205 results about "Tenofovir" patented technology

The invention discloses an industrial production process for tenofovir disoproxil fumarate represented by a structural formula (II). The production process comprises the following steps of: (1) preparing R-9-(2-hydroxypropyl)adenine by taking adenine and R-propylene carbonate as initial raw materials; (2) performing a condensation reaction on the obtained R-9-(2-hydroxypropyl)adenine and diethyl(tosyloxy)methylphosphonate under the catalytic action of magnesium alkoxide to prepare R-9[2-(diethyl-phosphonic acid methoxy)propyl]adenine; (3) hydrolyzing R-9[2-(diethyl-phosphonic acid methoxy)propyl]adenine to obtain tenofovir; and (4) performing condensation on the tenofovir and the chloromethyl isopropyl carbonate under the catalytic action of triethylamine to prepare the tenofovir disoproxil fumarate. The process of the invention has the characteristics of low cost, safe process, high product quality and suitability for industrial production.

The present invention provides a process for the preparation of tenofovir. The present invention also provides a process for the preparation of tenofovir disoproxil or a salt thereof and its pharmaceutical composition using the tenofovir of the present invention.

The invention relates to a novel crystal of a tenofovir prodrug (HTS), and specifically discloses the crystal of (2R, 4S)-2-((((R)-(6-amino-9-ly)propane-ly)oxygen)methyl)-(3-chlorophenyl)-2oxygen-1,3,2-dioxaphosphorinsuccinate (HTS), and the prodrug and a preparation method of the crystal.

The present invention provides a novel crystalline form of Tenofovir disoproxil fumarate (Tenofovir DF), designated Co-crystal TDFA 2:1, methods for the preparation thereof and its use in pharmaceutical applications, in particular in anti-HIV medicaments. The crystalline form TDFA 2:1 can be used in combination with other anti-HIV medicaments such as Efavirenz, Emtricitabine, Ritonavir and/or TMC114.

The invention relates to a solid of tenofovir disoproxil. The solid is (1) a tenofovir disoproxil compound represented by a formula IV or (2) a tenofovir disoproxil cocrystal or salt represented by a formula V. The invention further relates to a preparation method for the solid of tenofovir disoproxil, a pharmaceutical composition containing the solid and application of the solid in preparation of drugs used for preventing and/or treating virus infection, especially hepatitis b virus (HBV) and/or human immunodeficiency virus (HIV) infection.

The invention discloses a group of tenofovir disoproxil compounds with activity for inhibiting HIV-1/HBV virus replication and pharmaceutically acceptable salts thereof, and a preparation method and pharmaceutical applications thereof. The group of the compounds have a general formula I, wherein X=H, Y=H, R1=-CH2(CH2)mCH2O(CH2)nCH3, m=0-4, n=10-20, and R2, R3 and R4 are respectively described in the specification. The invention also discloses a pharmaceutical composition containing the group of the compounds. Experiments show that one of the compounds has the advantages that an activity for inhibiting HIV-1 virus replication is 20 times that of a positive control medicine zidovudine (AZT), 1,000 times that of TDF that is the best medicine for treating Aids and about 9 times that of CMX157 in a clinical stage, and lipid solubility is about 2 times that of CMX157. Experiments also show that the compounds provided by the invention have the activity for inhibiting HBV virus replication, and can be used for development of drugs for treating the Aids and hepatitis B.

The invention discloses tenofovir disoproxil fumarate dispersible tablets and a preparation method thereof. The tenofovir disoproxil fumarate dispersible tablets are prepared from tenofovir disoproxil fumarate as an effective pharmaceutical ingredient and pharmaceutically acceptable auxiliary ingredients, wherein the pharmaceutically acceptable auxiliary ingredients comprise a filler, a disintegrant, a lubricant, a surfactant and a flavoring agent. The tenofovir disoproxil fumarate dispersible tablets prepared by the invention have appropriate hardness, small weight difference, bright and clean tablet surfaces and good taste, fully meet the requirements on the disintegration time and dispersion uniformity of dispersible tablets, and notably improve the pharmaceutical bioavailability, and in addition, the tenofovir disoproxil fumarate dispersible tablets have quick dissolution rate, the dissolution percentage of the product is about 80-90% in 2 minutes, and the product is almost completely dissolved in 5 minutes.

The invention relates to a method for preparing high-purity tenofovir disoproxil fumarate. The method comprises the following steps: preparing (R)-4-methyl-1,3-dioxolan-2-one, synthesizing (R)-9-(2-hydroxypropyl)adenine, synthesizing a tenofovir hydrate, refining by virtue of dehydrating and synthesizing tenofovir disoproxil fumarate. The corresponding product is refined and the target product is detected by dehydrating through tenofovir and using alkali-soluble acid-analysis manners, the reaction, separation and purification processes in the subsequent steps are facilitated and the purity and yield of the product are increased. The technical scheme disclosed by the invention has the advantages of simple operation, relatively inexpensive selected reagents, small side effects, high yield and less three wastes produced in the reaction and the environmental protection is facilitated.

