Tipranavir

Base Information

• Chemical Name: Tipranavir
• CAS No.: 174484-41-4
• Molecular Formula: C31H33F3N2O5S
• Molecular Weight: 602.675
• Mol file: 174484-41-4.mol

Synonyms:2-Pyridinesulfonamide,N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-,[R-(R*,R*)]-;Aptivus;PNU 140690;Tipranavir;U 140690;

Chemical Property of Tipranavir

Chemical Property:

• Appearance/Colour: White Solid
• Vapor Pressure: 0mmHg at 25°C
• Melting Point: 86-89 °C
• Refractive Index: 1.579
• Boiling Point: 680 °C at 760 mmHg
• PKA: 4.50±1.00(Predicted)
• Flash Point: 365.1 °C
• PSA: 113.97000
• Density: 1.313 g/cm³
• LogP: 8.47930
• Storage Temp.: -20°C Freezer
• Solubility.: Methanol (Slightly)

Purity/Quality:

98%,99%, ^*data from raw suppliers

Tipranavir| ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Description: Tipranavir, an oral non-peptidic HIV protease inhibitor, was granted accelerated approval for use in combination with ritanovir and was subsequently launched the same month in 2005. The targeted patient population includes HIV-1 infected adults with evidence of viral replication and demonstrated resistance to multiple protease inhibitors. As with other protease inhibitors, binding at the HIV-1 protease’s active site inhibits the virus-specific processing of the Gag and Gag-Pol polyproteins in HIV-1-infected cells resulting in the production of non-infectious virions. An effective regimen to reduce viral load and to preserve immune function typically consists of a cocktail of a protease inhibitor and at least one nucleoside reverse transcriptase inhibitor. It is believed that tipranavir has been effective where other protease inhibitors have encountered resistance because, as a non-peptidic inhibitor, it was designed by structure-based analysis to have increased flexibility making it acquiescent to conformational alterations at the binding site. Boosting with ritonavir (200 mg) increased tipranavir Cmin 4-fold and Cmax 20-fold. The primary route of excretion is through the feces (83%) with an effective mean elimination half-life of 4.8 h in healthy volunteers and 6.0 h in HIV-infected adults. The efficacy of tipranavir/ritonavir combination therapy has been evaluated in multiple clinical trials. In general, the adverse events included nausea, vomiting, and diarrhea. While tipranavir is a CYP3A4 inducer and substrate, as previously stated, its co-administration with the CYP3A4 inhibitor ritonavir results in net inhibition; therefore, patients should avoid the concomitant use of drugs highly dependent on CYP3A4 for clearance. The complete list of contraindicated drugs can be found in the package insert, but the general classes include antiarrhythmics, antihistamines, antimycobacterials, neuroleptics, sedatives, ergot derivatives, GI motility agents, and the herbal supplement St. John’s wort. Finally, as the elevated liver enzyme levels suggest, tipranavir should not be taken by patients with severe liver disease. Patients with clinical symptoms of hepatitis should immediately discontinue use of tipranavir. It is highly recommended that liver function tests be performed prior to treatment and throughout the course of therapy.
• Uses: Nonpeptidic HIV protease inhibitor (NPPI). Antiviral. Nonpeptidic HIV protease inhibitor (NPPI). Antiviral
• Clinical Use: Treatment (in combination with other antiretroviral drugs) of HIV-1 infection in patients unresponsive to more than one other protease inhibitor
• Drug interactions: Potentially hazardous interactions with other drugs Antacids: avoid giving for 2 hours after tipranavir administration. Antibacterials: plasma concentration of clarithromycin and other macrolides increased - reduce dose of clarithromycin in renal impairment; concentration increased by clarithromycin; rifabutin concentration increased (risk of uveitis) - reduce dose; concentration possibly reduced by rifampicin - avoid; avoid with telithromycin in severe renal and hepatic failure. Anticoagulants: avoid with apixaban and rivaroxaban. Antidepressants: concentration possibly reduced by St John’s wort - avoid. Antimalarials: use artemether/lumefantrine with caution; concentration of quinine increased. Antipsychotics: possibly increases aripiprazole concentration - reduce aripiprazole dose; possibly increases quetiapine concentration - avoid. Antivirals: reduces concentration of abacavir, dolutegravir, didanosine, fosamprenavir, lopinavir, saquinavir and zidovudine; concentration increased by atazanavir, also concentration of atazanavir reduced; concentration reduced by etravirine, also concentration of tipranavir increased - avoid. Beta-blockers: avoid with metoprolol for heart failure. Ciclosporin: levels possibly altered by tipranavir. Cobicistat: concentration of both drugs reduced - avoid. Lipid-lowering drugs: increased risk of myopathy with atorvastatin, max dose 10 mg; avoid with lomitapide; concentration of rosuvastatin increased - reduce rosuvastatin dose; concentration of simvastatin increased - avoid.1 Orlistat: absorption possibly reduced by orlistat. Ranolazine: possibly increases ranolazine concentration - avoid. Sirolimus: levels possibly altered by tipranavir. Tacrolimus: levels possibly altered by tipranavir. Ulcer-healing drugs: concentration of esomeprazole and omeprazole reduced.

