WO2024064726A1 - Process for the preparation of tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate and related compounds - Google Patents
Process for the preparation of tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate and related compounds Download PDFInfo
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- WO2024064726A1 WO2024064726A1 PCT/US2023/074645 US2023074645W WO2024064726A1 WO 2024064726 A1 WO2024064726 A1 WO 2024064726A1 US 2023074645 W US2023074645 W US 2023074645W WO 2024064726 A1 WO2024064726 A1 WO 2024064726A1
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 548
- 238000000034 method Methods 0.000 title claims abstract description 252
- -1 tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate Chemical compound 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims description 314
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 183
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 151
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 120
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 114
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 102
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 73
- 238000006243 chemical reaction Methods 0.000 claims description 69
- 125000006239 protecting group Chemical group 0.000 claims description 63
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 57
- 239000003960 organic solvent Substances 0.000 claims description 48
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 45
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 41
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 150000004820 halides Chemical group 0.000 claims description 33
- 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 claims description 30
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 30
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 25
- 239000000010 aprotic solvent Substances 0.000 claims description 24
- 229910052723 transition metal Inorganic materials 0.000 claims description 24
- 150000003624 transition metals Chemical class 0.000 claims description 24
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 23
- 125000002252 acyl group Chemical group 0.000 claims description 23
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 23
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 23
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 claims description 23
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 21
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 claims description 20
- 239000003638 chemical reducing agent Substances 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 14
- 229960003750 ethyl chloride Drugs 0.000 claims description 14
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 230000003301 hydrolyzing effect Effects 0.000 claims description 13
- 150000003141 primary amines Chemical group 0.000 claims description 13
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 11
- 150000007529 inorganic bases Chemical class 0.000 claims description 10
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 9
- 229950005499 carbon tetrachloride Drugs 0.000 claims description 9
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 9
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 9
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 230000000269 nucleophilic effect Effects 0.000 claims description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical group CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 6
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 claims description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 6
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 6
- 229910000085 borane Inorganic materials 0.000 claims description 6
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 6
- QFLQJPFCNMSTJZ-UHFFFAOYSA-N boron;triphenylphosphane Chemical compound [B].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QFLQJPFCNMSTJZ-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 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 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052987 metal hydride Inorganic materials 0.000 claims description 6
- 150000004681 metal hydrides Chemical group 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 239000012530 fluid Substances 0.000 claims description 3
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 claims 2
- VIQPSHPJGFFPRB-UHFFFAOYSA-N 2-azabicyclo[2.2.1]heptan-4-amine Chemical compound C1CC2NCC1(N)C2 VIQPSHPJGFFPRB-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 102000001253 Protein Kinase Human genes 0.000 abstract description 2
- 108060006633 protein kinase Proteins 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 29
- 238000003786 synthesis reaction Methods 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 20
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 238000000926 separation method Methods 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- ZKODPGZNBMIZFX-UHFFFAOYSA-N 2-(2-bromoethyl)oxirane Chemical compound BrCCC1CO1 ZKODPGZNBMIZFX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-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
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000004985 diamines Chemical class 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 3
- 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 2
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 2
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QCXJEYYXVJIFCE-UHFFFAOYSA-N 4-acetamidobenzoic acid Chemical compound CC(=O)NC1=CC=C(C(O)=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
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- 229960001948 caffeine Drugs 0.000 description 1
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- 239000010949 copper Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HUGXFMRALYWGEC-UHFFFAOYSA-N diethyl 3-aminocyclopentane-1,1-dicarboxylate Chemical compound CCOC(=O)C1(C(=O)OCC)CCC(N)C1 HUGXFMRALYWGEC-UHFFFAOYSA-N 0.000 description 1
- MLOZQIXOIZCXKB-UHFFFAOYSA-N diethyl 3-hydroxycyclopentane-1,1-dicarboxylate Chemical compound CCOC(=O)C1(C(=O)OCC)CCC(O)C1 MLOZQIXOIZCXKB-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- CLJMMQGDJNYDER-UHFFFAOYSA-N heptan-4-amine Chemical compound CCCC(N)CCC CLJMMQGDJNYDER-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 229940098695 palmitic acid Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229940116353 sebacic acid Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Definitions
- the present disclosure relates generally to methods of preparing tert-butyl (2- azabicyclo[2.2.1]heptan-4-yl)carbamate, its enantiomers, and novel intermediate compounds.
- the compound 2-azabicyclo[2.2.1]heptan-4-amine (designated herein as a compound of Formula T-l) is a key structural motif found in a number of synthetic compounds that are inhibitors of rho-associated protein kinase. These inhibitors are potentially useful for treating or preventing various diseases or conditions. See, e.g., US Publication No. 2011/0144150.
- the chemical structure of a compound of Formula T-l is shown below:
- any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
- any number range recited herein relating to any physical feature, such as polymer subunits, size, or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
- the terms “about” and “approximately” mean ⁇ 20%, ⁇ 10%, ⁇ 5%, or ⁇ 1% of the indicated range, value, or structure, unless otherwise indicated.
- salt refers to acid or base salts of the compounds disclosed herein. It is understood that “pharmaceutically acceptable salts” are non-toxic. Non-limiting examples of pharmaceutically acceptable salts include acid addition salts and base addition salts.
- Pharmaceutically acceptable acid addition salts are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic
- Pharmaceutically acceptable base addition salts are prepared from addition of an inorganic base or an organic base to the free acid.
- Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
- Non-limiting examples of inorganic salts include ammonium, sodium, potassium, calcium, and magnesium salts.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, non-limiting examples of which include ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins, and the like.
- “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
- “optionally converting Compound X to a salt thereof’ means that Compound X may or may not be converted to a salt. In some embodiments, Compound X is converted to a salt, whereas in other embodiments Compound X is not converted to a salt.
- Pgi or a salt thereof comprising the following steps: (a) reacting a compound of Formula 1: or a salt thereof, with a compound of Formula 2:
- step (a) is carried out in the presence of a base.
- the base is sodium hydride, potassium tert-butoxide, or sodium ethoxide. In other embodiments, the base is sodium ethoxide.
- step (a) is carried out using an alcohol as solvent.
- the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is ethanol.
- step (a) is carried out at a temperature of between about 0-30 °C. In some embodiments, step (a) is carried out at a starting temperature of about 0-10 °C, then at 20-30 °C.
- step (a) is carried out with the compound of Formula 1, or a salt thereof, that is separated into enantiomers, Formula la and Formula lb, or salts thereof, using kinetic resolution.
- the kinetic resolution is Jacobsen’s kinetic resolution.
- the kinetic resolution is hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
- step (b) further comprises triphenylphosphine and diisopropyl azodi carb oxy late.
- step (b) is carried out using an aprotic solvent.
- the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof.
- the aprotic solvent is tetrahydrofuran.
- step (b) is carried out at a temperature of between about 0- 30 °C. In some embodiments, step (b) is carried out at a starting temperature of about 0-10 °C, then at 20-30 °C.
- step (c) is carried out in the presence of a base.
- the base is sodium borohydride, methylamine, methylhydrazine, or hydrazine. In other embodiments, the base is hydrazine.
- step (c) is carried out using a mixture of alcohol and an organic solvent.
- the alcohol is methanol, ethanol, or isopropanol.
- the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, or 2-methyltetrahydrofuran.
- the alcohol is methanol and the organic solvent is dichloromethane.
- step (d) is carried out using an inorganic base.
- the inorganic base is sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, or cesium carbonate. In other embodiments, the inorganic base is cesium carbonate.
- step (d) is carried out using an alcohol as solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.
- step (d) is carried out at a temperature of between about 25- 80 °C. In certain embodiments, step (d) is carried out at a temperature of between about 50-70 °C.
- step (e) is carried out using an amine base.
- the amine base is 2,2,6,6-tetramethylpiperidine, trimethylamine, triethylamine, or N,N-diisoproypylethylamine.
- the amine base is N,N- dii soproy py 1 ethyl amine .
- step (e) is carried out using an organic solvent.
- the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 2- methyltetrahydrofuran, or a mixture thereof.
- the organic solvent is 2- methyltetrahydrofuran.
- step (e) is carried out at a starting temperature of between about 40-70 °C, then at a reflux temperature above 50-120 °C. In certain embodiments, step (e) is carried out at a starting temperature of about 50-60 °C, then at a reflux temperature above 70- 100 °C.
- step (e) is carried out at a temperature of between about 40- 70 °C, then at a temperature between about 50-120 °C. In certain embodiments, step (e) is carried out at a temperature of about 50-60 °C or about 50-70 °C, then at a temperature between about 70-100 °C.
- step (e) the compound of Formula 7, or a salt thereof, is separated into enantiomers, Formula 7a and Formula 7b, or salts thereof, using super fluid chromatography.
- step (f) is carried out in the presence of a non-nucleophilic base.
- the non-nucleophilic base is N,N-diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, or lithium bis(trimethylsilyl)amide.
- the non-nucleophilic base is lithium bis(trimethylsilyl)amide.
- step (f) is carried out using an ether solvent.
- the ether solvent is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, or a mixture thereof.
- the ether solvent is tetrahydrofuran.
- step (g) is catalyzed by a transition metal.
- the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C). In other embodiments, the transition metal is palladium on carbon (Pd/C).
- step (g) is carried out using an alcohol as solvent.
- the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.
- step (h) is carried out using a reducing agent.
- the reducing agent is a metal hydride, aluminum hydride, borohydride, or borane reagent.
- the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran, or borane dimethylsulfide.
- the reducing agent is borane dimethyl sulfide.
- step (h) is carried out using an aprotic solvent.
- the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof.
- the aprotic solvent is tetrahydrofuran.
- step (h) is carried out at a temperature of between about 25- 80 °C. In certain embodiments, step (h) is carried out at a temperature of about 60-70 °C.
- step (i) is carried out using an organic solvent.
- the organic solvent is chloroform, dichloroethane, toluene, methanol, ethanol, isopropanol, or 2-methyl-THF, dioxane, ethyl acetate, or tetrahydrofuran.
- the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran.
- step (j) is catalyzed by a transition metal.
- the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C). In other embodiments, the transition metal is palladium on carbon (Pd/C).
- step (j) is carried out using an alcohol as solvent.
- the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.
- step (a) is catalyzed by a transition metal.
- the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C). In other embodiments, the transition metal is palladium on carbon (Pd/C).
- step (a) is carried out using an alcohol as solvent.
- the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.
- step (a) is carried out using an organic solvent.
- the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.
- the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran.
- step (b) is carried out with an acid.
- the acid is trifluoroacetic acid, hydrochloride, or phosphoric acid. In certain embodiments, the acid is trifluoroacetic acid.
- step (b) is carried out using an organic solvent.
- the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.
- the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran.
- step (b) is carried out at a temperature of about 20-30 °C.
- step (c) is carried out using a reducing agent.
- the reducing agent is a metal hydride, aluminum hydride, borohydride, or borane reagent.
- the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran, or borane dimethylsulfide.
- the reducing agent is lithium aluminum hydride.
- step (c) is carried out using an aprotic solvent.
- the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof.
- the aprotic solvent is diethyl ether, tetrahydrofuran, or a mixture thereof.
- step (d) is carried out using an organic solvent.
- the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.
- the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran.
- the selective deprotection of the substituent amine in step (d) is carried out using an acid.
- the acid is hydrochloric acid.
- T-2 or a salt thereof, wherein Pgi is a first protecting group.
- Pgi is tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, or fluorenylmethyloxy carbonyl.
- Pgi is tert-butyloxy carbonyl.
- the compound of Formula T-2 is separated into enantiomers, compounds of Formula T-3 and Formula T-4: Pgi Pgi or salts thereof.
- novel intermediate compounds that are useful in the synthesis of the compound of Formula T-2 or a salt thereof.
- the novel intermediate compound is: or a sa t t ereo .
- Pg2 is a second protecting group.
- Pg2 is tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, or fluorenylmethyloxy carbonyl.
- Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
- Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group.
- novel intermediate compounds are separated into enantiomers, and a novel intermediate compound is:
- T-2 or a salt thereof comprising: reducing a compound of Formula (11): or a salt thereof, wherein Pgi is a first protecting group;
- Pg2 is a second protecting group; to form the compound of Formula (T-2).
- Pgi and the compound of Formula (11) is the compound of Formula (Ila):
- compound of Formula (T-2) is the compound of Formula (T-4):
- Pgi and the compound of Formula (11) is the compound of Formula (11b):
- Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
- Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
- Pg2 is a second protecting group; to form the compound of Formula (11).
- Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.
- Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
- Pgi and the compound of Formula (10) is the compound of Formula (10a): b) the compound of Formula (11) is the compound of Formula (11b): and the compound of Formula (10) is the compound of Formula (10b):
- a method of preparing a compound of Formula (10), or a salt thereof, comprising: reducing a compound of Formula (9): or a salt thereof, wherein Pg2 is a second protecting group, to form the compound of Formula (10).
- Pg2 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.
- Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
- aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, di chloromethane, di chloroethane, chloroform, or a mixture thereof.
- Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group;
- Pg2 is a second protecting group to form the compound of Formula (9).
- Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group;
- Pg2 is a second protecting group to form a compound of Formula (9).
- Pg2 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.
- Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
- Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group;
- Pg2 is a second protecting group
- X is a leaving group
- Pg 2.N ⁇ NH or a salt thereof comprising: reacting a compound of Formula (7): or a salt thereof, with Pg 2 X, wherein:
- Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group;
- Pg 2 is a second protecting group
- X is a leaving group
- Pg2 is selected from tertbutyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
- non-nucleophilic base is N,N- diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert- butoxide, or lithium bis(trimethylsilyl)amide.
- ether solvent is tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, or a mixture thereof.
- Pg2 is a second protecting group, comprising: sequential protection of the substituent and heterocyclic amines of a compound of Formula (9.5):
- Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.
- aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, di chloromethane, di chloroethane, chloroform, or a mixture thereof.
- Pgi is selected from tertbutyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
- Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group, to form the compound of Formula (7.5).
- Pgi is selected from tertbutyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
- a method of preparing a compound of Formula (7), or a salt thereof, wherein Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group comprising: reacting a compound of Formula (6): or a salt thereof, with R3OH, wherein R3 is a benzyl optionally substituted by Ci-Ce alkoxy, Ci- Ce alkyl, or halide, in the presence of diphenylphosphoryl azide and an amine base, to form the compound of Formula (7).
- amine base is 2, 2,6,6- tetramethylpiperidine, trimethylamine, triethylamine, or N,N-diisoproypylethylamine.
- a method of preparing a compound of Formula (6), or a salt thereof, comprising: reacting a compound of Formula (5):
- a method of preparing a compound of Formula (5), or a salt thereof, comprising: deprotecting a compound of Formula (4): or a salt thereof, to form the compound of Formula (5).
- a method of preparing a compound of Formula (4), or a salt thereof, comprising, reacting a compound of Formula (3): or a salt thereof, with phthalimide to form the compound of Formula (4).
- aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, di chloromethane, di chloroethane, chloroform, or a mixture thereof.
- the aprotic solvent is tetrahydrofuran.
- a method of preparing a compound of Formula (3), or a salt thereof, comprising: reacting a compound of Formula (1):
- R3 is benzyl optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide;
- Ri is benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide;
- Pgi is a first protecting group
- Pg2 is a second protecting group
- X is a leaving group
- a method of preparing a compound of Formula (T-2), or a salt thereof, comprising the following steps:
- Ri is benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide;
- Pgi is a first protecting group
- Pg2 is a second protecting group
- X is a leaving group
- Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
- Pgi or a salt thereof, wherein Pgi is a first protecting group.
- Pgi or a salt thereof, wherein Pgi is a first protecting group.
- a compound of Formula (3) or a salt thereof.
- the compound of embodiment 163, wherein the compound of Formula (3), or a salt thereof, is a compound of Formula (3a): or a salt thereof; or a compound of Formula (3b): or a salt thereof.
- the compound of embodiment 165, wherein the compound of Formula (4), or a salt thereof, is a compound of Formula (4a): or a salt thereof; or a compound of Formula (4b): or a salt thereof.
- the compound of embodiment 167, wherein the compound of Formula (5), or a salt thereof, is a compound of Formula (5a): or a salt thereof; or a compound of Formula (5b): or a salt thereof.
- a compound of Formula (6) or a salt thereof.
- the compound of embodiment 169, wherein the compound of Formula (6), or a salt thereof, is a compound of Formula (6a): or a salt thereof; or a compound of Formula (6b): or a salt thereof.
- the compound of embodiment 171, wherein the compound of Formula (7), or a salt thereof, is a compound of Formula (7a): or a salt thereof; or a compound of Formula (7b): or a salt thereof.
- a compound of Formula (8) or a salt thereof, wherein:
- Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group;
- Pg2 is a second protecting group.
- the compound of embodiment 173, wherein the compound of Formula (8), or a salt thereof, is a compound of Formula (8a): or a salt thereof; or a compound of Formula (8b): or a salt thereof.
- the compound of embodiment 183, wherein the compound of Formula (10), or a salt thereof, is a compound of Formula (10a): or a salt thereof; or a compound of Formula (10b): or a salt thereof.
- Pgi is a first protecting group
- Pg2 is a second protecting group.
- reaction mixture was then stirred for 18 h.
- the reaction vessel was then degased and filled with N2 multiple times.
- the reaction mixture was then filtered through a celite pad and concentrated in vacuo to give tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate (1.3g, 6.12 mmol, 93 % yield) as white solid.
- Compound T-3 an enantiomer of compound T-2, was prepared from an enantiomer 7a, obtained by chiral separation of compound 7.
- the kinetic resolution method used for chiral separation was Jacobsen’s kinetic resolution.
- the kinetic resolution method used for chiral separation was hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
- Compound T-3 an enantiomer of compound T-2, was prepared from an enantiomer 7a, obtained by chiral separation of compound 7.
- the kinetic resolution method used for chiral separation was Jacobsen’s kinetic resolution.
- the kinetic resolution method used for chiral separation was hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
- Compound T-4 an enantiomer of compound T-2, was prepared from an enantiomer 7b, obtained by chiral separation of compound 7.
- the kinetic resolution method used for chiral separation was Jacobsen’s kinetic resolution.
- the kinetic resolution method used for chiral separation was hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
- Example S4.2 Synthesis of T-4 from chiral separated compound 7b via selective protection of diamine
- Compound T-4 an enantiomer of compound T-2, was prepared from an enantiomer 7b, obtained by chiral separation of compound 7.
- the kinetic resolution method used for chiral separation was Jacobsen’s kinetic resolution.
- the kinetic resolution method used for chiral separation was hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
- Compound T-4 an enantiomer of compound T-2, was prepared from an enantiomer lb, obtained by chiral separation of compound 1 using Jacobsen’s kinetic resolution.
- the reaction procedures were identical to those described in Example 1.
- the Jacobsen’s kinetic resolution method was identical to that described in Example S3.3.
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Abstract
Provided herein are methods for preparing 2-azabicyclo[2.2.1]heptan-4-amine, a key structural motif found in a number of synthetic compounds that are inhibitors of rho-associated protein kinase, and its primary amine-protected version tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate, and enantiomers thereof. Also provided herein are novel intermediate compounds and their enantiomers for use in preparing the aforementioned target 2-azabicyclo[2.2.1]heptanyl compounds.
Description
PROCESS FOR THE PREPARATION OF TERT-BUTYL (2- AZABICYCLO[2.2.1]HEPTAN-4-YL)CARBAMATE AND RELATED COMPOUNDS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority of US Provisional Application No. 63/408,695, filed September 21, 2022, which is incorporated by reference herein in its entirety for any purpose.
FIELD
[0002] The present disclosure relates generally to methods of preparing tert-butyl (2- azabicyclo[2.2.1]heptan-4-yl)carbamate, its enantiomers, and novel intermediate compounds.
BACKGROUND
[0003] The compound 2-azabicyclo[2.2.1]heptan-4-amine (designated herein as a compound of Formula T-l) is a key structural motif found in a number of synthetic compounds that are inhibitors of rho-associated protein kinase. These inhibitors are potentially useful for treating or preventing various diseases or conditions. See, e.g., US Publication No. 2011/0144150. The chemical structure of a compound of Formula T-l is shown below:
T-l
[0004] Selectively protected versions of a compound of Formula T-l and its enantiomers are of interest as building blocks for various compounds. Accordingly, in one aspect, provided herein are methods for preparing tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate, its enantiomers, and salts thereof. The chemical structure of a compound of Formula T-2, which is a primary amine-protected version of a compound of Formula T-l, is shown below:
T-2
[0005] Also provided herein are intermediate compounds for use in preparing T-l and/or T-
2.
SUMMARY
[0006] Described herein, in certain embodiments, are methods of preparing tert-butyl (2- azabicyclo[2.2.1]heptan-4-yl)carbamate, its enantiomers, and salts thereof as building blocks for various inhibitor compounds. Also described herein are intermediate compounds for use in preparing said compounds.
[0007] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.
[0008] In one aspect, provided herein are methods of preparing a compound of Formula T-2 or a salt thereof.
[0009] In another aspect, provided herein are methods of preparing compounds of Formula T-3 and T-4, which are enantiomers of a compound of Formula T-2, or salts thereof.
T-3 T-4
[0010] In certain aspects, provided herein are methods of preparing a compound of Formula
T-2:
T-2 or a salt thereof, comprising the following steps:
(b) reacting a compound of Formula 3, or a salt thereof, with phthalimide to form a compound of Formula 4:
or a salt thereof;
(c) deprotecting a compound of Formula 4, or a salt thereof, to form a compound of
(d) reacting a compound of Formula 5, or a salt thereof, with a base to form a compound of Formula 6:
or a salt thereof;
(e) reacting a compound of Formula 6, or a salt thereof, with R3OH, in the presence of diphenylphosphoryl azide and an amine base acid to form a compound of Formula 7:
or a salt thereof; and
(f) reacting a compound of Formula 7, or a salt thereof, with Pg2X to form a compound of Formula 8:
O Ri
Pg2^N^^NH
8 or a salt thereof; and
(g) reducing a compound of Formula 8, or a salt thereof, to form a compound of Formula 9:
O
Pg2xN^^NH2
9 or a salt thereof; and
10 or a salt thereof; and
(i) protecting the primary amine group of a compound of Formula 10, or a salt thereof, to form a compound of Formula 11:
Pgi
Pg2^N^^NH
11 or a salt thereof; and
(j) reducing a compound of Formula 11, or a salt thereof, to form a compound of Formula T-2.
[0011] In certain aspects, also provided herein are methods of preparing a compound of Formula T-2:
7.5
(b) hydrolyzing a compound of Formula 7.5, or a salt thereof, to form a compound of
8.5 or a salt thereof; and
(c) reducing a compound of Formula 8.5, or a salt thereof, to form a compound of
9.5 or a salt thereof; and
(d) sequentially protecting the substituent and heterocyclic amines of a compound of Formula 9.5, or a salt thereof, and selectively deprotecting the substituent amine to form a compound of Formula 10:
10 or a salt thereof.
DETAILED DESCRIPTION
Definitions
[0012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. To the extent any material incorporated herein by reference is inconsistent with the express content of this disclosure, the express content controls. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an”, and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.
[0013] Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to”.
[0014] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size, or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the terms “about” and “approximately” mean ± 20%, ± 10%, ± 5%, or ± 1% of the indicated range, value, or structure, unless otherwise indicated.
[0015] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0016] As used herein, the term “salt” refers to acid or base salts of the compounds disclosed
herein. It is understood that “pharmaceutically acceptable salts” are non-toxic. Non-limiting examples of pharmaceutically acceptable salts include acid addition salts and base addition salts. [0017] Pharmaceutically acceptable acid addition salts are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,_maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthal ene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, -toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.
[0018] Pharmaceutically acceptable base addition salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Non-limiting examples of inorganic salts include ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, non-limiting examples of which include ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins, and the like.
[0019] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally converting Compound X to a salt thereof’ means that Compound X may or may not be converted to a salt. In some embodiments, Compound X is converted to a salt, whereas in other
embodiments Compound X is not converted to a salt.
[0020] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment.
Synthesis Route 1
[0021] In one aspect, provided herein is a method of preparing a compound of Formula T-2 or a salt thereof accordingly to the synthetic route outlined in Scheme 1 (“Synthesis Route 1”).
[0022] Thus, in certain embodiments, disclosed herein are methods of preparing a compound of Formula T-2:
Pgi
or a salt thereof, comprising the following steps:
(a) reacting a compound of Formula 1:
or a salt thereof, with a compound of Formula 2:
CH2(COOEt)2
(b) reacting a compound of Formula 3, or a salt thereof, with phthalimide to form a compound of Formula 4:
or a salt thereof;
(c) deprotecting a compound of Formula 4, or a salt thereof, to form a compound of
Formula 5:
EtO2C CO2Et
NHo or a salt thereof;
(d) reacting a compound of Formula 5, or a salt thereof, with a base to form a compound of Formula 6:
or a salt thereof;
7 or a salt thereof; and
8 or a salt thereof; and
(g) reducing a compound of Formula 8, or a salt thereof, to form a compound of
Formula 9:
O
Pg2^N^^NH2
9 or a salt thereof; and
(h) reducing a compound of Formula 9, or a salt thereof, to form a compound of
Formula 10:
Pg2^N^^NH2
10 or a salt thereof; and
(i) protecting the primary amine group of a compound of Formula 10, or a salt thereof, to form a compound of Formula 11:
Pgi
Pg2^N^^NH
11 or a salt thereof; and
(j) reducing a compound of Formula 11, or a salt thereof, to form a compound of Formula T-2.
[0023] In certain embodiments, step (a) is carried out in the presence of a base. In some embodiments, the base is sodium hydride, potassium tert-butoxide, or sodium ethoxide. In other embodiments, the base is sodium ethoxide.
[0024] In certain embodiments, step (a) is carried out using an alcohol as solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is ethanol.
[0025] In certain embodiments, step (a) is carried out at a temperature of between about 0-30 °C. In some embodiments, step (a) is carried out at a starting temperature of about 0-10 °C, then at 20-30 °C.
