162401-62-9

Basic information

• Product Name: 3-Cyclopropylmethoxy-4-difluoromethoxy-benzoic acid
• Synonyms: 3-Cyclopropylmethoxy-4-difluoromethoxy-benzoic acid;3-CyclopropyMethoxy-4-difluoroMethoxy benzoic acid;Benzoic acid, 3-(cyclopropylMethoxy)-4-(difluoroMethoxy)-;CYCLOPROPYL DIFLUOROMETHOXYBENOZOIC ACID;3-CyclopropylMethoxy-4-isopropoxy-benzoic acid;RofluMilast InterMediate II;3-Cyclopropylmethoxy-4-difluoromethoxybenzoic acid, >=98%;Roflumilast intermediate B
• CAS NO: 162401-62-9
• Molecular Formula: C₁₂H₁₂F₂O₄
• Molecular Weight: 258.219
• EINECS: 1806241-263-5
• Product Categories: Intermediates;Roflumilast interemdiate
• Mol File: 162401-62-9.mol
• Article Data: 21

Chemical Properties

• Melting Point: 118-120℃
• Boiling Point: 356.4 °C at 760 mmHg
• Flash Point: 169.4 °C
• Appearance: /Solid
• Density: 1.355 g/cm³
• Vapor Pressure: 1.07E-05mmHg at 25°C
• Refractive Index: 1.528
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 3.87±0.10(Predicted)
• CAS DataBase Reference: 3-Cyclopropylmethoxy-4-difluoromethoxy-benzoic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Cyclopropylmethoxy-4-difluoromethoxy-benzoic acid(162401-62-9)
• EPA Substance Registry System: 3-Cyclopropylmethoxy-4-difluoromethoxy-benzoic acid(162401-62-9)

Safety Data

• Hazard Codes: T
• Statements: 25
• Safety Statements: 45
• RIDADR: 2811
• HazardClass: 6.1
• PackingGroup: Ⅲ
• Hazardous Substances Data: 162401-62-9(Hazardous Substances Data)

Usage

Description

3-Cyclopropylmethoxy-4-difluoromethoxy-benzoic acid is an organic compound characterized by its cyclopropylmethoxy and difluoromethoxy functional groups attached to a benzoic acid backbone. This molecule is known for its potential applications in the pharmaceutical industry due to its unique structural features and chemical properties.

Uses

Used in Pharmaceutical Industry:
3-Cyclopropylmethoxy-4-difluoromethoxy-benzoic acid is used as an impurity and intermediate for the preparation of Roflumilast (R639700), a selective phosphodiesterase 4 (PDE4) inhibitor. It plays a crucial role in the synthesis process, contributing to the development of this medication, which is utilized for the treatment of chronic obstructive pulmonary disease (COPD) and other inflammatory conditions.
As an intermediate, 3-Cyclopropylmethoxy-4-difluoromethoxy-benzoic acid is essential in the chemical reactions that lead to the formation of the final drug product, Roflumilast. Its presence in the synthesis process ensures the successful production of the desired PDE4 inhibitor, which is known for its anti-inflammatory and immunomodulatory effects, making it a valuable compound in the pharmaceutical sector.

InChI:InChI=1/C12H12F2O4/c13-12(14)18-9-4-3-8(11(15)16)5-10(9)17-6-7-1-2-7/h3-5,7,12H,1-2,6H2,(H,15,16)

Synthetic route

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

Conditions	Yield
With sodium hydroxide In methanol at 50℃; for 3h;	99%
With hydrogenchloride; water at 20 - 55℃; pH=3 - 4;

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde (151103-09-2) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
With sodium chlorite; aminosulfonic acid In water; acetic acid at 20℃; for 1h;	97%
With dihydrogen peroxide; potassium hydroxide In methanol at 65℃; for 1h;	97%
With sodium chlorite; aminosulfonic acid In water; acetic acid at 20℃; for 1h; Concentration;	97.3%

4-bromo-2-(cyclopropylmethoxy)-1-(difluoromethoxy)benzene (680184-55-8) + carbon dioxide (124-38-9) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Stage #1: 4-bromo-2-(cyclopropylmethoxy)-1-(difluoromethoxy)benzene With ethylmagnesium chloride In tetrahydrofuran; 1,2-dimethoxyethane for 1h; Reflux; Stage #2: carbon dioxide In tetrahydrofuran; 1,2-dimethoxyethane Stage #3: With hydrogenchloride In tetrahydrofuran; 1,2-dimethoxyethane; water Temperature; Solvent; Reagent/catalyst; Acidic conditions;	95%

3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester + sodium chlorodifluoroacetate (1895-39-2) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Stage #1: 3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester; sodium chlorodifluoroacetate With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 0.5h; Stage #2: With water; sodium hydroxide In methanol at 50℃; for 2h;	81.4%

