KR101870918B1 - Method for preparing ticagrelor and novel intermediate used therefor - Google Patents
Method for preparing ticagrelor and novel intermediate used therefor Download PDFInfo
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- KR101870918B1 KR101870918B1 KR1020160000552A KR20160000552A KR101870918B1 KR 101870918 B1 KR101870918 B1 KR 101870918B1 KR 1020160000552 A KR1020160000552 A KR 1020160000552A KR 20160000552 A KR20160000552 A KR 20160000552A KR 101870918 B1 KR101870918 B1 KR 101870918B1
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- 238000000034 method Methods 0.000 title claims description 35
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 title abstract 2
- 229960002528 ticagrelor Drugs 0.000 title 1
- -1 3-benzyloxyphenyl Chemical group 0.000 claims description 72
- 150000001875 compounds Chemical class 0.000 claims description 64
- 125000004432 carbon atom Chemical group C* 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 20
- 238000004519 manufacturing process Methods 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 150000001642 boronic acid derivatives Chemical class 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000010288 sodium nitrite Nutrition 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 90
- 230000015572 biosynthetic process Effects 0.000 description 48
- 238000003786 synthesis reaction Methods 0.000 description 46
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 17
- 230000008569 process Effects 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- 238000000113 differential scanning calorimetry Methods 0.000 description 9
- 238000005259 measurement Methods 0.000 description 8
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 5
- YDWQJACVMWFKSN-UHFFFAOYSA-N 7-chloro-5-propylsulfanyl-2h-triazolo[4,5-d]pyrimidine Chemical compound N1=C(SCCC)N=C(Cl)C2=NNN=C21 YDWQJACVMWFKSN-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 3
- 125000005907 alkyl ester group Chemical group 0.000 description 3
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960003116 amyl nitrite Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- IMYLOCHFFLYHPS-RDNZEXAOSA-N (1r,2s)-2-(3,4-difluorophenyl)cyclopropan-1-amine;hydrochloride Chemical compound Cl.N[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 IMYLOCHFFLYHPS-RDNZEXAOSA-N 0.000 description 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- SQTUYFKNCCBFRR-UHFFFAOYSA-N (2,4-dimethoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C(OC)=C1 SQTUYFKNCCBFRR-UHFFFAOYSA-N 0.000 description 1
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- WIJNYNBSPQMJGO-UHFFFAOYSA-N (3-phenylmethoxyphenyl)boronic acid Chemical compound OB(O)C1=CC=CC(OCC=2C=CC=CC=2)=C1 WIJNYNBSPQMJGO-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
- QPKFVRWIISEVCW-UHFFFAOYSA-N 1-butane boronic acid Chemical compound CCCCB(O)O QPKFVRWIISEVCW-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ZSONPNZCXQKRFE-UHFFFAOYSA-N 2-(5-amino-6aH-cyclopenta[d][1,3,2]dioxaborol-2-yl)benzoic acid Chemical compound NC1=CC2C(OB(O2)C2=C(C(=O)O)C=CC=C2)=C1 ZSONPNZCXQKRFE-UHFFFAOYSA-N 0.000 description 1
- GIIGHSIIKVOWKZ-UHFFFAOYSA-N 2h-triazolo[4,5-d]pyrimidine Chemical class N1=CN=CC2=NNN=C21 GIIGHSIIKVOWKZ-UHFFFAOYSA-N 0.000 description 1
- CJJLJBFJNXMANZ-UHFFFAOYSA-N 4,6-dichloro-2-propylsulfanylpyrimidin-5-amine Chemical compound CCCSC1=NC(Cl)=C(N)C(Cl)=N1 CJJLJBFJNXMANZ-UHFFFAOYSA-N 0.000 description 1
- DDEDQHVHVPJFAC-UHFFFAOYSA-N 4,6-dichloro-5-nitro-2-propylsulfanylpyrimidine Chemical compound CCCSC1=NC(Cl)=C([N+]([O-])=O)C(Cl)=N1 DDEDQHVHVPJFAC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DANLZOIRUUHIIX-UHFFFAOYSA-N 4-[1-[2-chloro-6-(trifluoromethyl)benzoyl]indazol-3-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C(C1=CC=CC=C11)=NN1C(=O)C1=C(Cl)C=CC=C1C(F)(F)F DANLZOIRUUHIIX-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- UKMPCAMBJGVHPA-UHFFFAOYSA-N N1(N=CC=2N=CN=CC21)O.CC Chemical compound N1(N=CC=2N=CN=CC21)O.CC UKMPCAMBJGVHPA-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- NDVJJEADFLTFCD-UHFFFAOYSA-N [4-(methanesulfonamido)phenyl]boronic acid Chemical compound CS(=O)(=O)NC1=CC=C(B(O)O)C=C1 NDVJJEADFLTFCD-UHFFFAOYSA-N 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclo-pentanone Natural products O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 1
- XDRVAZAFNWDVOE-UHFFFAOYSA-N cyclohexylboronic acid Chemical compound OB(O)C1CCCCC1 XDRVAZAFNWDVOE-UHFFFAOYSA-N 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- KPTRDYONBVUWPD-UHFFFAOYSA-N naphthalen-2-ylboronic acid Chemical compound C1=CC=CC2=CC(B(O)O)=CC=C21 KPTRDYONBVUWPD-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229940019331 other antithrombotic agent in atc Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- QNMBSXGYAQZCTN-UHFFFAOYSA-N thiophen-3-ylboronic acid Chemical compound OB(O)C=1C=CSC=1 QNMBSXGYAQZCTN-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/05—Cyclic compounds having at least one ring containing boron but no carbon in the ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
(1S, 2S, 3R, 5S) -3- [7 - [(1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamino ] -5- (propyl thio) -3 H - [1,2,3] triazolo [4,5- d] pyrimidin-3-yl] -5- (2-hydroxyethoxy) cyclopentane -1 , 2-diols and novel intermediates used therefor. According to the present invention, tikageler can be easily prepared from a novel intermediate:
≪ Formula 1 >
Description
The present invention relates to a method for producing (1S, 2S, 3R, 5S) -3- [7 - [(1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamino] novel [1,2,3] triazolo [4,5- d] pyrimidin-3-yl] -5- (2-hydroxyethoxy) cyclopentane-1,2-diol-thio) -3 H And to useful intermediates used therefor.
It has been confirmed that adenosine 5'-diphosphate (ADP) acts as a major mediator of thrombosis. Adenosine 5'-diphosphate (ADP) -induced platelet aggregation is mediated by the P2Y 12 receptor subtypes located on the platelet membrane. P2Y 12 receptors (also known as P 2T , P2Y ADP, or P2T AC ) are G protein coupled receptors primarily involved in mediating platelet activation / aggregation.
In this regard, WO 99/05143 discloses a series of triazolo [4,5- d ] pyrimidine compounds having activity as P 2T (also known as P2Y 12 , P2Y ADP or P2T AC ) A new class of direct (befrodruk) P 2 T receptor antagonists has been disclosed, which recently provided significant improvements over other antithrombotic agents. Furthermore, WO 00/34283 discloses novel direct P 2 T receptor antagonists, including compounds of Tikageler (Formula I).
In the meantime, various synthetic methods for the production of tikageler have been studied. Specifically, Astra Zeneca, which is a original developer, is carried out as illustrated in the following
[Reaction Scheme 1]
The process for preparing tikageler disclosed in WO 00/34283
However, in the method disclosed in the patent, there are various problems as follows: 1) the synthesis route is very long and the synthesis route is very long, and 2) DIBAL-H, sodium hydride, amyl nitrite and bromomethane (3) the amino group reacts with 2 - (((trifluoromethyl) sulfonyl) oxy) acetate as a side reaction in the MATAM reaction in ATAM, And 4) it is not easy to mass-produce in general accompanied by purification by column chromatography.
On the other hand, as a later improved method, WO 01/92263 and WO < RTI ID = 0.0 > 10/030224 < / RTI > disclose a process for preparing tikageler as illustrated in Scheme 2 below. As can be seen in the following scheme 2, the hydroxyethyl chain of AMALCINAA in this method is introduced by a three-step synthetic route in the initial synthesis of AMAL, the triazole ring of CLTAMA is introduced by reacting AMALCINAA with sodium nitrite, , Tikageler is synthesized using hydrochloric acid. However, the improved process described below still has a substantially long 7- to 8-fold synthetic route and the benzyloxycarbonyl protecting group is removed using the catalyst palladium / carbon via hydrogenation during the three step AMAL synthesis and another catalyst platinum / carbon To synthesize CLINA by reducing CLIDA:
[Reaction Scheme 2]
The process for preparing tikageler disclosed in WO 01/92263
Further, in addition to the above-described method for producing tikageler, methods for synthesizing the tikageler and the intermediate described in the prior art documents include a long synthesis process, a plurality of crystallization processes, a purification process by column chromatography, Amyl nitrite, bromomethane, diazomethane and the like, which are accompanied by troublesome processes and consequently the yield of the product is low. Thus, it is possible to provide a simple, economical, safe, industrial bulk There is a strong demand for development of a manufacturing method of tikageler suitable for production.
Accordingly, the present invention relates to a process for producing tikageler using a novel intermediate, which is carried out by a simple process, does not require a purification process by column chromatography, is safe without using harmful substances, And an object of the present invention is to provide a novel production method suitable for production and a novel intermediate for the production method.
