45 results about "Dolutegravir" patented technology

The invention relates to an improved method for synthesizing dolutegravir and belongs to the field of medicinal chemistry. The method takes maltol (compound 1) as a raw material, and a target is synthesized by the following route. The process raw material is cheap and easy to obtain, a reaction solvent can be recycled, the post-treatment operation is simple, the yield and the purity are high, especially the carbamoylation and debenzylation reaction are carried out in one step, the synthesis route is simplified, the cost is reduced, and the large-scale industrial production is facilitated.

The present invention provides (R)-3-Amino-1-butanol (D)-tartarate (IIb); process for its preparation and its conversion to Dolutegravir. The present invention also provides an improved process for the preparation of Dolutegravir (I) or pharmaceutically acceptable salts wherein compound (XVI) is reacted with an optically active acid addition salt of (R)-3-amino-1-butanol (IIa).

The invention discloses a novel method for preparing dolutegravir (E) defined in the description, and relates to the field of medicinal chemistry. The method comprises the following steps of 1) performing a condensation reaction of a compound (A) and 2,4-difluorobenzylamine to prepare a compound (B) defined in the description; 2) performing aldehyde group protecting group removal on the compound (B) to obtain a compound (C) defined in the description; 3) performing a cyclization reaction of the compound (C) and R-3-amino-1-butanol to prepare a compound (D) defined in the description; and 4) performing a demethylation reaction of the compound (D) to obtain the dolutegravir (E). According to the method, a novel route is adopted, and reaction conditions are continuously optimized, so that the total yield is greatly increased; and the total yield calculated by taking the compound (A) as a starting material is 75% or more, and the yields of single reactions are all 90% or more.

The invention discloses a preparation method of dolutegravir ring-opening impurities. The preparation method comprises steps of preparation of an impurity A and an impurity B, specifically comprises following steps: taking a compound 1 as an initial raw material, condensing with a compound 2 to generate a compound 3, hydrolyzing into a compound 4 under an alkaline condition, then reacting with a compound 5 to generate a compound 6, obtaining the impurity A from the compound 6 by adopting a protection-ring closing-deprotection method, and further reacting to obtain the impurity B. The inventionalso discloses the impurities. Compared with the prior art, the preparation method disclosed by the invention has the advantages that the preparation of the impurity A and the impurity B of the dolutegravir bulk drug is completed by using a new synthetic route disclosed for the first time; the designed impurity synthesis route is simple and mild in reaction condition, good in yield and safe in reaction operation, and the problems that the dolutegravir degradation impurities A and B are small in amount in an acid-base damage test and cannot be separated are solved; characterization work of theimpurity A and the impurity B is completed, and subsequent further research on the impurity A and the impurity B is facilitated.

The invention discloses a novel production method which is concise and green in route, low in cost and easy to industrialize to prepare 2,4-difluorobenzylamine. The method comprises the following twosteps: a) at certain pressure, carrying out a carbonylation reaction on m-difluorobenzene and CO in the presence of a catalyst so as to generate 2,4-difluorobenzaldehyde, or carrying out a formylationreaction on m-difluorobenzene, namely carrying out chlorocarbene substitution on m-difluorobenzene in a chloroform strong base system, and further carrying out hydrolysis so as to prepare a product 2,4-difluorobenzaldehyde (Reimer-Tiemann reactions); b) putting the product 2,4-difluorobenzaldehyde of the step a) into an alcohol solvent, at certain pressure, in the presence of the catalyst, carrying out a reduction ammonolysis reaction on the component with an ammonia gas and hydrogen directly in the presence of a catalyst, or enabling the component to react with ammonium formate, thereby obtaining the 2,4-difluorobenzylamine. The preparation method disclosed by the invention is simple and easy in raw material obtaining, concise in route, green and environmentally friendly, low in cost andeasy in industrial production.

The invention discloses a synthesis method of an dolutegravir key intermediate, and relates to the field of dolutegravir compounds. The method includes the synthesis of 1-(2,2-dimethoxyethyl)-5-methoxyl-6-methoxycarbonyl-4-oxo-1,4-dihydropyridine-3 carboxylic acid, 4-methoxyl-2-methoxymethylene acetoacetate or 4-methoxyl-2-ethoxymethylene acetoacetate is taken as a raw material to synthesize the target product 1-(2,2-dimethoxyethyl)-5-methoxy-6-methoxycarbonyl-4-oxo-1,4-dihydropyridine-3 carboxylic acid through substitution, cyclization and hydrolysis reaction. The operation of synthesis is simple, the reaction conditions are mild, the cost is low, the product quality is good, the yield is high, the total yield is more than 90%, and the dolutegravir key intermediate is suitable for large-scale industrial production.

The present invention is related to an anti-retroviral composition. In particular, the present invention relates to a solid oral composition comprising combination of multi-class drugs particularly darunavir, dolutegravir and cobicistat and process for preparing the same.

The present invention relates to processes for preparing substances with antiviral activity, in particular the integrase inhibitors dolutegravir and cabotegravir and analogues thereof, as well as intermediates useful in the processes.

