KR20210139317A - 2급 아민을 함유하는 화합물의 아민 부분에 중수소 저급 알킬을 도입하는 방법 - Google Patents
2급 아민을 함유하는 화합물의 아민 부분에 중수소 저급 알킬을 도입하는 방법 Download PDFInfo
- Publication number
- KR20210139317A KR20210139317A KR1020217032236A KR20217032236A KR20210139317A KR 20210139317 A KR20210139317 A KR 20210139317A KR 1020217032236 A KR1020217032236 A KR 1020217032236A KR 20217032236 A KR20217032236 A KR 20217032236A KR 20210139317 A KR20210139317 A KR 20210139317A
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- deuterium
- ethyl
- amine
- lower alkyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 39
- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 32
- 150000001875 compounds Chemical class 0.000 title claims abstract description 23
- 150000001412 amines Chemical group 0.000 title claims abstract description 18
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 title 1
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 57
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 53
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 21
- 239000002168 alkylating agent Substances 0.000 claims abstract description 17
- 229940100198 alkylating agent Drugs 0.000 claims abstract description 17
- 230000007935 neutral effect Effects 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- -1 alkyllithium Chemical compound 0.000 claims description 38
- 150000003335 secondary amines Chemical class 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000012022 methylating agents Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- RMNJNEUWTBBZPT-FIBGUPNXSA-N trideuteriomethyl 4-nitrobenzenesulfonate Chemical compound [2H]C([2H])([2H])OS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 RMNJNEUWTBBZPT-FIBGUPNXSA-N 0.000 claims description 5
- CZXGXYBOQYQXQD-FIBGUPNXSA-N trideuteriomethyl benzenesulfonate Chemical compound [2H]C([2H])([2H])OS(=O)(=O)c1ccccc1 CZXGXYBOQYQXQD-FIBGUPNXSA-N 0.000 claims description 5
- MBABOKRGFJTBAE-FIBGUPNXSA-N trideuteriomethyl methanesulfonate Chemical group [2H]C([2H])([2H])OS(C)(=O)=O MBABOKRGFJTBAE-FIBGUPNXSA-N 0.000 claims description 5
- XSMPTAFRHKDINV-ZBJDZAJPSA-N 1,1,2,2,2-pentadeuterioethyl 2-nitrobenzenesulfonate Chemical compound [2H]C([2H])([2H])C([2H])([2H])OS(=O)(=O)C1=CC=CC=C1[N+](=O)[O-] XSMPTAFRHKDINV-ZBJDZAJPSA-N 0.000 claims description 4
- VRZVPALEJCLXPR-WNWXXORZSA-N 1,1,2,2,2-pentadeuterioethyl 4-methylbenzenesulfonate Chemical compound [2H]C([2H])([2H])C([2H])([2H])OS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-WNWXXORZSA-N 0.000 claims description 4
- MHGHMVLMYWTSMK-ZBJDZAJPSA-N 1,1,2,2,2-pentadeuterioethyl 4-nitrobenzenesulfonate Chemical compound [2H]C([2H])([2H])C([2H])([2H])OS(=O)(=O)C1=CC=C(C=C1)[N+](=O)[O-] MHGHMVLMYWTSMK-ZBJDZAJPSA-N 0.000 claims description 4
- XDRMBCMMABGNMM-ZBJDZAJPSA-N 1,1,2,2,2-pentadeuterioethyl benzenesulfonate Chemical compound [2H]C([2H])([2H])C([2H])([2H])OS(=O)(=O)C1=CC=CC=C1 XDRMBCMMABGNMM-ZBJDZAJPSA-N 0.000 claims description 4
- PLUBXMRUUVWRLT-WNWXXORZSA-N 1,1,2,2,2-pentadeuterioethyl methanesulfonate Chemical group [2H]C([2H])([2H])C([2H])([2H])OS(C)(=O)=O PLUBXMRUUVWRLT-WNWXXORZSA-N 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- BRRWEJXLJPHMBE-FIBGUPNXSA-N trideuteriomethyl 2-nitrobenzenesulfonate Chemical compound [N+](=O)([O-])C1=C(C=CC=C1)S(=O)(=O)OC([2H])([2H])[2H] BRRWEJXLJPHMBE-FIBGUPNXSA-N 0.000 claims description 4
- IEJIGPNLZYLLBP-WFGJKAKNSA-N bis(trideuteriomethyl) carbonate Chemical compound [2H]C([2H])([2H])OC(=O)OC([2H])([2H])[2H] IEJIGPNLZYLLBP-WFGJKAKNSA-N 0.000 claims description 3
- 239000012021 ethylating agents Substances 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- INQOMBQAUSQDDS-FIBGUPNXSA-N trideuterio(iodo)methane Chemical compound [2H]C([2H])([2H])I INQOMBQAUSQDDS-FIBGUPNXSA-N 0.000 claims description 3
- OIRDBPQYVWXNSJ-FIBGUPNXSA-N trideuteriomethyl trifluoromethanesulfonate Chemical compound [2H]C([2H])([2H])OS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-FIBGUPNXSA-N 0.000 claims description 3
- UVECLJDRPFNRRQ-ZBJDZAJPSA-N 1,1,2,2,2-pentadeuterioethyl trifluoromethanesulfonate Chemical compound [2H]C([2H])([2H])C([2H])([2H])OS(=O)(=O)C(F)(F)F UVECLJDRPFNRRQ-ZBJDZAJPSA-N 0.000 claims description 2
- OIFBSDVPJOWBCH-MWUKXHIBSA-N [2H]C([2H])([2H])C([2H])([2H])OC(=O)OC([2H])([2H])C([2H])([2H])[2H] Chemical compound [2H]C([2H])([2H])C([2H])([2H])OC(=O)OC([2H])([2H])C([2H])([2H])[2H] OIFBSDVPJOWBCH-MWUKXHIBSA-N 0.000 claims description 2
- 150000001537 azepanes Chemical class 0.000 claims description 2
- 238000003795 desorption Methods 0.000 claims description 2
- 150000000117 diazepanes Chemical class 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 150000003235 pyrrolidines Chemical class 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims 2
- 229940102396 methyl bromide Drugs 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 abstract description 9
- 230000029936 alkylation Effects 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 description 47
- 239000000047 product Substances 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 41
- 239000000243 solution Substances 0.000 description 41
- 239000002904 solvent Substances 0.000 description 36
- 239000000203 mixture Substances 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- 239000001257 hydrogen Substances 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000000605 extraction Methods 0.000 description 13
- 235000011121 sodium hydroxide Nutrition 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 0 *N1CCNCC1 Chemical compound *N1CCNCC1 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 6
- 235000009518 sodium iodide Nutrition 0.000 description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 6
- PVOAHINGSUIXLS-FIBGUPNXSA-N 1-(trideuteriomethyl)piperazine Chemical compound [2H]C([2H])([2H])N1CCNCC1 PVOAHINGSUIXLS-FIBGUPNXSA-N 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CHLICZRVGGXEOD-UHFFFAOYSA-N 1-Methoxy-4-methylbenzene Chemical compound COC1=CC=C(C)C=C1 CHLICZRVGGXEOD-UHFFFAOYSA-N 0.000 description 4
- DCTOHCCUXLBQMS-UHFFFAOYSA-N 1-undecene Chemical compound CCCCCCCCCC=C DCTOHCCUXLBQMS-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- GYQYAJJFPNQOOW-UHFFFAOYSA-N gilteritinib Chemical compound N1=C(NC2CCOCC2)C(CC)=NC(C(N)=O)=C1NC(C=C1OC)=CC=C1N(CC1)CCC1N1CCN(C)CC1 GYQYAJJFPNQOOW-UHFFFAOYSA-N 0.000 description 3
- 229950006304 gilteritinib Drugs 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 235000011118 potassium hydroxide Nutrition 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 2
- 229940077398 4-methyl anisole Drugs 0.000 description 2
- VPNPQPBLZMODLO-AZBDZEDCSA-N 5-[(E)-2-(benzenesulfonyl)ethenyl]-3-[[(2S)-1-benzylpyrrolidin-2-yl]methyl]-1H-indole Chemical compound C1C[C@H](N(C1)CC2=CC=CC=C2)CC3=CNC4=C3C=C(C=C4)/C=C/S(=O)(=O)C5=CC=CC=C5 VPNPQPBLZMODLO-AZBDZEDCSA-N 0.000 description 2
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 description 2
- AYXHHLMYJIJTGZ-UHFFFAOYSA-N 9-benzyl-1,4-dioxa-9-azaspiro[4.6]undec-2-ene Chemical compound C1CC2(CCN(C1)CC3=CC=CC=C3)OC=CO2 AYXHHLMYJIJTGZ-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
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Abstract
본 발명은, 아르알킬로 보호된 아민을 함유하는 화합물의 아민 부분에 모노중수소 저급 알킬화하는 방법이며, 중성 또는 염기성 조건 하에 중수소 저급 알킬화제로 해당 아민에 모노중수소 저급 알킬을 도입하고, 이어서 아르알킬기를 탈보호하는 것을 포함하는 방법에 관한 것이다.
