.19 - 7.25 (m, 1 H)
同様にして下記化合物を得た。
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-(ベンジルオキシ)フェニル)メタンアミン
MS (ESI pos.) m/z : 337([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 0.98 - 1.07 (m, 1 H), 1.29 - 1.45 (m, 3 H), 1.45 - 1.54 (m, 1 H), 1.58 - 1.68 (m, 1 H), 2.62 - 2.73 (m, 2 H), 3.00 - 3.09 (m, 1 H), 3.32 - 3.45 (m, 2 H), 4.15 (d, J=9.6 Hz, 1 H), 5.07 (s, 2 H), 5.11 - 5.16 (m, 1 H), 5.19 - 5.24 (m, 1 H), 5.85 - 5.93 (m, 1 H), 6.85 - 6.88 (m, 1 H), 6.95 (d, J=7.8 Hz, 1 H), 7.00 - 7.04 (m, 1 H), 7.20 - 7.25 (m, 1 H), 7.29 - 7.35 (m, 1 H), 7.35 - 7.41 (m, 2 H), 7.41 - 7.46 (m, 2 H)
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-ビフェニル-3-イルメタンアミン
MS (ESI pos.) m/z : 307([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.02 - 1.12 (m, 1 H), 1.29 - 1.46 (m, 3 H), 1.46 - 1.56 (m, 1 H), 1.60 - 1.74 (m, 1 H), 2.66 - 2.75 (m, 2 H), 3.02 - 3.10 (m, 1 H), 3.33 - 3.45 (m, 2 H), 4.27 (d, J=9.6 Hz, 1 H), 5.09 - 5.27 (m, 2 H), 5.86 - 5.95 (m, 1 H), 7.28 - 7.52 (m, 6 H), 7.54 - 7.66 (m, 3 H)
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-ビフェニル-4-イルメタンアミン
MS (ESI pos.) m/z : 307([M+H]+)
(1) A solution of potassium hydroxide (39 g) in a methanol solution (400 ml) of tert-butyl (2S) -2-((S) -hydroxy (3-methoxyphenyl) methyl) piperidine-1-carboxylate (22 g) (350 ml) was added and stirred at 100 ° C. for 16 hours. After cooling to room temperature, the organic solvent was distilled off, water was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure to obtain a solid. The obtained solid was washed with a mixed solvent of hexane / ethyl acetate = 19: 1 to obtain (S)-(3-methoxyphenyl) ((2S) -piperidin-2-yl) methanol (19 g) as a colorless solid. It was.
MS (ESI pos.) M / z: 222 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.20-1.32 (m, 2 H), 1.34-1.44 (m, 2 H), 1.54-1.61 (m, 1 H), 1.73-1.79 (m, 1 H), 2.56-2.63 (m, 1 H), 2.63-2.68 (m, 1 H), 3.06-3.11 (m, 1 H), 3.82 (s, 3 H), 4.37 (d, J = 6.9 Hz, 1 H) , 6.79-6.85 (m, 1 H), 6.88-6.94 (m, 2 H), 7.23-7.28 (m, 1 H)
(2) Potassium carbonate (16 g) and allyl bromide (7.3 ml) in a DMF solution (200 ml) of (S)-(3-methoxyphenyl) ((2S) -piperidin-2-yl) methanol (17 g) in a nitrogen atmosphere ) And stirred at 50 ° C. for 2 hours. The reaction mixture was ice-cooled, water and ethyl acetate were added, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane / ethyl acetate = 19: 1), and (S)-((2S) -1-allylpiperidin-2-yl) (3-methoxyphenyl) methanol (17 g) Was obtained as a colorless oil.
MS (ESI pos.) M / z: 262 ([M + H] +)
1H NMR (200 MHz, CDCl3) δ ppm 1.12-1.77 (m, 6 H), 2.56-2.81 (m, 2 H), 2.93-3.11 (m, 1 H), 3.27-3.51 (m, 2 H), 3.81 (s, 3 H), 4.72 (d, J = 9.7 Hz, 1 H), 5.11-5.26 (m, 2 H), 5.76-5.99 (m, 1 H), 6.76-6.85 (m, 1 H) , 6.89-6.97 (m, 2 H), 7.18-7.28 (m, 1 H)
(3) A nitrogen solution of (S)-((2S) -1-allylpiperidin-2-yl) (3-methoxyphenyl) methanol (17 g) and triethylamine (15 ml) in chloroform (160 ml) was ice-cooled, Methanesulfonyl chloride (6.9 ml) was added dropwise. After stirring for 1.5 hours under ice-cooling and further for 30 minutes at room temperature, the reaction mixture was concentrated under reduced pressure, 8M ammonia / methanol solution (150 ml) was added, and the mixture was stirred at 40 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform / methanol / 28% aqueous ammonia = 50: 1: 0.5) to give the title compound (13 g) as a yellow oil.
MS (ESI pos.) M / z: 261 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.01-1.07 (m, 1 H), 1.29-1.54 (m, 4 H), 1.59-1.69 (m, 1 H), 2.62-2.71 (m, 2 H), 3.01-3.08 (m, 1 H), 3.32-3.42 (m, 2 H), 3.81 (s, 3 H), 4.17 (d, J = 9.6 Hz, 1 H), 5.10-5.15 (m, 1 H) , 5.18-5.24 (m, 1 H), 5.84-5.93 (m, 1 H), 6.76-6.80 (m, 1 H), 6.91-6.96 (m, 2 H), 7.19-7.25 (m, 1 H)
In the same manner, the following compound was obtained.
(S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3- (benzyloxy) phenyl) methanamine
MS (ESI pos.) M / z: 337 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 0.98-1.07 (m, 1 H), 1.29-1.45 (m, 3 H), 1.45-1.54 (m, 1 H), 1.58-1.68 (m, 1 H), 2.62-2.73 (m, 2 H), 3.00-3.09 (m, 1 H), 3.32-3.45 (m, 2 H), 4.15 (d, J = 9.6 Hz, 1 H), 5.07 (s, 2 H) , 5.11-5.16 (m, 1 H), 5.19-5.24 (m, 1 H), 5.85-5.93 (m, 1 H), 6.85-6.88 (m, 1 H), 6.95 (d, J = 7.8 Hz, 1 H), 7.00-7.04 (m, 1 H), 7.20-7.25 (m, 1 H), 7.29-7.35 (m, 1 H), 7.35-7.41 (m, 2 H), 7.41-7.46 (m, 2 H)
(S) -1-((2S) -1-allylpiperidin-2-yl) -1-biphenyl-3-ylmethanamine
MS (ESI pos.) M / z: 307 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.02-1.12 (m, 1 H), 1.29-1.46 (m, 3 H), 1.46-1.56 (m, 1 H), 1.60-1.74 (m, 1 H), 2.66-2.75 (m, 2 H), 3.02-3.10 (m, 1 H), 3.33-3.45 (m, 2 H), 4.27 (d, J = 9.6 Hz, 1 H), 5.09-5.27 (m, 2 H), 5.86-5.95 (m, 1 H), 7.28-7.52 (m, 6 H), 7.54-7.66 (m, 3 H)
(S) -1-((2S) -1-allylpiperidin-2-yl) -1-biphenyl-4-ylmethanamine
MS (ESI pos.) M / z: 307 ([M + H] +)
製造例4 3-((S)-((2S)-1-アリルピペリジン-2-イル)((2-クロロ-3-(トリフルオロメチル)ベンゾイル)アミノ)メチル)フェニル トリフルオロメタンスルホナートの合成 Production Example 4 Synthesis of 3-((S)-((2S) -1-allylpiperidin-2-yl) ((2-chloro-3- (trifluoromethyl) benzoyl) amino) methyl) phenyl trifluoromethanesulfonate
(1)2−クロロ−3−トリフルオロメチル安息香酸(2.6g)のDMF溶液(15ml)にHOBt・H2O(2.2g)及びEDC・HCl(2.5g)を加え、室温で30分間攪拌後、(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-メトキシフェニル)メタンアミン(3.0g)のDMF溶液(15ml)を加え、室温で3時間攪拌した。酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加え、分液後、水層を酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=50:1)で精製し、N-((S)-((2S)-1-アリルピペリジン-2-イル)(3-メトキシフェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド(3.4g)を無色固体として得た。
MS (ESI pos.) m/z : 467([M+H]+), (ESI neg.) m/z : 465([M-H]-)
1H NMR (200 MHz, CDCl3) δ ppm 1.25 - 1.88 (m, 6 H), 2.45 - 2.64 (m, 1 H), 2.75 - 3.03 (m, 2 H), 3.10 - 3.38 (m, 2 H), 3.81 (s, 3 H), 4.88 - 4.98 (m, 1 H), 5.02 - 5.17 (m, 2 H), 5.61 - 5.83 (m, 1 H), 6.75 - 6.84 (m, 1 H), 6.90 - 7.01 (m, 2 H), 7.19 - 7.32 (m, 1 H), 7.36 - 7.48 (m, 1 H), 7.64 - 7.81 (m, 3 H)
(2)窒素雰囲気下N-((S)-((2S)-1-アリルピペリジン-2-イル)(3-メトキシフェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド(3.3g)のクロロホルム溶液(30ml)を氷冷後、BBr3(2.0ml)を加え、氷冷下1.5時間攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮した。残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=100:0〜88:12)で精製し、化合物N-((S)-((2S)-1-アリルピペリジン-2-イル)(3-ヒドロキシフェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド(3.2g)を無色アモルファスとして得た。
MS (ESI pos.) m/z : 453([M+H]+), (ESI neg.) m/z : 451([M-H]-)
1H NMR (300 MHz, CDCl3) δ ppm 1.28 - 1.63 (m, 5 H), 1.70 - 1.86 (m, 1 H), 2.51 - 2.65 (m, 1 H), 2.74 - 3.03 (m, 2 H), 3.16 - 3.37 (m, 2 H), 4.90 (d, J=9.2 Hz, 1 H), 5.04 - 5.20 (m, 2 H), 5.62 - 5.82 (m, 1 H), 6.59 - 6.67 (m, 1 H), 6.78 - 6.93 (m, 2 H), 7.10 - 7.20 (m, 1 H), 7.37 - 7.45 (m, 1 H), 7.65 - 7.93 (m, 3 H)
(3)窒素雰囲気下N-((S)-((2S)-1-アリルピペリジン-2-イル)(3-ヒドロキシフェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド(3.0g)のクロロホルム溶液(20ml)にピリジン(2.6ml)を加え、氷冷後、トリフルオロメタンスルホン酸無水物(1.3ml)を2分間かけて滴下した。氷冷下30分さらに室温にて1.5時間攪拌後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した後、有機層を水及び食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=100:0〜97:3)で精製し、表題化合物(3.4g)を赤褐色油状物質として得た。
MS (ESI pos.) m/z : 585([M+H]+), (ESI neg.) m/z : 583([M-H]-)
1H NMR (200 MHz, CDCl3) δ ppm 1.22 - 1.91 (m, 6 H), 2.49 - 2.70 (m, 1 H), 2.71 - 3.03 (m, 2 H), 3.12 - 3.38 (m, 2 H), 4.92 - 5.03 (m, 1 H), 5.05 - 5.20 (m, 2 H), 5.61 - 5.84 (m, 1 H), 7.12 - 7.34 (m, 2 H), 7.37 - 7.50 (m, 3 H), 7.65 - 7.85 (m, 3 H)
同様にして以下の化合物を合成した。
3-((S)-((2S)-1-アリルピロリジン-2-イル)((2-クロロ-3-(トリフルオロメチル)ベンゾイル)アミノ)メチル)フェニル トリフルオロメタンスルホナート
MS (ESI pos.) m/z : 571([M+H]+)
1H NMR (600 MHz, CDCl3) δ (ppm) ; 1.64 - 1.78 (m, 2 H), 1.80 - 1.90 (m, 1 H), 2.15 - 2.24 (m, 1 H), 2.32 - 2.39 (m, 1 H), 2.55 (dd, J=14.0, 7.6 Hz, 1 H), 2.70 (dd, J=13.8, 5.0 Hz, 1 H), 3.02 - 3.08 (m, 1 H), 3.14 - 3.19 (m, 1 H), 4.84 (d, J=16.0 Hz, 1 H), 4.95 (d, J=10.1 Hz, 1 H), 5.19 (d, J=7.3 Hz, 1 H), 5.56 - 5.66 (m, 1 H), 7.15 - 7.19 (m, 1 H), 7.30 (s, 1 H), 7.37 - 7.41 (m, 1 H), 7.41 - 7.51 (m, 3 H), 7.75 (d, J=7.8 Hz, 1 H), 7.79 - 7.83 (m, 1 H)
3-((S)-((2S)-1-アリルピペリジン-2-イル)((2,6-ジクロロ-3-(トリフルオロメチル)ベンゾイル)アミノ)メチル)フェニル トリフルオロメタンスルホナート
(ESI pos.) m/z : 619([M+H]+), (ESI neg.) m/z : 617([M-H]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.29 - 1.86 (m, 6 H), 2.55 - 2.63 (m, 1 H), 2.74 - 2.81 (m, 1 H), 2.92 - 2.99 (m, 1 H), 3.20 - 3.31 (m, 2 H), 4.94 - 5.02 (m, 1 H), 5.05 - 5.15 (m, 2 H), 5.65 - 5.75 (m, 1 H), 7.17 - 7.69 (m, 7 H)
3-((S)-((2S)-1-アリルピペリジン-2-イル)((2,3-ジクロロベンゾイル)アミノ)メチル)フェニル トリフルオロメタンスルホナート
(ESI pos.) m/z : 551([M+H]+), (ESI neg.) m/z : 549([M-H]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.27 - 1.42 (m, 2 H), 1.49 - 1.64 (m, 3 H), 1.74 - 1.85 (m, 1 H), 2.53 - 2.60 (m, 1 H), 2.75 - 2.82 (m, 1 H), 2.89 - 2.95 (m, 1 H), 3.17 (dd, J=13.8, 6.0 Hz, 1 H), 3.28 (dd, J=14.0, 6.6 Hz, 1 H), 4.96 (dd, J=8.9, 3.4 Hz, 1 H), 5.06 - 5.15 (m, 2 H), 5.67 - 5.78 (m, 1 H), 7.14 - 7.20 (m, 1 H), 7.27 - 7.31 (m, 2 H), 7.39 - 7.48 (m, 3 H), 7.55 (dd, J=8.0, 1.6 Hz, 1 H), 7.82 (br. s., 1 H)
3-((S)-((2S)-1-アリルピペリジン-2-イル)((3-クロロ-2-メチルベンゾイル)アミノ)メチル)フェニル トリフルオロメタンスルホナート
MS (ESI pos.) m/z : 531([M+H]+), (ESI neg.) m/z : 529([M-H]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.23 - 1.33 (m, 1 H), 1.36 - 1.45 (m, 1 H), 1.48 - 1.60 (m, 3 H), 1.74 - 1.84 (m, 1 H), 2.41 (s, 3 H), 2.55 - 2.64 (m, 1 H), 2.73 - 2.82 (m, 1 H), 2.87 - 2.96 (m, 1 H), 3.14 - 3.22 (m, 1 H), 3.27 (dd, J=13.8, 6.4 Hz, 1 H), 4.95 (dd, J=8.9, 3.4 Hz, 1 H), 5.04 - 5.19 (m, 2 H), 5.65 - 5.75 (m, 1 H), 7.15 - 7.21 (m, 2 H), 7.21 - 7.31 (m, 2 H), 7.33 - 7.50 (m, 4 H)
(1) To a DMF solution (15 ml) of 2-chloro-3-trifluoromethylbenzoic acid (2.6 g), HOBt · H 2 O (2.2 g) and EDC · HCl (2.5 g) were added, and at room temperature. After stirring for 30 minutes, a DMF solution (15 ml) of (S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3-methoxyphenyl) methanamine (3.0 g) was added, and room temperature was added. For 3 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and after liquid separation, the aqueous layer was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 50: 1), and N-((S)-( (2S) -1-allylpiperidin-2-yl) (3-methoxyphenyl) methyl) -2-chloro-3- (trifluoromethyl) benzamide (3.4 g) was obtained as a colorless solid.
MS (ESI pos.) M / z: 467 ([M + H] +), (ESI neg.) M / z: 465 ([MH]-)
1H NMR (200 MHz, CDCl3) δ ppm 1.25-1.88 (m, 6 H), 2.45-2.64 (m, 1 H), 2.75-3.03 (m, 2 H), 3.10-3.38 (m, 2 H), 3.81 (s, 3 H), 4.88-4.98 (m, 1 H), 5.02-5.17 (m, 2 H), 5.61-5.83 (m, 1 H), 6.75-6.84 (m, 1 H), 6.90- 7.01 (m, 2 H), 7.19-7.32 (m, 1 H), 7.36-7.48 (m, 1 H), 7.64-7.81 (m, 3 H)
(2) N-((S)-((2S) -1-allylpiperidin-2-yl) (3-methoxyphenyl) methyl) -2-chloro-3- (trifluoromethyl) benzamide (3) under nitrogen atmosphere .3 g) in chloroform (30 ml) was cooled with ice, BBr 3 (2.0 ml) was added, and the mixture was stirred under ice cooling for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 100: 0 to 88:12), and compound N-((S)-((2S) -1-allylpiperidin-2-yl) (3-hydroxy Phenyl) methyl) -2-chloro-3- (trifluoromethyl) benzamide (3.2 g) was obtained as a colorless amorphous.
MS (ESI pos.) M / z: 453 ([M + H] +), (ESI neg.) M / z: 451 ([MH]-)
1H NMR (300 MHz, CDCl3) δ ppm 1.28-1.63 (m, 5 H), 1.70-1.86 (m, 1 H), 2.51-2.65 (m, 1 H), 2.74-3.03 (m, 2 H), 3.16-3.37 (m, 2 H), 4.90 (d, J = 9.2 Hz, 1 H), 5.04-5.20 (m, 2 H), 5.62-5.82 (m, 1 H), 6.59-6.67 (m, 1 H), 6.78-6.93 (m, 2 H), 7.10-7.20 (m, 1 H), 7.37-7.45 (m, 1 H), 7.65-7.93 (m, 3 H)
(3) N-((S)-((2S) -1-allylpiperidin-2-yl) (3-hydroxyphenyl) methyl) -2-chloro-3- (trifluoromethyl) benzamide (3 0.0 g) in chloroform (20 ml) was added pyridine (2.6 ml), and after ice cooling, trifluoromethanesulfonic anhydride (1.3 ml) was added dropwise over 2 minutes. The mixture was stirred for 30 minutes under ice-cooling and further at room temperature for 1.5 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 100: 0 to 97: 3) to give the title compound (3 0.4 g) was obtained as a reddish brown oil.
MS (ESI pos.) M / z: 585 ([M + H] +), (ESI neg.) M / z: 583 ([MH]-)
1H NMR (200 MHz, CDCl3) δ ppm 1.22-1.91 (m, 6 H), 2.49-2.70 (m, 1 H), 2.71-3.03 (m, 2 H), 3.12-3.38 (m, 2 H), 4.92-5.03 (m, 1 H), 5.05-5.20 (m, 2 H), 5.61-5.84 (m, 1 H), 7.12-7.34 (m, 2 H), 7.37-7.50 (m, 3 H), 7.65-7.85 (m, 3 H)
The following compounds were synthesized in the same manner.
3-((S)-((2S) -1-allylpyrrolidin-2-yl) ((2-chloro-3- (trifluoromethyl) benzoyl) amino) methyl) phenyl trifluoromethanesulfonate
MS (ESI pos.) M / z: 571 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ (ppm); 1.64-1.78 (m, 2 H), 1.80-1.90 (m, 1 H), 2.15-2.24 (m, 1 H), 2.32-2.39 (m, 1 H), 2.55 (dd, J = 14.0, 7.6 Hz, 1 H), 2.70 (dd, J = 13.8, 5.0 Hz, 1 H), 3.02-3.08 (m, 1 H), 3.14-3.19 (m, 1 H), 4.84 (d, J = 16.0 Hz, 1 H), 4.95 (d, J = 10.1 Hz, 1 H), 5.19 (d, J = 7.3 Hz, 1 H), 5.56-5.66 (m, 1 H ), 7.15-7.19 (m, 1 H), 7.30 (s, 1 H), 7.37-7.41 (m, 1 H), 7.41-7.51 (m, 3 H), 7.75 (d, J = 7.8 Hz, 1 H), 7.79-7.83 (m, 1 H)
3-((S)-((2S) -1-allylpiperidin-2-yl) ((2,6-dichloro-3- (trifluoromethyl) benzoyl) amino) methyl) phenyl trifluoromethanesulfonate
(ESI pos.) M / z: 619 ([M + H] +), (ESI neg.) M / z: 617 ([MH]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.29-1.86 (m, 6 H), 2.55-2.63 (m, 1 H), 2.74-2.81 (m, 1 H), 2.92-2.99 (m, 1 H), 3.20-3.31 (m, 2 H), 4.94-5.02 (m, 1 H), 5.05-5.15 (m, 2 H), 5.65-5.75 (m, 1 H), 7.17-7.69 (m, 7 H)
3-((S)-((2S) -1-allylpiperidin-2-yl) ((2,3-dichlorobenzoyl) amino) methyl) phenyl trifluoromethanesulfonate
(ESI pos.) M / z: 551 ([M + H] +), (ESI neg.) M / z: 549 ([MH]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.27-1.42 (m, 2 H), 1.49-1.64 (m, 3 H), 1.74-1.85 (m, 1 H), 2.53-2.60 (m, 1 H), 2.75-2.82 (m, 1 H), 2.89-2.95 (m, 1 H), 3.17 (dd, J = 13.8, 6.0 Hz, 1 H), 3.28 (dd, J = 14.0, 6.6 Hz, 1 H), 4.96 (dd, J = 8.9, 3.4 Hz, 1 H), 5.06-5.15 (m, 2 H), 5.67-5.78 (m, 1 H), 7.14-7.20 (m, 1 H), 7.27-7.31 (m , 2 H), 7.39-7.48 (m, 3 H), 7.55 (dd, J = 8.0, 1.6 Hz, 1 H), 7.82 (br. S., 1 H)
3-((S)-((2S) -1-allylpiperidin-2-yl) ((3-chloro-2-methylbenzoyl) amino) methyl) phenyl trifluoromethanesulfonate
MS (ESI pos.) M / z: 531 ([M + H] +), (ESI neg.) M / z: 529 ([MH]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.23-1.33 (m, 1 H), 1.36-1.45 (m, 1 H), 1.48-1.60 (m, 3 H), 1.74-1.84 (m, 1 H), 2.41 (s, 3 H), 2.55-2.64 (m, 1 H), 2.73-2.82 (m, 1 H), 2.87-2.96 (m, 1 H), 3.14-3.22 (m, 1 H), 3.27 ( dd, J = 13.8, 6.4 Hz, 1 H), 4.95 (dd, J = 8.9, 3.4 Hz, 1 H), 5.04-5.19 (m, 2 H), 5.65-5.75 (m, 1 H), 7.15- 7.21 (m, 2 H), 7.21-7.31 (m, 2 H), 7.33-7.50 (m, 4 H)
製造例5 3-((S)-((2-クロロ-3-(トリフルオロメチル)ベンゾイル)アミノ)((2S)-1-メチルピペリジン-2-イル)メチル)フェニル トリフルオロメタンスルホナートの合成 Production Example 5 Synthesis of 3-((S)-((2-chloro-3- (trifluoromethyl) benzoyl) amino) ((2S) -1-methylpiperidin-2-yl) methyl) phenyl trifluoromethanesulfonate
(1)窒素雰囲気下、tert-ブチル(2S)-2-((S)-(3-(ベンジルオキシ)フェニル)(ヒドロキシ)メチル)ピペリジン-1-カルボキシラート(8.7g)のテトラヒドロフラン溶液(120ml)を氷冷し、水素化アルミニウムリチウム(4.2g)を少しずつ加えた。80℃で1時間加熱攪拌した。反応混合物を氷冷後、飽和酒石酸カリウムナトリウム水溶液及び10%水酸化ナトリウム水溶液を加え、室温で30分間攪拌した。無水硫酸マグネシウムを固く敷き詰めた漏斗を用いて不溶物を濾別した後、濾液を減圧下濃縮後、(S)-(3-(ベンジルオキシ)フェニル)((2S)-1-メチルピペリジン-2-イル)メタノール(6.8g)を無色油状物質として得た。
MS (ESI pos.) m/z : 312([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.24 - 1.29 (m, 1 H), 1.37 - 1.49 (m, 3 H), 1.53 - 1.60 (m, 1 H), 1.63 - 1.72 (m, 1 H), 2.47 - 2.53 (m, 4 H), 2.61 - 2.67 (m, 1 H), 2.99 - 3.05 (m, 1 H), 4.60 (d, J=9.2 Hz, 1 H), 5.07 (s, 2 H), 6.87 - 6.89 (m, 1 H), 6.94 - 6.98 (m, 1 H), 7.02 - 7.04 (m, 1 H), 7.24 (t, J=8.0 Hz, 1 H), 7.30 - 7.34 (m, 1 H), 7.36 - 7.40 (m, 2 H), 7.42 - 7.45 (m, 2 H)
(2)(S)-(3-(ベンジルオキシ)フェニル)((2S)-1-メチルピペリジン-2-イル)メタノール(6.8g)及びトリエチルアミン(4.2ml)のクロロホルム溶液(50ml)を氷冷後、メタンスルホニルクロリド(1.9ml)を滴下した。氷冷下で30分間攪拌後、反応液を減圧下濃縮した。残渣を8Mアンモニア/メタノール溶液(40ml)に溶解させ、室温で4日間攪拌した。反応液を減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール/28%アンモニア水=50:1:0.5〜30:1:0.3)で精製し、(S)-1-(3-(ベンジルオキシ)フェニル)-1-((2S)-1-メチルピペリジン-2-イル)メタンアミン(4.8g)を黄色油状物質として得た。
MS (ESI pos.) m/z : 311([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.10 - 1.19 (m, 1 H), 1.22 - 1.35 (m, 2 H), 1.37 - 1.52 (m, 2 H), 1.61 - 1.69 (m, 1 H), 2.44 (s, 3 H), 2.49 - 2.54 (m, 1 H), 2.59 - 2.66 (m, 1 H), 2.97 - 3.02 (m, 1 H), 3.99 (d, J=8.3 Hz, 1 H), 5.07 (s, 2 H), 6.86 (dd, J=8.0, 2.5 Hz, 1 H), 6.94 - 6.97 (m, 1 H), 7.02 - 7.04 (m, 1 H), 7.23 (t, J=7.8 Hz, 1 H), 7.30 - 7.34 (m, 1 H), 7.36 - 7.40 (m, 2 H), 7.42 - 7.46 (m, 2 H)
(3)製造例4(1)と同様の方法にて(S)-1-(3-(ベンジルオキシ)フェニル)-1-((2S)-1-メチルピペリジン-2-イル)メタンアミン(4.0g)及び2−クロロ−3−トリフルオロ安息香酸(2.9g)からN-((S)-(3-(ベンジルオキシ)フェニル)((2S)-1-メチルピペリジン-2-イル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド(4.7g)を無色固体として得た。
MS (ESI pos.) m/z : 517([M+H]+), (ESI neg.) m/z : 515([M-H]-)
(4)窒素雰囲気下N-((S)-(3-(ベンジルオキシ)フェニル)((2S)-1-メチルピペリジン-2-イル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド(4.6g)のクロロホルム溶液(20ml)を−50〜−40℃に冷却し、BBr3(2.0ml)のクロロホルム溶液(20ml)を5分間かけて加えた後、−40℃で15分間静置した。飽和炭酸水素ナトリウム水溶液を滴下した後、室温で10分間攪拌し、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮した。残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=9:1)で精製し、2-クロロ-N-((S)-(3-ヒドロキシフェニル)((2S)-1-メチルピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド(3.8g)を無色固体として得た。
MS (ESI pos.) m/z : 427([M+H]+), (ESI neg.) m/z : 425([M-H]-)
(5)製造例4(3)と同様の方法にて2-クロロ-N-((S)-(3-ヒドロキシフェニル)((2S)-1-メチルピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド(1.0g)から表題化合物(0.86g)を茶色アモルファスとして得た。
MS (ESI pos.) m/z : 559([M+H]+), (ESI neg.) m/z : 557([M-H]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.34 - 1.43 (m, 1 H), 1.44 - 1.57 (m, 3 H), 1.57 - 1.66 (m, 1 H), 1.75 - 1.84 (m, 1 H), 2.15 (br. s., 3 H), 2.37 - 2.46 (m, 1 H), 2.61 - 2.69 (m, 1 H), 2.82 - 2.91 (m, 1 H), 4.92 - 4.96 (m, 1 H), 7.15 - 7.20 (m, 1 H), 7.30 - 7.34 (m, 1 H), 7.41 - 7.50 (m, 3 H), 7.59 - 7.75 (m, 2 H), 7.78 - 7.82 (m, 1 H)
(1) A tetrahydrofuran solution of tert-butyl (2S) -2-((S)-(3- (benzyloxy) phenyl) (hydroxy) methyl) piperidine-1-carboxylate (8.7 g) under a nitrogen atmosphere ( 120 ml) was ice-cooled, and lithium aluminum hydride (4.2 g) was added little by little. The mixture was heated and stirred at 80 ° C. for 1 hour. The reaction mixture was ice-cooled, saturated aqueous potassium sodium tartrate solution and 10% aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off using a funnel filled with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, and then (S)-(3- (benzyloxy) phenyl) ((2S) -1-methylpiperidine-2 -Yl) methanol (6.8 g) was obtained as a colorless oil.