3-hydroxy-4-iodobenzoic acid (58123-77-6) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 6 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 View Scheme

methyl 3-hydroxy-4-iodobenzoate (157942-12-6) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 View Scheme

methyl 3-(cyclopropylmethoxy)-4-iodobenzoate (1392191-29-5) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 View Scheme

3-(cyclopropylmethoxy)-4-hydroxybenzoic acid (1243391-44-7) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride / 3 h / 50 °C 2: N,N-dimethyl-formamide / Heating 3: sodium hydroxide / methanol / 3 h / 50 °C View Scheme

3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 1.25 h / 95 °C 2: sodium hydroxide / methanol / 3 h / 50 °C View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / Heating 2: sodium hydroxide / methanol / 3 h / 50 °C View Scheme

4-difluoromethoxy-3-hydroxybenzaldehyde (151103-08-1) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / tetrahydrofuran / 14 h / 0 °C / Reflux 2: acetic acid; aminosulfonic acid; sodium chlorite / water / 1 h / 20 °C View Scheme
Multi-step reaction with 2 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 View Scheme

3,4-dihydroxybenzaldehyde (139-85-5) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / N,N-dimethyl-formamide; water / 2 h / 120 °C 2: potassium carbonate / tetrahydrofuran / 14 h / 0 °C / Reflux 3: acetic acid; aminosulfonic acid; sodium chlorite / water / 1 h / 20 °C View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide / N,N-dimethyl-formamide; water / 2 h / 120 °C 2: caesium carbonate / N,N-dimethyl-formamide / 1 h / 65 °C 3: potassium hydroxide; dihydrogen peroxide / methanol / 1 h / 20 °C View Scheme

4-benzyloxy-3-hydroxy-benzaldehyde (4049-39-2) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: caesium carbonate / N,N-dimethyl-formamide / 1 h / 65 °C 2: palladium 10% on activated carbon; hydrogen / ethyl acetate / 2 h / 20 °C 3: sodium hydroxide / N,N-dimethyl-formamide / 2 h / 120 °C 4: potassium hydroxide; dihydrogen peroxide / methanol / 1 h / 65 °C View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C 2.1: N-iodo-succinimide; potassium carbonate / 24 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 18 h 4.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 100 °C 4.2: 2 h / 50 °C View Scheme

4-(benzyloxy)-3-(cyclopropylmethoxy)benzaldehyde (1381886-14-1) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / ethyl acetate / 2 h / 20 °C 2: sodium hydroxide / N,N-dimethyl-formamide / 2 h / 120 °C 3: potassium hydroxide; dihydrogen peroxide / methanol / 1 h / 65 °C View Scheme
Multi-step reaction with 3 steps 1.1: N-iodo-succinimide; potassium carbonate / 24 h / 20 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 18 h 3.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 100 °C 3.2: 2 h / 50 °C View Scheme

3-(cyclopropylmethoxy)-4-hydroxybenzaldehyde (25934-52-5) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / N,N-dimethyl-formamide / 2 h / 120 °C 2: potassium hydroxide; dihydrogen peroxide / methanol / 1 h / 65 °C View Scheme

vanillin (121-33-5) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydroxide / N,N-dimethyl-formamide / 2 h / 90 °C 2.1: lithium chloride / N,N-dimethyl-formamide / Reflux 3.1: potassium carbonate / tetrahydrofuran / 1 h / 20 °C 4.1: acetic acid / 0.5 h / 20 °C 4.2: 5 - 20 °C View Scheme

4-(difluoromethoxy)-3-methoxybenzaldehyde (162401-70-9) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium chloride / N,N-dimethyl-formamide / Reflux 2.1: potassium carbonate / tetrahydrofuran / 1 h / 20 °C 3.1: acetic acid / 0.5 h / 20 °C 3.2: 5 - 20 °C View Scheme

3-fluoro-4-hydroxybenzaldehyde (405-05-0) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / N,N-dimethyl-formamide; water / 2 h / 95 - 100 °C 2: potassium tert-butylate / 1,4-dioxane / 4 h / 70 - 75 °C 3: aminosulfonic acid; sodium chlorite; acetic acid / water / 0.5 h / 0 - 10 °C View Scheme

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride (672883-68-0)

Conditions	Yield
With thionyl chloride In toluene for 2h; Heating / reflux;	100%
With thionyl chloride In toluene for 2h; Reflux;	100%
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25℃; for 3h;	100%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + methyl iodide (74-88-4) → 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid methyl ester

Conditions	Yield
With potassium carbonate In N,N-dimethyl acetamide at 75 - 85℃; for 1h;	98.1%
With potassium carbonate In N,N-dimethyl acetamide at 75 - 85℃; for 1h;	98.1%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + 3,5-dichloro-4-aminopyridine (22889-78-7) → roflumilast (162401-32-3)

