US20070244334A1 - Processes and intermediates for preparing steric compounds - Google Patents
Processes and intermediates for preparing steric compounds Download PDFInfo
- Publication number
- US20070244334A1 US20070244334A1 US11/724,002 US72400207A US2007244334A1 US 20070244334 A1 US20070244334 A1 US 20070244334A1 US 72400207 A US72400207 A US 72400207A US 2007244334 A1 US2007244334 A1 US 2007244334A1
- Authority
- US
- United States
- Prior art keywords
- optionally substituted
- compound
- formula
- cyclopropyl
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 69
- 238000000034 method Methods 0.000 title claims abstract description 44
- 230000008569 process Effects 0.000 title claims abstract description 34
- 239000000543 intermediate Substances 0.000 title abstract description 16
- -1 azide salt Chemical class 0.000 claims description 75
- 239000000203 mixture Substances 0.000 claims description 36
- 125000001931 aliphatic group Chemical group 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- DRNGSSWBFKDSEE-UHFFFAOYSA-N 3-amino-n-cyclopropyl-2-hydroxyhexanamide Chemical compound CCCC(N)C(O)C(=O)NC1CC1 DRNGSSWBFKDSEE-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- ARDZPNHBMYHPHZ-UHFFFAOYSA-N n-cyclopropyl-3-propyloxirane-2-carboxamide Chemical compound CCCC1OC1C(=O)NC1CC1 ARDZPNHBMYHPHZ-UHFFFAOYSA-N 0.000 claims description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 9
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical group CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 9
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical group OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 229960003964 deoxycholic acid Drugs 0.000 claims description 5
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 claims description 3
- TYSGBKLKELJYLP-UHFFFAOYSA-N 3-azido-n-cyclopropyl-2-hydroxyhexanamide Chemical compound CCCC(N=[N+]=[N-])C(O)C(=O)NC1CC1 TYSGBKLKELJYLP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- DRNGSSWBFKDSEE-YUMQZZPRSA-N (2s,3s)-3-amino-n-cyclopropyl-2-hydroxyhexanamide Chemical compound CCC[C@H](N)[C@H](O)C(=O)NC1CC1 DRNGSSWBFKDSEE-YUMQZZPRSA-N 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- ZTEHTGMWGUKFNE-UHFFFAOYSA-N methyl 3-[[2-(diaminomethylideneamino)-1,3-thiazol-4-yl]methylsulfanyl]propanimidate Chemical compound COC(=N)CCSCC1=CSC(N=C(N)N)=N1 ZTEHTGMWGUKFNE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- HJCRVWSKQNDSPZ-UHFFFAOYSA-N propan-2-olate;samarium(3+) Chemical compound [Sm+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] HJCRVWSKQNDSPZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 6
- 239000012069 chiral reagent Substances 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 23
- 239000000243 solution Substances 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 125000000217 alkyl group Chemical group 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 29
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 125000001072 heteroaryl group Chemical group 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 25
- 125000004429 atom Chemical group 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 125000001424 substituent group Chemical group 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 0 *C([1*])(N)C(O)C(=O)N[2*] Chemical compound *C([1*])(N)C(O)C(=O)N[2*] 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 125000003545 alkoxy group Chemical group 0.000 description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 15
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 15
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 125000004414 alkyl thio group Chemical group 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 11
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 125000003710 aryl alkyl group Chemical group 0.000 description 11
- 125000004093 cyano group Chemical group *C#N 0.000 description 11
- 125000004122 cyclic group Chemical group 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 125000005843 halogen group Chemical group 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 125000004043 oxo group Chemical group O=* 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 9
- 125000000304 alkynyl group Chemical group 0.000 description 9
- 125000002619 bicyclic group Chemical group 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 125000001188 haloalkyl group Chemical group 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 8
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 description 8
- NWGPLYYBECWONP-UHFFFAOYSA-N (carbamoylamino) hydrogen sulfate Chemical compound NC(=O)NOS(O)(=O)=O NWGPLYYBECWONP-UHFFFAOYSA-N 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 7
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 7
- 125000003435 aroyl group Chemical group 0.000 description 7
- 125000005126 aryl alkyl carbonyl amino group Chemical group 0.000 description 7
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 7
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 7
- 125000004104 aryloxy group Chemical group 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 125000000000 cycloalkoxy group Chemical group 0.000 description 7
- 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 description 7
- 125000004475 heteroaralkyl group Chemical group 0.000 description 7
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 description 7
- 125000005553 heteroaryloxy group Chemical group 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 150000002924 oxiranes Chemical class 0.000 description 7
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000006735 epoxidation reaction Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 5
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- NIONDZDPPYHYKY-SNAWJCMRSA-N (2E)-hexenoic acid Chemical compound CCC\C=C\C(O)=O NIONDZDPPYHYKY-SNAWJCMRSA-N 0.000 description 4
- NSJDRLWFFAWSFP-NSHDSACASA-N (2s)-2-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound CCC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 NSJDRLWFFAWSFP-NSHDSACASA-N 0.000 description 4
- OOWKCUTWLYXPLW-SNAWJCMRSA-N (e)-n-cyclopropylhex-2-enamide Chemical compound CCC\C=C\C(=O)NC1CC1 OOWKCUTWLYXPLW-SNAWJCMRSA-N 0.000 description 4
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 4
- NIONDZDPPYHYKY-UHFFFAOYSA-N Z-hexenoic acid Natural products CCCC=CC(O)=O NIONDZDPPYHYKY-UHFFFAOYSA-N 0.000 description 4
- 238000005576 amination reaction Methods 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 150000001540 azides Chemical class 0.000 description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 4
- 208000006454 hepatitis Diseases 0.000 description 4
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000005176 Hepatitis C Diseases 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 3
- 206010042618 Surgical procedure repeated Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000001414 amino alcohols Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 3
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000012026 peptide coupling reagents Substances 0.000 description 3
- 239000003001 serine protease inhibitor Substances 0.000 description 3
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 208000018191 liver inflammation Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ZUSSTQCWRDLYJA-UHFFFAOYSA-N n-hydroxy-5-norbornene-2,3-dicarboximide Chemical compound C1=CC2CC1C1C2C(=O)N(O)C1=O ZUSSTQCWRDLYJA-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 125000005889 octahydrochromenyl group Chemical group 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
- SQQWBSBBCSFQGC-JLHYYAGUSA-N ubiquinone-2 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CCC=C(C)C)=C(C)C1=O SQQWBSBBCSFQGC-JLHYYAGUSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/20—Preparation of optical isomers by separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
- C07C247/06—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
-
- 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
- C07D209/52—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 condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- This invention relates to processes and intermediates for the preparation of protease inhibitors, in particular, serine protease inhibitors.
