Dabrafenib
Katalognummer B601069
Molekulargewicht: 519.6 g/mol
InChI-Schlüssel: BFSMGDJOXZAERB-UHFFFAOYSA-N
Achtung: Nur für Forschungszwecke. Nicht für den menschlichen oder tierärztlichen Gebrauch.
Patent
US08642759B2
Procedure details
In 1 gal pressure reactor, a mixture of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (120 g) prepared in accordance with Step C, above, and ammonium hydroxide (28-30%, 2.4 L, 20 vol) was heated in the sealed pressure reactor to 98-103° C. and stirred at this temperature for 2 hours. The reaction was cooled slowly to room temperature (20° C.) and stirred overnight. The solids were filtered and washed with minimum amount of the mother liquor and dried under vacuum. The solids were added to a mixture of EtOAc (15 vol)/water (2 vol) and heated to complete dissolution at 60-70° C. and the aqueous layer was removed and discarded. The EtOAC layer was charged with water (1 vol) and neutralized with aq. HCl to ˜pH 5.4-5.5. and added water (1 vol). The aqueous layer was removed and discarded at 60-70° C. The organic layer was washed with water (1 vol) at 60-70° C. and the aqueous layer was removed and discarded. The organic layer was filtered at 60° C. and concentrated to 3 volumes. EtOAc (6 vol) was charged into the mixture and heated and stirred at 72° C. for 10 min, then cooled to 20° C. and stirred overnight. EtOAc was removed via vacuum distillation to concentrate the reaction mixture to ˜3 volumes. The reaction mixture was maintained at ˜65-70° C. for ˜30 mins. Product crystals having the same crystal form as those prepared in Example 58b (and preparable by the procedure of Example 58b), above, in heptanes slurry were charged. Heptane (9 vol) was slowly added at 65-70° C. The slurry was stirred at 65-70° C. for 2-3 hours and then cooled slowly to 0-5° C. The product was filtered, washed with EtOAc/heptane (3/1 v/v, 4 vol) and dried at 45° C. under vacuum to obtain N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (102.3 g, 88%).
Quantity
120 g
Type
reactant
Reaction Step One
Identifiers
|
REACTION_CXSMILES
|
Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>CCCCCCC>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1 |f:1.2|
|
Inputs
Step One
|
Name
|
|
|
Quantity
|
120 g
|
|
Type
|
reactant
|
|
Smiles
|
ClC1=NC=CC(=N1)C1=C(N=C(S1)C(C)(C)C)C=1C(=C(C=CC1)NS(=O)(=O)C1=C(C=CC=C1F)F)F
|
Step Two
|
Name
|
|
|
Quantity
|
2.4 L
|
|
Type
|
reactant
|
|
Smiles
|
[OH-].[NH4+]
|
Step Three
|
Name
|
|
|
Quantity
|
0 (± 1) mol
|
|
Type
|
solvent
|
|
Smiles
|
CCCCCCC
|
Conditions
Temperature
|
Control Type
|
AMBIENT
|
|
Setpoint
|
20 °C
|
Stirring
|
Type
|
CUSTOM
|
|
Details
|
stirred at this temperature for 2 hours
|
|
Rate
|
UNSPECIFIED
|
|
RPM
|
0
|
Other
|
Conditions are dynamic
|
1
|
|
Details
|
See reaction.notes.procedure_details.
|
Workups
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
prepared in accordance with Step C
|
STIRRING
|
Type
|
STIRRING
|
|
Details
|
stirred overnight
|
|
Duration
|
8 (± 8) h
|
FILTRATION
|
Type
|
FILTRATION
|
|
Details
|
The solids were filtered
|
WASH
|
Type
|
WASH
|
|
Details
|
washed with minimum amount of the mother liquor
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
dried under vacuum
|
ADDITION
|
Type
|
ADDITION
|
|
Details
|
The solids were added to a mixture of EtOAc (15 vol)/water (2 vol)
|
TEMPERATURE
|
Type
|
TEMPERATURE
|
|
Details
|
heated
|
DISSOLUTION
|
Type
|
DISSOLUTION
|
|
Details
|
dissolution at 60-70° C.
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
the aqueous layer was removed
|
ADDITION
|
Type
|
ADDITION
|
|
Details
|
The EtOAC layer was charged with water (1 vol)
|
ADDITION
|
Type
|
ADDITION
|
|
Details
|
and added water (1 vol)
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
The aqueous layer was removed
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
discarded at 60-70° C
|
WASH
|
Type
|
WASH
|
|
Details
|
The organic layer was washed with water (1 vol) at 60-70° C.
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
the aqueous layer was removed
|
FILTRATION
|
Type
|
FILTRATION
|
|
Details
|
The organic layer was filtered at 60° C.
|
CONCENTRATION
|
Type
|
CONCENTRATION
|
|
Details
|
concentrated to 3 volumes
|
ADDITION
|
Type
|
ADDITION
|
|
Details
|
EtOAc (6 vol) was charged into the mixture
|
TEMPERATURE
|
Type
|
TEMPERATURE
|
|
Details
|
heated
|
STIRRING
|
Type
|
STIRRING
|
|
Details
|
stirred at 72° C. for 10 min
|
|
Duration
|
10 min
|
TEMPERATURE
|
Type
|
TEMPERATURE
|
|
Details
|
cooled to 20° C.
|
STIRRING
|
Type
|
STIRRING
|
|
Details
|
stirred overnight
|
|
Duration
|
8 (± 8) h
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
EtOAc was removed via vacuum distillation
|
CONCENTRATION
|
Type
|
CONCENTRATION
|
|
Details
|
to concentrate the reaction mixture to ˜3 volumes
|
TEMPERATURE
|
Type
|
TEMPERATURE
|
|
Details
|
The reaction mixture was maintained at ˜65-70° C. for ˜30 mins
|
|
Duration
|
30 min
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
those prepared in Example 58b (and preparable by the procedure of Example 58b), above, in heptanes slurry
|
ADDITION
|
Type
|
ADDITION
|
|
Details
|
were charged
|
STIRRING
|
Type
|
STIRRING
|
|
Details
|
The slurry was stirred at 65-70° C. for 2-3 hours
|
|
Duration
|
2.5 (± 0.5) h
|
TEMPERATURE
|
Type
|
TEMPERATURE
|
|
Details
|
cooled slowly to 0-5° C
|
FILTRATION
|
Type
|
FILTRATION
|
|
Details
|
The product was filtered
|
WASH
|
Type
|
WASH
|
|
Details
|
washed with EtOAc/heptane (3/1 v/v, 4 vol)
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
dried at 45° C. under vacuum
|
Outcomes
Product
Details
Reaction Time |
2 h |
|
Name
|
|
|
Type
|
product
|
|
Smiles
|
NC1=NC=CC(=N1)C1=C(N=C(S1)C(C)(C)C)C=1C(=C(C=CC1)NS(=O)(=O)C1=C(C=CC=C1F)F)F
|
Measurements
| Type | Value | Analysis |
|---|---|---|
| AMOUNT: MASS | 102.3 g | |
| YIELD: PERCENTYIELD | 88% |
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. |
