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molecular formula C15H14N4O B3026168 Nevirapine-D4 CAS No. 1051418-95-1

Nevirapine-D4

Cat. No. B3026168
M. Wt: 270.32 g/mol
InChI Key: NQDJXKOVJZTUJA-CQOLUAMGSA-N
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Patent
US05569760

Procedure details

117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 23.3 kg of calcium oxide and 59.4 kg of cyclopropylamine (molar ratio: 1:1:2.5) are heated to between 135° and 145° C. in 235 l ofdiglyme (diethylene glycoldimethylether) in a 500 l VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 58.8 l of diglyme. The filtrates are combined and initially 200 l of solvent is distilled off. The residue is then diluted with a further 117.5 l of diglyme. The resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 55.8 l of diglyme, and the mixture is stirred at a temperature of between 130° and 140° C. for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470 l of water. After cooling to a temperature of about 25° C., 235.0 l of cyclohexane and 57.11 of glacial acetic acid are added to the reaction mixture. The mixture is then stirred for about 1 hour at temperature of 10° to 25° C. The resultant suspension is centrifuged and the centrifuged material is then washed with 235.0 l of methyl-tert.-butylether and subsequently with 353.5 l of water and finally with 235 l of ethanol. In this way, after drying, 92.5 kg (83.5% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (nevirapine) is isolated.
Quantity
117.5 kg
Type
reactant
Reaction Step One
Quantity
23.3 kg
Type
reactant
Reaction Step One
Quantity
59.4 kg
Type
reactant
Reaction Step One
[Compound]
Name
diethylene
Quantity
0 (± 1) mol
Type
reactant
Reaction Step One

Identifiers

REACTION_CXSMILES
Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-2].[Ca+2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1>>[CH:21]1([N:24]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[NH:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[N:13][C:12]2=3)[CH2:23][CH2:22]1 |f:1.2|

Inputs

Step One
Name
Quantity
117.5 kg
Type
reactant
Smiles
ClC1=NC=CC=C1C(=O)NC=1C(=NC=CC1C)Cl
Name
Quantity
23.3 kg
Type
reactant
Smiles
[O-2].[Ca+2]
Name
Quantity
59.4 kg
Type
reactant
Smiles
C1(CC1)N
Name
diethylene
Quantity
0 (± 1) mol
Type
reactant
Smiles

Conditions

Temperature
Control Type
UNSPECIFIED
Setpoint
130 °C
Stirring
Type
CUSTOM
Details
the mixture is stirred at a temperature of between 130° and 140° C. for a further 30 to 60 minutes
Rate
UNSPECIFIED
RPM
0
Other
Conditions are dynamic
1
Details
See reaction.notes.procedure_details.

Workups

TEMPERATURE
Type
TEMPERATURE
Details
The reaction mixture is then cooled to a temperature of 20° to 30° C.
FILTRATION
Type
FILTRATION
Details
filtered
WASH
Type
WASH
Details
The filter cake is washed with 58.8 l of diglyme
DISTILLATION
Type
DISTILLATION
Details
initially 200 l of solvent is distilled off
ADDITION
Type
ADDITION
Details
The residue is then diluted with a further 117.5 l of diglyme
ADDITION
Type
ADDITION
Details
The resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 l of diglyme
Duration
30 (± 10) min
WASH
Type
WASH
Details
The storage vessel and conduits are rinsed with a further 55.8 l of diglyme
DISTILLATION
Type
DISTILLATION
Details
The majority of the diglyme is then distilled off
ADDITION
Type
ADDITION
Details
Finally, the remaining residue is carefully mixed with 470 l of water
TEMPERATURE
Type
TEMPERATURE
Details
After cooling to a temperature of about 25° C., 235.0 l of cyclohexane and 57.11 of glacial acetic acid
ADDITION
Type
ADDITION
Details
are added to the reaction mixture
STIRRING
Type
STIRRING
Details
The mixture is then stirred for about 1 hour at temperature of 10° to 25° C
Duration
1 h
WASH
Type
WASH
Details
the centrifuged material is then washed with 235.0 l of methyl-tert.-butylether and subsequently with 353.5 l of water and finally with 235 l of ethanol
CUSTOM
Type
CUSTOM
Details
In this way, after drying

Outcomes

Product
Details
Reaction Time
45 (± 15) min
Name
Type
product
Smiles
C1(CC1)N1C2=C(NC(C3=C1N=CC=C3)=O)C(=CC=N2)C
Measurements
Type Value Analysis
AMOUNT: MASS 92.5 kg
YIELD: PERCENTYIELD 83.5%
YIELD: CALCULATEDPERCENTYIELD 83.4%

