Darunavir CAS 206361-99-1
Introduction：Basic information about Darunavir CAS 206361-99-1, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Darunavir Basic informationAIDS treatment
| Product Name: | Darunavir |
| Synonyms: | [(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenyl-methyl)propyl]carabamic Acid (3R,3aS,6aR)-Hexahydrofuro[2,3-b]-furan-3-yl Ester;Darunavir;TMC-114;UIC-94017;[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenyl-methyl)propyl]carabamic Acid (3R,3aS,6aR)-Hexahydrofuro[2,3-β]-furan-3-yl Ester;D03656;Darunavir (usan/inn);(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl](2-methylpropyl)amino}-3-hydroxy-1-phenylbutan-2-yl]carbamate |
| CAS: | 206361-99-1 |
| MF: | C27H37N3O7S |
| MW: | 547.66 |
| EINECS: | 606-590-1 |
| Product Categories: | Intermediates & Fine Chemicals;Pharmaceuticals;Antiviral Agents;peptides;Aromatics;Heterocycles;Inhibitors |
| Mol File: | 206361-99-1.mol |
Darunavir Chemical Properties
| Melting point | 74-760C |
| density | 1.34±0.1 g/cm3(Predicted) |
| storage temp. | -20°C |
| solubility | Soluble in DMSO (>25 mg/ml) |
| form | powder |
| pka | 11.43±0.46(Predicted) |
| color | white to beige |
| 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. |
| InChIKey | CJBJHOAVZSMMDJ-HEXNFIEUSA-N |
| SMILES | C(O[C@H]1CO[C@@]2([H])OCC[C@]21[H])(=O)N[C@@H](CC1=CC=CC=C1)[C@H](O)CN(S(C1=CC=C(N)C=C1)(=O)=O)CC(C)C |
Safety Information
| WGK Germany | 3 |
| Storage Class | 11 - Combustible Solids |
| Hazardous Substances Data | 206361-99-1(Hazardous Substances Data) |
| AIDS treatment | Darunavir is a new kind of non peptide anti retroviral protease inhibitors in AIDS therapy. It is first developed by the Johnson pharmaceutical Iceland branch, Tibotec. It is of the highest bioavailability in the 6 protease inhibitors (saquinavir, ritonavirvir, indinavir, naphthalene nelfinavir, amprenavir and ABT378/r). It acts by blocking the formation of new and mature virus particles from the surface of the infected host cells and inhibiting the virus's protease. When the product is used for a long time, it usually can reduce the HIV virus vector in blood, increase the count of CD4 cells, reduce the chance of HIV infection, improve the quality of life and prolong life. It is suitable for adults who are infected with the HIV virus but have no effect on the use of existing antiretroviral drugs. The drug must be combined with the use of low doses of ritonavir or other antiretroviral agents, in order to improve the efficacy. The antiviral activity in vitro can be evaluated by being against acute and chronic infected lymphocytes and lymphocytes in peripheral blood. The IC50 is 0.012 to 0.08 mmol/ L for acute infected cells and 0.41 mmol/L for chronic infected cells. For oral administration, recommended dose is 1,200mg once and twice per day. The doseshould be reduced for patients with mild to moderate liver dysfunction and those with renal dysfunction. The adverse reaction of darunavir is mainly gastrointestinal reaction, flushing, itching and perioral numbness, depression, mood disorders, taste disorder etc. This product is not recommended for patients with moderate to severe liver dysfunction. Because of the sulfonamides in this component, it is prohibited for those who are allergic to sulfanilamide and any component in the prescription of this product. |
| Description | Darunavir is the latest weapon in the arsenal of agents to combat humanimmunodeficiency virus type 1(HIV-1). As an HIV-1 protease inhibitor, its mechanismof action involves blocking the cleavage of the gag and gag–pol polyproteinsinto functional proteins essential for the production of infectious progenyvirus; the result is the production of immature, noninfectious viral particles.Compared to predecessor HIV protease inhibitors, darunavir retains activityagainst resistant stains, a critical factor with the continual emergence of multidrug-resistant (MDR) mutants. Despite experiencing a 13-fold reduction in bindingto MDR HIV-1 protease, this binding is 1.5 orders of magnitude tighter thanthe first-generation protease inhibitors. Furthermore, darunavir exhibits less thana 10-fold decrease in susceptibility in cell culture against 90% of 3309 clinicalisolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir,ritonavir, saquinavir, and tipranavir. In contrast, darunavir-resistant viruses displaylimited susceptibility to only tipranavir, suggesting limited cross-resistancebetween these two protease inhibitors. To avoid the issues of the peptide-basedprotease inhibitors, darunavir has evolved from a structure-based design effort tominimize peptidic features and reduce molecular weight and complexity. |
| Chemical Properties | White Amorphous Solid |
| Originator | Tibotec/J&J (US) |
| Uses | Second generation HIV-1-protease inhibitor; structurally similar to amprenavir. Antiviral. It is a COVID19-related research product. |