Description
본 발명은, 2급 아민을 함유하는 화합물의 아민 부분에 중수소 저급 알킬을 도입하는 방법에 관한 것이다. 보다 구체적으로는, 아르알킬로 보호된 쇄상 또는 환상 아민에 중성 또는 염기성 조건 하에서 중수소 저급 알킬화하는 방법에 관한 것이다.
의약품은 일반적으로 간장 중의 효소로 대사되어 효과가 소실되므로, 여기에서의 대사 안정성을 개선하는 것은 안전성, 유효성, 용인성 및 편리성과 같은 치료상의 이점을 초래하는 것을 기대할 수 있다.
대사에 의해 구조가 변환되는 부위는 의약품의 화학 구조에 따라서 다르지만, N-메틸은 주요한 대사 부위의 하나이다. 화학 구조 중에 N-메틸을 갖는 의약품은 대사에 의해 N-탈메틸화되어, 그 효과가 실활될 수 있는 것이 알려져 있다. 그래서, N-메틸의 수소를 중수소로 치환함으로써 그의 메틸 부분의 성질을 바꾸는 것은, N-탈메틸화를 늦추어 대사 안정성을 개선하는 것을 기대할 수 있고, 나아가서는 상술한 치료상의 이점을 초래할 것이 기대되는 점에서, 각종 그에 대한 대처가 이루어고 있다(특허문헌 1, 비특허문헌 1 및 2).
수소를 중수소로 치환하는 방법으로서, 메틸-d34-메틸벤젠술포네이트를 사용하여 피페라진 유도체에 중수소메틸을 도입하는 방법이 개시되어 있다(특허문헌 2). 그러나, 이 도입 방법에서는 N,N-디메틸체가 부생성물로서 생성되는데, N,N-디메틸화를 억제할 수 없는 점에서 수율이 저하되는 문제가 있다.
ARKIVOC, (iii) 182-193(2008)
J Label Compd Radiopharm, 45, 1153(2002)
쇄상 또는 환상의 2급 아민에, 부생성물의 생성을 억제하여 모노중수소 저급 알킬을 도입할 수 있는, 범용성이 있으며 또한 고수율로 제조되는 방법이 요망되고 있다.
본 발명자들은 각종 연구를 거듭한 결과, 2급 아민 상의 수소 원자를 벤질과 같은 아르알킬로 치환하고, 얻어진 쇄상 또는 환상 아민 유도체를 중성 또는 염기성 조건 하에 중수소 저급 알킬화제로 중수소 저급 알킬화하고, 이어서 아르알킬을 탈리함으로써, 디중수소 저급 알킬화된 부생성물을 생성하지 않고, 목적으로 하는 N-모노중수소 저급 알킬 화합물을 고수율로 얻어지는 것을 발견하고, 본 발명의 완성에 이르렀다.
본 발명은 하기 양태의 것을 포함한다.
[항 1]
2급 아민을 함유하는 화합물에 있어서, 해당 아민 상의 수소 원자를 아르알킬로 치환하고, 중성 또는 염기성 조건 하에 중수소 저급 알킬화제로 해당 아민에 중수소 저급 알킬을 도입하고, 이어서 아르알킬을 탈리함으로써, 해당 아민에 모노중수소 저급 알킬을 도입하는 방법.
[항2]
2급 아민이 피페리딘환을 구성하지 않는, 항 1의 방법.
[항3]
중수소 저급 알킬이 중수소메틸 또는 중수소에틸이며, 중수소 저급 알킬화제가 중수소메틸화제 또는 중수소에틸화제인, 항 1 또는 2의 방법.
[항4]
중수소 저급 알킬이 중수소메틸이며, 중수소 저급 알킬화제가 메틸-d3메탄술포네이트, 메틸-d3벤젠술포네이트, 메틸-d34-메틸벤젠술포네이트, 메틸-d32-니트로벤젠술포네이트, 메틸-d34-니트로벤젠술포네이트, 디메틸-d6황산, 탄산디메틸-d6, 메틸-d3트리플루오로메탄술포네이트, 브롬화메틸-d3 또는 요오드화메틸-d3인, 항 1 내지 3 중 어느 것의 방법.
[항 5]
중수소 저급 알킬이 중수소에틸이며, 중수소 저급 알킬화제가 에틸-d5메탄술포네이트, 에틸-d5벤젠술포네이트, 에틸-d54-메틸벤젠술포네이트, 에틸-d52-니트로벤젠술포네이트, 에틸-d54-니트로벤젠술포네이트, 디에틸-d10황산, 탄산디에틸-d10, 에틸-d5트리플루오로메탄술포네이트, 브롬화에틸-d5 또는 요오드화에틸-d5인, 항 1 내지 3 중 어느 것의 방법.
[항 6]
아르알킬이 벤질 유도체인, 항 1 내지 5 중 어느 것의 방법.
[항 7]
벤질 유도체가 벤질 또는 4-메톡시벤질인, 항 6의 방법.
[항 8]
아르알킬의 탈리가 수소 첨가에 의해 행해지는, 항 6 또는 7의 방법.
[항 9]
염기성 조건 하가 탄산나트륨, 탄산세슘, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨, 수소화나트륨, 수소화칼륨, 수산화나트륨, 수산화칼륨, 나트륨tert-부톡시드, 칼륨tert-부톡시드, 알킬리튬(예를 들어, 노르말부틸리튬, sec-부틸리튬, tert-부틸리튬, 노르말헥실리튬), 리튬아미드(예를 들어, 리튬디이소프로필아미드, 리튬헥사메틸디실라지드), 나트륨메톡시드 또는 tert-아민(예를 들어, 트리메틸아민, 트리에틸아민, 트리이소프로필아민, 디이소프로필에틸아민)에 의한 염기성 조건인, 항 1 내지 8 중 어느 것의 방법.
[항 10]
2급 아민을 함유하는 화합물이 피페라진 유도체, 피롤리딘 유도체, 아제판 유도체, 디아제판 유도체, 쇄상 아민으로부터 선택되는, 항 1 내지 9 중 어느 것의 방법.
본 발명에 따르면, 2급 아민에 중수소 저급 알킬을 도입하는 데 있어서, 해당 아민 상의 수소 원자를 아르알킬로 일단 치환하고, 해당 아민을 중수소 저급 알킬화제로 중수소 저급 알킬화하고, 이어서 아르알킬을 탈보호함으로써, 디중수소 저급 알킬화된 부생성물을 생성하지 않고, 효율적으로 모노중수소 저급 알킬화할 수 있다.
본 발명에 따르면, N,N-디중수소 저급 알킬체 등의 부생성물의 산생을 억제함으로써, 고가인 d3-메틸화제, d5-에틸화제를 기준으로 한 목적물의 수율을 최대화할 수 있을 뿐 아니라, 미반응의 아민의 잔존을 최소화할 수 있기 때문에 공업 생산 비용을 억제할 수 있다. 또한 여기에서 사용할 수 있는 d3-메틸화제의 메틸-d3메탄술포네이트나 메틸-d3벤젠술포네이트는 중수소원으로서 범용 가능한 고순도의 중메탄올(CD3OD, 메탄올-d4)로부터 조제 가능한 점에서, 한층 더한 비용 절감 등의 효과를 기대할 수 있다. 또한, 이들 술포네이트를 갖는 중수소메틸화제의 원료가 되는 중메탄올은 CD3I와 같은 변이원성이 없으므로, 수송 등을 포함한 취급에 있어서도 안전성이 높다.
본 명세서 중에서 사용하는 어구 및 용어에 대하여, 이하에 상세하게 설명한다.
본 발명에 있어서 2급 아민을 보호하는 「아르알킬」이란, 알킬의 수소 원자의 하나가 아릴로 치환되어 있는 알킬을 말하고, 구체적으로는 벤질 유도체를 들 수 있고, 보다 구체적으로는 벤질, 4-니트로벤질, 4-메톡시벤질, 2-니트로벤질, 4-클로로벤질, 2,6-디클로로벤질, 4-메틸벤질, 2,4,6-트리메틸벤질을 들 수 있다. 바람직하게는 벤질 또는 4-메톡시벤질이다.
이들 아르알킬을 2급 아민에 도입하는 방법은, 예를 들어 문헌[T. W. Greene and P. G. M. Wuts, 「Greene's Protective Groups in Organic Synthesis」, 제4판, Wiley, New York 2006년]에 기재된 방법 또는 그것에 준한 방법을 들 수 있다. 예를 들어, 염기 존재 하에 할로겐화벤질을 작용시키는 방법, 또는 벤즈알데히드류와의 이민 형성 후에 환원제(예를 들어, 수소화붕소나트륨, 시아노수소화붕소나트륨, 수소화트리아세톡시붕소나트륨)를 작용시키는 환원적 아미노화 방법을 들 수 있다.
