Ledipasvir
货号 B612246
分子量: 889.0 g/mol
InChI 键: VRTWBAAJJOHBQU-KMWAZVGDSA-N
注意: 仅供研究使用。不适用于人类或兽医用途。
Patent
US08088368B2
Procedure details
3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (115 mg, 0.138 mmol) was dissolved in DCM (2 mL) and HCl in dioxane (4M, 2 mL) was added and stirring at room temperature was continued. After 20 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and DIEA (53.4 mg, 0.414 mmol) was added. A solution of 2-(L) Methoxycarbonylamino-3-methyl-butyric acid (24.2 mg, 0.138 mmol), HATU (52.4 mg, 0.138 mmol) and DIEA (17.8 mg, 0.138 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA) to yield the product (1-{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (76 mg). LCMS-ESI+: calc'd for C49H54F2N8O6: 888.9 (M+). Found: 890.0 (M+H+).
Identifiers
|
REACTION_CXSMILES
|
C([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:35]=[CH:34][C:33]5[C:32]6[C:27](=[CH:28][C:29]([C:36]7[NH:37][C:38]([CH:41]8[CH2:47][C:44]9([CH2:46][CH2:45]9)[CH2:43][N:42]8[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])=[N:39][CH:40]=7)=[CH:30][CH:31]=6)[C:26]([F:60])([F:59])[C:25]=5[CH:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH:12]2[CH2:61][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[CH3:72][O:73][C:74]([NH:76][CH:77]([CH:81]([CH3:83])[CH3:82])C(O)=O)=[O:75].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.CN(C=O)C.CCOC(C)=O>[CH3:72][O:73][C:74](=[O:75])[NH:76][CH:77]([C:6]([N:8]1[CH:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:35]=[CH:34][C:33]5[C:32]6[C:27](=[CH:28][C:29]([C:36]7[NH:37][C:38]([CH:41]8[CH2:47][C:44]9([CH2:45][CH2:46]9)[CH2:43][N:42]8[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:51])[CH3:52])=[N:39][CH:40]=7)=[CH:30][CH:31]=6)[C:26]([F:59])([F:60])[C:25]=5[CH:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH:12]2[CH2:61][CH:9]1[CH2:10][CH2:11]2)=[O:5])[CH:81]([CH3:83])[CH3:82] |f:4.5|
|
Inputs
Step One
|
Name
|
|
|
Quantity
|
0 (± 1) mol
|
|
Type
|
solvent
|
|
Smiles
|
CCOC(=O)C
|
Step Two
|
Name
|
|
|
Quantity
|
115 mg
|
|
Type
|
reactant
|
|
Smiles
|
C(C)(C)(C)OC(=O)N1C2CCC(C1C1=NC3=C(N1)C=C(C=C3)C3=CC=1C(C4=CC(=CC=C4C1C=C3)C=3NC(=NC3)C3N(CC1(CC1)C3)C(C(C(C)C)NC(=O)OC)=O)(F)F)C2
|
|
Name
|
|
|
Quantity
|
2 mL
|
|
Type
|
solvent
|
|
Smiles
|
C(Cl)Cl
|
Step Three
Step Four
|
Name
|
|
|
Quantity
|
53.4 mg
|
|
Type
|
reactant
|
|
Smiles
|
CCN(C(C)C)C(C)C
|
Step Five
|
Name
|
|
|
Quantity
|
24.2 mg
|
|
Type
|
reactant
|
|
Smiles
|
COC(=O)NC(C(=O)O)C(C)C
|
|
Name
|
|
|
Quantity
|
52.4 mg
|
|
Type
|
reactant
|
|
Smiles
|
CN(C)C(=[N+](C)C)ON1C2=C(C=CC=N2)N=N1.F[P-](F)(F)(F)(F)F
|
|
Name
|
|
|
Quantity
|
17.8 mg
|
|
Type
|
reactant
|
|
Smiles
|
CCN(C(C)C)C(C)C
|
|
Name
|
|
|
Quantity
|
1 mL
|
|
Type
|
solvent
|
|
Smiles
|
CN(C)C=O
|
Conditions
Temperature
|
Control Type
|
AMBIENT
|
Stirring
|
Type
|
CUSTOM
|
|
Details
|
stirring at room temperature
|
|
Rate
|
UNSPECIFIED
|
|
RPM
|
0
|
Other
|
Conditions are dynamic
|
1
|
|
Details
|
See reaction.notes.procedure_details.