The present invention belongs to the technical field of medicine, and relates to a tenofovir disoproxil fumarate synthesis method, wherein (R)-1,2-propanediol and carbonate are adopted as raw materials, and condensation, etherification, hydrolysis, esterification salification and other steps are performed to prepare the finished product. According to the present invention, the process improving and the reaction intermediate treatment are performed so as to easily achieve the reactions in the subsequent steps and the separation and purification, improve the yield and the corresponding purity of the target product, and obtain the tenofovir disoproxil fumarate meeting the medical standard.

The invention discloses a preparation method of tenofovir disoproxil fumarate, belonging to the technical field of synthesis of tenofovir disoproxil fumarate. The preparation method comprises the following steps: preparing tenofovir disoproxil, preparing a tenofovir disoproxil fumarate crude product and refining the tenofovir disoproxil fumarate, wherein in the step of refining the tenofovir disoproxil fumarate, by virtue of a 65% ethanol solution which is used as a tenofovir disoproxil fumarate recrystallizing solvent, the tenofovir disoproxil fumarate is kept in an environment at 5-10 DEG C for 3-6h until the tenofovir disoproxil fumarate is naturally separated out and crystallized. The preparation method disclosed by the invention can be used for solving the problems of high contents of organic residue and side reactant in the process of preparing the tenofovir disoproxil fumarate, and the total yield can reach more than 40%; in addition, the tenofovir disoproxil fumarate occupies a high content in a final product, and the preparation method is simple and convenient to operate in the recrystallizing process, low in cost, and free from toxic and harmful side reactions or products.

The invention relates to a salt compound of tenofovir disoproxil fumarate and a preparation method and medicinal application thereof. The preparation method comprises the following steps: heating to dissolve the tenofovir disoproxil fumarate with isopropanol in an amount which is 5 to 20 times the weight of the tenofovir disoproxil fumarate, stirring, regulating pH with phosphoric acid to between 2 and 3, and performing reaction for 30 minutes; and cooling to 0 DEG C, standing for crystallization, filtering, washing twice with a small amount of isopropanol, and performing vacuum drying.

The invention relates to an antiviral drug tenofovir disoproxil fumarate and a novel preparation method thereof, belonging to the field of medicines. Content of related substances in the tenofovir disoproxil fumarate, especially content of impurity K is effectively lowered by taking toluenesulfonyloxy diethyl methylphosphonate as a starting material through hydrolysis, condensation and salifying. Moreover, the preparation method is gentle in reaction condition, low in production cost, simple and convenient to operate, and suitable for large-scale industrial production.

The invention relates to the field of pharmaceutical chemistry and provides a preparation method of tenofovir disoproxil fumarate hemifumarate. The tenofovir disoproxil fumarate hemifumarate is a eutectic composed of tenofovir disoproxil fumarate and fumaric acid with the ratio of tenofovir disoproxil fumarate to fumaric acid being 2:1. According to the preparation method, (R)-9-(2-hydroxy propyl) adenine is used as a starting material, and condensation, hydrolysis and esterification are carried out to prepare free tenofovir disoproxil fumarate; and the free tenofovir disoproxil fumarate and fumaric acid in a solvent undergo salt formation and crystallization to prepare the tenofovir disoproxil fumarate hemifumarate.

An industrial production process of tenofovir, the production process steps are as follows: add R-1,2-propylene glycol, diethyl carbonate and sodium ethylate into the reaction kettle; add absolute ethanol and diphosphite Ethyl ester, stirring, after the stirring is completed, put in paraformaldehyde and triethylamine, after the reaction is complete, add anhydrous sodium sulfate, dry, filter, and distill out, the distilled product is diethyl p-toluenesulfonyloxymethylphosphonate Fine product; add adenine, R-propylene carbonate, DMF and NaOH in the reaction kettle, after the reaction is complete, add magnesium tert-butoxide, drop diethyl p-toluenesulfonyl phosphate, after the reaction is complete, add acetic acid, Concentrate under reduced pressure, add hydrochloric acid, filter, filter out the solid and dry under normal pressure to obtain PMPA fine product. The method has the advantages of high yield, high product purity and low impurity content, and can be fully industrialized.

