Product Name

  • Name

    Roflumilast

  • EINECS 685-382-2
  • CAS No. 162401-32-3
  • Article Data18
  • CAS DataBase
  • Density 1.471 g/cm3
  • Solubility
  • Melting Point 158 °C
  • Formula C17H14Cl2F2N2O3
  • Boiling Point 430.6 °C at 760 mmHg
  • Molecular Weight 403.213
  • Flash Point 214.2 °C
  • Transport Information
  • Appearance Crystalline solid
  • Safety 26
  • Risk Codes 36/37/38
  • Molecular Structure Molecular Structure of 162401-32-3 (Roflumilast)
  • Hazard Symbols Xi
  • Synonyms B 9302-107;BY 217;BYK 20869;Daxas;3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide;
  • PSA 60.45000
  • LogP 5.10390

Synthetic route

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid
162401-62-9

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid

3,5-dichloro-4-aminopyridine
22889-78-7

3,5-dichloro-4-aminopyridine

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Stage #1: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid With pyridine; 2,4,6-trinitrochlorobenzene In 1,4-dioxane at 20 - 35℃; for 3h; Industrial scale;
Stage #2: 3,5-dichloro-4-aminopyridine In 1,4-dioxane for 2h; Reagent/catalyst; Solvent; Temperature; Industrial scale;		95%
Stage #1: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In dichloromethane at 0 - 20℃; for 3h;
Stage #2: 3,5-dichloro-4-aminopyridine In dichloromethane for 2h; Concentration;		91%
Stage #1: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid With pivaloyl chloride; sodium carbonate In tetrahydrofuran at 25℃; for 2h;
Stage #2: 3,5-dichloro-4-aminopyridine In tetrahydrofuran at 50℃; for 4h; Temperature; Solvent; Reagent/catalyst;		64%
Stage #1: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid With thionyl chloride In toluene Heating / reflux;
Stage #2: 3,5-dichloro-4-aminopyridine With sodium hydride In tetrahydrofuran for 1h; Cooling;		58.6%
3,5-dichloro-4-aminopyridine
22889-78-7

3,5-dichloro-4-aminopyridine

3-(difluoromethoxy)-4-(cyclopropylmethoxy)-benzoic acid
162401-69-6

3-(difluoromethoxy)-4-(cyclopropylmethoxy)-benzoic acid

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Stage #1: 3-(difluoromethoxy)-4-(cyclopropylmethoxy)-benzoic acid With thionyl chloride In toluene for 2h; Reflux;
Stage #2: 3,5-dichloro-4-aminopyridine With sodium hydride In tetrahydrofuran at 15 - 20℃;		95%
3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid
162401-62-9

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Large scale;93%
Multi-step reaction with 2 steps
1.1: dimethyl sulfoxide / 3 h / 20 °C
2.1: cesium fluoride / dimethyl sulfoxide / 3 h / 90 °C
2.2: 6.5 h / 90 - 95 °C
View Scheme
3,5-dichloro-N-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzylidene)pyridin-4-amine
1454574-39-0

3,5-dichloro-N-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzylidene)pyridin-4-amine

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
With sodium chlorite; 2-methyl-but-2-ene; acetic acid In water; acetonitrile at 20 - 30℃; for 3h; Cooling with ice;92.4%
With sodium chlorite; 2-methyl-but-2-ene; acetic acid In water; acetonitrile at 20 - 30℃; for 2h; Reagent/catalyst; Cooling with ice;82%
With sodium chlorite; sodium dihydrogenphosphate; 2-methyl-but-2-ene In tetrahydrofuran; water57%
3,5-dichloro-4-aminopyridine
22889-78-7

3,5-dichloro-4-aminopyridine

(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(1H-imidazol-1-yl)methanone
1590361-85-5

(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(1H-imidazol-1-yl)methanone

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Stage #1: 3,5-dichloro-4-aminopyridine With cesium fluoride In dimethyl sulfoxide at 90℃; for 3h;
Stage #2: (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(1H-imidazol-1-yl)methanone In dimethyl sulfoxide at 90 - 95℃; for 6.5h; Reagent/catalyst;		88%
BYK20839
1391052-76-8