- HCV hepatitis C virus
- protease inhibitors and in particular serine protease inhibitors, useful in the treatment of HCV infections are disclosed in WO 02/18369. Also disclosed therein are processes and intermediates for the preparation of these compounds. There remains however, a need for economical processes for the preparation of these compounds.
- This invention relates to processes and intermediates for the preparation of an alpha-amino beta-hydroxy acid of Formula 1 wherein the variables R 1 , R′ 1 and R 2 are defined herein and the compound of Formula 1 has an enantiomeric excess (ee) of 55% or greater.
- the process comprises the steps of oxidizing an unsaturated amide or ester to form the corresponding epoxide, forming an alpha-hydroxy, beta-amino acid with an appropriate aminating reagent and resolving the amino-alcohol amide.
- the invention features processes and intermediates used in the preparation of the serine protease inhibitor of Formula 3.
- the term “enantimoeric excess (ee) of 55% or greater” means that one enantiomer is present 55% or more than the other in a chemical substance.
- the enantiomer can be a result of either the carbon center to which the amino group is bonded (shown with an asterisk) in Formula 1 or the carbon center to which the hydroxyl group is bonded (also shown with an asterisk) in Formula 1, or both carbon centers.
- the compound can be (2S,3S), (2S,3R), (2R, 3R) or (2R, 3S) in these two carbon centers.
- trialkylamines e.g. diethylisopropylamine, triethylamine, N-methylmorpholine and the like
- heteroaryl amines e.g. pyridine, quinoline, and the like.
- aliphatic encompasses alkyl, alkenyl, and alkynyl.
- an “alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms.
- An alkyl group can be straight or branched. Examples of an alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and 2-ethylhexyl.
- An alkyl group can be optionally substituted with one or more substituents such as cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl.cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroary
- an “alkenyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
- An alkenyl group can be optionally substituted with one or more substituents such as cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl.cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, hetero
- an “alkynyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond.
- An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl.
- An alkynyl group can be optionally substituted with one or more substituents such as cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy
- an “amino” group refers to —NRXRY wherein each of RX and RY is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl each of which are defined herein and are optionally substituted.
- RX has the same meaning as defined above.
- an “aryl” group used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to phenyl, naphthyl, or a benzofused group having 2 to 3 rings.
- a benzofused group includes phenyl fused with one or two C4-8 carbocyclic moieties, e.g., 1, 2, 3, 4-tetrahydronaphthyl, indanyl, or fluorenyl.
- An aryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloal
- an “aralkyl” group refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” are defined herein. An example of an aralkyl group is benzyl. An “heteroaralkyl” group refers to an alkyl group that is substituted with a heteroaryl. Both “alkyl” and “heteroaryl” are defined herein. As used herein, a “cyclcoaliphatic” group encompasses a “cycloalkyl” group and a “cycloalkenyl” group.
- a “cycloalkyl” group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms.
- Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, and bicyclo[3.3.2.]decyl, and adamantyl.
- a “cycloalkenyl” group refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bond.
- Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl.
- a cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkyl
- heterocycloaliphatic encompasses a heterocycloalkyl group and a heterocycloalkenyl group.
- heterocycloalkyl refers to a 3- to 10-membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom, e.g., N, O, or S.
- heterocycloalkyl group examples include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, dioxolanyl, oxazolidinyl, isooxazolidinyl, morpholinyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, anad 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.
- a monocyclic heterocycloalkyl group may be fused with a phenyl moiety such as tetrahydroisoquinoline.
- a “heterocycloalkenyl” group refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom, e.g., N, O, or S.
- a heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl (such as a benzimidazolidinyl), (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alky
- a “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring structure having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom, e.g., N, O, or S and wherein one or more rings of the bicyclic or tricyclic ring structure is aromatic.
- a heteroaryl group includes a benzofused ring system having 2 to 3 rings.
- a benzofused group includes phenyl fused with one or two C 4-8 heterocyclic moieties, e.g., indolinyl and tertahydroquinolinyl.
- heteroaryl examples include azetidinyl, pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, and benzo[1,3]dioxole.
- a heteroaryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloal
- heteroaryl group refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above.