|
Workups
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
all volatiles were removed in vacuo
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
The crude material was used in the next step without further purification
|
DISSOLUTION
|
Type
|
DISSOLUTION
|
|
Details
|
The crude material was dissolved in DMF (1.5 mL)
|
STIRRING
|
Type
|
STIRRING
|
|
Details
|
The reaction was stirred at room temperature
|
WAIT
|
Type
|
WAIT
|
|
Details
|
After 20 minutes
|
|
Duration
|
20 min
|
WASH
|
Type
|
WASH
|
|
Details
|
was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine
|
DRY_WITH_MATERIAL
|
Type
|
DRY_WITH_MATERIAL
|
|
Details
|
was dried over sodium sulfate
|
FILTRATION
|
Type
|
FILTRATION
|
|
Details
|
Filtration and removal of solvents in vacuo
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
gave the crude material, which
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA)
|
Outcomes
Product
Details
Reaction Time |
20 min |
|
Name
|
|
|
Type
|
product
|
|
Smiles
|
COC(NC(C(C)C)C(=O)N1C2CCC(C1C1=NC3=C(N1)C=C(C=C3)C3=CC=1C(C4=CC(=CC=C4C1C=C3)C=3NC(=NC3)C3N(CC1(CC1)C3)C(C(C(C)C)NC(=O)OC)=O)(F)F)C2)=O
|
Measurements
| Type | Value | Analysis |
|---|---|---|
| AMOUNT: MASS | 76 mg | |
| YIELD: CALCULATEDPERCENTYIELD | 61.9% |
Source
|
Source
|
Open Reaction Database (ORD) |
|
Description
|
The Open Reaction Database (ORD) is an open-access schema and infrastructure for structuring and sharing organic reaction data, including a centralized data repository. The ORD schema supports conventional and emerging technologies, from benchtop reactions to automated high-throughput experiments and flow chemistry. Our vision is that a consistent data representation and infrastructure to support data sharing will enable downstream applications that will greatly improve the state of the art with respect to computer-aided synthesis planning, reaction prediction, and other predictive chemistry tasks. |
Patent
US08088368B2
Procedure details
3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (115 mg, 0.138 mmol) was dissolved in DCM (2 mL) and HCl in dioxane (4M, 2 mL) was added and stirring at room temperature was continued. After 20 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and DIEA (53.4 mg, 0.414 mmol) was added. A solution of 2-(L) Methoxycarbonylamino-3-methyl-butyric acid (24.2 mg, 0.138 mmol), HATU (52.4 mg, 0.138 mmol) and DIEA (17.8 mg, 0.138 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA) to yield the product (1-{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (76 mg). LCMS-ESI+: calc'd for C49H54F2N8O6: 888.9 (M+). Found: 890.0 (M+H+).
Identifiers
|
REACTION_CXSMILES
|
C([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:35]=[CH:34][C:33]5[C:32]6[C:27](=[CH:28][C:29]([C:36]7[NH:37][C:38]([CH:41]8[CH2:47][C:44]9([CH2:46][CH2:45]9)[CH2:43][N:42]8[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])=[N:39][CH:40]=7)=[CH:30][CH:31]=6)[C:26]([F:60])([F:59])[C:25]=5[CH:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH:12]2[CH2:61][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[CH3:72][O:73][C:74]([NH:76][CH:77]([CH:81]([CH3:83])[CH3:82])C(O)=O)=[O:75].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.CN(C=O)C.CCOC(C)=O>[CH3:72][O:73][C:74](=[O:75])[NH:76][CH:77]([C:6]([N:8]1[CH:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:35]=[CH:34][C:33]5[C:32]6[C:27](=[CH:28][C:29]([C:36]7[NH:37][C:38]([CH:41]8[CH2:47][C:44]9([CH2:45][CH2:46]9)[CH2:43][N:42]8[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:51])[CH3:52])=[N:39][CH:40]=7)=[CH:30][CH:31]=6)[C:26]([F:59])([F:60])[C:25]=5[CH:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH:12]2[CH2:61][CH:9]1[CH2:10][CH2:11]2)=[O:5])[CH:81]([CH3:83])[CH3:82] |f:4.5|