According to one aspect of the present invention, the present invention relates to a process for producing tikageler represented by the following formula (1), comprising the steps of:
(a) reacting a compound of formula (3) with a compound of formula (4) in the presence of a tertiary amine to produce a compound of formula (5);
(b) reacting the compound of formula (5) with a nitrite to produce a compound of formula (6);
(c) reacting the compound of Formula 6 with a compound of Formula 7 to prepare a compound of Formula 8; And
(d) deprotecting the compound of formula (8) prepared in step (c) to prepare a tikageler of formula (1).
Specifically, the preparation method can be schematized as shown in Reaction Scheme 3 below.
[Reaction Scheme 3]
In the above Reaction Scheme 3, R is alkyl having 1 to 6 carbon atoms; Cycloalkyl having 3 to 7 carbon atoms; Substituted or unsubstituted aryl having 4 to 15 carbon atoms; Or 4 to 15-membered substituted or unsubstituted heteroaryl, but is not limited thereto, and more specifically, alkyl having 3 to 6 carbon atoms; Cycloalkyl having 3 to 6 carbon atoms; Alkyloxy having 1 to 4 carbon atoms, alkyloxy having 1 to 6 carbon atoms, alkyl ester having 1 to 6 carbon atoms, or alkyl group having 1 to 6 carbon atoms substituted at one or more positions with halogen, alkoxy having 1 to 6 carbon atoms, aryloxy having 6 to 10 carbon atoms, aryl having 6 to 10 carbon atoms, Aryl having 6 to 10 carbon atoms, unsubstituted or substituted with alkylsulfonylamino having 1 to 6 carbon atoms; Or 4 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of O, N and S, and more specifically, butyl, cyclohexyl, phenyl, 4-chlorophenyl, 3-benzyloxyphenyl, naphthyl, thiophene, 3-carboxyphenyl, 4-ethoxyphenyl, 2,4-dimethoxyphenyl or 4-methylsulfonylaminophenyl.
Hereinafter, each step of the manufacturing method according to the present invention will be described in detail.
In step (a) above, the compound of formula (3) is reacted with a compound of formula (4) in the presence of a tertiary amine to produce a compound of formula (5). The present reaction can be carried out in a polar solvent at 80 to 100, but it is not limited thereto. More specifically, the tertiary amine may be tri (C 1 -C 6 ) alkylamine, more specifically triethylamine. As the polar solvent, an alcohol having 1 to 6 carbon atoms, N-methyl-2 But are not limited to, pyrrolidone, ethylene glycol, acetonitrile, dimethylsulfoxide, dimethylformamide, or mixed solvents thereof.
(3)
≪ Formula 4 >
≪ Formula 5 >
In one embodiment of the present invention, the compound of Formula 3 may be prepared by reacting a compound of Formula 2 with a boronic acid derivative (RB (OH) 2 ) as shown in Reaction Scheme 4 below. In the following Reaction Scheme 4, the R group is the same as defined in Scheme 3.
[Reaction Scheme 4]
The reaction may be carried out at 20 to 30 ° C and may be carried out in a reaction solvent, preferably methanol, toluene, acetonitrile, dimethylsulfoxide, dimethylformamide, or a mixed solvent thereof for 3 to 24 hours. The process is simple and does not involve the use of explosive materials conventionally used in the preparation of tikaguler, and a novel intermediate compound of formula 3 can be obtained as a solid without further purification, Not accompanied.
On the other hand, in the prior art, a compound of the following
≪ Formula 10 >
As described above, the present invention can provide a simple and safe process for preparing tikageler without additional salt formation and purification process and a novel intermediate compound which makes it possible, And can be easily manufactured in a large amount by a safe method.
On the other hand, as a specific embodiment, the compound of the formula (4) which forms the formula (5) in combination with the formula (3) can be prepared as described in WO 2005/095358. 4,6-Dichloro-5-nitro-2- (propylthio) pyrimidine can also be prepared by the method described in EP 0931053, EP 084292, Other methods for the reduction of aromatic nitro groups other than platinum / vanadium complex catalysts as described in Larock Comprehensive Organic Transformations, ISBN 0-89573-710-8, VCH Publishers Inc., 1989, And can be used as a reaction material of the present invention.
In step (b), the compound of formula (5) is reacted with a nitrite to prepare a compound of formula (6). The present reaction can be carried out in the presence of an acid at 20 to 30 for 1 to 12 hours, but is not limited thereto. The reaction solvent to be used is preferably toluene.
Specific examples of the nitrite include, but are not limited to, an alkali metal nitrite such as sodium nitrite and an organic nitrite such as iso-amyl nitrite. The nitrite may be added dropwise to the mixture of the compound of
(6)
In step (c), the compound of formula (6) is reacted with the compound of formula (7) to prepare a compound of formula (8). The present reaction can be carried out in the presence of a base at 20 to 30 for 1 to 12 hours, but is not limited thereto. The reaction solvent to be used is preferably toluene.
More specifically, the base may be potassium carbonate, and the compound of formula (VII) may be used in the form of a salt, more specifically a hydrochloride salt, but is not limited thereto.
≪ Formula 7 >
(8)
In the above step (d), the compound of formula (8) is deprotected to prepare a tikageler of the following formula (1). The reaction may be carried out in the presence of hydrogen peroxide at 20 to 30 for 1 minute to 6 hours. The reaction solvent may be methanol, acetonitrile, dimethylsulfoxide, dimethylformamide, or ethyl acetate, but is not limited thereto. It may preferably be ethyl acetate.
≪
In another embodiment, the present invention provides a compound represented by the following formula (3), (5), (6) or (8) used as an intermediate in the production of the ticaguller.
(3)
≪
(6)
(8)
In
The present invention relates to a method for producing a to Mathematica that relreo for preparing intermediates represented by the formula (3), comprising the step of formula (II) compounds reacting with the acid derivative (RB (OH) 2) boronic the compound as illustrated in scheme 4 .
[Reaction Scheme 4]
The reaction may be carried out at 20 to 30 ° C and may be carried out in a reaction solvent, preferably methanol, toluene or a mixed solvent thereof for 3 to 24 hours. The process has the advantage that it does not involve the use of a simple, explosive material, and the novel intermediate compound of formula (III) can be obtained as a solid without further purification steps, without the need for a separate salt formation step.
In the above formulas (3) and (4), R is alkyl having 1 to 6 carbon atoms; Cycloalkyl having 3 to 7 carbon atoms; Substituted or unsubstituted aryl having 4 to 15 carbon atoms; Or 4 to 15-membered substituted or unsubstituted heteroaryl, but is not limited thereto, and more specifically, alkyl having 3 to 6 carbon atoms; Cycloalkyl having 3 to 6 carbon atoms; Alkyloxy having 1 to 4 carbon atoms, alkyloxy having 1 to 6 carbon atoms, alkyl ester having 1 to 6 carbon atoms, or alkyl group having 1 to 6 carbon atoms substituted at one or more positions with halogen, alkoxy having 1 to 6 carbon atoms, aryloxy having 6 to 10 carbon atoms, aryl having 6 to 10 carbon atoms, Aryl having 6 to 10 carbon atoms, unsubstituted or substituted with alkylsulfonylamino having 1 to 6 carbon atoms; Or 4 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of O, N and S, and more specifically, butyl, cyclohexyl, phenyl, 4-chlorophenyl, 3-benzyloxyphenyl, naphthyl, thiophene, 3-carboxyphenyl, 4-ethoxyphenyl, 2,4-dimethoxyphenyl or 4-methylsulfonylaminophenyl.
The tikageler production method of the present invention has an advantage that tikageler can be manufactured through a simple process using easily prepared starting materials and novel intermediates, in a safe and easily applicable to mass production.
Figure 1 is a graph of differential scanning calorimetry (DSC) measurement of compound 3a.
Fig. 2 is a graph of differential scanning calorimetry (DSC) measurement results of compound 5a.
FIG. 3 is a graph showing the result of differential scanning calorimetry (DSC) measurement of Compound 11.
BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. It should be noted, however, that the following examples are illustrative of the present invention, and the scope of the present invention is not limited to these examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
< Experimental Example >
The following experimental examples are intended to provide experimental examples that are commonly applied to the respective embodiments according to the present invention.
