162401-32-3

Basic information

• Product Name: Roflumilast
• Synonyms: ROFLUMILAST;3-(Cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)benzamide;B 9302-107;BY 217;BYK 20869;Daxas;Roflumilast / 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide;3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide
• CAS NO: 162401-32-3
• Molecular Formula: C₁₇H₁₄Cl₂F₂N₂O₃
• Molecular Weight: 403.2074664
• EINECS: 223-583-8
• Product Categories: All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;APIs;Roflumilast;Daxas;API
• Mol File: 162401-32-3.mol

Chemical Properties

• Melting Point: 158°C
• Boiling Point: 430.6 °C at 760 mmHg
• Flash Point: 214.2 °C
• Appearance: white to beige/
• Density: 1.471 g/cm³
• Vapor Pressure: 1.28E-07mmHg at 25°C
• Refractive Index: 1.603
• Storage Temp.: Refrigerator
• Solubility: DMSO: soluble20mg/mL, clear
• PKA: 9.89±0.70(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• Merck: 14,8249
• CAS DataBase Reference: Roflumilast(CAS DataBase Reference)
• NIST Chemistry Reference: Roflumilast(162401-32-3)
• EPA Substance Registry System: Roflumilast(162401-32-3)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26
• WGK Germany: 3
• RTECS: CV3325600
• Hazardous Substances Data: 162401-32-3(Hazardous Substances Data)

Usage

Uses

1. Used in Pharmaceutical Industry:
Roflumilast is used as an anti-asthmatic agent for the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD). It helps in reducing inflammation and improving lung function in patients with these conditions.
2. Used in Respiratory Disease Treatment:
Roflumilast is used as an add-on to bronchodilator treatment for maintenance therapy of severe chronic obstructive pulmonary disorder (COPD) associated with chronic bronchitis in adult patients with a history of frequent exacerbations.
3. Used in Ophthalmic Solutions:
Roflumilast is also used in the development of ophthalmic solutions, although the specific application reason is not provided in the materials.
4. Used in Inflammatory Condition Treatment:
Roflumilast is a selective, long-acting PDE-4 inhibitor approved for the treatment of inflammatory conditions of the lungs, such as asthma and COPD. It has demonstrated anti-inflammatory effects in preclinical cellular and animal models.
5. Used in Drug Synthesis:
Roflumilast is synthesized in four steps from 3-(cyclopropylmethoxy)-4-hydroxybenzaldehyde, and its primary metabolite, roflumilast N-oxide, is also a potent and competitive inhibitor of PDE4. The drug's synthesis and metabolism involve various chemical reactions and are mediated by CYP3A4 and CYP1A2.
Despite its effectiveness, Roflumilast has some dose-limiting side effects, including mild nausea, diarrhea, and weight loss. However, these symptoms typically subside after a few weeks of treatment.

Indications and Usage

Roflumilast is a selective oral phosphodiesterase-4 (PDE-4) inhibitor and a benzamide compound. It was developed by the German company Altana in 1993 and is the only oral PDE-4 inhibitor used to treat respiratory tract diseases approved for sale. Roflumilast is the first drug of its kind to target severe chronic obstructive pulmonary disease (COPD), and it is also the first oral anti-inflammation drug specifically developed for COPD patients. Its unique properties can help regulate COPD: when used in combination with bronchodilators to treat extremely severe COPD patients, roflumilast can has the advantage of further reducing symptoms and deterioration rate, thus making it the first drug that targets patients with recurring deteriorating phenotype-specific COPD and severe air flow obstruction related to chronic coughing and excess phlegm. Besides being a treatment for severe COPD, roflumilast can also be used to prevent and treat livestock respiratory tract diseases, excess mucosa bronchitis cough, asthmatic bronchitis, and acute bronchitis and air sacculitis accompanied by abnormal respiratory tract secretion.

Mechanisms of Action

Roflumilast selectively inhibits PDE4 to prevent the signal transduction for inflammatory reactions, and it then inhibits the damage on lung tissue caused by respiratory tract diseases such as COPD and asthma.

Pharmacokinetics

Roflumilast is taken orally and is metabolized by cytochrome oxidase P45(CYP)3A4 and CYP1A2 enzyme into N-oxide. Roflumilast N-oxide’s activity is only 2-3 times weaker than that of roflumilast, and it also has relatively high PDE-4 selectivity. 90% of PDE-4 inhibition in the body is achieved by roflumilast N-oxide, while the other 10% is achieved by the original drug. A daily 500ng oral dose of roflumilast for a healthy person will produce a free blood concentration of roflumilast N-oxide in 24 hours of about 1-2 nmol?L-1, and its serum protein binding rate is about 97%. Smoking has little impact on roflumilast’s pharmacokinetics. Roflumilast mostly affects inflammation cells related to asthma, including eosinophils, neutrophils, and mast cells. This drug can specifically affect a certain enzyme that participates in smooth muscle contraction, it can prevent cAMP decomposition, thus preventing the signal transduction for inflammatory reactions, and it is anti-inflammatory, giving it relatively good curative effects in clinically treating asthma and COPD. Roflumilast can also significantly extend the deterioration of respiratory symptoms while also dramatically increasing patients’ quality of life.