BYK20839

cyclopropylcarbinyl bromide
7051-34-5

cyclopropylcarbinyl bromide

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Temperature;82.3%
3,5-dichloro-4-aminopyridine
22889-78-7

3,5-dichloro-4-aminopyridine

(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(1H-1,2,4-triazol-1-yl)methanone
1601300-21-3

(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(1H-1,2,4-triazol-1-yl)methanone

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Stage #1: 3,5-dichloro-4-aminopyridine With cesium fluoride In dimethyl sulfoxide at 90℃; for 3h;
Stage #2: (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(1H-1,2,4-triazol-1-yl)methanone In dimethyl sulfoxide at 90 - 95℃; for 3h;		79%
Potassium salt of 4-amino-3, 5-dichloropyridine

Potassium salt of 4-amino-3, 5-dichloropyridine

3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride
672883-68-0

3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
In DMF (N,N-dimethyl-formamide) at 15 - 40℃;
In 1-methyl-pyrrolidin-2-one at 15 - 40℃;
In DMF (N,N-dimethyl-formamide) at 15 - 40℃;
In DMF (N,N-dimethyl-formamide) at 15 - 40℃;
In tetrahydrofuran at 0 - 10℃; for 2.5h;
3,5-dichloro-4-aminopyridine
22889-78-7

3,5-dichloro-4-aminopyridine

3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride
672883-68-0

3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
With sodium hydride In tetrahydrofuran at 0℃; for 0.5h;
Stage #1: 3,5-dichloro-4-aminopyridine With sodium hydroxide In toluene for 2h;
Stage #2: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride In toluene for 6h; Concentration; Temperature; Time; Reflux;		89.2 %Chromat.
Stage #1: 3,5-dichloro-4-aminopyridine With sodium hydride In tetrahydrofuran for 0.5h;
Stage #2: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride In tetrahydrofuran at 20 - 30℃; for 1h;
3-hydroxy-4-iodobenzoic acid
58123-77-6

3-hydroxy-4-iodobenzoic acid

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 7 steps
1: thionyl chloride / 3 h / 50 °C
2: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Large scale
3: potassium hydroxide; copper(l) iodide; 8-quinolinol / dimethyl sulfoxide / 30 h / 100 °C / Inert atmosphere; Large scale
4: thionyl chloride / 3 h / 50 °C
5: potassium carbonate / N,N-dimethyl-formamide / 1.25 h / 95 °C
6: sodium hydroxide / methanol / 3 h / 50 °C
7: Large scale
View Scheme
Multi-step reaction with 7 steps
1: thionyl chloride / 3 h / 50 °C
2: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Large scale
3: potassium hydroxide; copper(l) iodide; 8-quinolinol / dimethyl sulfoxide / 30 h / 100 °C / Inert atmosphere; Large scale
4: thionyl chloride / 3 h / 50 °C
5: N,N-dimethyl-formamide / Heating
6: sodium hydroxide / methanol / 3 h / 50 °C
7: Large scale
View Scheme
methyl 3-hydroxy-4-iodobenzoate
157942-12-6

methyl 3-hydroxy-4-iodobenzoate

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Large scale
2: potassium hydroxide; copper(l) iodide; 8-quinolinol / dimethyl sulfoxide / 30 h / 100 °C / Inert atmosphere; Large scale
3: thionyl chloride / 3 h / 50 °C
4: potassium carbonate / N,N-dimethyl-formamide / 1.25 h / 95 °C
5: sodium hydroxide / methanol / 3 h / 50 °C
6: Large scale
View Scheme
Multi-step reaction with 6 steps
1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C / Large scale
2: potassium hydroxide; copper(l) iodide; 8-quinolinol / dimethyl sulfoxide / 30 h / 100 °C / Inert atmosphere; Large scale
3: thionyl chloride / 3 h / 50 °C
4: N,N-dimethyl-formamide / Heating
5: sodium hydroxide / methanol / 3 h / 50 °C
6: Large scale
View Scheme
methyl 3-(cyclopropylmethoxy)-4-iodobenzoate
1392191-29-5