- cyclic moiety includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously.
- an “acyl” group refers to a formyl group or alkyl-C( ⁇ O)— where “alkyl” has been defined previously. Acetyl and pivaloyl are examples of acyl groups.
- a “carbamoyl” group refers to a group having the structure —O—CO—NRxRy or —NRx—CO—O-Rz wherein Rx and Ry have been defined above and Rz can be alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.
- a “carboxy” and a “sulfo” group refer to —COOH or —COOR X and —SO 3 H or —SO 3 R X , respectively.
- alkoxy refers to an alkyl-O— group where “alkyl” has been defined previously.
- a “sulfoxy” group refers to —O—SO—R X or —SO—O—R X , where R X has been defined above.
- a “sulfonyl” group refers to —S(O) 2 —R X , wherein R X has been defined above.
- sulfinyl refers to —S(O)—R X , wherein R X has been defined above.
- sulfanyl group refers to —S—R X , wherein R X has been defined above.
- halogen or “halo” group refers to fluorine, chlorine, bromine or iodine.
- haloaliphatic refers to an aliphatic group substituted with 1-3 halogen.
- haloalkyl includes the group —CF 3 .
- a “sulfamoyl” group refers to the structure —S(O) 2 —NR x R y or —NR x , —S(O) 2 —Rz wherein Rx, Ry, and Rz have been defined above.
- sulfamide refers to the structure —NR X —S(O) 2 —NR Y R Z wherein R X , R Y , and R Z have been defined above.
- a “carbonylamino” group used alone or in connection with another group refers to an amido group such as —C(O)—NR X —, —NR X —C(O)—, and —C(O)—N(R X ) 2 .
- an alkylcarbonylamino includes alkyl-C(O)—NR X — and alkyl-NR X —C(O)—.
- urea refers to the structure —NR X —CO—NR Y R Z and a “thiourea” group refers to the structure —NR X —CS—NR Y R Z .
- R X , R Y , and R Z have been defined above.
- an alkyl group may be substituted with alkylsulfanyl and the alkylsulfanyl may be optionally substituted with one to three of halo, cyano, alkoxy, hydroxyl, nitro, haloalkyl, and alkyl.
- the cycloalkyl portion of a (cycloalkyl)carbonylamino may be optionally substituted with one to three of halo, cyano, alkoxy, hydroxyl, nitro, haloalkyl, and alkyl.
- substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
- Specific substituents are described above in the definitions and below in the description of compounds and examples thereof.
- an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
- a ring substituent such as a heterocycloalkyl
- substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
- stable or chemically feasible refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
- a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
- bicyclic fused ring system or “bicyclic ring system” refers to two rings which share two atoms. Either ring may be saturated, partially unsaturated, or aromatic. Each ring also may contain 1 to 3 heteroatoms.
- tricyclic fused ring system or “tricyclic ring system” refers to a bicyclic ring system in which a third ring is fused to the bicyclic ring system such that the third ring shares at least two atoms with the bicyclic ring system. In some embodiments, all three rings share at least one common atom. Any of the rings in the tricyclic ring system may be saturated, partially unsaturated, or aromatic. Each of the rings may include 1 to 3 heteroatoms.
- aliphatic groups, alkyl groups, aryl groups, heterocyclic groups, carbocyclic groups, and bicyclic or tricyclic ring systems contain one or more substituents.
- the substituents are selected from those that will be stable under the reaction conditions of the present process, as would be generally known to those skilled in the art.
- substituents include halogen, -Q 1 , —OQ 1 , —OH, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NHQ 1 , —N(Q 1 ) 2 , —NHCOQ 1 , —NHCONHQ 1 , —NQ 1 CONHQ 1 , —NHCON(Q 1 ) 2 , —NQ 1 CON(Q 1 ) 2 , —NQ 1 COQ 1 , —NHCO 2 Q 1 , —NQ 1 CO 2 Q 1 , —CO 2 Q 1 , —COQ 1 , —CONHQ 1 , —CON(Q 1 ) 2 , —S(O) 2 Q 1 , —SONH 2 , —S(O)Q 1 , —SO 2 NHQ 1 , —SO 2 N(Q 1 ) 2 ,
- nitrogen atoms on a heterocyclic ring may be optionally substituted. Suitable substituents on the nitrogen atom include Q 2 , COQ 2 , S(O) 2 Q 2 , and CO 2 Q 2 , where Q 2 is an aliphatic group or a substituted aliphatic group.
- structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
- substantially pure refers to the stereochemical purity of a compound that is greater than 90%. In some embodiments, the stereochemical purity of a compound is greater than 95%. And in still others, the stereochemical purity of a compound is 99% or greater.
- selective crystallization means crystallization of a substantially pure isomer from a solvent containing a mixture of isomers.
- dynamic crystallization means crystallization of a substantially pure isomer from a solvent containing a mixture of isomers under conditions which cause isomerization of the mixture of isomers to an isomer which selectively crystallizes.
- isomerization of the more soluble enantiomer to the less soluble isomer results in crystallization of the less soluble isomer as the equilibrium between the isomers is driven by crystallization toward the less soluble enantiomer.
- a specific example of dynamic crystallization may include the epimerization of an anomeric carbon in a solvent under conditions which selectively crystallizes one substantially pure enantiomer.
- structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
- amine capping groups may be used in the methods of this invention.