Pharmacokinetics

Roflumilast is well absorbed on oral administration and has a half-life of 10 hours. Roflumilast is metabolized in the liver to its N-oxide derivative, which also is a PDE4 inhibitor, and it has a plasma half-life of 20 hours.

Originator

BYK Gulden Lomberg Chemische Fabrik GmbH (Germany)

Biochem/physiol Actions

Roflumilast is a highly potent, orally active, and selective phosphodiesterase 4 (PDE4) inhibitor with an IC50 of 0.8 nM. Roflumilast has anti-inflammatory properties and is used clinically to treat COPD.

Mechanism of action

Roflumilast is the more potent of the two drugs, and along with its active metabolite, roflumilast-N-oxide, it is nonselective in its inhibitory action on PDE4B and PDE4D. The PDE4B appears to be the most closely linked to anti-inflammatory effects, whereas the PDE4D receptor subtype is thought to be linked to nausea, possibly through a central effect. Roflumilast exhibits 80% oral bioavailability and has an elimination half-life of 10 hours, whereas the N-oxide has an elimination half-life of 20 hours and has shown no drug interactions. Clinical trials in patients with asthma or COPD are quite promising.

Clinical Use

Roflumilast is currently undergoing clinical trials in Europe for use in the treatment of both asthma and COPD.

Synthesis

The straightforward preparation of roflumilast begins with commercially available methyl 3,4-dihydroxybenzoate (130). Alkylation of the more reactive 3- hydroxyl group with (bromomethyl)cyclopropane (131) preceded a second alkylation of the remaining p-phenol with chlorodifluoromethane in aqueous sodium hydroxide. These phase-transfer conditions saponified the ester within 130 and after acidic quench, carboxylic acid 132 was ultimately furnished in excellent yield (97%) over the three step protocol. Activation of 132 as the corresponding acyl halide through use of thionyl chloride (SOCl2) and subsequent exposure to commercial aminopyridine 133 provided roflumilast (XII) in 81% yield.

References

1) Hatzelmann?et al.?(2010),?The preclinical pharmacology of roflumilast—a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease; Pulm, Pharmacol. Ther.,?23?235 2) Rabe?et al.?(2011),?Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease; Br. J. Pharmacol,?163?53 3) Heckman?et al.?(2018),?Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial; Psychopharmacology (Berl.),?235?301 4) Vanmierlo?et al.?(2016),?The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses;?Behav. Brain Res.,?303?26 5) Tikoo?et al.?(2014),?Calorie restriction mimicking effects of roflumilast prevents diabetic nephropathy; Biochem. Biophy. Res. Commun.,?450?1581 6) Mollmann?et al.?(2017),?The PDE4 inhibitor roflumilast reduced weight gain by increasing energy expenditure and leads to improved glucose metabolism; Diabetes Obes. Metab.,?19?496

InChI:InChI=1/C17H14Cl2F2N2O3/c18-11-6-22-7-12(19)15(11)23-16(24)10-3-4-13(26-17(20)21)14(5-10)25-8-9-1-2-9/h3-7,9,17H,1-2,8H2,(H,22,23,24)

Synthetic route

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%

3,5-dichloro-4-aminopyridine (22889-78-7) + 3-(difluoromethoxy)-4-(cyclopropylmethoxy)-benzoic acid (162401-69-6) → roflumilast (162401-32-3)

Conditions	Yield
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) → 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

3,5-dichloro-N-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzylidene)pyridin-4-amine (1454574-39-0) → roflumilast (162401-32-3)

Conditions	Yield
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; water	57%

3,5-dichloro-4-aminopyridine (22889-78-7) + (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(1H-imidazol-1-yl)methanone (1590361-85-5) → roflumilast (162401-32-3)

Conditions	Yield
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) + cyclopropylcarbinyl bromide (7051-34-5) → roflumilast (162401-32-3)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Temperature;	82.3%

3,5-dichloro-4-aminopyridine (22889-78-7) + (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(1H-1,2,4-triazol-1-yl)methanone (1601300-21-3) → roflumilast (162401-32-3)

Conditions	Yield
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 + 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride (672883-68-0) → roflumilast (162401-32-3)

Conditions	Yield
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-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride (672883-68-0) → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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 → roflumilast (162401-32-3)