MS (ESI pos.) M / z: 312 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.24-1.29 (m, 1 H), 1.37-1.49 (m, 3 H), 1.53-1.60 (m, 1 H), 1.63-1.72 (m, 1 H), 2.47-2.53 (m, 4 H), 2.61-2.67 (m, 1 H), 2.99-3.05 (m, 1 H), 4.60 (d, J = 9.2 Hz, 1 H), 5.07 (s, 2 H) , 6.87-6.89 (m, 1 H), 6.94-6.98 (m, 1 H), 7.02-7.04 (m, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.36-7.40 (m, 2 H), 7.42-7.45 (m, 2 H)
(2) A chloroform solution (50 ml) of (S)-(3- (benzyloxy) phenyl) ((2S) -1-methylpiperidin-2-yl) methanol (6.8 g) and triethylamine (4.2 ml). After ice cooling, methanesulfonyl chloride (1.9 ml) was added dropwise. After stirring for 30 minutes under ice cooling, the reaction solution was concentrated under reduced pressure. The residue was dissolved in 8M ammonia / methanol solution (40 ml) and stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform / methanol / 28% aqueous ammonia = 50: 1: 0.5 to 30: 1: 0.3), and (S) -1 -(3- (Benzyloxy) phenyl) -1-((2S) -1-methylpiperidin-2-yl) methanamine (4.8 g) was obtained as a yellow oil.
MS (ESI pos.) M / z: 311 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.10-1.19 (m, 1 H), 1.22-1.35 (m, 2 H), 1.37-1.52 (m, 2 H), 1.61-1.69 (m, 1 H), 2.44 (s, 3 H), 2.49-2.54 (m, 1 H), 2.59-2.66 (m, 1 H), 2.97-3.02 (m, 1 H), 3.99 (d, J = 8.3 Hz, 1 H) , 5.07 (s, 2 H), 6.86 (dd, J = 8.0, 2.5 Hz, 1 H), 6.94-6.97 (m, 1 H), 7.02-7.04 (m, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.36-7.40 (m, 2 H), 7.42-7.46 (m, 2 H)
(3) (S) -1- (3- (Benzyloxy) phenyl) -1-((2S) -1-methylpiperidin-2-yl) methanamine (4) in the same manner as in Production Example 4 (1) 0.0 g) and 2-chloro-3-trifluorobenzoic acid (2.9 g) to N-((S)-(3- (benzyloxy) phenyl) ((2S) -1-methylpiperidin-2-yl) Methyl) -2-chloro-3- (trifluoromethyl) benzamide (4.7 g) was obtained as a colorless solid.
MS (ESI pos.) M / z: 517 ([M + H] +), (ESI neg.) M / z: 515 ([MH]-)
(4) N-((S)-(3- (benzyloxy) phenyl) ((2S) -1-methylpiperidin-2-yl) methyl) -2-chloro-3- (trifluoromethyl) under nitrogen atmosphere A chloroform solution (20 ml) of benzamide (4.6 g) was cooled to −50 to −40 ° C., a chloroform solution (20 ml) of BBr 3 (2.0 ml) was added over 5 minutes, and then 15 ° C. at −40 ° C. Let stand for a minute. Saturated aqueous sodium hydrogen carbonate solution was added dropwise, and the mixture was stirred at room temperature for 10 min and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 9: 1) and 2-chloro-N-((S)-(3-hydroxyphenyl) ((2S) -1-methylpiperidin-2-yl ) Methyl) -3- (trifluoromethyl) benzamide (3.8 g) was obtained as a colorless solid.
MS (ESI pos.) M / z: 427 ([M + H] +), (ESI neg.) M / z: 425 ([MH]-)
(5) 2-Chloro-N-((S)-(3-hydroxyphenyl) ((2S) -1-methylpiperidin-2-yl) methyl) -3 in the same manner as in Production Example 4 (3) The title compound (0.86 g) was obtained as a brown amorphous form from-(trifluoromethyl) benzamide (1.0 g).
MS (ESI pos.) M / z: 559 ([M + H] +), (ESI neg.) M / z: 557 ([MH]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.34-1.43 (m, 1 H), 1.44-1.57 (m, 3 H), 1.57-1.66 (m, 1 H), 1.75-1.84 (m, 1 H), 2.15 (br. S., 3 H), 2.37-2.46 (m, 1 H), 2.61-2.69 (m, 1 H), 2.82-2.91 (m, 1 H), 4.92-4.96 (m, 1 H) , 7.15-7.20 (m, 1 H), 7.30-7.34 (m, 1 H), 7.41-7.50 (m, 3 H), 7.59-7.75 (m, 2 H), 7.78-7.82 (m, 1 H)
製造例6 tert-ブチル(2S)-2-(4-(((トリフルオロメチル)スルホニル)オキシ)ベンゾイル)ピペリジン-1-カルボキシラートの合成 Production Example 6 Synthesis of tert-butyl (2S) -2- (4-(((trifluoromethyl) sulfonyl) oxy) benzoyl) piperidine-1-carboxylate
(1)製造例2(1)と同様にして合成したtert-ブチル(2S)-2-(4-(ベンジルオキシ)ベンゾイル)ピペリジン-1-カルボキシラート(9.9g)及びメタノール(120ml)の混合物に5%パラジウム炭素(1.0g)を加え、水素雰囲気下室温で1晩攪拌した。セライト(商標)を使用して触媒を濾別し、濾液を減圧下濃縮した。残渣をヘキサン/酢酸エチル(=2:1)混合溶媒で固化させ、析出した固体を濾取し、tert-ブチル (2S)-2-(4-ヒドロキシベンゾイル)ピペリジン-1-カルボキシラート(4.9g)を得た。
MS (ESI pos.) m/z : 306([M+H]+), (ESI neg.) m/z : 304([M-H]-)
1H NMR (600 MHz, DMSO-d6) δ ppm 1.08 - 2.04 (m, 15 H), 3.10 - 3.21 (m, 1 H), 3.76 - 3.84 (m, 1 H), 5.42 - 5.54 (m, 1 H), 6.82 - 6.86 (m, 2 H), 7.80 - 7.85 (m, 2 H)
(2)製造例4(3)と同様の方法にてtert-ブチル (2S)-2-(4-ヒドロキシベンゾイル)ピペリジン-1-カルボキシラート(4.9g)から表題化合物(6.8g)を淡黄色固体として得た。
MS (ESI pos.) m/z : 438([M+H]+), (ESI pos.) m/z : 460([M+Na]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.30 - 2.16 (m, 15 H), 2.96 - 3.26 (m, 1 H), 3.83 - 4.05 (m, 1 H), 5.35 - 5.65 (m, 1 H), 7.32 - 7.43 (m, 2 H), 7.99 - 8.11 (m, 2 H)
同様にして以下の化合物を合成した。
tert-ブチル(2S)-2-(3-(((トリフルオロメチル)スルホニル)オキシ)ベンゾイル)ピペリジン-1-カルボキシラート
MS (ESI pos.) m/z : 438([M+H]+), (ESI pos.) m/z : 460([M+Na]+)
1H NMR (600 MHz, CDCl3) δ (ppm) ; 1.29 - 2.16 (m, 15 H), 2.96 - 3.25 (m, 1 H), 3.80 - 4.00 (m, 1 H), 5.29 - 5.61 (m, 1 H), 7.40 - 7.62 (m, 2 H), 7.75 - 8.02 (m, 2 H)
(1) Preparation of tert-butyl (2S) -2- (4- (benzyloxy) benzoyl) piperidine-1-carboxylate (9.9 g) and methanol (120 ml) synthesized in the same manner as in Production Example 2 (1) 5% palladium carbon (1.0 g) was added to the mixture, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off using Celite (trademark), and the filtrate was concentrated under reduced pressure. The residue was solidified with a mixed solvent of hexane / ethyl acetate (= 2: 1), the precipitated solid was collected by filtration, and tert-butyl (2S) -2- (4-hydroxybenzoyl) piperidine-1-carboxylate (4. 9 g) was obtained.
MS (ESI pos.) M / z: 306 ([M + H] +), (ESI neg.) M / z: 304 ([MH]-)
1H NMR (600 MHz, DMSO-d6) δ ppm 1.08-2.04 (m, 15 H), 3.10-3.21 (m, 1 H), 3.76-3.84 (m, 1 H), 5.42-5.54 (m, 1 H ), 6.82-6.86 (m, 2 H), 7.80-7.85 (m, 2 H)
(2) In the same manner as in Production Example 4 (3), the title compound (6.8 g) was obtained from tert-butyl (2S) -2- (4-hydroxybenzoyl) piperidine-1-carboxylate (4.9 g). Obtained as a pale yellow solid.
MS (ESI pos.) M / z: 438 ([M + H] +), (ESI pos.) M / z: 460 ([M + Na] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.30-2.16 (m, 15 H), 2.96-3.26 (m, 1 H), 3.83-4.05 (m, 1 H), 5.35-5.65 (m, 1 H), 7.32-7.43 (m, 2 H), 7.99-8.11 (m, 2 H)
The following compounds were synthesized in the same manner.
tert-Butyl (2S) -2- (3-(((trifluoromethyl) sulfonyl) oxy) benzoyl) piperidine-1-carboxylate
MS (ESI pos.) M / z: 438 ([M + H] +), (ESI pos.) M / z: 460 ([M + Na] +)
1H NMR (600 MHz, CDCl3) δ (ppm); 1.29-2.16 (m, 15 H), 2.96-3.25 (m, 1 H), 3.80-4.00 (m, 1 H), 5.29-5.61 (m, 1 H), 7.40-7.62 (m, 2 H), 7.75-8.02 (m, 2 H)
製造例7(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(4-ピリジン-3-イルフェニル)メタンアミンの合成 Production Example 7 Synthesis of (S) -1-((2S) -1-allylpiperidin-2-yl) -1- (4-pyridin-3-ylphenyl) methanamine
(1)製造例2(2)と同様の方法にてtert-ブチル(2S)-2-(4-(((トリフルオロメチル)スルホニル)オキシ)ベンゾイル)ピペリジン-1-カルボキシラート(6.7g)からtert-ブチル(2S)-2-((S)-ヒドロキシ(4-(((トリフルオロメチル)スルホニル)オキシ)フェニル)メチル)ピペリジン-1-カルボキシラート(6.3g)を得た。
MS (ESI pos.) m/z : 440([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.21 - 1.32 (m, 1 H), 1.37 - 1.76 (m, 14 H), 2.85 - 3.17 (m, 1 H), 3.96 - 4.50 (m, 2 H), 4.87 - 5.00 (m, 1 H), 7.26 - 7.37 (m, 2 H), 7.44 - 7.55 (m, 2 H)
(2)tert-ブチル(2S)-2-((S)-ヒドロキシ(4-(((トリフルオロメチル)スルホニル)オキシ)フェニル)メチル)ピペリジン-1-カルボキシラート(6.0g)をDMF(90ml)及びエタノール(45ml)の混合溶媒に溶解させ、炭酸カリウム(2.8g)及び3−ピリジンホウ酸(2.5g)を加えた後、窒素置換後、Pd(PPh3)4(0.47g)を加え、90℃で1.5時間加熱攪拌した。減圧下エタノールを留去した後、酢酸エチル及び水を加え、分液した。水層を酢酸エチルで抽出後、有機層を水及び飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=3:1〜1:2)で精製し、tert-ブチル(2S)-2-((S)-ヒドロキシ(4-ピリジン-3-イルフェニル)メチル)ピペリジン-1-カルボキシラート(4.4g)を淡黄色固体として得た。
MS (ESI pos.) m/z : 369([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.31 - 1.38 (m, 1 H), 1.40 - 1.55 (m, 11 H), 1.56 - 1.84 (m, 3 H), 2.97 - 3.16 (m, 1 H), 3.99 - 4.50 (m, 2 H), 4.89 - 5.01 (m, 1 H), 7.35 - 7.39 (m, 1 H), 7.45 - 7.62 (m, 4 H), 7.85 - 7.90 (m, 1 H), 8.56 - 8.61 (m, 1 H), 8.82 - 8.86 (m, 1 H)
(3)tert-ブチル(2S)-2-((S)-ヒドロキシ(4-ピリジン-3-イルフェニル)メチル)ピペリジン-1-カルボキシラート(4.2g)のメタノール溶液(50ml)に水酸化カリウム(3.2g)の水溶液(40ml)を加え、100℃で2時間攪拌した。反応混合物を減圧下濃縮し、水を加えた後、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=1:1続いて酢酸エチル/メタノール=19:1)で精製し、(S)-(2S)-ピペリジン-2-イル(4-ピリジン-3-イルフェニル)メタノール(1.5g)を無色固体として得た。
MS (ESI pos.) m/z : 269([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.24 - 1.36 (m, 2 H), 1.37 - 1.47 (m, 2 H), 1.57 - 1.64 (m, 1 H), 1.76 - 1.82 (m, 1 H), 2.60 - 2.67 (m, 1 H), 2.68 - 2.73 (m, 1 H), 3.11 - 3.16 (m, 1 H), 4.46 (d, J=6.9 Hz, 1 H), 7.35 - 7.38 (m, 1 H), 7.45 - 7.48 (m, 2 H), 7.56 - 7.59 (m, 2 H), 7.85 - 7.89 (m, 1 H), 8.58 - 8.60 (m, 1 H), 8.83 - 8.85 (m, 1 H)
(4)(S)-(2S)-ピペリジン-2-イル(4-ピリジン-3-イルフェニル)メタノール(1.4g)のDMF溶液(15ml)に炭酸カリウム(1.5g)及びアリルブロミド(0.52ml)を加え、80℃で1.5時間加熱攪拌を行った。水及びクロロホルムを加え、水層をクロロホルムで抽出した後、有機層を水及び飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=4:1〜3:1)で精製し、(S)-((2S)-1-アリルピペリジン-2-イル)(4-ピリジン-3-イルフェニル)メタノール(0.68g)を黄色固体として得た。
MS (ESI pos.) m/z : 309([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.20 - 1.28 (m, 1 H), 1.31 - 1.40 (m, 1 H), 1.51 - 1.67 (m, 3 H), 1.69 - 1.78 (m, 1 H), 2.63 - 2.70 (m, 1 H), 2.74 - 2.80 (m, 1 H), 3.01 - 3.09 (m, 1 H), 3.32 - 3.41 (m, 1 H), 3.42 - 3.49 (m, 1 H), 4.81 (d, J=10.1 Hz, 1 H), 5.16 - 5.25 (m, 2 H), 5.85 - 5.93 (m, 1 H), 7.34 - 7.37 (m, 1 H), 7.47 - 7.49 (m, 2 H), 7.54 - 7.57 (m, 2 H), 7.85 - 7.88 (m, 1 H), 8.58 (dd, J=4.8, 1.6 Hz, 1 H), 8.85 (d, J=2.3 Hz, 1 H)
(5)(S)-((2S)-1-アリルピペリジン-2-イル)(4-ピリジン-3-イルフェニル)メタノール(1.1g)のクロロホルム溶液(15ml)にトリエチルアミン(0.7ml)を加え、氷冷後、メタンスルホニルクロリド(0.31ml)を滴下した。氷冷下で30分間攪拌後、反応液を減圧下濃縮した。残渣を8Mアンモニア/メタノール溶液(8ml)に溶解させ、マイクロウェーヴ反応装置にて120℃で20分間反応を行った。反応液を減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール/28%アンモニア水=19:1:0.2、続いてNHシリカゲル、ヘキサン/酢酸エチル=4:1〜1:1)で精製し、表題化合物(0.92g)を黄色油状物質として得た。
MS (ESI pos.) m/z : 308([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.04 - 1.12 (m, 1 H), 1.23 - 1.56 (m, 4 H), 1.62 - 1.72 (m, 1 H), 2.67 - 2.74 (m, 2 H), 3.03 - 3.11 (m, 1 H), 3.36 - 3.42 (m, 2 H), 4.28 (d, J=10.1 Hz, 1 H), 5.12 - 5.16 (m, 1 H), 5.20 - 5.25 (m, 1 H), 5.87 - 5.95 (m, 1 H), 7.33 - 7.37 (m, 1 H), 7.47 - 7.50 (m, 2 H), 7.52 - 7.56 (m, 2 H), 7.85 - 7.89 (m, 1 H), 8.57 - 8.59 (m, 1 H), 8.85 (d, J=2.3 Hz, 1 H)
同様にして以下の化合物を合成した。
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(4-(1-メチル-1H-ピラゾール-4-イル)フェニル)メタンアミン
MS (ESI pos.) m/z : 311([M+H]+)
1H NMR (600 MHz, CDCl3) δ (ppm) ; 1.11 - 4.00 (m, 14 H), 4.09 (d, J=10.5 Hz, 1 H), 5.22 - 5.35 (m, 2 H), 5.90 - 6.03 (m, 1 H), 7.35 - 7.39 (m, 2 H), 7.39 - 7.46 (m, 2 H), 7.57 - 7.58 (m, 1 H), 7.71 - 7.73 (m, 1 H)
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(4-ピリミジン-5-イルフェニル)メタンアミン
MS (ESI pos.) m/z : 309([M+H]+)
1H NMR (600 MHz, CDCl3) δ (ppm) ; 1.31 - 4.44 (m, 12 H), 5.46 (d, J=11.0 Hz, 2 H), 6.05 - 6.19 (m, 1 H), 7.49 - 7.72 (m, 4 H), 8.89 - 8.92 (m, 2 H), 9.20 (s, 1 H)
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)メタンアミン
MS (ESI pos.) m/z : 311([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.01 - 1.09 (m, 1 H), 1.29 - 1.55 (m, 4 H), 1.60 - 1.89 (m, 1 H), 2.65 - 2.72 (m, 2 H), 3.02 - 3.08 (m, 1 H), 3.33 - 3.43 (m, 2 H), 3.94 (s, 3 H), 4.22 (d, J=10.1 Hz, 1 H), 5.13 (dd, J=10.1, 1.8 Hz, 1 H), 5.19 - 5.24 (m, 1 H), 5.86 - 5.94 (m, 1 H), 7.18 - 7.21 (m, 1 H), 7.30 (t, J=7.8 Hz, 1 H), 7.34 - 7.37 (m, 1 H), 7.46 - 7.50 (m, 1 H), 7.64 (s, 1 H), 7.77 (s, 1 H)
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-ピリジン-3-イルフェニル)メタンアミン
MS (ESI pos.) m/z : 308([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.03 - 1.11 (m, 1 H), 1.31 - 1.57 (m, 4 H), 1.63 - 1.71 (m, 1 H), 2.66 - 2.76 (m, 2 H), 3.03 - 3.11 (m, 1 H), 3.35 - 3.44 (m, 2 H), 4.29 (d, J=10.1 Hz, 1 H), 5.12 - 5.17 (m, 1 H), 5.20 - 5.25 (m, 1 H), 5.86 - 5.95 (m, 1 H), 7.34 - 7.38 (m, 1 H), 7.39 - 7.52 (m, 3 H), 7.58 - 7.61 (m, 1 H), 7.87 - 7.91 (m, 1 H), 8.57 - 8.60 (m, 1 H), 8.85 - 8.86 (m, 1 H)
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-ピリミジン-5-イルフェニル)メタンアミン
MS (ESI pos.) m/z : 309([M+H]+)
1H NMR (600 MHz, CDCl3) δ (ppm) ; 1.15 - 1.78 (m, 6 H), 2.59 - 2.68 (m, 1 H), 2.76 (d, J=14.2 Hz, 1 H), 2.97 - 3.08 (m, 1 H), 3.30 - 3.47 (m, 2 H), 4.83 (d, J=10.1 Hz, 1 H), 5.14 - 5.26 (m, 2 H), 5.81 - 5.95 (m, 1 H), 7.38 - 7.71 (m, 4 H), 8.95 (s, 2 H), 9.20 (s, 1 H)
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-(1-イソプロピル-1H-ピラゾール-4-イル)フェニル)メタンアミン
MS (ESI pos.) m/z : 339([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.02 - 1.09 (m, 1 H), 1.30 - 1.59 (m, 4 H), 1.55 (d, J=6.9 Hz, 6 H), 1.61 - 1.85 (m, 1 H), 2.67 - 2.73 (m, 2 H), 3.03 - 3.09 (m, 1 H), 3.34 - 3.43 (m, 2 H), 4.23 (d, J=9.6 Hz, 1 H), 4.50 - 4.56 (m, 1 H), 5.11 - 5.15 (m, 1 H), 5.19 - 5.25 (m, 1 H), 5.86 - 5.95 (m, 1 H), 7.16 - 7.19 (m, 1 H), 7.29 (t, J=7.6 Hz, 1 H), 7.36 - 7.39 (m, 1 H), 7.50 - 7.52 (m, 1 H), 7.71 (s, 1 H), 7.79 (s, 1 H)
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-(1-プロピル-1H-ピラゾール-4-イル)フェニル)メタンアミン
MS (ESI pos.) m/z : 339([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 0.95 (t, J=7.3 Hz, 3 H), 1.03 - 1.11 (m, 1 H), 1.29 - 1.73 (m, 5 H), 1.89 - 1.96 (m, 2 H), 2.67 - 2.73 (m, 2 H), 3.02 - 3.10 (m, 1 H), 3.33 - 3.44 (m, 2 H), 4.11 (t, J=7.1 Hz, 2 H), 4.22 (d, J=9.6 Hz, 1 H), 5.10 - 5.16 (m, 1 H), 5.19 - 5.25 (m, 1 H), 5.85 - 5.96 (m, 1 H), 7.17 - 7.20 (m, 1 H), 7.30 (t, J=7.6 Hz, 1 H), 7.35 - 7.39 (m, 1 H), 7.49 - 7.52 (m, 1 H), 7.66 (s, 1 H), 7.79 (s, 1 H)
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-(1-エチル-1H-ピラゾール-4-イル)フェニル)メタンアミン
MS (ESI pos.) m/z : 325([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.02 - 1.10 (m, 1 H), 1.30 - 1.57 (m, 4 H), 1.53 (t, J=7.3 Hz, 3 H), 1.58 - 1.84 (m, 1 H), 2.67 - 2.73 (m, 2 H), 3.03 - 3.09 (m, 1 H), 3.34 - 3.44 (m, 2 H), 4.18 - 4.24 (m, 3 H), 5.11 - 5.16 (m, 1 H), 5.18 - 5.26 (m, 1 H), 5.85 - 5.95 (m, 1 H), 7.19 (d, J=7.8 Hz, 1 H), 7.30 (t, J=7.8 Hz, 1 H), 7.35 - 7.38 (m, 1 H), 7.50 (br. s., 1 H), 7.68 (s, 1 H), 7.78 (s, 1 H)
(1) tert-Butyl (2S) -2- (4-(((trifluoromethyl) sulfonyl) oxy) benzoyl) piperidine-1-carboxylate (6.7 g) in the same manner as in Production Example 2 (2) ) Gave tert-butyl (2S) -2-((S) -hydroxy (4-(((trifluoromethyl) sulfonyl) oxy) phenyl) methyl) piperidine-1-carboxylate (6.3 g).