- examples of amine capping groups or protecting groups include, but are not limited to, -Q 7 , —C(S)Q 7 , —C(O)OQ 7 , —SOQ 7 , —SO 2 Q 7 , —SO 3 Q 7 , —SO 2 N(Q 7 ) 2 , —C(O)C(O)Q 7 , —C(O)C(O)OQ 7 , —C(O)CH 2 C(O)Q 7 , —C(O)N(Q 7 ) 2 , —(CH 2 ) 0-2 NHC(O)Q 7 , —C( ⁇ NH)N(Q 7 ) 2 , —C(O)N(OQ 7 )Q 7 , —C( ⁇ NOQ 7 )Q 7 , —P(O)(Q 7 ) 2 , and —P(O)(Q 7 ) 2 , and
- Q 7 is C 1-12 aliphatic, C 3-10 cycloaliphatic, (C 3-10 cycloaliphatic)-C 1-12 aliphatic, C 6-10 aryl, (C 6-10 aryl)-(C 1-12 aliphatic)-, C 3-10 heterocyclyl, (C 6-10 heterocyclyl)-C 1-12 aliphatic, C 5-10 heteroaryl, or (C 5-10 heteroaryl)-(C 1-12 aliphatic)-.
- lewis acid refers to moiety capable of sharing or accepting an electron pair.
- lewis acids include, but are not limited to, BF 3 -etherates and metal halides, alkoxides, and mixed halide/alkoxides (e.g., Al(O-alkyl) 2 Cl, Al(O-alkyl)Cl 2 ).
- the metals can be aluminum, titanium, zirconium, magnesium, copper, zinc, iron, tin, boron, ytterbium, lanthanum, and samarium.
- EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
- HOBt is 1-hydroxybenzotriazole.
- HOSuc is N-hydroxysuccinimide.
- THF is tetrahydrofuran.
- TFA is trifluoroacetic acid.
- DCM is dichloromethane.
- DMAP is 4-dimethylaminopyridine.
- DIPEA is diisopropylethylamine.
- DMF is dimethylformamide.
- TFA is trifluoroacetic acid.
- CBZ is benzyloxycarbonyl. 1 H NMR is proton nuclear magnetic resonance.
- TLC is thin layer chromatography.
- TEMPO is 2,2,6,6-Tetramethylpiperidinyloxy free radical.
- this invention relates to processes for and intermediates used in the preparation of steric-specific compounds.
- R 3 is RW— or a P4-L3-P3-L2-P2-;
- R 4 is —NH—CR 1 R′ 1 —CH(OH)C(O)—NHR 2 ;
- Each W is independently a bond, —NR 4 , —O— or —S—;
- Each of P2, P3 and P4 is independently a bond, H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted alkoxy, an optionally substituted alkylsufanyl, an optionally substituted aralkoxy, an optionally substituted aralkylsulfanyl, an optionally substituted mono- or dialkylamino, an optionally substituted mono- or diarylamino or an optionally substituted mono- or diheteroarylamino, provided that when L2 is absent and P3 is H, that L3 and P4 are absent;
- P3 when P3 is not a terminal group, that P3 is bound to L2, if present, or P2, if L2 is absent, and P3 is also bound to L3, if present, or P4, if L3 is absent;
- Each L2 or L3 is independently a bond, —C(O)— or —SO 2 —;
- Each R 1 and R′ 1 is independently H, an optionally substituted aliphatic, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaliphatic or an optionally substituted heteroaralkyl, or each R 1 and R′ 1 together with the atom to which they are attached may form a 3 to 7 membered optionally substituted cycloaliphatic ring.
- R 3 is P2-, which is represented by the structure: wherein
- Each T is independently a bond, H, —C(O)—, —O—C(O)—, —NHC(O)—, —C(O)C(O)— or —SO 2 —;
- Each R is independently H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocyclic, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl or an optionally substituted heteroaryl; and
- Each R 5 and R 6 is independently H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl, an optionally substituted aralkyl or an optionally substituted heteroarylalkyl, or
- R 5 and the adjacent R 6 taken together with the atoms to which they are attached form a 5- to 7-membered, optionally substituted monocyclic heterocycle, or a 6- to 12-membered, optionally substituted bicyclic heterocycle, in which each heterocycle ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 4 —; and
- Each R 7 is independently H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted heteroaryl, or an optionally substituted phenyl.
- R 1 is P3-L2-P2 which is represented by the structure:
- R 3 is P4-L3-P3- L2-P2 which is represented by the structure: wherein
- Each T is independently a bond, H, —C(O)—, —O—C(O)—, —NHC(O)—, —C(O)C(O)— or —SO 2 —;
- Each R is independently H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocyclic, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl or an optionally substituted heteroaryl;
- Each R 5 , R 6 , R 7 and R 8 is independently H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl, an optionally substituted aralkyl or an optionally substituted heteroarylalkyl, or
- R 7 and the adjacent R 6 together with the atoms to which they are attached may form a 5 to 7 membered, optionally substituted monocyclic heterocycle, a 5 to 7 membered, optionally substituted monocyclic aryl, a 6 to 12 membered, optionally substituted bicyclic heterocycle, or a 6 to 12 membered, optionally substituted bicyclic aryl, in which each heterocycle or aryl ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 4 —;
- R 8 and the adjacent R 6 together with the atoms to which they are attached may form a 5 to 7 membered, optionally substituted monocyclic heterocycle, a 5 to 7 membered, optionally substituted monocyclic heteroaryl, a 6 to 12 membered, optionally substituted bicyclic heterocycle, or a 6 to 12 membered, optionally substituted bicyclic heteroaryl, in which each heterocycle or heteroaryl ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 4 —;
- R 8 and R together with the atoms to which they are attached may form a 5 to 7 membered, optionally substituted monocyclic heterocycle, a 5 to 7 membered, optionally substituted monocyclic aryl, a 6 to 12 membered, optionally substituted bicyclic heterocycle, or a 6 to 12 membered, optionally substituted bicyclic aryl, in which each heterocycle or aryl ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 4 —;
- R 7 and the ring system formed by R 5 and R 6 may form an 8- to 14-membered optionally substituted bicyclic fused ring system, wherein the bicyclic fused ring system is optionally further fused with an optionally substituted phenyl to form an optionally substituted 10- to 16-membered tricyclic fused ring system.