Conditions	Yield
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 → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde (151103-09-2) → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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 → roflumilast (162401-32-3)

Conditions	Yield
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-) → roflumilast (162401-32-3)

Conditions	Yield
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-) → roflumilast (162401-32-3)

Conditions	Yield
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+) → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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) + 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-hydroxybenzamide → roflumilast (162401-32-3)

Conditions	Yield
With sulfuric acid at 140℃; for 7h; Inert atmosphere;	20.76 g

2-chloro-1-methoxy-4-methylbenzene (22002-44-4) → roflumilast (162401-32-3)

Conditions	Yield
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) → roflumilast (162401-32-3)

Conditions	Yield
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 N-oxide

Conditions	Yield
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) + roflumilast (162401-32-3) → C21H23Cl2F2N3O4S

Conditions	Yield
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) + roflumilast (162401-32-3) → C24H21Cl2F2N3O4S

Conditions	Yield
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) + roflumilast (162401-32-3) → C22H23Cl2F2N3O4S

Conditions	Yield
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) + roflumilast (162401-32-3) → C19H19Cl2F2N3O4S

Conditions	Yield
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) + roflumilast (162401-32-3) → N-cyanomethyl-N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

Conditions	Yield
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) + roflumilast (162401-32-3) → 3-(cyclopropylmethoxy)-N-(3,5-dichloro-2,6-dicyclohexylpyridin-4-yl)-4-(difluoromethoxy)benzamide

Conditions	Yield
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 + roflumilast (162401-32-3) → tert-butyl (3,5-dichloro-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamido)pyridin-2-yl)carbamate

Conditions	Yield
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) + roflumilast (162401-32-3) → N-(3,5-dichloropyrid-4-yl)-N-methoxymethyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

Conditions	Yield
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) + roflumilast (162401-32-3) → N-(3,5-dichloropyrid-4-yl)-N-(3-tert-butyldimethylsilyloxypropan-1-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

Conditions	Yield
With sodium hydride In mineral oil at 20 - 70℃; for 12h; Inert atmosphere;	31%

Chloroacetamide (79-07-2) + roflumilast (162401-32-3) → N-carbamoylmethyl-N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide

Conditions	Yield
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) + roflumilast (162401-32-3) → C23H24Cl2F2N2O5

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

Upstream product

• 672883-68-0 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride 
• 22889-78-7 3,5-dichloro-4-aminopyridine 
• 162401-62-9 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid 
• 58123-77-6 3-hydroxy-4-iodobenzoic acid 
• 157942-12-6 methyl 3-hydroxy-4-iodobenzoate 
• 1392191-29-5 methyl 3-(cyclopropylmethoxy)-4-iodobenzoate 
• 1243391-44-7 3-(cyclopropylmethoxy)-4-hydroxybenzoic acid 
• 848574-60-7 3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester 
• 151103-08-1 4-difluoromethoxy-3-hydroxybenzaldehyde 
• 151103-09-2 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde 
• 1454574-39-0 3,5-dichloro-N-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzylidene)pyridin-4-amine 
• 1454798-33-4 C₁₄H₁₈F₂O₄ 
• 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 

Downstream Products

• 292135-78-5 roflumilast N-oxide 
• 1616666-83-1 N-(3,5-dichloropyrid-4-yl)-N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide 

Relevant articles and documents

Production and preparation method of roflumilast crystalline powder bulk drug

The invention discloses a production and preparation method of a roflumilast crystalline powder bulk drug. The method comprises the following steps of: 1) acylation reaction: dropwise adding thionyl chloride into a toluene solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, and heating the reaction mixture to reflux, carrying out reaction for 2h, then conducting reduced pressure concentration to remove the solvent, dissolving the residue left by concentration in tetrahydrofuran, controlling the temperature of the solution at 15-20DEG C under stirring and dropwise adding the solution into a tetrahydrofuran solution of 4-amino-3, 5-dichloropyridine and sodium hydride; and 2) refining. The method has the beneficial effects that: a commercially available starting material of 1 (3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid) and a starting material of 2 (4-amino-3, 5-dichloropyridine) are selected as the starting materials, acylation and refining are carried out to obtain roflumilast, the process is stable, the yield is high, and industrial production is easy.

A preparation method of roflumilast

The invention discloses a method for preparation of roflumilast, comprises the following steps: 4 - (methoxy) benzoic acid chlorization reaction to obtain 4 - (methoxy) benzoyl chloride; with 3, 5 - dichloro - 4 - aminopyridine by amidation reaction to obtain N - (3, 5 - dichloro - 4 - pyridyl) - 4 - (methoxy) benzamide; then by Vismeier reaction to obtain N - (3, 5 - dichloro - 4 - pyridyl) - 4 - (methoxy) - 3 - formyl-benzoyl; through the Baeyer - villiger - hydrolysis reaction to obtain N - (3, 5 - dichloro - 4 - pyridyl) - 4 - (methoxy) - 3 - hydroxy benzoyl; then with the [...] yl cyclopropane ether to obtain roflumilast. The invention starting raw material is cheap, the reaction conditions are mild and controllable, synthetic route green environmental protection, high yield, the prepared Roflumilast purity is good.