methyl 3-(cyclopropylmethoxy)-4-iodobenzoate

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: potassium hydroxide; copper(l) iodide; 8-quinolinol / dimethyl sulfoxide / 30 h / 100 °C / Inert atmosphere; Large scale
2: thionyl chloride / 3 h / 50 °C
3: N,N-dimethyl-formamide / Heating
4: sodium hydroxide / methanol / 3 h / 50 °C
5: Large scale
View Scheme
Multi-step reaction with 5 steps
1: potassium hydroxide; copper(l) iodide; 8-quinolinol / dimethyl sulfoxide / 30 h / 100 °C / Inert atmosphere; Large scale
2: thionyl chloride / 3 h / 50 °C
3: potassium carbonate / N,N-dimethyl-formamide / 1.25 h / 95 °C
4: sodium hydroxide / methanol / 3 h / 50 °C
5: Large scale
View Scheme
3-(cyclopropylmethoxy)-4-hydroxybenzoic acid
1243391-44-7

3-(cyclopropylmethoxy)-4-hydroxybenzoic acid

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: thionyl chloride / 3 h / 50 °C
2: potassium carbonate / N,N-dimethyl-formamide / 1.25 h / 95 °C
3: sodium hydroxide / methanol / 3 h / 50 °C
4: Large scale
View Scheme
Multi-step reaction with 4 steps
1: thionyl chloride / 3 h / 50 °C
2: N,N-dimethyl-formamide / Heating
3: sodium hydroxide / methanol / 3 h / 50 °C
4: Large scale
View Scheme
3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester

3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: potassium carbonate / N,N-dimethyl-formamide / 1.25 h / 95 °C
2: sodium hydroxide / methanol / 3 h / 50 °C
3: Large scale
View Scheme
Multi-step reaction with 3 steps
1: N,N-dimethyl-formamide / Heating
2: sodium hydroxide / methanol / 3 h / 50 °C
3: Large scale
View Scheme
3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid methyl ester

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid methyl ester

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: sodium hydroxide / methanol / 3 h / 50 °C
2: Large scale
View Scheme
4-difluoromethoxy-3-hydroxybenzaldehyde
151103-08-1

4-difluoromethoxy-3-hydroxybenzaldehyde

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1.1: potassium carbonate; potassium iodide / acetone / 0.5 h / Inert atmosphere; Reflux
1.2: 12.5 h / 20 °C / Inert atmosphere; Reflux
2.1: aminosulfonic acid; sodium chlorite / water; acetonitrile / 5 h / 0 - 20 °C
3.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 3 h / Reflux
4.1: sodium hydroxide / toluene / 2 h
4.2: 6 h / Reflux
View Scheme
Multi-step reaction with 4 steps
1.1: potassium carbonate; potassium iodide / dimethyl sulfoxide / 1 h / 70 °C
1.2: 4 h / 70 °C
2.1: acetic acid; aminosulfonic acid / 5 - 20 °C
3.1: dimethyl sulfoxide / 2 h / 20 °C
4.1: cesium fluoride / dimethyl sulfoxide / 3 h / 90 °C
4.2: 3 h / 90 - 95 °C
View Scheme
Multi-step reaction with 4 steps
1.1: potassium carbonate; potassium iodide / dimethyl sulfoxide / 1 h / 70 °C
1.2: 4 h / 70 °C
2.1: acetic acid; aminosulfonic acid / 5 - 20 °C
3.1: dimethyl sulfoxide / 3 h / 20 °C
4.1: cesium fluoride / dimethyl sulfoxide / 3 h / 90 °C
4.2: 6.5 h / 90 - 95 °C
View Scheme
3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde
151103-09-2