- HCV protease inhibitors of Formula 2 is the compound of Formula 3 shown below.
- the invention provides processes and intermediates for producing an x-hydroxy- ⁇ -amino acid derivative of Formula 1, which is useful in producing protease inhibitors:
- R 1 and R′ 1 are each independently H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic and R 2 is H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic and the amino-alcohol amide of Formula 1 has an enantiomeric excess (ee) of greater than 55% (for the definition of ee see, e.g., Jerry March, Advanced Organic Chemistry , John Wiley and Sons, Inc., 1992, p. 125).
- ee enantiomeric excess
- the invention provides a process and intermediates for preparing a compound of Formula 1 as outlined in Scheme 1.
- R 1 and R′ 1 are as previously described;
- R′ 2 is —NHR 2 or —OE wherein R 2 is as previously described and E is C 1 -C 5 alkyl or optionally substituted benzyl.
- the unsaturated compound i is converted the epoxide ii (step a) using known methods, e.g., oxidation with a peracid such as, for example, meta-chlorperbenzoic acid or peracetic acid (see, e.g., R. S. Porto, M. L. A. A. Vasconcellos, E. Ventura, F.
- urea-hydrogen peroxide also called urea hydroperoxide
- the epoxide ii may be obtained by using a glycidic ester condensation (see, e.g., M. Ballester, Chem. Revs. 55, 283-300 (1955); D. M. Burness, Organic Synthesis, Collective Volume 4, p. 649).
- the epoxidation may be performed to provide optically enriched epoxides (see, e.g., H. Kakei, R. Tsuji, T. Ohshima, M. Shibasaki, J. Am. Chem. Soc., 2005, 127, 8962-8963; M. Marigo, J. Franzen, T. B. Poulsen, W. Zhuang, K. A. Jorgensen, J. Am. Chem. Soc., 2005, 127, 6284-6289; M. Shibisaki, et. al., U.S. Pat. No. 6,833,442 (BINOL Ars complex); R. Kino, K. Daikai, T.
- the ester is subsequently converted to an amide. It is within the scope of the invention that formation of the amide can be performed at any stage of the process using known methods and protecting groups where appropriate.
- Suitable amination reagents are those which may be converted to the amino compound III.
- suitable amination reagents include azide, phthalimide and an optionally substituted benzyl amine.
- step c the mixture of amino alcohols of Formula iii is resolved to provide the optically active compound of Formula iv.
- Suitable methods for resolving the mixture iii include, for example, formation of a salt with a suitable optically active organic acid.
- Suitable optically active organic acids include, but are not limited to, tartaric acid, malic acid, di-isopropylidenegulonic acid and deoxycholic acid.
- R′ 2 of Formula i is —NHR 2
- the epoxidation of i is performed using tert-butyl hydroperoxide in the presence of a base such as, for example, sodium hydroxide or butyl lithium.
- the epoxidation is performed using potassium monopersulfate, ethylenediamine tetraacetic acid and an optionally optically active ketone.
- the amino-alcohol of Formula iii has a trans configuration.
- the compound of Formula iv has a 2-(S), 3(S) configuration.
- the amination of ii to give the amino alcohol iii is performed by reaction of ii with sodium azide followed by reduction of the intermediate azide with hydrogen in the presence of a palladium on carbon catalyst.
- the resolution of iii to iv is performed by forming a salt with an optically active acid and crystallizing the thus obtained salt.
- the optically active organic acid is tartaric acid.
- the optically active organic acid is deoxycholic acid.
- R 1 is C 1 -C 6 alkyl and R′ 1 is H.
- R 2 is C 1 -C 6 alkyl or C 1 -C 6 cycloalkyl.
- R 2 is cyclopropyl
- amino-hydroxy compounds of formula iii may be prepared according to methods described in U.S. Pat. Nos. 6,020,518, 6,087,530 and 6,639,094, each of which is incorporated herein in its entirety by reference.
- this invention provides a process and intermediates for preparing a compound of Formula 3.
- Removing the protecting group Z in the tripeptide of Formula 9 provides the free amino-tripeptide of Formula 10.
- the desired protease inhibitor may be derived by attaching the appropriate P 2 , P 2 —P 3 , or P 2 —P 3 —P 4 moiety.
- a coupling of an amine with such a moiety may be carried out using the corresponding carboxylic acid, or reactive equivalent thereof, under standard amide bond-forming or coupling conditions.
- a typical coupling reaction includes a suitable solvent, the amine in a concentration ranging from about 0.01 to 10 M, preferably about 0.1 to 1.0 M, the requisite carboxylic acid, a base and a peptide coupling reagent.