The invention relates to a novel synthesis method of three impurities of tenofovir disoproxil fumarate, and the method has an important significance for synthesizing high-quality tenofovir disoproxil fumarate. The invention mainly aims at researching the synthesis of a tenofovir disoproxil fumarate isopropyl ester impurity (R)-9-(2-phosphonomethoxy propyl) adenyl isopropyl oxycarbonyl methoxy isopropyl ester (IV), a tenofovir disoproxil fumarate methoxycarbonyl methoxy ester impurity (R)-9-(2-phosphonomethoxy propyl) adenyl isopropyl oxycarbonyl methoxy ester methoxycarbonyl methoxy ester (VI) and a tenofovir disoproxil fumarate n-propyl oxycarbonyl methoxy ester impurity (R)-9-(2-phosphonomethoxy propyl) adenyl isopropy oxycarbonyl methoxy ester n-propyl oxycarbonyl methoxy ester (VII). The synthetic routes of the three impurities of tenofovir disoproxil fumarate are as shown in the specification.

Compounds of Formula I:

and their pharmaceutically acceptable salts are useful for the inhibition of HIV reverse transcriptase. The compounds may also be useful for the prophylaxis or treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antiviral agents, immunomodulators, antibiotics or vaccines

The invention relates to tenofovir disoproxil fumarate fine granules. The tenofovir disoproxil fumarate fine granules are formed by the following steps of: mixing tenofovir and a sweetening agent according to a mass ratio of 1: (0-6); mixing the mixture with a polymer for hot melting extrusion according to a mass ratio of 1: (2-15); then carrying out hot melting extrusion through a hot melting extruder; and crushing into the fine granules with the grain diameter less than or equal to 30 meshes. The tenofovir disoproxil fumarate fine granules disclosed by the invention overcome the disadvantages that the taste of tenofovir disoproxil fumarate is very bitter and the taste masking effect of an existing preparation is not enough, and the medicine-taking compliance of a patient is greatly improved.

The invention discloses the technical field of medicines and particularly discloses a new prodrug, namely (R)-9-(2-(phosphonyl methoxyl)propenyl) adenine, a cyclodextrin inclusion compound of the prodrug and a non-toxic and pharmaceutically acceptable salt of the prodrug. The prodrug disclosed by the invention can be metabolized into PMPA in vivo, and has the bioavailability of about 39%, and the bioavailability of the prodrug is better than that of tenofovir disoproxil fumarate (Bis-(POC)-PMPA); and the prodrug has more excellent antiviral activity and better safety compared with the tenofovir disoproxil fumarate.

The invention relates to a preparing method for realizing industrial mass production of tenofovir disoproxil fumarate.The preparing method includes the following steps of preparing (R)-9-[2-(diethoxyphosphonylmethoxy) propyl] adenine, synthesizing tenofovir, refining tenofovir, dewatering tenofovir, synthesizing tenofovir disoproxil and synthesizing tenofovir disoproxil fumarate.The technical scheme is easy to operate, selected reagents are low in price, the number of side reactions is small, the yield is high, few three wastes are generated in the reaction process, and the preparing method is beneficial for environment protection and suitable for industrial mass production.

The present invention provides a novel process for the preparation of acyclic phosphonate nucleotide analogs using novel intermediates. Thus, for example, (R)-9-(2-phosphonomethoxypropyl)adenine is reacted with dimethylformamide dimethylacetal to give N⁴-dimethylaminomethyledino-9-(2-phosphonomethoxy ethyl) adenine, which is then reacted with chloromethyl-2-propyl carbonate in presence of triethylamine to give (R)—N⁴-Dimethylaminomethyledino-9-(2-phosphono methoxypropyl) adenine disoproxil, followed by deprotection with acetic acid to get tenofovir disoproxil. Tenofovir disoproxil is then treated with fumaric acid to give tenofovir disoproxil fumarate.

The invention discloses a method for synthesizing (R)-9-(2-hydroxy propyl) adenine. The method sequentially comprises the following steps: (1) primary amino acetylation: dissolving adenine in an organic solvent, adding alkali and a catalyst, stirring, and dripping acetic anhydride at 0-10 DEG C; holding at 80-85 DEG C, stirring and reacting for 6-10 h to obtain reaction liquid; (2) N-hydroxy propylation: regulating the pH of the reaction liquid to 9-10, adding propylene carbonate, stirring and reacting at 120-140 DEG C, cooling to 70-80 DEG C, adding toluene, stirring for 2-3 h, and separating and drying to obtain a solid product; (3) deacetylation reaction: adding the solid product into a sodium hydroxide aqueous solution, stirring to react at 90-95 DEG C for 2-4 h, cooling to the room temperature, neutralizing the pH to 6-8 through concentrated hydrochloric acid, separating and drying to obtain the product. The method provided by the invention is used for greatly increasing the reaction selectivity, avoiding the generation of byproduct (R)-6-(2-hydroxy propyl) adenine, increasing the yield of the (R)-9-(2-hydroxy propyl) adenine by more than 90% and greatly lowering the production cost of tenofovir disoproxil fumarate.