How to measure
1) < 1 > H, 13C NMR
- Manufacturer: Varian, Agilent
- Device name: Varian 400 MHz, Agilent 600 MHz model
-DMSO-d 6 : Merck
2) Differential Scanning Calorimetry (DSC)
- Manufacturer: METTLER TOLEDO
- Device name: DSC1 STAR System
- Temperature increase rate: 10 / min
3) Melting point measurement
- Manufacturer: METTLER TOLEDO
- Device name: FP81HT, FP90
- Temperature increase rate: 10 / min
< Example 1 > 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- Phenyltetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol Tikagueler synthesis
1) 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- Phenyltetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol (scheme 4)
(482 ml), toluene (482 ml), phenylboronic acid (50 ml), and the like were added to 49.91 g of (1S, 2S, 3R, 5S) (33.19 g) was added thereto, and stirred overnight at room temperature. The reaction solution was concentrated and the concentrate was dried to obtain 2 - (((3aS, 4S, 6R, 6aS) -6-amino-2-phenyltetrahydro-4H-cyclopenta [d] [1,3,2] Yl) oxy) ethan-l-ol was quantitatively obtained.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 1.60-1.66 (1H, m) 1.97-2.03 (1H, m), 3.17-3.18 (1H, m), 3.47-3.55 (4H, m) (2H, d), 3.85 (1H, s), 4.68-4.70 (1H, m)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 21.49, 58.52, 60.67, 70.89, 85.88, 125.75, 127.44, 128.64, 129.33, 134.51, 137.78
2) 2 - ((( 3aS, 4S, 6S, 6aS ) -6 - ((5-amino-6- Chloro -2-( Propyl thio Yl) amino) -2-phenyltetrahydro-4H-cyclopenta [d] [1,3,2] dioxaborol-4yl) oxy) ethan- Step a)
Cyclopenta [d] [l, 3,2] dioxaborol-4-yl) oxy) ethane-lH- (16.8 ml), N-methyl-2-pyrrolidone (10.5 ml), and 4,6-dichloro-2-propylthiopyrimidin-5-amine (3.8 g) Triethylamine (8.9 ml), and the mixture was heated and stirred at 90 to 100 ° C overnight. After cooling to room temperature, ethanol (50 ml) was added dropwise and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration and dried to obtain 2 - (((3aS, 4S, 6S, 6aS) -6 - ((5-amino-6-chloro-2- (propylthio) pyrimidin- Cyclopenta [d] [1,3,2] dioxaborol-4-yl) oxy) ethan-1-ol (3.94 g, 53%).
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.92 (3H, t), 1.63 (2H, q), 1.77-1.84 (1H, m), 2.23-2.29 (1H, m), 2.93- (2H, m), 4.94 (2H, m), 4.04-4.03 (2H, m) (1H, m), 7.86 (2H, d), 7.96 (1H,
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.75, 23.31, 32.58, 32.84, 67.66, 60.76, 71.11, 84.64, 85.16, 85.35, 120.38, 128.42, 132.19, 134.98, 138.76, 152.35, 155.94
3) Preparation of 2 - (((3aS, 4S, 6S, 6aS) -6- (7-chloro-5- (propylthio) -3H- [1,2,3] triazolo [4,5- d] pyrimidine Yl) oxy) ethan-1-ol (step b of scheme 3)
Amino) -2-phenyltetrahydro-4H-pyrrolo [2,3-c] pyridin-2- Toluene (12 ml) and acetic acid (2.2 ml) were added to a suspension of cyclopenta [d] [1,3] dioxaborol-4-yl) oxy) ethan- 0.49 g / 1.5 ml) was gradually added dropwise and the mixture was stirred at room temperature for 3 hours. Potassium carbonate solution (2.68 g / 6 ml) was slowly added dropwise, and ethyl acetate (15 ml) was added. After stirring for 10 minutes, the organic layer was washed twice with saturated brine. The organic layer was dehydrated, filtered and concentrated, and the concentrate was dried to obtain 2 - ((3aS, 4S, 6S, 6aS) -6- (7-chloro-5- (propylthio) Cyclopenta [d] [1,3,2] dioxaborol-4-yl) oxy) ethane-lH-pyrazolo [4,5- d] pyrimidin- 1-ol was quantitatively obtained.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.98 (3H, t), 1.75 (2H, q), 2.44-2.52 (1H, m), 2.65-2.71 (1H, m), 3.12- (2H, m), 3.25-3.56 (3H, m), 3.60-3.65 (1H, m), 4.20-4.25 ), 7.39-7.43 (2H, m), 7.50-7.54 (1H, m), 7.73 (2H, d)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.66, 22.26, 33.35, 33.39, 60.56, 63.45, 71.50, 83.11, 83.67, 85.24, 128.39, 132.19, 132.41, 134.98, 150.97, 152.39, 170.38
4) Synthesis of 2 - ((3aS, 4S, 6S, 6aS) -6- (7 - ((2- (3,4- difluorophenyl) cyclopropyl) amino) [1,2,3] triazolo [4,5-d] pyrimidin-3-yl) -2-phenyltetrahydro-4H- cyclopenta [d] [1,3,2] dioxaborol- Yl) oxy) ethan-1-ol Synthesis (step c of Scheme 3)
3H] [1,2,3] triazolo [4,5-d] pyrimidin-3 (3S, 4S, 6S, 6aS) Yl) oxy) ethan-1-ol (2.7 g) in toluene (22 ml) was added to a solution of 4- . (1R, 2S) -2- (3,4-difluorophenyl) cyclopropanamine hydrochloride (1.3 g) was added to and dissolved in an aqueous solution of potassium carbonate (1.29 g / 16 ml) Lt; / RTI > for 3 hours. Water (8 ml) was added, stirred for 10 minutes, layered, and the organic layer was washed twice with 0.2% aqueous acetic acid (17 ml) and twice with saturated brine (13.5 ml). The organic layer was dehydrated, filtered and concentrated, and the concentrate was dried to obtain 2 - {(3aS, 4S, 6S, 6aS) -6- (7 - ((2- (3,4-difluorophenyl) cyclopropyl) D] pyrimidin-3-yl) -2-phenyltetrahydro-4H-cyclopenta [d] 1,3,2] dioxaborol-4-yl) oxy) ethan-l-ol was quantitatively obtained.
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.80 (3H, t), 1.35-1.40 (1H, m), 1.46-1.58 (3H, m), 2.11-2.16 (2H, m), 2.54-2.62 (1H, m), 2.87-2.91 (2H, m), 3.13-3.18 (1H, m), 3.51-3.55 (1H, m), 4.66-4.68 (1H, m), 4.94-4.98 (1H, m), 5.27-5.33 (1H, m), 5.47-5.51 (2H, m), 7.38-7.42 (2H, m), 7.50-7.54 (1H, m), 7.73
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.45, 15.43, 22.79, 24.44, 32.83, 33.76, 34.52, 60.59, 62.28, 71.51, 83.06, 83.67, 85.23, 115.18, 115.36, 117.38, 117.55, 123.69, 125.73, 128.38, 128.62, 129.32, 132.16, 135.00, 149.57, 154.40
5) Tikagueler Synthesis (step d of scheme 3)
Amino] -5- (propylthio) -3H- [1, 3-dihydroxyphenyl] , 2,3] triazolo [4,5-d] pyrimidin-3-yl) -2-phenyltetrahydro-4H- cyclopenta [d] [1,3,2] dioxaborol- (3 ml) was added ethyl acetate (30 ml) and 35% hydrogen peroxide (1.1 ml), and the mixture was stirred at room temperature for 1 hour. Water (30 ml) was added, stirred for 15 minutes, layered, and the organic layer was washed twice with water (24 ml) and then twice with saturated brine (30 ml). The organic layer was dehydrated, filtered, and concentrated. To the concentrate, ethyl acetate (18 ml) was added, and the mixture was completely dissolved by heating at 50 ° C for 30 minutes, iso-octane (18 ml) . The reactor was cooled to room temperature and stirred at 0? 5 占 폚 for 3 hours. The precipitated solid was filtered and dried to obtain tikagalerer (2.1 g, 81%).
1 H NMR (DMSO-d 6 , 400 MHz): 0.80 (3H, t), 1.34-1.57 (4H, m), 1.98-2.03 (1H, m), 2.05-2.11 (1H, m), 2.58-2.66 (1H, m), 2.79-2.86 (1H, m), 2.89-2.96 (1H, m), 3.10-3.17 (1H, m), 3.43-3.51 (1H, br s), 4.52-4.61 (2H, m), 4.91-4.98 (1H, m), 5.05 -7.34 (2 H, m), 9.15 (1 H, d)
13 C NMR (DMSO-d 6 , 100 MHz): 13.39,15.46,22.71,24.47,32.74,33.68,34.55,60.71,60.90,71.27,74.08,74.78,82.19,115.13,115.30,117.38,117.55,123.58,149.84, 154.36, 169.57
< Example 2> 2-((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (4- Chlorophenyl ) Tetrahydro -4H- Cyclopenta [d] [1, 3, 2] Dioxaborol Yl) Oxy ) Ethan-1-ol Tikagueler synthesis
1) 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (4- Chlorophenyl ) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol (scheme 4)
Was obtained quantitatively in the same manner as in step 1) of Example 1, except that 4-chlorophenylboronic acid was used instead of phenylboronic acid in 1) reaction of Example 1.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 1.69 (1H, br s), 1.85 (1H, br s), 3.03 (1H, br s), 3.42-4.48 (4H, m), 3.71 (1H, br s), 4.48-4.54 (2H, m), 7.11-7.26 (3H, m), 7.44-7.45
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 21.48, 48.97, 58.39, 60.62, 70.71, 85.68, 125.75, 127.23, 128.64, 129.33, 134.83, 137.78
Amino) -2- (4-chloro-2- (propylthio) pyrimidin-4-yl) 4-yl) oxy) ethan-1-ol (step a) of Scheme 3)
Using the product of step 1), 51% of the product was obtained in the same manner as in step 2) of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.90 (3H, t), 1.61 (2H, q), 1.78-1.84 (1H, m), 2.24-2.30 (2H, m), 3.52-3.62 (4H, m), 3.98-4.01 (1H, m), 4.42-4.46 7.27 (1H, d), 7.47 (2H, d), 7.70 (2H, d)
13 C NMR (DMSO-d 6 , 100 MHz)? (Ppm): 13.74,23.28,32.58,33.08,57.47,60.73,71.20,84.49,85.24,85.34,120.54,128.59,136.74,137.13,138.48,152.35,155.68
3) Preparation of 2 - (((3aS, 4S, 6S, 6aS) -6- (7-chloro-5- (propylthio) -3H- [1,2,3] triazolo [4,5- d] pyrimidine D] [1,3,2] dioxaborol-4-yl) oxy) ethan-1-ol Synthesis (Reaction Scheme 3) Synthesis of 3-chloro- Step b)
Was obtained quantitatively in the same manner as in step 3) of Example 1, using the product of step 2).