MS (ESI pos.) M / z: 440 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.21-1.32 (m, 1 H), 1.37-1.76 (m, 14 H), 2.85-3.17 (m, 1 H), 3.96-4.50 (m, 2 H), 4.87-5.00 (m, 1 H), 7.26-7.37 (m, 2 H), 7.44-7.55 (m, 2 H)
(2) tert-butyl (2S) -2-((S) -hydroxy (4-(((trifluoromethyl) sulfonyl) oxy) phenyl) methyl) piperidine-1-carboxylate (6.0 g) was added to DMF ( 90 ml) and ethanol (45 ml), and potassium carbonate (2.8 g) and 3-pyridine boric acid (2.5 g) were added. After nitrogen substitution, Pd (PPh 3 ) 4 (0.47 g ) And heated and stirred at 90 ° C. for 1.5 hours. Ethanol was distilled off under reduced pressure, and then ethyl acetate and water were added for liquid separation. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane / ethyl acetate = 3: 1 to 1: 2), and tert- Butyl (2S) -2-((S) -hydroxy (4-pyridin-3-ylphenyl) methyl) piperidine-1-carboxylate (4.4 g) was obtained as a pale yellow solid.
MS (ESI pos.) M / z: 369 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.31-1.38 (m, 1 H), 1.40-1.55 (m, 11 H), 1.56-1.84 (m, 3 H), 2.97-3.16 (m, 1 H), 3.99-4.50 (m, 2 H), 4.89-5.01 (m, 1 H), 7.35-7.39 (m, 1 H), 7.45-7.62 (m, 4 H), 7.85-7.90 (m, 1 H), 8.56-8.61 (m, 1 H), 8.82-8.86 (m, 1 H)
(3) tert-butyl (2S) -2-((S) -hydroxy (4-pyridin-3-ylphenyl) methyl) piperidine-1-carboxylate (4.2 g) in a methanol solution (50 ml) was hydroxylated An aqueous solution (40 ml) of potassium (3.2 g) was added, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure, and the residue was subjected to column chromatography (NH silica gel, hexane / ethyl acetate = 1: 1, then ethyl acetate / methanol = 19: 1). To give (S)-(2S) -piperidin-2-yl (4-pyridin-3-ylphenyl) methanol (1.5 g) as a colorless solid.
MS (ESI pos.) M / z: 269 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.24-1.36 (m, 2 H), 1.37-1.47 (m, 2 H), 1.57-1.64 (m, 1 H), 1.76-1.82 (m, 1 H), 2.60-2.67 (m, 1 H), 2.68-2.73 (m, 1 H), 3.11-3.16 (m, 1 H), 4.46 (d, J = 6.9 Hz, 1 H), 7.35-7.38 (m, 1 H), 7.45-7.48 (m, 2 H), 7.56-7.59 (m, 2 H), 7.85-7.89 (m, 1 H), 8.58-8.60 (m, 1 H), 8.83-8.85 (m, 1 H)
(4) (S)-(2S) -piperidin-2-yl (4-pyridin-3-ylphenyl) methanol (1.4 g) in DMF solution (15 ml) was added potassium carbonate (1.5 g) and allyl bromide ( 0.52 ml) was added, and the mixture was heated and stirred at 80 ° C. for 1.5 hours. Water and chloroform were added, the aqueous layer was extracted with chloroform, and the organic layer was washed with water and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane / ethyl acetate = 4: 1 to 3: 1), and (S )-((2S) -1-allylpiperidin-2-yl) (4-pyridin-3-ylphenyl) methanol (0.68 g) was obtained as a yellow solid.
MS (ESI pos.) M / z: 309 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.20-1.28 (m, 1 H), 1.31-1.40 (m, 1 H), 1.51-1.67 (m, 3 H), 1.69-1.78 (m, 1 H), 2.63-2.70 (m, 1 H), 2.74-2.80 (m, 1 H), 3.01-3.09 (m, 1 H), 3.32-3.41 (m, 1 H), 3.42-3.49 (m, 1 H), 4.81 (d, J = 10.1 Hz, 1 H), 5.16-5.25 (m, 2 H), 5.85-5.93 (m, 1 H), 7.34-7.37 (m, 1 H), 7.47-7.49 (m, 2 H), 7.54-7.57 (m, 2 H), 7.85-7.88 (m, 1 H), 8.58 (dd, J = 4.8, 1.6 Hz, 1 H), 8.85 (d, J = 2.3 Hz, 1 H)
(5) (S)-((2S) -1-allylpiperidin-2-yl) (4-pyridin-3-ylphenyl) methanol (1.1 g) in chloroform solution (15 ml) and triethylamine (0.7 ml) After cooling with ice, methanesulfonyl chloride (0.31 ml) was added dropwise. After stirring for 30 minutes under ice cooling, the reaction solution was concentrated under reduced pressure. The residue was dissolved in 8M ammonia / methanol solution (8 ml), and reacted at 120 ° C. for 20 minutes in a microwave reactor. After the reaction solution was concentrated under reduced pressure, the residue was subjected to column chromatography (silica gel, chloroform / methanol / 28% aqueous ammonia = 19: 1: 0.2, followed by NH silica gel, hexane / ethyl acetate = 4: 1 to 1: 1). ) To give the title compound (0.92 g) as a yellow oil.
MS (ESI pos.) M / z: 308 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.04-1.12 (m, 1 H), 1.23-1.56 (m, 4 H), 1.62-1.72 (m, 1 H), 2.67-2.74 (m, 2 H), 3.03-3.11 (m, 1 H), 3.36-3.42 (m, 2 H), 4.28 (d, J = 10.1 Hz, 1 H), 5.12-5.16 (m, 1 H), 5.20-5.25 (m, 1 H), 5.87-5.95 (m, 1 H), 7.33-7.37 (m, 1 H), 7.47-7.50 (m, 2 H), 7.52-7.56 (m, 2 H), 7.85-7.89 (m, 1 H), 8.57-8.59 (m, 1 H), 8.85 (d, J = 2.3 Hz, 1 H)
The following compounds were synthesized in the same manner.
(S) -1-((2S) -1-allylpiperidin-2-yl) -1- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) methanamine
MS (ESI pos.) M / z: 311 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ (ppm); 1.11-4.00 (m, 14 H), 4.09 (d, J = 10.5 Hz, 1 H), 5.22-5.35 (m, 2 H), 5.90-6.03 ( m, 1 H), 7.35-7.39 (m, 2 H), 7.39-7.46 (m, 2 H), 7.57-7.58 (m, 1 H), 7.71-7.73 (m, 1 H)
(S) -1-((2S) -1-Allylpiperidin-2-yl) -1- (4-pyrimidin-5-ylphenyl) methanamine
MS (ESI pos.) M / z: 309 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ (ppm); 1.31-4.44 (m, 12 H), 5.46 (d, J = 11.0 Hz, 2 H), 6.05-6.19 (m, 1 H), 7.49-7.72 ( m, 4 H), 8.89-8.92 (m, 2 H), 9.20 (s, 1 H)
(S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) methanamine
MS (ESI pos.) M / z: 311 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.01-1.09 (m, 1 H), 1.29-1.55 (m, 4 H), 1.60-1.89 (m, 1 H), 2.65-2.72 (m, 2 H), 3.02-3.08 (m, 1 H), 3.33-3.43 (m, 2 H), 3.94 (s, 3 H), 4.22 (d, J = 10.1 Hz, 1 H), 5.13 (dd, J = 10.1, 1.8 Hz, 1 H), 5.19-5.24 (m, 1 H), 5.86-5.94 (m, 1 H), 7.18-7.21 (m, 1 H), 7.30 (t, J = 7.8 Hz, 1 H), 7.34 -7.37 (m, 1 H), 7.46-7.50 (m, 1 H), 7.64 (s, 1 H), 7.77 (s, 1 H)
(S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3-pyridin-3-ylphenyl) methanamine
MS (ESI pos.) M / z: 308 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.03-1.11 (m, 1 H), 1.31-1.57 (m, 4 H), 1.63-1.71 (m, 1 H), 2.66-2.76 (m, 2 H), 3.03-3.11 (m, 1 H), 3.35-3.44 (m, 2 H), 4.29 (d, J = 10.1 Hz, 1 H), 5.12-5.17 (m, 1 H), 5.20-5.25 (m, 1 H), 5.86-5.95 (m, 1 H), 7.34-7.38 (m, 1 H), 7.39-7.52 (m, 3 H), 7.58-7.61 (m, 1 H), 7.87-7.91 (m, 1 H), 8.57-8.60 (m, 1 H), 8.85-8.86 (m, 1 H)
(S) -1-((2S) -1-Allylpiperidin-2-yl) -1- (3-pyrimidin-5-ylphenyl) methanamine
MS (ESI pos.) M / z: 309 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ (ppm); 1.15-1.78 (m, 6 H), 2.59-2.68 (m, 1 H), 2.76 (d, J = 14.2 Hz, 1 H), 2.97-3.08 ( m, 1 H), 3.30-3.47 (m, 2 H), 4.83 (d, J = 10.1 Hz, 1 H), 5.14-5.26 (m, 2 H), 5.81-5.95 (m, 1 H), 7.38 -7.71 (m, 4 H), 8.95 (s, 2 H), 9.20 (s, 1 H)
(S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3- (1-isopropyl-1H-pyrazol-4-yl) phenyl) methanamine
MS (ESI pos.) M / z: 339 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.02-1.09 (m, 1 H), 1.30-1.59 (m, 4 H), 1.55 (d, J = 6.9 Hz, 6 H), 1.61-1.85 (m, 1 H), 2.67-2.73 (m, 2 H), 3.03-3.09 (m, 1 H), 3.34-3.43 (m, 2 H), 4.23 (d, J = 9.6 Hz, 1 H), 4.50-4.56 ( m, 1 H), 5.11-5.15 (m, 1 H), 5.19-5.25 (m, 1 H), 5.86-5.95 (m, 1 H), 7.16-7.19 (m, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.36-7.39 (m, 1 H), 7.50-7.52 (m, 1 H), 7.71 (s, 1 H), 7.79 (s, 1 H)
(S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3- (1-propyl-1H-pyrazol-4-yl) phenyl) methanamine
MS (ESI pos.) M / z: 339 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 0.95 (t, J = 7.3 Hz, 3 H), 1.03-1.11 (m, 1 H), 1.29-1.73 (m, 5 H), 1.89-1.96 (m, 2 H), 2.67-2.73 (m, 2 H), 3.02-3.10 (m, 1 H), 3.33-3.44 (m, 2 H), 4.11 (t, J = 7.1 Hz, 2 H), 4.22 (d, J = 9.6 Hz, 1 H), 5.10-5.16 (m, 1 H), 5.19-5.25 (m, 1 H), 5.85-5.96 (m, 1 H), 7.17-7.20 (m, 1 H), 7.30 (t, J = 7.6 Hz, 1 H), 7.35-7.39 (m, 1 H), 7.49-7.52 (m, 1 H), 7.66 (s, 1 H), 7.79 (s, 1 H)
(S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3- (1-ethyl-1H-pyrazol-4-yl) phenyl) methanamine
MS (ESI pos.) M / z: 325 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.02-1.10 (m, 1 H), 1.30-1.57 (m, 4 H), 1.53 (t, J = 7.3 Hz, 3 H), 1.58-1.84 (m, 1 H), 2.67-2.73 (m, 2 H), 3.03-3.09 (m, 1 H), 3.34-3.44 (m, 2 H), 4.18-4.24 (m, 3 H), 5.11-5.16 (m, 1 H), 5.18-5.26 (m, 1 H), 5.85-5.95 (m, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 7.30 (t, J = 7.8 Hz, 1 H), 7.35 -7.38 (m, 1 H), 7.50 (br. S., 1 H), 7.68 (s, 1 H), 7.78 (s, 1 H)
製造例8 (S)-1-ビフェニル-4-イル-1-((2S)-1-メチルピペリジン-2-イル)メタンアミンの合成 Production Example 8 Synthesis of (S) -1-biphenyl-4-yl-1-((2S) -1-methylpiperidin-2-yl) methanamine
(1)窒素雰囲気下tert-ブチル(2S)-2-((S)-ビフェニル-4-イル(ヒドロキシ)メチル)ピペリジン-1-カルボキシラート(3.5g)をTHF(60ml)に溶解し、氷冷後水素化リチウムアルミニウム(1.4g)を少しずつ加えた後、80℃で2時間加熱攪拌した。反応混合物を氷冷後、飽和酒石酸カリウムナトリウム水溶液及び10%水酸化ナトリウム水溶液を加え、室温で30分間攪拌した。無水硫酸マグネシウムを敷き詰めた漏斗を用いて不溶物を濾別した後、濾液を減圧下濃縮し、(S)-ビフェニル-4-イル((2S)-1-メチルピペリジン-2-イル)メタノール(2.6g)を無色固体として得た。
MS (ESI pos.) m/z : 282([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.28 - 1.35 (m, 1 H), 1.39 - 1.54 (m, 2 H), 1.54 - 1.62 (m, 1 H), 1.66 - 1.76 (m, 1 H), 1.82 - 1.88 (m, 1 H), 2.52 (s, 3 H), 2.54 - 2.59 (m, 1 H), 2.63 - 2.69 (m, 1 H), 3.02 - 3.08 (m, 1 H), 4.69 (d, J=9.2 Hz, 1 H), 7.31 - 7.35 (m, 1 H), 7.41 - 7.46 (m, 4 H), 7.54 - 7.61 (m, 4 H)
(2)製造例7(5)と同様の方法にて(S)-ビフェニル-4-イル((2S)-1-メチルピペリジン-2-イル)メタノール(1.7g)から表題化合物(1.2g)を茶褐色油状物質として得た。
MS (ESI pos.) m/z : 281([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.15 - 1.23 (m, 1 H), 1.29 - 1.38 (m, 2 H), 1.40 - 1.53 (m, 2 H), 1.65 - 1.72 (m, 1 H), 2.47 (s, 3 H), 2.51 - 2.56 (m, 1 H), 2.57 - 2.64 (m, 1 H), 2.98 - 3.04 (m, 1 H), 4.11 (d, J=8.3 Hz, 1 H), 7.31 - 7.35 (m, 1 H), 7.40 - 7.46 (m, 4 H), 7.53 - 7.62 (m, 4 H)
同様にして以下の化合物を合成した。
(S)-1-ビフェニル-3-イル-1-((2S)-1-メチルピペリジン-2-イル)メタンアミン
MS (ESI pos.) m/z : 281([M+H]+)
(1) Dissolve tert-butyl (2S) -2-((S) -biphenyl-4-yl (hydroxy) methyl) piperidine-1-carboxylate (3.5 g) in THF (60 ml) under a nitrogen atmosphere; After cooling with ice, lithium aluminum hydride (1.4 g) was added little by little, and the mixture was stirred with heating at 80 ° C. for 2 hr. The reaction mixture was ice-cooled, saturated aqueous potassium sodium tartrate solution and 10% aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 30 min. Insoluble matter was filtered off using a funnel filled with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give (S) -biphenyl-4-yl ((2S) -1-methylpiperidin-2-yl) methanol ( 2.6 g) was obtained as a colorless solid.
MS (ESI pos.) M / z: 282 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.28-1.35 (m, 1 H), 1.39-1.54 (m, 2 H), 1.54-1.62 (m, 1 H), 1.66-1.76 (m, 1 H), 1.82-1.88 (m, 1 H), 2.52 (s, 3 H), 2.54-2.59 (m, 1 H), 2.63-2.69 (m, 1 H), 3.02-3.08 (m, 1 H), 4.69 ( d, J = 9.2 Hz, 1 H), 7.31-7.35 (m, 1 H), 7.41-7.46 (m, 4 H), 7.54-7.61 (m, 4 H)
(2) (S) -Biphenyl-4-yl ((2S) -1-methylpiperidin-2-yl) methanol (1.7 g) from the title compound (1. 2 g) was obtained as a brown oil.
MS (ESI pos.) M / z: 281 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.15-1.23 (m, 1 H), 1.29-1.38 (m, 2 H), 1.40-1.53 (m, 2 H), 1.65-1.72 (m, 1 H), 2.47 (s, 3 H), 2.51-2.56 (m, 1 H), 2.57-2.64 (m, 1 H), 2.98-3.04 (m, 1 H), 4.11 (d, J = 8.3 Hz, 1 H) , 7.31-7.35 (m, 1 H), 7.40-7.46 (m, 4 H), 7.53-7.62 (m, 4 H)
The following compounds were synthesized in the same manner.
(S) -1-Biphenyl-3-yl-1-((2S) -1-methylpiperidin-2-yl) methanamine
MS (ESI pos.) M / z: 281 ([M + H] +)
製造例9 (S)-1-((2S)-1-アリルピロリジン-2-イル)-1-(3-メトキシフェニル)メタンアミンの合成 Production Example 9 Synthesis of (S) -1-((2S) -1-allylpyrrolidin-2-yl) -1- (3-methoxyphenyl) methanamine
(1)tert-ブチル(2S)-2-((S)-ヒドロキシ(3-メトキシフェニル)メチル)ピロリジン-1-カルボキシラート(50g)及びトリエチルアミン(50g)をクロロホルム(600ml)に溶解させ、氷冷後ピバロイルクロリド(40g)及びN,N−ジメチルアミノピリジン(2.0g)を加え、室温で9時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した.有機層を無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をカラムクロマトグラフィー(シリカゲル、ヘキサン/酢酸エチル=20:1)で精製し、tert-ブチル(2S)-2-((S)-((2,2-ジメチルプロパノイル)オキシ)(3-メトキシフェニル)メチル)ピロリジン-1-カルボキシラート(54g)を黄色油状物質として得た。
MS (ESI pos.) m/z : 392([M+H]+)
1H NMR (600 MHz, DMSO-d6) δ (ppm) ; 0.90 - 3.47 (m, 24 H), 3.66 - 3.73 (m, 3 H), 3.89 - 4.08 (m, 1 H), 5.72 - 6.24 (m, 1 H), 6.64 - 6.91 (m, 3 H), 7.21 - 7.32 (m, 1 H)
(2)tert-ブチル(2S)-2-((S)-((2,2-ジメチルプロパノイル)オキシ)(3-メトキシフェニル)メチル)ピロリジン-1-カルボキシラート(54g)のジエチルエーテル溶液(200ml)に4M HCl/酢酸エチル溶液(250ml)を加え、室温で7時間攪拌した。析出した固体を濾取し、ジエチルエーテルで洗浄後、減圧下乾燥し、(S)-(3-メトキシフェニル)((2S)-ピロリジン-2-イル)メチル ピバラート1塩酸塩(19g)を得た。濾液を濃縮後、ジエチルエーテルを加え、一晩攪拌した。析出した結晶を濾取し、ジエチルエーテルで洗浄後、減圧下乾燥し、さらに(S)-(3-メトキシフェニル)((2S)-ピロリジン-2-イル)メチル ピバラート1塩酸塩(12g)を得た。
MS (ESI pos.) m/z : 292([M+H]+)
1H NMR (600 MHz, CDCl3) δ (ppm) ; 1.28 (s, 9 H), 1.73 - 1.86 (m, 2 H), 1.86 - 1.97 (m, 1 H), 1.97 - 2.05 (m, 1 H), 3.31 - 3.45 (m, 2 H), 3.77 (s, 3 H), 3.92 - 4.01 (m, 1 H), 5.88 (d, J=8.3 Hz, 1 H), 6.82 - 6.87 (m, 1 H), 6.96 - 7.00 (m, 2 H), 7.21 - 7.30 (m, 1 H), 9.22 - 9.31 (m, 1 H), 10.29 - 10.37 (m, 1 H)
(3)(S)-(3-メトキシフェニル)((2S)-ピロリジン-2-イル)メチル ピバラート1塩酸塩(30g)をDMF(200ml)に溶解させ、炭酸カリウム(38g)及びアリルブロミド(13g)を加え、90℃で6時間攪拌した後、水を加え、酢酸エチルにて抽出した。有機層を水及び飽和食塩水で洗浄し、カラムクロマトグラフィー(シリカゲル、ヘキサン/酢酸エチル=4:1)で精製し、(S)-((2S)-1-アリルピロリジン-2-イル)(3-メトキシフェニル)メチル ピバラート(26g)を無色油状物質として得た。
MS (ESI pos.) m/z : 332([M+H]+)
1H NMR (600 MHz, CDCl3) δ (ppm) ; 1.20 (s, 9 H), 1.38 - 1.68 (m, 4 H), 2.23 - 2.32 (m, 1 H), 2.92 - 3.09 (m, 3 H), 3.63 (dd, J=13.8, 5.0 Hz, 1 H), 3.78 (s, 3 H), 5.08 (d, J=10.1 Hz, 1 H), 5.18 (d, J=16.0 Hz, 1 H), 5.56 (d, J=6.9 Hz, 1 H), 5.85 - 5.97 (m, 1 H), 6.79 (dd, J=8.3, 2.8 Hz, 1 H), 6.87 - 6.91 (m, 1 H), 6.93 (d, J=7.8 Hz, 1 H), 7.20 (t, J=7.8 Hz, 1 H)
(4)水素化リチウムアルミニウム(3.3g)を乾燥テトラヒドロフラン(100ml)に懸濁させ、(S)-((2S)-1-アリルピロリジン-2-イル)(3-メトキシフェニル)メチル ピバラート(26g)のテトラヒドロフラン溶液(30ml)を加えた後、室温で1時間攪拌した。反応混合物に水及び10%水酸化ナトリウム水溶液を加え、室温にて30分間攪拌した。無水硫酸マグネシウムを固く敷き詰めた漏斗を用いて不溶物を濾別した後、濾液を減圧下濃縮し、粗の(S)-((2S)-1-アリルピロリジン-2-イル)(3-メトキシフェニル)メタノール(22g)を無色油状物質として得た。
MS (ESI pos.) m/z : 248([M+H]+)
1H NMR (600 MHz, CDCl3) δ (ppm) ; 1.66 - 1.95 (m, 4 H), 2.40 - 2.53 (m, 1 H), 2.85 - 3.00 (m, 2 H), 3.05 - 3.17 (m, 2 H), 3.80 (s, 3 H), 4.25 (d, J=5.5 Hz, 1 H), 4.27 - 4.37 (m, 1 H), 5.02 - 5.14 (m, 2 H), 5.74 - 5.90 (m, 1 H), 6.78 (dd, J=8.5, 2.5 Hz, 1 H), 6.89 - 6.95 (m, 2 H), 7.18 - 7.26 (m, 1 H)
(5)製造例3(3)と同様な方法により、粗の(S)-((2S)-1-アリルピロリジン-2-イル)(3-メトキシフェニル)メタノール(22g)から(S)-1-((2S)-1-アリルピロリジン-2-イル)-1-(3-メトキシフェニル)メタンアミン(12g)を得た。
MS (ESI pos.) m/z : 247([M+H]+)
1H NMR (600 MHz, CDCl3) δ (ppm) ; 1.45 - 1.83 (m, 4 H), 2.32 - 2.43 (m, 1 H), 2.79 - 2.89 (m, 1 H), 2.93 - 3.01 (m, 1 H), 3.01 - 3.08 (m, 1 H), 3.36 (dd, J=13.8, 5.0 Hz, 1 H), 3.70 (d, J=6.9 Hz, 1 H), 3.80 (s, 3 H), 5.06 (d, J=10.1 Hz, 1 H), 5.14 (d, J=17.0 Hz, 1 H), 5.82 - 5.95 (m, 1 H), 6.73 - 6.79 (m, 1 H), 6.88 - 6.95 (m, 2 H), 7.21 (t, J=7.8 Hz, 1 H)
(1) tert-butyl (2S) -2-((S) -hydroxy (3-methoxyphenyl) methyl) pyrrolidine-1-carboxylate (50 g) and triethylamine (50 g) were dissolved in chloroform (600 ml) and ice After cooling, pivaloyl chloride (40 g) and N, N-dimethylaminopyridine (2.0 g) were added, and the mixture was stirred at room temperature for 9 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 20: 1) and tert-butyl (2S) -2-((S)-((2 , 2-Dimethylpropanoyl) oxy) (3-methoxyphenyl) methyl) pyrrolidine-1-carboxylate (54 g) was obtained as a yellow oil.
MS (ESI pos.) M / z: 392 ([M + H] +)
1H NMR (600 MHz, DMSO-d6) δ (ppm); 0.90-3.47 (m, 24 H), 3.66-3.73 (m, 3 H), 3.89-4.08 (m, 1 H), 5.72-6.24 (m , 1 H), 6.64-6.91 (m, 3 H), 7.21-7.32 (m, 1 H)
(2) Diethyl ether solution of tert-butyl (2S) -2-((S)-((2,2-dimethylpropanoyl) oxy) (3-methoxyphenyl) methyl) pyrrolidine-1-carboxylate (54 g) (200 ml) was added 4M HCl / ethyl acetate solution (250 ml) and stirred at room temperature for 7 hours. The precipitated solid was collected by filtration, washed with diethyl ether and then dried under reduced pressure to obtain (S)-(3-methoxyphenyl) ((2S) -pyrrolidin-2-yl) methyl pivalate monohydrochloride (19 g). It was. After the filtrate was concentrated, diethyl ether was added and stirred overnight. The precipitated crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure. Further, (S)-(3-methoxyphenyl) ((2S) -pyrrolidin-2-yl) methyl pivalate monohydrochloride (12 g) was added. Obtained.