아르알킬을 탈리(탈보호)하는 방법은 문헌[T. W. Greene and P. G. M. Wuts, 「Greene's Protective Groups in Organic Synthesis」, 제4판, Wiley, New York 2006년]에 기재된 방법 또는 그것에 준한 방법으로 행하면 되고, 구체적으로는 벤질이나 p-메톡시벤질이면, 예를 들어 팔라듐을 촉매로 한 수소 첨가나 DDQ나 CAN 등의 온화한 산화 조건에 의해 탈보호할 수 있다.
본 발명에 있어서 「중수소 저급 알킬」이란, 저급 알킬의 하나 이상의 수소를 중수소로 치환한 알킬을 말하고, 예를 들어 저급 알킬은 메틸 또는 에틸을 들 수 있고, 바람직하게는 메틸이다. 또한, 메틸 또는 에틸에 있어서는 모든 수소가 중수소로 치환된 중수소 저급 알킬이 바람직하고, 구체적으로는 메틸-d3이나 에틸-d5를 들 수 있다. 또한, 본 발명에 있어서 중수소는 d, D, 2H로 나타내고, 예를 들어 3개의 수소 원자가 모두 중수소 원자로 치환된 메틸기를 메틸-d3, d3-메틸, 중메틸, CD3, [2H3]메틸 등으로 나타낸다.
본 발명에 있어서 「중수소 저급 알킬화제」란, 중수소 저급 알킬에 적당한 탈리기가 결합된 것을 말하고, 중수소 저급 알킬에 대하여는 상기에 정의된 것을 들 수 있고, 탈리기에 대하여는 할로겐(예를 들어, 요오드, 브롬), 술포네이트(예를 들어, 메탄술포네이트, 벤젠술포네이트, 4-메틸벤젠술포네이트, 2-니트로벤젠술포네이트, 4-니트로벤젠술포네이트, 트리플루오로메탄술포네이트)가 바람직하고, 또한 2개의 알킬이 결합 가능한 2가의 탈리기인 술페이트, 카르보네이트도 바람직하다. 구체적인 중수소 저급 알킬화제로서는, 메틸-d3메탄술포네이트, 메틸-d3벤젠술포네이트, 메틸-d34-메틸벤젠술포네이트, 메틸-d32-니트로벤젠술포네이트, 메틸-d34-니트로벤젠술포네이트, 디메틸-d6황산, 탄산디메틸-d6, 메틸-d3트리플루오로메탄술폰산, 브롬화메틸-d3, 요오드화메틸-d3, 에틸-d5메탄술포네이트, 에틸-d5벤젠술포네이트, 에틸-d54-메틸벤젠술포네이트, 에틸-d52-니트로벤젠술포네이트, 에틸-d54-니트로벤젠술포네이트, 디에틸-d10황산, 탄산디에틸-d10, 에틸-d5트리플루오로메탄술포네이트, 브롬화에틸-d5, 요오드화에틸-d5 등을 들 수 있고, 메틸-d3메탄술포네이트, 메틸-d3벤젠술포네이트, 메틸-d34-메틸술포네이트, 메틸-d32-니트로벤젠술포네이트, 메틸-d34-니트로벤젠술포네이트, 에틸-d5메탄술포네이트, 에틸-d5벤젠술포네이트, 에틸-d54-메틸벤젠술포네이트, 에틸-d52-니트로벤젠술포네이트, 에틸-d54-니트로벤젠술포네이트가 바람직하다.
「중수소 저급 알킬화제」 중에서 술포네이트를 포함하는 알킬화제는, 예를 들어 중메탄올 또는 중에탄올을 사용하여 통상의 방법에 의해 조제할 수 있다. 구체적으로는 하기 참고예에 나타내는 바와 같이, 술포닐클로라이드 시약과 중메탄올 또는 중에탄올을 염기성 조건 하에 반응시켜 얻을 수 있다.
메틸-d3메탄술포네이트는 미국 특허 공개 제2008/0194529호 공보, 메틸-d3벤젠술포네이트는 문헌[Journal of Labelled Compounds and Radiopharmaceuticals, 25, 1267(1988)], 메틸-d34-메틸술포네이트는 문헌[Journal of Organic Chemistry, 81, 7675(2016)], 메틸-d34-니트로벤젠술포네이트는 문헌[Physical Organic Chemistry, 11, 1741(1991)]에 기재된 방법에 따라서 제조할 수 있다.
2급 아민에 대한 중수소 저급 알킬화는, 해당 아민 상의 수소 원자를 아르알킬로 치환한 아민 유도체를 불활성 용매 중, 중성 또는 염기성 조건 하에 해당 아민 유도체와 중수소 저급 알킬화제를 반응시킴으로써 달성된다. 여기서 「중성 조건」은 원료, 시약, 용매 등에 의해 얻어지는 pH로, 특별히 pH 조정을 행하지 않은 상태 또는 하기 염기성 조건에서 사용되는 시약을 첨가하여 얻어지는 중성 부근의 pH 조건을 의미하고, 구체적인 pH로서는 6 내지 8 정도의 범위를 가리키고, 바람직하게는 6.5 내지 7.5를 가리킨다. 여기에서 사용하는 「염기성 조건」은 탄산나트륨, 탄산세슘, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨, 수소화나트륨, 수소화칼륨, 수산화나트륨, 수산화칼륨, 나트륨tert-부톡시드, 칼륨tert-부톡시드, 알킬리튬(예를 들어, 노르말부틸리튬, sec-부틸리튬, tert-부틸리튬, 노르말헥실리튬), 리튬아미드(예를 들어, 리튬디이소프로필아미드, 리튬헥사메틸디실라지드), 나트륨메톡시드 또는 tert-아민(예를 들어, 트리메틸아민, 트리에틸아민, 트리이소프로필아민, 디이소프로필에틸아민)에 의한 염기성 조건을 들 수 있고, 바람직하게는 탄산나트륨, 탄산세슘, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨이며, 특히 탄산수소나트륨이 바람직하다. 이들 염기성 화합물은 1종 단독으로 또는 2종 이상 혼합하여 사용된다. 염기성 화합물의 사용량은 출발 물질의 화합물 1몰에 대하여, 통상 1몰 내지 10몰 정도, 바람직하게는 1몰 내지 6몰 정도이다.
본 발명의 중수소 저급 알킬화 반응에 있어서는 불활성 용매 중에서 행해도 되고, 불활성 용매로서는 적절히 반응 조건에 따라 선택되지만, 예를 들어 물; 디옥산, 테트라히드로푸란, 디에틸에테르, 1,2-디메톡시에탄, 디에틸렌글리콜디메틸에테르, 에틸렌글리콜디메틸에테르 등의 에테르계 용매; 벤젠, 톨루엔, 크실렌 등의 방향족 탄화수소계 용매; 메탄올, 에탄올, 이소프로판올 등의 저급 알코올계 용매; 아세톤, 메틸에틸케톤 등의 케톤계 용매; N,N-디메틸포름아미드(DMF), N,N-디메틸아세트아미드(DMA), 디메틸술폭시드(DMSO), 헥사메틸인산트리아미드, 아세토니트릴 등의 극성 용제를 들 수 있다. 이들 불활성 용매는 1종 단독으로 또는 2종 이상 혼합하여 사용된다.
본 발명의 반응에 있어서는, 상압 하에 질소, 아르곤 등의 불활성 가스 분위기 하에서 행하는 것도, 또한 가압 하에서도 행할 수 있다. 상기 반응은 통상 실온 내지 200℃, 바람직하게는 실온 내지 150℃의 온도 조건 하에서 행해지고, 일반적으로 1 내지 30시간 정도에서 종료된다.
본 발명의 2급 아민을 함유하는 화합물로서는, 구조 중에 2급 아민을 갖고 있으면 특별히 한정되지 않지만, 피페라진, 피롤리딘, 아제판, 디아제판, 모르폴린을 구조 중에 갖고 있는 화합물을 들 수 있다. 또한, 이들 골격은 단환계에 한정되지 않고, 2환계, 3환계, 4환계의 일부를 구성하고 있어도 된다. 또한, 쇄상 아민이어도 된다. 중수소 저급 알킬을 도입할 수 있는 N-알킬피페라진을 함유하는 구체적인 의약품 화합물로서는, 예를 들어 이마티닙, 길테리티닙, 네투피탄트, 아베마시클립, 블로난세린, 바데나필, 마시티닙, 올란자핀, 닌테다닙, 레보플록사신, 실데나필, 보수티닙, 브리가티닙, 미르타자핀을 들 수 있다. N-알킬피롤리딘을 함유하는 구체적인 의약품 화합물로서, 아트로핀, 트로피세트론, 일레트립탄, 니코틴, 펜세린, 유데나필, 아미술프리드를 들 수 있다. N-알킬아제판을 함유하는 구체적인 의약품 화합물로서, 아젤라스틴을 들 수 있다. N-알킬-1,4-디아제판을 함유하는 구체적인 의약품 화합물로서, 에메다스틴, CX-5461을 들 수 있다. N-알킬 쇄상 아민을 함유하는 구체적인 의약품 화합물로서, 베라파밀을 들 수 있다.