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1.1: aminosulfonic acid; sodium chlorite / water; acetonitrile / 5 h / 0 - 20 °C
2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 3 h / Reflux
3.1: sodium hydroxide / toluene / 2 h
3.2: 6 h / Reflux
View Scheme
Multi-step reaction with 3 steps
1: amberlyst 15 wet (9.0 g, 30percent w/w) / toluene / 20 °C / Inert atmosphere; Reflux
2: trifluoroacetic acid / toluene / 40 - 110 °C
3: sodium chlorite; acetic acid; 2-methyl-but-2-ene / water; acetonitrile / 2 h / 20 - 30 °C / Cooling with ice
View Scheme
Multi-step reaction with 3 steps
1.1: acetic acid; aminosulfonic acid / 5 - 20 °C
2.1: dimethyl sulfoxide / 2 h / 20 °C
3.1: cesium fluoride / dimethyl sulfoxide / 3 h / 90 °C
3.2: 3 h / 90 - 95 °C
View Scheme
3,5-dichloro-4-aminopyridine
22889-78-7

3,5-dichloro-4-aminopyridine

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde
151103-09-2

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: N,O-Bis(trimethylsilyl)trifluoroacetamide; toluene-4-sulfonic acid / acetonitrile / 48 h / Reflux
2: sodium chlorite; acetic acid; 2-methyl-but-2-ene / water; acetonitrile / 2 h / 20 - 30 °C / Cooling with ice
View Scheme
Multi-step reaction with 2 steps
1.1: trifluoroacetic acid; trimethyl orthoformate / toluene / 20 - 30 °C / Inert atmosphere; Reflux
1.2: 40 - 110 °C
2.1: sodium chlorite; acetic acid; 2-methyl-but-2-ene / water; acetonitrile / 3 h / 20 - 30 °C / Cooling with ice
View Scheme
C14H18F2O4
1454798-33-4

C14H18F2O4

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: trifluoroacetic acid / toluene / 40 - 110 °C
2: sodium chlorite; acetic acid; 2-methyl-but-2-ene / water; acetonitrile / 2 h / 20 - 30 °C / Cooling with ice
View Scheme
3,4-dihydroxybenzaldehyde
139-85-5

3,4-dihydroxybenzaldehyde

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 20 - 85 °C
1.2: 8 - 10 h / Inert atmosphere
2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran / 6 h / 75 - 80 °C
3.1: aminosulfonic acid; acetic acid / water / 5 - 10 °C
3.2: 1 h / 5 - 10 °C
4.1: thionyl chloride / tetrahydrofuran / 0.5 h / 20 - 45 °C
5.1: sodium hydride / tetrahydrofuran / 0.5 h
5.2: 1 h / 20 - 30 °C
View Scheme
Multi-step reaction with 4 steps
1.1: tetrabutylammonium hydrogen sulfide; sodium hydroxide / 3 h / 60 - 65 °C
2.1: potassium carbonate; potassium iodide; trimethylbenzylammonium bromide / tetrahydrofuran / 0 °C / Reflux
3.1: sodium chlorite; aminosulfonic acid / acetic acid; water / 1 h / 20 °C
4.1: 2-chloro-4,6-dimethoxy-1 ,3,5-triazine; 4-methyl-morpholine / dichloromethane / 3 h / 0 - 20 °C
4.2: 2 h
View Scheme
Multi-step reaction with 5 steps
1: sodium hydroxide / water / Heating
2: potassium carbonate / tetrahydrofuran / 14 h / Reflux
3: sodium chlorite; acetic acid; aminosulfonic acid / Cooling with ice
4: thionyl chloride / N,N-dimethyl-formamide; toluene / 3 h / 80 °C
5: tetrahydrofuran / 2.5 h / 0 - 10 °C
View Scheme
sodium 5-methyl-2-methoxyphenolate

sodium 5-methyl-2-methoxyphenolate

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 7 steps
1: potassium permanganate; sulfuric acid
2: thionyl chloride / N,N-dimethyl-formamide / Reflux
3: triethylamine / water / 3 °C
4: hydrogenchloride
5: sulfuric acid / 7 h / 140 °C / Inert atmosphere
6: hydrogen iodide / ethanol / 2 h
7: sulfuric acid / 7 h / 140 °C / Inert atmosphere
View Scheme
Na(1+)*C8H7O4(1-)