The invention discloses a production route which is concise and green in route, low in cost and easy to industrialize to prepare 2,4-difluorobenzylamine. The route comprises the following four steps:a) by taking m-difluorobenzene as an initial raw material, under catalysis of lewis acid, carrying out a Foucault alkylation reaction with ethylene oxide so as to prepare an intermediate 2,4-difluorobenzene ethanol; b) carrying out a second step of reactions on the product of the step a) without separation or purification, and oxidizing the 2,4-difluorobenzene ethanol to generate 2,4-difluorobenzene phenylacetic acid; c) enabling the product 2,4-difluorobenzene phenylacetic acid of the step b) with sulfoxide chloride and an ammonia gas to react so as to prepare 2,4-difluorophenylacetamide; d)under induction of bromine, enabling the product 2,4-difluorophenylacetamide of the step c) to react with a sodium hypochlorite solution, and carrying out Hofmann degradation, thereby obtaining a target product 2,4-difluorobenzylamine. The preparation method disclosed by the invention is simple and easy in raw material obtaining, concise in route, green and environmentally friendly, low in cost and easy in industrial production.

The invention relates to the technical field of synthesis of drug intermediates and particularly relates to a preparation method of dolutegravir intermediate (R)-3-aminobutanol, comprising: using 3-(Boc-amino)butyric acid as a starting material, chirally splitting to obtain a compound of formula I; reducing with sodium borohydride and Lewis acid to obtain a compound of formula II; performing amino deprotection to obtain (R)-3-aminobutanol. The materials used herein are low in price and easy to obtain, the reaction conditions are mild, the safety is reliable, process stability is high, the yield is high, optical purity is high, and the preparation method is green and suitable for industrial production.

The present invention relates to pharmaceutical antiretroviral compositions comprising a combination of antiretroviral agents (darunavir, dolutegravir and ritonavir), the manufacturing process thereof and use of the said compositions for the prevention, treatment or prophylaxis of HIV infection.

The invention discloses an antiretroviral pharmaceutical composition. The pharmaceutical composition comprises a nucleoside reverse transcriptase inhibitor, an integrase inhibitor and one or more pharmaceutically acceptable excipients, wherein the weight ratio of the nucleoside reverse transcriptase inhibitor to the integrase inhibitor is 4: 1. The invention also discloses a preparation method ofthe composition. In the preparation method, plasma-modified mesoporous silica is used as a carrier to prepare a dolutegravir and modified mesoporous silica solid dispersion, so that the bioavailability of dolutegravir is improved; a tablet is designed into a coated tablet core, and permeation holes are formed in the tablet core, so that the dissolution rate of the main drug dolutegravir in the tablet core is increased, the dissolution rates of the two main drugs dolutegravir and emtricitabine are synchronous, the synergistic effect of the two main drugs is increased, the stability of the tablet is improved, and the curative effect is enhanced; and the prepared compound coated tablet core is high in bioavailability, good in dissolution effect of active ingredients, good in stability and lowin content of related substances.

Invented are methods for treating HIV in a human in need thereof which comprises the administration of a therapeutically effective amount of a combination of dolutegravir or a pharmaceutically acceptable salt thereof and lamivudine or a pharmaceutically acceptable salt thereof, to such human.

The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a dolutegravir derivative with biological activity and a preparation method thereof. The structural formula of the derivative is shown in the specification, wherein R1 is methyl or hydrogen; R2 is methyl, isopropyl, phenyl, benzyl, a nitrogen-containing heterocyclic ring, a sulfur-containing heterocyclic ring or an oxygen-containing heterocyclic ring; and R3 is hydrogen, methyl, ethyl, phenyl, benzyl, a nitrogen-containing heterocyclic ring, a sulfur-containing heterocyclic ring or an oxygen-containing heterocyclic ring. The preparation method comprises the following steps of: deprotecting 1-(2, 2-dimethoxyethyl)-1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid-2-methyl ester to obtain aldehyde, cyclizing the aldehyde with aminobutanol, then carrying out acylation reaction on the cyclized aldehyde and an amino compound, and finally carrying out click reaction with azide to obtain a target compound. The derivative provided by the invention has proliferation inhibition activity on human tumor cells.

Methods are provided for treating or preventing human immunodeficiency virus-1 (HIV-1) or human immunodeficiency virus-2 (HIV-2) in a virologically suppressed patient in need thereof comprising switching the patient from an antiretroviral treatment regimen comprising at least three antiretroviral agents to a treatment regimen comprising only two antiretroviral agents. In one aspect the two treatment regimen consists of dolutegravir, rilpivirine and at least one pharmaceutically acceptable excipient, diluent or carrier. In another aspect of the invention, there is provided a multilayer tablet comprising dolutegravir or a pharmaceutically acceptable salt thereof and rilpivirine or a pharmaceutically acceptable salt thereof.

The invention provides a synthesis method of diastereoisomer impurities in dolutegravir raw materials and intermediates. The synthesis method comprises the following steps: 1) with a compound V as a starting raw material, performing a reaction with a large-steric-hindrance protecting group under an alkaline condition to generate a compound VII; 2) carrying out alcoholysis on the compound VII and areaction solvent under an alkaline condition to generate a compound VIII; and 3) carrying out hydrolysis on the compound VIII and an alcohol solvent under an alkaline condition to obtain a compound IX. The invention provides the synthesis method of the diastereoisomer impurities in dolutegravir raw materials and intermediates, which is simple in process and easily available in raw materials. Theprepared new impurity can provide a reference substance for quality analysis of dolutegravir, so that the quality standard of dolutegravir is improved.