Osimertinib D6
Cat. No. B2766964
M. Wt: 505.656
InChI Key: DUYJMQONPNNFPI-XERRXZQWSA-N
Attention: For research use only. Not for human or veterinary use.
Patent
US08946235B2
Procedure details
To a stirred solution of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 10 g, 21.32 mmol) in THF (95 mL) and water (9.5 mL) at 0° C. was added the 3-chloropropanoyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at r.t. for 15 minutes then NaOH (3.48 g, 85.28 mmol) was added. The resulting mixture was heated to 65° C. for 10 h. The mixture was then cooled to r.t. and CH3OH (40 mL) and water (70 mL) were added. The resulting mixture was stirred overnight. The resulting solid was collected by filtration, washed with water (25 mL) and dried at 50° C. for 12 h to give the title compound (7.0 g, 94%) as a solid form identified herein as polymorphic Form D. 1H NMR: 2.69 (3H, s) 2.83 (6H, d) 3.35 (4H, s) 3.84 (3H, s) 3.91 (3H, s) 5.75 (1H, d) 6.28 (1H, d) 6.67 (1H, dd) 7.05-7.23 (2H, m) 7.29 (1H, t) 7.43 (1H, d) 7.56 (1H, d) 8.21 (2H, s) 8.81 (1H, s) 9.47 (1H, s) 9.52 (1H, s) ES+ MH+ 500.26.
Quantity
10 g
Type
reactant
Reaction Step One
Name
Yield
94%
Identifiers
|
REACTION_CXSMILES
|
[CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][N:5]([CH3:32])[C:6]1[C:7]([NH2:31])=[CH:8][C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[C:10]([O:12][CH3:13])[CH:11]=1.Cl[CH2:35][CH2:36][C:37](Cl)=[O:38].[OH-].[Na+].CO>C1COCC1.O>[CH3:33][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:32])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[CH:8][C:7]=1[NH:31][C:37](=[O:38])[CH:36]=[CH2:35] |f:2.3|
|
Inputs
Step One
|
Name
|
|
|
Quantity
|
10 g
|
|
Type
|
reactant
|
|
Smiles
|
CN(CCN(C=1C(=CC(=C(C1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)N)C)C
|
|
Name
|
|
|
Quantity
|
0 (± 1) mol
|
|
Type
|
reactant
|
|
Smiles
|
CN(CCN(C=1C(=CC(=C(C1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)N)C)C
|
|
Name
|
|
|
Quantity
|
3.28 g
|
|
Type
|
reactant
|
|
Smiles
|
ClCCC(=O)Cl
|
|
Name
|
|
|
Quantity
|
95 mL
|
|
Type
|
solvent
|
|
Smiles
|
C1CCOC1
|
|
Name
|
|
|
Quantity
|
9.5 mL
|
|
Type
|
solvent
|
|
Smiles
|
O
|
Step Two
|
Name
|
|
|
Quantity
|
3.48 g
|
|
Type
|
reactant
|
|
Smiles
|
[OH-].[Na+]
|
Conditions
Temperature
|
Control Type
|
AMBIENT
|
Stirring
|
Type
|
CUSTOM
|
|
Details
|
The mixture was stirred at r.t. for 15 minutes
|
|
Rate
|
UNSPECIFIED
|
|
RPM
|
0
|
Other
|
Conditions are dynamic
|
1
|
|
Details
|
See reaction.notes.procedure_details.
|
Workups
TEMPERATURE
|
Type
|
TEMPERATURE
|
|
Details
|
The resulting mixture was heated to 65° C. for 10 h
|
|
Duration
|
10 h
|
TEMPERATURE
|
Type
|
TEMPERATURE
|
|
Details
|
The mixture was then cooled to r.t.