- the coupling may be carried out in situ in the solvent of the reaction mixture used in the preparation of the amine, or in a different solvent.
- the requisite carboxylic acid may be added and the reaction maintained at a temperature in the range of about 0 to 100° C., preferably between about 20 to about 40° C.
- the base and peptide coupling reagent are then added to the mixture, which is maintained at a temperature in the range of from about 0 to about 60° C., preferably between about 20 to about 40° C.
- the base is typically a tertiary amine base, such as triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN, N-methylimidazole, preferably triethylamine or diisopropylethylamine.
- the amount of base used is generally up to about 20 equivalents per equivalent of the amine, preferably at least about 3 equivalents of base.
- peptide coupling reagents examples include DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), di-p-toluoylcarbodiimide, BDP (1-benzotriazole diethylphosphate-1-cyclohexyl-3-(2-morpholinylethyl)carbodiimide), EDC (1-(3-dimethylaminopropyl-3-ethyl-carbodiimide hydrochloride), cyanuric fluoride, cyanuric chloride, TFFH (tetramethyl fluoroformamidinium hexafluorophosphosphate), DPPA (diphenylphosphorazidate), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), HBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl
- EDC, HOAT, BOP—Cl and PyBrOP are preferred peptide coupling reagents.
- the amount of peptide coupling reagent is in the range of about 1.0 to about 10.0 equivalents.
- Optional reagents that may be used in the amide bond-forming reaction include DMAP (4-dimethylaminopyridine) or active ester reagents, such as HOBT (1-hydroxybenzotriazole), HOAT (hydroxyazabenzotriazole), HOSu (hydroxysuccinimide), HONB (endo-N-hydroxy-5-norbornene-2,3-dicarboxamide), in amounts ranging from about 1.0 to about 10.0 equivalents.
- —C( ⁇ O)X 1 is a group that is more reactive than COOH in the coupling reaction.
- Acid and amine protecting groups as used herein are known in the art (see, e.g., T. W. Greene & P. G. M Wutz, Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, Inc. (1999) and the earlier editions of this book).
- P 3 —P 2 portion of the protease inhibitor.
- Examples of such P 3 —P 2 — groups are included in U.S. Application No. 60/709,964, which is also incorporated hereto by reference in its entirety.
- Example 1 A flask equipped with a stir bar, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with the acid of Example 1 (5.0 g, 38 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI; 8.1 g, 42 mmol), 1-hydroxybenzotriazole hydrate (HOBt; 5.7 g, 42 mmol) and N,N-dimethylformamide (DMF; 50 mL) then cooled to 0 ⁇ 5° C.
- the addition funnel was charged with NMM (5.9 mL, 54 mmol) which was then added to the reaction mixture maintaining the temperature at 0 ⁇ 5° C.
- the reaction mixture washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated.
- Sodium hydroxide 500 mL, 1.0 N was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated.
- Water 500 mL was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated.
- the combined organic phases were concentrated under reduced pressure to 1 ⁇ 3 original volume then IPAc (600 mL) was added; this was repeated two times when a white precipate formed.
- Example 4 (19.80 g, 130 mmol) in THF (20 mL) was added maintaining the temperature at 0 ⁇ 5° C. after which the temperature was increased to 25 ⁇ 5° C. and the reaction stirred for 12 hours.
- IPAc 200 mL
- saturated aqueous sodium hydrosulfite 200 mL
- the layers were separated and the aqueous layer extracted with IPAc (twice, 75 mL each).
- the combined organic phases were dried over sodium sulfate (Na 2 SO 4 ), filtered and concentrated under reduced pressure to provide the title compound (21.87 g, 99%).
- the reaction mixture was then again cooled to 0° C. and quenched by adding saturated NaHCO 3 (5 vol.) slowly and stirring for 30 minutes.
- the organic layer was separated, and the aqueous layer was extracted with CH 2 Cl 2 (50 mL, 5 vol).
- the combined organic layer was dried and evaporated to afford 10.0 g (90%) of the crude the product, N-cyclopropyl-3-propyloxirane-2-carboxamide, as a pale yellow oil.
- the crude product was used for the next step without further purification.
- Example 7 The azide of Example 7 (15.1 g, 71.3 mmol), Pd/C (1.5 g, 5 wt %, 50% wet) and MeOH (150 mL) was charged to a pressure vessel then purged with nitrogen gas for 5 min. The vessel was sealed, pressurized to 1 bar with nitrogen gas then released three times. The same was repeated with hydrogen gas. After the third purge with hydrogen the vessel was charged with 3 bar of hydrogen. Agitation was begun and a temperature of 25 ⁇ 5° C. was maintained. Reaction was stirred in this manner for 14 hours after which time the reaction mixture was filtered through a pad of Celite 545 and the solvent removed to provide crude amino-alcohol (8.48 g) as a yellow solid.
- the sultam shown above vi is prepared by known methods such as those described in Y. Elemes and U. Ragnarsson, J. of Chem. Soc., Perkin 1, 1996, 6, p. 537; W. Oppolzer, et. al., Helv. Chim. Acta., 1994, 25: 2363), by using the corresponding unsubstituted sultam and propyl iodide.