MS (ESI pos.) M / z: 292 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ (ppm); 1.28 (s, 9 H), 1.73-1.86 (m, 2 H), 1.86-1.97 (m, 1 H), 1.97-2.05 (m, 1 H) , 3.31-3.45 (m, 2 H), 3.77 (s, 3 H), 3.92-4.01 (m, 1 H), 5.88 (d, J = 8.3 Hz, 1 H), 6.82-6.87 (m, 1 H ), 6.96-7.00 (m, 2 H), 7.21-7.30 (m, 1 H), 9.22-9.31 (m, 1 H), 10.29-10.37 (m, 1 H)
(3) (S)-(3-methoxyphenyl) ((2S) -pyrrolidin-2-yl) methyl pivalate monohydrochloride (30 g) was dissolved in DMF (200 ml), and potassium carbonate (38 g) and allyl bromide ( 13 g) was added, and the mixture was stirred at 90 ° C. for 6 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and purified by column chromatography (silica gel, hexane / ethyl acetate = 4: 1) to give (S)-((2S) -1-allylpyrrolidin-2-yl) ( 3-Methoxyphenyl) methyl pivalate (26 g) was obtained as a colorless oil.
MS (ESI pos.) M / z: 332 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ (ppm); 1.20 (s, 9 H), 1.38-1.68 (m, 4 H), 2.23-2.32 (m, 1 H), 2.92-3.09 (m, 3 H) , 3.63 (dd, J = 13.8, 5.0 Hz, 1 H), 3.78 (s, 3 H), 5.08 (d, J = 10.1 Hz, 1 H), 5.18 (d, J = 16.0 Hz, 1 H), 5.56 (d, J = 6.9 Hz, 1 H), 5.85-5.97 (m, 1 H), 6.79 (dd, J = 8.3, 2.8 Hz, 1 H), 6.87-6.91 (m, 1 H), 6.93 ( d, J = 7.8 Hz, 1 H), 7.20 (t, J = 7.8 Hz, 1 H)
(4) Lithium aluminum hydride (3.3 g) was suspended in dry tetrahydrofuran (100 ml), and (S)-((2S) -1-allylpyrrolidin-2-yl) (3-methoxyphenyl) methyl pivalate ( 26 g) in tetrahydrofuran (30 ml) was added, and the mixture was stirred at room temperature for 1 hour. Water and 10% aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was filtered off using a funnel filled with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give crude (S)-((2S) -1-allylpyrrolidin-2-yl) (3-methoxy Phenyl) methanol (22 g) was obtained as a colorless oil.
MS (ESI pos.) M / z: 248 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ (ppm); 1.66-1.95 (m, 4 H), 2.40-2.53 (m, 1 H), 2.85-3.00 (m, 2 H), 3.05-3.17 (m, 2 H), 3.80 (s, 3 H), 4.25 (d, J = 5.5 Hz, 1 H), 4.27-4.37 (m, 1 H), 5.02-5.14 (m, 2 H), 5.74-5.90 (m, 1 H), 6.78 (dd, J = 8.5, 2.5 Hz, 1 H), 6.89-6.95 (m, 2 H), 7.18-7.26 (m, 1 H)
(5) In the same manner as in Production Example 3 (3), from crude (S)-((2S) -1-allylpyrrolidin-2-yl) (3-methoxyphenyl) methanol (22 g) to (S)- 1-((2S) -1-allylpyrrolidin-2-yl) -1- (3-methoxyphenyl) methanamine (12 g) was obtained.
MS (ESI pos.) M / z: 247 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ (ppm); 1.45-1.83 (m, 4 H), 2.32-2.43 (m, 1 H), 2.79-2.89 (m, 1 H), 2.93-3.01 (m, 1 H), 3.01-3.08 (m, 1 H), 3.36 (dd, J = 13.8, 5.0 Hz, 1 H), 3.70 (d, J = 6.9 Hz, 1 H), 3.80 (s, 3 H), 5.06 (d, J = 10.1 Hz, 1 H), 5.14 (d, J = 17.0 Hz, 1 H), 5.82-5.95 (m, 1 H), 6.73-6.79 (m, 1 H), 6.88-6.95 (m , 2 H), 7.21 (t, J = 7.8 Hz, 1 H)
製造例10 (S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-ピラジン-2-イルフェニル)メタンアミンの合成 Production Example 10 Synthesis of (S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3-pyrazin-2-ylphenyl) methanamine
(1)製造例7(1)と同様にして合成したtert-ブチル(2S)-2-((S)-ヒドロキシ(3-(((トリフルオロメチル)スルホニル)オキシ)フェニル)メチル)ピペリジン-1-カルボキシラート(7.9g)をジオキサン(150ml)に溶解させ、窒素置換後、酢酸カリウム(5.3g)、Pd(dppf)Cl2(1.46g)、ビスピナコールボラン(5.0g)及びdppf(1.2g)を加え、80℃で3時間加熱攪拌した。室温まで冷却後、水を加え、酢酸エチルにて抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をカラムクロマトグラフィー(シリカゲル、ヘキサン/酢酸エチル=3:1〜2:1)で精製し、tert-ブチル (2S)-2-((S)-ヒドロキシ(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メチル)ピペリジン-1-カルボキシラート(6.8g)を淡黄色アモルファスとして得た。
MS (ESI pos.) m/z : 418([M+H]+)
(2)tert-ブチル(2S)-2-((S)-ヒドロキシ(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メチル)ピペリジン-1-カルボキシラート(1.2g)及び炭酸カリウム(0.77g)をDMF/エタノール(=2:1)の混合溶媒(18ml)に懸濁させ、窒素置換後、2−クロロピラジン(0.64g)、Pd(PPh3)4(96mg)を加え、90℃で2時間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を水及び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をカラムクロマトグラフィー(シリカゲル、ヘキサン/酢酸エチル=2:1〜1:2)で精製し、tert-ブチル(2S)-2-((S)-ヒドロキシ(3-ピラジン-2-イルフェニル)メチル)ピペリジン-1-カルボキシラート(0.79g)を無色アモルファスとして得た。
MS (ESI pos.) m/z : 370([M+H]+)
1H NMR (200 MHz, CDCl3) δ ppm 1.32 - 1.86 (m, 15 H), 2.91 - 3.18 (m, 1 H), 3.99 - 4.25 (m, 1 H), 4.35 - 4.54 (m, 1 H), 5.00 (d, J=10.5 Hz, 1 H), 7.48 - 7.57 (m, 2 H), 7.92 - 7.99 (m, 1 H), 8.03 - 8.08 (m, 1 H), 8.52 (d, J=2.6 Hz, 1 H), 8.62 - 8.66 (m, 1 H), 9.04 (d, J=1.3 Hz, 1 H)
(3)製造例3(1)と同様の方法にてtert-ブチル(2S)-2-((S)-ヒドロキシ(3-ピラジン-2-イルフェニル)メチル)ピペリジン-1-カルボキシラート(0.75g)から(S)-(2S)-ピペリジン-2-イル(3-ピラジン-2-イルフェニル)メタノール(0.52g)を得た。
MS (ESI pos.) m/z : 270([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.21 - 1.32 (m, 2 H), 1.35 - 1.44 (m, 2 H), 1.55 - 1.61 (m, 1 H), 1.72 - 1.78 (m, 1 H), 2.57 - 2.64 (m, 1 H), 2.69 - 2.74 (m, 1 H), 3.07 - 3.12 (m, 1 H), 4.47 (d, J=6.9 Hz, 1 H), 7.45 - 7.52 (m, 2 H), 7.90 - 7.93 (m, 1 H), 8.00 - 8.02 (m, 1 H), 8.51 (d, J=2.8 Hz, 1 H), 8.62 - 8.63 (m, 1 H), 9.03 (d, J=1.4 Hz, 1 H)
(4)製造例3(2)と同様の方法にて(S)-(2S)-ピペリジン-2-イル(3-ピラジン-2-イルフェニル)メタノール(0.47g)から(S)-((2S)-1-アリルピペリジン-2-イル)(3-ピラジン-2-イルフェニル)メタノール(0.31g)を得た。
(ESI pos.) m/z : 310([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.21 - 1.79 (m, 6 H), 2.65 - 2.73 (m, 1 H), 2.74 - 2.81 (m, 1 H), 3.00 - 3.09 (m, 1 H), 3.33 - 3.40 (m, 1 H), 3.42 - 3.51 (m, 1 H), 4.86 (d, J=10.1 Hz, 1 H), 5.15 - 5.25 (m, 2 H), 5.85 - 5.94 (m, 1 H), 7.46 - 7.51 (m, 2 H), 7.91 - 7.95 (m, 1 H), 8.01 - 8.03 (m, 1 H), 8.51 (d, J=2.8 Hz, 1 H), 8.62 - 8.65 (m, 1 H), 9.04 (d, J=1.8 Hz, 1 H)
(5)製造例3(3)と同様の方法にて(S)-((2S)-1-アリルピペリジン-2-イル)(3-ピラジン-2-イルフェニル)メタノール(0.28g)から表題化合物(0.24g)を得た。
MS (ESI pos.) m/z : 309([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.04 - 1.11 (m, 1 H), 1.31 - 1.77 (m, 5 H), 2.67 - 2.77 (m, 2 H), 3.04 - 3.11 (m, 1 H), 3.34 - 3.46 (m, 2 H), 4.32 (d, J=10.1 Hz, 1 H), 5.13 - 5.16 (m, 1 H), 5.20 - 5.25 (m, 1 H), 5.87 - 5.96 (m, 1 H), 7.45 - 7.52 (m, 2 H), 7.88 - 7.91 (m, 1 H), 8.02 - 8.04 (m, 1 H), 8.50 - 8.52 (m, 1 H), 8.63 - 8.65 (m, 1 H), 9.04 - 9.06 (m, 1 H)
同様の方法にて以下の化合物を合成した。
(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-(1-メチル-1H-イミダゾール-5-イル)フェニル)メタンアミン
MS (ESI pos.) m/z : 311([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.02 - 1.09 (m, 1 H), 1.31 - 1.68 (m, 5 H), 2.65 - 2.72 (m, 2 H), 3.02 - 3.09 (m, 1 H), 3.36 - 3.41 (m, 2 H), 3.67 (s, 3 H), 4.25 (d, J=10.1 Hz, 1 H), 5.11 - 5.16 (m, 1 H), 5.19 - 5.26 (m, 1 H), 5.85 - 5.95 (m, 1 H), 7.10 - 7.11 (m, 1 H), 7.27 - 7.29 (m, 1 H), 7.36 - 7.41 (m, 3 H), 7.51 (s, 1 H)
(1) tert-butyl (2S) -2-((S) -hydroxy (3-(((trifluoromethyl) sulfonyl) oxy) phenyl) methyl) piperidine- synthesized in the same manner as in Production Example 7 (1) 1-carboxylate (7.9 g) was dissolved in dioxane (150 ml), and after nitrogen substitution, potassium acetate (5.3 g), Pd (dppf) Cl 2 (1.46 g), bispinacol borane (5.0 g) And dppf (1.2 g) were added, and the mixture was heated with stirring at 80 ° C. for 3 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 3: 1 to 2: 1), and tert-butyl (2S) -2-((S) -Hydroxy (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methyl) piperidine-1-carboxylate (6.8 g) was obtained as a pale yellow amorphous substance. It was.
MS (ESI pos.) M / z: 418 ([M + H] +)
(2) tert-butyl (2S) -2-((S) -hydroxy (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methyl) piperidine -1-carboxylate (1.2 g) and potassium carbonate (0.77 g) were suspended in a mixed solvent (18 ml) of DMF / ethanol (= 2: 1), and after nitrogen substitution, 2-chloropyrazine (0. 64 g) and Pd (PPh 3 ) 4 (96 mg) were added, and the mixture was stirred at 90 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 2: 1 to 1: 2), and tert-butyl (2S) -2-((S) -Hydroxy (3-pyrazin-2-ylphenyl) methyl) piperidine-1-carboxylate (0.79 g) was obtained as a colorless amorphous.
MS (ESI pos.) M / z: 370 ([M + H] +)
1H NMR (200 MHz, CDCl3) δ ppm 1.32-1.86 (m, 15 H), 2.91-3.18 (m, 1 H), 3.99-4.25 (m, 1 H), 4.35-4.54 (m, 1 H), 5.00 (d, J = 10.5 Hz, 1 H), 7.48-7.57 (m, 2 H), 7.92-7.99 (m, 1 H), 8.03-8.08 (m, 1 H), 8.52 (d, J = 2.6 Hz, 1 H), 8.62-8.66 (m, 1 H), 9.04 (d, J = 1.3 Hz, 1 H)
(3) tert-Butyl (2S) -2-((S) -hydroxy (3-pyrazin-2-ylphenyl) methyl) piperidine-1-carboxylate (0) in the same manner as in Production Example 3 (1) (75)) gave (S)-(2S) -piperidin-2-yl (3-pyrazin-2-ylphenyl) methanol (0.52 g).
MS (ESI pos.) M / z: 270 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.21-1.32 (m, 2 H), 1.35-1.44 (m, 2 H), 1.55-1.61 (m, 1 H), 1.72-1.78 (m, 1 H), 2.57-2.64 (m, 1 H), 2.69-2.74 (m, 1 H), 3.07-3.12 (m, 1 H), 4.47 (d, J = 6.9 Hz, 1 H), 7.45-7.52 (m, 2 H), 7.90-7.93 (m, 1 H), 8.00-8.02 (m, 1 H), 8.51 (d, J = 2.8 Hz, 1 H), 8.62-8.63 (m, 1 H), 9.03 (d, (J = 1.4 Hz, 1 H)
(4) In the same manner as in Production Example 3 (2), (S)-(2S) -piperidin-2-yl (3-pyrazin-2-ylphenyl) methanol (0.47 g) to (S)-( (2S) -1-allylpiperidin-2-yl) (3-pyrazin-2-ylphenyl) methanol (0.31 g) was obtained.
(ESI pos.) M / z: 310 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.21-1.79 (m, 6 H), 2.65-2.73 (m, 1 H), 2.74-2.81 (m, 1 H), 3.00-3.09 (m, 1 H), 3.33-3.40 (m, 1 H), 3.42-3.51 (m, 1 H), 4.86 (d, J = 10.1 Hz, 1 H), 5.15-5.25 (m, 2 H), 5.85-5.94 (m, 1 H), 7.46-7.51 (m, 2 H), 7.91-7.95 (m, 1 H), 8.01-8.03 (m, 1 H), 8.51 (d, J = 2.8 Hz, 1 H), 8.62-8.65 ( m, 1 H), 9.04 (d, J = 1.8 Hz, 1 H)
(5) From (S)-((2S) -1-allylpiperidin-2-yl) (3-pyrazin-2-ylphenyl) methanol (0.28 g) in the same manner as in Production Example 3 (3) The title compound (0.24 g) was obtained.
MS (ESI pos.) M / z: 309 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.04-1.11 (m, 1 H), 1.31-1.77 (m, 5 H), 2.67-2.77 (m, 2 H), 3.04-3.11 (m, 1 H), 3.34-3.46 (m, 2 H), 4.32 (d, J = 10.1 Hz, 1 H), 5.13-5.16 (m, 1 H), 5.20-5.25 (m, 1 H), 5.87-5.96 (m, 1 H), 7.45-7.52 (m, 2 H), 7.88-7.91 (m, 1 H), 8.02-8.04 (m, 1 H), 8.50-8.52 (m, 1 H), 8.63-8.65 (m, 1 H), 9.04-9.06 (m, 1 H)
The following compounds were synthesized in the same manner.
(S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3- (1-methyl-1H-imidazol-5-yl) phenyl) methanamine
MS (ESI pos.) M / z: 311 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.02-1.09 (m, 1 H), 1.31-1.68 (m, 5 H), 2.65-2.72 (m, 2 H), 3.02-3.09 (m, 1 H), 3.36-3.41 (m, 2 H), 3.67 (s, 3 H), 4.25 (d, J = 10.1 Hz, 1 H), 5.11-5.16 (m, 1 H), 5.19-5.26 (m, 1 H) , 5.85-5.95 (m, 1 H), 7.10-7.11 (m, 1 H), 7.27-7.29 (m, 1 H), 7.36-7.41 (m, 3 H), 7.51 (s, 1 H)
製造例11 (S)-1-((2S)-1-メチルピペリジン-2-イル)-1-(4-ピリジン-3-イルフェニル)メタンアミンの合成 Production Example 11 Synthesis of (S) -1-((2S) -1-methylpiperidin-2-yl) -1- (4-pyridin-3-ylphenyl) methanamine
(1)製造例8(1)と同様にしてtert-ブチル(2S)-2-((S)-(4-((tert-ブチル(ジメチル)シリル)オキシ)フェニル)(ヒドロキシ)メチル)ピペリジン-1-カルボキシラート(14g)から4-((S)-ヒドロキシ((2S)-1-メチルピペリジン-2-イル)メチル)フェノール(6.3g)を無色固体として得た。
MS (ESI pos.) m/z : 222([M+H]+), (ESI neg.) m/z : 220([M-H]-)
1H NMR (600 MHz, DMSO-d6) δ ppm 0.79 - 0.88 (m, 1 H), 1.10 - 1.20 (m, 1 H), 1.21 - 1.31 (m, 1 H), 1.35 - 1.46 (m, 2 H), 1.52 - 1.61 (m, 1 H), 2.15 - 2.22 (m, 2 H), 2.39 (s, 3 H), 2.78 - 2.84 (m, 1 H), 4.69 (d, J=6.0 Hz, 1 H), 6.65 - 6.69 (m, 2 H), 7.09 - 7.13 (m, 2 H), 9.18 (br. s., 1 H)
(2)4-((S)-ヒドロキシ((2S)-1-メチルピペリジン-2-イル)メチル)フェノール(1.0g)をDMF(20ml)に溶解し、イミダゾール(1.3g)、t−ブチルジメチルシリルクロリド(2.2g)、及びDMAP(触媒量)を加え、室温で3日間攪拌した。酢酸エチル及び水を加え、分液後、水層を酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=9:1)で精製し、(2S)-2-((S)-((tert-ブチル(ジメチル)シリル)オキシ)(4-((tert-ブチル(ジメチル)シリル)オキシ)フェニル)メチル)-1-メチルピペリジン(1.6g)を無色油状物質として得た。
MS (ESI pos.) m/z : 450([M+H]+)
(3)水酸化カリウム(0.27g)のエタノール溶液(5ml)に(2S)-2-((S)-((tert-ブチル(ジメチル)シリル)オキシ)(4-((tert-ブチル(ジメチル)シリル)オキシ)フェニル)メチル)-1-メチルピペリジン(1.5g)のエタノール溶液(5ml)を加え、室温で2日間攪拌した。反応液を減圧下濃縮し、水を加えた後、飽和塩化アンモニウム水溶液を用いて中性にした。酢酸エチルで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=4:1〜3:1)で精製し、4-((S)-((tert-ブチル(ジメチル)シリル)オキシ)((2S)-1-メチルピペリジン-2-イル)メチル)フェノール(0.73g)を無色固体として得た。
MS (ESI pos.) m/z : 336([M+H]+)
1H NMR (600 MHz, DMSO-d6) δ ppm -0.12 (s, 3 H), 0.04 (s, 3 H), 0.64 - 0.72 (m, 1 H), 0.86 (s, 9 H), 1.01 - 1.12 (m, 1 H), 1.11 - 1.21 (m, 1 H), 1.36 - 1.43 (m, 1 H), 1.52 - 1.65 (m, 2 H), 1.93 - 2.03 (m, 2 H), 2.39 (s, 3 H), 2.72 - 2.78 (m, 1 H), 5.03 (d, J=4.1 Hz, 1 H), 6.63 - 6.69 (m, 2 H), 7.07 - 7.11 (m, 2 H), 9.17 (s, 1 H)
(4)製造例4(3)と同様の方法にて4-((S)-((tert-ブチル(ジメチル)シリル)オキシ)((2S)-1-メチルピペリジン-2-イル)メチル)フェノール(0.69g)から4-((S)-((tert-ブチル(ジメチル)シリル)オキシ)((2S)-1-メチルピペリジン-2-イル)メチル)フェニル トリフルオロメタンスルホナート(0.89g)を得た。
MS (ESI pos.) m/z : 468([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm -0.07 (s, 3 H), 0.08 (s, 3 H), 0.55 - 0.64 (m, 1 H), 0.91 (s, 9 H), 1.09 - 1.18 (m, 1 H), 1.23 - 1.33 (m, 1 H), 1.45 - 1.52 (m, 1 H), 1.58 - 1.64 (m, 1 H), 1.64 - 1.72 (m, 1 H), 2.01 - 2.12 (m, 2 H), 2.49 (s, 3 H), 2.84 - 2.91 (m, 1 H), 5.12 - 5.19 (m, 1 H), 7.17 - 7.22 (m, 2 H), 7.45 - 7.49 (m, 2 H)
(5)製造例7(2)と同様の方法にて4-((S)-((tert-ブチル(ジメチル)シリル)オキシ)((2S)-1-メチルピペリジン-2-イル)メチル)フェニル トリフルオロメタンスルホナート(0.84g)から3-(4-((S)-((tert-ブチル(ジメチル)シリル)オキシ)((2S)-1-メチルピペリジン-2-イル)メチル)フェニル)ピリジン(0.71g)を淡黄色油状物質として得た。
MS (ESI pos.) m/z : 397([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm -0.06 (s, 3 H), 0.10 (s, 3 H), 0.73 - 0.82 (m, 1 H), 0.93 (s, 9 H), 1.12 - 1.22 (m, 1 H), 1.28 - 1.38 (m, 1 H), 1.46 - 1.53 (m, 1 H), 1.59 - 1.67 (m, 1 H), 1.74 - 1.80 (m, 1 H), 2.04 - 2.16 (m, 2 H), 2.54 (s, 3 H), 2.86 - 2.93 (m, 1 H), 5.18 (d, J=3.7 Hz, 1 H), 7.33 - 7.36 (m, 1 H), 7.45 - 7.49 (m, 2 H), 7.51 - 7.54 (m, 2 H), 7.87 - 7.90 (m, 1 H), 8.55 - 8.58 (m, 1 H), 8.86 - 8.88 (m, 1 H)
(6)3-(4-((S)-((tert-ブチル(ジメチル)シリル)オキシ)((2S)-1-メチルピペリジン-2-イル)メチル)フェニル)ピリジン(0.67g)のテトラヒドロフラン(5ml)溶液に1M TBAF/THF溶液(3.4ml)を加え、室温で8時間攪拌後、さらに1M TBAF/THF溶液(3.4ml)加え、室温で16時間攪拌した。飽和炭酸水素ナトリウム水溶液(30ml)を加えた後、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=4:1〜2:1)で精製し、(S)-((2S)-1-メチルピペリジン-2-イル)(4-ピリジン-3-イルフェニル)メタノール(0.44g)を無色油状物質として得た。
MS (ESI pos.) m/z : 283([M+H]+)
1H NMR (200 MHz, CDCl3) δ ppm 1.30 - 1.84 (m, 6 H), 2.52 (s, 3 H), 2.53 - 2.75 (m, 2 H), 2.97 - 3.14 (m, 1 H), 4.70 (d, J=8.8 Hz, 1 H), 7.31 - 7.40 (m, 1 H), 7.44 - 7.60 (m, 4 H), 7.83 - 7.91 (m, 1 H), 8.55 - 8.61 (m, 1 H), 8.83 - 8.87 (m, 1 H)
(7)製造例3(3)と同様の方法にて(S)-((2S)-1-メチルピペリジン-2-イル)(4-ピリジン-3-イルフェニル)メタノール(0.40g)から(S)-1-((2S)-1-メチルピペリジン-2-イル)-1-(4-ピリジン-3-イルフェニル)メタンアミン(0.27g)を得た。
MS (ESI pos.) m/z : 282([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.13 - 1.21 (m, 1 H), 1.29 - 1.38 (m, 2 H), 1.40 - 1.53 (m, 2 H), 1.65 - 1.73 (m, 1 H), 2.47 (s, 3 H), 2.50 - 2.55 (m, 1 H), 2.57 - 2.63 (m, 1 H), 2.98 - 3.04 (m, 1 H), 4.14 (d, J=7.8 Hz, 1 H), 7.34 - 7.37 (m, 1 H), 7.47 - 7.50 (m, 2 H), 7.53 - 7.56 (m, 2 H), 7.85 - 7.89 (m, 1 H), 8.56 - 8.59 (m, 1 H), 8.84 - 8.86 (m, 1 H)
同様の方法にて以下の化合物を合成した。
(S)-1-((2S)-1-メチルピペリジン-2-イル)-1-(4-ピリジン-4-イルフェニル)メタンアミン
MS (ESI pos.) m/z : 282([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.12 - 1.73 (m, 6 H), 2.47 (s, 3 H), 2.49 - 2.54 (m, 1 H), 2.56 - 2.63 (m, 1 H), 2.98 - 3.03 (m, 1 H), 4.15 (d, J=7.8 Hz, 1 H), 7.47 - 7.64 (m, 6 H), 8.62 - 8.67 (m, 2 H)
(1) In the same manner as in Production Example 8 (1), tert-butyl (2S) -2-((S)-(4-((tert-butyl (dimethyl) silyl) oxy) phenyl) (hydroxy) methyl) piperidine 4-((S) -Hydroxy ((2S) -1-methylpiperidin-2-yl) methyl) phenol (6.3 g) was obtained as a colorless solid from -1-carboxylate (14 g).
MS (ESI pos.) M / z: 222 ([M + H] +), (ESI neg.) M / z: 220 ([MH]-)
1H NMR (600 MHz, DMSO-d6) δ ppm 0.79-0.88 (m, 1 H), 1.10-1.20 (m, 1 H), 1.21-1.31 (m, 1 H), 1.35-1.46 (m, 2 H ), 1.52-1.61 (m, 1 H), 2.15-2.22 (m, 2 H), 2.39 (s, 3 H), 2.78-2.84 (m, 1 H), 4.69 (d, J = 6.0 Hz, 1 H), 6.65-6.69 (m, 2 H), 7.09-7.13 (m, 2 H), 9.18 (br. S., 1 H)
(2) 4-((S) -Hydroxy ((2S) -1-methylpiperidin-2-yl) methyl) phenol (1.0 g) was dissolved in DMF (20 ml), imidazole (1.3 g), t -Butyldimethylsilyl chloride (2.2 g) and DMAP (catalytic amount) were added, and the mixture was stirred at room temperature for 3 days. Ethyl acetate and water were added, and after liquid separation, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 9: 1) and (2S) -2-((S)-((tert-butyl (dimethyl) ) Silyl) oxy) (4-((tert-butyl (dimethyl) silyl) oxy) phenyl) methyl) -1-methylpiperidine (1.6 g) was obtained as a colorless oil.