본 발명에는, 중수소 저급 알킬을 도입할 수 있는 N-알킬아민을 함유하는 의약품 화합물을 제조하기 위해 사용할 수 있는 중간체가 포함된다. 구체적으로는, 본 발명에 의해 제조되는 중수소 저급 알킬이 모노 치환된 아민 화합물로, 이 아민 화합물을 각종 합성 방법에 의해 다른 구조와 결합시켜, 중수소 저급 알킬이 도입된 의약품 화합물로 제조할 수 있다. 여기에서의 중간체의 기본 골격이 되는 2급 아민 화합물 구조로서는, 아제티딘, 피롤리딘, 피페리딘, 아제판, 아조칸, 아제파논, 피페라진, 피페라지논, 모르폴린, 인돌린, 이소인돌린, 디히드로벤즈이미다졸, 인다졸린, 디히드로트리아졸로피리다진, 디히드로퀴놀린, 테트라히드로퀴놀린, 데카히드로퀴놀린, 디히드로이소퀴놀린, 테트라히드로이소퀴놀린, 테트라히드로나프티리딘, 헥사히드로나프티리딘, 디히드로퀴녹살린, 테트라히드로퀴녹살린, 디히드로퀴나졸린, 테트라히드로퀴나졸린, 벤조아제핀, 테트라히드로벤조아제핀, 테트라히드로피리도인돌, 디히드로페난트리딘, 디아자스피로헵탄, 아자스피로운데칸 등을 들 수 있다.
본 발명의 제조 방법에 있어서는, 통상의 방법에 의해 제조되는 아르알킬로 치환된 아민을 함유하는 화합물에 중수소 저급 알킬화제를 반응시켜 중수소 저급 알킬이 부가된 4급 아민을 일단 형성시킨 후, 생성물을 단리하지 않고, 아르알킬을 탈보호함으로써, 목적으로 하는 중수소 저급 알킬이 2급 아민에 모노 치환된 목적으로 하는 화합물을 제조할 수 있다.
본 발명에 있어서는, 출발 물질, 중간체 및/또는 목적 화합물이 염 화합물이어도 되고, 염 화합물을 포함한 제조 방법도 본 발명에 포함된다. 염 화합물로서는, 산 부가염 또는 치환기의 종류에 따라서는 염기와의 염을 형성하는 경우도 있다. 이러한 산의 예로서는, 염산, 브롬화수소산, 질산, 황산, 인산 등의 무기산; 및 메탄술폰산, p-톨루엔술폰산, 아세트산, 옥살산, 시트르산, 타르타르산, 말레산, 푸마르산, 말산, 락트산 등의 유기산 등을 들 수 있다. 이러한 염기의 예로서는, 수산화나트륨, 수산화칼륨, 수산화칼슘, 탄산나트륨, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨 등의 무기 염기; 및 메틸아민, 디에틸아민, 트리메틸아민, 트리에틸아민, 에탄올아민, 디에탄올아민, 트리에탄올아민, 에틸렌디아민, 트리스(히드록시메틸)메틸아민, 디시클로헥실아민, N,N'-디벤질에틸렌디아민, 구아니딘, 피리딘, 피콜린, 콜린 등의 유기 염기; 및 암모늄염 등을 들 수 있다. 또한, 예를 들어 리신, 아르기닌, 아스파르트산, 글루탐산 등의 아미노산과 염을 형성해도 된다.
본 명세서에 있어서 인용되는 모든 특허문헌 및 비특허문헌의 개시는, 전체로서 본 명세서에 참조에 의해 도입된다.
실시예
본 발명은 또한 이하의 참고예 및 실시예에 의해 상세하게 설명되지만, 이들은 본 발명을 한정하는 것은 아니고, 또한 본 발명의 범위를 일탈하지 않는 범위에서 변화시켜도 된다.
본 명세서에 있어서, 이하의 약어를 사용하는 경우가 있다.
1H-NMR(프로톤 핵자기 공명 스펙트럼)은 푸리에 변환형 NMR(Bruker AVANCE NEO(400MHz) 및 Bruker AVANCE III HD(500MHz) 중 어느 것)로 측정하였다.
참고예 1 내지 5. (9S,13S,14S)-3-(메톡시-d
3
)-17-(메틸-d
3
)-모르피난의 합성
표 1에 나타낸 중수소메틸화제를 사용하여 목적으로 하는 화합물을 제조하였다.
제조 방법 1
(9S,13S,14S)-3-히드록시-17-벤질모르피난브롬화수소산염(24mmol)을 DMF(60mL)에 현탁시키고, NaOtBu(51mmol), 중수소메틸화제(26mmol)를 10℃ 이하에서 첨가하여 추가로 3시간 교반하였다. 반응 후, 톨루엔, 물을 첨가하고, 유기층을 분리하고, 유기층을 물로 세정하고, 용매를 증류 제거하였다. 잔사에 NaHCO3(5mmol), 중수소메틸화제(29mmol), MeCN(40mL)을 첨가하고, 10시간 가열 환류시켰다. 또한 NaHCO3(5mmol)과 물(20mL)을 첨가하고, 80℃에서 1시간 교반하였다. 냉각 후, 5% Pd/C(0.5g)를 첨가하고, 수소 분위기 하에 실온에서 16시간 교반하였다. 반응 용액을 셀라이트 여과하고, MeOH와 물로 세정 후, 대부분의 유기 용매를 증류 제거하였다. 농축물에 톨루엔, 물, 25% NaOH 수용액을 첨가하고, 유기층을 분리하고, 유기층을 물로 세정하고, 용매를 증류 제거하여 목적물을 얻었다.
제조 방법 2
(9S,13S,14S)-3-히드록시-17-벤질모르피난(24mmol), 중수소메틸화제(50mmol) 및 NaHCO3(6mmol)을 MeCN(25mL)에 현탁시켜 4시간 환류시켰다. 반응 종료 후, 이 용액을 0℃로 냉각시키고, 48% NaOH 수용액(3.0g)을 첨가하고, 0℃에서 16시간 교반하고, 추가로 80℃에서 4시간 교반 후, 실온까지 냉각시켰다. 10% Pd/C(0.6g)를 첨가하고, 수소 분위기 하에 실온에서 19시간 교반하였다. 반응 용액을 셀라이트 여과하고, MeCN과 정제수로 세정 후, 대부분의 유기 용매를 증류 제거하였다. 농축물에 MeCN, 정제수, 25% NaOH 수용액(5.5mL)을 첨가하고, 유기층을 분리하고, 유기층을 물로 세정 후, 용매를 증류 제거하여 목적물을 얻었다.
실시예 1. N-메틸-d
3
피페라진의 제조
벤질피페라진-1-카르복실레이트(14.18g)와 4-아니스알데히드(8.85g)를 THF(200mL)에 용해 후 10℃ 이하로 냉각시키고, 수소화트리아세톡시붕소나트륨(16.37g)을 첨가하여 5 내지 25℃에서 2시간 교반하였다. 정제수(20ml)를 첨가한 후, 감압 하에 대부분의 용매를 증류 제거하고, 5N NaOH 수용액(20ml)을 첨가하고 MTBE로 추출하고, 용매를 증류 제거하였다. 잔사에 메틸-d34-메틸벤젠술포네이트(13.32g, 함량 92%) 및 NaHCO3(0.54g)을 첨가하여 MeCN에 현탁시키고, 4시간 가열 환류 후, 실온에서 16시간 교반하였다. 이어서 NH4Cl(0.34g)을 첨가하여 1시간 가열 환류한 후 실온까지 냉각시켰다. 얻어진 현탁액에 메탄올(50mL)을 첨가하고, 계 내를 질소로 치환하였다. 여기에 10% Pd(OH)2/C(0.5g)를 첨가하여 1 기압의 수소 분위기 하에 50℃에서 8시간, 이어서 실온에서 16시간 교반하였다. 반응액을 여과하고, 용매를 증류 제거하였다. 잔사에 THF(50mL)를 첨가하고, 0℃로 냉각 후 48% NaOH 수용액(4.3ml)을 적하하였다. 얻어진 현탁액을 여과하여 MTBE와 소량의 THF로 세정한 후, 감압 하에 대부분의 용매를 증류 제거하였다. 잔사를 감압 증류하여, 목적물을 4-메틸아니솔과의 혼합물(3.89g, 함량 77.4%)로서 얻었다.
1H-NMR(CDCl3) δ; 2.88-2.91(8H, m)
실시예 2. N-메틸-d
3
-아제판-4-온의 제조
1) 8-벤질-1,4-디옥사-8-아자스피로[4,6]운데센의 제조
1-벤질아제판-4-온(2.5g)과 파라톨루엔술폰산 수화물(2.34g)에 톨루엔(25mL)을 첨가하여 1시간 가열 환류시켰다. 60℃로 냉각 후 에틸렌글리콜(0.75mL)을 첨가하고, 추가로 2시간 가열 환류시켰다. 실온으로 냉각 후, 25% NaOH 수용액을 첨가하고 유기층을 분리하였다. 얻어진 유기층을 농축하고, 잔사를 칼럼 크로마토그래피(AcOEt/헥산)로 정제하여 목적물(535mg)을 얻었다.