Conditions	Yield
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-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) → roflumilast (162401-32-3)

Conditions	Yield
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-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + glycine ethyl ester hydrochloride (5680-79-5) → 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamido)acetic acid methyl ester

Conditions	Yield
Stage #1: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: glycine ethyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 10h;	87%
Stage #1: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: glycine ethyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 10h;	87%
Stage #1: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: glycine ethyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Cooling with ice;	86.1%
Stage #1: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: glycine ethyl ester hydrochloride With N-ethyl-N,N-diisopropylamine at 20℃; Cooling with ice;	86.1%

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

Conditions	Yield
With diethylamino-sulfur trifluoride In dichloromethane at 0℃; for 0.5h;	80%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanone (1113061-20-3, 1239278-70-6, 1246537-42-7) → 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl)ethyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate (1113061-14-5)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 72h;	77%

2-hydroxypyridin (142-08-5) + 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) → pyridin-2-yl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere;	76%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + ethyl Bromopyruvate (70-23-5) → C17H16F2O6

Conditions	Yield
With dipotassium hydrogenphosphate; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; silver(I) acetate In 2,2,2-trifluoroethanol at 140℃; for 24h;	75%
With dipotassium hydrogenphosphate; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate; silver(I) acetate; XPhos In 2,2,2-trifluoroethanol at 140℃; for 24h; Sealed tube;	75%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide → (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide (1548868-68-3)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	71%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + 3-bromo-1,1,1-trifluoroacetone (431-35-6) → C15H11F5O4

Conditions	Yield
With dipotassium hydrogenphosphate; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; silver(I) acetate In 2,2,2-trifluoroethanol at 140℃; for 24h;	71%
With dipotassium hydrogenphosphate; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate; silver(I) acetate; XPhos In 2,2,2-trifluoroethanol at 140℃; for 24h; Sealed tube;	71%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + (S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanol → (S)-(-)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl)ethyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate (1548868-62-7)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 3h;	70%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + N-(p-toluenesulfonyl)aziridine (3634-89-7) → C21H23F2NO6S

Conditions	Yield
With mesitylenecarboxylic acid; palladium diacetate; caesium carbonate at 50℃; for 24h; Sealed tube;	67%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + 1-(4-nitro-benzenesulfonyl)-aziridine (43090-97-7) → C20H20F2N2O8S

Conditions	Yield
With mesitylenecarboxylic acid; palladium diacetate; caesium carbonate at 50℃; for 24h; Sealed tube;	64%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + 2,2,2-trifluoroethanol (75-89-8) + (3,3-difluoronon-4-yn-1-yl)benzene → 2,2,2-trifluoroethyl 5-(cyclopropylmethoxy)-4-(difluoromethoxy)-2-(6-oxo-9-phenylnon-4-en-5-yl)benzoate

Conditions	Yield
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; sodium carbonate In 1,2-dichloro-ethane at 60℃; for 24h;	61%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + methyl iodide (74-88-4) → C26H26F4O8

Conditions	Yield
Stage #1: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid With rhodium(III) chloride trihydrate; tetrabutylammonium acetate In N,N-dimethyl-formamide at 80℃; for 20h; Electrolysis; Stage #2: methyl iodide	56%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + C22H25F4N3O2 → C34H35F6N3O5

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 2h;	55%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + 1-tosyl-2-methylaziridine (25856-77-3) → C22H25F2NO6S

Conditions	Yield
With mesitylenecarboxylic acid; palladium diacetate; caesium carbonate at 50℃; for 24h; Sealed tube;	52%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + (3,3-difluoronon-4-yn-1-yl)benzene → 4-butyl-7-(cyclopropylmethoxy)-3-(1,1-difluoro-3-phenylpropyl)-6-(difluoromethoxy)-1H-isochromen-1-one

Conditions	Yield
With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; silver(I) acetate In 2,2,2-trifluoroethanol at 20℃; for 24h;	44%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + (3,3-difluoronon-4-yn-1-yl)benzene → (E)-4-butyl-7-(cyclopropylmethoxy)-6-(difluoromethoxy)-3-(3-phenylprop-1-en-1-yl)-1H-isochromen-1-one

Conditions	Yield
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; cesium acetate; Trimethylacetic acid In methanol at 80℃; for 24h;	40%

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (162401-62-9) + C18H17F4N3O3 → C30H27F6N3O6

