Synthesis routes of N-(3-(3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino)phenyl)acetamide

N-(3-(3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino)phenyl)acetamide

Numéro de catalogue B1429255

: 871700-25-3

Poids moléculaire: 615.4 g/mol

Clé InChI: VUCVSBZRQBGJPT-UHFFFAOYSA-N

Attention: Uniquement pour un usage de recherche. Non destiné à un usage humain ou vétérinaire.

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Patent

US09181243B2

Procedure details

Under a nitrogen atmosphere, tetrahydrofuran (40 mL) was added to N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide (5 g) and a methanol solution (1.57 g) containing 28% sodium methoxide was added and the mixture was stirred at room temperature for 4 hours. Acetic acid (0.56 mL) was added to the mixture and the mixture was stirred at room temperature for 30 min. And then water (40 mL) was added and the mixture was further stirred for 1 hour. The crystals were collected by filtration and dried under reduced pressure at 40° C. to give trametinib (4.75 g). Its HPLC content of A impurity is 0.42 wt %.

Name

tetrahydrofuran

Quantity

40 mL

Type

reactant

Reaction Step One

Name

N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide

Quantity

5 g

Type

reactant

Reaction Step One

Name

methanol

Quantity

1.57 g

Type

reactant

Reaction Step Two

Name

sodium methoxide

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Two

Name

water

Quantity

40 mL

Type

solvent

Reaction Step Three

Name

Acetic acid

Quantity

0.56 mL

Type

solvent

Reaction Step Four

Name

trametinib

Identifiers

REACTION_CXSMILES

O1CCCC1.[CH:6]1([N:9]2[C:14](=[O:15])[C:13]3[C:16]([NH:23][C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=4)=[C:17]([CH3:22])[C:18](=[O:21])[N:19]([CH3:20])[C:12]=3[N:11]([C:34]3[CH:39]=[CH:38][C:37]([I:40])=[CH:36][C:35]=3[F:41])[C:10]2=[O:42])[CH2:8][CH2:7]1.CO.C[O-].[Na+]>O.C(O)(=O)C>[CH3:22][C:17]1[C:18](=[O:21])[N:19]([CH3:20])[C:12]([NH:11][C:34]2[CH:39]=[CH:38][C:37]([I:40])=[CH:36][C:35]=2[F:41])=[C:13]2[C:14]([N:9]([CH:6]3[CH2:8][CH2:7]3)[C:10]([N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([CH3:32])=[O:33])[CH:25]=3)[C:16]=12)=[O:42])=[O:15] |f:3.4|

Inputs

Step One

Name	tetrahydrofuran
Quantity	40 mL
Type	reactant
Smiles	O1CCCC1

Name	N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide
Quantity	5 g
Type	reactant
Smiles	C1(CC1)N1C(N(C2=C(C1=O)C(=C(C(N2C)=O)C)NC=2C=C(C=CC2)NC(C)=O)C2=C(C=C(C=C2)I)F)=O

Step Two

Name	methanol
Quantity	1.57 g
Type	reactant
Smiles	CO

Name	sodium methoxide
Quantity	0 (± 1) mol
Type	reactant
Smiles	C[O-].[Na+]

Step Three

Name	water
Quantity	40 mL
Type	solvent
Smiles	O

Step Four

Name	Acetic acid
Quantity	0.56 mL
Type	solvent
Smiles	C(C)(=O)O

Conditions

Temperature

Control Type

AMBIENT

Stirring

Type	CUSTOM
Details	the mixture was stirred at room temperature for 4 hours
Rate	UNSPECIFIED
RPM	0

Other

Conditions are dynamic	1
Details	See reaction.notes.procedure_details.

Workups

ADDITION

Type	ADDITION
Details	was added

STIRRING

Type	STIRRING
Details	the mixture was stirred at room temperature for 30 min
Duration	30 min

STIRRING

Type	STIRRING
Details	the mixture was further stirred for 1 hour
Duration	1 h

FILTRATION

Type	FILTRATION
Details	The crystals were collected by filtration

CUSTOM

Type	CUSTOM
Details	dried under reduced pressure at 40° C.

Outcomes

Product

Details

Reaction Time

4 h

Name	trametinib
Type	product
Smiles	CC1=C2C(=C(N(C1=O)C)NC=3C=CC(=CC3F)I)C(=O)N(C(=O)N2C=4C=CC=C(C4)NC(=O)C)C5CC5

Measurements

Type	Value	Analysis
AMOUNT: MASS	4.75 g
YIELD: CALCULATEDPERCENTYIELD	95%

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.