Na(1+)*C8H7O4(1-)

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: thionyl chloride / N,N-dimethyl-formamide / Reflux
2: triethylamine / water / 3 °C
3: hydrogenchloride
4: sulfuric acid / 7 h / 140 °C / Inert atmosphere
5: hydrogen iodide / ethanol / 2 h
6: sulfuric acid / 7 h / 140 °C / Inert atmosphere
View Scheme
Na(1+)*C8H6ClO3(1-)

Na(1+)*C8H6ClO3(1-)

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: triethylamine / water / 3 °C
2: hydrogenchloride
3: sulfuric acid / 7 h / 140 °C / Inert atmosphere
4: hydrogen iodide / ethanol / 2 h
5: sulfuric acid / 7 h / 140 °C / Inert atmosphere
View Scheme
C13H9Cl2N2O3(1-)*Na(1+)

C13H9Cl2N2O3(1-)*Na(1+)

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: hydrogenchloride
2: sulfuric acid / 7 h / 140 °C / Inert atmosphere
3: hydrogen iodide / ethanol / 2 h
4: sulfuric acid / 7 h / 140 °C / Inert atmosphere
View Scheme
3-hydroxy-N-(3,5-dichloropyridin-4-yl)-4-methoxybenzamide
144036-24-8

3-hydroxy-N-(3,5-dichloropyridin-4-yl)-4-methoxybenzamide

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: sulfuric acid / 7 h / 140 °C / Inert atmosphere
2: hydrogen iodide / ethanol / 2 h
3: sulfuric acid / 7 h / 140 °C / Inert atmosphere
View Scheme
3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(methoxy)benzamide
159782-26-0

3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(methoxy)benzamide

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: hydrogen iodide / ethanol / 2 h
2: sulfuric acid / 7 h / 140 °C / Inert atmosphere
View Scheme
difluoromethyl alcohol
1426-06-8

difluoromethyl alcohol

3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-hydroxybenzamide

3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-hydroxybenzamide

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
With sulfuric acid at 140℃; for 7h; Inert atmosphere;20.76 g
2-chloro-1-methoxy-4-methylbenzene
22002-44-4

2-chloro-1-methoxy-4-methylbenzene

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 8 steps
1: sodium hydroxide / toluene / 360 °C / 150015 Torr
2: potassium permanganate; sulfuric acid
3: thionyl chloride / N,N-dimethyl-formamide / Reflux
4: triethylamine / water / 3 °C
5: hydrogenchloride
6: sulfuric acid / 7 h / 140 °C / Inert atmosphere
7: hydrogen iodide / ethanol / 2 h
8: sulfuric acid / 7 h / 140 °C / Inert atmosphere
View Scheme
4-(difluoromethoxy)benzoic acid
4837-20-1

4-(difluoromethoxy)benzoic acid

roflumilast
162401-32-3

roflumilast

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: bis(trichloromethyl) carbonate; triethylamine / toluene / 6 h / 90 °C
2: potassium tert-butylate / tetrahydrofuran / 3 h / 20 °C
3: trichlorophosphate / 21 h / 30 - 80 °C / Inert atmosphere
4: dihydrogen peroxide; sulfuric acid / methanol / 10 h / 20 - 30 °C
5: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C
View Scheme
roflumilast
162401-32-3

roflumilast

roflumilast N-oxide

roflumilast N-oxide

Conditions
ConditionsYield
With 3-chloro-benzenecarboperoxoic acid In chloroform at 20℃; for 44h; Product distribution / selectivity;93%
With dihydrogen peroxide; acetic acid at 70℃; for 6h; Temperature;82.7%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 18h;
diethyl(imino)-λ6-sulfanone
92523-32-5

diethyl(imino)-λ6-sulfanone

roflumilast
162401-32-3

roflumilast

C21H23Cl2F2N3O4S

C21H23Cl2F2N3O4S

Conditions
ConditionsYield
With TEMPO; 3,6‐di‐tert‐butyl‐9‐mesityl‐10‐phenylacridin‐10‐ium tetrafluoroborate; oxygen In 1,2-dichloro-ethane at 37℃; for 14h; Sealed tube; Irradiation; regioselective reaction;62%
S-methyl-S-phenylsulfoximine
4381-25-3