[0026] In certain embodiments, step (a) is carried out with the compound of Formula 1, or a salt thereof, that is separated into enantiomers, Formula la and Formula lb, or salts thereof, using kinetic resolution. In certain embodiments, the kinetic resolution is Jacobsen’s kinetic resolution. In certain embodiments, the kinetic resolution is hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
[0027] In certain embodiments, step (b) further comprises triphenylphosphine and diisopropyl azodi carb oxy late.
[0028] In certain embodiments, step (b) is carried out using an aprotic solvent. In some embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. In certain embodiments, the aprotic solvent is tetrahydrofuran.
[0029] In certain embodiments, step (b) is carried out at a temperature of between about 0- 30 °C. In some embodiments, step (b) is carried out at a starting temperature of about 0-10 °C, then at 20-30 °C.
[0030] In certain embodiments, step (c) is carried out in the presence of a base. In some embodiments, the base is sodium borohydride, methylamine, methylhydrazine, or hydrazine. In other embodiments, the base is hydrazine.
[0031] In certain embodiments, step (c) is carried out using a mixture of alcohol and an organic solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In some embodiments, the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, or 2-methyltetrahydrofuran. In certain embodiments, the alcohol is methanol and the organic solvent is dichloromethane.
[0032] In certain embodiments, step (d) is carried out using an inorganic base. In some embodiments, the inorganic base is sodium tert-butoxide, potassium tert-butoxide, potassium
carbonate, or cesium carbonate. In other embodiments, the inorganic base is cesium carbonate. [0033] In certain embodiments, step (d) is carried out using an alcohol as solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.
[0034] In certain embodiments, step (d) is carried out at a temperature of between about 25- 80 °C. In certain embodiments, step (d) is carried out at a temperature of between about 50-70 °C.
[0035] In certain embodiments, step (e) is carried out using an amine base. In some embodiments, the amine base is 2,2,6,6-tetramethylpiperidine, trimethylamine, triethylamine, or N,N-diisoproypylethylamine. In other embodiments, the amine base is N,N- dii soproy py 1 ethyl amine .
[0036] In certain embodiments, step (e) is carried out using an organic solvent. In some embodiments, the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 2- methyltetrahydrofuran, or a mixture thereof. In certain embodiments, the organic solvent is 2- methyltetrahydrofuran.
[0037] In certain embodiments, step (e) is carried out at a starting temperature of between about 40-70 °C, then at a reflux temperature above 50-120 °C. In certain embodiments, step (e) is carried out at a starting temperature of about 50-60 °C, then at a reflux temperature above 70- 100 °C.
[0038] In certain embodiments, step (e) is carried out at a temperature of between about 40- 70 °C, then at a temperature between about 50-120 °C. In certain embodiments, step (e) is carried out at a temperature of about 50-60 °C or about 50-70 °C, then at a temperature between about 70-100 °C.
[0039] In certain embodiments, following step (e), the compound of Formula 7, or a salt thereof, is separated into enantiomers, Formula 7a and Formula 7b, or salts thereof, using super fluid chromatography.
[0040] In certain embodiments, step (f) is carried out in the presence of a non-nucleophilic base. In some embodiments, the non-nucleophilic base is N,N-diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, or lithium bis(trimethylsilyl)amide. In other embodiments, the non-nucleophilic base is lithium bis(trimethylsilyl)amide.
[0041] In certain embodiments, step (f) is carried out using an ether solvent. In some embodiments, the ether solvent is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, or a mixture thereof. In certain embodiments, the ether solvent is tetrahydrofuran.
[0042] In certain embodiments, step (g) is catalyzed by a transition metal. In some embodiments, the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C). In other embodiments, the transition metal is palladium on carbon (Pd/C).
[0043] In certain embodiments, step (g) is carried out using an alcohol as solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.
[0044] In certain embodiments, step (h) is carried out using a reducing agent. In some embodiments, the reducing agent is a metal hydride, aluminum hydride, borohydride, or borane reagent. In some embodiments, the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran, or borane dimethylsulfide. In other embodiments, the reducing agent is borane dimethyl sulfide.
[0045] In certain embodiments, step (h) is carried out using an aprotic solvent. In some embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. In certain embodiments, the aprotic solvent is tetrahydrofuran.
[0046] In certain embodiments, step (h) is carried out at a temperature of between about 25- 80 °C. In certain embodiments, step (h) is carried out at a temperature of about 60-70 °C. [0047] In certain embodiments, step (i) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloroethane, toluene, methanol, ethanol, isopropanol, or 2-methyl-THF, dioxane, ethyl acetate, or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran. [0048] In certain embodiments, step (j) is catalyzed by a transition metal. In some embodiments, the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C). In other embodiments, the transition metal is palladium on carbon (Pd/C).
[0049] In certain embodiments, step (j) is carried out using an alcohol as solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.
Synthesis Route 2
[0050] In another aspect, provided herein is a method of preparing the compound Formula T-2 or a salt thereof accordingly to the synthetic route outlined in Scheme 2 (“Synthesis Route 2”).
Scheme 2. Synthesis Route 2 of the compound of Formula T-2.
[0051] Thus, in certain embodiments, disclosed herein are methods of preparing a compound of Formula T-2:
T-2 or a salt thereof, comprising the following steps:
7.5
(b) hydrolyzing a compound of Formula 7.5, or a salt thereof, to form a compound of
8.5 or a salt thereof; and
(c) reducing a compound of Formula 8.5, or a salt thereof, to form a compound of
9.5 or a salt thereof; and
(d) sequentially protecting the substituent and heterocyclic amines of a compound of Formula 9.5, or a salt thereof, and selectively deprotecting the substituent amine to form a compound of Formula 10:
10 or a salt thereof.
[0052] In certain embodiments, step (a) is catalyzed by a transition metal. In some embodiments, the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C). In other embodiments, the transition metal is palladium on carbon (Pd/C).
[0053] In certain embodiments, step (a) is carried out using an alcohol as solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.
[0054] In certain embodiments, step (a) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran.
[0055] In certain embodiments, step (b) is carried out with an acid. In some embodiments, the acid is trifluoroacetic acid, hydrochloride, or phosphoric acid. In certain embodiments, the acid is trifluoroacetic acid.
[0056] In certain embodiments, step (b) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran. In certain
embodiments, the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran. [0057] In certain embodiments, step (b) is carried out at a temperature of about 20-30 °C.
[0058] In certain embodiments, step (c) is carried out using a reducing agent. In some embodiments, the reducing agent is a metal hydride, aluminum hydride, borohydride, or borane reagent. In some embodiments, the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran, or borane dimethylsulfide. In other embodiments, the reducing agent is lithium aluminum hydride.
[0059] In certain embodiments, step (c) is carried out using an aprotic solvent. In some embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. In certain embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, or a mixture thereof.
[0060] In certain embodiments, step (d) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran. [0061] In certain embodiments, the selective deprotection of the substituent amine in step (d) is carried out using an acid. In some embodiments, the acid is hydrochloric acid.
Compounds
[0062] In one aspect, provided herein is a compound of Formula T-2:
T-2 or a salt thereof, wherein Pgi is a first protecting group.
[0063] In certain embodiments, Pgi is tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, or fluorenylmethyloxy carbonyl. In certain embodiments, Pgi is tert-butyloxy carbonyl.
[0064] In certain embodiments, the compound of Formula T-2 is separated into enantiomers, compounds of Formula T-3 and Formula T-4:
Pgi Pgi
or salts thereof.
[0065] In one aspect, provided herein are novel intermediate compounds that are useful in the synthesis of the compound of Formula T-2 or a salt thereof. In certain embodiments, the novel intermediate compound is:
or a sa t t ereo .
[0066] In certain embodiments, Pg2 is a second protecting group. In certain embodiments, Pg2 is tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, or fluorenylmethyloxy carbonyl. In certain embodiments, Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
[0067] In certain embodiments, Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group.
[0068] In certain embodiments, the novel intermediate compounds are separated into enantiomers, and a novel intermediate compound is:
CERTAIN NONLIMITING EMBODIMENTS
[0069] Certain aspects of the present invention are provided in the following numbered embodiments.
1. A method of preparing a compound of Formula (T-2):
T-2 or a salt thereof, comprising: reducing a compound of Formula (11):
or a salt thereof, wherein Pgi is a first protecting group; and
Pg2 is a second protecting group; to form the compound of Formula (T-2).
2. The method of embodiment 1, wherein: a) the compound of Formula (T-2) is the compound of Formula (T-3):
Pgi
and the compound of Formula (11) is the compound of Formula (Ila):
b) compound of Formula (T-2) is the compound of Formula (T-4):
3. The method of embodiment 1 or embodiment 2, wherein Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
4. The method of embodiment 1 or embodiment 2, wherein Pgi is tert-butyloxy carbonyl.
5. The method of embodiment 1 or embodiment 2, wherein Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
6. The method of any one of embodiments 1-5, wherein the reduction of Formula (11), or a salt thereof, is catalyzed by a transition metal to form the compound of Formula (T-2), or a salt thereof.
7. The method of embodiment 6, wherein the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C).
8. The method of embodiment 6, wherein the transition metal is palladium on carbon (Pd/C).
9. The method of any one of embodiments 1-8, wherein the reaction is carried out using an alcohol as solvent.
10. The method of embodiment 9, wherein the alcohol is methanol, ethanol, or isopropanol.
11. The method of embodiment 9, wherein the alcohol is methanol.
12. The method of any one of embodiments 1-11, wherein the compound of Formula (11), or a salt thereof, is prepared by protecting the primary amine group of a compound of Formula (10):
Pg2.^Q^NH2
10 or a salt thereof.
13. A method of preparing a compound of Formula (11),
10 or a salt thereof, wherein: wherein Pgi is a first protecting group; and
Pg2 is a second protecting group; to form the compound of Formula (11).
14. The method of embodiment 13, wherein Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.
15. The method of embodiment 13, wherein Pgi is tert-butyloxy carbonyl.
16. The method of embodiment 13, wherein Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
17. The method of any one of embodiments 12-16, wherein: a) the compound of Formula (11) is the compound of Formula (Ila):
Pgi
and the compound of Formula (10) is the compound of Formula (10a):
b) the compound of Formula (11) is the compound of Formula (11b):
and the compound of Formula (10) is the compound of Formula (10b):
18. The method of any one of embodiments 12-17, wherein the reaction is carried out using an organic solvent.
19. The method of embodiment 18, wherein the organic solvent is chloroform, di chloroethane, toluene, methanol, ethanol, isopropanol, or 2-methyl-THF, dioxane, ethyl acetate, or tetrahydrofuran.
20. The method of embodiment 18, wherein the organic solvent is di chloromethane, methanol, toluene, or tetrahydrofuran.
21. The method of any one of embodiments 1-20, wherein the compound of Formula (10), or a salt thereof, is prepared by sequential protection of the substituent and heterocyclic amines of a compound of Formula (9.5):
or a salt thereof, with Pg2 and Pgi, respectively, followed by selective deprotection of the substituent amine to form the compound of Formula (10).
22. The method of any one of embodiments 1-20, wherein the compound of Formula (10), or a salt thereof, is prepared by reducing a compound of Formula (9):
or a salt thereof, to form the compound of Formula (10).
23. A method of preparing a compound of Formula (10),
or a salt thereof, comprising: reducing a compound of Formula (9):
or a salt thereof, wherein Pg2 is a second protecting group, to form the compound of Formula (10).
24. The method of embodiment 23, wherein Pg2 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.
25. The method of embodiment 23, wherein Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
26. The method of any one of embodiments 22-25, wherein: a) the compound of Formula (10) is the compound of Formula (10a):
and the compound of Formula (9) is the compound of Formula (9a):
or. b) the compound of Formula (10) is the compound of Formula (10b):
and the compound of Formula (9) is the compound of Formula (9b):
27. The method of any one of embodiments 22-26, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride, or borane reagent.
28. The method of embodiment 27, wherein the reducing agent is lithium aluminum hydride,
triphenylphosphine borane, borane tetrahydrofuran, or borane dimethylsulfide.
29. The method of embodiment 27, wherein the reducing agent is borane dimethylsulfide.
30. The method of any one of embodiments 22-29, wherein the reaction is carried out using an aprotic solvent.
31. The method of embodiment 30, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, di chloromethane, di chloroethane, chloroform, or a mixture thereof.
32. The method of embodiment 30, wherein the aprotic solvent is tetrahydrofuran.
33. The method of any one of embodiments 22-32, wherein the reaction is carried out at a temperature of about 25-80 °C.
34. The method of embodiment 33, wherein the reaction is carried out at a temperature of about 60-70 °C.
35. The method of any one of embodiments 22-34, wherein the compound of Formula (9), or a salt thereof, is prepared by reducing a compound of Formula (8):
8 or a salt thereof, wherein:
Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group; and
Pg2 is a second protecting group to form the compound of Formula (9).
9 or a salt thereof, comprising: reducing a compound of Formula (8):
or a salt thereof, wherein:
Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group; and
Pg2 is a second protecting group to form a compound of Formula (9).