MS (ESI pos.) M / z: 450 ([M + H] +)
(3) To an ethanol solution (5 ml) of potassium hydroxide (0.27 g), add (2S) -2-((S)-((tert-butyl (dimethyl) silyl) oxy) (4-((tert-butyl ( Ethanol solution (5 ml) of dimethyl) silyl) oxy) phenyl) methyl) -1-methylpiperidine (1.5 g) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was neutralized with a saturated aqueous ammonium chloride solution. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane / ethyl acetate = 4: 1 to 3: 1), and 4-((S)-((tert-butyl (Dimethyl) silyl) oxy) ((2S) -1-methylpiperidin-2-yl) methyl) phenol (0.73 g) was obtained as a colorless solid.
MS (ESI pos.) M / z: 336 ([M + H] +)
1H NMR (600 MHz, DMSO-d6) δ ppm -0.12 (s, 3 H), 0.04 (s, 3 H), 0.64-0.72 (m, 1 H), 0.86 (s, 9 H), 1.01-1.12 (m, 1 H), 1.11-1.21 (m, 1 H), 1.36-1.43 (m, 1 H), 1.52-1.65 (m, 2 H), 1.93-2.03 (m, 2 H), 2.39 (s , 3 H), 2.72-2.78 (m, 1 H), 5.03 (d, J = 4.1 Hz, 1 H), 6.63-6.69 (m, 2 H), 7.07-7.11 (m, 2 H), 9.17 ( s, 1 H)
(4) 4-((S)-((tert-butyl (dimethyl) silyl) oxy) ((2S) -1-methylpiperidin-2-yl) methyl) in the same manner as in Production Example 4 (3) Phenol (0.69 g) to 4-((S)-((tert-butyl (dimethyl) silyl) oxy) ((2S) -1-methylpiperidin-2-yl) methyl) phenyl trifluoromethanesulfonate (0. 89 g) was obtained.
MS (ESI pos.) M / z: 468 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm -0.07 (s, 3 H), 0.08 (s, 3 H), 0.55-0.64 (m, 1 H), 0.91 (s, 9 H), 1.09-1.18 (m , 1 H), 1.23-1.33 (m, 1 H), 1.45-1.52 (m, 1 H), 1.58-1.64 (m, 1 H), 1.64-1.72 (m, 1 H), 2.01-2.12 (m , 2 H), 2.49 (s, 3 H), 2.84-2.91 (m, 1 H), 5.12-5.19 (m, 1 H), 7.17-7.22 (m, 2 H), 7.45-7.49 (m, 2 H)
(5) 4-((S)-((tert-butyl (dimethyl) silyl) oxy) ((2S) -1-methylpiperidin-2-yl) methyl) in the same manner as in Production Example 7 (2) Phenyl trifluoromethanesulfonate (0.84 g) to 3- (4-((S)-((tert-butyl (dimethyl) silyl) oxy) ((2S) -1-methylpiperidin-2-yl) methyl) phenyl ) Pyridine (0.71 g) was obtained as a pale yellow oil.
MS (ESI pos.) M / z: 397 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm -0.06 (s, 3 H), 0.10 (s, 3 H), 0.73-0.82 (m, 1 H), 0.93 (s, 9 H), 1.12-1.22 (m , 1 H), 1.28-1.38 (m, 1 H), 1.46-1.53 (m, 1 H), 1.59-1.67 (m, 1 H), 1.74-1.80 (m, 1 H), 2.04-2.16 (m , 2 H), 2.54 (s, 3 H), 2.86-2.93 (m, 1 H), 5.18 (d, J = 3.7 Hz, 1 H), 7.33-7.36 (m, 1 H), 7.45-7.49 ( m, 2 H), 7.51-7.54 (m, 2 H), 7.87-7.90 (m, 1 H), 8.55-8.58 (m, 1 H), 8.86-8.88 (m, 1 H)
(6) 3- (4-((S)-((tert-butyl (dimethyl) silyl) oxy) ((2S) -1-methylpiperidin-2-yl) methyl) phenyl) pyridine (0.67 g) A 1M TBAF / THF solution (3.4 ml) was added to a tetrahydrofuran (5 ml) solution, and the mixture was stirred at room temperature for 8 hours. Further, a 1M TBAF / THF solution (3.4 ml) was added, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution (30 ml) was added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane / ethyl acetate = 4: 1 to 2: 1) and (S)-((2S) -1-methyl. Piperidin-2-yl) (4-pyridin-3-ylphenyl) methanol (0.44 g) was obtained as a colorless oil.
MS (ESI pos.) M / z: 283 ([M + H] +)
1H NMR (200 MHz, CDCl3) δ ppm 1.30-1.84 (m, 6 H), 2.52 (s, 3 H), 2.53-2.75 (m, 2 H), 2.97-3.14 (m, 1 H), 4.70 ( d, J = 8.8 Hz, 1 H), 7.31-7.40 (m, 1 H), 7.44-7.60 (m, 4 H), 7.83-7.91 (m, 1 H), 8.55-8.61 (m, 1 H) , 8.83-8.87 (m, 1 H)
(7) From (S)-((2S) -1-methylpiperidin-2-yl) (4-pyridin-3-ylphenyl) methanol (0.40 g) in the same manner as in Production Example 3 (3) (S) -1-((2S) -1-methylpiperidin-2-yl) -1- (4-pyridin-3-ylphenyl) methanamine (0.27 g) was obtained.
MS (ESI pos.) M / z: 282 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.13-1.21 (m, 1 H), 1.29-1.38 (m, 2 H), 1.40-1.53 (m, 2 H), 1.65-1.73 (m, 1 H), 2.47 (s, 3 H), 2.50-2.55 (m, 1 H), 2.57-2.63 (m, 1 H), 2.98-3.04 (m, 1 H), 4.14 (d, J = 7.8 Hz, 1 H) , 7.34-7.37 (m, 1 H), 7.47-7.50 (m, 2 H), 7.53-7.56 (m, 2 H), 7.85-7.89 (m, 1 H), 8.56-8.59 (m, 1 H) , 8.84-8.86 (m, 1 H)
The following compounds were synthesized in the same manner.
(S) -1-((2S) -1-Methylpiperidin-2-yl) -1- (4-pyridin-4-ylphenyl) methanamine
MS (ESI pos.) M / z: 282 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.12-1.73 (m, 6 H), 2.47 (s, 3 H), 2.49-2.54 (m, 1 H), 2.56-2.63 (m, 1 H), 2.98- 3.03 (m, 1 H), 4.15 (d, J = 7.8 Hz, 1 H), 7.47-7.64 (m, 6 H), 8.62-8.67 (m, 2 H)
製造例12 (S)-1-((2S)-1-メチルピペリジン-2-イル)-1-(3-ピリジン-4-イルフェニル)メタンアミンの合成 Production Example 12 Synthesis of (S) -1-((2S) -1-methylpiperidin-2-yl) -1- (3-pyridin-4-ylphenyl) methanamine
(1)製造例2(1)と同様にして得たtert-ブチル(2S)-2-(3-((tert-ブチル(ジメチル)シリル)オキシ)ベンゾイル)ピペリジン-1-カルボキシラート(9.3g)から製造例11(6)と同様の方法にてtert-ブチル (2S)-2-(3-ヒドロキシベンゾイル)ピペリジン-1-カルボキシラート(6.6g)を淡茶褐色固体として得た。
MS (ESI pos.) m/z : 328([M+Na]+), (ESI neg.) m/z : 304([M-H]-)
1H NMR (200 MHz, DMSO-d6) δ ppm 1.01 - 2.04 (m, 15 H), 3.00 - 3.25 (m, 1 H), 3.71 - 3.89 (m, 1 H), 5.41 - 5.53 (m, 1 H), 6.98 - 7.09 (m, 1 H), 7.22 - 7.43 (m, 3 H), 9.82 (s, 1 H)
(2)製造例4(3)と同様の方法にてtert-ブチル (2S)-2-(3-ヒドロキシベンゾイル)ピペリジン-1-カルボキシラート(5.0g)からtert-ブチル(2S)-2-(3-(((トリフルオロメチル)スルホニル)オキシ)ベンゾイル)ピペリジン-1-カルボキシラート(6.4g)を黄色油状物質として得た。
MS (ESI pos.) m/z : 460([M+Na]+), (ESI neg.) m/z : 436([M-H]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.31 - 1.53 (m, 11 H), 1.57 - 1.75 (m, 2 H), 1.76 - 1.90 (m, 1 H), 1.97 - 2.15 (m, 1 H), 2.99 - 3.22 (m, 1 H), 3.82 - 4.00 (m, 1 H), 5.33 - 5.61 (m, 1 H), 7.43 - 7.50 (m, 1 H), 7.51 - 7.64 (m, 1 H), 7.75 - 7.88 (m, 1 H), 7.88 - 8.03 (m, 1 H)
(3)製造例2(2)と同様の方法にてtert-ブチル(2S)-2-(3-(((トリフルオロメチル)スルホニル)オキシ)ベンゾイル)ピペリジン-1-カルボキシラート(5.8g)からtert-ブチル(2S)-2-((S)-ヒドロキシ(3-(((トリフルオロメチル)スルホニル)オキシ)フェニル)メチル)ピペリジン-1-カルボキシラート(5.6g)を淡黄色油状物質として得た。
MS (ESI pos.) m/z : 440([M+H]+), (ESI pos.) m/z : 462([M+Na]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.22 - 1.28 (m, 1 H), 1.38 - 1.63 (m, 13 H), 1.66 - 1.73 (m, 1 H), 2.82 - 3.15 (m, 1 H), 3.94 - 4.39 (m, 2 H), 4.88 - 4.96 (m, 1 H), 7.19 - 7.23 (m, 1 H), 7.27 - 7.31 (m, 1 H), 7.39 - 7.48 (m, 2 H)
(4)製造例7(2)と同様の方法にてtert-ブチル(2S)-2-((S)-ヒドロキシ(3-(((トリフルオロメチル)スルホニル)オキシ)フェニル)メチル)ピペリジン-1-カルボキシラート(1.25g)からtert-ブチル(2S)-2-((S)-ヒドロキシ(3-ピリジン-4-イルフェニル)メチル)ピペリジン-1-カルボキシラート(1.0g)を無色アモルファスとして得た。
MS (ESI pos.) m/z : 369([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.29 - 1.37 (m, 1 H), 1.39 - 1.54 (m, 11 H), 1.54 - 1.65 (m, 2 H), 1.66 - 1.75 (m, 1 H), 2.96 - 3.15 (m, 1 H), 3.98 - 4.52 (m, 2 H), 4.97 (d, J=10.1 Hz, 1 H), 7.43 - 7.55 (m, 4 H), 7.55 - 7.59 (m, 1 H), 7.64 - 7.69 (m, 1 H), 8.64 - 8.67 (m, 2 H)
(5)製造例8(1)と同様にしてtert-ブチル(2S)-2-((S)-ヒドロキシ(3-ピリジン-4-イルフェニル)メチル)ピペリジン-1-カルボキシラート(0.98g)から(S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリジン-4-イルフェニル)メタノール(0.35g)を淡黄色油状物質として得た。
MS (ESI pos.) m/z : 283([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.28 - 1.35 (m, 1 H), 1.40 - 1.54 (m, 3 H), 1.54 - 1.63 (m, 1 H), 1.68 - 1.76 (m, 1 H), 2.52 (s, 3 H), 2.54 - 2.59 (m, 1 H), 2.64 - 2.71 (m, 1 H), 3.02 - 3.08 (m, 1 H), 4.72 (d, J=9.2 Hz, 1 H), 7.41 - 7.49 (m, 2 H), 7.51 - 7.57 (m, 3 H), 7.65 - 7.69 (m, 1 H), 8.64 - 8.67 (m, 2 H)
(6)製造例3(3)と同様にして(S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリジン-4-イルフェニル)メタノール(0.30g)から表題化合物(0.12g)を淡黄色油状物質として得た。
MS (ESI pos.) m/z : 282([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.15 - 1.23 (m, 1 H), 1.29 - 1.39 (m, 2 H), 1.40 - 1.73 (m, 3 H), 2.48 (s, 3 H), 2.54 - 2.60 (m, 1 H), 2.60 - 2.67 (m, 1 H), 2.99 - 3.04 (m, 1 H), 4.14 (d, J=7.8 Hz, 1 H), 7.42 - 7.46 (m, 2 H), 7.51 - 7.55 (m, 3 H), 7.67 - 7.69 (m, 1 H), 8.64 - 8.67 (m, 2 H)
同様にして以下の化合物を合成した。
(S)-1-((2S)-1-メチルピペリジン-2-イル)-1-(3-ピリジン-3-イルフェニル)メタンアミン
MS (ESI pos.) m/z : 282([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.15 - 1.71 (m, 6 H), 2.48 (s, 3 H), 2.54 - 2.60 (m, 1 H), 2.60 - 2.66 (m, 1 H), 2.99 - 3.04 (m, 1 H), 4.14 (d, J=8.3 Hz, 1 H), 7.34 - 7.38 (m, 1 H), 7.40 - 7.49 (m, 3 H), 7.60 - 7.62 (m, 1 H), 7.88 - 7.91 (m, 1 H), 8.59 (dd, J=4.6, 1.4 Hz, 1 H), 8.86 (d, J=2.3 Hz, 1 H)
(1) tert-butyl (2S) -2- (3-((tert-butyl (dimethyl) silyl) oxy) benzoyl) piperidine-1-carboxylate (9.) obtained in the same manner as in Production Example 2 (1). From 3 g), tert-butyl (2S) -2- (3-hydroxybenzoyl) piperidine-1-carboxylate (6.6 g) was obtained as a light brown solid in the same manner as in Production Example 11 (6).
MS (ESI pos.) M / z: 328 ([M + Na] +), (ESI neg.) M / z: 304 ([MH]-)
1H NMR (200 MHz, DMSO-d6) δ ppm 1.01-2.04 (m, 15 H), 3.00-3.25 (m, 1 H), 3.71-3.89 (m, 1 H), 5.41-5.53 (m, 1 H ), 6.98-7.09 (m, 1 H), 7.22-7.43 (m, 3 H), 9.82 (s, 1 H)
(2) tert-butyl (2S) -2- (3-hydroxybenzoyl) piperidine-1-carboxylate (5.0 g) to tert-butyl (2S) -2 in the same manner as in Production Example 4 (3) -(3-((((trifluoromethyl) sulfonyl) oxy) benzoyl) piperidine-1-carboxylate (6.4 g) was obtained as a yellow oil.
MS (ESI pos.) M / z: 460 ([M + Na] +), (ESI neg.) M / z: 436 ([MH]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.31-1.53 (m, 11 H), 1.57-1.75 (m, 2 H), 1.76-1.90 (m, 1 H), 1.97-2.15 (m, 1 H), 2.99-3.22 (m, 1 H), 3.82-4.00 (m, 1 H), 5.33-5.61 (m, 1 H), 7.43-7.50 (m, 1 H), 7.51-7.64 (m, 1 H), 7.75-7.88 (m, 1 H), 7.88-8.03 (m, 1 H)
(3) tert-Butyl (2S) -2- (3-(((trifluoromethyl) sulfonyl) oxy) benzoyl) piperidine-1-carboxylate (5.8 g) in the same manner as in Production Example 2 (2) ) To tert-butyl (2S) -2-((S) -hydroxy (3-(((trifluoromethyl) sulfonyl) oxy) phenyl) methyl) piperidine-1-carboxylate (5.6 g) as a pale yellow oil Obtained as material.
MS (ESI pos.) M / z: 440 ([M + H] +), (ESI pos.) M / z: 462 ([M + Na] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.22-1.28 (m, 1 H), 1.38-1.63 (m, 13 H), 1.66-1.73 (m, 1 H), 2.82-3.15 (m, 1 H), 3.94-4.39 (m, 2 H), 4.88-4.96 (m, 1 H), 7.19-7.23 (m, 1 H), 7.27-7.31 (m, 1 H), 7.39-7.48 (m, 2 H)
(4) tert-Butyl (2S) -2-((S) -hydroxy (3-(((trifluoromethyl) sulfonyl) oxy) phenyl) methyl) piperidine- in the same manner as in Production Example 7 (2) From 1-carboxylate (1.25 g) to tert-butyl (2S) -2-((S) -hydroxy (3-pyridin-4-ylphenyl) methyl) piperidine-1-carboxylate (1.0 g) is colorless. Obtained as amorphous.
MS (ESI pos.) M / z: 369 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.29-1.37 (m, 1 H), 1.39-1.54 (m, 11 H), 1.54-1.65 (m, 2 H), 1.66-1.75 (m, 1 H), 2.96-3.15 (m, 1 H), 3.98-4.52 (m, 2 H), 4.97 (d, J = 10.1 Hz, 1 H), 7.43-7.55 (m, 4 H), 7.55-7.59 (m, 1 H), 7.64-7.69 (m, 1 H), 8.64-8.67 (m, 2 H)
(5) tert-Butyl (2S) -2-((S) -hydroxy (3-pyridin-4-ylphenyl) methyl) piperidine-1-carboxylate (0.98 g) as in Production Example 8 (1) ) Gave (S)-((2S) -1-methylpiperidin-2-yl) (3-pyridin-4-ylphenyl) methanol (0.35 g) as a pale yellow oil.
MS (ESI pos.) M / z: 283 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.28-1.35 (m, 1 H), 1.40-1.54 (m, 3 H), 1.54-1.63 (m, 1 H), 1.68-1.76 (m, 1 H), 2.52 (s, 3 H), 2.54-2.59 (m, 1 H), 2.64-2.71 (m, 1 H), 3.02-3.08 (m, 1 H), 4.72 (d, J = 9.2 Hz, 1 H) , 7.41-7.49 (m, 2 H), 7.51-7.57 (m, 3 H), 7.65-7.69 (m, 1 H), 8.64-8.67 (m, 2 H)
(6) In the same manner as in Production Example 3 (3), the title compound was obtained from (S)-((2S) -1-methylpiperidin-2-yl) (3-pyridin-4-ylphenyl) methanol (0.30 g). (0.12 g) was obtained as a pale yellow oil.
MS (ESI pos.) M / z: 282 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.15-1.23 (m, 1 H), 1.29-1.39 (m, 2 H), 1.40-1.73 (m, 3 H), 2.48 (s, 3 H), 2.54- 2.60 (m, 1 H), 2.60-2.67 (m, 1 H), 2.99-3.04 (m, 1 H), 4.14 (d, J = 7.8 Hz, 1 H), 7.42-7.46 (m, 2 H) , 7.51-7.55 (m, 3 H), 7.67-7.69 (m, 1 H), 8.64-8.67 (m, 2 H)
The following compounds were synthesized in the same manner.
(S) -1-((2S) -1-Methylpiperidin-2-yl) -1- (3-pyridin-3-ylphenyl) methanamine
MS (ESI pos.) M / z: 282 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.15-1.71 (m, 6 H), 2.48 (s, 3 H), 2.54-2.60 (m, 1 H), 2.60-2.66 (m, 1 H), 2.99- 3.04 (m, 1 H), 4.14 (d, J = 8.3 Hz, 1 H), 7.34-7.38 (m, 1 H), 7.40-7.49 (m, 3 H), 7.60-7.62 (m, 1 H) , 7.88-7.91 (m, 1 H), 8.59 (dd, J = 4.6, 1.4 Hz, 1 H), 8.86 (d, J = 2.3 Hz, 1 H)
製造例13 (S)-1-((2S)-1-メチルピペリジン-2-イル)-1-(3-ピリジン-2-イルフェニル)メタンアミンの合成 Production Example 13 Synthesis of (S) -1-((2S) -1-methylpiperidin-2-yl) -1- (3-pyridin-2-ylphenyl) methanamine
(1)製造例10(1)と同様にしてtert-ブチル(2S)-2-((S)-ヒドロキシ(3-(((トリフルオロメチル)スルホニル)オキシ)フェニル)メチル)ピペリジン-1-カルボキシラート(1.5g)からtert-ブチル(2S)-2-((S)-ヒドロキシ(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メチル)ピペリジン-1-カルボキシラート(1.3g)を無色油状物質として得た。
MS (ESI pos.) m/z : 418([M+H]+)
(2)製造例10(2)と同様にしてtert-ブチル(2S)-2-((S)-ヒドロキシ(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メチル)ピペリジン-1-カルボキシラート(1.2g)及び2−ブロモピリジン(0.68g)からtert-ブチル(2S)-2-((S)-ヒドロキシ(3-ピリジン-2-イルフェニル)メチル)ピペリジン-1-カルボキシラート(0.50g)を無色油状物質として得た。
MS (ESI pos.) m/z : 369([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.31 - 1.37 (m, 1 H), 1.37 - 1.66 (m, 13 H), 1.66 - 1.74 (m, 1 H), 2.90 - 3.17 (m, 1 H), 3.98 - 4.53 (m, 2 H), 4.96 - 5.01 (m, 1 H), 7.22 - 7.26 (m, 1 H), 7.42 - 7.51 (m, 2 H), 7.74 - 7.78 (m, 2 H), 7.92 - 7.97 (m, 1 H), 7.99 - 8.01 (m, 1 H), 8.68 - 8.71 (m, 1 H)
(3)製造例5(1)と同様にしてtert-ブチル (2S)-2-((S)-ヒドロキシ(3-ピリジン-2-イルフェニル)メチル)ピペリジン-1-カルボキシラート(0.47g)から(S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリジン-2-イルフェニル)メタノール(0.36g)を淡黄色油状物質として得た。
MS (ESI pos.) m/z : 283([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.30 - 1.77 (m, 6 H), 2.53 (s, 3 H), 2.62 - 2.72 (m, 2 H), 3.02 - 3.09 (m, 1 H), 4.72 (d, J=8.7 Hz, 1 H), 7.20 - 7.25 (m, 1 H), 7.41 - 7.47 (m, 2 H), 7.72 - 7.77 (m, 2 H), 7.88 - 7.92 (m, 1 H), 7.99 - 8.03 (m, 1 H), 8.68 - 8.71 (m, 1 H)
(4)製造例5(2)と同様にして(S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリジン-2-イルフェニル)メタノール(0.32g)から表題化合物(0.13g)を黄色油状物質として得た。
MS (ESI pos.) m/z : 282([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.17 - 1.24 (m, 1 H), 1.28 - 1.37 (m, 2 H), 1.38 - 1.53 (m, 2 H), 1.64 - 1.71 (m, 1 H), 2.48 (s, 3 H), 2.58 - 2.70 (m, 2 H), 2.99 - 3.05 (m, 1 H), 4.12 - 4.15 (m, 1 H), 7.20 - 7.25 (m, 1 H), 7.41 - 7.46 (m, 2 H), 7.73 - 7.77 (m, 2 H), 7.84 - 7.88 (m, 1 H), 7.98 - 8.00 (m, 1 H), 8.68 - 8.71 (m, 1 H)
(1) In the same manner as in Production Example 10 (1), tert-butyl (2S) -2-((S) -hydroxy (3-(((trifluoromethyl) sulfonyl) oxy) phenyl) methyl) piperidine-1- Carboxylate (1.5 g) to tert-butyl (2S) -2-((S) -hydroxy (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl) methyl) piperidine-1-carboxylate (1.3 g) was obtained as a colorless oil.
MS (ESI pos.) M / z: 418 ([M + H] +)
(2) tert-butyl (2S) -2-((S) -hydroxy (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in the same manner as in Production Example 10 (2) -2-yl) phenyl) methyl) piperidine-1-carboxylate (1.2 g) and 2-bromopyridine (0.68 g) to tert-butyl (2S) -2-((S) -hydroxy (3-pyridine) -2-ylphenyl) methyl) piperidine-1-carboxylate (0.50 g) was obtained as a colorless oil.
MS (ESI pos.) M / z: 369 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.31-1.37 (m, 1 H), 1.37-1.66 (m, 13 H), 1.66-1.74 (m, 1 H), 2.90-3.17 (m, 1 H), 3.98-4.53 (m, 2 H), 4.96-5.01 (m, 1 H), 7.22-7.26 (m, 1 H), 7.42-7.51 (m, 2 H), 7.74-7.78 (m, 2 H), 7.92-7.97 (m, 1 H), 7.99-8.01 (m, 1 H), 8.68-8.71 (m, 1 H)
(3) In the same manner as in Production Example 5 (1), tert-butyl (2S) -2-((S) -hydroxy (3-pyridin-2-ylphenyl) methyl) piperidine-1-carboxylate (0.47 g ) Gave (S)-((2S) -1-methylpiperidin-2-yl) (3-pyridin-2-ylphenyl) methanol (0.36 g) as a pale yellow oil.
MS (ESI pos.) M / z: 283 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.30-1.77 (m, 6 H), 2.53 (s, 3 H), 2.62-2.72 (m, 2 H), 3.02-3.09 (m, 1 H), 4.72 ( d, J = 8.7 Hz, 1 H), 7.20-7.25 (m, 1 H), 7.41-7.47 (m, 2 H), 7.72-7.77 (m, 2 H), 7.88-7.92 (m, 1 H) , 7.99-8.03 (m, 1 H), 8.68-8.71 (m, 1 H)
(4) In the same manner as in Production Example 5 (2), the title compound was obtained from (S)-((2S) -1-methylpiperidin-2-yl) (3-pyridin-2-ylphenyl) methanol (0.32 g). (0.13 g) was obtained as a yellow oil.
