- Preparation method of ritonavir
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The invention provides a preparation method shown I, N - [(2S, 3S, 5R) -3 - hydroxyl -5 - [(2S) -3 - methyl -2 - [[methyl - [(2 - isopropyl -1, 3 - thiazole -4 - yl) methyl] carbamoyl] amino] -1, 6 - diphenyl - hexyl -2 -] carbamic acid 5 - thiazolyl methyl ester. The invention provides a new method for preparing ritonavir.
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Paragraph 0004; 0005; 0007; 0008; 0010
(2021/10/13)
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- Novel method for synthesizing ritonavir
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The invention discloses a novel method for synthesizing ritonavir, and relates to the field of pharmaceutical chemistry. The method comprises the following steps: at -5 to 10 DEG C, adding pivaloyl chloride into an intermediate V, dropwise adding an organic alkali, keeping the temperature in the reaction kettle at -5 to 10 DEG C after dropwise adding, stirring for reacting for T1, adding 4-dimethylaminopyridine, stirring for T2 time, finally adding a dichloromethane solution of an intermediate VI, raising the reaction temperature to 25 to 35 DEG C after adding, and stirring until the reactionis finished. Common industrial raw materials and reagents are used, so the method is suitable for industrial mass production, and through simple purification002C the yield is 85% or above, and the purity is 99.5% or above.
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Paragraph 0025-0026
(2020/09/20)
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- Preparation method of ritonavir
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The invention relates to the technical field of medicine, in particular to a preparation method of ritonavir. According to the preparation method of the ritonavir, (2-isopropyl thiazole-4-yl)-nitrogen-methyl methylamine is taken as a raw material, and the ritonavir is synthesized through a three-step reaction; a urea bond is built by trichloroethanol chloroformate, paratoluensulfonyl chloride which is cheap and easy to obtain is adopted as a condensing agent for amide, the ritonavir is synthesized with the high yield, and the yield of the ritonavir is 79%; and compared with an existing preparation method, the preparation method has the advantages of low cost, environment friendliness, easy scale production and the like, and has good application prospects.
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- Preparation method of ritonavir
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The invention discloses a preparation method of ritonavir. According to the preparation method, N-[N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)aminocarbonyl]-L-valine is taken as a raw material, and is reacted with thionyl chloride so as to obtain an intermediate I; the intermediate I is reacted with ((2S, 3S, 5S)-5-amino-3-hydroxy-1.6-diphenylhexane-2-yl) tert-butyl carbamate so as to obtain intermediate II; the intermediate II is subjected to hydrolysis to remove tertbutyloxycarbonyl so as to obtain an intermediate III; the intermediate III is reacted with ((5-Thiazolyl)methyl)-(4-nitrophenyl)carbonate so as to obtain finished product ritonavir. The preparation method is short in synthesis route; the raw materials are simple and are easily available; the reaction sequence is reasonable;using of expensive palladium catalyst and condensing agents such as DCC, EDC, HATU, DEPBT, and toxic triphosgene is avoided; the preparation method is green, is friendly to the environment; reaction conditions are mild; side product is less; synthesis yield is high; the purity of obtain ritonavir is high; production cost is low; and the preparation method is suitable for industrialized production.
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- Method for preparing Ritonavir
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The invention relates to a method for preparing Ritonavir applied to the technical field of pharmaceutical synthesis. According to the method, under the conditions of organic alkali and an organic solvent, DIC is used as a condensing agent, N-[2-Isopropylthiazol-4-ylmethyl(methyl)carbamoyl]-L-valine and (2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane are subjected to an acidamide reaction, and then a certain post-treatment is performed, so that the Ritonavir is obtained. According to the method disclosed by the invention, the synthesis yield of the Ritonavir is increased, the purity is high, and the cost of raw materials is effectively reduced. Besides, the feed is simple, nitrogen protection is not needed, and feeding temperature needs to be appropriately controlled, so that reaction by-products can be easy to wash away, the preparation time is greatly shortened, the working efficiency is improved, and the method is suitable for industrial production.
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Paragraph 0020; 0021; 0022; 0023
(2017/08/29)
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- Method for preparing Ritonavir as anti-AIDS drug
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The invention relates to a method for preparing Ritonavir applied to the technical field of pharmaceutical synthesis. According to the method, under the conditions of organic alkali and an organic solvent, HATU is used as a condensing agent, N-[2-Isopropylthiazol-4-ylmethyl(methyl)carbamoyl]-L-valine and (2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane are subjected to an acidamide reaction, and then a certain post-treatment is performed, so that the Ritonavir is obtained. According to the method disclosed by the invention, the synthesis yield of the Ritonavir is increased, the purity is high, and the cost of raw materials is effectively reduced. Besides, the reaction time is short, the feed is simple, nitrogen protection is not needed, and feeding temperature needs to be appropriately controlled, so that by-products of HATU can be easy to wash away, the preparation time is greatly shortened, the working efficiency is improved, and the method is suitable for industrial production.