2) 8-메틸-d
3
-1,4-디옥사-8-아자스피로[4,6]운데센의 제조
8-벤질-1,4-디옥사-8-아자스피로[4,6]운데센(0.53g)에 메틸-d34-메틸벤젠술포네이트(0.51g, 함량 87%), NaI(32mg), NaHCO3(18mg)을 첨가하여 MeCN(3mL)에 현탁시키고, 봉함 반응 용기 중 95℃에서 4시간 교반하였다. 실온으로 냉각 후, TEA(0.15mL)를 첨가하고, 50℃에서 2시간 교반을 행하였다. 얻어진 용액에 10% Pd/C(50mg)를 첨가하여 1 기압의 수소 분위기 하에 실온에서 16시간 교반하였다. 반응액을 셀라이트 여과하고, 여액을 DCM으로부터 추출하여 목적물(342mg)을 얻었다.
1H-NMR(CDCl3) δ; 1.65-1.75(2H, m), 1.89(2H, t, J=5.6Hz), 1.97(2H, t, J=5.6Hz), 2.53(2H, t, J=5.6Hz), 2.59(2H, t, J=5.6Hz), 3.89(4H, s).
3) N-메틸-d
3
-아제판-4-온의 제조
8-메틸-d3-1,4-디옥사-8-아자스피로[4,6]운데센(340mg)을 THF(2.0mL)에 용해시키고 농염산(0.5mL)을 첨가하여 60℃에서 3시간 교반하였다. 반응 용액을 실온으로 냉각시키고 용매를 증류 제거하여, 목적물의 염산염을 정량적으로 얻었다. 얻어진 목적물은 정제하지 않고 다음 공정에 사용하였다.
실시예 3. 1-(메틸-d
3
)-1,4-디아제판의 제조
1) 벤질4-벤질-1,4-디아제판-1-카르복실레이트의 제조
N-벤질호모피페라진(4.18mL)과 DCM(21.5mL)을 혼합하고, 클로로포름산벤질(CbzCl)(3.55mL)을 천천히 적하하였다. 반응액을 실온 하에서 철야 교반하고, 반응의 진척을 확인하면서 적절히 CbzCl(0.65mL)을 추가하였다. 용매를 증류 제거한 후, AcOEt를 첨가하였다. 용매를 증류 제거하여 목적물을 얻었다.
1H-NMR(CDCl3) δ; 1.77-1.91(2H, m), 2.56-2.72(4H, m), 3.49-3.60(4H, m), 3.61(2H, d, J=3.3Hz), 5.14(2H, d, J=2.4Hz), 7.25-7.43(10H, m).
2) 벤질4-(메틸-d
3
)-1,4-디아제판-1-카르복실레이트의 제조
벤질4-벤질-1,4-디아제판-1-카르복실레이트(6.6g), 메틸-d34-메틸벤젠술포네이트(4.32g), NaHCO3(0.34g), NaI(0.31g), MeCN(20mL)을 혼합하고, 환류 하에서 8시간 교반하였다. 물(13mL)과 NH4Cl(0.33g)을 첨가하고, 1.5시간 가열 환류시켰다. 용매를 증류 제거 후, 잔사에 MeCN(27mL), 물(3mL), 10% Pd/C(660mg)를 첨가하고, 0.4MPa의 수소 분위기 하에 40℃에서 8시간 교반하였다. 반응액을 여과하고, 용매를 증류 제거하고, 잔사에 AcOEt와 물을 첨가하였다. 5N NaOH 수용액으로 염기성으로 하고, AcOEt로 추출하였다. 용매를 증류 제거하여 목적물(3.81g)을 얻었다.
1H-NMR(CDCl3) δ; 1.83-1.92(2H, m), 2.52-2.63(4H, m), 3.51-3.64(4H. m), 5.14(2H, s), 7.28-7.39(5H, m).
3) 1-(메틸-d
3
)-1,4-디아제판의 제조
벤질4-(메틸-d3)-1,4-디아제판-1-카르복실레이트(3.81g), 10% Pd/C(380mg), AcOEt(20mL), MeOH(5mL)를 혼합하고, 0.4MPa의 수소 분위기 하에 50℃에서 8시간 교반하였다. 반응액을 여과하고, 용매를 증류 제거하여 목적물(1.74g)을 얻었다.
1H-NMR(CDCl3) δ; 1.81(2H, quint, J=6.0Hz), 2.58-2.64(4H, m), 2.77(1H, br s), 2.91-3.00(4H. m).
실시예 4 내지 22
실시예 1 내지 3과 마찬가지로 하여, 표 2에 나타낸 출발 화합물로부터 합성 중간체를 얻는다.
실시예 23. N-(4-메틸-3-(4-(피리딘-3-일)피리미딘-2-일아미노)페닐)-4-((4-메틸-d
3
-피페라진-1-일)메틸)벤즈아미드(중수소화이마티닙)의 제조
4-(클로로메틸)-N-(4-메틸-3-((4-(피리딘-3-일)피리미딘-2-일)아미노)페닐)벤즈아미드(0.43g)와 N-메틸-d3-피페라진(1.33g, 함량 77%)을 MeCN(40mL)에 용해시켜 6시간 가열 환류시켰다. 반응액을 15mL 정도가 될 때까지 농축하여 0℃에서 교반하였다. 얻어진 결정을 여과 취출하고, MeCN으로 세정하여 목적물(370mg)을 얻었다.
1H-NMR(DMSO-d6); 2.23(3H, s), 2.20-2.50(8H, m), 3.52(2H, s), 7.21(1H, d, J=8.0Hz), 7.40-7.57(5H, m), 7.91(1H, d, J=8.0Hz), 8.08(1H, d, J=2.0Hz), 8.48(1H, dt, J=2.0, 8.0Hz), 8.51(1H, d, J=4.8Hz), 8.69(1H, dd, J=2.0, 4.8Hz), 8.99(1H, s), 9.28(1H, d, J=2.0Hz), 10.18(1H, s).
실시예 24. N-(5-((4-(에틸-d
5
)피페라진-1-일)메틸)피리딘-2-일)-5-플루오로-4-(4-플루오로-1-이소프로필-2-메틸-1H-벤조[d]이미다졸-6-일)피리미딘-2-아민(중수소화아베마시클립)의 제조
6-((5-플루오로-4-(4-플루오로-1-이소프로필-2-메틸-1H-벤조[d]이미다졸-6-일)피리미딘-2-일)아미노)니코틴알데히드, N-에틸-d5-피페라진을 사용하여, 문헌[Tetrahedron Letters, 56, 949(2015)]에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 25. 2-(4-(에틸-d
5
)피페라진-1-일)-4-(4-플루오로페닐)-5,6,7,8,9,10-헥사히드로시클로옥타[b]피리딘(중수소화블로난세린)의 제조
2-클로로-4-(4-플루오로페닐)-5,6,7,8,9,10-헥사히드로시클로옥타[b]피리딘, N-에틸-d5-피페라진을 사용하여, 미국 특허 제5,021,421호 공보에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 26. 2-(2-에톡시-5-((4-(에틸-d
5
)피페라진-1-일)술포닐)페닐)-5-메틸-7-프로필이미다조[5,1-f][1,2,4]트리아진-4(3H)-온(중수소화바데나필)의 제조
4-에톡시-3-(5-메틸-4-옥소-7-프로필-3,4-디히드로이미다조[5,1-f][1,2,4]트리아진-2-일)벤젠술포닐클로라이드, N-에틸-d5-피페라진을 사용하여, WO1999/024433호 공보에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 27. 2-메틸-4-(4-(메틸-d
3
)피페라진-1-일)-10H-벤조[b]티에노[2,3-e][1,4]디아제핀(중수소화올란자핀)의 제조
2-메틸-10H-벤조[b]티에노[2,3-e][1,4]디아제핀-4-아민, N-메틸-d3-피페라진을 사용하여, 미국 특허 제5,229,382호 공보에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 28. (S)-9-플루오로-3-메틸-10-(4-(메틸-d
3
)피페라진-1-일)-7-옥소-2,3-디히드로-7H-[1,4]옥사지노[2,3,4-ij]퀴놀린-6-카르복실산(중수소화레보플록사신)의 제조
(S)-9,10-디플루오로-3-메틸-7-옥소-2,3-디히드로-7H-[1,4]옥사지노[2,3,4-ij]퀴놀린-6-카르복실산, N-메틸-d3-피페라진을 사용하여, 문헌[Journal of Medicinal Chemistry, 30, 2283(1987)]에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 29. 4-((2,4-디클로로-5-메톡시페닐)아미노)-6-메톡시-7-(3-(4-(메틸-d
3
)피페라진-1-일)프로폭시)퀴놀린-3-카르보니트릴(중수소화보수티닙)의 제조
7-(3-클로로프로폭시)-4-((2,4-디클로로-5-메톡시페닐)아미노)-6-메톡시퀴놀린-3-카르보니트릴, N-메틸-d3-피페라진을 사용하여, 문헌[Journal of Medicinal Chemistry, 44, 3965(2001)]에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 30. (2-((5-클로로-2-((2-메톡시-4-(4-(4-(메틸-d