37. The method of embodiment 36, wherein Pg2 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.
38. The method of embodiment 36, wherein Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
39. The method of any one of embodiments 35-38, wherein: a) the compound of Formula (9) is the compound of Formula (9a):
and the compound of Formula (8) is the compound of Formula (8a):
b) the compound of Formula (9) is the compound of Formula (9b):
and the compound of Formula (8) is the compound of Formula (8b):
40. The method of any one of embodiments 35-39, wherein the reduction is catalyzed by a transition metal.
41. The method of embodiment 40, wherein the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C).
42. The method of embodiment 40, wherein the transition metal is palladium on carbon
(Pd/C).
43. The method of any one of embodiments 35-42, wherein the reaction is carried out using an alcohol as solvent.
44. The method of embodiment 43, wherein the alcohol is methanol, ethanol, or isopropanol.
45. The method of embodiment 43, wherein the alcohol is methanol.
46. The method of any one of embodiments 35-45, wherein the compound of Formula (8), or a salt thereof, is prepared by reacting a compound of Formula (7):
or a salt thereof, with Pg2X, wherein:
Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group;
Pg2 is a second protecting group; and
X is a leaving group; to form the compound of Formula (8).
47. A method of preparing a compound of Formula (8),
O Ri
Pg2.N^^NH
or a salt thereof, comprising: reacting a compound of Formula (7):
or a salt thereof, with Pg2X, wherein:
Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group;
Pg2 is a second protecting group; and
X is a leaving group; to form the compound of Formula (8).
48. The method of embodiment 46 or embodiment 47, wherein:
a) the compound of Formula (8) is the compound of Formula (8a):
and the compound of Formula (7) is the compound of Formula (7a):
b) the compound of Formula (8) is the compound of Formula (8b):
and the compound of Formula (7) is the compound of Formula (7b):
49. The method of any one of embodiments 46-48, wherein Pg2 is selected from tertbutyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
50. The method of any one of embodiments 46-48, wherein Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide
51. The method of any one of embodiments 46-50, wherein the reaction is carried out in the presence of a non-nucleophilic base.
52. The method of embodiment 51, wherein the non-nucleophilic base is N,N- diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert- butoxide, or lithium bis(trimethylsilyl)amide.
53. The method of embodiment 51, wherein the non-nucleophilic base used in the reaction with the compound of Formula (7) is lithium bis(trimethylsilyl)amide.
54. The method of any one of embodiments 46-53, wherein the reaction is carried out using an ether solvent.
55. The method of embodiment 54, wherein the ether solvent is tetrahydrofuran, 2-
methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, or a mixture thereof.
56. The method of embodiment 54, wherein the ether solvent is tetrahydrofuran.
10 or a salt thereof, wherein Pg2 is a second protecting group, comprising: sequential protection of the substituent and heterocyclic amines of a compound of Formula (9.5):
9.5 or a salt thereof, with Pg2 and Pgi, respectively, followed by selective deprotection of the substituent amine to form the compound of Formula (10).
58. The method of embodiment 57, wherein Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.
59. The method of embodiment 57, wherein Pgi is optionally substituted benzyl.
60. The method of embodiment 57, wherein Pg2 is an optionally substituted carboxybenzyl.
61. The method of any one of embodiments 21 or 57-60, wherein: a) the compound of Formula (10) is the compound of Formula (10a):
and the compound of Formula (9.5) is the compound of Formula (9.5a):
b) the compound of Formula (10) is the compound of Formula (10b):
and the compound of Formula (9.5) is the compound of Formula (9.5b):
62. The method of any one of embodiments 21 or 57-61, wherein the protection reactions are carried out using an organic solvent.
63. The method of embodiment 62, wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.
64. The method of embodiment 62, wherein the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran.
65. The method of any one of embodiments 21 or 57-64, wherein the selective deprotection of the substituent amine is carried out with an acid.
66. The method of embodiment 65, wherein the acid is hydrochloric acid.
67. The method of any one of embodiments 21 or 57-66, wherein the compound of Formula (9.5), or a salt thereof, is prepared by reducing a compound of Formula (8.5),
or a salt thereof, to form the compound of Formula (9.5).
8.5 or a salt thereof, to form a compound of Formula (9.5).
69. The method of embodiment 67 or embodiment 68, wherein: a) the compound of Formula (9.5) is the compound of Formula (9.5a):
and the compound of Formula (8.5) is the compound of Formula (8.5a):
c) the compound of Formula (9.5) is the compound of Formula (9.5b):
and the compound of Formula (8.5) is the compound of Formula (8.5b):
70. The method of any one of embodiments 67-69, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride, or borane reagent.
71. The method of embodiment 70, wherein the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran, or borane dimethylsulfide.
72. The method of embodiment 70, wherein the reducing agent is lithium aluminum hydride.
73. The method of any one of embodiments 67-72, wherein the reaction is carried out using an aprotic solvent.
74. The method of embodiment 73, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, di chloromethane, di chloroethane, chloroform, or a mixture thereof.
75. The method of embodiment 73, wherein the aprotic solvent is diethyl ether, tetrahydrofuran or a mixture thereof.
76. The method of any one of embodiments 67-75, wherein the compound of Formula (8.5), or a salt thereof, is prepared by hydrolyzing a compound of Formula (7.5): o Pgi
or a salt thereof, wherein Pgi is a first protecting group to form a compound of Formula (8.5).
77. A method of preparing a compound of Formula (8.5),
7.5 or a salt thereof, wherein Pgi is a first protecting group to form a compound of Formula (8.5).
78. The method of embodiment 76 or embodiment 77, wherein Pgi is selected from tertbutyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
79. The method of embodiment 76 or embodiment 77, wherein Pgi is tert-butyloxy carbonyl.
80. The method of any one of embodiments 76-79, wherein: a) the compound of Formula (8.5) is the compound of Formula (8.5a):
and the compound of Formula (7) is the compound of Formula (7a):
d) the compound of Formula (8.5) is the compound of Formula (8.5b):
and the compound of Formula (7.5) is the compound of Formula (7.5b):
81. The method of any one of embodiments 76-80, wherein the hydrolysis is carried out with an acid.
82. The method of embodiment 81, wherein the acid is trifluoroacetic acid, hydrochloride, or phosphoric acid.
83. The method of embodiment 81, wherein the acid is trifluoroacetic acid.
84. The method of any one of embodiments 76-83, wherein the protection reactions are carried out using an organic solvent.
85. The method of embodiment 84, wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.
86. The method of embodiment 84, wherein the organic solvent is dichloromethane, methanol, or toluene.
87. The method of any one of embodiments 76-86, wherein the reaction is carried out at a temperature of about 20-30 °C.
88. The method of any one of embodiments 76-87, wherein the compound of Formula (7.5), or a salt thereof, is prepared by deprotecting and subsequently protecting the primary amine group of a compound of Formula (7),
or a salt thereof.
89. A method of preparing a compound of Formula (7.5),
or a salt thereof, wherein Pgi is a first protecting group, wherein the method comprises: deprotecting and subsequently protecting the primary amine group of a compound of Formula (7),
7 or a salt thereof, wherein Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group, to form the compound of Formula (7.5).
90. The method of embodiment 88 or embodiment 89, wherein Pgi is selected from tertbutyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
91. The method of embodiment 88 or embodiment 89, wherein Pgi is tert-butyloxy carbonyl.
92. The method of any one of embodiments 88-91, wherein: a) the compound of Formula (7.5) is the compound of Formula (7.5a):
Pgi
NH
and the compound of Formula (7) is the compound of Formula (7a):
b) the compound of Formula (7.5) is the compound of Formula (7.5b):
and the compound of Formula (7) is the compound of Formula (7b):
93. The method of any one of embodiments 88-92, wherein the deprotection is catalyzed by a transition metal.
94. The method of embodiment 93, wherein the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C).
95. The method of embodiment 93, wherein the transition metal is palladium on carbon (Pd/C).
96. The method of any one of embodiments 88-95, wherein the reaction is carried out using an alcohol as solvent.
97. The method of embodiment 96, wherein the alcohol is methanol, ethanol, or isopropanol.
98. The method of embodiment 96, wherein the alcohol is methanol.
99. The method of any one of embodiments 88-98, wherein the protection reaction is carried out using an organic solvent.
100. The method of embodiment 99, wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.
101. The method of embodiment 99, wherein the organic solvent is di chloromethane, methanol, toluene, or tetrahydrofuran.
102. The method of any one of embodiments 46-56 or 88-101, wherein the compound of Formula (7), or a salt thereof, is prepared by reacting a compound of Formula (6):
or a salt thereof, with R3OH, wherein R3 is benzyl optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide, in the presence of diphenylphosphoryl azide and an amine base, to form the compound of Formula (7).
103. A method of preparing a compound of Formula (7),
or a salt thereof, wherein Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group, comprising: reacting a compound of Formula (6):
or a salt thereof, with R3OH, wherein R3 is a benzyl optionally substituted by Ci-Ce alkoxy, Ci- Ce alkyl, or halide, in the presence of diphenylphosphoryl azide and an amine base, to form the compound of Formula (7).
104. The method of embodiment 102 or embodiment 103, wherein: a) the compound of Formula (7) is the compound of Formula (7a):
and the compound of Formula (6) is the compound of Formula (6a):
b) the compound of Formula (7) is the compound of Formula (7b):
and the compound of Formula (6) is the compound of Formula (6b):
105. The method of any one of embodiments 102-104, wherein the amine base is 2, 2,6,6- tetramethylpiperidine, trimethylamine, triethylamine, or N,N-diisoproypylethylamine.
106. The method of embodiment 105, wherein the amine base is N,N-diisoproypylethylamine.
107. The method of any one of embodiments 102-106, wherein the reaction is carried out using an organic solvent.
108. The method of embodiment 107, wherein the organic solvent used in the reaction is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof.
109. The method of embodiment 107, wherein the organic solvent used in the reaction is 2- methyltetrahydrofuran.
110. The method of any one of embodiments 102-109, wherein the reaction is carried out at a starting temperature of about 40-70 °C, then at a reflux temperature above 50-120 °C.
111. The method of embodiment 110, wherein the reaction is carried out at a starting temperature of about 50-60 °C or about 60-70 °C, then at a reflux temperature of about 70-100 °C.
112. The method of any one of embodiments 102-111, wherein the compound of Formula (7), or a salt thereof, is separated into enantiomers, a compound of Formula (7a) and a compound of Formula (7b), or salts thereof, using super fluid chromatography.
113. The method of any one of embodiments 102-112, wherein the compound of Formula (6), or a salt thereof, is prepared by reacting a compound of Formula (5):
EtO2C CO2Et
NH2
5 or a salt thereof, with a base to form the compound of Formula (6).
114. A method of preparing a compound of Formula (6),
or a salt thereof, comprising: reacting a compound of Formula (5):
EtO2C CO2Et
NH2
5 or a salt thereof, with a base to form the compound of Formula (6).
115. The method of embodiment 113 or 114, wherein: a) the compound of Formula (6) is a compound of Formula (6a):
and the compound of Formula (5) is a compound of Formula (5a),
b) the compound of Formula (6) is a compound of Formula (6b):
and the compound of Formula (5) is a compound of Formula (5b),
116. The method of any one of embodiments 113-115, wherein the base is an inorganic base.
117. The method of embodiment 116, wherein the inorganic base is sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, or cesium carbonate.
118. The method of embodiment 116, wherein the inorganic base is cesium carbonate.
119. The method of any one of embodiments 113-118, wherein the reaction is carried out using an alcohol as solvent.
120. The method of embodiment 119, wherein the alcohol is methanol, ethanol, or isopropanol.
121. The method of embodiment 119, wherein the alcohol is methanol.
122. The method of any one of embodiments 113-121, wherein the reaction is carried out at a temperature of about 25-80 °C.
123. The method of embodiment 122, wherein the reaction is carried out at a temperature of about 50-70 °C.
124. The method of any one of embodiments 113-123, wherein the compound of Formula (5), or a salt thereof, is prepared by deprotecting the amine of a compound of Formula (4):
or a salt thereof, to form the compound of Formula (5).
125. A method of preparing a compound of Formula (5),
or a salt thereof, comprising: deprotecting a compound of Formula (4):
or a salt thereof, to form the compound of Formula (5).
126. The method of embodiment 124 or embodiment 125, wherein: a) the compound of Formula (5) is a compound of Formula (5a):
and the compound of Formula (4) is a compound of Formula (4a),
b) the compound of Formula (5) is a compound of Formula (5b):
and the compound of Formula (4) is a compound of Formula (4b),
127. The method of any one of embodiments 124-126, wherein the deprotection is carried out using a base.
128. The method of embodiment 127, wherein the base is sodium borohydride, methylamine, methylhydrazine, or hydrazine.
129. The method of embodiment 127, wherein the base is hydrazine.
130. The method of any one of embodiments 124-129, wherein the reaction is carried out using a mixture of alcohol and an organic solvent.
131. The method of embodiment 130, wherein the alcohol is methanol, ethanol, or isopropanol.
132. The method of embodiment 130, wherein the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, or 2-methyltetrahydrofuran.