MS (ESI pos.) M / z: 282 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.17-1.24 (m, 1 H), 1.28-1.37 (m, 2 H), 1.38-1.53 (m, 2 H), 1.64-1.71 (m, 1 H), 2.48 (s, 3 H), 2.58-2.70 (m, 2 H), 2.99-3.05 (m, 1 H), 4.12-4.15 (m, 1 H), 7.20-7.25 (m, 1 H), 7.41- 7.46 (m, 2 H), 7.73-7.77 (m, 2 H), 7.84-7.88 (m, 1 H), 7.98-8.00 (m, 1 H), 8.68-8.71 (m, 1 H)
製造例14 (S)-1-((2S)-1-メチルピペリジン-2-イル)-1-(4-ピリジン-2-イルフェニル)メタンアミンの合成 Production Example 14 Synthesis of (S) -1-((2S) -1-methylpiperidin-2-yl) -1- (4-pyridin-2-ylphenyl) methanamine
(1)製造例10(1)と同様にして4-((S)-((tert-ブチル(ジメチル)シリル)オキシ)((2S)-1-メチルピペリジン-2-イル)メチル)フェニル トリフルオロメタンスルホナート(1.2g)から(2S)-2-((S)-((tert-ブチル(ジメチル)シリル)オキシ)(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メチル)-1-メチルピペリジン(1.2g)を茶褐色油状物質として得た。
MS (ESI pos.) m/z : 446([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm -0.15 (s, 3 H), 0.05 (s, 3 H), 0.68 - 0.78 (m, 1 H), 0.89 (s, 9 H), 1.07 - 1.17 (m, 1 H), 1.26 - 1.38 (m, 13 H), 1.42 - 1.67 (m, 3 H), 2.02 - 2.14 (m, 2 H), 2.50 (s, 3 H), 2.81 - 2.87 (m, 1 H), 5.08 - 5.11 (m, 1 H), 7.33 - 7.37 (m, 2 H), 7.70 - 7.75 (m, 2 H)
(2)製造例10(2)と同様にして(2S)-2-((S)-((tert-ブチル(ジメチル)シリル)オキシ)(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メチル)-1-メチルピペリジン(1.1g)から2-(4-((S)-((tert-ブチル(ジメチル)シリル)オキシ)((2S)-1-メチルピペリジン-2-イル)メチル)フェニル)ピリジン(0.91g)を無色油状物質として得た。
MS (ESI pos.) m/z : 397([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm -0.10 (s, 3 H), 0.08 (s, 3 H), 0.75 - 0.84 (m, 1 H), 0.92 (s, 9 H), 1.10 - 1.21 (m, 1 H), 1.27 - 1.37 (m, 1 H), 1.44 - 1.51 (m, 1 H), 1.57 - 1.64 (m, 1 H), 1.69 - 1.76 (m, 1 H), 2.03 - 2.19 (m, 2 H), 2.54 (s, 3 H), 2.81 - 2.93 (m, 1 H), 5.13 - 5.20 (m, 1 H), 7.18 - 7.23 (m, 1 H), 7.44 - 7.48 (m, 2 H), 7.70 - 7.75 (m, 2 H), 7.90 - 7.94 (m, 2 H), 8.67 - 8.69 (m, 1 H)
(3)製造例11(6)と同様にして2-(4-((S)-((tert-ブチル(ジメチル)シリル)オキシ)((2S)-1-メチルピペリジン-2-イル)メチル)フェニル)ピリジン(0.85g)から(S)-((2S)-1-メチルピペリジン-2-イル)(4-ピリジン-2-イルフェニル)メタノール(0.38g)を無色油状物質として得た。
MS (ESI pos.) m/z : 283([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.29 - 1.35 (m, 1 H), 1.40 - 1.63 (m, 4 H), 1.68 - 1.76 (m, 1 H), 2.51 (s, 3 H), 2.55 - 2.60 (m, 1 H), 2.64 - 2.70 (m, 1 H), 3.02 - 3.08 (m, 1 H), 4.70 (d, J=8.7 Hz, 1 H), 7.19 - 7.24 (m, 1 H), 7.47 - 7.50 (m, 2 H), 7.71 - 7.77 (m, 2 H), 7.94 - 7.99 (m, 2 H), 8.67 - 8.70 (m, 1 H)
(4)製造例3(3)と同様にして(S)-((2S)-1-メチルピペリジン-2-イル)(4-ピリジン-2-イルフェニル)メタノール(0.29g)から(S)-1-((2S)-1-メチルピペリジン-2-イル)-1-(4-ピリジン-2-イルフェニル)メタンアミン(0.12g)を淡黄色固体として得た。
MS (ESI pos.) m/z : 282([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.16 - 1.72 (m, 6 H), 2.49 (s, 3 H), 2.57 - 2.72 (m, 2 H), 3.00 - 3.06 (m, 1 H), 4.09 (d, J=8.3 Hz, 1 H), 7.20 - 7.25 (m, 1 H), 7.45 - 7.50 (m, 2 H), 7.70 - 7.77 (m, 2 H), 7.93 - 7.98 (m, 2 H), 8.67 - 8.71 (m, 1 H)
(1) 4-((S)-((tert-butyl (dimethyl) silyl) oxy) ((2S) -1-methylpiperidin-2-yl) methyl) phenyl trifluoro in the same manner as in Production Example 10 (1) Lomethanesulfonate (1.2 g) to (2S) -2-((S)-((tert-butyl (dimethyl) silyl) oxy) (4- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) phenyl) methyl) -1-methylpiperidine (1.2 g) was obtained as a brown oil.
MS (ESI pos.) M / z: 446 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm -0.15 (s, 3 H), 0.05 (s, 3 H), 0.68-0.78 (m, 1 H), 0.89 (s, 9 H), 1.07-1.17 (m , 1 H), 1.26-1.38 (m, 13 H), 1.42-1.67 (m, 3 H), 2.02-2.14 (m, 2 H), 2.50 (s, 3 H), 2.81-2.87 (m, 1 H), 5.08-5.11 (m, 1 H), 7.33-7.37 (m, 2 H), 7.70-7.75 (m, 2 H)
(2) (2S) -2-((S)-((tert-butyl (dimethyl) silyl) oxy) (4- (4,4,5,5-tetramethyl) in the same manner as in Production Example 10 (2) -1,3,2-dioxaborolan-2-yl) phenyl) methyl) -1-methylpiperidine (1.1 g) to 2- (4-((S)-((tert-butyl (dimethyl) silyl) oxy) ((2S) -1-methylpiperidin-2-yl) methyl) phenyl) pyridine (0.91 g) was obtained as a colorless oil.
MS (ESI pos.) M / z: 397 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm -0.10 (s, 3 H), 0.08 (s, 3 H), 0.75-0.84 (m, 1 H), 0.92 (s, 9 H), 1.10-1.21 (m , 1 H), 1.27-1.37 (m, 1 H), 1.44-1.51 (m, 1 H), 1.57-1.64 (m, 1 H), 1.69-1.76 (m, 1 H), 2.03-2.19 (m , 2 H), 2.54 (s, 3 H), 2.81-2.93 (m, 1 H), 5.13-5.20 (m, 1 H), 7.18-7.23 (m, 1 H), 7.44-7.48 (m, 2 H), 7.70-7.75 (m, 2 H), 7.90-7.94 (m, 2 H), 8.67-8.69 (m, 1 H)
(3) 2- (4-((S)-((tert-butyl (dimethyl) silyl) oxy) ((2S) -1-methylpiperidin-2-yl) methyl in the same manner as in Production Example 11 (6) ) Phenyl) pyridine (0.85 g) to give (S)-((2S) -1-methylpiperidin-2-yl) (4-pyridin-2-ylphenyl) methanol (0.38 g) as a colorless oil. It was.
MS (ESI pos.) M / z: 283 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.29-1.35 (m, 1 H), 1.40-1.63 (m, 4 H), 1.68-1.76 (m, 1 H), 2.51 (s, 3 H), 2.55- 2.60 (m, 1 H), 2.64-2.70 (m, 1 H), 3.02-3.08 (m, 1 H), 4.70 (d, J = 8.7 Hz, 1 H), 7.19-7.24 (m, 1 H) , 7.47-7.50 (m, 2 H), 7.71-7.77 (m, 2 H), 7.94-7.99 (m, 2 H), 8.67-8.70 (m, 1 H)
(4) In the same manner as in Production Example 3 (3), from (S)-((2S) -1-methylpiperidin-2-yl) (4-pyridin-2-ylphenyl) methanol (0.29 g) to (S ) -1-((2S) -1-methylpiperidin-2-yl) -1- (4-pyridin-2-ylphenyl) methanamine (0.12 g) was obtained as a pale yellow solid.
MS (ESI pos.) M / z: 282 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.16-1.72 (m, 6 H), 2.49 (s, 3 H), 2.57-2.72 (m, 2 H), 3.00-3.06 (m, 1 H), 4.09 ( d, J = 8.3 Hz, 1 H), 7.20-7.25 (m, 1 H), 7.45-7.50 (m, 2 H), 7.70-7.77 (m, 2 H), 7.93-7.98 (m, 2 H) , 8.67-8.71 (m, 1 H)
製造例15 N-((S)-((2S)-1-アリルピペリジン-2-イル)(3-ブロモフェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミドの合成 Production Example 15 Synthesis of N-((S)-((2S) -1-allylpiperidin-2-yl) (3-bromophenyl) methyl) -2-chloro-3- (trifluoromethyl) benzamide
(1)tert-ブチル(2S)-2-((S)-ヒドロキシ(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メチル)ピペリジン-1-カルボキシラート(1.9g)のメタノール溶液(25ml)にCuBr2(3.1g)の水溶液(25ml)を加え、100℃で4時間攪拌した。反応液を減圧下濃縮し、クロロホルム及び飽和炭酸水素ナトリウム水溶液を注ぎ、攪拌した後、不溶物をセライト(商標)を用いて濾別した。濾液を分液し、水層をクロロホルムで抽出後、有機層を無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下濃縮し、残渣をカラムクロマトグラフィー(NHシリカゲル、クロロホルム/メタノール=100:0〜9:1)で精製し、(S)-(3-ブロモフェニル)((2S)-ピペリジン-2-イル)メタノール(0.99g)を青色固体として得た。
MS (ESI pos.) m/z : 270([M+H]+), (ESI pos.) m/z : 272([M+3]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.20 - 1.64 (m, 5 H), 1.74 - 1.81 (m, 1 H), 2.56 - 2.66 (m, 2 H), 3.05 - 3.11 (m, 1 H), 4.33 - 4.39 (m, 1 H), 7.18 - 7.24 (m, 1 H), 7.25 - 7.29 (m, 1 H), 7.39 - 7.43 (m, 1 H), 7.51 - 7.54 (m, 1 H)
(2)製造例3(2)と同様の方法にて(S)-(3-ブロモフェニル)((2S)-ピペリジン-2-イル)メタノール(0.95g)から(S)-((2S)-1-アリルピペリジン-2-イル)(3-ブロモフェニル)メタノール(0.68g)を無色油状物質として得た。
MS (ESI pos.) m/z : 310([M+H]+), (ESI pos.) m/z : 312([M+3]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.15 - 1.22 (m, 1 H), 1.30 - 1.37 (m, 1 H), 1.47 - 1.73 (m, 4 H), 2.55 - 2.60 (m, 1 H), 2.71 - 2.77 (m, 1 H), 2.96 - 3.03 (m, 1 H), 3.30 - 3.36 (m, 1 H), 3.39 - 3.45 (m, 1 H), 4.70 (d, J=9.6 Hz, 1 H), 5.15 - 5.23 (m, 2 H), 5.81 - 5.90 (m, 1 H), 7.19 (t, J=7.8 Hz, 1 H), 7.25 - 7.28 (m, 1 H), 7.37 - 7.41 (m, 1 H), 7.51 - 7.54 (m, 1 H)
(3)製造例3(3)と同様の方法にて(S)-((2S)-1-アリルピペリジン-2-イル)(3-ブロモフェニル)メタノール(0.64g)から(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-ブロモフェニル)メタンアミン(0.42g)を黄色油状物質として得た。
MS (ESI pos.) m/z : 309([M+H]+), (ESI pos.) m/z : 311([M+3]+)
1H NMR (600 MHz, CDCl3) δ ppm 0.97 - 1.04 (m, 1 H), 1.29 - 1.66 (m, 5 H), 2.59 - 2.69 (m, 2 H), 2.99 - 3.05 (m, 1 H), 3.33 - 3.37 (m, 2 H), 4.17 (d, J=9.6 Hz, 1 H), 5.11 - 5.15 (m, 1 H), 5.18 - 5.23 (m, 1 H), 5.84 - 5.92 (m, 1 H), 7.17 (t, J=7.8 Hz, 1 H), 7.27 - 7.29 (m, 1 H), 7.35 - 7.38 (m, 1 H), 7.52 - 7.54 (m, 1 H)
(4)製造例4(1)と同様の方法にて(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-ブロモフェニル)メタンアミン(0.39g)からN-((S)-((2S)-1-アリルピペリジン-2-イル)(3-ブロモフェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド(0.52g)を無色固体として得た。
MS (ESI pos.) m/z : 515([M+H]+), (ESI pos.) m/z : 517([M+3]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.28 - 1.35 (m, 1 H), 1.35 - 1.43 (m, 1 H), 1.48 - 1.60 (m, 3 H), 1.74 - 1.82 (m, 1 H), 2.54 - 2.62 (m, 1 H), 2.77 - 2.82 (m, 1 H), 2.88 - 2.96 (m, 1 H), 3.17 - 3.24 (m, 1 H), 3.25 - 3.32 (m, 1 H), 4.87 - 4.93 (m, 1 H), 5.07 - 5.16 (m, 2 H), 5.68 - 5.77 (m, 1 H), 7.22 (t, J=7.8 Hz, 1 H), 7.30 - 7.34 (m, 1 H), 7.37 - 7.46 (m, 2 H), 7.49 - 7.52 (m, 1 H), 7.69 - 7.79 (m, 3 H)
(1) tert-butyl (2S) -2-((S) -hydroxy (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methyl) piperidine An aqueous solution (25 ml) of CuBr 2 (3.1 g) was added to a methanol solution (25 ml) of -1-carboxylate (1.9 g), and the mixture was stirred at 100 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, chloroform and a saturated aqueous sodium hydrogen carbonate solution were poured, and the mixture was stirred, and the insoluble material was filtered off using Celite (trademark). The filtrate was separated, the aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, chloroform / methanol = 100: 0 to 9: 1), and (S)-(3-bromophenyl) ( (2S) -piperidin-2-yl) methanol (0.99 g) was obtained as a blue solid.
MS (ESI pos.) M / z: 270 ([M + H] +), (ESI pos.) M / z: 272 ([M + 3] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.20-1.64 (m, 5 H), 1.74-1.81 (m, 1 H), 2.56-2.66 (m, 2 H), 3.05-3.11 (m, 1 H), 4.33-4.39 (m, 1 H), 7.18-7.24 (m, 1 H), 7.25-7.29 (m, 1 H), 7.39-7.43 (m, 1 H), 7.51-7.54 (m, 1 H)
(2) (S)-(3-Bromophenyl) ((2S) -piperidin-2-yl) methanol (0.95 g) to (S)-((2S) in the same manner as in Production Example 3 (2) ) -1-Allylpiperidin-2-yl) (3-bromophenyl) methanol (0.68 g) was obtained as a colorless oil.
MS (ESI pos.) M / z: 310 ([M + H] +), (ESI pos.) M / z: 312 ([M + 3] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.15-1.22 (m, 1 H), 1.30-1.37 (m, 1 H), 1.47-1.73 (m, 4 H), 2.55-2.60 (m, 1 H), 2.71-2.77 (m, 1 H), 2.96-3.03 (m, 1 H), 3.30-3.36 (m, 1 H), 3.39-3.45 (m, 1 H), 4.70 (d, J = 9.6 Hz, 1 H), 5.15-5.23 (m, 2 H), 5.81-5.90 (m, 1 H), 7.19 (t, J = 7.8 Hz, 1 H), 7.25-7.28 (m, 1 H), 7.37-7.41 ( m, 1 H), 7.51-7.54 (m, 1 H)
(3) From (S)-((2S) -1-allylpiperidin-2-yl) (3-bromophenyl) methanol (0.64 g) in the same manner as in Production Example 3 (3), (S)- 1-((2S) -1-allylpiperidin-2-yl) -1- (3-bromophenyl) methanamine (0.42 g) was obtained as a yellow oil.
MS (ESI pos.) M / z: 309 ([M + H] +), (ESI pos.) M / z: 311 ([M + 3] +)
1H NMR (600 MHz, CDCl3) δ ppm 0.97-1.04 (m, 1 H), 1.29-1.66 (m, 5 H), 2.59-2.69 (m, 2 H), 2.99-3.05 (m, 1 H), 3.33-3.37 (m, 2 H), 4.17 (d, J = 9.6 Hz, 1 H), 5.11-5.15 (m, 1 H), 5.18-5.23 (m, 1 H), 5.84-5.92 (m, 1 H), 7.17 (t, J = 7.8 Hz, 1 H), 7.27-7.29 (m, 1 H), 7.35-7.38 (m, 1 H), 7.52-7.54 (m, 1 H)
(4) (S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3-bromophenyl) methanamine (0.39 g) in the same manner as in Production Example 4 (1) To N-((S)-((2S) -1-allylpiperidin-2-yl) (3-bromophenyl) methyl) -2-chloro-3- (trifluoromethyl) benzamide (0.52 g) Obtained as a solid.
MS (ESI pos.) M / z: 515 ([M + H] +), (ESI pos.) M / z: 517 ([M + 3] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.28-1.35 (m, 1 H), 1.35-1.43 (m, 1 H), 1.48-1.60 (m, 3 H), 1.74-1.82 (m, 1 H), 2.54-2.62 (m, 1 H), 2.77-2.82 (m, 1 H), 2.88-2.96 (m, 1 H), 3.17-3.24 (m, 1 H), 3.25-3.32 (m, 1 H), 4.87-4.93 (m, 1 H), 5.07-5.16 (m, 2 H), 5.68-5.77 (m, 1 H), 7.22 (t, J = 7.8 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.37-7.46 (m, 2 H), 7.49-7.52 (m, 1 H), 7.69-7.79 (m, 3 H)
本発明化合物の製造に用いる原料化合物は以下のように合成した。
(A) 3−クロロ−4−トリフルオロメチルピリジン−2−カルボン酸の合成
The raw material compound used for the production of the compound of the present invention was synthesized as follows.
(A) Synthesis of 3-chloro-4-trifluoromethylpyridine-2-carboxylic acid
(1)Tetrahedron (1993) 49 (1), 49に記載の方法にて3−クロロピリジンから3−クロロ−4−ヨードピリジンを得た。
(2)Eur. J. Org. Chem., (2004), 3793に記載の方法にて3−クロロ−4−ヨードピリジンから3−クロロ−4−トリフルオロメチルピリジンを得た。
(3)Eur. J. Org. Chem., (2004), 3793に記載の方法にて3−クロロ−4−トリフルオロメチルピリジンから表題化合物を得た。
(1) 3-Chloro-4-iodopyridine was obtained from 3-chloropyridine by the method described in Tetrahedron (1993) 49 (1), 49.
(2) 3-Chloro-4-trifluoromethylpyridine was obtained from 3-chloro-4-iodopyridine by the method described in Eur. J. Org. Chem., (2004), 3793.
(3) The title compound was obtained from 3-chloro-4-trifluoromethylpyridine by the method described in Eur. J. Org. Chem., (2004), 3793.
(B) 3−クロロ−2−トリフルオロメチルイソニコチン酸の合成 (B) Synthesis of 3-chloro-2-trifluoromethylisonicotinic acid
(1)Eur. J. Org. Chem., (2002), 4181に記載の方法にて2,3−ジクロロピリジンから3−クロロ−2−ヨードピリジンを得た。
(2)Synthesis, (2004) 1619に記載の方法にて3−クロロ−2−ヨードピリジンから3−クロロ−2−トリフルオロピリジンを得た。
(3)Synthesis, (2004) 1619に記載の方法にて3−クロロ−2−トリフルオロピリジンから表題化合物を得た。
(1) 3-Chloro-2-iodopyridine was obtained from 2,3-dichloropyridine by the method described in Eur. J. Org. Chem., (2002), 4181.
(2) 3-chloro-2-trifluoropyridine was obtained from 3-chloro-2-iodopyridine by the method described in Synthesis, (2004) 1619.
(3) The title compound was obtained from 3-chloro-2-trifluoropyridine by the method described in Synthesis, (2004) 1619.
(C) ピラゾールホウ酸ピナコールエステルの合成
1−メチル−5−(4,4,5,5−テトラメチル−[1,3,2]ジオキソボロラン−2−イル)−1H−ピラゾール、1−エチル−5−(4,4,5,5−テトラメチル−[1,3,2]ジオキソボロラン−2−イル)−1H−ピラゾール、1−エチル−4−(4,4,5,5−テトラメチル−[1,3,2]ジオキソボロラン−2−イル)−1H−ピラゾール、1−イソプロピル−4−(4,4,5,5−テトラメチル−[1,3,2]ジオキソボロラン−2−イル)−1H−ピラゾール、及び1−n−プロピル−4−(4,4,5,5−テトラメチル−[1,3,2]ジオキソボロラン−2−イル)−1H−ピラゾールはJournal of Heterocyclic Chemistry 41, 931 (2004)に記載の方法又は同様の方法にて合成した。
(C) Synthesis of pyrazoleboric acid pinacol ester 1-methyl-5- (4,4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -1H-pyrazole, 1-ethyl- 5- (4,4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -1H-pyrazole, 1-ethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -1H-pyrazole, 1-isopropyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl)- 1H-pyrazole and 1-n-propyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -1H-pyrazole are obtained from Journal of Heterocyclic Chemistry 41, 931. (2004) or similar method It was synthesized by the method.
実施例1Example 1
2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド 1塩酸塩(化合物21)の合成2-Chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- (trifluoromethyl) Synthesis of benzamide monohydrochloride (compound 21)
(1)3-((S)-((2S)-1-アリルピペリジン-2-イル)((2-クロロ-3-(トリフルオロメチル)ベンゾイル)アミノ)メチル)フェニル トリフルオロメタンスルホナート(3.3g)、1−メチル−1H−ピラゾール−4−ホウ酸ピナコールエステル(1.8g)、及び炭酸カリウム(1.8g)をDMF/エタノール(=2:1)の混合溶媒(40ml)に懸濁させ、窒素置換後、Pd(PPh3)4(0.33g)を加え、90℃で3時間攪拌下加熱した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(NHシリカゲル、クロロホルム/メタノール=9:1)で精製し、N-((S)-((2S)-1-アリルピペリジン-2-イル)(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド(2.1g)を淡黄色アモルファスとして得た。
MS (ESI pos.) m/z : 517([M+H]+), (ESI neg.) m/z : 515([M-H]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.32 - 1.44 (m, 2 H), 1.47 - 1.64 (m, 3 H), 1.76 - 1.86 (m, 1 H), 2.55 - 2.60 (m, 1 H), 2.84 - 2.88 (m, 1 H), 2.93 - 2.99 (m, 1 H), 3.20 - 3.25 (m, 1 H), 3.28 - 3.34 (m, 1 H), 3.95 (s, 3 H), 4.92 - 5.00 (m, 1 H), 5.07 - 5.16 (m, 2 H), 5.69 - 5.78 (m, 1 H), 7.21 - 7.79 (m, 10 H)
(2)窒素雰囲気下、N-((S)-((2S)-1-アリルピペリジン-2-イル)(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド(2.1g)のクロロホルム溶液(20ml)に1,3−ジメチルバルビツール酸(1.9g)及びPd(PPh3)4(46mg)を加え、室温で2時間攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=9:1、及びNHシリカゲル、クロロホルム/メタノール=9:1)で精製し、2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド(1.3g)を得た。この化合物をエタノール(13ml)に溶解させ、氷冷下4M HCl/酢酸エチル溶液(1.1ml)を加えた。減圧下濃縮後、酢酸エチルを加えることにより固化させ、析出した固体を濾取し、表題化合物(1.2g)を得た。
(1) 3-((S)-((2S) -1-allylpiperidin-2-yl) ((2-chloro-3- (trifluoromethyl) benzoyl) amino) methyl) phenyl trifluoromethanesulfonate (3 3 g), 1-methyl-1H-pyrazole-4-boric acid pinacol ester (1.8 g), and potassium carbonate (1.8 g) were suspended in a mixed solvent (40 ml) of DMF / ethanol (= 2: 1). After turbidity and substitution with nitrogen, Pd (PPh 3 ) 4 (0.33 g) was added, and the mixture was heated at 90 ° C. with stirring for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol = 9: 1), and N-((S)- ((2S) -1-allylpiperidin-2-yl) (3- (1-methyl-1H-pyrazol-4-yl) phenyl) methyl) -2-chloro-3- (trifluoromethyl) benzamide (2. 1 g) was obtained as a pale yellow amorphous.
MS (ESI pos.) M / z: 517 ([M + H] +), (ESI neg.) M / z: 515 ([MH]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.32-1.44 (m, 2 H), 1.47-1.64 (m, 3 H), 1.76-1.86 (m, 1 H), 2.55-2.60 (m, 1 H), 2.84-2.88 (m, 1 H), 2.93-2.99 (m, 1 H), 3.20-3.25 (m, 1 H), 3.28-3.34 (m, 1 H), 3.95 (s, 3 H), 4.92- 5.00 (m, 1 H), 5.07-5.16 (m, 2 H), 5.69-5.78 (m, 1 H), 7.21-7.79 (m, 10 H)
(2) N-((S)-((2S) -1-allylpiperidin-2-yl) (3- (1-methyl-1H-pyrazol-4-yl) phenyl) methyl) -2 under nitrogen atmosphere 1,3-dimethylbarbituric acid (1.9 g) and Pd (PPh 3 ) 4 (46 mg) were added to a chloroform solution (20 ml) of -chloro-3- (trifluoromethyl) benzamide (2.1 g) at room temperature. For 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, chloroform / methanol = 9: 1, and NH silica gel, chloroform / methanol = 9: 1). 2-chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- ( Trifluoromethyl) benzamide (1.3 g) was obtained. This compound was dissolved in ethanol (13 ml), and 4M HCl / ethyl acetate solution (1.1 ml) was added under ice cooling. After concentration under reduced pressure, the mixture was solidified by adding ethyl acetate, and the precipitated solid was collected by filtration to give the title compound (1.2 g).