3
)피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)디메틸포스핀옥시드(중수소화브리가티닙)의 제조
1) 1-(메틸-d
3
)-4-(피페리딘-4-일)피페라진의 제조
1-벤질피페리딘-4-온, N-메틸-d3-피페라진을 사용하여, 일본 특허 공개 제2008-050307호 공보에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
2) 중수소화브리가티닙의 제조
1-(메틸-d3)-4-(피페리딘-4-일)피페라진을 사용하여, 문헌[Journal of Medicinal Chemistry, 59, 4948(2016)]에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 31. 2-(3,5-비스(트리플루오로메틸)페닐)-N,2-디메틸-N-(6-(4-(메틸-d
3
)피페라진-1-일)-4-(o-톨릴)피리딘-3-일)프로파나미드(중수소화네투피탄트)의 제조
2-(3,5-비스(트리플루오로메틸)페닐)-N-(6-클로로-(4-(o-톨릴)피리딘-3-일)-N,2-디메틸프로파나미드, N-메틸-d3-피페라진을 사용하여, 중국 특허 공개 제107698500호 공보에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 32. 메틸(Z)-3-(((4-(N-메틸-2-(4-(메틸-d
3
)피페라진-1-일)아세트아미드)페닐)아미노)(페닐)메틸렌)-2-옥소인돌린-6-카르복실레이트(중수소화닌테다닙)의 제조
메틸(Z)-3-(((4-(2-클로로-N-메틸아세트아미드)페닐)아미노)(페닐)메틸렌)-2-옥소인돌린-6-카르복실레이트, N-메틸-d3-피페라진을 사용하여, 문헌[Synthetic Communications, 47, 975(2017)]에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 33. 6-에틸-3-((3-메톡시-4-(4-(4-(메틸-d
3
)피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-((테트라히드로-2H-피란-4-일)아미노)피라진-2-카르복사미드(중수소화길테리티닙)의 제조
1) 1-(메틸-d
3
)-4-(피페리딘-4-일)피페라진염산염의 제조
tert-부틸4-옥소피페리딘-1-카르복실레이트, N-메틸-d3-피페라진을 사용하여, WO2015/177326호 공보에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
2) 중수소화길테리티닙의 제조
1-(메틸-d3)-4-(피페리딘-4-일)피페라진염산염을 사용하여, WO2010/128659호 공보에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 34. 4-(4-클로로벤질)-2-(1-메틸-d
3
-아제판-4-일)프탈라진-1(2H)-온(중수소화아젤라스틴)의 제조
4-(4-클로로벤질)-2-(1-벤질-아제판-4-일)프탈라진-1(2H)-온(0.5g)과 메틸-d34-메틸벤젠술포네이트(0.25g, 함량 92%), NaI(16mg) 및 NaHCO3(18mg)을 MeCN(4ml)에 현탁시키고, 봉함 반응 용기 중 95℃에서 4시간 교반하였다. 또한, 개방계로 50℃에서 30분 교반을 행한 후 NH4Cl(18mg)과 정제수(1mL)를 첨가하고 추가로 70℃에서 1시간 교반을 행하였다. 얻어진 용액에 10% Pd/C(25mg)를 첨가하여 1 기압의 수소 분위기 하에 실온에서 1.5시간 교반하였다. 반응액을 셀라이트 여과하고, 여액에 암모니아수를 첨가하고, AcOEt로 추출하였다. 용매를 증류 제거하고, 잔사를 칼럼 크로마토그래피(AcOEt/헥산)로 정제하여 목적물(368mg)을 얻었다.
1H-NMR(CDCl3) δ; 1.65-1.80(1H, m), 1.90-2.15(4H, m), 2.15-2.30(1H, m), 2.50-2.80(4H, m), 4.26(2H, s), 5.30-5.40(1H, m), 7.18-7.21(2H, m), 7.25-7.27(2H, m), 7.67-7.71(3H, m), 8.44-8.47(1H, m).
실시예 35. 1-(2-에톡시에틸)-2-(4-메틸-d
3
-1,4-디아제판-1-일)-1H-벤조[d]이미다졸(중수소화에메다스틴)의 제조
2-클로로-(2-에톡시에틸)벤즈이미다졸(106mg), 1-(메틸-d3)-1,4-디아제판(83mg), 트리에틸아민(0.5mL), MeCN(0.5mL)을 혼합하고, 8일간 가열 환류시켰다. AcOEt와 물을 첨가하고, AcOEt 추출하고, 용매를 증류 제거하였다. 잔사를 칼럼 크로마토그래피(AcOEt/MeOH)로 정제하여 목적물(84mg)을 얻었다.
1H-NMR(CDCl3) δ; 1.15(3H, t, J=7.0Hz), 2.02(2H, quint, J=5.8Hz), 2.70-2.80(4H, m), 3.46(2H, q, J=7.0Hz), 3.62-3.71(4H, m), 3.78(2H, t, J=6.1Hz), 4.18(2H, t, J=6.1Hz), 7.07-7.18(2H, m), 7.22-7.27(1H, m), 7.51-7.56(1H, m).
실시예 36. 2-(4-(메틸-d
3
)-1,4-디아제판-1-일)-N-((5-메틸피라진-2-일)메틸)-5-옥소-5H-벤조[4,5]티아졸로[3,2-a][1,8]나프티리딘-6-카르복사미드(중수소화CX-5461)의 제조
1) 메틸2-(4-(메틸-d
3
)-1,4-디아제판-1-일)-5-옥소-5H-벤조[4,5]티아졸로[3,2-a][1,8]나프티리딘-6-카르복실레이트의 합성
메틸2-클로로-5-옥소-5H-벤조[4,5]티아졸로[3,2-a][1,8]나프티리딘-6-카르복실레이트, 1-(메틸-d3)-1,4-디아제판을 사용하여, 문헌[ACS Medicinal Chemistry Letters, 3, 602(2012)]에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
2) 중수소화CX-5461의 제조
메틸2-(4-(메틸-d3)-1,4-디아제판-1-일)-5-옥소-5H-벤조[4,5]티아졸로[3,2-a][1,8]나프티리딘-6-카르복실레이트를 사용하여, 문헌[ACS Medicinal Chemistry Letters, 3, 602(2012)]에 기재된 방법과 마찬가지로 하여 목적물을 얻는다.
실시예 37. N-[2-(1-메틸-d
3
-피롤리딘-2-일)에틸]-3-[(4,7-디히드로-7-옥소-1-메틸-3-프로필-1H-피라졸로[4,3-d]피리미딘)-5-일]-4-프로폭시벤젠술폰아미드(중수소화유데나필)의 제조
3-((5-카르바모일-1-메틸-3-프로필-1H-피라졸-4-일)카르바모일)-4-프로폭시벤젠술포닐클로라이드와 2-(1-(메틸-d3)피롤리딘-2-일)에탄-1-아민을 혼합하고, DCM 중 실온에서 교반한다. 반응 후, NaHCO3 수용액을 첨가하고, AcOEt로 추출하고, 용매를 증류 제거한다. 잔사에 tert-부탄올을 첨가하고, 칼륨tert-부톡시드와 함께 가열 환류한다. 반응액에 물을 첨가하고, AcOEt로 추출하고, 용매를 증류 제거하여 목적물을 얻는다.
실시예 38. N-((1-에틸-d
5
-2-피롤리디닐)메틸)-2-메톡시-4-아미노-5-(에틸술포닐)벤즈아미드(중수소화아미술프리드)의 제조
5-(에틸술포닐)-2-메톡시-4-니트로벤조산과 (1-(에틸-d5)피롤리딘-2-일)메탄아민을 디옥산 중, TEA와 클로로포름산에틸 존재 하에 혼합하여 실온에서 교반한다. 반응 후, 물을 첨가하고, AcOEt로 추출하고, 용매를 증류 제거한다. 잔사에 EtOH와 레이니 니켈을 첨가하고, 수소 분위기 하에 교반한다. 반응액을 여과하여 불용물을 제거하고, 용매를 증류 제거하여 목적물을 얻는다.
실시예 39. (1R,3r,5S)-8-메틸-d
3
-8-아자비시클로[3.2.1]옥탄-3-일3-히드록시-2-페닐프로파노에이트(중수소화아트로핀)의 제조
3-클로로-3-옥소-2-페닐프로필아세테이트와 (1R,3r,5S)-8-(메틸-d3)-8-아자비시클로[3,2,1]옥탄-3-올을 혼합하고, DCM 중 메탄술폰산과 실온에서 교반한다. 반응 후, NaHCO3 수용액을 첨가하고, AcOEt로 추출하고, 용매를 증류 제거한다. 잔사에 MeOH를 첨가하고, 나트륨메톡시드와 실온에서 교반한다. 반응액에 물을 첨가하고, AcOEt로 추출하고, 용매를 증류 제거하여 목적물을 얻는다.
