Riociguat

Base Information

• Chemical Name: Riociguat
• CAS No.: 625115-55-1
• Molecular Formula: C₂₀H₁₉FN₈O₂
• Molecular Weight: 422.422
• Mol file: 625115-55-1.mol

Synonyms:BAY 632521;BAY 63-2521;Carbamicacid, [4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]methyl-,methyl ester (9CI);N-[4,6-Diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methylcarbamic acid methyl ester;Methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl}methylcarbamate;Carbamic acid,N-[4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methyl-,methyl ester;

Chemical Property of Riociguat

Chemical Property:

• Boiling Point: 567.202 °C at 760 mmHg
• PKA: 1.51±0.50(Predicted)
• Flash Point: 296.833 °C
• PSA: 138.80000
• Density: 1.513 g/cm³
• LogP: 2.95400
• Storage Temp.: Refrigerator
• Solubility.: DMSO (Slightly, Heated), Methanol (Slightly, Heated)

Purity/Quality:

99% ^*data from raw suppliers

Riociguat ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Production Method: Synthetic key of Riociguat is the synthesis of three heterocyclic ring. Compounds 1 and 2 directly close the pyrazole ring to generate 3,3 and 4 and then close the pyrazole ring to obtain5, ethyl of 5 is dehydrated using trifluoroacetic anhydride to give a cyano group after amidation by the ammonia , the cyano group is treated with methanol sodium and chloride ammonium to get amidine 6. The two nitrogen atoms on Amidine 6 as dinucleophile, with two cyano on compound 7 as the electrophile ,directly close the pyrimidine ring to give 8. pyrimidine 5-position amino group on 8 with a strong nucleophilic, directly reacts with methyl chloride and then methylates to give riociguat. Figure 1 is a chemical reactions road map of Riociguat production .
• Description: In September 2013, Health Canada approved riociguat (also referred to as BAY 63-2521), for the treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) after surgical treatment or inoperable CTEPH and for the treatment of adults with pulmonary arterial hypertension (PAH). Riociguat has a dual mode of action and works by (a) sensitizing sGC to the body’s NO by stabilizing NO–sGC binding and (b) an NO-independent, direct stimulation of sGC via a different binding site. This process restores the NO–sGC–cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.Headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation were the most common adverse events ( 3%) observed during riociguat clinical trials. Riociguat comes with a black box warning for embryo-fetal toxicity.
• Uses: Riocguat is used in the treatment for pulmonary hypertension. Riociguat is used in the treatment for pulmonary hypertension.
• Clinical Use: Guanylate cyclase stimulator: Treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH)
• Drug interactions: Potentially hazardous interactions with other drugs Avanafil, sildenafil, tadalafil, vardenafil: enhanced hypotensive effect - avoid. Nicorandil: possibly enhanced hypotensive effect - avoid. Nitrates: possibly enhanced hypotensive effect - avoid.

Technology Process of Riociguat

There total 14 articles about Riociguat 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: 93.52%

4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl amino acid methyl ester + methyl iodide (74-88-4) → Riociguat (625115-55-1)

Guidance literature:

With potassium carbonate; In methanol; N,N-dimethyl-formamide; at 0 - 10 ℃; for 24h; Reagent/catalyst; Solvent; Concentration; Inert atmosphere;

Reference yield: 90.0%

methyl N-methylcarbamate (6642-30-4) + 2-{1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-iodopyrimidine-4,6-diamine → Riociguat (625115-55-1)

Guidance literature:

With triethylamine; In N,N-dimethyl-formamide; at 20 ℃; for 3h;

Reference yield: 90.0%

methyl N-methylcarbamate (6642-30-4) + 4,6-diamino-2-{1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-5-yl methanesulfonate → Riociguat (625115-55-1)

Guidance literature:

With triethylamine; In N,N-dimethyl-formamide; at 0 - 20 ℃; for 2h;

upstream raw materials:

methyl iodide

2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6- triamine

C₂₃H₁₈FN₉

2-{1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-N-methylpyrimidine-4,5,6-triamine

Refernces

• 1、 -. "PROCESS FOR THE PREPARATION OF METHYL 4,6-DIAMINO-2-[1-(2-FLUOROBENZYL)-1H-PYRAZOLO[3,4-B]PYRIDIN-3-YL]-5-PYRIMIDINYL(METHYL)CARBAMATE AND ITS POLYMORPHS THEREOF". Page/Page column 17-18. . Retrieved 2018/06/12.
• 2、 -. "The preparation method of the west leo gua (by machine translation)". Paragraph 0086; 0087; 0088; 0092; 0093. . Retrieved 2017/10/05.