Roflumilast

Base Information

• Chemical Name: Roflumilast
• CAS No.: 162401-32-3
• Molecular Formula: C17H14Cl2F2N2O3
• Molecular Weight: 403.213
• European Community (EC) Number: 685-382-2
• UNII: 0P6C6ZOP5U
• DSSTox Substance ID: DTXSID8044123
• Nikkaji Number: J1.365.537E
• Wikipedia: Roflumilast
• Wikidata: Q693482
• NCI Thesaurus Code: C76890
• RXCUI: 1091836
• Pharos Ligand ID: LAJCMJDNMUA5
• Metabolomics Workbench ID: 56780
• ChEMBL ID: CHEMBL193240
• Mol file: 162401-32-3.mol

Synonyms:3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-di-chloropyrid-4-yl)benzamide;daliresp;roflumilast

Chemical Property of Roflumilast

Chemical Property:

• Appearance/Colour: Crystalline solid
• Vapor Pressure: 1.28E-07mmHg at 25°C
• Melting Point: 158 °C
• Refractive Index: 1.603
• Boiling Point: 430.6 °C at 760 mmHg
• PKA: 9.89±0.70(Predicted)
• Flash Point: 214.2 °C
• PSA: 60.45000
• Density: 1.471 g/cm³
• LogP: 5.10390
• Storage Temp.: Refrigerator
• Solubility.: DMSO: soluble20mg/mL, clear
• XLogP3: 4.6
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 6
• Rotatable Bond Count: 7
• Exact Mass: 402.0349540
• Heavy Atom Count: 26
• Complexity: 475

Purity/Quality:

99%min , ^*data from raw suppliers

Roflumilast ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xi
• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Pulmonary Disease Agents
• Canonical SMILES: C1CC1COC2=C(C=CC(=C2)C(=O)NC3=C(C=NC=C3Cl)Cl)OC(F)F
• Recent ClinicalTrials: Roflumilast Versus Methotrexate in Psoriasis
• Recent EU Clinical Trials: Efficacy and safety of oral roflumilast in the treatment of palmoplantar pustulosis – a randomised controlled trial
• Description: Type 4 cyclic nucleotide phosphodiesterase (PDE4) isoforms selectively inactivate the second messenger cAMP by hydrolyzing the phosphodiester bond, producing AMP. Roflumilast is a potent, cell-permeable inhibitor of PDE4 (IC50 = < 1 nM for both human PDE4B and PDE4D). It is selective for PDE4, with IC50 values against other PDE forms being greater than 10 μM. Roflumilast demonstrates good bioavailability and has applications in respiratory diseases, including asthma and chronic obstructive pulmonary disease. Roflumilast is a selective, orally active PDE4 inhibitor thatwas approved in Germany in July 2010 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 . Roflumilast and its primary metabolite roflumilast N-oxide are potent and competitive inhibitors of PDE4 and are equipotent against PDE4A, B, andD but inactive against PDE4C and the other ten members of the PDE family (PDEs 1–3, 5–11). Despite its inhibition of PDE4D (IC50=0.80 nM, N-oxide IC50=2.0 nM), roflumilast shows the lowest incidence of nausea (3–5%) among the PDE4 inhibitors investigated in clinical trials.Anti-inflammatory effects of roflumilast have been demonstrated in preclinical cellular and animal models. Roflumilast is synthesized in four steps from 3-(cyclopropylmethoxy)-4-hydroxybenzaldehyde. The difluoromethyl ether is introduced by alkylation of the free phenolic group with chlorodifluoromethane and base. The aldehyde moiety is oxidized to the benzoic acid, which is then converted to an acid chloride and coupled with 3,5-dichloro-4-aminopyridine. Roflumilast is rapidly absorbed and metabolized to its active metabolite, roflumilast N-oxide. Metabolism is mediated by CYP3A4 and CYP1A2.
• Uses: Selective phosphodiesterase 4(PDE4) inhibitor. Antiasthmatic; in treatment of chronic obstructive pulmonary disease Roflumilast (Daxas) is a selective inhibitor of PDE4 with IC50 of 0.2-4.3 nM. ophthalmic solution Roflumilast is a selective, long-acting PDE-4 inhibitor approved in 2010 for the treatment of inflammatory conditions of the lungs such as asthma and chronic obstructive pulmonary disorder. Marketed under the trade name Daxas?, roflumilast was developed by researchers at the University of Liverpool in partnership with Nycomed. Although the dose-limiting side effects of the drug are mild nausea, diarrhea, and weight loss, these symptoms subsided after a few weeks of treatment.
• Clinical Use: Roflumilast is currently undergoing clinical trials in Europe for use in the treatment of both asthma and COPD.

Technology Process of Roflumilast

There total 32 articles about Roflumilast which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 95.0%

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

Guidance literature:

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid; With pyridine; 2,4,6-trinitrochlorobenzene; In 1,4-dioxane; at 20 - 35 ℃; for 3h; Industrial scale;

3,5-dichloro-4-aminopyridine; In 1,4-dioxane; for 2h; Reagent/catalyst; Solvent; Temperature; Industrial scale;

Reference yield: 95.0%

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

Guidance literature:

3-(difluoromethoxy)-4-(cyclopropylmethoxy)-benzoic acid; With thionyl chloride; In toluene; for 2h; Reflux;

3,5-dichloro-4-aminopyridine; With sodium hydride; In tetrahydrofuran; at 15 - 20 ℃;

Reference yield: 93.0%

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

Guidance literature:

Large scale;

DOI:10.1055/s-0032-1317527

upstream raw materials:

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

3,5-dichloro-4-aminopyridine

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

3-hydroxy-4-iodobenzoic acid

Downstream raw materials:

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

Refernces

• 1、 -. "A preparation method of roflumilast". Paragraph 0102-0107; 0108-0113; 0114-0119; 0120-0125. . Retrieved 2019/04/13.
• 2、 -. "Preparation methods of anti-inflammatory agent roflumilast for inhibiting PDE4 enzymatic activity and intermediate of roflumilast". Paragraph 0017; 0018; 0021. . Retrieved 2018/06/21.