394735-23-0

Usage

Uses

Used in Pharmaceutical Industry:
β-AMino-α-hydroxycyclobutanebutanaMide Hydrochloride is used as an intermediate in the synthesis of Boceprevir, an HCV NS3 serine protease inhibitor. This application is crucial for the development of antiviral drugs that target Hepatitis C virus (HCV) and help in the treatment of the disease.
As a chemical intermediate, β-AMino-α-hydroxycyclobutanebutanaMide Hydrochloride plays a vital role in the production of Boceprevir, which is specifically designed to inhibit the NS3 serine protease enzyme in HCV. This inhibition prevents the virus from replicating and helps in managing the progression of Hepatitis C.

Upstream product

• 1433545-53-9 ethyl 2-chloro-4-cyclobutyl-3-oxobutanoate 
• 1433545-62-0 4-cyclobutyl-1-ethoxy-1,3-dioxobutan-2-yl 4-methoxybenzoate 
• 1433545-74-4 (2E)-3-amino-4-cyclobutyl-1-ethoxy-1-oxobut-2-en-2-yl 4-methoxybenzoate 
• 1433545-85-7 3-[(tert-butoxycarbonyl)amino]-4-cyclobutyl-1-ethoxy-1-oxobut-2-yl 4-methoxybenzoate 
• 4426-03-3 cyclobutyl acetonitrile 
• 63659-30-3 cyclobutylmethyl methanesulfonate 
• 4415-82-1 cyclobutanemethanol 
• 885280-12-6 ethyl 4-cyclobutyl-3-oxobutanoate 
• 1416790-87-8 5-[1-[(tert-butylsulfinyl)amino]-2-cyclobutylethyl]-2-phenyl-1,3-oxazol-4-yl trifluoromethanesulfonate 
• 1416790-86-7 C₁₀H₁₉NOS 
• 918662-57-4 (2-cyclobutyl-1S-formylethyl)-carbamic acid tert-butyl ester 
• 1607806-55-2 C₁₃H₂₄N₂O₄ 
• 1036931-37-9 3-amino-4-cyclobutyl-2-hydroxybutanoic acid 
• 17247-58-4 (Bromomethyl)cyclobutane 

Downstream Products

• 394735-28-5 (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicylo[3.1.0]-hexane-2-carboxamide 
• 394735-28-5 C₂₇H₄₇N₅O₅ 
• 394735-28-5 C₂₇H₄₇N₅O₅ 
• 1428533-54-3 3-(2-(6-benzyl-3-(3-(tert-butyl)ureido)-5-chloro-2-oxopyrazin-1(2H)-yl)acetamido)-4-cyclobutyl-2-oxobutanamide 

Relevant academic research and scientific papers

N - benzyl -4 - cyclobutyl -2 - hydroxy -3 - nitryl Ding amide and use thereof

The invention relates to a new compound, and in particular relates to N-benzyl-4-cyclobutyl-2-hydroxy-3-nitrobutyrylamide and use thereof, and belongs to the technical field of the preparation of medicine and other fine chemical products. The structural formula of the N-benzyl-4-cyclobutyl-2-hydroxy-3-nitrobutyrylamide is shown in the specification; the compound is used for synthesizing beta-amino-alpha-hydroxy cyclobutane butyrylamide hydrochloride (formula I). According to the preparation method of N-benzyl-4-cyclobutyl-2-hydroxy-3-nitrobutyrylamide, the raw materials 2-nitroethyl cyclobutane (formula III) and N-benzyl-2-oxoacetamide (formula IV) are condensed in an alkaline environment in the presence of an organic solvent to obtain N-benzyl-4-cyclobutyl-2-hydroxy-3-nitrobutyrylamide.

A New and convenient synthesis of the boceprevir P1 fragment, β-aminoα-hydroxy amide

A new and convenient synthesis of the P1 fragment of HCV inhibitor, boceprevir is described. This approach efficiently provides P1 fragment of boceprevir using simple and easy handling reagents suitable for scale up. This synthetic route involves the conversion of ester intermediate into novel intermediate, α-chloro ketone via chloroacetate Claisen condensation, followed by further simple conversions to β-amino-α-hydroxy amide, P1 fragment of boceprevir in high yield.