133. The method of embodiment 130, wherein the alcohol is methanol, and the organic solvent is dichloromethane.
134. The method of any one of embodiments 124-133, wherein the compound of Formula (4), or a salt thereof, is prepared by reacting a compound of Formula (3):
or a salt thereof, with phthalimide to form the compound of Formula (4).
135. A method of preparing a compound of Formula (4),
or a salt thereof, comprising, reacting a compound of Formula (3):
or a salt thereof, with phthalimide to form the compound of Formula (4).
136. The method of embodiment 134 or embodiment 135, wherein: a) the compound of Formula (4) is a compound of Formula (4a):
and the compound of Formula (3) is the compound of Formula (3a),
b) the compound of Formula (4) is a compound of Formula (4b):
and the compound of Formula (3) is a compound of Formula (3b),
137. The method of any one of embodiments 134-136, wherein the reaction further comprises triphenylphosphine and diisopropyl azodi carb oxy late.
138. The method of any one of embodiments 134-137, where in the reaction is carried out using an aprotic solvent.
139. The method of embodiment 138, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, di chloromethane, di chloroethane, chloroform, or a mixture thereof.
140. The method of embodiment 138, wherein the aprotic solvent is tetrahydrofuran.
141. The method of any one of embodiments 134-140, wherein the reaction is carried out at a temperature of about 0-30 °C.
142. The method of embodiment 141, wherein the reaction is carried out at a starting temperature of about 0-10 °C, then at 20-30 °C.
143. The method of any one of embodiments 134-142, wherein the compound of Formula (3), or a salt thereof, is prepared by reacting a compound of Formula (1):
1 or a salt thereof, and a compound of Formula (2):
CH2(COOEt)2
2 or a salt thereof, to form the compound of Formula (3).
144. A method of preparing a compound of Formula (3),
or a salt thereof, comprising: reacting a compound of Formula (1):
1 or a salt thereof, and a compound of Formula (2):
CH2(COOEt)2
2 or a salt thereof, to form the compound of Formula (3).
145. The method of embodiment 143 or embodiment 144, wherein: a) the compound of Formula (3) is a compound of Formula (3a):
and the compound of Formula (1) is a compound of Formula (la),
b) the compound of Formula (3) is a compound of Formula (3b):
and the compound of Formula (1) is the compound of Formula (lb),
146. The method of any one of embodiments 143-145, wherein the reaction is carried out in the presence of a base.
147. The method of embodiment 146, wherein the base is sodium hydride, potassium tert- butoxide, or sodium ethoxide.
148. The method of embodiment 146, wherein the base is sodium ethoxide.
149. The method of any one of embodiments 143-148, wherein the reaction is carried out using an alcohol as solvent.
150. The method of embodiment 149, wherein the alcohol is methanol, ethanol, or isopropanol.
151. The method of embodiment 149, wherein the alcohol is ethanol.
152. The method of any one of embodiments 143-151, wherein the reaction is carried out at a temperature of about 0-30 °C.
153. The method of embodiment 152, wherein the reaction is carried out at a starting temperature of about 0-10 °C, then at 20-30 °C.
154. The method of any one of embodiments 143-153, wherein the compound of Formula (1), or a salt thereof, is separated into enantiomers, Formula (la) and Formula (lb), or salts thereof, using kinetic resolution.
155. The method of embodiment 154, wherein the kinetic resolution is Jacobsen’s kinetic resolution or hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
156. A method of preparing a compound of Formula (T-2), or a salt thereof, comprising the following steps:
wherein:
R3 is benzyl optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide;
Ri is benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide;
Pgi is a first protecting group;
Pg2 is a second protecting group; and
X is a leaving group.
157. A method of preparing a compound of Formula (T-2), or a salt thereof, comprising the following steps:
Ri is benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide;
Pgi is a first protecting group;
Pg2 is a second protecting group; and
X is a leaving group.
158. The method of embodiment 156 or embodiment 157, wherein Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
159. A compound of Formula (T-3):
160. A compound of Formula (T-4):
161. The compound of embodiment 159 or embodiment 160, wherein Pgi is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl,
optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
162. The compound of embodiment 159 or embodiment 160, wherein Pgi is tertbutyloxy carbonyl .
164. The compound of embodiment 163, wherein the compound of Formula (3), or a salt thereof, is a compound of Formula (3a):
or a salt thereof; or a compound of Formula (3b):
or a salt thereof.
166. The compound of embodiment 165, wherein the compound of Formula (4), or a salt thereof, is a compound of Formula (4a):
or a salt thereof; or a compound of Formula (4b):
or a salt thereof.
168. The compound of embodiment 167, wherein the compound of Formula (5), or a salt thereof, is a compound of Formula (5a):
or a salt thereof; or a compound of Formula (5b):
or a salt thereof.
170. The compound of embodiment 169, wherein the compound of Formula (6), or a salt thereof, is a compound of Formula (6a):
or a salt thereof; or a compound of Formula (6b):
or a salt thereof.
171. A compound of Formula (7):
or a salt thereof, wherein Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide, or an amino protecting group.
172. The compound of embodiment 171, wherein the compound of Formula (7), or a salt thereof, is a compound of Formula (7a):
or a salt thereof; or a compound of Formula (7b):
or a salt thereof.
Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group; and
Pg2 is a second protecting group.
174. The compound of embodiment 173, wherein the compound of Formula (8), or a salt thereof, is a compound of Formula (8a):
or a salt thereof; or a compound of Formula (8b):
or a salt thereof.
9 or a salt thereof, wherein Pg2 is a second protecting group.
176. The compound of embodiment 175, wherein the compound of Formula (9), or a salt thereof, is a compound of Formula (9a):
or a salt thereof; or a compound of Formula (9b):
or a salt thereof.
7.5 or a salt thereof, wherein Pgi is a first protecting group.
178. The compound of embodiment 177, wherein the compound of Formula (7.5), or a salt thereof, is a compound of Formula (7.5a):
8.5 or a salt thereof.
180. The compound of embodiment 179, wherein the compound of Formula (8.5), or a salt thereof, is a compound of Formula (8.5a):
or a salt thereof; or a compound of Formula (8.5b):
or a salt thereof.
182. The compound of embodiment 181, wherein the compound of Formula (9.5), or a salt thereof, is a compound of Formula (9.5a):
or a salt thereof; or a compound of Formula (9.5b):
Hfj NH2 9.5b or a salt thereof.
183. A compound of Formula (10):
Pg2^N^^NH2
10 or a salt thereof, wherein Pg2 is a second protecting group.
184. The compound of embodiment 183, wherein the compound of Formula (10), or a salt thereof, is a compound of Formula (10a):
or a salt thereof; or a compound of Formula (10b):
or a salt thereof.
185. A compound of Formula (11):
11 or a salt thereof, wherein:
Pgi is a first protecting group; and
Pg2 is a second protecting group.
186. The compound of embodiment 185, wherein the compound of Formula (11), or a salt thereof, is a compound of Formula (Ila):
187. The compound of embodiment 185 or embodiment 186, wherein Pgi is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
188. The compound of embodiment 185 or embodiment 186, wherein Pgi is tertbutyloxycarbonyl .
189. The compound of any one of embodiments 233-242, wherein Pg2 is selected from tertbutyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
190. The compound of any one of embodiments 173-176 or 183-189, wherein Pg2 is a benzyl group optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide.
EXAMPLES
[0070] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
[0072] To a 3 L 3-neck round bottom flask was added diethyl malonate (156 g, 964 mmol) and EtOH (740 mL). The solution was cooled to 0-5 °C. A brown solution of sodium ethoxide (396 mL, 21 wt% in EtOH, 1060 mmol) was added through an additional funnel over 20 min. The temperature was then slightly increased to 9 °C. After stirring the reaction mixture at 0-5 °C for 15 min, 2-(2-bromoethyl)oxirane (150 g, 964 mmol) was added, and the reaction mixture was stirred at room temperature to give a brown suspension. After stirring for 18 h at room temperature, the reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (1 L) and brine (500 mL). The aqueous layer was extracted with EtOAc (300 mL) again. The combined organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the product diethyl 3 -hydroxy cyclopentane- 1,1 -dicarboxylate (200 g, 782 mmol, 81 % yield) as a brown oil with -90% purity, which was used directly for next step without further purification.
LC-MS [M+l] 231.
’H NMR (400 MHz, CHLOROFORM-d) 54.44 - 4.36 (m, 1H), 4.26 - 4.15 (m, 4H), 2.47 - 2.26 (m, 3H), 2.07 (br d, J=4.5 Hz, 1H), 1.94 (dtd, J=13.5, 8.5, 5.2 Hz, 1H), 1.84 - 1.67 (m, 1H), 1.33 - 1.20 (m, 6H).
To a 5 L 3-neck round bottom 53orti was added triphenylphosphine (PPhs, 117 g, 443 mmol) and THF (1400 mL). The colorless solution was cooled to 5 °C with an ice-water bath, and diisopropyl azodi carb oxy late (DIAD, 86 mL, 443 mmol) was added dropwise over 35 min through an additional funnel, while the internal temperature was kept below 15 °C. The yellow color of DIAD was allowed to almost disappear before each addition. The clear reaction mixture became a white suspension during the addition of DIAD. The white thick suspension was stirred in an ice-water bath for 30 min. Formation of a pure white thick slurry indicated successful preparation of a PPhs-DIAD complex. A solution of diethyl 3 -hydroxy cyclopentane- 1,1 -di carb oxy late (108 g, 422 mmol) was poured into the reaction mixture and the temperature was increased to 15 °C. Isoindoline-1, 3-dione (59.9 g, 407 mmol) was then added in small portions while keeping the reaction temperature below 15 °C. After addition, the reaction mixture was allowed to warm to room temperature. The reaction mixture became a light orange solution and was stirred at room temperature overnight. The reaction mixture was quenched with brine (400 mL) and the aqueous layer was separated and extracted with EtOAc (300 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to 1 L. Precipitation of colorless crystals (triphenylphosphine oxide (Ph3P=O)) from the concentrated EtOAc solution was observed. The suspension was allowed to sit at room temperature overnight. The filtrate brown oil was added into a stirring 500 mL Et2O in a 2 L beaker which formed a suspension. After 30 min, the resulting peach color solid was removed by filtration. The Et2O filtrate was filtered one more time and then concentrated to give a crude brown oil. It was added to MeOH (200 mL) to form a white suspension. The precipitated pure product was collected by filtration and washed with methanol to give a white solid. The mother liquid was concentrated and purified on ISCO column chromatography with a gradient 0 - 10% acetone/hexane. A total of 93 g (yield 61%) diethyl 3-(l,3-dioxoisoindolin-2-yl)cyclopentane-
1,1 -di carb oxy late was obtained as a white solid.
LC-MS [M+l] 360.0.
XH NMR (400 MHz, CHLOROFORM-d) 5 7.83 (dd, J=5.5, 3.0 Hz, 2H), 7.73 - 7.69 (m, 2H), 4.81 (quin, J=8.8 Hz, 1H), 4.29 - 4.20 (m, 4H), 2.78 - 2.66 (m, 3H), 2.36 - 2.28 (m, 1H), 2.19 (dt, J=13.3, 7.5 Hz, 1H), 2.11 - 2.04 (m, 1H), 1.29 (td, J=7.1, 2.6 Hz, 6H).
[0073] To a 5 L 3-necked flask equipped with a mechanic stirrer was added diethyl 3 -(1 ,3 - dioxoisoindolin-2-yl)cyclopentane-l,l-dicarboxylate (120 g, 334 mmol), MeOH (1580 mL), DCM (1050 mL), and hydrazine (121 mL, 1336 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The reaction became a thick suspension, which was filtered. The filter cake was rinsed with DCM (500 mL), and the combined filtrates were concentrated in vacuo. To the residue was then added DCM (900 mL) and 1 N NaOH (440 mL). The organic phase was collected, washed with water (200 mL) and brine (200 mL), dried over Na2SO4, and filtered and concentrated in vacuo to give the product diethyl 3- aminocy cl opentane- 1,1 -dicarboxylate as a slightly yellow oil (68 g). The combined water phase was back extracted with DCM to give additional 3 g product. The combined desired product was 71g (93% yield), which was which was used directly for the next step without further purification.
LC-MS [M+l]: 230.
’H NMR (400 MHz, CHLOROFORM-d) 54.19 (quin, J=7.1 Hz, 4H), 3.45 (t, J=6.7 Hz, 1H), 2.55 - 2.39 (m, 2H), 2.17 (dt, J=13.8, 7.9 Hz, 1H), 2.01 - 1.90 (m, 2H), 1.64 - 1.37 (m, 3H), 1.25 (td, J=7.1, 3.7 Hz, 6H).