Preparation methods of anti-inflammatory agent roflumilast for inhibiting PDE4 enzymatic activity and intermediate of roflumilast

The invention discloses preparation methods of an anti-inflammatory agent roflumilast for inhibiting the PDE4 enzymatic activity and an intermediate of the roflumilast. A chemical name of the anti-inflammatory agent roflumilast for inhibiting the PDE4 enzymatic activity is 3-(cyclopropyl methoxy)-N-(3,3-dichloropyridine-4-yl)-4-(difluoromethoxy) benzamide, the chemical formula of the roflumilast is C17H14C12F2N2O3, and the structural formula of the roflumilast is described as follow: (the structural formula is shown in the description). The preparation methods are concise in preparation technological process, available in raw material, simple in synthetic condition and high in yield and purity of a product, is environmentally friendly, is beneficial to realizing industrialization, lowers the production cost and is suitable for mass production; and the searched novel preparation methods of the roflumilast and the intermediate thereof have great significance on economical technology of the roflumilast.

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.

Preparation method for high-purity roflumilast

The invention belongs to the technical field of medicine, and particularly relates to a preparation method for high-purity roflumilast and an intermediate 3-hydroxy-4-diflouromethylbenzaldehyde of the roflumilast. The preparation method comprises the steps that the 3-hydroxy-4-diflouromethylbenzaldehyde is firstly obtained by taking 3-hydroxy-4-dihydroxybenzaldehyde as raw materails at higher yield and purity and then synthesized into 3-cyclopropylmethoxy-4-diflouromethylbenzaldehyde, the 3-cyclopropylmethoxy-4-diflouromethylbenzaldehyde is oxidized to obtain 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, and finally the 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid reacts with 4-amino-3,5-dichloropyridine to obtain the roflumilast. Due to the fact that the 3-hydroxy-4-diflouromethylbenzaldehyde with the higher yield and purity is obtained, the total yield of the roflumilast is increased, and many by-products which are difficult to separate cannot be generated.

A process for the preparation of roflumilast

The invention belongs to the technical field of drug synthesis, and specifically relates to a preparation method of roflumilast. The preparation method comprises the following steps: (1) dissolving an activating reagent into a solvent, adding 3-cyclopropylmethoxyl-4-difluoromethoxylbenzoic acid into the solvent to carry out reactions in the presence of an alkali; (2) adding 3,5-dichloro-4-aminopyridine into the solution obtained in the step (1) to carry out reactions so as to obtain the roflumilast. The 2,4-dimethoxyl-6-chloro-1,3-5-s-triazine and other reagents used in the preparation method are conventional reagents in production, and are easily available. Moreover, the production conditions are simple. Sulfoxide chloride, which has high requirements on production conditions and severely pollutes the environment, is replaced; and conditions that are not suitable for industrialization such as high temperature reduced pressure distillation, and the like are avoided at the same time, so the preparation method is a novel synthesis method suitable for industrial operation. Because the synthesis route is reasonably designed, and the reaction activity is high, the reaction yield is prominently improved, and can reach 86-95%.

PROCESS FOR PREPARATION OF ROFLUMILAST

The present invention provides novel processes for the preparation of N-substituted benzamides having the formula (VIc). In some embodiments, the invention provides a process for preparation of roflumilast and other pharmaceutically active species. Novel compounds, including intermediates for the synthesis of roflumilast, are also provided.

PROCESS FOR PREPARING ROFLUMILAST

The invention relates to a process for the preparation of Roflumilast by reaction of an activated form of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid with an activating agent selected from (a) carbonyldiimidazole (CDI), (b) 1,1'-carbonyl-di-(1,2,4-triazol) (CDT), (c) 1,1'-carbonyl-bis-(2-methylimidazol), (d),1'-carbonyl-dipyperidin, (e) N,N'-dicyclohexylcarbodiimide (DCC), (f) N,N′-diisopropylcarbodiimide (DIC), (g) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and a combination of one of the previous (a)-(g) with (h) N-hydroxysuccinimide or (i) N-hydroxyphthalimide, and the subsequent reaction with 3,5-dichloropyridine-4-amine in the presence of an inorganic base. The invention also relates to the synthesis intermediates.

PROCESS FOR THE PREPARATION OF ROFLUMILAST

The present invention relates to an improved process for the preparation of Roflumilast. The present invention also relates to crystalline Form-I of Roflumilast.