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.98 (3H, t), 1.74 (2H, q), 2.43-2.51 (1H, m), 2.65-2.71 (1H, m), 3.13- (2H, m), 3.49-3.55 (3H, m), 3.59-3.65 (1H, m), 4.20-4.25 ), 7.48 (2H, d), 7.72 (2H, d)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.66, 22.27, 33.35, 60.55, 63.35, 71.50, 83.17, 83.57, 85.35, 125.74, 128.57, 128.62, 129.32, 132.42, 136.70, 137.06, 150.97, 152.40, 170.38
4) Synthesis of 2 - ((3aS, 4S, 6S, 6aS) -2- (4-chlorophenyl) -6- D] pyrimidin-3-yl) tetrahydro-4H-cyclopenta [d] [l, 3,2] di Yl) oxy) ethan-1-ol < / RTI > synthesis (step c)
The product obtained in the above step 3) was quantitatively obtained in the same manner as in step 4) of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.79 (3H, t), 1.35-1.56 (4H, m), 2.10-2.15 (1H, m), 2.55-2.60 (2H, m), 3.13-3.17 (1H, m), 3.54-3.64 (4H, m), 4.17-4.21 (1H, m), 4.65-4.68 m), 5.27-5.32 (1H, m), 5.47-5.50 (1H, m), 7.05-7.07 (1H, br s), 7.26-7.33 2H, < / RTI > d), 9.43 (1H, d)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.45, 15.43, 22.78, 24.44, 32.83, 33.77, 34.52, 60.59, 62.18, 71.52, 83.14, 83.57, 85.35, 115.17, 115.35, 117.38, 117.55, 123.68, 125.73, 127.86, 128.54, 128.62, 129.32, 136.38, 136.72, 137.04, 149.56, 154.40, 170.08
5) Tikagueler Synthesis (step d of scheme 3)
The product was obtained in 71% yield in the same manner as in step 5) of Example 1, using the product of step 4).
< Example 3 > 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (3- ( Benzyloxy ) Phenyl) Tetrahydro -4H-cyclopenta [d] [1, 3,2] Dioxaborol Yl) Oxy ) Ethan-1-ol Tikagueler synthesis
1) 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (3- ( Benzyloxy ) Phenyl) Tetrahydro -4H- Cyclopenta [d] [1, 3, 2] Dioxaborol Yl) Oxy ) Ethan-1-ol Synthesis (Scheme 4)
The title compound was obtained in a similar manner to the step 1) of Example 1 using 3- (benzyloxy) phenylboronic acid instead of phenylboronic acid in 1) reaction of Example 1.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 1.63 (1H, br s), 1.90 (1H, br s), 3.07 (1H, s), 3.44-3.52 (4H, m), 3.76 ( (1H, s), 4.59 (1H, s), 4.62 (1H, s), 5.05 (2H, s), 6.94 -7.43 (4 H, m)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 21.49, 34.53, 58.48, 60.67, 69.32, 70.93, 84.41, 85.72, 119.49, 125.75, 126.38, 127.97, 128.03, 128.11, 128.64, 128.80, 128.99, 129.33, 137.81, 158.06
Amino) -2- (3- ((3-chloro-2-methylpropylthio) pyrimidin- 4-yl) oxy) ethan-1-ol (step a) of Scheme 3)
Using the product of step 1), 47% of the product was obtained in the same manner as in step 2) of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.92 (3H, t), 1.63 (2H, q), 1.78-1.84 (1H, m), 2.23-2.29 M), 4.81 (2H, s), 4.88 (2H, s), 4.95 (2H, (1H, d), 7.29-7.34 (4H, m), 7.36-7.44 (4H, m)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.76, 23.29, 32.61, 32.86, 57.64, 60.77, 69.47, 71.11, 84.62, 85.20, 85.38, 118.97, 120.38, 120.43, 127.48, 127.98, 128.22, 128.85, 129.80, 137.47, 138.78, 138.79, 152.36, 155.96, 155.98, 158.31
3) Preparation of 2 - ((3aS, 4S, 6S, 6aS) -2- (3- (benzyloxy) phenyl) -6- (7-chloro-5- (propylthio) ] Triazolo [4,5-d] pyrimidin-3-yl) tetrahydro-4H-cyclopenta [d] [1,3,2] dioxaborol-4- yl) oxy) ethan- (Step b of scheme 3)
Was obtained quantitatively in the same manner as in step 3) of Example 1, using the product of step 2).
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.98 (3H, t), 1.74 (2H, q), 2.46-2.52 (1H, m), 2.65-2.71 (1H, m), 3.15- (2H, m), 3.50-3.65 (4H, m), 4.20-4.25 (1H, m), 4.96-5.00 5.52-5.55 (1H, m), 7.15-7.18 (1H, m), 7.29-7.45 (8H, m)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.64, 22.24, 33.36, 60.56, 63.43, 69.49, 71.49, 83.12, 83.64, 85.26, 118.85, 120.57, 125.74, 127.48, 127.98, 128.05, 128.22, 128.63, 128.84, 129.33, 129.79, 132.43, 137.47, 150.98, 152.39, 158.29, 170.37
4) Preparation of 2 - ((3aS, 4S, 6S, 6aS) -2- (3- (benzyloxy) Amino] -5- (propylthio) -3H- [1,2,3] triazolo [4,5- d] pyrimidin-3- yl) , 2] dioxaborol-4-yl) oxy) ethan-1-ol (step c)
The product obtained in the above step 3) was quantitatively obtained in the same manner as in step 4) of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.79 (3H, t), 1.36-1.40 (1H, m), 1.48-1.58 (3H, m), 2.11-2.15 M), 3.14-3.17 (1H, m), 3.54-3.56 (3H, m), 3.60-3.64 m), 4.66-4.69 (1H, m), 4.94-4.97 (1H, m), 5.10 (12 H, m), 9.44 (1 H, d)
13 C NMR (DMSO-d 6 , 100 MHz)? (Ppm): 13.73, 15.43. 21.46, 22.78, 24.44, 32.84, 33.74, 34.52, 60.59, 62.28, 69.48, 71.51, 83.07, 83.64, 85.26, 115.19, 115.36, 117.38, 117.55, 118.89, 120.48, 123.24, 123.70, 125.73, 127.50, 127.98, 128.05, 128.19, 128.61, 128.82, 129.75, 137.48, 149.57, 154.40, 158.29, 170.10
5) Tikagueler Synthesis (step d of scheme 3)
Was obtained in a yield of 77% in the same manner as in the step 5) of Example 1, using the product of the above step 4).
< Example 4 > 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (naphthalen-2-yl) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol Tikagueler synthesis
1) 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (naphthalen-2-yl) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol (scheme 4)
Was obtained quantitatively in the same manner as in the step 1) of Example 1 using 2-naphthylboronic acid instead of phenylboronic acid in 1) reaction of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz)? (Ppm): 1.52 (1H, br s), 1.91-2.02 (2H, m), 7.62 (1H, d), 7.71 (1H, d), 7.77-7.82 (2H, , < / RTI > m), 8.04 (1H, s)
13 C NMR (DMSO-d 6 , 100 MHz)? (Ppm): 21.49,58.59,60.71,70.95,80.81,80.93,81.94,85.90,86.57,128.64,129.33,133.00
Amino) -2- (naphthalene-2-yl) amino] -2 - {(3S, 4S, 6S, 6aS) Yl) oxy) ethan-1-ol Synthesis (Step a) of Scheme 3 [0156] < EMI ID =
Using the product of step 1), 43% of the product was obtained in the same manner as in step 2) of Example 1.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.92 (3H, t), 1.63 (2H, q), 1.81-1.84 (1H, m), 2.27-2.32 (1H, m), 2.95- (2H, m), 4.94 (3H, s), 3.07 (2H, m), 3.47-3.67 (4H, m), 4.06-4.08 D), 7.99 (1H, d), 7.90 (1H, d)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.77, 23.29, 32.97, 46.12, 57.65, 60.78, 71.16, 84.65, 85.29, 85.41, 120.41, 126.69, 127.61, 127.93, 128.08, 128.97, 130.43, 132.75, 135.05, 136.62, 138.80, 152.41, 156.02
3) Preparation of 2 - (((3aS, 4S, 6S, 6aS) -6- (7-chloro-5- (propylthio) -3H- [1,2,3] triazolo [4,5- d] pyrimidine Cyclopenta [d] [1,3,2] dioxaborol-4-yl) oxy) ethan-1-ol Step b)
Was obtained quantitatively in the same manner as in step 3) of Example 1, using the product of step 2).