- Step b Preparation of (S)-2-(benzyloxycarbonylamino)-Pentanoic Acid (Compound viii Shown Above)
- Compound vii (15.39 g, 32.1 mmol) is combined with THF (100 mL) and 1N HCl (50 mL). The resulting emulsion is stirred overnight at the room temperature and then concentrated under reduced vacuum to provide a thick oil. The oil is dissolved in THF (100 mL), water (25 mL) and LiOH (3.08 g, 128 mmol) is added. The resultant solution is stirred overnight at the room temperature and then concentrated to remove the THF, resulting a hazy light yellow emulsion. The emulsion is diluted with water (25 mL) and extracted with CH 2 Cl 2 (3 ⁇ 50 mL).
- the aqueous phase is diluted with THF (200 mL) and then cooled to 0° C. while stirring rapidly and CBZ-Cl (7.6 mL, 54 mmol) is added dropwise over 15 minutes. After 1 hour at 0° C., the THF is removed in vacuo and the residue is acidified by addition of 50 mL of 1 N HCl. This is extracted with EtOAc (3 ⁇ 100 mL) and the organic phase is dried over Na 2 SO 4 and concentrated to provide an oil. The residue is dissolved in EtOAc (25 mL) and heptane (150 mL), seeded and stirred overnight at the room temperature.
- Step d Preparation of (S)-benzyl 1-(methoxy(methyl)amino)-1-oxo-2-pentan-2-ylcarbamate
- Step d the Cbz-protected amino acid of Step d is converted to the title compound. Specifically, into a flask containing 1.0 eq. of (S)-benzyl 1-(methoxy(methyl)amino)-1-oxo-2-pentan-2-ylcarbamate (810 mg, 2.75 mmol) in 10 mL of dry THF maintained at 0° C. (in an ice bath) is added slowly 1.7 eq. of a solution of lithium borohydride (1.0M) (4.67 mL). After about 10 minutes, the ice bath is removed and the reaction continue for an hour. The reaction solution is quenched at 0° C.
- Step f Preparation of benzyl (3S)-1-(cyclopropylamino)-2-hydroxy-1-oxo-hexan-3-ylcarbamate.
- Cyclopropyl isocyanide is prepared according to the scheme shown below.
- Step g Preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide
- Step h Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((35)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide
- the title compound is prepared from the hydroxy-amino amide product of Step g by condensation with the appropriate acid in the presence of a coupling reagent such as, e.g., EDCI and HOSu. Specifically, in a flask containing 1.2 eq. of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (1.59 g) in 20 mL of DMF, is added 2.5 eq.
- a coupling reagent such as, e.g., EDCI and HOSu.
- Step i Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N—((S)-1-(cyclopropylamino)-1,2-dioxo-hexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide
- the title compound is prepared by oxidation of the product of Step h with a suitable oxidizing reagent such as Dess-Martin periodinane or TEMPO and sodium hypochlorite.
- a suitable oxidizing reagent such as Dess-Martin periodinane or TEMPO and sodium hypochlorite.
- a suitable oxidizing reagent such as Dess-Martin periodinane or TEMPO and sodium hypochlorite.
- the stirring is stopped and the organic layer is separated and the aqueous layer is extracted with EtOAc (3 vol ⁇ 3).
- the organic layers are combined and concentrated in vacuo until the total volume becomes 3 vol.
- the resulting solution was extracted with 1 N NaOH (3 vol ⁇ 3) and the remaining organic layer was discarded.
- the combined aqueous solution was acidified with 6 N HCl until the pH became 1.0.
- the solution is extracted with CH 2 Cl 2 (3 vol ⁇ 5).
- the combined organic layer are dried over MgSO 4 and concentrated to get the product (i.e., compound 4).
- the reaction mixture is washed with 1 N NaOH (3 vol ⁇ 2), 1N HCl (3 vol ⁇ 2), and brine solution (3 vol), and water (3 vol).
- the organic layer is dried over MgSO 4 and concentrated to afford the crude product as oil.
- the crude product is dissolved with heptane (5 vol) and cooled to ⁇ 78° C. with stirring.
- the precipitated solid is filtered and dried to give the product (i.e., compound 5).
- reaction mixture is filtered through a pad of Celite® to afford a clear solution.
- the product is isolated by concentrating the solution at 20 ⁇ 5° C. until 3 vol of the solution remains. The solid is collected by filtration, washed (IPAC, 3 vol), and dried to give the product (i.e., compound 8).