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
US05569760

Procedure details

117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 23.3 kg of calcium oxide and 59.4 kg of cyclopropylamine (molar ratio: 1:1:2.5) are heated to between 135° and 145° C. in 235 l ofdiglyme (diethylene glycoldimethylether) in a 500 l VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 58.8 l of diglyme. The filtrates are combined and initially 200 l of solvent is distilled off. The residue is then diluted with a further 117.5 l of diglyme. The resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 55.8 l of diglyme, and the mixture is stirred at a temperature of between 130° and 140° C. for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470 l of water. After cooling to a temperature of about 25° C., 235.0 l of cyclohexane and 57.11 of glacial acetic acid are added to the reaction mixture. The mixture is then stirred for about 1 hour at temperature of 10° to 25° C. The resultant suspension is centrifuged and the centrifuged material is then washed with 235.0 l of methyl-tert.-butylether and subsequently with 353.5 l of water and finally with 235 l of ethanol. In this way, after drying, 92.5 kg (83.5% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (nevirapine) is isolated.
Quantity
117.5 kg
Type
reactant
Reaction Step One
Quantity
23.3 kg
Type
reactant
Reaction Step One
Quantity
59.4 kg
Type
reactant
Reaction Step One
[Compound]
Name
diethylene
Quantity
0 (± 1) mol
Type
reactant
Reaction Step One

Identifiers

REACTION_CXSMILES
Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-2].[Ca+2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1>>[CH:21]1([N:24]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[NH:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[N:13][C:12]2=3)[CH2:23][CH2:22]1 |f:1.2|

Inputs

Step One
Name
Quantity
117.5 kg
Type
reactant
Smiles
ClC1=NC=CC=C1C(=O)NC=1C(=NC=CC1C)Cl
Name
Quantity
23.3 kg
Type
reactant
Smiles
[O-2].[Ca+2]
Name
Quantity
59.4 kg
Type
reactant
Smiles
C1(CC1)N
Name
diethylene
Quantity
0 (± 1) mol
Type
reactant
Smiles

Conditions

Temperature
Control Type
UNSPECIFIED
Setpoint
130 °C
Stirring
Type
CUSTOM
Details
the mixture is stirred at a temperature of between 130° and 140° C. for a further 30 to 60 minutes
Rate
UNSPECIFIED
RPM
0
Other
Conditions are dynamic
1
Details
See reaction.notes.procedure_details.

Workups

TEMPERATURE
Type
TEMPERATURE
Details
The reaction mixture is then cooled to a temperature of 20° to 30° C.
FILTRATION
Type
FILTRATION
Details
filtered
WASH
Type
WASH
Details
The filter cake is washed with 58.8 l of diglyme
DISTILLATION
Type
DISTILLATION
Details
initially 200 l of solvent is distilled off
ADDITION
Type
ADDITION
Details
The residue is then diluted with a further 117.5 l of diglyme
ADDITION
Type
ADDITION
Details
The resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 l of diglyme
Duration
30 (± 10) min
WASH
Type
WASH
Details
The storage vessel and conduits are rinsed with a further 55.8 l of diglyme
DISTILLATION
Type
DISTILLATION
Details
The majority of the diglyme is then distilled off
ADDITION
Type
ADDITION
Details
Finally, the remaining residue is carefully mixed with 470 l of water
TEMPERATURE
Type
TEMPERATURE
Details
After cooling to a temperature of about 25° C., 235.0 l of cyclohexane and 57.11 of glacial acetic acid
ADDITION
Type
ADDITION
Details
are added to the reaction mixture
STIRRING
Type
STIRRING
Details
The mixture is then stirred for about 1 hour at temperature of 10° to 25° C
Duration
1 h
WASH
Type
WASH
Details
the centrifuged material is then washed with 235.0 l of methyl-tert.-butylether and subsequently with 353.5 l of water and finally with 235 l of ethanol
CUSTOM
Type
CUSTOM
Details
In this way, after drying

Outcomes

Product
Details
Reaction Time
45 (± 15) min
Name
Type
product
Smiles
C1(CC1)N1C2=C(NC(C3=C1N=CC=C3)=O)C(=CC=N2)C
Measurements
Type Value Analysis
AMOUNT: MASS 92.5 kg
YIELD: PERCENTYIELD 83.5%
YIELD: CALCULATEDPERCENTYIELD 83.4%

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.
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