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.98 (3H, t), 1.75 (2H, q), 2.46-2.54 (1H, m), 2.68-2.74 M), 3.63-3.77 (1H, m), 4.26-4.31 (1H, m), 5.03-5.05 (1H, m), 7.52-7.60 ), 7.77 (1H, d), 7.93 (2H, m), 8.02
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.66, 22.28, 33.36, 60.59, 71.55, 83.67, 125.74, 126.69, 127.60, 127.94, 128.08, 128.63, 129.00, 129.32, 130.44, 132.76, 135.05, 136.58, 148.94, 160.00, 152.42, 155.88, 162.67, 170.40
4) Synthesis of 2 - ((3aS, 4S, 6S, 6aS) -6- (7 - ((2- (3,4- difluorophenyl) cyclopropyl) amino) [1,2,3] triazolo [4,5-d] pyrimidin-3-yl) -2- (naphthalen-2-yl) tetrahydro- Dioxaborol-4-yl) oxy) ethan-1-ol (step c)
The product obtained in the above step 3) was quantitatively obtained in the same manner as in step 4) of Example 1.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.77 (3H, t), 1.33-1.38 (1H, m), 1.41-1.56 (3H, m), 2.09-2.14 (1H, m), (1H, m), 2.50-2.62 (1H, m), 2.86-2.89 (2H, m), 3.09-3.17 (1H, m), 3.44-3.57 m), 4.66 (1H, br s), 4.96-5.01 (1H, m), 5.30-5.36 (1H, m), 5.50-5.54 D), 8.00 (1H, d), 8.35 (1H, s), 9.43 (1H, d), 7.34 (2H, m), 7.49-7.57
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.45, 15.46, 22.80, 24.44, 32.83, 34.53, 60.62, 60.72, 62.31, 71.56, 83.15, 83.68, 85.36, 115.19, 115.36, 117.40, 117.56, 123.71, 125.75, 126.66, 127.57, 127.91, 128.07, 128.63, 129.02, 129.33, 130.48, 132.76, 135.04, 136.59, 149.60, 154.42, 170.10
5) Tikagueler Synthesis (step d of scheme 3)
Was obtained in 48% yield in the same manner as in step 5) of Example 1, using the product of step 4).
< Example 5 > 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (thiophen-3-yl) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol Tikagueler synthesis
1) 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (thiophen-3-yl) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol (scheme 4)
Was obtained quantitatively in the same manner as in 1) of Example 1 using 3-thiopheneboronic acid instead of phenylboronic acid in 1) reaction of Example 1.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 1.61 (1H, br s), 1.94 (1H, br s), 3.08 (1H, s), 3.38-3.56 (4H, m), 3.75 ( S), 4.51 (1H, s), 4.57 (1H, s), 7.11-7.25
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 21.48, 49.00, 58.47, 60.67, 70.90, 86.37, 125.75, 128.64, 129.33, 132.37, 137.78
Amino) -2- (thiophen-2-ylmethyl) -2 - ((3aS, 4S, 6S, 6aS) -6 - 4-yl) oxy) ethan-1-ol (step a) of Scheme 3)
Was obtained in a yield of 42% in the same manner as in the step 2) of Example 1, using the product of the above step 1).
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.92 (3H, t), 1.63 (2H, q), 1.76-1.82 (1H, m), 2.22-2.29 (1H, m), 2.92- (2H, s), 4.92 (2H, s), 4.92 (1H, t), 3.06 (2H, m), 3.50-3.62 , 6.85 (1H, d), 7.31 (1H, d), 7.60-7.62
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.75, 23.31, 32.59, 32.92, 57.61, 60.76, 71.11, 84.60, 84.96, 85.10, 120.37, 127.09, 132.10, 138.03, 138.79, 152.37, 155.99
3) Preparation of 2 - (((3aS, 4S, 6S, 6aS) -6- (7-chloro-5- (propylthio) -3H- [1,2,3] triazolo [4,5- d] pyrimidine Cyclopenta [d] [1,3,2] dioxaborol-4-yl) oxy) ethan-1-ol Step b) of Scheme 3
Was obtained quantitatively in the same manner as in step 3) of Example 1, using the product of step 2).
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.99 (3H, t), 1.74 (2H, q), 2.45-2.49 (1H, m), 2.65-2.69 (1H, m), 3.14- (2H, m), 3.49-3.54 (3H, m), 3.55-3.64 (1H, m), 4.19-4.24 (1H, m), 5.45-5.51 ), 7.33 (IH, d), 7.60-7.62 (IH, m), 8.08
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.67, 22.27, 33.48, 33.63, 60.55, 63.46, 71.49, 82.85, 83.62, 85.05, 125.72, 127.07, 132.13, 132.41, 138.09, 150.95, 152.39, 170.37
4) Synthesis of 2 - ((3aS, 4S, 6S, 6aS) -6- (7 - ((2- (3,4- difluorophenyl) cyclopropyl) amino) [1,2,3] triazolo [4,5-d] pyrimidin-3-yl) -2- (thiophen-3-yl) tetrahydro-4H-cyclopenta [ ] Dioxaborol-4-yl) oxy) ethan-1-ol (step c)
The product obtained in the above step 3) was quantitatively obtained in the same manner as in step 4) of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.77 (3H, t), 1.32-1.37 (1H, m), 1.40-1.54 (3H, m), 2.08-2.13 (1H, m), 3.12-3.14 (1H, m), 2.50-2.61 (1H, m), 2.79-2.91 ), 4.64 (1H, br s), 4.84-4.91 (1H, m), 5.21-5.27 (1H, m), 5.41-5.45 (1H, m), 7.01-7.04 3H, m), 7.56-7.58 (IH, m), 8.04 (IH, d), 9.37
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.45, 15.45, 21.47, 22.79, 24.44, 32.83, 34.53, 60.59, 62.30, 71.49, 82.79, 83.64, 84.99, 115.17, 115.34, 117.39, 117.56, 123.68, 125.74, 126.96, 128.63, 129.33, 132.18, 137.78, 149.56, 154.40, 170.06
5) Tikagueler Synthesis (step d of scheme 3)
Was obtained in a yield of 65% in the same manner as in step 5) of Example 1, using the product of the above step 4).
< Example 6 > 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- Butyl tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol Tikagueler synthesis
1) 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- Butyl tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol (scheme 4)
Was obtained quantitatively in the same manner as in 1) of Example 1 using 1) butylboronic acid instead of phenylboronic acid in 1) reaction of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.65-0.68 (2H, m), 0.82 (3H, t), 1.18-1.29 (4H, m), 1.47-1.53 D), 4.59 (1H, d), 4.86 (1H, s)
13 C NMR (DMSO-d 6 , 100 MHz)? (Ppm): 14.17,25.16,26.26,35.62,48.97,58.58,60.61,70.99,84.88,85.49,88.22
2) 2 - ((( 3aS, 4S, 6S, 6aS ) -6 - ((5-amino-6- Chloro -2-( Propyl thio Yl) amino) -2-butyltetrahydro-4H-cyclopenta [d] [1,3,2] dioxaborol-4- yl) oxy) ethan- Step a)
The product was obtained in 45% yield in the same manner as in step 2) of Example 1, using the product of step 1).
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.74 (2H, t), 0.83 (3H, t), 0.95 (3H, t), 1.22-1.35 (2H, m), 1.73-1.79 (1H, m), 2.13-2.20 (1H, m), 2.93-3.02 S), 4.77 (2H, s), 4.93 (1H, t), 6.76 (1H,
13 C NMR (DMSO-d 6 , 100 MHz)? (Ppm): 13.73,14.20,23.33,25.12,26.17,32.56,32.64,57.79,60.72,71.01,84.42,84.66,84.76,201.33,138.74,152.30,155.94
3) Synthesis of 2 - ((3aS, 4S, 6S, 6aS) -2-butyl-6- (7-chloro-5- (propylthio) d] pyrimidin-3-yl) tetrahydro-4H-cyclopenta [d] [1,3,2] dioxaborol-4- yl) oxy)
Was obtained quantitatively in the same manner as in step 3) of Example 1, using the product of step 2).
1 H NMR (DMSO-d 6 , 400 MHz)? (Ppm): 0.76-0.86 (5H, m), 1.00 (3H, t), 1.25-1.39 (2H, m), 3.43-3.57 (4H, m), 4.02-4.09 (1H, m), 4.75-4.78 (1H, , < / RTI > m), 5.25-5.34 (2H, m)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.66, 14.20, 22.26, 25.15, 26.10, 33.31, 60.49, 63.60, 71.40, 82.45, 83.81, 84.54, 125.72, 128.61, 129.31, 132.36, 150.92, 152.35, 170.31
4) Synthesis of 2 - ((3aS, 4S, 6S, 6aS) -2-butyl-6- (7 - (((2S) -2- (3,4- difluorophenyl) cyclopropyl) - (propylthio) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-3- yl) tetrahydro-4H- cyclopenta [d] [1,3,2] Yl) oxy) ethan-1-ol (step c of Scheme 3)
The product obtained in the above step 3) was quantitatively obtained in the same manner as in step 4) of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm): 0.75-0.85 (8H, m), 1.23-1.38 (5H, m), 1.45-1.56 (3H, m), 2.09-2.14 ), 2.49-2.56 (1H, m), 2.85-2.91 (2H, m), 3.11-3.15 (1H, m), 3.46-3.57 (4H, m), 4.00-4.06 (1H, m), 7.25-7.34 (2H, m), 4.72-4.75 (1H, m), 5.07-5.13
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.43, 14.17, 15.40, 22.78, 24.41, 25.14, 26.11, 32.80, 33.67, 34.49, 60.53, 62.44, 71.42, 82.40, 83.83, 84.52, 115.17, 115.34, 117.35, 117.52, 123.21, 123.63, 128.59, 129.29, 139.69, 149.51, 154.36, 170.03
5) Tikagueler Synthesis (step d of scheme 3)
Using the product of step 4), the title compound was obtained in 66% yield in the same manner as in step 5) of Example 1.