[0074] To a 2 L 3 -neck flask with a condenser was added diethyl 3 -aminocyclopentane- 1,1- dicarboxylate (71 g, 310 mmol), cesium carbonate (202 g, 619 mmol) and MeOH (670 mL) under N2. The reaction mixture was stirred at 65 °C for 4 h. The reaction was completed after 4 h and was cooled to room temperature and then concentrated in vacuo below 35 °C to remove
MeOH to give a yellow oil. To the yellow residue was added H2O (30ml) and 2-MeTHF (120 mL), and the mixture was acidified with aqueous NaHSC (149 g in 170 mL H2O) to pH -3. Then the resulting solution was extracted with 2-MeTHF (200 mL x 4). Combined extracts were concentrated by removal of solvent in vacuo to give a yellow solid. The solid was then suspended in benzene (500 mL) and heated with a Dean-Stark apparatus (Azeotropy) to remove water, which gave 43.5g of yellow powder. The powder was co-rotovapped with toluene (200 mL x 3) to remove any remaining moisture to offer the desired product (42.8g, yield 89%) as a yellow powder, which was used without further purification for the next step reaction.
LC-MS [M+l]: 156.0.
’H NMR (400 MHz, METHANOL-d4) 5 3.91 - 3.87 (m, 1H), 2.23 - 2.10 (m, 2H), 2.08 - 1.91 (m, 1H), 1.84 - 1.66 (m, 3H).
[0075] To a suspension of 3-oxo-2-azabicyclo[2.2.1]heptane-4-carboxylic acid (37.0 g, 238 mmol) in 2-Me-THF (610 mL) was added N,N-diisopropylethylamine (104 mL, 596 mmol) and diphenyl phosphorazidate (DPP A, 58.1 mL, 262 mmol). The reaction mixture was heated to 70 °C until it became a clear solution (within 5 min). LC/MS confirmed that the starting material was fully consumed within 20 min. After stirring at 70 °C for 50 min, benzyl alcohol (64.5 mL, 620 mmol) was added at 70 °C in one portion, and the reaction mixture was stirred at 80 °C for a total of 9 h until the reaction was completed. After cooling to room temperature, most of 2- MeTHF (-650 mL) was removed in vacuo. The residue was diluted with EtOAc (650 mL), washed with water (250 mL) and brine (200 mL), dried over Na2SO4, and filtered and concentrated in vacuo to give an extract as a yellow oil. The water and brine washes were combined and back-extracted with EtOAc (350 mL x 8). The organic extracts were each dried, concentrated, and combined to give a crude product as a yellow oil (177g). The crude was first purified on ISCO column chromatography with a 0-50% acetone/hexanes gradient followed by SFC to give two enantiomers: peak 1 : 23.7g (yield 38.2%); and peak 2: 23.5g (yield 37.9%). LC/MS [M+l]: 260.7.
’H NMR (400 MHz, CHLOROFORM-d) 5 7.39 - 7.31 (m, 5H), 5.69 (br s, 2H), 5.12 (br s, 2H), 3.87 (br s, 1H), 2.53 - 2.44 (m, 1H), 2.41 (br d, J=9.1 Hz, 1H), 2.06 (br s, 1H), 1.92 (dq, J=9.2,
2.3 Hz, 1H), 1.78 - 1.67 (m, 1H), 1.52 - 1.41 (m, 1H).
[0076] To a solution of benzyl (3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (1.66 g, 6.38 mmol) in THF (36 mL) was added LHMDS (IM in THF, 6.70 mL, 6.70 mmol) dropwise at 0 ~5 °C. After stirring for 10 min, benzyl bromide (0.834 mL, 7.02 mmol) was added dropwise. The reaction was slowly warmed to room temperature and stirred for 20 h. Sat.
NH4Q solution (20 mL) was added to quench the reaction. EtOAc (20 mL) was added next, and the organic layer was collected. The water layer was washed with EtOAc (15 mL). The organic layer and wash were combined and washed with brine (30 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by ISCO column chromatography with a 50-100% EtOAc/heptanes gradient to give benzyl (2-benzyl-3-oxo-2-azabicyclo[2.2.1]heptan-4- yl)carbamate (2.0 g, 5.71 mmol, 89 % yield) as white solid.
LC/MS [M+l]: 351.3.
'H N R (400 MHz, CHLOROFORM-7) 5 ppm 1.25 - 1.51 (m, 1 H) 1.52 - 1.61 (m, 1 H) 1.76 - 1.94 (m, 2 H) 2.37 (br d, 7=9.05 Hz, 1 H) 2.47 (td, 7=11.43, 4.28 Hz, 1 H) 3.67 (br s, 1 H) 4.10 (d, 7=15.16 Hz, 1 H) 4.73 (d, 7=14.92 Hz, 1 H) 5.13 (s, 2 H) 5.79 (s, 1 H) 7.23 - 7.41 (m, 10 H) Example SI.7 Synthesis of compound 9
[0077] To a 250 mL three neck round bottom flask was charged a solution of benzyl (2- benzyl-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (3.15 g, 8.99 mmol) in MeOH (30 mL). The solution was bubbled with N2 for 10 min. 10% wet Pd/C (300 mg, 10% w/w) was added under N2. The reaction mixture was then degased until no bubbles was seen. A H2 balloon was inserted, and the reaction mixture was stirred for 20 h. LC/MS indicated the completion of the reaction. The H2 balloon was removed, and the reaction mixture was degased until no bubbles seen. The flask was then filled with N2. The mixture was filtered through a celite pad. The filtrate was concentrated in vacuo to give the product 4-amino-2-benzyl-2- azabicyclo[2.2.1]heptan-3-one (1.9 g, 8.78 mmol, 98% yield) as a colorless oil.
LC/MS [M+l]: 217.4.
’H NMR (400 MHz, CHLOROFORM-7) 5 ppm 1.55 - 1.63 (m, 2 H) 1.66 - 1.92 (m, 6 H) 3.58
- 3.61 (m, 1 H) 4.03 (d, 7=15.16 Hz, 1 H) 4.73 (d, 7=15.16 Hz, 1 H) 7.25 - 7.37 (m, 5 H) Example SI.8 Synthesis of compound 10
To a solution of 4-amino-2-benzyl-2-azabicyclo[2.2.1]heptan-3-one (320 mg, 1.480 mmol) in THF (15 mL) was added borane dimethyl sulfide complex (2.22 mL, 4.44 mmol) dropwise at room temperature. The reaction mixture was heated to 65 °C and stirred for 20 h. After cooling to room temperature, 6 N HC1 solution (4.0 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was then heated to 50 °C and stirred for 20 h. After cooling to room temperature, brine (20 mL) and EtOAc (20 mL) were added, followed by addition of 1 N NaOH to adjust the pH of the aqueous layer to ~14. DCM (20 mL x3) was then used to extract the amine product. The yield of 2-benzyl-2-azabicyclo[2.2. l]heptan-4-amine was assumed to be 100%.
LC/MS [M+l]: 203.4
Example SI.9 Synthesis of compound 11
[0078] To a DCM solution (10 mL) containing ~300mg of 2-benzyl-2- azabicyclo[2.2.1]heptan-4-amine was added di-tert-butyl dicarbonate (355 mg, 1.627 mmol) and stirred for 1 h. After removing DCM, the residue was purified by ISCO column chromatography with a 20-100% EtOAc/heptanes gradient to give tert-butyl (2-benzyl-2- azabicyclo[2.2.1]heptan-4-yl)carbamate (330 mg, 1.091 mmol, 73.8 % yield).
LC/MS [M+l]: 303.3.
’H NMR (400 MHz, CHLOROFORM-7) 5 ppm 1.37 - 1.53 (m, 9 H) 1.59 - 1.72 (m, 2 H) 1.75 - 1.88 (m, 2 H) 1.92 - 2.14 (m, 2 H) 2.45 - 2.68 (m, 1 H) 2.87 - 3.09 (m, 1 H) 3.11 - 3.30 (m, 1 H) 3.59 - 3.85 (m, 2 H) 4.63 - 5.00 (m, 1 H) 7.16 - 7.46 (m, 5 H)
[0079] Tert-butyl (2-benzyl-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (2.0 g, 6.61 mmol)
was dissolved in ethanol (6 mL), to which was added 10% Pd(OH)2/C (200mg, 10% w/w ). The reaction vessel was degassed, filled with N2, degassed, and filled with H2 with a H2 balloon.
The reaction mixture was then stirred for 18 h. The reaction vessel was then degased and filled with N2 multiple times. The reaction mixture was then filtered through a celite pad and concentrated in vacuo to give tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate (1.3g, 6.12 mmol, 93 % yield) as white solid.
LC/MS [M+l]: 213.3.
’H NMR (400 MHz, CHLOROFORM-tZ) 5 ppm 1.45 (s, 9 H) 1.57 - 1.67 (m, 1 H) 1.69 - 1.78 (m, 1 H) 1.81 - 1.97 (m, 5 H) 3.01 (s, 2 H) 3.40 (s, 1 H) 4.92 (s, 1 H)
[0080] To a solution of benzyl (3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (5.2 g, 19.98 mmol) in MeOH (100 mL) was added di-tert-butyl dicarbonate (4.80 g, 21.98 mmol) and 10% Pd/C (0.52 g, 0.489 mmol, 10% W/W). The reaction vessel was degassed, filled with N2, degassed, and filled with H2 with a H2 balloon. The reaction mixture was stirred for 18 h., and the reaction vessel was then degassed and filled with N2 for multiple times. The reaction mixture was then filtered through a celite pad and concentrated in vacuo to give the crude product which was then triturated with 2-MeTHF at room temperature to -20 °C to give the product tert-butyl (3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (4.3 g, 19.00 mmol, 95 % yield).
LC/MS [M+l]: 227.3
[0081] To a 100 mL flask was added tert-butyl (3-oxo-2-azabicyclo[2.2.1]heptan-4- yl)carbamate (872 mg, 3.85 mmol) and DCM (10 mL). The mixture was stirred at room temperature until all the solids were dissolved and then trifluoroacetic acid (2.97 mL, 38.5 mmol) was added. The mixture was stirred at room temperature overnight and concentrated in vacuo. The mixture was co-evaporated with toluene (10 mL) twice in vacuo to afford 4-amino- 2-azabicyclo[2.2.1]heptan-3-one 2,2,2-trifluoroacetate (918 mg, 3.82 mmol, 99 % yield). XH NMR (400 MHz, DMSO-d6) 5 ppm 8.81 (br s, 3 H) 8.36 (s, 1 H) 3.86 (s, 1 H) 1.98 - 2.09 (m, 1 H) 1.84 - 1.96 (m, 2 H) 1.76 (d, J=8.8 Hz, 1 H) 1.52 - 1.68 (m, 2 H)
[0082] A 100 mL flask was charged with 4-amino-2-azabicyclo[2.2.1]heptan-3-one
2,2,2-trifluoroacetate (711 mg, 2.96 mmol) and THF (15 mL). The mixture was cooled in a water-ice bath, and lithium aluminum hydride (IM in THF) (14.80 mL, 14.80 mmol) was added dropwise. The mixture was stirred for 10 min and was allowed to reach room temperature by removing the bath. The mixture was heated at 55 °C (heating block temperature) for 5 h and stirred at room temperature overnight. The mixture was cooled to 0 °C and water (0.5 mL) was added dropwise. After stirring for 10 min, 15% NaOH solution (0.5 mL) was added followed by water (1.5 mL). The mixture was diluted with ether (15 mL) and stirred for 1 h. The suspension was filtered through a pad of celite and washed with ether (15 mL). The filtrate was dried with Na2SO4, filtered and concentrated to afford crude 2-azabicyclo[2.2.1]heptan-4-amine that was used without purification on the next step (assumed 100% yield).
’H NMR (400 MHz, DMSO-d6) 5 ppm 9.90 (br s, 1 H) 9.36 (s, 1 H) 9.16 (s, 2 H) 8.96 (s, 1 H) 3.96 (s, 1 H) 3.09 - 3.28 (m, 2 H) 1.83 - 2.11 (m, 6 H) 1.71 - 1.83 (m, 1 H)
Example S2.4 Synthesis of compound 10
3. Acid-base workup
9.5 10
[0083] The crude 2-azabicyclo[2.2.1]heptan-4-amine (330 mg, 2.94 mmol) was dissolved in DCM (10 mL) and MeOH (10 mL), in which benzaldehyde (0.313 mL, 3.09 mmol) and magnesium sulfate (2.08 g, 17.28 mmol) were added. The mixture was stirred at room temperature overnight and then cooled down to 0 °C. A solution of Cbz-OSu (0.770 g, 3.09 mmol) in 1 : 1 MeOH/DCM (5 mL) was added dropwise. The mixture was stirred for 30 min at 0 °C, filtered through a pad of celite, and concentrated in vacuo. The residue was redissolved in 15 mL MeOH and IN hydrochloric acid (15 mL, 15.00 mmol). The mixture was stirred for 30 min at room temperature to hydrolyze the imine. Most of methanol was then removed in vacuo and the aqueous layer was extracted with DCM (10 mL x 2). The first extraction was discarded and the aqueous layer was basified with IN NaOH solution to pH 12, followed by extraction with DCM (10 mL x 3). The combined organic extracts were concentrated in vacuo to afford benzyl 4-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate (367 mg, 1.490 mmol, 50.6 % yield) as yellow oil.