|
Inputs
Step One
|
Name
|
|
|
Quantity
|
0 (± 1) mol
|
|
Type
|
solvent
|
|
Smiles
|
CCOC(=O)C
|
Step Two
|
Name
|
|
|
Quantity
|
115 mg
|
|
Type
|
reactant
|
|
Smiles
|
C(C)(C)(C)OC(=O)N1C2CCC(C1C1=NC3=C(N1)C=C(C=C3)C3=CC=1C(C4=CC(=CC=C4C1C=C3)C=3NC(=NC3)C3N(CC1(CC1)C3)C(C(C(C)C)NC(=O)OC)=O)(F)F)C2
|
|
Name
|
|
|
Quantity
|
2 mL
|
|
Type
|
solvent
|
|
Smiles
|
C(Cl)Cl
|
Step Three
Step Four
|
Name
|
|
|
Quantity
|
53.4 mg
|
|
Type
|
reactant
|
|
Smiles
|
CCN(C(C)C)C(C)C
|
Step Five
|
Name
|
|
|
Quantity
|
24.2 mg
|
|
Type
|
reactant
|
|
Smiles
|
COC(=O)NC(C(=O)O)C(C)C
|
|
Name
|
|
|
Quantity
|
52.4 mg
|
|
Type
|
reactant
|
|
Smiles
|
CN(C)C(=[N+](C)C)ON1C2=C(C=CC=N2)N=N1.F[P-](F)(F)(F)(F)F
|
|
Name
|
|
|
Quantity
|
17.8 mg
|
|
Type
|
reactant
|
|
Smiles
|
CCN(C(C)C)C(C)C
|
|
Name
|
|
|
Quantity
|
1 mL
|
|
Type
|
solvent
|
|
Smiles
|
CN(C)C=O
|
Conditions
Temperature
|
Control Type
|
AMBIENT
|
Stirring
|
Type
|
CUSTOM
|
|
Details
|
stirring at room temperature
|
|
Rate
|
UNSPECIFIED
|
|
RPM
|
0
|
Other
|
Conditions are dynamic
|
1
|
|
Details
|
See reaction.notes.procedure_details.
|
Workups
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
all volatiles were removed in vacuo
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
The crude material was used in the next step without further purification
|
DISSOLUTION
|
Type
|
DISSOLUTION
|
|
Details
|
The crude material was dissolved in DMF (1.5 mL)
|
STIRRING
|
Type
|
STIRRING
|
|
Details
|
The reaction was stirred at room temperature
|
WAIT
|
Type
|
WAIT
|
|
Details
|
After 20 minutes
|
|
Duration
|
20 min
|
WASH
|
Type
|
WASH
|
|
Details
|
was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine
|
DRY_WITH_MATERIAL
|
Type
|
DRY_WITH_MATERIAL
|
|
Details
|
was dried over sodium sulfate
|
FILTRATION
|
Type
|
FILTRATION
|
|
Details
|
Filtration and removal of solvents in vacuo
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
gave the crude material, which
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA)
|
Outcomes
Product
Details
Reaction Time |
20 min |
|
Name
|
|
|
Type
|
product
|
|
Smiles
|
COC(NC(C(C)C)C(=O)N1C2CCC(C1C1=NC3=C(N1)C=C(C=C3)C3=CC=1C(C4=CC(=CC=C4C1C=C3)C=3NC(=NC3)C3N(CC1(CC1)C3)C(C(C(C)C)NC(=O)OC)=O)(F)F)C2)=O
|
Measurements
| Type | Value | Analysis |
|---|---|---|
| AMOUNT: MASS | 76 mg | |
| YIELD: CALCULATEDPERCENTYIELD | 61.9% |
Source
|
Source
|
Open Reaction Database (ORD) |
|
Description
|
The Open Reaction Database (ORD) is an open-access schema and infrastructure for structuring and sharing organic reaction data, including a centralized data repository. The ORD schema supports conventional and emerging technologies, from benchtop reactions to automated high-throughput experiments and flow chemistry. Our vision is that a consistent data representation and infrastructure to support data sharing will enable downstream applications that will greatly improve the state of the art with respect to computer-aided synthesis planning, reaction prediction, and other predictive chemistry tasks. |