| Definition | ChEBI: An N,N-disubstituted benzenesulfonamide bearing an unsubstituted amino group at the 4-position, used for the treatment of HIV infection. A second-generation HIV protease inhibitor, darunavir was designed to form robustinteractions with the protease enzyme from many strains of HIV, including those from treatment-experienced patients with multiple resistance mutations to other protease inhibitors. |
| Brand name | Prezista |
| Acquired resistance | Darunavir is less affected than other protease inhibitorsby mutations to resistance, but subgroups with more than10 cumulative mutations show a >10-fold (median value)decrease in susceptibility. The major resistance mutationsoccur at positions 50 (150V), 54 (I50M/L), 76 (L76V) and84 (I84V) of the protease gene. |
| Pharmaceutical Applications | A synthetic compound formulated as the ethanolate for oraluse in combination with ritonavir. |
| Biochem/physiol Actions | Darunavir has been sanctioned by the food and drug administration (FDA) as the first treatment of drug-resistant human immunodeficiency virus (HIV). |
| Pharmacokinetics | Oral absorption: c. 82% Cmax 600 mg once daily + ritonavir 100mg twice daily:c. 6500 μg/L Cmin 600 mg oral + ritonavir100 mg twice daily:c. 3578 μg/L Plasma half-life: c. 15 h Volume of distribution: c. 131 L Plasma protein binding: c. 95% A single 600 mg dose given orally in combination with ritonavir100 mg every 12 h increased the systemic exposure ofdarunavir approximately 14-fold. The relative bioavailabilityis 30% lower when administered with food in the presence oflow-dose ritonavir. Distribution into human CSF, semen orbreast milk has not yet been determined. At least three oxidative metabolites, mediated predominantlythrough CYP3A4, have been identified in humans;all are at least 10-fold less active than the parent compoundagainst HIV. Around 80% and 14% of the dose is found in thefeces and urine, respectively. It should be used with cautionin mild–moderate hepatic impairment and avoided in patientswith more severe impairment. |
| Clinical Use | Treatment of HIV infection (in combination with other antiretroviral drugs) |
| Side effects | In phase III studies the most common adverse events werediarrhea, nausea, headache and nasopharyngitis. Patients coinfectedwith hepatitis B or C did not have a higher incidenceof adverse events. |
| Synthesis | Several routes to the synthesisof darunavir have been reported utilizing the chiralhexahydro-furo[2,3-b]furan-3-ol carbonate 12 andseveral chiral syntheses of bisfuranol 12 have been disclosedas well. One route that has been performed on kilogramscale is highlighted in the scheme. Thus 2,3-Oisopropylidene-glyceraldehyde 5 was stirred with dimethylmalonate at RT for 3 h in tetrahydrofuran followed by additionof pyridine and heating to 45oC. Then acetic anhydridewas added at 45oC over 4h and stirred at that temperature for12 h. Concentration of the reaction followed by basicworkup and extraction with toluene and solvent swap tomethanol gave the products as a 23.6% solution in methanol.Nitromethane was added to this methanol solution followedby the addition of DBU over 30 min keeping the reactiontemperature below 25oC. Stirring the reaction for an additional3 h afforded intermediate 7. The reaction was cooled to 0oC and sodium methoxide was added dropwise over 30min After stirring the reaction for 30 min, the reaction wasadded slowly over 1h to conc. H2SO4 in methanol at 0oCwhile ensuring the temperature did not exceed 10oC. Thiscooled reaction mixture (0oC) was then added to a vigorouslystirred mixture of ethyl acetate and 1N sodium hydrogencarbonate at 0oC. The organic layer was separated, washedwith brine and concentrated to give the residue containing amixture of 8 and 9. This mixture was dissolved in methanolthen water and potassium hydroxide were added and the resultingmixture was heated at reflux for 2 h. The reactionwas cooled to 35oC and acetic acid was added and the resultingmixture concentrated. Additional acetic acid was addedand stirred at room temperature for 2 h. The mixture wasconcentrated, diluted with water and extracted with ethylacetate.The ethylacetate layer was washed with 1N sodium bicarbonatethree times and the organic layer was concentratedand diluted with isopropanol. The isopropanol mixture wasthen heated to 60-70oC and further evaporation of isopropanolunder reduced pressure to a concentrated volume withcooling to 0oC over 4-5 h, allowed for the crystallization ofproduct 10. After filtration and drying, the intermediate lactone10 was dissolved in THF and treated over 30 min with asolution of lithium borohydride in THF. The reaction waswarmed to 50oC over 1 h and stirred at that temperature for2h. The resulting suspension was cooled to -10oC and conc.HCl was added slowly over 4h, while