XH NMR (400 MHz, DMSO-d6) 7.27 - 7.52 (m, 5 H) 5.04 - 5.25 (m, 2 H) 4.09 - 4.35 (m, 1 H) 3.09 - 3.28 (m, 2 H) 1.35 - 1.98 (m, 8 H)
Example S2.5 Synthesis of compound 11
[0084] To a solution of benzyl 4-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate (362 mg, 1.470 mmol) in DCM (10 mL) was added Boc-anhydride (385 mg, 1.764 mmol). The mixture was stirred at room temperature for 20 h. LCMS showed almost all of the SM was consumed.
Solvent was evaporated and the residue was purified by ISCO colum chromtography with a 20- 100% EtOAc/heptanes gradient to afford benzyl 4-((tert-butoxycarbonyl)amino)-2- azabicyclo[2.2.1]heptane-2-carboxylate (478 mg, 1.380 mmol, 94% yield).
’H NMR (400 MHz, DMSO-d6) 7.30 - 7.43 (m, 5 H) 5.08 - 5.21 (m, 2 H) 4.78 - 4.92 (m, 1 H)
4.09 - 4.32 (m, 1 H) 3.46 - 3.59 (m, 1 H) 3.36 - 3.45 (m , 1 H) 1.65 - 2.05 (m, 6 H) 1.45 (s, 9 H)
11
[0085] Benzyl 4-((tert-butoxycarbonyl)amino)-2-azabicyclo[2.2. l]heptane-2-carboxylate (478 mg, 1.380 mmol) in MeOH (10 mL) was hydrogenated overnight with a Hz filled balloon in the presence of 10% Pd/C (50 mg, 0.047 mmol). The resulting mixture was filtered through a pad of celite, washed with methanol, and concentrated to afford tert-butyl (2- azabicyclo[2.2.1]heptan-4-yl)carbamate (284 mg, 1.338 mmol, 97 % yield).
LC/MS [M+l]: 213.3.
Example 3. Synthesis of T-3
[0086] Compound T-3, an enantiomer of compound T-2, was prepared from an enantiomer 7a, obtained by chiral separation of compound 7. Each of the reaction procedures that led from compounds 7a to 8a, 8a to 9a, 9a to 10a, 10a to Ila, and Ila to T-3, were identical to those described in Examples 1.6, 1.7, 1.8, 1.9, and 1.10, respectively. In some embodiments, the kinetic resolution method used for chiral separation was Jacobsen’s kinetic resolution. In some embodiments, the kinetic resolution method used for chiral separation was hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
Example S3.2 Synthesis of T-3 from chiral separated compound 7a via selective protection of diamine
[0087] Compound T-3, an enantiomer of compound T-2, was prepared from an enantiomer 7a, obtained by chiral separation of compound 7. Each of the reaction procedures that led from compounds 7a to 7.5a, 7.5a to 8.5a, 8.5a to 9.5a, 9.5a to 10a, and Ila to T-3, were identical to those described in Examples 2.1, 2.2, 2.3, 2.4, 1.9, and 1.10, respectively. In some embodiments, the kinetic resolution method used for chiral separation was Jacobsen’s kinetic resolution. In some embodiments, the kinetic resolution method used for chiral separation was hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
[0088] Compound T-3, an enantiomer of compound T-2, was prepared from an enantiomer la, obtained by chiral separation of compound 1 using Jacobsen’s kinetic resolution. The reaction procedures were identical to those described in Example 1. The Jacobsen’s kinetic resolution method used to prepare la is described below.
[0089] A 500 mL flask was charged with S,S-Co-Salen (6.12 g, 10.13 mmol) and DCM (60 mL). After stirring for 10 min at room temperature, nonafluoro-tert-butanol (7.08 mL, 50.7 mmol) was added dropwise, and the mixture was vigorously stirred open to air for 1 h. The mixture changed color from dark-red to black. The mixture was concentrated to dryness using a rotary evaporator. The solids were scraped from walls with spatula and dried in vacuo for 2 h to give the active catalyst. A separate 250 mL flask was charged with racemic 2-(2-
bromoethyl)oxirane (102 g, 675 mmol), phenol (35.0 g, 372 mmol), and MTBE (50 mL). The mixture was cooled to 3-5 °C in an ice-water bath and then added to the flask containing the dry catalyst placed in a water/ice bath. The mixture was stirred in the bath for 30 min, then kept at
0-5 °C for 20 h. The flask was then allowed to warm to room temperature and MTBE was distilled off using a rotary evaporator (40 °C / 70 mmHg). A short-path distillation adapter was then attached to the flask and the mixture was distilled at reduced presure to give 47 g of the product (bp 66-68 °C / 25 mmHg, then 43-45 °C / 8 mmHg). At the end of distillation, the bath was heated to 100 °C and vacuum was lowered to 5-6 mmHg to maximize the recovery of the epoxide. NMR showed 89% purity. The crude material was re-distilled from a 100 mL flask using the same short-path distillation adapter to give (S)-2-(2-bromoethyl)oxirane (36.0 g, 212 mmol, 31.4 % yield). Purity by NMR -95%.
XH NMR (400 MHz, CHLOROFORM-d) 5 = 3.53 (dd, J= 6.0, 7.4 Hz, 2H), 3.11 (dtd, J= 2.7, 4.2, 6.8 Hz, 1H), 2.86 (dd, J= 3.8, 4.9 Hz, 1H), 2.60 (dd, J= 2.7, 4.9 Hz, 1H), 2.18 (dtd, J= 4.6, 7.5, 15.0 Hz, 1H), 2.07 (qd, J= 6.0, 15.0 Hz, 1H)
Example 4. Synthesis of T-4
[0090] Compound T-4, an enantiomer of compound T-2, was prepared from an enantiomer 7b, obtained by chiral separation of compound 7. Each of the reaction procedures that led from compounds 7b to 8b, 8b to 9b, 9b to 10b, 10b to 11b, and 11b to T-4, were identical to those described in Examples 1.6, 1.7, 1.8, 1.9, and 1.10, respectively. In some embodiments, the kinetic resolution method used for chiral separation was Jacobsen’s kinetic resolution. In some embodiments, the kinetic resolution method used for chiral separation was hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
Example S4.2 Synthesis of T-4 from chiral separated compound 7b via selective protection of diamine
[0091] Compound T-4, an enantiomer of compound T-2, was prepared from an enantiomer 7b, obtained by chiral separation of compound 7. Each of the reaction procedures that led from compounds 7b to 7.5b, 7.5b to 8.5b, 8.5b to 9.5b, 9.5b to 10b, and 11b to T-4, were identical to those described in Examples 2.1, 2.2, 2.3, 2.4, 1.9, and 1.10, respectively. In some embodiments, the kinetic resolution method used for chiral separation was Jacobsen’s kinetic resolution. In some embodiments, the kinetic resolution method used for chiral separation was hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
[0092] Compound T-4, an enantiomer of compound T-2, was prepared from an enantiomer lb, obtained by chiral separation of compound 1 using Jacobsen’s kinetic resolution. The reaction procedures were identical to those described in Example 1. The Jacobsen’s kinetic resolution method was identical to that described in Example S3.3.
Claims
1. A method of preparing a compound of Formula (T-2):
Pgi
or a salt thereof, comprising: reducing a compound of Formula (11):
or a salt thereof, wherein Pgi is a first protecting group; and
Pg2 is a second protecting group; to form the compound of Formula (T-2).
2. The method of claim 1, wherein: a) the compound of Formula (T-2) is the compound of Formula (T-3):
Pgi
and the compound of Formula (11) is the compound of Formula (Ila):
c) compound of Formula (T-2) is the compound of Formula (T-4):
3. The method of claim 1 or claim 2, wherein the reduction of Formula (11), or a salt thereof, is catalyzed by a transition metal to form the compound of Formula (T-2), or a salt thereof.
4. The method of claim 3, wherein the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C).
5. The method of any one of claims 1-4, wherein the reaction is carried out using an alcohol as solvent, optionally wherein the alcohol is methanol, ethanol, or isopropanol.
6. The method of any one of claims 1-5, wherein the compound of Formula (11), or a salt thereof, is prepared by protecting the primary amine group of a compound of Formula (10):
Pg2'N^^NH2
10 or a salt thereof.
7. A method of preparing a compound of Formula (11),
11 or a salt thereof, comprising: protecting the primary amine group of a compound of Formula (10): Pg2^N^^NH2
10 or a salt thereof, wherein: wherein Pgi is a first protecting group; and
Pg2 is a second protecting group; to form the compound of Formula (11).
8. The method of any one of claims 1-7, wherein Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
9. The method of any one of claims 6-8, wherein the reaction is carried out using an organic solvent, optionally wherein the organic solvent is chloroform, di chloroethane, toluene, methanol, ethanol, isopropanol, or 2-methyl-THF, dioxane, ethyl acetate, or tetrahydrofuran.
10. The method of any one of claims 1-9, wherein the compound of Formula (10), or a salt thereof, is prepared by sequential protection of the substituent and heterocyclic amines of a compound of Formula (9.5):
9.5
Or a salt thereof, with Pg2 and Pgi, respectively, followed by selective deprotection of the substituent amine to form the compound of Formula (10); or wherein the compound of Formula (10), or a salt thereof, is prepared by reducing a compound of Formula (9):
or a salt thereof, to form the compound of Formula (10).
11. A method of preparing a compound of Formula (10),
or a salt thereof, comprising: reducing a compound of Formula (9):
9 or a salt thereof, wherein Pg2 is a second protecting group, to form the compound of Formula (10), optionally wherein Pg2 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
12. The method of claim 10 or 11, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride, or borane reagent, optionally wherein the reducing agent is
lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran, or borane dimethylsulfide.
13. The method of any one of claims 10-12, wherein the reaction is carried out using an aprotic solvent, optionally wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, di chloromethane, dichloroethane, chloroform, or a mixture thereof.
14. The method of any one of claims 10-13, wherein the compound of Formula (9), or a salt thereof, is prepared by reducing a compound of Formula (8):
or a salt thereof, wherein:
Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group; and
Pg2 is a second protecting group to form the compound of Formula (9).
Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide, or an amino protecting group; and
Pg2 is a second protecting group to form a compound of Formula (9), optionally wherein Pg2 is selected from tertbutyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl,
diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
16. The method of claim 14 or 15, wherein the reduction is catalyzed by a transition metal, optionally wherein the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C).
17. The method of any one of claims 14-16, wherein the reaction is carried out using an alcohol as solvent, optionally wherein the alcohol is methanol, ethanol, or isopropanol.
18. The method of any one of claims 14-17, wherein the compound of Formula (8), or a salt thereof, is prepared by reacting a compound of Formula (7):
7 or a salt thereof, with Pg2X, wherein:
Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group;
Pg2 is a second protecting group; and
X is a leaving group; to form the compound of Formula (8).
7 or a salt thereof, with Pg2X, wherein:
Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group;
Pg2 is a second protecting group; and
X is a leaving group; to form the compound of Formula (8), optionally wherein Pg2 is selected from tert-
butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
20. The method of claim 18 or 19, wherein the reaction is carried out in the presence of a non-nucleophilic base, optionally wherein the non-nucleophilic base is N,N- diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert- butoxide, or lithium bis(trimethylsilyl)amide.
21. The method of any one of claims 18-20, wherein the reaction is carried out using an ether solvent, optionally wherein the ether solvent is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, or a mixture thereof.
10 or a salt thereof, wherein Pg2 is a second protecting group, comprising: sequential protection of the substituent and heterocyclic amines of a compound of Formula (9.5):
9.5 or a salt thereof, with Pg2 and Pgi, respectively, followed by selective deprotection of the substituent amine to form the compound of Formula (10), optionally wherein Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl .
23. The method of claim 10 or 22, wherein the protection reactions are carried out using an organic solvent, optionally wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.
24. The method of any one of claims 10, 22, and 23, wherein the selective deprotection of the substituent amine is carried out with an acid, optionally wherein the acid is hydrochloric acid.
25. The method of any one of claims 10 or 22-24, wherein the compound of Formula (9.5), or a salt thereof, is prepared by reducing a compound of Formula (8.5),
8.5 or a salt thereof, to form the compound of Formula (9.5).
8.5 or a salt thereof, to form a compound of Formula (9.5).
27. The method of claim 25 or 26, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride, or borane reagent, optionally wherein the reducing agent is lithium aluminum hydride, triphenylphosphine borane, borane tetrahydrofuran, or borane dimethylsulfide.
28. The method of any one of claims 25-27, wherein the reaction is carried out using an aprotic solvent, optionally wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, di chloromethane, dichloroethane, chloroform, or a mixture thereof.
29. The method of any one of claims 25-28, wherein the compound of Formula (8.5), or a salt thereof, is prepared by hydrolyzing a compound of Formula (7.5):
7.5 or a salt thereof, wherein Pgi is a first protecting group to form a compound of Formula (8.5).
7.5 or a salt thereof, wherein Pgi is a first protecting group to form a compound of Formula (8.5), optionally wherein Pgi is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl .
31. The method of claim 29 or 30, wherein the hydrolysis is carried out with an acid, optionally wherein the acid is trifluoroacetic acid, hydrochloride, or phosphoric acid.
32. The method of any one of claims 29-31, wherein the protection reactions are carried out using an organic solvent, optionally wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.