実施例2Example 2
3-クロロ-N-((S)-(2S)-ピペリジン-2-イル(4-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド 2塩酸塩(化合物18)の合成3-chloro-N-((S)-(2S) -piperidin-2-yl (4-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2-carboxamide dihydrochloride (compound 18) Synthesis
(1)3−クロロ−4−トリフルオロメチルピリジン−2−カルボン酸(0.24g)のDMF溶液(7ml)にHOBt・H2O(0.21g)及びEDC・HCl(0.25g)を加え、室温で15分間攪拌後、(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(4-ピリジン-3-イルフェニル)メタンアミン(0.30g)を加え、室温で4時間攪拌した。酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加え、分液後、水層を酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=6:1〜1:1)で精製し、N-((S)-((2S)-1-アリルピペリジン-2-イル)(4-ピリジン-3-イルフェニル)メチル)-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.24g)を淡黄色アモルファスとして得た。
MS (ESI pos.) m/z : 515([M+H]+), (ESI neg.) m/z : 513([M-H]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.33 - 1.47 (m, 2 H), 1.48 - 1.64 (m, 3 H), 1.78 - 1.85 (m, 1 H), 2.57 - 2.63 (m, 1 H), 2.90 - 2.96 (m, 1 H), 2.96 - 3.03 (m, 1 H), 3.20 - 3.28 (m, 1 H), 3.32 - 3.39 (m, 1 H), 4.98 - 5.03 (m, 1 H), 5.09 - 5.14 (m, 1 H), 5.18 - 5.23 (m, 1 H), 5.77 - 5.88 (m, 1 H), 7.33 - 7.37 (m, 1 H), 7.47 - 7.51 (m, 2 H), 7.53 - 7.57 (m, 2 H), 7.71 (d, J=5.0 Hz, 1 H), 7.84 - 7.87 (m, 1 H), 8.56 - 8.59 (m, 1 H), 8.69 (d, J=4.6 Hz, 1 H), 8.80 - 8.85 (m, 2 H)
(2)窒素雰囲気下、N-((S)-((2S)-1-アリルピペリジン-2-イル)(4-ピリジン-3-イルフェニル)メチル)-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.20g)のクロロホルム溶液(3ml)に1,3−ジメチルバルビツール酸(0.18g)及びPd(PPh3)4(4.4mg)を加え、室温で1晩攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール/28%NH3アンモニア水溶液=49:1:0.5)で精製し、3-クロロ-N-((S)-(2S)-ピペリジン-2-イル(4-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.17g)を淡赤色アモルファスとして得た。得られた生成物を酢酸エチル(8ml)に溶解させ、氷冷下4M HCl/酢酸エチル溶液(1ml)を加え、室温で1時間攪拌した。析出した固体を濾取し、表題化合物(0.17g)を得た。
(1) HOBt · H 2 O (0.21 g) and EDC · HCl (0.25 g) were added to a DMF solution (7 ml) of 3-chloro-4-trifluoromethylpyridine-2-carboxylic acid (0.24 g). After stirring for 15 minutes at room temperature, (S) -1-((2S) -1-allylpiperidin-2-yl) -1- (4-pyridin-3-ylphenyl) methanamine (0.30 g) was added. And stirred at room temperature for 4 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and after liquid separation, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane / ethyl acetate = 6: 1 to 1: 1), and N- ((S)-((2S) -1-allylpiperidin-2-yl) (4-pyridin-3-ylphenyl) methyl) -3-chloro-4- (trifluoromethyl) pyridine-2-carboxamide (0 .24 g) was obtained as a pale yellow amorphous.
MS (ESI pos.) M / z: 515 ([M + H] +), (ESI neg.) M / z: 513 ([MH]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.33-1.47 (m, 2 H), 1.48-1.64 (m, 3 H), 1.78-1.85 (m, 1 H), 2.57-2.63 (m, 1 H), 2.90-2.96 (m, 1 H), 2.96-3.03 (m, 1 H), 3.20-3.28 (m, 1 H), 3.32-3.39 (m, 1 H), 4.98-5.03 (m, 1 H), 5.09-5.14 (m, 1 H), 5.18-5.23 (m, 1 H), 5.77-5.88 (m, 1 H), 7.33-7.37 (m, 1 H), 7.47-7.51 (m, 2 H), 7.53-7.57 (m, 2 H), 7.71 (d, J = 5.0 Hz, 1 H), 7.84-7.87 (m, 1 H), 8.56-8.59 (m, 1 H), 8.69 (d, J = 4.6 Hz, 1 H), 8.80-8.85 (m, 2 H)
(2) Under nitrogen atmosphere, N-((S)-((2S) -1-allylpiperidin-2-yl) (4-pyridin-3-ylphenyl) methyl) -3-chloro-4- (trifluoro 1,3-Dimethylbarbituric acid (0.18 g) and Pd (PPh 3 ) 4 (4.4 mg) were added to a chloroform solution (3 ml) of methyl) pyridine-2-carboxamide (0.20 g), and 1 at room temperature. Stir overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the desiccant is filtered off and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, chloroform / methanol / 28% NH 3 aqueous ammonia solution = 49: 1: 0.5). Purified and purified 3-chloro-N-((S)-(2S) -piperidin-2-yl (4-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2-carboxamide (0 .17 g) was obtained as a pale red amorphous. The obtained product was dissolved in ethyl acetate (8 ml), 4M HCl / ethyl acetate solution (1 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to obtain the title compound (0.17 g).
N-((S)-ビフェニル-3-イル((2S)-ピペリジン-2-イル)メチル)-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド 1塩酸塩(化合物16)の合成N-((S) -biphenyl-3-yl ((2S) -piperidin-2-yl) methyl) -3-chloro-4- (trifluoromethyl) pyridine-2-carboxamide monohydrochloride (compound 16) Composition
(1)3−クロロ−4−トリフルオロメチルピリジン−2−カルボン酸(0.34g)のDMF溶液(5ml)にHOBt・H2O(0.30g)及びEDC・HCl(0.34g)を加え、室温で15分間攪拌後、(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-ビフェニル-3-イルメタンアミン(0.40g)を加え、室温で一晩攪拌した。酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加え、分液後、水層を酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=99:1〜49:1)で精製し、N-[(S)-[(2S)-1-アリルピペリジン-2-イル](ビフェニル-3-イル)メチル]-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.53g)を淡黄色アモルファスとして得た。
(ESI pos.) m/z : 514([M+H]+), (ESI neg.) m/z : 512([M-H]-)
(2)窒素雰囲気下、N-[(S)-[(2S)-1-アリルピペリジン-2-イル](ビフェニル-3-イル)メチル]-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.46g)のクロロホルム溶液(5ml)に1,3−ジメチルバルビツール酸(0.42g)及びPd(PPh3)4(10mg)を加え、室温で2時間攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール/28%NH3アンモニウム水溶液=49:1:0.5、続いてNHシリカゲル、ヘキサン/酢酸エチル=3:1〜2:1)で精製し、N-{(S)-ビフェニル-3-イル[(2S)-ピペリジン-2-イル]メチル}-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.30g)を無色アモルファスとして得た。得られた生成物を酢酸エチル(3ml)に溶解させ、4M HCl/酢酸エチル溶液(1ml)を加えた後減圧下濃縮し、表題化合物(0.25g)を無色アモルファスとして得た。
(1) HOBt · H 2 O (0.30 g) and EDC · HCl (0.34 g) were added to a DMF solution (5 ml) of 3-chloro-4-trifluoromethylpyridine-2-carboxylic acid (0.34 g). After stirring at room temperature for 15 minutes, (S) -1-((2S) -1-allylpiperidin-2-yl) -1-biphenyl-3-ylmethanamine (0.40 g) was added, and the mixture was stirred at room temperature. Stir overnight. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and after liquid separation, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 99: 1 to 49: 1), and N-[( S)-[(2S) -1-allylpiperidin-2-yl] (biphenyl-3-yl) methyl] -3-chloro-4- (trifluoromethyl) pyridine-2-carboxamide (0.53 g) Obtained as a yellow amorphous.
(ESI pos.) M / z: 514 ([M + H] +), (ESI neg.) M / z: 512 ([MH]-)
(2) N-[(S)-[(2S) -1-allylpiperidin-2-yl] (biphenyl-3-yl) methyl] -3-chloro-4- (trifluoromethyl) pyridine under nitrogen atmosphere 1,3-Dimethylbarbituric acid (0.42 g) and Pd (PPh 3 ) 4 (10 mg) were added to a chloroform solution (5 ml) of -2-carboxamide (0.46 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, chloroform / methanol / 28% NH 3 ammonium aqueous solution = 49: 1: 0.5, then NH silica gel, hexane / ethyl acetate = 3: 1 to 2: 1), and N-{(S) -biphenyl-3-yl [(2S) -piperidin-2-yl] methyl} -3-chloro -4- (Trifluoromethyl) pyridine-2-carboxamide (0.30 g) was obtained as a colorless amorphous. The obtained product was dissolved in ethyl acetate (3 ml), 4M HCl / ethyl acetate solution (1 ml) was added, and the mixture was concentrated under reduced pressure to give the title compound (0.25 g) as a colorless amorphous product.
3-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピリジン-3-イルフェニル)メチル]-4-(トリフルオロメチル)ピリジン-2-カルボキサミド 2塩酸塩(化合物20)の合成3-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyridin-3-ylphenyl) methyl] -4- (trifluoromethyl) pyridine-2-carboxamide dihydrochloride (compound 20) Synthesis
(1)3−クロロ−4−トリフルオロメチルピリジン−2−カルボン酸(0.24g)のDMF溶液(7ml)にHOBt・H2O(0.22g)及びEDC・HCl(0.25g)を加え、室温で15分間攪拌後、(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-ピリジン-3-イルフェニル)メタンアミン(0.30g)を加え、室温で一晩攪拌した。酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加え、分液後、水層を酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=99:1〜30:1)で精製し、N-[(S)-[(2S)-1-アリルピペリジン-2-イル](3-ピリジン-3-イルフェニル)メチル]-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.38g)を黄色固体として得た。
MS (ESI pos.) m/z : 515([M+H]+), (ESI neg.) m/z : 513([M-H]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.34 - 1.46 (m, 2 H), 1.48 - 1.64 (m, 3 H), 1.77 - 1.86 (m, 1 H), 2.56 - 2.63 (m, 1 H), 2.90 - 3.02 (m, 2 H), 3.20 - 3.26 (m, 1 H), 3.29 - 3.37 (m, 1 H), 5.03 (dd, J=8.9, 4.4 Hz, 1 H), 5.08 - 5.13 (m, 1 H), 5.16 - 5.22 (m, 1 H), 5.76 - 5.86 (m, 1 H), 7.33 - 7.37 (m, 1 H), 7.42 - 7.48 (m, 3 H), 7.56 - 7.59 (m, 1 H), 7.71 (d, J=5.0 Hz, 1 H), 7.85 - 7.89 (m, 1 H), 8.58 (dd, J=4.6, 1.4 Hz, 1 H), 8.69 (d, J=4.6 Hz, 1 H), 8.79 - 8.85 (m, 2 H)
(2)窒素雰囲気下、N-[(S)-[(2S)-1-アリルピペリジン-2-イル](3-ピリジン-3-イルフェニル)メチル]-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.27g)のクロロホルム溶液(5ml)に1,3−ジメチルバルビツール酸(0.24g)及びPd(PPh3)4(6mg)を加え、室温で4時間攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール/28%NH3水溶液=50:1:0.5)で精製し、3-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピリジン-3-イルフェニル)メチル]-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.24g)を淡黄色アモルファスとして得た。得られた精製物を酢酸エチル(8ml)に溶解させ、氷冷下4M HCl/酢酸エチル溶液(1ml)を加え、室温で1時間攪拌した。析出した固体を濾取し、表題化合物(0.24g)を無色固体として得た。
(1) HOBt · H 2 O (0.22 g) and EDC · HCl (0.25 g) were added to a DMF solution (7 ml) of 3-chloro-4-trifluoromethylpyridine-2-carboxylic acid (0.24 g). After stirring at room temperature for 15 minutes, (S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3-pyridin-3-ylphenyl) methanamine (0.30 g) was added. Stir at room temperature overnight. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and after liquid separation, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 99: 1 to 30: 1), and N-[( S)-[(2S) -1-allylpiperidin-2-yl] (3-pyridin-3-ylphenyl) methyl] -3-chloro-4- (trifluoromethyl) pyridine-2-carboxamide (0.38 g ) Was obtained as a yellow solid.
MS (ESI pos.) M / z: 515 ([M + H] +), (ESI neg.) M / z: 513 ([MH]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.34-1.46 (m, 2 H), 1.48-1.64 (m, 3 H), 1.77-1.86 (m, 1 H), 2.56-2.63 (m, 1 H), 2.90-3.02 (m, 2 H), 3.20-3.26 (m, 1 H), 3.29-3.37 (m, 1 H), 5.03 (dd, J = 8.9, 4.4 Hz, 1 H), 5.08-5.13 (m , 1 H), 5.16-5.22 (m, 1 H), 5.76-5.86 (m, 1 H), 7.33-7.37 (m, 1 H), 7.42-7.48 (m, 3 H), 7.56-7.59 (m , 1 H), 7.71 (d, J = 5.0 Hz, 1 H), 7.85-7.89 (m, 1 H), 8.58 (dd, J = 4.6, 1.4 Hz, 1 H), 8.69 (d, J = 4.6 Hz, 1 H), 8.79-8.85 (m, 2 H)
(2) Under nitrogen atmosphere, N-[(S)-[(2S) -1-allylpiperidin-2-yl] (3-pyridin-3-ylphenyl) methyl] -3-chloro-4- (trifluoro 1,3-Dimethylbarbituric acid (0.24 g) and Pd (PPh 3 ) 4 (6 mg) were added to a chloroform solution (5 ml) of methyl) pyridine-2-carboxamide (0.27 g), and the mixture was stirred at room temperature for 4 hours. did. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the desiccant is filtered off and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, chloroform / methanol / 28% NH 3 aqueous solution = 50: 1: 0.5). 3-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyridin-3-ylphenyl) methyl] -4- (trifluoromethyl) pyridine-2-carboxamide (0. 24 g) was obtained as a pale yellow amorphous. The purified product thus obtained was dissolved in ethyl acetate (8 ml), 4M HCl / ethyl acetate solution (1 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give the title compound (0.24 g) as a colorless solid.
2-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピラジン-2-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド 1塩酸塩(化合物39)の合成Synthesis of 2-chloro-N-((S)-(2S) -piperidin-2-yl (3-pyrazin-2-ylphenyl) methyl) -3- (trifluoromethyl) benzamide monohydrochloride (compound 39)
(1)2−クロロ−3−トリフルオロメチル安息香酸(0.18g)のDMF溶液(4ml)にHOBt・H2O(0.14g)及びEDC・HCl(0.17g)を加え、室温で15分間攪拌後、(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-ピラジン-2-イルフェニル)メタンアミン(0.22g)を加え、室温で一晩攪拌した。酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加え、分液後、水層を酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=100:0〜97:3)で精製し、N-[(S)-[(2S)-1-アリルピペリジン-2-イル](3-ピラジン-2-イルフェニル)メチル]-2-クロロ-3-(トリフルオロメチル)ベンズアミド(0.25g)を淡黄色固体として得た。
MS (ESI pos.) m/z : (ESI pos.) m/z : 515([M+H]+), (ESI neg.) m/z : 513([M-H]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.34 - 1.87 (m, 6 H), 2.56 - 2.63 (m, 1 H), 2.87 - 3.01 (m, 2 H), 3.20 - 3.27 (m, 1 H), 3.28 - 3.34 (m, 1 H), 5.02 - 5.16 (m, 3 H), 5.70 - 5.79 (m, 1 H), 7.41 - 7.45 (m, 1 H), 7.49 - 7.53 (m, 2 H), 7.70 - 7.74 (m, 1 H), 7.76 - 7.79 (m, 1 H), 7.80 - 7.86 (m, 1 H), 7.90 - 7.94 (m, 1 H), 8.05 - 8.08 (m, 1 H), 8.50 - 8.52 (m, 1 H), 8.63 - 8.66 (m, 1 H), 9.03 - 9.05 (m, 1 H)
(2)窒素雰囲気下、N-[(S)-[(2S)-1-アリルピペリジン-2-イル](3-ピラジン-2-イルフェニル)メチル]-2-クロロ-3-(トリフルオロメチル)ベンズアミド(0.20g)のクロロホルム溶液(2ml)に1,3−ジメチルバルビツール酸(0.18g)及びPd(PPh3)4(4.5mg)を加え、室温で4時間攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=75:25)及びTLC(シリカゲル、クロロホルム/メタノール=9:1)で精製し、2-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピラジン-2-イルフェニル)メチル]-3-(トリフルオロメチル)ベンズアミド(0.14g)を得た。得られた精製物を酢酸エチル(2ml)に溶解させ、氷冷下4M HCl/酢酸エチル溶液(0.15ml)を加え、減圧下溶媒を留去し、表題化合物(0.11g)を無色アモルファスとして得た。
(1) HOBt · H 2 O (0.14 g) and EDC · HCl (0.17 g) were added to a DMF solution (4 ml) of 2-chloro-3-trifluoromethylbenzoic acid (0.18 g) at room temperature. After stirring for 15 minutes, (S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3-pyrazin-2-ylphenyl) methanamine (0.22 g) was added and mixed at room temperature. Stir overnight. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and after liquid separation, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 100: 0 to 97: 3), and N-[( S)-[(2S) -1-allylpiperidin-2-yl] (3-pyrazin-2-ylphenyl) methyl] -2-chloro-3- (trifluoromethyl) benzamide (0.25 g) was pale yellow Obtained as a solid.
MS (ESI pos.) M / z: (ESI pos.) M / z: 515 ([M + H] +), (ESI neg.) M / z: 513 ([MH]-)
1H NMR (600 MHz, CDCl3) δ ppm 1.34-1.87 (m, 6 H), 2.56-2.63 (m, 1 H), 2.87-3.01 (m, 2 H), 3.20-3.27 (m, 1 H), 3.28-3.34 (m, 1 H), 5.02-5.16 (m, 3 H), 5.70-5.79 (m, 1 H), 7.41-7.45 (m, 1 H), 7.49-7.53 (m, 2 H), 7.70-7.74 (m, 1 H), 7.76-7.79 (m, 1 H), 7.80-7.86 (m, 1 H), 7.90-7.94 (m, 1 H), 8.05-8.08 (m, 1 H), 8.50-8.52 (m, 1 H), 8.63-8.66 (m, 1 H), 9.03-9.05 (m, 1 H)
(2) Under nitrogen atmosphere, N-[(S)-[(2S) -1-allylpiperidin-2-yl] (3-pyrazin-2-ylphenyl) methyl] -2-chloro-3- (trifluoro 1,3-Dimethylbarbituric acid (0.18 g) and Pd (PPh 3 ) 4 (4.5 mg) were added to a chloroform solution (2 ml) of methyl) benzamide (0.20 g), and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was subjected to column chromatography (NH silica gel, hexane / ethyl acetate = 75: 25) and TLC (silica gel, chloroform / methanol = 9). 1) and 2-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyrazin-2-ylphenyl) methyl] -3- (trifluoromethyl) benzamide (0 .14 g) was obtained. The obtained purified product was dissolved in ethyl acetate (2 ml), 4M HCl / ethyl acetate solution (0.15 ml) was added under ice cooling, the solvent was distilled off under reduced pressure, and the title compound (0.11 g) was purified as a colorless amorphous product. Got as.
2-クロロ-N-{(S)-[3-(1-メチル-1H-イミダゾール-5-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-3-(トリフルオロメチル)ベンズアミド 2塩酸塩(化合物70)の合成2-Chloro-N-{(S)-[3- (1-methyl-1H-imidazol-5-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -3- (trifluoromethyl) Synthesis of benzamide dihydrochloride (compound 70)
(1)2−クロロ−3−トリフルオロメチル安息香酸(0.15g)のDMF溶液(4ml)にHOBt・H2O(0.11g)及びEDC・HCl(0.14g)を加え、室温で15分間攪拌後、(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-(1-メチル-1H-イミダゾール-5-イル)フェニル)メタンアミン(0.19g)を加え、室温で一晩攪拌した。酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加え、分液後、水層を酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=67:33〜0:100、続いてシリカゲル、クロロホルム/メタノール=100:0〜97:3)で精製し、N-{(S)-[(2S)-1-アリルピペリジン-2-イル][3-(1-メチル-1H-イミダゾール-5-イル)フェニル]メチル}-2-クロロ-3-(トリフルオロメチル)ベンズアミド(0.21g)を無色アモルファスとして得た。
MS(ESI pos.) m/z : 517([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.30 - 1.93 (m, 6 H), 2.54 - 2.62 (m, 1 H), 2.83 - 2.91 (m, 1 H), 2.91 - 2.99 (m, 1 H), 3.18 - 3.25 (m, 1 H), 3.28 - 3.36 (m, 1 H), 3.67 (s, 3 H), 4.94 - 5.02 (m, 1 H), 5.05 - 5.15 (m, 2 H), 5.68 - 5.79 (m, 1 H), 7.10 (s, 1 H), 7.28 - 7.32 (m, 1 H), 7.37 - 7.46 (m, 4 H), 7.52 (s, 1 H), 7.67 - 7.73 (m, 1 H), 7.76 - 7.84 (m, 2 H)
(2)窒素雰囲気下、N-{(S)-[(2S)-1-アリルピペリジン-2-イル][3-(1-メチル-1H-イミダゾール-5-イル)フェニル]メチル}-2-クロロ-3-(トリフルオロメチル)ベンズアミド(0.19g)のクロロホルム溶液(2ml)に1,3−ジメチルバルビツール酸(0.17g)及びPd(PPh3)4(4.2mg)を加え、室温で一晩攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=67:33〜0:100)及びTLC(シリカゲル、クロロホルム/メタノール=9:1)で精製し2-クロロ-N-{(S)-[3-(1-メチル-1H-イミダゾール-5-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-3-(トリフルオロメチル)ベンズアミド(0.12g)を得た。得られた精製物を酢酸エチル(2ml)に溶解させ、氷冷下4M HCl/酢酸エチル溶液(0.2ml)を加え、室温で30分間攪拌した。析出した固体を濾取し、表題化合物(0.12g)を得た。
(1) HOBt · H 2 O (0.11 g) and EDC · HCl (0.14 g) were added to a DMF solution (4 ml) of 2-chloro-3-trifluoromethylbenzoic acid (0.15 g) at room temperature. After stirring for 15 minutes, (S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3- (1-methyl-1H-imidazol-5-yl) phenyl) methanamine (0. 19 g) was added and stirred at room temperature overnight. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and after liquid separation, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. Methanol = 100: 0 to 97: 3) and purified by N-{(S)-[(2S) -1-allylpiperidin-2-yl] [3- (1-methyl-1H-imidazol-5-yl ) Phenyl] methyl} -2-chloro-3- (trifluoromethyl) benzamide (0.21 g) was obtained as a colorless amorphous.
MS (ESI pos.) M / z: 517 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.30-1.93 (m, 6 H), 2.54-2.62 (m, 1 H), 2.83-2.91 (m, 1 H), 2.91-2.99 (m, 1 H), 3.18-3.25 (m, 1 H), 3.28-3.36 (m, 1 H), 3.67 (s, 3 H), 4.94-5.02 (m, 1 H), 5.05-5.15 (m, 2 H), 5.68- 5.79 (m, 1 H), 7.10 (s, 1 H), 7.28-7.32 (m, 1 H), 7.37-7.46 (m, 4 H), 7.52 (s, 1 H), 7.67-7.73 (m, 1 H), 7.76-7.84 (m, 2 H)
(2) N-{(S)-[(2S) -1-allylpiperidin-2-yl] [3- (1-methyl-1H-imidazol-5-yl) phenyl] methyl} -2 under nitrogen atmosphere 1,3-Dimethylbarbituric acid (0.17 g) and Pd (PPh 3 ) 4 (4.2 mg) were added to a chloroform solution (2 ml) of -chloro-3- (trifluoromethyl) benzamide (0.19 g). Stir at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was subjected to column chromatography (NH silica gel, hexane / ethyl acetate = 67: 33-0: 100) and TLC (silica gel, chloroform). / Methanol = 9: 1) and purified by 2-chloro-N-{(S)-[3- (1-methyl-1H-imidazol-5-yl) phenyl] [(2S) -piperidin-2-yl] Methyl} -3- (trifluoromethyl) benzamide (0.12 g) was obtained. The purified product thus obtained was dissolved in ethyl acetate (2 ml), 4M HCl / ethyl acetate solution (0.2 ml) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration to obtain the title compound (0.12 g).