실시예 40. 1H-인돌-3-카르복실산(1α,5α)-8-메틸-d
3
-8-아자비시클로[3.2.1]옥탄-3β-일(중수소화트로피세트론)의 제조
1H-인돌-3-카르복실산과 (1R,3r,5S)-8-(메틸-d3)-8-아자비시클로[3,2,1]옥탄-3-올을 혼합하고, 클로로포름 중 p-톨루엔술폰산을 첨가하여 가열 환류한다. 반응 후, NaHCO3 수용액을 첨가하고, AcOEt로 추출하고, 용매를 증류 제거하여 목적물을 얻는다.
실시예 41. (R)-3-((1-메틸-d
3
-피롤리딘-2-일)메틸)-5-(2-(페닐술포닐)에틸)-1H-인돌(중수소화일레트립탄)의 제조
1) (S,E)-3-((1-벤질피롤리딘-2-일)메틸)-5-(2-(페닐술포닐)비닐)-1H-인돌의 제조
벤질d-프롤리노일클로라이드, 에틸마그네슘브로마이드, 염화아연, 5-브로모인돌의 Et2O 용액을 실온에서 교반한다. 반응 후, 물을 첨가하고 AcOEt로 추출하고, 용매를 증류 제거한다. 잔사에 수소화알루미늄, THF를 첨가하여 실온부터 60℃에서 교반 후, MeOH를 첨가하고 불용물을 여과 제거하고, 여액을 농축한다. 잔사에 MeCN을 첨가하고 페닐비닐술폰, 아세트산팔라듐, 트리스오르토톨릴포스핀, 트리에틸아민을 첨가하여 가열 환류한다. 물을 첨가하고 AcOEt로 추출하고, 용매를 증류 제거하여 목적물을 얻는다.
2) 중수소화일레트립탄의 제조
(S,E)-3-((1-벤질피롤리딘-2-일)메틸)-5-(2-(페닐술포닐)비닐)-1H-인돌, 메틸-d34-메틸벤젠술포네이트를 사용하여, 참고예 1 내지 5와 마찬가지의 방법에 의해 목적물을 얻는다.
실시예 42. (S)-3-(1-메틸-d
3
-피롤리딘-2-일)피리딘(중수소화니코틴)의 제조
1) 디벤질노르니코티늄의 제조
노르니코틴, Na2CO3, 벤질브로마이드를 MeOH 중 실온에서 교반하고, 용매를 증류 제거하여 디벤질노르니코티늄을 얻는다.
2) 중수소화니코틴의 제조
디벤질노르니코티늄을 사용하여 참고예 1 내지 5와 마찬가지의 반응에 의해 목적물을 얻는다.
실시예 43. (3aR,8aS)-3a,8-디메틸-1-(메틸-d
3
)-1,2,3,3a,8,8a-헥사히드로피롤로[2,3-b]인돌-5-일페닐카르바메이트(중수소화펜세린)의 제조
1) (3aR,8aS)-5-메톡시-3a,8-디메틸-1-(메틸-d
3
)-1,2,3,3a,8,8a-헥사히드로피롤로[2,3-b]인돌의 제조
(3aR,8aS)-1-벤질-5-메톡시-3a,8-디메틸-1,2,3,3a,8,8a-헥사히드로피롤로[2,3-b]인돌(5.0g), 메틸-d34-메틸벤젠술포네이트(3.37g), NaHCO3(272mg), NaI(243mg), MeCN(20mL)을 혼합하여, 봉함 반응 용기 중 90℃에서 7시간 교반하였다. NH4Cl(260mg), 물(10mL)을 첨가하고, 봉함 반응 용기 중 70℃에서 1시간 교반하였다. 10% Pd/C(500mg)를 첨가하고, 0.4MPa의 수소 분위기 하에 40℃에서 6시간 교반하였다. 반응액을 셀라이트 여과하고, 여액에 AcOEt와 물을 첨가하고, 5N NaOH 수용액으로 염기성으로 한 후, AcOEt로 추출하였다. 용매를 증류 제거하고, 잔사를 칼럼 크로마토그래피(AcOEt/헥산)로 정제하여 목적물(1.67g)을 얻었다.
1H-NMR(CDCl3) δ; 1.43(3H, s), 1.91-1.97(2H, m), 2.59-2.74(2H, m), 2.89(3H, s), 3.75(3H, s), 4.05(1H, s), 6.36(1H, d, J=8.4Hz), 6.61-6.68(2H. m).
2) (3aR,8aS)-3a,8-디메틸-1-(메틸-d
3
)-1,2,3,3a,8,8a-헥사히드로피롤로[2,3-b]인돌-5-올의 제조
(3aR,8aS)-5-메톡시-3a,8-디메틸-1-(메틸-d3)-1,2,3,3a,8,8a-헥사히드로피롤로[2,3-b]인돌(367mg)과 DCM(6mL)을 혼합하고, 빙랭하였다. BBr3(1.59mL, 17% DCM 용액)을 천천히 적하하였다. 반응액을 실온 하에서 6시간 교반하고, 반응의 진척을 확인하면서 적절히 BBr3(0.48mL, 17% DCM 용액)을 추가하였다. 용매를 증류 제거하고, 잔사에 물과 포화 중조수를 첨가하고, AcOEt로 추출하였다. 용매를 증류 제거하고, 잔사를 칼럼 크로마토그래피(AcOEt/MeOH)로 정제하여 목적물(163mg)을 얻었다.
1H-NMR(DMSO-d6) δ; 1.32(3H, s), 1.68-1.86(2H, m), 2.37-2.46(1H, m), 2.58-2.66(1H, m), 2.75(3H, s), 3.95(1H, s), 6.26(1H, d, J=8.1Hz), 6.40-6.46(2H. m), 8.54(1H, s).
3) 중수소화펜세린의 제조
(3aR,8aS)-3a,8-디메틸-1-(메틸-d3)-1,2,3,3a,8,8a-헥사히드로피롤로[2,3-b]인돌-5-올(143mg)과 THF(13mL)를 혼합하고, 수소화나트륨(2.8mg)을 첨가하고, 실온 하에서 10분 교반하였다. 이소시안산페닐(85μL)을 첨가하고, 실온 하에서 5시간 교반하였다. 용매를 증류 제거하고, 잔사에 물과 포화 중조수를 첨가하고, AcOEt로 추출하였다. 용매를 증류 제거하고, 잔사를 칼럼 크로마토그래피(AcOEt/헥산)로 정제하여 목적물(146mg)을 얻었다.
1H-NMR(DMSO-d6) δ; 1.36(3H, s), 1.78-1.87(2H, m), 2.44-2.53(1H, m), 2.61-2.67(1H, m), 2.86(3H, s), 4.10(1H, s), 6.39(1H, d, J=8.4Hz), 6.80(1H, dd, J=8.4, 2.4Hz), 6.85(1H, d, J=2.4Hz), 6.99-7.05(1H. m), 7.27-7.33(2H, m), 7.50(2H, d, J=7.7Hz), 10.05(1H, s).
실시예 44. 2-메틸-d
3
-1,2,3,4,10,14b-헥사히드로벤조[c]피라지노[1,2-a]피리도[3,2-f]아제핀(중수소화미르타자핀)의 제조
1) 2-벤질-1,2,3,4,10,14b-헥사히드로벤조[c]피라지노[1,2-a]피리도[3,2-f]아제핀의 제조
1,2,3,4,10,14b-헥사히드로벤조[c]피라지노[1,2-a]피리도[3,2-f]아제핀(607mg), K2CO3(434mg), 벤질브로마이드(475mg)를 DMF 중 실온에서 3시간 교반하였다. 반응액에 물을 첨가하고, AcOEt 추출 후, 용매를 증류 제거하여 목적물(570mg)을 얻었다.
1H-NMR(CDCl3) δ; 2.36(1H, dt, J=3.2, 10.8Hz), 2.52(1H, t, J=10.8Hz), 2.90-3.00(2H, m), 3.43(1H, d, J=13.2Hz), 3.48(1H, dt, J=2.8, 12.4Hz), 3.72(1H, dt, J=2.8, 13.2Hz), 3.86(2H, s), 4.36(1H, d, J=8.0Hz), 4.52(1H, d, J=13.2Hz), 6.73(1H, dd, J=4.8, 7.2Hz), 7.10-7.20(4H, m), 7.30-7.40(6H, m), 8.16(1H, d, J=3.2Hz).
2) 중수소화미르타자핀의 제조
2-벤질-1,2,3,4,10,14b-헥사히드로벤조[c]피라지노[1,2-a]피리도[3,2-f]아제핀(435mg), 메틸-d34-메틸벤젠술포네이트(297mg) 및 NaHCO3(16mg)을 MeCN(5mL)에 현탁시켜 4시간 가열 환류시켰다. 반응 종료 후, 이 용액을 0℃로 냉각시키고, NH4Cl 수용액(31mg/0.8mL)을 첨가하고, 60℃에서 3시간 교반 후, 실온까지 냉각시켰다. 10% Pd/C(50mg)를 첨가하고, 수소 분위기 하에 실온에서 18시간 교반하였다. 반응 용액을 셀라이트 여과하고, 여액 중의 대부분의 유기 용매를 증류 제거하였다. 잔사를 칼럼 크로마토그래피(AcOEt/헥산)에 의해 정제하여 목적물(110mg)을 얻었다.