33. The method of any one of claims 29-32, wherein the compound of Formula (7.5), or a salt thereof, is prepared by deprotecting and subsequently protecting the primary amine group of a compound of Formula (7),
7 or a salt thereof.
7.5 or a salt thereof, wherein Pgi is a first protecting group, wherein the method comprises:
deprotecting and subsequently protecting the primary amine group of a compound of Formula (7),
or a salt thereof, wherein Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, halide, or an amino protecting group, to form the compound of Formula (7.5), optionally wherein Pgi is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
35. The method of claim 33 or 34, wherein the deprotection is catalyzed by a transition metal, optionally wherein the transition metal is palladium chloride, palladium on barium sulfate, or palladium on carbon (Pd/C).
36. The method of any one of claims 33-35, wherein the reaction is carried out using an alcohol as solvent, optionally wherein the alcohol is methanol, ethanol, or isopropanol.
37. The method of any one of claims 33-36, wherein the protection reaction is carried out using an organic solvent, optionally wherein the organic solvent is chloroform, dichloromethane, tetrachloromethane, di chloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.
38. The method of any one of claims 18, 19, and 33-37, wherein the compound of Formula (7), or a salt thereof, is prepared by reacting a compound of Formula (6):
or a salt thereof, with R3OH, wherein R3 is benzyl optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide, in the presence of diphenylphosphoryl azide and an amine base, to form the compound of Formula (7).
7 or a salt thereof, wherein Ri is a benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce
alkyl, halide, or an amino protecting group, comprising: reacting a compound of Formula (6):
6 or a salt thereof, with R3OH, wherein R3 is a benzyl optionally substituted by Ci-Ce alkoxy, Ci- Ce alkyl, or halide, in the presence of diphenylphosphoryl azide and an amine base, to form the compound of Formula (7).
40. The method of claim 38 or 39, wherein the amine base is 2, 2,6,6- tetramethylpiperidine, trimethylamine, triethylamine, or N,N-diisoproypylethylamine.
41. The method of any one of claims 38-40, wherein the reaction is carried out using an organic solvent, optionally wherein the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof.
42. The method of any one of claims 38-41, wherein the compound of Formula (7), or a salt thereof, is separated into enantiomers, a compound of Formula (7a) and a compound of Formula (7b), or salts thereof, using super fluid chromatography.
43. The method of any one of claims 38-42, wherein the compound of Formula (6), or a salt thereof, is prepared by reacting a compound of Formula (5):
EtO2C CO2Et
NH2
5 or a salt thereof, with a base to form the compound of Formula (6).
44. A method of preparing a compound of Formula (6),
or a salt thereof, comprising: reacting a compound of Formula (5):
EtO2C CO2Et
NHo
or a salt thereof, with a base to form the compound of Formula (6).
45. The method of claim 43 or 44, wherein the base is an inorganic base, optionally wherein the inorganic base is sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, or cesium carbonate.
46. The method of any one of claims 43-45, wherein the reaction is carried out using an alcohol as solvent, optionally wherein the alcohol is methanol, ethanol, or isopropanol.
49. The method of claim 47 or 48, wherein the deprotection is carried out using a base, optionally wherein the base is sodium borohydride, methylamine, methylhydrazine, or hydrazine.
50. The method of any one of claims 47-49, wherein the reaction is carried out using a mixture of alcohol and an organic solvent, optionally wherein the alcohol is methanol, ethanol, or isopropanol, and the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, or 2-methyltetrahydrofuran.
53. The method of claim 51 or 52, wherein the reaction further comprises triphenylphosphine and diisopropyl azodi carb oxy late.
54. The method of any one of claims 51-53, where in the reaction is carried out using an aprotic solvent, optionally wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, acetonitrile, 1,4-di oxane, toluene, di chloromethane, dichloroethane, chloroform, or a mixture thereof.
55. The method of any one of claims 51-54, wherein the compound of Formula (3), or a salt thereof, is prepared by reacting a compound of Formula (1):
1 or a salt thereof, and a compound of Formula (2):
CH2(COOEt)2
2 or a salt thereof, to form the compound of Formula (3).
56. A method of preparing a compound of Formula (3),
or a salt thereof, comprising: reacting a compound of Formula (1):
or a salt thereof, and a compound of Formula (2):
CH2(COOEt)2
2 or a salt thereof, to form the compound of Formula (3).
57. The method of claim 55 or 56, wherein the reaction is carried out in the presence of a base, optionally wherein the base is sodium hydride, potassium tert-butoxide, or sodium ethoxide.
58. The method of any one of claims 55-57, wherein the reaction is carried out using an alcohol as solvent, optionally wherein the alcohol is methanol, ethanol, or isopropanol.
59. The method of any one of claims 55-58, wherein the compound of Formula (1), or a salt thereof, is separated into enantiomers, Formula (la) and Formula (lb), or salts thereof, using kinetic resolution, optionally wherein the kinetic resolution is Jacobsen’s kinetic resolution or hydrolytic kinetic resolution catalyzed by chiral cobalt-salen complexes.
60. A method of preparing a compound of Formula (T-2), or a salt thereof, comprising the following steps:
R3 is benzyl optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide;
Ri is benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide;
Pgi is a first protecting group;
Pg2 is a second protecting group; and
X is a leaving group.
61. A method of preparing a compound of Formula (T-2), or a salt thereof, comprising the following steps:
Ri is benzyl carbamate optionally substituted by Ci-Ce alkoxy, Ci-Ce alkyl, or halide;
Pgi is a first protecting group;
Pg2 is a second protecting group; and
X is a leaving group.
62. The method of claim 156 or claim 157, wherein Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxy carbonyl.
63. A compound select from:
(a) a compound of Formula (T-3) or Formula (T-4):
T-3 T-4 or a salt thereof;
(b) a compound of Formula (3):
or a salt thereof, optionally wherein the compound of Formula (3), or a salt thereof, is a compound of Formula (3a):
or a salt thereof; or a compound of Formula (3b):
or a salt thereof;
(c) a compound of Formula (4):
or a salt thereof, optionally wherein the compound of Formula (4), or a salt thereof, is a compound of Formula (4a):
or a salt thereof; or a compound of Formula (4b):
or a salt thereof;
(d) a compound of Formula (5):
or a salt thereof, optionally wherein the compound of Formula (5), or a salt thereof, is a compound of Formula (5a):
or a salt thereof; or a compound of Formula (5b):
or a salt thereof;
6 or a salt thereof, optionally wherein the compound of Formula (6), or a salt thereof, is a compound of Formula (6a):
or a salt thereof; or a compound of Formula (6b):
or a salt thereof.
7 or a salt thereof, optionally wherein the compound of Formula (7), or a salt thereof, is a compound of Formula (7a):
or a salt thereof; or a compound of Formula (7b):
or a salt thereof;
8 or a salt thereof, optionally wherein the compound of Formula (8), or a salt thereof, is a compound of Formula (8a):
or a salt thereof; or a compound of Formula (8b):
or a salt thereof.
9 or a salt thereof, optionally wherein the compound of Formula (9), or a salt thereof, is a compound of Formula (9a):
or a salt thereof; or a compound of Formula (9b):
or a salt thereof.
7.5 or a salt thereof, optionally wherein the compound of Formula (7.5), or a salt thereof, is a compound of Formula (7.5a):
or a salt thereof; or a compound of Formula (7.5b):
or a salt thereof;
8.5 or a salt thereof, optionally wherein the compound of Formula (8.5), or a salt thereof, is a compound of Formula (8.5a):
or a salt thereof; or a compound of Formula (8.5b):
or a salt thereof;
(k) a compound of Formula (9.5):
or a salt thereof, optionally wherein the compound of Formula (9.5), or a salt thereof, is a compound of Formula (9.5a):
or a salt thereof; or a compound of Formula (9.5b):
or a salt thereof;
(1) a compound of Formula (10):
or a salt thereof, wherein Pg2 is a second protecting group, optionally wherein the compound of Formula (10), or a salt thereof, is a compound of Formula (10a):
or a salt thereof; or a compound of Formula (10b):
or a salt thereof; and
(m) a compound of Formula (11):
Pgi l Pg2^N^^NH
11 or a salt thereof, optionally wherein the compound of Formula (11), or a salt thereof, is a compound of Formula (Ila):
64. The compound of claim 63, wherein Pgi and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.
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US20110144150A1 (en) * | 2009-12-14 | 2011-06-16 | Lampe John W | Bridged bicyclic rho kinase inhibitor compounds, composition and use |
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US20110144150A1 (en) * | 2009-12-14 | 2011-06-16 | Lampe John W | Bridged bicyclic rho kinase inhibitor compounds, composition and use |
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Title |
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DATABASE PUBCHEM COMPOUND 12 August 2020 (2020-08-12), ANONYMOUS: "4-Aminobicyclo[2.2.1]heptan-2-one", XP093156912, retrieved from PUBCHEM Database accession no. 147496797 * |
DATABASE PUBCHEM COMPOUND 16 December 2011 (2011-12-16), ANONYMOUS: "tert-butyl N-{2azabicyclo[2.2.1]heptan-7-yl}carbamate", XP093156871, retrieved from PUBCHEM Database accession no. 54595555 * |
DATABASE PUBCHEM COMPOUND 22 April 2021 (2021-04-22), ANONYMOUS: "Benzyl 3-oxo-2-azabicyclo[2.2.1] heptane-2-carboxylate", XP093156884, retrieved from PUBCHEM Database accession no. 155895895 * |
DATABASE PUBCHEM COMPOUND 22 April 2022 (2022-04-22), ANONYMOUS: "tert-Butyl (2azabicyclo[2.2.1]heptan-4yl)carbamate", XP093156799, retrieved from PUBCHEM Database accession no. 155895082 * |
DATABASE PUBCHEM COMPOUND 25 January 2017 (2017-01-25), ANONYMOUS: "4-Amino-2-benzyl-2azabicyclo[2.2.1]heptan-3-one", XP093156841, retrieved from PUBCHEM Database accession no. 123678905 * |
DATABASE PUBCHEM COMPOUND 26 March 2005 (2005-03-26), ANONYMOUS: "2-Oxobicyclo[2.2.1]heptane-1- carboxylic acid", XP093156918, retrieved from PUBCHEM Database accession no. 382538 * |
DATABASE PUBCHEM COMPOUND 29 May 2009 (2009-05-29), ANONYMOUS: "(1S,4S)-2-azabicyclo[2.2.1]heptane4-carboxylic acid", XP093156915, retrieved from PUBCHEM Database accession no. 39872459 * |
DATABASE PUBCHEM COMPOUND 30 November 2012 (2012-11-30), ANONYMOUS: "2-Azabicyclo[2.2.1]heptan-4-amine", XP093156905, retrieved from PUBCHEM Database accession no. 67234457 * |
DATABASE PUBCHEM COMPOUND 30 November 2012 (2012-11-30), ANONYMOUS: "Tert-butyl 4-amino-2- azabicyclo[2.2.1]heptane-2- carboxylate", XP093156851, retrieved from PUBCHEM Database accession no. 67234570 * |
DATABASE PUBCHEM COMPOUND 4 August 2014 (2014-08-04), ANONYMOUS: "Diethyl 3-aminocyclopentane-1,1dicarboxylate", XP093156857, retrieved from PUBCHEM Database accession no. 76641638 * |
DATABASE PUBCHEM COMPOUND 4 August 2017 (2017-08-04), ANONYMOUS: "Benzyl 6-amino-2azabicyclo[2.2.1]heptane-2carboxylate", XP093156889, retrieved from PUBCHEM Database accession no. 129237433 * |
DATABASE PUBCHEM COMPOUND 4 December 2007 (2007-12-04), ANONYMOUS: "Diethyl 3-hydroxycyclopentane-1,1dicarboxylate", XP093156865, retrieved from PUBCHEM Database accession no. 18970186 * |
DATABASE PUBCHEM COMPOUND 5 December 2007 (2007-12-05), ANONYMOUS: "3-Hydroxycyclopentane-1,1dicarboxylic acid", XP093156925, retrieved from PUBCHEM Database accession no. 23117405 * |
DATABASE PUBCHEM COMPOUND 5 December 2007 (2007-12-05), ANONYMOUS: "tert-Butyl 3-oxo-2- azabicyclo[2.2.1]heptane-2- carboxylate", XP093156878, retrieved from PUBCHEM Database accession no. 22408688 * |
DATABASE PUBCHEM COMPOUND 8 February 2007 (2007-02-08), ANONYMOUS: "2-Azabicyclo[2.2.1]heptan-3-one", XP093156910, retrieved from PUBCHEM Database accession no. 13078198 * |
DATABASE PUBCHEM COMPOUND 8 February 2007 (2007-02-08), ANONYMOUS: "2-Cyclopentyl-1H-isoindole-1,3(2H)dione", XP093156920, retrieved from PUBCHEM Database accession no. 13765724 * |
DATABASE PUBCHEM COMPOUND 8 February 2007 (2007-02-08), ANONYMOUS: "3-(1,3-Dioxoisoindol-2yl)cyclopentane-1-carboxylic acid", XP093156923, retrieved from PUBCHEM Database accession no. 12645060 * |
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