< Example 7 > 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- Cyclohexyltetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol Tikagueler synthesis
1) 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- Cyclohexyltetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol (scheme 4)
Was obtained quantitatively in the same manner as in 1) of Example 1 using cyclohexylboronic acid instead of phenylboronic acid in 1) reaction of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz)? (Ppm): 0.92 (1H, br s), 1.17-1.25 (5H, m), 1.49-1.54 (7H, m), 1.84-1.91 (1H, d), 4.60 (1H, d), 2.97-3.00 (1H, m), 3.41-3.49
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 26.67, 26.98, 28.06, 35.55, 58.66, 60.61, 70.99, 84.87, 85.54, 88.27
Amino) -2-cyclohexyltetrahydro-2-methyl-2-oxo-pyrrolidin- 4H-cyclopenta [d] [1,3,2] dioxaborol-4-yl) oxy) ethan-1-ol (step a)
Was obtained in 52% yield in the same manner as in step 2) of Example 1, using the product of step 1).
1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm): 0.93-1.00 (4H, m), 1.18-1.36 (5H, m), 1.49-1.66 (7H, m), 1.76-1.81 ), 2.10-2.16 (1H, m), 2.93-3.01 (2H, m), 3.46-3.57 (4H, m), 3.86-3.88 ), 4.94-4.96 (IH, m), 6.75 (IH, d)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.72, 23.34, 26.65, 26.94, 27.99, 32.52, 32.58, 57.90, 60.74, 71.00, 84.41, 84.71, 84.87, 120.32, 138.79, 152.28, 155.96
3) Preparation of 2 - (((3aS, 4S, 6S, 6aS) -6- (7-chloro-5- (propylthio) -3H- [1,2,3] triazolo [4,5- d] pyrimidine Yl) oxy) ethan-1-ol (Step b of Scheme 3) [0186] < EMI ID =
Was obtained quantitatively in the same manner as in step 3) of Example 1, using the product of step 2).
1 H NMR (DMSO-d 6 , 600MHz) δ (ppm): 0.94-1.06 (4H, m), 1.22-1.35 (5H, m), 1.49-1.58 (3H, m), 1.59-1.66 (2H, m ), 1.71-1.78 (2H, m), 2.41-2.47 (1H, m), 2.59-2.63 (1H, m), 3.13-3.18 (1H, m), 3.53-3.57 (1H, m), 4.03-4.06 (1H, m), 4.76-4.78
13 C NMR (DMSO-d 6 , 150MHz) δ (ppm): 13.66, 22.26, 26.69, 26.98, 27.96, 33.27, 33.33, 60.51, 63.69, 71.41, 82.54, 83.94, 84.56, 125.75, 128.64, 129.33, 132.38, 150.95, 152.37, 170.35
4) Synthesis of 2 - ((3aS, 4S, 6S, 6aS) -2-cyclohexyl-6- (7 - (((2S) -2- (3,4- difluorophenyl) D] pyrimidin-3-yl) tetrahydro-4H-cyclopenta [d] [l, 3,2] di Yl) oxy) ethan-1-ol < / RTI > synthesis (step c)
The product obtained in the above step 3) was quantitatively obtained in the same manner as in step 4) of Example 1.
1 H NMR (DMSO-d 6 , 600 MHz) 隆 (ppm): 0.80 (3H, t), 0.98-1.02 (1H, m), 1.24-1.33 (5H, m), 1.47-1.65 (2H, m), 3.10-3.13 (1H, m), 3.45-3.48 (3H, m), 2.08-2.14 (1H, m), 2.28-2.36 m), 3.49-3.56 (1H, m), 3.99-4.02 (1H, m), 4.61-4.63 (1H, m), 4.73-4.75 (2H, m), 9.40 (1H, d), 7.23-7.32 (2H,
13 C NMR (DMSO-d 6 , 150MHz) δ (ppm): 13.44, 15.37, 21.44, 22.78, 24.41, 26.66, 26.95, 27.93, 32.80, 33.62, 34.46, 60.53, 62.54, 71.41, 82.44, 83.94, 84.53, 115.20, 115.37, 117.34, 117.51, 123.63, 125.70, 128.59, 129.29, 149.50, 154.36, 170.05
5) Tikagueler Synthesis (step d of scheme 3)
Was obtained in a yield of 76% in the same manner as in step 5) of Example 1, using the product of the above step 4).
< Example 8 > 3 - (( 3aS, 4R, 6S, 6aS ) -4-amino-6- (2- Hydroxyethoxy ) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol -2-yl) benzoic acid Tikagueler synthesis
1) 3 - (( 3aS, 4R, 6S, 6aS ) -4-amino-6- (2- Hydroxyethoxy ) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) benzoic acid (Scheme 4)
Was obtained quantitatively in the same manner as in 1) of Example 1 using 3-carboxyboronic acid instead of phenylboronic acid in 1) reaction of Example 1.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 1.80-1.86 (1H, m) 2.18-2.24 (1H, m), 3.45-3.55 (4H, m), 3.56-3.61 (1H, m) , 3.94 (1H, s), 4.74-4.75 (1H, m), 4.91 (1H, s), 7.40-7.45 (1H, s)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 32.50, 56.51, 60.69, 60.78, 71.38, 83.05, 84.56, 128.14, 131.36, 135.22, 135.68, 138.13, 138.76, 168.17
2) Synthesis of 3 - ((3aS, 4R, 6S, 6aS) -4 - ((5-amino- Cyclopenta [d] [1,3,2] dioxaborol-2-yl) benzoic acid (step a in scheme 3)
The product was obtained in 45% yield in the same manner as in step 2) of Example 1, using the product of step 1).
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.92 (3H, t), 1.61 (2H, q), 1.78-1.84 (1H, m), 2.23-2.29 (1H, m), 2.94- (2H, m), 3.54-3.58 (4H, m), 3.61-3.65 (1H, m), 4.01-4.04 7.40-7.45 (1H, m), 7.79 (1H, d), 7.91-7.98 (2H, m)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.0, 21.6, 33.0, 38.9, 60.5, 70.7, 72.8, 77.0, 77.3, 81.3, 119.3, 128.6, 130.2, 130.3, 131.4, 138.6, 142.3, 148.7, 150.2, 160.8, 169.3
3) (3S, 4R, 6S, 6aS) -4- (7-chloro-5- (propylthio) -3H- [1,2,3] triazolo [4,5- d] pyrimidine- D] [1,3,2] dioxaborol-2-yl) benzoic acid (step b) of Scheme 3)
Using the product of step 2), the title compound was obtained in 94% yield in the same manner as in step 3) of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.98 (3H, t), 1.73 (2H, q), 2.48-2.50 (1H, m), 2.66-2.72 (2H, m), 3.25-3.57 (3H, m), 3.61-3.66 (1H, m), 4.21-4.26 (1H, m), 4.98-5.01 ), 7.40-7.45 (1H, m), 7.79 (1H, d), 7.91-7.98
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.0, 21.6, 28.4, 38.9, 58.9, 70.7, 71.9, 82.8, 77.3, 81.3, 128.6, 130.2, 130.3, 130.7, 131.4, 138.6, 142.3, 152.3, 158.7, 169.3, 172.5
4) 3 - ((3aS, 4R, 6S, 6aS) -4- (7 - (((1R, 2S) -2- (3,4- difluorophenyl) cyclopropyl) amino) D] pyrimidin-3-yl) -6- (2-hydroxyethoxy) tetrahydro-4H-cyclopenta [ 1,3,2] dioxoborol-2-yl) benzoic acid (step c)
Using the product of step 3), the title compound was obtained in 89% yield in the same manner as in step 4) of Example 1.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.80 (3H, t), 0.82-1.00 (1H, m), 1.37-1.42 (1H, m), 1.45-1.58 (2H, m), M), 3.60-3.63 (1H, m), 2.50-2.30 (2H, m) m), 4.17-4.23 (1H, m), 4.64-4.68 (1H, m), 4.92-4.97 (1H, m), 5.29-5.32 (1H, m), 7.79 (1H, m), 7.25-7.30 (2H, m), 7.40-7.45
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.0, 14.6, 21.6, 23.0, 28.4, 38.9, 39.6, 58.9, 70.7, 71.9, 72.8, 77.3, 81.3, 113.6, 116.5, 123.2, 123.8, 128.6, 130.2, 130.3, 131.4, 138.6, 140.5, 142.3, 145.9, 148.9, 152.3, 167.7, 169.3, 171.0
5) Tikagueler Synthesis (step d of scheme 3)
Was obtained in 54% yield in the same manner as in step 5) of Example 1 using the product of step 4).