Technology Process of Tipranavir

There total 24 articles about Tipranavir 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: 81.0%

5-trifluoromethyl-pyridin-2-ylsulfonylchloride (174485-72-4) + (R)-3-[(R)-1-(3-Amino-phenyl)-propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-pyran-2-one (174485-90-6) → tipranavir (174484-41-4,174484-81-2,174590-27-3)

Guidance literature:

With pyridine; In dichloromethane;

DOI:10.1021/ja963434w

Reference yield: 77.4%

(R)-3-[(R)-1-(3-Amino-phenyl)-propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-pyran-2-one (174485-90-6) + 4-(trifluoromethyl)pyridine-2-sulfonyl chloride (174485-71-3) → tipranavir (174484-41-4,174484-81-2,174590-27-3)

Guidance literature:

In dichloromethane; dimethyl sulfoxide; at -30 - -25 ℃; for 2h;

DOI:10.1021/jo9809229

Reference yield:

(E)-pent-2-enoyl chloride (33698-85-0) → tipranavir (174484-41-4,174484-81-2,174590-27-3)

Guidance literature:

Multi-step reaction with 8 steps

1: 95 percent / n-BuLi / tetrahydrofuran / -78 °C

2: CuBr, DMS / tetrahydrofuran / 1 h / 0 °C

3: 1.) H₃O⁺, 2.) Na₂CO₃ / 2.) H₂O, CH₂Cl₂

6: 67 percent / t-BuOK / tetrahydrofuran / 0 °C

7: H₂ / Pd/C / methanol; ethyl acetate

8: 81 percent / pyridine / CH₂Cl₂

With pyridine; n-butyllithium; 2,3-dimercapto-succinic acid; oxonium; potassium tert-butylate; hydrogen; sodium carbonate; copper(I) bromide; palladium on activated charcoal; In tetrahydrofuran; methanol; dichloromethane; ethyl acetate;

DOI:10.1021/ja963434w

upstream raw materials:

5-trifluoromethyl-pyridin-2-ylsulfonylchloride

(R)-3-[(R)-1-(3-Amino-phenyl)-propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-pyran-2-one

4-(trifluoromethyl)pyridine-2-sulfonyl chloride

1-phenylhexan-3-one

Refernces

• 1、 -. "Process to produce a protease inhibitor". . . Retrieved 2008/06/13.
• 2、 Fors, Kristina S.,Gage, James R.,Heier, Richard F.,Kelly, Robert G.,Perrault, William R.,Wicnienski, Nancy. "A convergent, scalable synthesis of HIV protease inhibitor PNU-140690". . p. 7348 - 7356. Retrieved 2007/10/03.