S-methyl-S-phenylsulfoximine

roflumilast
162401-32-3

roflumilast

C24H21Cl2F2N3O4S

C24H21Cl2F2N3O4S

Conditions
ConditionsYield
With TEMPO; 3,6‐di‐tert‐butyl‐9‐mesityl‐10‐phenylacridin‐10‐ium tetrafluoroborate; oxygen In 1,2-dichloro-ethane at 37℃; for 14h; Sealed tube; Irradiation; regioselective reaction;57%
1-iminohexahydro-1λ6-thiopyran-1-oxide
35188-35-3

1-iminohexahydro-1λ6-thiopyran-1-oxide

roflumilast
162401-32-3

roflumilast

C22H23Cl2F2N3O4S

C22H23Cl2F2N3O4S

Conditions
ConditionsYield
With TEMPO; 3,6‐di‐tert‐butyl‐9‐mesityl‐10‐phenylacridin‐10‐ium tetrafluoroborate; oxygen In 1,2-dichloro-ethane at 37℃; for 14h; Sealed tube; Irradiation; regioselective reaction;53%
dimethylsulfoximine
1520-31-6

dimethylsulfoximine

roflumilast
162401-32-3

roflumilast

C19H19Cl2F2N3O4S

C19H19Cl2F2N3O4S

Conditions
ConditionsYield
With TEMPO; 3,6‐di‐tert‐butyl‐9‐mesityl‐10‐phenylacridin‐10‐ium tetrafluoroborate; oxygen In 1,2-dichloro-ethane at 37℃; for 14h; Sealed tube; Irradiation; regioselective reaction;51%
chloroacetonitrile
107-14-2

chloroacetonitrile

roflumilast
162401-32-3

roflumilast

N-cyanomethyl-N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

N-cyanomethyl-N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

Conditions
ConditionsYield
Stage #1: roflumilast With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.25h; Inert atmosphere;
Stage #2: chloroacetonitrile With sodium iodide In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h; Inert atmosphere;		48%
cyclohexane
110-82-7

cyclohexane

roflumilast
162401-32-3

roflumilast

3-(cyclopropylmethoxy)-N-(3,5-dichloro-2,6-dicyclohexylpyridin-4-yl)-4-(difluoromethoxy)benzamide

3-(cyclopropylmethoxy)-N-(3,5-dichloro-2,6-dicyclohexylpyridin-4-yl)-4-(difluoromethoxy)benzamide

Conditions
ConditionsYield
With hydrogenchloride; dihydrogen peroxide In water; acetonitrile at 20℃; for 18h; Minisci Aromatic Substitution; Inert atmosphere; Irradiation; Green chemistry;48%
With hydrogenchloride; tetraethylammonium chloride In water; acetonitrile at 34 - 42℃; Electrochemical reaction; Irradiation; Inert atmosphere;44%
tert-butyl ((3-chloro-5,6-dicyanopyrazin-2-yl)oxy)carbamate

tert-butyl ((3-chloro-5,6-dicyanopyrazin-2-yl)oxy)carbamate

roflumilast
162401-32-3

roflumilast

tert-butyl (3,5-dichloro-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamido)pyridin-2-yl)carbamate

tert-butyl (3,5-dichloro-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamido)pyridin-2-yl)carbamate

Conditions
ConditionsYield
Stage #1: tert-butyl ((3-chloro-5,6-dicyanopyrazin-2-yl)oxy)carbamate; roflumilast With N,O-bis-(trimethylsilyl)-acetamide In 1,4-dioxane at 80℃; for 3h;
Stage #2: With acetic acid; zinc In 1,4-dioxane at 20℃; for 3h; chemoselective reaction;		42%
bromethyl methyl ether
13057-17-5

bromethyl methyl ether

roflumilast
162401-32-3

roflumilast

N-(3,5-dichloropyrid-4-yl)-N-methoxymethyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