< Example 9> 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (4- Ethoxyphenyl ) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol Tikagueler synthesis
1) 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (4- Ethoxyphenyl ) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol (scheme 4)
Was obtained quantitatively in the same manner as in 1) of Example 1 using 4-ethoxycarbonic acid instead of phenylboronic acid in 1) reaction of Example 1.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 1.29-1.33 (3H, t), 1.83-1.90 (1H, m) 2.15-2.22 (1H, m), 3.46-3.55 (4H, m) (1H, d), 6.89 (2H, d), 7.65 (2H, d), 3.56-3.59 (1H, m), 3.95-3.98 (2H, d)
13 C NMR (DMSO-d 6 , 100 MHz)? (Ppm): 15.15,32.67,56.16,60.62,63.48,71.45,83.55,84.20,84.88,114.55,119.00,136.91,161.87
Amino) -2- (4-amino-6-chloro-2- (propylthio) pyrimidin- 4-yl) oxy) ethan-1-ol (step a) of Scheme 3)
Was obtained in a yield of 78% in the same manner as in the step 2) of Example 1, using the product of the above step 1).
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.93 (3H, t), 1.32 (3H, t), 1.63 (2H, q), 1.79-1.83 (1H, m), 2.93-3.05 (2H, m), 3.52-3.63 (4H, m), 3.99-4.01 4.91 (2H, m), 6.93 (2H, d), 7.63 (2H, d)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.8, 15.0, 23.3, 32.6, 32.9, 57.8, 60.8, 63.4, 70.2, 71.1, 84.8, 85.1, 85.3, 114.5, 120.4, 136.9, 138.9, 152.4, 156.1, 161.9
3) Preparation of 2 - (((3aS, 4S, 6R, 6aS) -6- (7-chloro-5- (propylthio) -3H- [1,2,3] triazolo [4,5- d] pyrimidine D] [1,3,2] dioxaborol-4-yl) oxy) ethan-1-ol (scheme Step b)
Was obtained quantitatively in the same manner as in step 3) of Example 1, using the product of step 2).
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.97 (3H, t), 1.32 (3H, t), 1.73 (2H, q), 2.44-2.52 (1H, m), 3.13-3.27 (2H, m), 3.49-3.55 (3H, m), 3.59-3.65 (1H, d), 7.63 (2H, d), 7.93 (1H,
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.6, 15.0, 22.3, 32.7, 33.4, 60.6, 62.9, 63.4, 63.6, 71.5, 83.1, 83.8, 85.2, 114.5, 125.8, 136.9, 137.8, 152.4, 155.9, 161.9
4) Preparation of 2 - ((3aS, 4S, 6R, 6aS) -6- (7 - (((1R, 2S) -2- (3,4- difluorophenyl) cyclopropyl) amino) D] pyrimidin-3-yl) -2- (4-ethoxyphenyl) tetrahydro-4H-cyclopenta [ 1,3,2] dioxoborol-4-yl) oxy) ethan-1-ol (step c)
Using the product of step 3), the title compound was obtained in 91% yield in the same manner as in step 4) of Example 1.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.81 (3H, t), 0.94-0.97 (1H, m), 1.35 (3H, t), 1.35-1.44 (1H, m), 1.47- (1H, m), 1.51 (1H, m), 1.56 (3H, m), 2.14-2.16 (1H, m), 2.55-2.58 (1H, m), 2.86-2.93 ), 3.59-3.63 (1H, m), 4.05 (2H, q), 4.14-4.20 (1H, m), 4.91-4.97 (1H, m), 5.22-5.28 m), 6.93 (2H, d), 7.05-7.07 (1H, m), 7.25-7.30 (2H,
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.0, 13.8, 14.6, 21.6, 23.0, 28.4, 38.9, 39.6, 58.9, 64.6, 70.7, 71.9, 72.8, 77.3, 81.3, 113.6, 114.4, 114.4, 116.5, 123.1, 123.2, 123.8, 135.5, 135.5, 140.5, 145.9, 148.9, 152.3, 159.4, 167.7, 171.0
5) Tikagueler Synthesis (step d of scheme 3)
The product was obtained in 62% yield in the same manner as in 5) of Example 1, using the product of the above step 4).
< Example 10 > 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (2,4- Dimethoxyphenyl ) Tetrahydro -4H-cyclopenta [d] [1,3,2] dioxaborol-4-yl) oxy) ethan- Tikagueler synthesis
1) 2 - ((( 3aS, 4S, 6R, 6aS ) -6-amino-2- (2,4- Dimethoxyphenyl ) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) oxy) ethan-1-ol (scheme 4)
Was obtained quantitatively in the same manner as in 1) of Example 1 using the 2,4-dimethoxyphenylboronic acid instead of phenylboronic acid in 1) reaction of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz)? (Ppm): 1.70-1.76 (1H, m), 1.94-2.01 (1H, m), 3.20-3.23 ), 3.71 (3H, s), 3.76 (3H, s), 3.84-3.86
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 35.6, 43.4, 55.8, 56.2, 70.7, 72.8, 77.0, 79.6, 81.0, 100.4, 106.6, 116.4, 135.4, 161.6, 163.3
Amino) -2- (2, 4-dihydroxy-propyl) -pyrrolidin-2- 4-yl) oxy) ethan-1-ol (step a) of Scheme 3)
Was obtained in 52% yield in the same manner as in step 2) of Example 1, using the product of step 1).
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.93 (3H, t), 1.63 (2H, q), 1.79-1.81 (1H, m), 2.18-2.23 (1H, m), 2.93- (2H, m), 3.46-3.62 (4H, m), 3.72 (3H, s), 3.78 4.83 (2H, m), 6.49-6.53 (2H, m), 7.53 (1H, d)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.6, 23.3, 32.7, 32.9, 55.7, 57.9, 60.7, 60.8, 70.2, 71.1, 72.8, 84.6, 84.7, 84.9, 98.3, 105.6, 120.4, 138.7, 138.9, 152.4, 156.1, 164.3, 166.3
3) Preparation of 2 - (((3aS, 4S, 6R, 6aS) -6- (7-chloro-5- (propylthio) -3H- [1,2,3] triazolo [4,5- d] pyrimidine Cyclopenta [d] [1,3,2] dioxaborol-4-yl) oxy) ethan-1-ol Synthesis was carried out in the same manner as in Synthesis Example 1 (Step b of scheme 3)
Was obtained quantitatively in the same manner as in step 3) of Example 1, using the product of step 2).
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.98 (3H, t), 1.72 (2H, q), 2.43-2.51 (1H, m), 2.62-2.68 (1H, m), 3.24 (2H, m), 3.47-3.53 (3H, m), 3.56-3.62 (2H, m), 7.56 (1 H, d), 4.93 (1 H, m)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.0, 21.6, 28.4, 38.9, 55.8, 56.2, 58.9, 70.7, 71.9, 72.8, 77.3, 81.3, 100.4, 106.6, 116.4, 130.7, 135.4, 152.3, 158.7, 161.6, 163.3, 172.5
4) Preparation of 2 - ((3aS, 4S, 6R, 6aS) -6- (7 - (((1R, 2S) -2- (3,4- difluorophenyl) cyclopropyl) amino) Yl) -2- (2,4-dimethoxyphenyl) tetrahydro-4H-cyclopenta [d] pyrimidin- ] [1,3,2] dioxaborol-4-yl) oxy) ethan-1-ol (step c)
The product obtained in the above step 3) was quantitatively obtained in the same manner as in step 4) of Example 1.
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.80 (3H, t), 0.82-1.00 (1H, m), 1.37-1.42 (1H, m), 1.45-1.58 (2H, m), M), 3.60-3.63 (1H, m), 2.50-2.30 (2H, m) m), 3.72 (3H, t), 3.78 (3H, t), 4.17-4.23 (1H, m), 4.64-4.68 (1H, m), 4.92-4.97 (1H, m), 5.43-5.49 (1H, m), 6.43-6.53 (2H, m), 7.05-7.07
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.0, 14.6, 21.6, 23.0, 28.4, 38.9, 39.6, 55.8, 56.2, 58.9, 70.7, 71.9, 72.8, 77.3, 81.3, 100.4, 106.6, 113.6, 116.4, 116.5, 123.2, 123.8, 135.4, 140.5, 145.9, 148.9, 152.3, 161.6, 163.3, 167.7, 171.0
5) Tikagueler Synthesis (step d of scheme 3)
Was obtained in a yield of 59% in the same manner as in step 5) of Example 1, using the product of the step 4).
< Example 11> N- (4 - (( 3aS, 4R, 6S, 6aS ) -4-amino-6- (2- Hydroxyethoxy ) Tetrahydro -4H-cyclopenta [d] [1,3,2] dioxaborol-2-yl) phenyl) methanesulfonamide from Tikagueler synthesis
1) N- (4 - (( 3aS, 4R, 6S, 6aS ) -4-amino-6- (2- Hydroxyethoxy ) Tetrahydro -4H- Cyclopenta [d] [l, 3,2] dioxaborol Yl) phenyl) methanesulfonamide (Scheme 4)
Was obtained quantitatively in the same manner as in 1) of Example 1 using 4-methylsulfonylaminophenylboronic acid instead of phenylboronic acid in 1) reaction of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz)? (Ppm): 1.69-1.75 (1H, m), 2.00-2.06 3.46-3.56 (4 H, m), 3.85-3.87 (1 H, m), 7.17 (2 H, d), 7.58
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 35.6, 42.9, 43.4, 70.7, 72.8, 77.0, 79.6, 81.0, 116.3, 116.3, 121.5, 134.2, 134.2, 137.7
2) Preparation of N- (4-amino-6-chloro-2- (propylthio) Yl) phenyl) methanesulfonamide (Step a) of Scheme 3) [0156] < EMI ID =
Was obtained in 52% yield in the same manner as in step 2) of Example 1, using the product of step 1).