3-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピリミジン-5-イルフェニル)メチル]-4-(トリフルオロメチル)ピリジン-2-カルボキサミド 1塩酸塩(化合物75)の合成3-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyrimidin-5-ylphenyl) methyl] -4- (trifluoromethyl) pyridine-2-carboxamide monohydrochloride (compound 75)
(1)3−クロロ−4−トリフルオロメチルピリジン−2−カルボン酸(0.38g)のDMF溶液(7ml)にHOBt・H2O(0.35g)及びEDC・HCl(0.40g)を加え、室温で30分間攪拌後、(S)-1-((2S)-1-アリルピペリジン-2-イル)-1-(3-ピリミジン-5-イルフェニル)メタンアミン(0.47g)のDMF溶液(3ml)を加え、室温で2時間攪拌した。酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加え、分液後、水層を酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、ヘキサン/酢酸エチル=1:2)で精製し、N-[(S)-[(2S)-1-アリルピペリジン-2-イル](3-ピリミジン-5-イルフェニル)メチル]-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.29g)を淡黄色アモルファスとして得た。
MS (ESI pos.) m/z : 516([M+H]+)
1H NMR (600 MHz, CDCl3) δ ppm 1.33 - 1.83 (m, 6 H), 2.47 - 2.55 (m, 1 H), 2.85 - 2.92 (m, 1 H), 2.97 - 3.05 (m, 1 H), 3.07 - 3.14 (m, 1 H), 3.34 - 3.41 (m, 1 H), 4.99 - 5.05 (m, 1 H), 5.06 - 5.16 (m, 2 H), 5.73 - 5.84 (m, 1 H), 6.94 (d, J=8.7 Hz, 1 H), 7.18 - 7.21 (m, 1 H), 7.26 - 7.33 (m, 2 H), 7.36 - 7.42 (m, 2 H), 7.58 - 7.59 (m, 1 H), 7.72 - 7.73 (m, 1 H), 8.09 - 8.10 (m, 1 H), 9.17 - 9.21 (m, 1 H)
(2)窒素雰囲気下、N-[(S)-[(2S)-1-アリルピペリジン-2-イル](3-ピリミジン-5-イルフェニル)メチル]-3-クロロ-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.28g)のクロロホルム溶液(10ml)に1,3−ジメチルバルビツール酸(0.25g)及びPd(PPh3)4(6.0mg)を加え、室温で一晩攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=95:5、続いてNHシリカゲル、ヘキサン/酢酸エチル=1:1)で精製し3-クロロ-N-[(S)-(2S)-ピペリジン-2-イル(3-ピリミジン-5-イルフェニル)メチル]-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(0.13g)を得た。得られた精製物を酢酸エチル(2ml)及びメタノール(1ml)に溶解させ、氷冷下4M HCl/酢酸エチル溶液(2ml)を加え、減圧下溶媒を留去し、表題化合物(0.14g)を得た。
(1) HOBt · H 2 O (0.35 g) and EDC · HCl (0.40 g) were added to a DMF solution (7 ml) of 3-chloro-4-trifluoromethylpyridine-2-carboxylic acid (0.38 g). In addition, after stirring at room temperature for 30 minutes, (S) -1-((2S) -1-allylpiperidin-2-yl) -1- (3-pyrimidin-5-ylphenyl) methanamine (0.47 g) in DMF The solution (3 ml) was added and stirred at room temperature for 2 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and after liquid separation, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 1: 2), and N-[(S)- [(2S) -1-allylpiperidin-2-yl] (3-pyrimidin-5-ylphenyl) methyl] -3-chloro-4- (trifluoromethyl) pyridine-2-carboxamide (0.29 g) Obtained as a yellow amorphous.
MS (ESI pos.) M / z: 516 ([M + H] +)
1H NMR (600 MHz, CDCl3) δ ppm 1.33-1.83 (m, 6 H), 2.47-2.55 (m, 1 H), 2.85-2.92 (m, 1 H), 2.97-3.05 (m, 1 H), 3.07-3.14 (m, 1 H), 3.34-3.41 (m, 1 H), 4.99-5.05 (m, 1 H), 5.06-5.16 (m, 2 H), 5.73-5.84 (m, 1 H), 6.94 (d, J = 8.7 Hz, 1 H), 7.18-7.21 (m, 1 H), 7.26-7.33 (m, 2 H), 7.36-7.42 (m, 2 H), 7.58-7.59 (m, 1 H), 7.72-7.73 (m, 1 H), 8.09-8.10 (m, 1 H), 9.17-9.21 (m, 1 H)
(2) N-[(S)-[(2S) -1-allylpiperidin-2-yl] (3-pyrimidin-5-ylphenyl) methyl] -3-chloro-4- (trifluoro) under nitrogen atmosphere 1,3-Dimethylbarbituric acid (0.25 g) and Pd (PPh 3 ) 4 (6.0 mg) were added to a chloroform solution (10 ml) of methyl) pyridine-2-carboxamide (0.28 g), and the mixture was added at room temperature. Stir overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, chloroform / methanol = 95: 5, followed by NH silica gel, hexane / ethyl acetate = 1: 1) 3-chloro-N-[(S)-(2S) -piperidin-2-yl (3-pyrimidin-5-ylphenyl) methyl] -4- (trifluoromethyl) pyridine-2-carboxamide (0.13 g) was obtained. The obtained purified product was dissolved in ethyl acetate (2 ml) and methanol (1 ml), 4M HCl / ethyl acetate solution (2 ml) was added under ice-cooling, and the solvent was evaporated under reduced pressure to give the title compound (0.14 g). Got.
実施例3Example 3
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリジン-3-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド 2塩酸塩の合成(化合物7)Of 2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyridin-3-ylphenyl) methyl) -3- (trifluoromethyl) benzamide dihydrochloride Synthesis (Compound 7)
2−クロロ−3−トリフルオロメチル安息香酸(96mg)のDMF溶液(3ml)にHOBt・H2O(87mg)及びEDC・HCl(98mg)を加え、室温で15分間攪拌後、(S)-1-((2S)-1-メチルピペリジン-2-イル)-1-(3-ピリジン-3-イルフェニル)メタンアミン(100mg)を加え、室温で4時間攪拌した。酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加え、分液後、水層を酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=3:1〜1:1)で精製し、2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピリジン-3-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド(0.14g)を無色アモルファルとして得た。得られた生成物を酢酸エチル(4ml)に溶解させ、4M HCl/酢酸エチル溶液(1ml)を加え、室温で30分間攪拌した。減圧下濃縮後残渣をクロロホルム(1ml)及びジイソプロピルエーテル(3ml)の混合溶媒で固化させ、析出した固体を濾取し、表題化合物(0.14g)を得た。 To a DMF solution (3 ml) of 2-chloro-3-trifluoromethylbenzoic acid (96 mg), HOBt · H 2 O (87 mg) and EDC · HCl (98 mg) were added, and after stirring at room temperature for 15 minutes, (S) − 1-((2S) -1-methylpiperidin-2-yl) -1- (3-pyridin-3-ylphenyl) methanamine (100 mg) was added and stirred at room temperature for 4 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and after liquid separation, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane / ethyl acetate = 3: 1 to 1: 1), and 2- Chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyridin-3-ylphenyl) methyl) -3- (trifluoromethyl) benzamide (0.14 g) Obtained as colorless amorphal. The obtained product was dissolved in ethyl acetate (4 ml), 4M HCl / ethyl acetate solution (1 ml) was added, and the mixture was stirred at room temperature for 30 min. After concentration under reduced pressure, the residue was solidified with a mixed solvent of chloroform (1 ml) and diisopropyl ether (3 ml), and the precipitated solid was collected by filtration to give the title compound (0.14 g).
実施例4Example 4
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド 1塩酸塩(化合物12)の合成2-Chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3- (1-methyl-1H-pyrazol-4-yl) phenyl) methyl) -3- (tri Synthesis of fluoromethyl) benzamide monohydrochloride (compound 12)
3-((S)-((2-クロロ-3-(トリフルオロメチル)ベンゾイル)アミノ)((2S)-1-メチルピペリジン-2-イル)メチル)フェニル トリフルオロメタンスルホナート(0.20g)及び1−メチル−1H−ピラゾール−4−ホウ酸ピナコールエステル(0.15g)から実施例1(1)と同様の方法にて表題化合物(88mg)を無色アモルファスとして得た。 3-((S)-((2-chloro-3- (trifluoromethyl) benzoyl) amino) ((2S) -1-methylpiperidin-2-yl) methyl) phenyl trifluoromethanesulfonate (0.20 g) And the title compound (88 mg) was obtained as colorless amorphous from 1-methyl-1H-pyrazole-4-boric acid pinacol ester (0.15 g) in the same manner as in Example 1 (1).
実施例5Example 5
2-クロロ-N-{(S)-[3-(3,5-ジメチルイソオキサゾール-4-イル)フェニル][(2S)-ピペリジン-2-イル]メチル}-3-(トリフルオロメチル)ベンズアミド 1塩酸塩(化合物69)の合成2-Chloro-N-{(S)-[3- (3,5-dimethylisoxazol-4-yl) phenyl] [(2S) -piperidin-2-yl] methyl} -3- (trifluoromethyl) Synthesis of benzamide monohydrochloride (compound 69)
N-((S)-((2S)-1-アリルピペリジン-2-イル)(3-ブロモフェニル)メチル)-2-クロロ-3-(トリフルオロメチル)ベンズアミド(53mg)をDMF/水(2:1)の混合溶媒(1ml)に溶解させ、窒素置換後、炭酸水素ナトリウム(52mg)、3,5−ジメチルイソオキサゾールホウ酸ピナコールエステル(91mg)及びPd(PPh3)4(4mg)を加え、100℃で1晩加熱した。室温まで冷却後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をTLC(NHシリカゲル、ヘキサン/酢酸エチル=1:2、続いてシリカゲル、クロロホルム/メタノール=9:1)で精製し、2-クロロ-N-((S)-(3-(3,5-ジメチルイソオキサゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド(12mg)を無色アモルファスとして得た。この精製物を酢酸エチル(1ml)に溶解させ、4M HCl/酢酸エチル(0.1ml)を加え、減圧濃縮し、表題化合物(12mg)を得た。 N-((S)-((2S) -1-allylpiperidin-2-yl) (3-bromophenyl) methyl) -2-chloro-3- (trifluoromethyl) benzamide (53 mg) was added to DMF / water ( 2: 1) dissolved in a mixed solvent (1 ml), and after nitrogen substitution, sodium bicarbonate (52 mg), 3,5-dimethylisoxazole boric acid pinacol ester (91 mg) and Pd (PPh 3 ) 4 (4 mg) were added. In addition, it was heated at 100 ° C. overnight. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was TLC (NH silica gel, hexane / ethyl acetate = 1: 2, then silica gel, chloroform / methanol = 9: 1). 2-chloro-N-((S)-(3- (3,5-dimethylisoxazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- ( Trifluoromethyl) benzamide (12 mg) was obtained as a colorless amorphous. This purified product was dissolved in ethyl acetate (1 ml), 4M HCl / ethyl acetate (0.1 ml) was added, and the mixture was concentrated under reduced pressure to give the title compound (12 mg).
実施例6Example 6
2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピラジン-2-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド 1塩酸塩(化合物14)の合成2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyrazin-2-ylphenyl) methyl) -3- (trifluoromethyl) benzamide monohydrochloride ( Synthesis of compound 14)
(1)3-((S)-((2-クロロ-3-(トリフルオロメチル)ベンゾイル)アミノ)((2S)-1-メチルピペリジン-2-イル)メチル)フェニル トリフルオロメタンスルホナート(0.30g)を1,4−ジオキサン(6.0ml)に溶解させ、窒素置換後、ビスピナコールボラン(274mg)、Pd(dppf)Cl2・CH2Cl2(44mg)、dppf(60mg)、及び酢酸カリウム(317mg)を加え、80℃で4時間加熱攪拌した。室温まで冷却後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=30:1)で精製し、2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド(0.23g)を黒色アモルファスとして得た。
(2)(1)で得た2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド(0.23g)、2−クロロピラジン(0.12g)及び炭酸カリウム(0.21g)をDMF/エタノール(=2:1)の混合溶媒(3ml)に懸濁させ、窒素置換後、Pd(PPh3)4(29mg)を加え、90℃で1.5時間攪拌下加熱した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール=19:1〜9:1、続いてNHシリカゲル、ヘキサン/酢酸エチル=3:1〜2:1)で精製し、2-クロロ-N-((S)-((2S)-1-メチルピペリジン-2-イル)(3-ピラジン-2-イルフェニル)メチル)-3-(トリフルオロメチル)ベンズアミド(58mg)を無色固体として得た。得られた固体を酢酸エチル(8ml)に溶解させ、4M HCl/酢酸エチル溶液(1ml)を加え、室温で30分間攪拌した。減圧下溶媒を留去し、表題化合物(58mg)を無色アモルファスとして得た。
(1) 3-((S)-((2-chloro-3- (trifluoromethyl) benzoyl) amino) ((2S) -1-methylpiperidin-2-yl) methyl) phenyl trifluoromethanesulfonate (0 .30 g) is dissolved in 1,4-dioxane (6.0 ml), and after nitrogen substitution, bispinacol borane (274 mg), Pd (dppf) Cl 2 .CH 2 Cl 2 (44 mg), dppf (60 mg), and Potassium acetate (317 mg) was added, and the mixture was heated with stirring at 80 ° C. for 4 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 30: 1) and 2-chloro-N-((S)-((2S) -1- Methylpiperidin-2-yl) (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methyl) -3- (trifluoromethyl) benzamide (0. 23 g) was obtained as a black amorphous.
(2) 2-chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3- (4,4,5,5-tetramethyl-1) obtained in (1) , 3,2-Dioxaborolan-2-yl) phenyl) methyl) -3- (trifluoromethyl) benzamide (0.23 g), 2-chloropyrazine (0.12 g) and potassium carbonate (0.21 g) in DMF / After suspending in a mixed solvent (3 ml) of ethanol (= 2: 1) and purging with nitrogen, Pd (PPh 3 ) 4 (29 mg) was added and heated at 90 ° C. with stirring for 1.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the desiccant is filtered off and concentrated under reduced pressure. 2-Chloro-N-((S)-((2S) -1-methylpiperidin-2-yl) (3-pyrazin-2-ylphenyl) methyl ) -3- (Trifluoromethyl) benzamide (58 mg) was obtained as a colorless solid. The obtained solid was dissolved in ethyl acetate (8 ml), 4M HCl / ethyl acetate solution (1 ml) was added, and the mixture was stirred at room temperature for 30 min. The solvent was distilled off under reduced pressure to obtain the title compound (58 mg) as a colorless amorphous.
実施例7Example 7
3-クロロ-N-((S)-((2S)-1-(シアノメチル)ピペリジン-2-イル)(3-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(化合物82)の合成3-Chloro-N-((S)-((2S) -1- (cyanomethyl) piperidin-2-yl) (3-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl) pyridine-2 -Synthesis of carboxamide (compound 82)
ブロモアセトニトリル(16mg)及びN,N−ジイソプロピルエチルアミン(16mg)のDMF溶液(1ml)に3-クロロ-N-((S)-(2S)-ピペリジン-2-イル(3-ピリジン-3-イルフェニル)メチル)-4-(トリフルオロメチル)ピリジン-2-カルボキサミド(30mg)を加え、90℃で2時間加熱攪拌を行った。反応混合物を酢酸エチル/ヘキサン(=2:1)の混合溶媒で希釈し、水及び飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をTLC(シリカゲル、ヘキサン/酢酸エチル=1:4)で精製し、表題化合物(18mg)を得た。 3-Chloro-N-((S)-(2S) -piperidin-2-yl (3-pyridin-3-yl) was added to a DMF solution (1 ml) of bromoacetonitrile (16 mg) and N, N-diisopropylethylamine (16 mg). Phenyl) methyl) -4- (trifluoromethyl) pyridine-2-carboxamide (30 mg) was added, and the mixture was stirred with heating at 90 ° C. for 2 hr. The reaction mixture was diluted with a mixed solvent of ethyl acetate / hexane (= 2: 1) and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure, and the residue was purified by TLC (silica gel, hexane / ethyl acetate = 1: 4) to obtain the title compound (18 mg).
実施例8Example 8
2-クロロ-N-((S)-((2S)-1-シクロプロピルピペリジン-2-イル)(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド 1塩酸塩(化合物83)の合成 2-Chloro-N-((S)-((2S) -1-cyclopropylpiperidin-2-yl) (3- (1-methyl-1H-pyrazol-4-yl) phenyl) methyl) -3- ( Synthesis of (trifluoromethyl) benzamide monohydrochloride (compound 83)
窒素雰囲気下、2-クロロ-N-((S)-(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)((2S)-ピペリジン-2-イル)メチル)-3-(トリフルオロメチル)ベンズアミド(0.12g)、[(1−エトキシシクロプロピル)オキシ]トリメチルシラン(0.30ml)及び酢酸(0.14ml)をメタノール(2ml)に溶解させ、粉状のモレキュラーシーブ3A(50mg)及びシアノトリヒドロホウ酸ナトリウム(51mg)を加え6時間加熱還流を行った。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、減圧下濃縮後、残渣をカラムクロマトグラフィー(NHシリカゲル、ヘキサン/酢酸エチル=4:1〜1:1、続いてシリカゲル、クロロホルム/メタノール=100:0〜97:3)で精製し、無色アモルファス状の2-クロロ-N-((S)-((2S)-1-シクロプロピルピペリジン-2-イル)(3-(1-メチル-1H-ピラゾール-4-イル)フェニル)メチル)-3-(トリフルオロメチル)ベンズアミド(81mg)を得た。得られた化合物を酢酸エチル(2ml)に溶解させ、4M HCl/酢酸エチル溶液(0.2ml)を加えた後、減圧下溶媒を留去した。析出した固体をヘキサン/酢酸エチル(=1:1)の混合溶媒で洗浄し、表題化合物(70mg)を得た。
実施例1から8で示した化合物と、同様の方法で合成した化合物の構造式を表1−1から表1−9までに示した。並びにそれらの機器データを表2−1から表2−13に示した。
Under a nitrogen atmosphere, 2-chloro-N-((S)-(3- (1-methyl-1H-pyrazol-4-yl) phenyl) ((2S) -piperidin-2-yl) methyl) -3- ( Trifluoromethyl) benzamide (0.12 g), [(1-ethoxycyclopropyl) oxy] trimethylsilane (0.30 ml) and acetic acid (0.14 ml) were dissolved in methanol (2 ml) to obtain a powdery molecular sieve 3A. (50 mg) and sodium cyanotrihydroborate (51 mg) were added, and the mixture was heated to reflux for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was subjected to column chromatography (NH silica gel, hexane / ethyl acetate = 4: 1 to 1: 1, followed by silica gel, chloroform / Purification by methanol = 100: 0 to 97: 3) and colorless amorphous 2-chloro-N-((S)-((2S) -1-cyclopropylpiperidin-2-yl) (3- (1- Methyl-1H-pyrazol-4-yl) phenyl) methyl) -3- (trifluoromethyl) benzamide (81 mg) was obtained. The obtained compound was dissolved in ethyl acetate (2 ml), 4M HCl / ethyl acetate solution (0.2 ml) was added, and the solvent was evaporated under reduced pressure. The precipitated solid was washed with a mixed solvent of hexane / ethyl acetate (= 1: 1) to obtain the title compound (70 mg).
The structural formulas of the compounds shown in Examples 1 to 8 and the compounds synthesized by the same method are shown in Table 1-1 to Table 1-9. The device data are shown in Tables 2-1 to 2-13.
試験例 [グリシン取り込み阻害実験]
グリシン取り込み実験はNeuron, 8, 927-935, 1992に掲載された方法に従って行った。ヒト1型グリシントランスポーター(GlyT1)を発現した神経膠腫であるT98G細胞を用いた。T98G細胞を96ウェルプレートに2.0×104個/ウェルにて播種し、炭酸ガスインキュベーター内にて一晩培養した。被検物質は100%DMSO溶液に溶解したのち、150mM塩化ナトリウム、1mM塩化カルシウム、5mM塩化カリウム、1mM塩化マグネシウム、10mMグルコースおよび0.2%ウシ血清アルブミンを含む10mMHEPES緩衝液(pH7.4)に溶解させた。細胞培養用培地を除去した後、被検物質および[3H]グリシン(最終濃度 250nM)を細胞に添加し、室温にて15分間反応させた。反応終了後、マニーホールドにて細胞外液を吸引し、細胞外に存在する余分な標識グリシンを除去したのち、0.5Mの水酸化ナトリウム水溶液にて細胞を溶解した。細胞内に存在するグリシン量は、細胞溶解液中の放射活性を液体シンチレーションカウンターで測定することにより求めた。10μMのALX5407存在下におけるグリシン取り込み量を非特異的取り込みとし、10μMのALX5407非存在下の総取り込み量から非特異的取り込み量を差し引いたものを特異的取り込み量とした。また、被検物質の10−10〜10−6濃度での抑制曲線からグリシン取り込み阻害活性(IC50値)を算出した。
Test example [Glycine uptake inhibition experiment]
The glycine uptake experiment was performed according to the method published in Neuron, 8, 927-935, 1992. T98G cells that are gliomas expressing human type 1 glycine transporter (GlyT1) were used. T98G cells were seeded in a 96-well plate at 2.0 × 10 4 cells / well, and cultured overnight in a carbon dioxide incubator. A test substance is dissolved in a 100% DMSO solution, and then dissolved in 10 mM HEPES buffer (pH 7.4) containing 150 mM sodium chloride, 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose, and 0.2% bovine serum albumin. Dissolved. After removing the cell culture medium, a test substance and [ 3 H] glycine (final concentration 250 nM) were added to the cells and allowed to react at room temperature for 15 minutes. After completion of the reaction, the extracellular fluid was aspirated with a manifold, the excess labeled glycine present outside the cells was removed, and then the cells were lysed with a 0.5 M aqueous sodium hydroxide solution. The amount of glycine present in the cells was determined by measuring the radioactivity in the cell lysate with a liquid scintillation counter. The glycine uptake in the presence of 10 μM ALX5407 was defined as nonspecific uptake, and the total uptake in the absence of 10 μM ALX5407 minus the nonspecific uptake was defined as the specific uptake. Moreover, the glycine uptake inhibitory activity (IC 50 value) was calculated from the inhibition curve at 10 −10 to 10 −6 concentration of the test substance.
本発明化合物のIC50値を表3に例示する。 Table 3 shows IC 50 values of the compounds of the present invention.
本発明化合物は、グリシントランスポーター阻害作用を有し、グリシントランスポーターに関連する疾患の治療薬、具体的には、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害(全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等)、うつ病、薬物依存、痙攣、振戦、及び睡眠障害等などの予防・治療薬として利用できる。 The compound of the present invention has a glycine transporter inhibitory action and is a therapeutic agent for diseases related to the glycine transporter, specifically, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder) Disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremor, sleep disorder, etc. Available as
Claims (19)
環Aは、N及びOから選択される1又は2個のヘテロ原子を環内原子として有する5員又は6員の芳香環であり(ここで、該芳香環は無置換又は1〜3個のC1−6アルキルで置換されている);
Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルは無置換、或いはハロゲン、C1−6アルキル、C1−6ハロアルキル、シアノ、C1−6アルコキシ、C1−6アシル、C1−6ハロアシル及びC1−6ハロアルコキシからなる群から選ばれる1から3個の基で置換されているか、又はメチレンオキシで置換されている);
R1は水素原子、C1−6アルキル、C3−6アルケニル、又はC3−8シクロアルキルであり(ここで、該C1−6アルキルは無置換又はシアノで置換されている)、
nは1又は2である]で表される化合物又はその医薬上許容される塩。 Formula [I]
Ring A is a 5- or 6-membered aromatic ring having 1 or 2 heteroatoms selected from N and O as ring atoms (wherein the aromatic ring is unsubstituted or 1 to 3 Substituted with C 1-6 alkyl);
Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are unsubstituted or halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 1-6 alkoxy, C 1-6 acyl, C 1 Substituted with 1 to 3 groups selected from the group consisting of 1-6 haloacyl and C 1-6 haloalkoxy, or substituted with methyleneoxy);
R 1 is a hydrogen atom, C 1-6 alkyl, C 3-6 alkenyl, or C 3-8 cycloalkyl (wherein the C 1-6 alkyl is unsubstituted or substituted with cyano);
n is 1 or 2] or a pharmaceutically acceptable salt thereof.
Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルは無置換、或いはハロゲン、C1−6アルキル、C1−6ハロアルキル、シアノ、C1−6アルコキシ、C1−6アシル、C1−6ハロアシル及びC1−6ハロアルコキシからなる群から選ばれる1から3個の基で置換されているか、又はメチレンオキシで置換されている)、
R1は水素原子、C1−6アルキル、C3−6アルケニル、又はC3−8シクロアルキルであり(ここで、該C1−6アルキルは無置換又はシアノで置換されている)、
nは1又は2である]で表される化合物又はその医薬上許容される塩。 Formula [I ′]
Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are unsubstituted or halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 1-6 alkoxy, C 1-6 acyl, C 1 Substituted with 1 to 3 groups selected from the group consisting of 1-6 haloacyl and C 1-6 haloalkoxy, or substituted with methyleneoxy),
R 1 is a hydrogen atom, C 1-6 alkyl, C 3-6 alkenyl, or C 3-8 cycloalkyl (wherein the C 1-6 alkyl is unsubstituted or substituted with cyano);
n is 1 or 2] or a pharmaceutically acceptable salt thereof.
環Aは1又は2個の窒素原子を環内原子として有する5員又は6員の芳香環であり(ここで、該芳香環は無置換又は1個のC1−6アルキルで置換されている)、
Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ及びC1−6ハロアルコキシからなる群から選ばれる1個から3個の基で置換されている)、
nは1又は2である]で表される請求項1記載の化合物又はその医薬上許容される塩。 Formula [II]
Ring A is a 5-membered or 6-membered aromatic ring having 1 or 2 nitrogen atoms as ring atoms (wherein the aromatic ring is unsubstituted or substituted by 1 C 1-6 alkyl) ),
Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy) Substituted with 3 to 3 groups),
The compound according to claim 1, wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof.
R2は水素原子又はC1−6アルキルであり、
nは1又は2であり、
ベンゼン環上におけるピラゾリルの置換位置は3位又は4位である]で表される請求項1記載の化合物又はその医薬上許容される塩。 Formula [III]
R 2 is a hydrogen atom or C 1-6 alkyl;
n is 1 or 2,
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the substitution position of pyrazolyl on the benzene ring is the 3-position or the 4-position.
[式中、Ar1はフェニル又はピリジルであり(ここで、該フェニル及びピリジルはハロゲン、C1−6アルキル及びC1−6ハロアルキルからなる群から選ばれる2又は3個の基で置換されている)、
nは1又は2であり、
ベンゼン環上におけるピリジルの置換位置は3位又は4位である]で表される請求項1記載の化合物又はその医薬上許容される塩。 Formula [IV]
[Wherein Ar 1 is phenyl or pyridyl (wherein the phenyl and pyridyl are substituted with 2 or 3 groups selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl) Is)
n is 1 or 2,
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the substitution position of pyridyl on the benzene ring is the 3-position or the 4-position.
nは1又は2であり、
ベンゼン環上におけるピリミジニルの置換位置は3位又は4位である]で表される請求項1記載の化合物又はその医薬上許容される塩。 Formula [V]
n is 1 or 2,
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the substitution position of pyrimidinyl on the benzene ring is the 3-position or the 4-position.
nは1又は2であり、
ベンゼン環上におけるピラジニルの置換位置は3位又は4位である]で表される請求項1記載の化合物又はその医薬上許容される塩。 Formula [VI]
n is 1 or 2,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the substitution position of pyrazinyl on the benzene ring is the 3-position or the 4-position.
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