N-(3,5-dichloropyrid-4-yl)-N-methoxymethyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

Conditions
ConditionsYield
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h; Inert atmosphere;34%
3-(tert-butyldimethylsilyloxy)propyl bromide
89031-84-5

3-(tert-butyldimethylsilyloxy)propyl bromide

roflumilast
162401-32-3

roflumilast

N-(3,5-dichloropyrid-4-yl)-N-(3-tert-butyldimethylsilyloxypropan-1-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

N-(3,5-dichloropyrid-4-yl)-N-(3-tert-butyldimethylsilyloxypropan-1-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

Conditions
ConditionsYield
With sodium hydride In mineral oil at 20 - 70℃; for 12h; Inert atmosphere;31%
Chloroacetamide
79-07-2

Chloroacetamide

roflumilast
162401-32-3

roflumilast

N-carbamoylmethyl-N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

N-carbamoylmethyl-N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

Conditions
ConditionsYield
Stage #1: roflumilast With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.25h; Inert atmosphere;
Stage #2: Chloroacetamide With sodium iodide In N,N-dimethyl-formamide; mineral oil at 20℃; for 12h; Inert atmosphere;		16%
4-iodomethyl-2,2-dimethyl-[1,3]dioxolane
23737-52-2

4-iodomethyl-2,2-dimethyl-[1,3]dioxolane

roflumilast
162401-32-3

roflumilast

C23H24Cl2F2N2O5

C23H24Cl2F2N2O5

Conditions
ConditionsYield
With potassium hydroxide In dimethyl sulfoxide at 100℃; for 24h; Inert atmosphere;14%

Roflumilast Specification

The IUPAC name of Roflumilast is 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide. With the CAS registry number 162401-32-3, it is also named as Benzamide, 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-. The product's categories are All Inhibitors; Inhibitors; Intermediates & Fine Chemicals; Pharmaceuticals. It is crystalline solid which is a drug which acts as a selective, long-acting inhibitor of the enzyme PDE-4.

The other characteristics of this product can be summarized as: (1)ACD/LogP4.24: ; (2)# of Rule of 5 Violations: 0; (3)ACD/LogD (pH 5.5): 4.24; (4)ACD/LogD (pH 7.4): 4.24; (5)ACD/BCF (pH 5.5): 975.07; (6)ACD/BCF (pH 7.4): 983.7; (7)ACD/KOC (pH 5.5): 4786.84; (8)ACD/KOC (pH 7.4): 4829.22; (9)#H bond acceptors: 5; (10)#H bond donors: 0; (11)#Freely Rotating Bonds: 7; (12)Index of Refraction: 1.599; (13)Molar Refractivity: 93.97 cm3; (14)Molar Volume: 274.8 cm3; (15)Polarizability: 37.25×10-24 cm3; (16)Surface Tension: 52.8 dyne/cm; (17)Enthalpy of Vaporization: 73.36 kJ/mol; (18)Vapour Pressure: 4.86E-09 mmHg at 25°C; (19)Rotatable Bond Count: 7; (20)Tautomer Count: 3; (21)Exact Mass: 402.034954; (22)MonoIsotopic Mass: 402.034954; (23)Topological Polar Surface Area: 60.4; (24)Heavy Atom Count: 26; (25)Complexity: 475.

Preparation of Roflumilast: It can be obtained by the following method:

Uses of Roflumilast: It has antiinflammatory effects and is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, and chronic obstructive pulmonary disease (COPD).

People can use the following data to convert to the molecule structure. 
1. SMILES:Clc3c(N(OCC1CC1)C(=O)c2ccc(OC(F)F)cc2)c(Cl)cnc3
2. InChI:InChI=1/C17H14Cl2F2N2O3/c18-13-7-22-8-14(19)15(13)23(25-9-10-1-2-10)16(24)11-3-5-12(6-4-11)26-17(20)21/h3-8,10,17H,1-2,9H2 
3. InChIKey:IWONQDOIPBAXGV-UHFFFAOYAH

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