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Paragraph 0021; 0022; 0023; 0024
(2017/08/29)
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- A method of preparing anti HIV drug ritonavir
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The invention discloses a method for preparing anti-HIV medicine ritonavir and belongs to the technical field of medicines. In conditions of proper temperature, taking weak base as acid-binding agent and certain organic solvent, N-[N(-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine and thionyl chloride are reacted to produice N(-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine acyl chloride, which is not required to be purified and can be directly subjected to amide reaction with (2s, 3s, 5s)-5-amino-2-((i)N(/i)-((5-thiazolyl)-methoxycarbonyl group) amino)-1, 6-diphenyl-3-hydroxy hexane at a room temperature, so as to obtain ritonavir; the mole ratio of the N-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine to thionyl chloride is 1:1 to 1:8; the mole ratio of the N-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine acyl chloride to weak base is 1:1 to 1:15. The method has the advantages that the price of thionyl chloride is low, the material cost is reduced, the production pollution is low, the pollution can be changed into soluble effluent brine, the method is simple to operate, the product yield is high, and the method is easy for separation and purification, and is applicable to industrial production.
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- A PROCESS FOR THE SYNTHESIS OF 2-AMINO-5-PROTECTED AMINO-3-HYDROXY-1, 6-DIPHENYLHEXANE OR A SALT THEREOF - AN INTERMEDIATE FOR ANTIVIRAL DRUGS
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The present invention relates to an improved process for preparing 2-amino-5-protected-amino-3-hydroxy-1,6-diphenylhexane compounds or acid addition salts thereof, which can be useful intermediates for preparing compounds with antiviral activity. The present invention further provides a process for preparing HIV protease inhibitors, lopinavir and ritonavir.
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Page/Page column 23-24
(2008/06/13)
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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 11-12
(2008/06/13)
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- New water-soluble prodrugs of HIV protease inhibitors based on O→N intramolecular acyl migration
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To improve the low water-solubility of HIV protease inhibitors, we synthesized water-soluble prodrugs of KNI-272 and KNI-279 which are potent HIV-1 protease inhibitors consisting of an Apns-Thz core structure (Apns; allophenylnorstatine, Thz; thiazolidine-4-carboxylic acid) as an inhibitory machinery. The prodrugs, which contained an O-acyl peptidomimetic structure with an ionized amino group leading to the increase of water-solubility, were designed to regenerate the corresponding parent drugs based on the O→N intramolecular acyl migration reaction at the α-hydroxy-β-amino acid residue, that is allophenylnorstatine. The synthetic prodrugs 3, 4, 6, and 7 improved the water-solubility (>300 mg/mL) more than 4000-fold in comparison with the parent compounds, which is the practically acceptable value as water-soluble drugs. These prodrugs were stable as an HCl salt and in a strongly acidic solution corresponding to gastric juice (pH 2.0), and could be converted to the parent compounds promptly in the aqueous condition from slightly acidic to basic pH at 37°C, with the suitable migration rate, via a five-membered ring intermediate. Using a similar method, we synthesized a prodrug (12) of ritonavir, a clinically useful HIV-1 protease inhibitor as an anti-AIDS drug. In contrast to the prodrugs 3, 4, 6, and 7, the prodrug 12 was very slowly converted to ritonavir probably through a six-membered ring intermediate, with the t1/2 value of 32 h that may not be suitable for practical use.
- Hamada, Yoshio,Ohtake, Jun,Sohma, Youhei,Kimura, Tooru,Hayashi, Yoshio,Kiso, Yoshiaki
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p. 4155 - 4167
(2007/10/03)
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- Process for the synthesis of ritonavir
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A process is described which permits the preparation of Ritonavir with only five intermediate stages using the same starting materials as those used in the process described in WO 94/14436; the process described here is also particularly satisfactory from the point of view of environmental impact because nearly all of the carbon atoms used are subsequently incorporated in the final molecule. Finally, the improvement afforded by this novel process is linked with the fact that an inexpensive reagent, such as bis-trichloromethyl carbonate (BTC), is used in two of the five stages.
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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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