A intermediate pope Switzerland Wei 2-hydroxy-3-amino-4-cyclobutyl butanamide hydrochloride synthetic method

The invention relates to a synthetic method of a boceprevir intermediate namely 2-hydroxy-3-amino-4-cyclobutane amide hydrochloride, belonging to the technical field of medicament synthesis. By adopting the synthetic method, the problems that a method for synthesizing the boceprevir intermediate is high in cost, complex in reaction, low in efficiency and the like in the prior art can be solved. The synthetic method comprises the following steps: by adopting cyclobutyl acetate and monomethyl mono potassium malonate as raw materials, reacting for 10-12 hours at room temperature under the action of an activating agent and magnesium chloride; sequentially adding an oxidizing agent, 4-cyclobutyl-3-oxo-ethyl butyrate and a catalyst into methanoic acid at 15-20 DEG C, and reacting for 1.5-2.5 hours at 15-20 DEG C; adding a condensation agent and organic alkali at 10-15 DEG C, performing condensation reaction with ammonium chloride at room temperature, and reacting for 10-12 hours; and finally performing ammoniation and acidification to obtain a final product. The synthetic method disclosed by the invention is relatively low in cost, simple in reaction condition, less in reaction step and short in time, and the final product, namely the boceprevir intermediate, is relatively high in purity and yield.

PROCESS FOR PREPARATION OF BOCEPREVIR AND INTERMEDIATES THEREOF

THE PRESENT INVENTION RELATES TO AN IMPROVED PROCESS FOR THE PREPARATION OF (1R,5S)-N-[3-AMINO-1-(CYCLOBUTYLMETHYL)-2,3-DIOXOPROPYL]-3-[2(S)-[[[(1,1-DIMETHYLETHYL)AMINO]CARBONYL] AMINO]-3,3-DIMETHYL-1-OXOBUTYL]-6,6-DIMETHYL-3-AZABICYCLO[3.1.0]HEXAN-2(S)-CARBOXAMIDE AND ITS INTERMEDIATES

Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pocket

Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

PROCESS AND INTERMEDIATES FOR THE PREPARATION OF 3-AMINO-4-CYCLOBUTYL-2-HYDROXYBUTANAMIDE AND SALTS THEREOF

The present invention relates to synthetic processes useful in the preparation of a compound of Formula (I), and salts thereof. Compounds of Formula (I) and salts thereof have application in the preparation of inhibitors of the hepatitis C virus, such as (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide. The present invention also encompasses intermediates useful in the disclosed synthetic processes and the methods of their preparation.

Stereoselective addition of 2-phenyloxazol-4-yl trifluoromethanesulfonate to N -sulfinyl imines: Application to the synthesis of the HCV protease inhibitor boceprevir

The stereoselective addition of 2-phenyloxazol-4-yl trifluoromethanesulfonate to N-sulfinylimines is described. Vinyl anions derived from enol triflate 2 undergo 1,2-addition with a variety of aldimines to afford the corresponding secondary sulfonamides as single diastereomers. The absolute stereochemistry was confirmed by X-ray crystallography which provides support that the reaction proceeds through an open, nonchelate transition state. This methodology has been applied to the synthesis of the ketoamide fragment of the protease inhibitor boceprevir.

PREPARATION OF 3-AMINO-3-(CYCLOBUTYLMETHYL)-2-(HYDROXY)-PROPIONAMIDE HYDROCHLORIDE

Disclosed is a process for preparing 3-(amino)-3-cyclobutylmethyl-2-hydroxy-propionamide hydrochloride, an intermediate useful in the preparation of the HCV protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide.

Pharmaceutical formulations and methods of treatment using the same

Pharmaceutical formulations containing at least one compound of Formulae I-XXVI herein and at least one surfactant. Pharmaceutically acceptable carriers and excipients may also be included in the formulations. The formulations of the present invention are suited for use in single unit dosages.

Liver/plasma concentration ratio for dosing hepatitis C virus protease inhibitor

Compositions and therapeutic combinations are provided including at least one compound selected from the group consisting of compounds of Formulae I to XXVI as defined herein as well as methods of treatment, prevention or amelioration of one or more symptoms of hepatitis C, treating disorders associated with HCV virus, modulating activity of HCV protease, in which liver to plasma concentration ratio of the compound ranges from about 2:1 to about 10:1.