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 1.5h;	38%

Upstream product

• 151103-09-2 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde 
• 405-05-0 3-fluoro-4-hydroxybenzaldehyde 
• 162401-70-9 4-(difluoromethoxy)-3-methoxybenzaldehyde 
• 121-33-5 vanillin 
• 680184-55-8 4-bromo-2-(cyclopropylmethoxy)-1-(difluoromethoxy)benzene 
• 124-38-9 carbon dioxide 
• 848574-60-7 3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester 
• 1895-39-2 sodium chlorodifluoroacetate 
• 25934-52-5 3-(cyclopropylmethoxy)-4-hydroxybenzaldehyde 
• 1381886-14-1 4-(benzyloxy)-3-(cyclopropylmethoxy)benzaldehyde 
• 4049-39-2 4-benzyloxy-3-hydroxy-benzaldehyde 
• 139-85-5 3,4-dihydroxybenzaldehyde 
• 151103-08-1 4-difluoromethoxy-3-hydroxybenzaldehyde 
• 1243391-44-7 3-(cyclopropylmethoxy)-4-hydroxybenzoic acid 

Downstream Products

• 162401-32-3 roflumilast 
• 151450-20-3 (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-methanol 
• 1428848-43-4 (S)-3,5-dichloro-4-(2-((3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzyloxy)carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide 
• 1113061-14-5 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl)ethyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate 
• 1001909-97-2 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanone 
• 1113061-15-6 3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide 
• 1590361-85-5 (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(1H-imidazol-1-yl)methanone 
• 1601300-21-3 (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(1H-1,2,4-triazol-1-yl)methanone 

Relevant articles and documents

A method for preparing raw material for roflumilast and detection method

The invention discloses a preparation method and a detection method of a roflumilast material. The preparation method comprises the following steps: mixing 3-cyclopropyl methoxy group-4-difluoro methoxy group benzoic acid SM-1, thionyl chloride, dimethyl formamide with toluene, and carrying out an acylating chlorination reaction to obtain a midbody 1; mixing 3,5-dichloro-4-aminopyridine SM-2, tetrahydrofuran with potassium tert-butoxide and carrying out a salt forming reaction to obtain tetrahydrofuran solution of a midbody 2; and then mixing the midbody 1 and the midbody 2 with tetrahydrofuran, carrying out amidation to obtain a crude product of roflumilast, and refining the crude product of roflumilast to prepare the roflumilast material. Aiming to overcome the shortage of the prior art, the preparation process of the roflumilast material is optimized, so that the curative effect for treating diseases such as chronic obstructive pulmonary disease (COPD) is more remarkable; and besides, a systematic, complete and effective composition identifying and content measuring method is provided, so that the quality of the medicine can be effectively controlled, and the clinical effect is ensured.

Synthesis method of roflumilast

The invention provides a synthetic method for roflumilast. The method comprises the following steps: (a), in an organic solvent, producing an exchange reaction of a compound (I) and magnesium or a Grignard reagent under the backflow condition to generate an intermediate, and producing a carbonyl insertion reaction of the intermediate and carbon dioxide at 0-50 DEG C to obtain a compound (II); or in the organic solvent, reacting the compound (I) with n-butyl lithium at 90 DEG C below zero to 70 DEG C below zero to generate an intermediate, and producing a carbonyl insertion reaction of the intermediate and carbon dioxide at 90 DEG C below zero to 70 DEG C below zero to obtain a compound (II); (b) in the organic solvent, reacting the compound (II) obtained in the step (a) with pivaloyl chloride or sulfonyl chloride at 0-50 DEG C in the presence of alkali to generate a mixed anhydride intermediate, and reacting the mixed anhydride intermediate with 3,5-dichloro-4-aminopyridine at 0-70 DEG C to obtain a compound (III) which is roflumilast. The method is short in process route, low in raw material and reagent costs, high in total yield, mild in reaction condition and suitable for industrialized production. The synthetic route of the method is as shown in the descriptions.

Roflumilast intermediate 3-cyclopropanecarboxylic methoxy-4-difluoro methoxylphenylboronic preparation of formic acid

The invention mainly aims to provide a simple method for preparing a roflumilast key intermediate 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid. In the process, 3-floro-4-hydroxy benzaldehyde is taken as a raw material and undergoes etherification reaction to obtain 4-difluoromethoxy-3-fluorobenzaldehyde, then 4-difluoromethoxy-3-fluorobenzaldehyde undergoes electrophilic substitution by using alkoxy phenylcyclofluorine to obtain 3-cyclopropyl methoxy-4-difluoromethoxy benzaldehyde and finally 3-cyclopropyl methoxy-4-difluoromethoxy benzaldehyde is oxidized by sodium chlorite to obtain 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid. The method has the beneficial effects that during the first-step reaction, the problem of selective etherification does not exist as hydroxy in the raw material substrate is single; the product is single; the yield and purity of the product are highe so that purification through column chromatography is not needed; poisons and hazardous materials are not used in the three reaction processes; the reaction conditions are mild; and the method is simple and convenient to operate, is simple in aftertreatment and is very suitable for industrial mass production; therefore the method is a low-cost and environment-friendly synthesis process.