|
STIRRING
|
Type
|
STIRRING
|
|
Details
|
The resulting mixture was stirred overnight
|
|
Duration
|
8 (± 8) h
|
FILTRATION
|
Type
|
FILTRATION
|
|
Details
|
The resulting solid was collected by filtration
|
WASH
|
Type
|
WASH
|
|
Details
|
washed with water (25 mL)
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
dried at 50° C. for 12 h
|
|
Duration
|
12 h
|
Outcomes
Product
Details
Reaction Time |
15 min |
|
Name
|
|
|
Type
|
product
|
|
Smiles
|
CN(CCN(C1=C(C=C(C(=C1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)NC(C=C)=O)C)C
|
Measurements
| Type | Value | Analysis |
|---|---|---|
| AMOUNT: MASS | 7 g | |
| YIELD: PERCENTYIELD | 94% | |
| YIELD: CALCULATEDPERCENTYIELD | 65.7% |
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
US08946235B2
Procedure details
To a stirred solution of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 10 g, 21.32 mmol) in THF (95 mL) and water (9.5 mL) at 0° C. was added the 3-chloropropanoyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at r.t. for 15 minutes then NaOH (3.48 g, 85.28 mmol) was added. The resulting mixture was heated to 65° C. for 10 h. The mixture was then cooled to r.t. and CH3OH (40 mL) and water (70 mL) were added. The resulting mixture was stirred overnight. The resulting solid was collected by filtration, washed with water (25 mL) and dried at 50° C. for 12 h to give the title compound (7.0 g, 94%) as a solid form identified herein as polymorphic Form D. 1H NMR: 2.69 (3H, s) 2.83 (6H, d) 3.35 (4H, s) 3.84 (3H, s) 3.91 (3H, s) 5.75 (1H, d) 6.28 (1H, d) 6.67 (1H, dd) 7.05-7.23 (2H, m) 7.29 (1H, t) 7.43 (1H, d) 7.56 (1H, d) 8.21 (2H, s) 8.81 (1H, s) 9.47 (1H, s) 9.52 (1H, s) ES+ MH+ 500.26.
Quantity
10 g
Type
reactant
Reaction Step One
Name
Yield
94%
Identifiers
|
REACTION_CXSMILES
|
[CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][N:5]([CH3:32])[C:6]1[C:7]([NH2:31])=[CH:8][C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[C:10]([O:12][CH3:13])[CH:11]=1.Cl[CH2:35][CH2:36][C:37](Cl)=[O:38].[OH-].[Na+].CO>C1COCC1.O>[CH3:33][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:32])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[CH:8][C:7]=1[NH:31][C:37](=[O:38])[CH:36]=[CH2:35] |f:2.3|
|
Inputs
Step One
|
Name
|
|
|
Quantity
|
10 g
|
|
Type
|
reactant
|
|
Smiles
|
CN(CCN(C=1C(=CC(=C(C1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)N)C)C
|
|
Name
|
|
|
Quantity
|
0 (± 1) mol
|
|
Type
|
reactant
|
|
Smiles
|
CN(CCN(C=1C(=CC(=C(C1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)N)C)C
|
|
Name
|
|
|
Quantity
|
3.28 g
|
|
Type
|
reactant
|
|
Smiles
|
ClCCC(=O)Cl
|
|
Name
|
|
|
Quantity
|
95 mL
|
|
Type
|
solvent
|
|
Smiles
|
C1CCOC1
|
|
Name
|
|
|
Quantity
|
9.5 mL
|
|
Type
|
solvent
|
|
Smiles
|
O
|
Step Two
|
Name
|
|
|
Quantity
|
3.48 g
|
|
Type
|
reactant
|
|
Smiles
|
[OH-].[Na+]
|
Conditions
Temperature
|
Control Type
|
AMBIENT
|
Stirring
|
Type
|
CUSTOM
|
|
Details
|
The mixture was stirred at r.t. for 15 minutes
|
|
Rate
|
UNSPECIFIED
|
|
RPM
|
0
|
Other
|
Conditions are dynamic
|
1
|
|
Details
|
See reaction.notes.procedure_details.
|
Workups
TEMPERATURE
|
Type
|
TEMPERATURE
|
|
Details
|
The resulting mixture was heated to 65° C. for 10 h
|
|
Duration
|
10 h
|
TEMPERATURE
|
Type
|
TEMPERATURE
|
|
Details
|
The mixture was then cooled to r.t.
|
STIRRING
|
Type
|
STIRRING
|
|
Details
|
The resulting mixture was stirred overnight
|
|
Duration
|
8 (± 8) h
|
FILTRATION
|
Type
|
FILTRATION
|
|
Details
|
The resulting solid was collected by filtration
|
WASH
|
Type
|
WASH
|
|
Details
|
washed with water (25 mL)
|
CUSTOM
|
Type
|
CUSTOM
|
|
Details
|
dried at 50° C. for 12 h
|
|
Duration
|
12 h
|
Outcomes
Product
Details
Reaction Time |
15 min |
|
Name
|
|
|
Type
|
product
|
|
Smiles
|
CN(CCN(C1=C(C=C(C(=C1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)NC(C=C)=O)C)C
|
Measurements
| Type | Value | Analysis |
|---|---|---|
| AMOUNT: MASS | 7 g | |
| YIELD: PERCENTYIELD | 94% | |
| YIELD: CALCULATEDPERCENTYIELD | 65.7% |
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. |