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US11/724,002 US20070244334A1 (en) | 2006-03-16 | 2007-03-14 | Processes and intermediates for preparing steric compounds |
US12/806,014 US8383858B2 (en) | 2006-03-16 | 2010-08-04 | Processes and intermediates for preparing steric compounds |
US13/740,707 US20130131359A1 (en) | 2006-03-16 | 2013-01-14 | Processes and intermediates for preparing steric compounds |
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US13/740,707 Abandoned US20130131359A1 (en) | 2006-03-16 | 2013-01-14 | Processes and intermediates for preparing steric compounds |
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JP (1) | JP5313124B2 (ru) |
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CA (1) | CA2646123A1 (ru) |
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US7964624B1 (en) | 2005-08-26 | 2011-06-21 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
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US8039475B2 (en) | 2006-02-27 | 2011-10-18 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
US8217048B2 (en) | 2003-09-05 | 2012-07-10 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
US8314141B2 (en) | 1996-10-18 | 2012-11-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease |
US8492546B2 (en) | 2007-08-30 | 2013-07-23 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
US8575208B2 (en) | 2007-02-27 | 2013-11-05 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
US8759353B2 (en) | 2007-02-27 | 2014-06-24 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
US8871904B2 (en) | 2005-08-19 | 2014-10-28 | Vertex Pharmaceuticals Incorporated | Processes and intermediates |
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- 2007-03-14 US US11/724,002 patent/US20070244334A1/en not_active Abandoned
- 2007-03-14 JP JP2009500435A patent/JP5313124B2/ja not_active Expired - Fee Related
- 2007-03-14 EP EP11172239A patent/EP2407448A3/en not_active Withdrawn
- 2007-03-14 AU AU2007227580A patent/AU2007227580A1/en not_active Abandoned
- 2007-03-14 EP EP10177438A patent/EP2295401A3/en not_active Withdrawn
- 2007-03-14 MX MX2008011869A patent/MX2008011869A/es active IP Right Grant
- 2007-03-14 WO PCT/US2007/006320 patent/WO2007109023A1/en active Application Filing
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- 2007-03-14 BR BRPI0709568-6A patent/BRPI0709568A2/pt not_active IP Right Cessation
- 2007-03-14 SG SG201101886-8A patent/SG170729A1/en unknown
- 2007-03-14 EP EP07752981A patent/EP1993993A1/en not_active Withdrawn
- 2007-03-16 TW TW96109169A patent/TWI466851B/zh not_active IP Right Cessation
- 2007-03-16 AR ARP070101077A patent/AR059916A1/es unknown
- 2007-03-16 TW TW102145986A patent/TW201416341A/zh unknown
-
2009
- 2009-11-18 HK HK09110787.7A patent/HK1132988A1/xx not_active IP Right Cessation
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2010
- 2010-08-04 US US12/806,014 patent/US8383858B2/en not_active Expired - Fee Related
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2013
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Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
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US8314141B2 (en) | 1996-10-18 | 2012-11-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease |
US7820671B2 (en) | 2000-08-31 | 2010-10-26 | Vertex Pharmaceuticals Incorporated | Peptidomimetic protease inhibitors |
US8529882B2 (en) | 2000-08-31 | 2013-09-10 | Vertex Pharmaceuticals Incorporated | Peptidomimetic protease inhibitors |
US8252923B2 (en) | 2000-08-31 | 2012-08-28 | Vertex Pharmaceuticals Incorporated | Peptidomimetic protease inhibitors |
US20050197299A1 (en) * | 2000-08-31 | 2005-09-08 | Babine Robert E. | Peptidomimetic protease inhibitors |
US8217048B2 (en) | 2003-09-05 | 2012-07-10 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
US8871904B2 (en) | 2005-08-19 | 2014-10-28 | Vertex Pharmaceuticals Incorporated | Processes and intermediates |
US8372873B2 (en) | 2005-08-26 | 2013-02-12 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
US7964624B1 (en) | 2005-08-26 | 2011-06-21 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
US7985762B2 (en) | 2005-08-26 | 2011-07-26 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
US8440706B2 (en) | 2005-08-26 | 2013-05-14 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
US8372846B2 (en) | 2006-02-27 | 2013-02-12 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
US8039475B2 (en) | 2006-02-27 | 2011-10-18 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
US8247532B2 (en) | 2006-03-16 | 2012-08-21 | Vertex Pharmaceuticals Incorporated | Deuterated hepatitis C protease inhibitors |
US20070225297A1 (en) * | 2006-03-16 | 2007-09-27 | Perni Robert B | Deuterated hepatitis C protease inhibitors |
US8575208B2 (en) | 2007-02-27 | 2013-11-05 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
US8759353B2 (en) | 2007-02-27 | 2014-06-24 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
US8492546B2 (en) | 2007-08-30 | 2013-07-23 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
CN110577506A (zh) * | 2018-06-07 | 2019-12-17 | 中国科学院上海有机化学研究所 | (﹣)-三尖杉碱的酯类衍生物的合成方法及其中间体 |
CN110577506B (zh) * | 2018-06-07 | 2023-04-07 | 中国科学院上海有机化学研究所 | (﹣)-三尖杉碱的酯类衍生物的合成方法及其中间体 |
Also Published As
Publication number | Publication date |
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EP2407448A2 (en) | 2012-01-18 |
RU2013105768A (ru) | 2014-08-20 |
US8383858B2 (en) | 2013-02-26 |
CA2646123A1 (en) | 2007-09-27 |
NZ571281A (en) | 2011-11-25 |
HK1132988A1 (en) | 2010-03-12 |
EP2407448A3 (en) | 2012-07-25 |
EP1993993A1 (en) | 2008-11-26 |
AR059916A1 (es) | 2008-05-07 |
RU2008140942A (ru) | 2010-04-27 |
SG170729A1 (en) | 2011-05-30 |
TW200812941A (en) | 2008-03-16 |
EP2295401A2 (en) | 2011-03-16 |
WO2007109023A1 (en) | 2007-09-27 |
KR101398259B1 (ko) | 2014-05-26 |
JP5313124B2 (ja) | 2013-10-09 |
AU2007227580A1 (en) | 2007-09-27 |
US20130131359A1 (en) | 2013-05-23 |
JP2009530282A (ja) | 2009-08-27 |
US20100298568A1 (en) | 2010-11-25 |
BRPI0709568A2 (pt) | 2011-07-12 |
MX2008011869A (es) | 2008-12-03 |
TWI466851B (zh) | 2015-01-01 |
TW201416341A (zh) | 2014-05-01 |
KR20080109028A (ko) | 2008-12-16 |
EP2295401A3 (en) | 2012-07-25 |
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