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.93 (3H, t), 1.63 (2H, q), 1.79-1.83 (1H, m), 2.22-2.25 (1H, m), 2.93- M), 3.05 (2H, m), 3.50 (3H, s), 3.52-3.63 (4H, m), 3.99-4.01 (1H, m), 4.10-4.43 7.22 (2 H, d), 7.66 (2 H, d)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.0, 21.6, 33.0, 38.9, 42.9, 60.5, 70.7, 72.8, 77.0, 77.3, 81.3, 116.3, 116.3, 119.3, 121.5, 134.2, 134.2, 137.7, 148.7, 150.2, 160.8
3) Preparation of N- (4 - ((3aS, 4R, 6S, 6aS) -4- (7-chloro-5- (propylthio) Cyclopenta [d] [1,3,2] dioxaborol-2-yl) phenyl) methanesulfonamide (prepared as described for the synthesis of (2-hydroxyphenyl) Step b) of Scheme 3
Was obtained quantitatively in the same manner as in step 3) of Example 1, using the product of step 2).
1 H NMR (DMSO-d 6 , 400MHz) δ (ppm): 0.97 (3H, t), 1.73 (2H, q), 2.44-2.52 (1H, m), 2.64-2.70 (1H, m), 3.03 ( (1H, m), 3.14-3.27 (2H, m), 3.49-3.55 (3H, m), 3.59-3.65 5.40-5.46 (1H, m), 5.50-5.53 (1H, m), 7.24 (2H, d), 7.68
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.0, 21.6, 28.4, 38.9, 42.9, 58.9, 70.7, 71.9, 72.8, 77.3, 81.3, 116.3, 116.3, 121.5, 130.7, 134.2, 134.2, 137.7, 152.3, 158.7, 172.5
4) Synthesis of N- (4 - ((3aS, 4R, 6S, 6S) -4- (7 - (((1R, 2S) -2- (3,4- difluorophenyl) cyclopropyl) - (propylthio) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-3- yl) -6- (2-hydroxyethoxy) tetrahydro-4H-cyclopenta [ d] [1,3,2] dioxaborol-2-yl) phenyl) methanesulfonamide (step c)
The product obtained in the above step 3) was quantitatively obtained in the same manner as in step 4) of Example 1.
1 H NMR (DMSO-d 6 , 400 MHz) 隆 (ppm): 0.81 (3H, t), 0.94-0.97 (1H, m), 1.35-1.44 (1H, m), 1.47-1.56 (1H, m), 2.55-2.58 (1H, m), 2.86-2.93 (2H, m), 3.02 (3H, s), 3.11-3.15 ), 3.59-3.63 (1H, m), 4.14-4.20 (1H, m), 4.91-4.97 (1H, m), 5.22-5.28 , d), 7.05-7.07 (1H, m), 7.25-7.30 (2H, m), 7.67 (2H, d)
13 C NMR (DMSO-d 6 , 100MHz) δ (ppm): 13.0, 14.6, 21.6, 23.0, 28.4, 38.9, 39.6, 42.9, 58.9, 70.7, 71.9, 72.8, 77.3, 81.3, 113.6, 116.3, 116.3, 116.5, 121.5, 123.2, 123.8, 134.2, 134.2, 137.7, 140.5, 145.9, 148.9, 152.3, 167.7, 171.0
5) Tikagueler Synthesis (step d of scheme 3)
Using the product of step 4), the title compound was obtained in a yield of 63% in the same manner as in step 5) of Example 1.
< Test Example 1>
(3aS, 4S, 6R, 6aS) -6-amino-2-phenyltetrahydro-4H-cyclopenta [d] [1,3,2] di (3aS, 4S, 6S, 6aS) -6- (4-fluoropyridin-4-yl) oxy) ethan- 1-ol (formula 3a) and the product of step 2) Amino] -2-phenyltetrahydro-4H-cyclopenta [d] [l, 3,2] dioxaborol- 4-yl) oxy) ethan-1-ol (formula 5a) and the following compound of
≪ EMI ID =
≪ Formula 5a &
≪
≪ Formula 11 >
The compound of formula (10) could not be measured by differential scanning calorimetry (DSC) and its melting point in the oil state, while the compound of formula (3a) was obtained as a solid and its differential scanning calorimetry (DSC) and melting point were measured. As a result of the measurement, it was confirmed that the compound of formula (5a), which is a newly synthesized tikagaler intermediate, has a melting point higher than that of the compound of formula (11) described in the above-mentioned patents. Thus, the intermediate compound of the present invention has excellent physical and chemical stability It can be expected to be used as an intermediate useful in the production of tikageler.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (21)
(a) reacting a compound of formula (3) with a compound of formula (4) in the presence of a tertiary amine in a polar solvent to produce a compound of formula (5);
(b) reacting the compound of formula (5) with a nitrite to produce a compound of formula (6);
(c) reacting the compound of formula (6) and the compound of formula (7) in the presence of a base to produce a compound of formula (8); And
(d) deprotecting the compound of formula (8) to produce a compound of formula (1).
[Reaction Scheme 3]
In the above Reaction Scheme 3, R is cycloalkyl having 3 to 6 carbon atoms; or
Is phenyl substituted in at least one position with at least one member selected from the group consisting of halogen, aryloxy having 6 to 10 carbon atoms and 3-benzyloxy.
Wherein the compound of Formula 3 is prepared by reacting a compound of Formula 2 with a boronic acid derivative (RB (OH) 2 ) as shown in Reaction Scheme 4 below.
[Reaction Scheme 4]
In the above Reaction Scheme 4, R is cycloalkyl having 3 to 6 carbon atoms; or
Is phenyl substituted in at least one position with at least one member selected from the group consisting of halogen, aryloxy having 6 to 10 carbon atoms and 3-benzyloxy.
Wherein R is cyclohexyl, phenyl, 4-chlorophenyl or 3-benzyloxyphenyl.
Wherein the tertiary amine in step (a) is tri (C 1 -C 6 alkyl) amine and the polar solvent is selected from the group consisting of alcohols, N-methyl-2-pyrrolidone, ethylene glycol, acetonitrile, dimethylsulfoxide, And a mixed solvent thereof. ≪ RTI ID = 0.0 > 11. < / RTI >
Wherein said step (a) is carried out at 80 to 100 DEG C for 2 to 24 hours.
Wherein the nitrite of step (b) is sodium nitrite or iso-amyl nitrite, and the reaction solvent is toluene.
Wherein said step (b) is carried out at 20 to 30 < 0 > C for 1 to 12 hours in the presence of an acid.
Wherein the acid is acetic acid.
Wherein the step (c) is carried out at 20 to 30 캜 for 1 to 12 hours.
Wherein the base is potassium carbonate.
Wherein the solvent of step (d) is selected from the group consisting of methanol, acetonitrile, dimethylsulfoxide, dimethylformamide, ethyl acetate, and a mixed solvent thereof.
Wherein step (d) is carried out in the presence of hydrogen peroxide at 20 to 30 DEG C for 1 minute to 6 hours.
(3)
In Formula 3, R is cycloalkyl having 3 to 6 carbon atoms; or
Is phenyl substituted in at least one position with at least one member selected from the group consisting of halogen, aryloxy having 6 to 10 carbon atoms and 3-benzyloxy.
[Chemical Formula 5]
In Formula 5, R is cycloalkyl having 3 to 6 carbon atoms; or
Is phenyl substituted in at least one position with at least one member selected from the group consisting of halogen, aryloxy having 6 to 10 carbon atoms and 3-benzyloxy.
[Chemical Formula 6]
In Formula 6, R is cycloalkyl having 3 to 6 carbon atoms; or
Is phenyl substituted in at least one position with at least one member selected from the group consisting of halogen, aryloxy having 6 to 10 carbon atoms and 3-benzyloxy.
[Chemical Formula 8]
In Formula 8, R is cycloalkyl having 3 to 6 carbon atoms; or
Is phenyl substituted in at least one position with at least one member selected from the group consisting of halogen, aryloxy having 6 to 10 carbon atoms and 3-benzyloxy.
Wherein R is cyclohexyl, phenyl, 4-chlorophenyl or 3-benzyloxyphenyl.
A process for preparing an intermediate compound for the preparation of tikageler represented by the general formula (3), comprising reacting a compound represented by the general formula ( 2 ) with a boronic acid derivative (RB (OH)
[Reaction Scheme 4]
In the above Reaction Scheme 4, R is cycloalkyl having 3 to 6 carbon atoms; or
Halogen at one or more positions. Aryloxy having 6 to 10 carbon atoms, and 3-benzyloxy.
Lt; RTI ID = 0.0 > 30 C, < / RTI >
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