- A N - methyl -2 - isopropyl -4 - thiazole preparation of method
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The present invention provides a N - methyl - 2 - isopropyl - 4 - thiazole preparation of method, relates to the technical field of drug synthesis, solves the problem of the ritonavir intermediate N - methyl - 2 - isopropyl - 4 - thiazole preparation of method the existence of toxicity is relatively large, not friendly to the environment the technical problem. The preparation method comprises the following steps: (1) acylated - cyclization reaction; (2) aromatization - substitution reaction; (3) reduction reaction. The invention provides N - methyl - 2 - isopropyl - 4 - thiazole preparation of method, through to the cheap and easy isobutyryl chloride with cysteine methyl ester hydrochloride as raw materials; - cyclization reaction by acylation, aromatization - substitution reaction, the reduction reaction of the three-step synthesizing the compound; compared with the prior preparation method, has environmental protection of green, easy large-scale industrial production and yield and the like, has good application prospect.
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Paragraph 0016; 0018; 0019; 0021
(2019/04/06)
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- A 2 - isopropyl -4 - (methyl amino methyl) thiazole synthesis method (by machine translation)
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The invention discloses a 2 - isopropyl - 4 - (methyl amino methyl) thiazole synthesis method, in order to 2, 2 - dimethyl - 4 - methylene - 1, 3 - dioxane as the starting material, with a halo reagent addition reaction with a further thio isobutyramide after condensation to produce 2 - isopropyl - 4 - hydroxymethyl thiazole, through chlorination obtained after 2 - isopropyl - 4 - chloro methyl thiazole, finally with the methylamine substitution reaction, to obtain 2 - isopropyl - 4 - (methyl amino methyl) thiazole. The method of the invention novel routes, to avoid the use of toxic chemicals as the raw material, the operation is simple, mild condition, has the potential development of industrialization. (by machine translation)
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Paragraph 0026; 0034; 0035; 0036; 0046; 0056; 0064-0066
(2017/05/10)
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- Preparation method for 2-isopropyl-4-(methyl aminomethyl) thiazole hydrochloride
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The invention belongs to the field of medical intermediate synthesis, relates to a preparation method for ritonavir intermediate synthesis and particularly relates to a preparation method for 2-isopropyl-4-(methyl aminomethyl) thiazole hydrochloride. Isobutyric acid firstly reacts with thionyl chloride, and then ammonium sulfide and ammonium hydroxide are subjected to sulfo-reaction and aminating reaction, the existing process of using phosphorus pentasulfide for performing sulfo-reaction after acylation is replaced, the heavy smell is prevented from generating in the preparation process to avoid the environmental pollution. According to the invention, 1,3-dihydroxy acetone is adopted for replacing 1,3-dichloroacetone with high price, heavy smell and high pollution, the cost is saved and the preparation is environmentally friendly. According to the preparation method provided by the invention, the process is simple, the yield higher than that of the prior art and the preparation method is suitable for industrial production.
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Paragraph 0042-0044
(2018/04/01)
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- Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers. Part II: P2/P3 region and discovery of cobicistat (GS-9350)
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The HIV protease inhibitor (PI) ritonavir (RTV) has been widely used as a pharmacoenhancer for other PIs, which are substrates of cytochrome P450 3A (CYP3A). However the potent anti-HIV activity of ritonavir may limit its use as a pharmacoenhancer with other classes of anti-HIV agents. Ritonavir is also associated with limitations such as poor physicochemical properties. To address these issues a series of compounds with replacements at the P2 and/or P3 region was designed and evaluated as novel CYP3A inhibitors. Through these efforts, a potent and selective inhibitor of CYP3A, GS-9350 (cobicistat) with improved physiochemical properties was discovered.
- Xu, Lianhong,Liu, Hongtao,Hong, Allen,Vivian, Randy,Murray, Bernard P.,Callebaut, Christian,Choi, You-Chul,Lee, Melody S.,Chau, Jennifer,Tsai, Luong K.,Stray, Kirsten M.,Strickley, Robert G.,Wang, Jianhong,Tong, Leah,Swaminathan, Swami,Rhodes, Gerry R.,Desai, Manoj C.
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p. 995 - 999
(2014/02/14)
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- ACID ADDITION SALT OF 2-ISOPROPYL-4-(((N-METHYL)AMINO)METHYL)THIAZOLE AND ITS?USE IN THE PREPARATION OF RITONAVIR
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The present invention relates to a novel acid addition salt of 2-Isopropyl-4-(((N-methyl)amino)methyl)thiazole of Formula (I) which is a useful intermediate for preparing HIV protease inhibitors. The present invention further provides a process for preparing ritonavir, a HIV protease inhibitor, using the compound of Formula (I).
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Page/Page column 8-9
(2008/06/13)
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- Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy
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The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 μM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.
- Kempf, Dale J.,Sham, Hing L.,Marsh, Kennan C.,Flentge, Charles A.,Betebenner, David,Green, Brian E.,McDonald, Edith,Vasavanonda, Sudthida,Saldivar, Ayda,Wideburg, Norman E.,Kati, Warren M.,Ruiz, Lisa,Zhao, Chen,Fino, Lynnmarie,Patterson, Jean,Molla, Akhteruzzaman,Plattner, Jacob J.,Norbeck, Daniel W.
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p. 602 - 617
(2007/10/03)
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- Pharmaceutical composition
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A solid pharmaceutical composition is disclosed which comprises a pharmaceutically acceptable adsorbent or a mixture of pharmaceutically acceptable adsorbents to which is adsorbed a mixture of (1) a pharmaceutically acceptable organic solvent or a mixture of pharmaceutically acceptable organic solvents, (2) an HIV protease inhibiting compound and (3) one or more pharmaceutically acceptable acids. The solid composition can optionally be encapsulated in a hard gelatin capsule.
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- Pharmaceutical composition for inhibiting HIV protease
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A pharmaceutical composition is disclosed which comprises a solution of an HIV protease inhibiting compound in a pharmaceutically acceptable organic solvent comprising a mixture of (1) (a) a solvent selected from propylene glycol and polyethylene glycol or (b) a solvent selected from polyoxyethyleneglycerol triricinoleate, polyethylene glycol 40 hydrogenated castor oil, fractionated coconut oil, polyoxyethylene (20) sorbitan monooleate and 2-(2-ethoxyethoxy)ethanol or (c) a mixture thereof and (2) ethanol or propylene glycol.
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- RETROVIRAL PROTEASE INHIBITING COMPOUNDS
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A retroviral protease inhibiting compound of the formula: STR1 is disclosed wherein R 1, R 2, R 5, R 6, Y m and Y' n are herein defined.
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- Thiazole derivate and process for its preparation
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The invention relates to a thiazole derivative represented by the formula (1) wherein R2 is an alkyl group having 1 to 4 carbon atoms. The thiazole derivative of the invention is prepared by reacting 2-isopropyl-4-chloromethylthiazole with an N-alkyl-acid amide-alkali metal salt in an aromatic hydrocarbon to give a thiazole-N-alkyl-acid amidated product, and hydrolyzing the resulting compound in the presence of an aromatic hydrocarbon. The thiazole derivative of the formula (1) prepared according to the invention can be suitably used as information display materials, antiglare materials, and intermediates for preparation of medicaments, agricultural chemicals.
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