1H-NMR(CDCl3) δ; 2.50(1H, td, J=10.8, 3.2Hz), 2.63(1H, t, J=10.8Hz), 3.02(1H, d, J=11.2Hz), 3.14(1H, d, J=11.2Hz), 3.42(1H, d, J=13.2Hz), 3.55(1H, td, J=2.8, 12.4Hz), 3.77(1H, dt, J=2.8, 13.2Hz), 4.47(1H, dd, J=2.4, 10.4Hz), 4.50(1H, d, J=13.2Hz), 6.79(1H, dd, J=5.2, 7.6Hz), 7.15(4H, m), 7.33(1H, d, J=8.4Hz), 8.16(1H, dd, J=2.0, 9.2Hz).
실시예 45. 5-((3,4-디메톡시페네틸)(메틸-d
3
)아미노)-2-(3,4-디메톡시페닐)-2-이소프로필펜탄니트릴(중수소화베라파밀)염산염의 제조
5-(벤질(3,4-디메톡시페네틸)아미노)-2-(3,4-디메톡시페닐)-2-이소프로필펜탄니트릴(100mg)과 메틸-d34-메틸벤젠술포네이트(43mg, 함량 92%), NaI(2.8mg) 및 NaHCO3(1.6mg)을 MeCN(0.5mL)에 현탁시키고, 봉함 반응 용기 중 95℃에서 5시간 교반 후, 실온에서 철야 교반하였다. NH4Cl(3.0mg)과 정제수(0.2mL)를 첨가하고 추가로 60℃에서 3시간 교반을 행하였다. 얻어진 용액에 20% Pd(OH)2/C(5mg)를 첨가하여 1 기압의 수소 분위기 하에 실온에서 16시간 교반하였다. 반응액을 셀라이트 여과하고, 여액에 NaOH 수용액을 첨가한 후 AcOEt에 의해 추출하고, 용매를 증류 제거하였다. 잔사를 톨루엔에 용해시켜 염화수소의 Et2O 용액(0.19mL)을 첨가하여 실온에서 1시간 교반하였다. 결정을 여과 취출하여 목적물(60mg)을 얻었다.
1H-NMR(CDCl3) δ: 0.79(3H, d, J=6.4Hz), 1.10-1.18(1H, m), 1.18(3H, d, J=6.4Hz), 1.49-1.65(1H, m), 1.78-1.88(1H, m), 2.00-2.15(2H, m), 2.28-2.41(2H, m), 2.45-2.55(2H, m), 2.60-2.70(2H, m), 3.85(3H, s), 3.87(3H, s), 3.88(3H, s), 3.88(3H, s), 6.67-6.71(2H, m), 6.77-6.86(3H, m), 6.88-6.93(1H, m).
실시예 46, 47
실시예 23, 26과 마찬가지로 하여, 표 3에 나타낸 출발 물질로부터 목적물을 얻는다.
실시예 48. N-에틸-d
5
피페라진의 제조
1) 벤질4-(에틸-d
5
)피페라진-1-카르복실레이트의 제조
벤질4-(4-메톡시벤질)피페라진-1-카르복실레이트(10g), 에틸-d54-메틸벤젠술포네이트(6.84g), NaHCO3(0.49g), 요오드화나트륨(0.44g), MeCN(40mL)을 혼합하여, 봉함 반응 용기에서 90℃에서 2일간 교반하였다. 물(20mL)과 NH4Cl(0.47g)을 첨가하여, 봉함 반응 용기에서 90℃에서 1시간 교반하였다. 10% Pd/C(1g)를 첨가하고, 0.4MPa의 수소 분위기 하에 40℃에서 4시간 교반하였다. 반응액을 셀라이트 여과하고, 여액을 농축 후, 잔사에 AcOEt와 물을 첨가하였다. 5N NaOH 수용액으로 염기성으로 하고, AcOEt로 추출하였다. 용매를 증류 제거하여 목적물(5.06g)을 얻었다.
1H-NMR(CDCl3) δ; 2.40(4H, br s), 3.53(4H, t, J=5.1Hz), 5.13(2H, s), 7.30-7.38(5H, m).
2) N-에틸-d
5
피페라진의 제조
벤질4-(에틸-d5)피페라진-1-카르복실레이트(5.06g), 10% Pd/C(500mg), AeOEt(26mL), MeOH(6.5mL)를 혼합하고, 0.4MPa의 수소 분위기 하에 50℃에서 12시간 교반하였다. 반응액을 셀라이트 여과하고, 여액을 농축하여, 목적물을 4-메틸아니솔과의 혼합물(2.09g, 함량 74.5%)로서 얻었다.
1H-NMR(CDCl3) δ; 2.84-2.93(8H, m).
본 발명은, 아민 부분에 모노중수소 저급 알킬화를 고수율로 저렴하게 제조하는 것을 가능하게 한다.
Claims (10)
- 2급 아민을 함유하는 화합물에 있어서, 해당 아민 상의 수소 원자를 아르알킬로 치환하고, 중성 또는 염기성 조건 하에 중수소 저급 알킬화제로 해당 아민에 중수소 저급 알킬을 도입하고, 이어서 아르알킬을 탈리함으로써, 해당 아민에 모노중수소 저급 알킬을 도입하는 방법.
- 제1항에 있어서, 2급 아민이 피페리딘환을 구성하지 않는 방법.
- 제1항 또는 제2항에 있어서, 중수소 저급 알킬이 중수소메틸 또는 중수소에틸이며, 중수소 저급 알킬화제가 중수소메틸화제 또는 중수소에틸화제인 방법.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 중수소 저급 알킬이 중수소메틸이며, 중수소 저급 알킬화제가 메틸-d3메탄술포네이트, 메틸-d3벤젠술포네이트, 메틸-d34-메틸벤젠술포네이트, 메틸-d32-니트로벤젠술포네이트, 메틸-d34-니트로벤젠술포네이트, 디메틸-d6황산, 탄산디메틸-d6, 메틸-d3트리플루오로메탄술포네이트, 브롬화메틸-d3 또는 요오드화메틸-d3인 방법.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 중수소 저급 알킬이 중수소에틸이며, 중수소 저급 알킬화제가 에틸-d5메탄술포네이트, 에틸-d5벤젠술포네이트, 에틸-d54-메틸벤젠술포네이트, 에틸-d52-니트로벤젠술포네이트, 에틸-d54-니트로벤젠술포네이트, 디에틸-d10황산, 탄산디에틸-d10, 에틸-d5트리플루오로메탄술포네이트, 브롬화에틸-d5 또는 요오드화에틸-d5인 방법.
- 제1항 내지 제5항 중 어느 한 항에 있어서, 아르알킬이 벤질 유도체인 방법.
- 제6항에 있어서, 벤질 유도체가 벤질 또는 4-메톡시벤질인 방법.
- 제6항 또는 제7항에 있어서, 아르알킬의 탈리가 수소 첨가에 의해 행해지는 방법.
- 제1항 내지 제8항 중 어느 한 항에 있어서, 염기성 조건 하가 탄산나트륨, 탄산세슘, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨, 수소화나트륨, 수소화칼륨, 수산화나트륨, 수산화칼륨, 나트륨tert-부톡시드, 칼륨tert-부톡시드, 알킬리튬, 리튬아미드(예를 들어, 리튬디이소프로필아미드, 리튬헥사메틸디실라지드), 나트륨메톡시드 또는 tert-아민에 의한 염기성 조건인 방법.
- 제1항 내지 제9항 중 어느 한 항에 있어서, 2급 아민을 함유하는 화합물이 피페라진 유도체, 피롤리딘 유도체, 아제판 유도체, 디아제판 유도체, 쇄상 아민으로부터 선택되는 방법.
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WO2023129667A1 (en) | 2021-12-30 | 2023-07-06 | Biomea Fusion, Inc. | Pyrazine compounds as inhibitors of flt3 |
WO2023227996A1 (en) * | 2022-05-24 | 2023-11-30 | Clearsynth Labs Limited | A deuterated amine compounds and process for synthesis thereof |
CN115166077A (zh) * | 2022-07-01 | 2022-10-11 | 中国水产科学研究院东海水产研究所 | 一种用于水产品中恩诺沙星残留测定的双内标试剂及检测方法 |
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US20080194529A1 (en) | 2007-02-12 | 2008-08-14 | Auspex Pharmaceuticals, Inc. | HIGHLY SELECTIVE and LONG-ACTING PDE5 MODULATORS |
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US20220127206A1 (en) | 2022-04-28 |
EP3939954A1 (en) | 2022-01-19 |
WO2020184670A1 (ja) | 2020-09-17 |
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CA3132953A1 (en) | 2020-09-17 |
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