maintaining the temperaturebelow 0oC. Solvent swap was done by concentratingto a small volume and addition of ethyl acetate and furtherconcentration of the solvent with continuous addition of ethylacetate.Following this procedure, when the final ratio ofTHF:ethylacetate reached 4:1 ratio, the mixture was cooledto 0oC and filtered off while washing the filter cake withmore ethylacetate. Concentration of the filtrate to drynessgave the hexahydro-furo [2,3-b]furan-3-ol 11 which wasconfirmed by NMR and chiral gas chromatography. Carbonateintermediate 12 was prepared in 66% yield by treating 11with disuccinimidyl carbonate at RT for 3h in the presenceof triethylamine. Since the process scale synthesis ofdarunavir has not been disclosed, the latest reported synthesisis highlighted. The commercially available epoxide13 was mixed with isobutyl amine in isopropanol at RT andrefluxed for 6h. The reaction was concentrated and purifiedby chromatography to provide amine 15 (99%). p-Nitrophenylsulfonyl chloride was added to a mixture of the amine 15in dichloromethane and saturated aqueous bicarbonate at RTand stirred for 12 h to give sulfonamide 16 in 96% yield afterpurification. Hydrogenation of 16 with 10% Pd/C under 1atm hydrogen for 11h at room temperature gave aniline 17 in95% yield. The BOC group was removed by treating 17 withTFA in dichloromethane and the resulting amine was reactedwith carbonate 12 in the presence of triethylamine for 3h toprovide the desired darunavir (II) in 89% yield. |
| target | HIV Protease |
| Drug interactions | Potentially hazardous interactions with other drugs Antibacterials: rifabutin concentration increased - reduce dose of rifabutin; darunavir concentration reduced by rifampicin - avoid. Anticoagulants: avoid with apixaban and rivaroxaban Antidepressants: possibly reduced concentration of paroxetine and sertraline; darunavir concentration reduced by St John’s wort - avoid. Antimalarials: concentration of lumefantrine increased; possibly increases concentration of quinine Antipsychotics: possibly increases concentration of aripiprazole (reduce dose of aripiprazole); possibly increases quetiapine concentration - avoid. Antivirals: avoid with boceprevir or telaprevir; take didanosine 1 hour before or 2 hours after darunavir administration; concentration reduced by efavirenz - adjust dose; concentration of both drugs increased with indinavir and simeprevir - avoid with simeprevir; concentration reduced by lopinavir, also concentration of lopinavir increased - avoid; concentration of maraviroc increased, consider reducing dose of maraviroc; concentration of paritaprevir increased and paritaprevir reduces darunavir concentration; concentration reduced by saquinavir; increased risk of rash with raltegravir; avoid with telaprevir. Cytotoxics: possibly increases bosutinib concentration, avoid or reduce dose of bosutinib; possibly increases everolimus concentration - avoid; possibly increases ibrutinib concentration - reduce ibrutinib dose. Ergot alkaloids: increased risk of ergotism - avoid. Lipid-lowering drugs: possibly increased risk of myopathy with atorvastatin and rosuvastatin, reduce dose of rosuvastatin; possibly increases pravastatin concentration; avoid with lomitapide; avoid with simvastatin.1 Orlistat: absorption of darunavir possibly reduced. Ranolazine: possibly increases ranolazine concentration - avoid. |
| Metabolism | Darunavir is metabolised by oxidation by the cytochrome P450 system (mainly the isoenzyme CYP3A4), with at least 3 metabolites showing some antiretroviral activity.About 80% of a dose is excreted in the faeces, with 41.2% of this as unchanged drug; 14% is excreted in the urine |
| storage | Store at -20°C |
| References | [1] YASUHIRO KOH. Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro.[J]. Antimicrobial Agents and Chemotherapy, 2003: 3123-3129. DOI:10.1128/aac.47.10.3123-3129.2003 [2] DOMINIQUE L. N. G. SURLERAUX. Discovery and Selection of TMC114, a Next Generation HIV-1 Protease Inhibitor§[J]. Journal of Medicinal Chemistry, 2004, 48 6: 1813-1822. DOI:10.1021/jm049560p [3] BO RAM BECK. Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model.[J]. ACS Applied Energy Materials, 2020: 784-790. DOI:10.1016/j.csbj.2020.03.025 [4] SALMAN ALI KHAN. Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach.[J]. Journal of Biomolecular Structure & Dynamics, 2021, 39 7: 2607-2616. DOI:10.1080/07391102.2020.1751298 [5] SANDRA DE MEYER . Lack of antiviral activity of darunavir against SARS-CoV-2[J]. International Journal of Infectious Diseases, 2020, 97: Pages 7-10. DOI:10.1016/j.ijid.2020.05.085 [6] EUN JIN KIM. Use of Darunavir-Cobicistat as a Treatment Option for Critically Ill Patients with SARS-CoV-2 Infection.[J]. Yonsei Medical Journal, 2020, 61 9: 826-830. DOI:10.3349/ymj.2020.61.9.826 |
Darunavir Preparation Products And Raw materials
