cas 178306-52-0, Benzenepropanoic acid,a-hydroxy-b-methoxy-b-phenyl-,(aS)-

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Preparation method of (S)-2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid
The invention discloses a preparation method of (S)-2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid, and relates to the field of drug synthesis. The method comprises the following steps: resolving (RS)-2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid by using a resolution reagent (1S, 2S)-2-amino-1-(4-nitrophenyl) propane-1, 3-diol, carrying out cooling crystallization, collecting solids to obtain a salt of an S-configuration diastereoisomer, adding water into the salt of the S-configuration diastereoisomer to dissolve the salt again, carrying out acidifying, and carrying out extracting, drying, concentrating and recrystallizing to obtain high-optical purity (S)-2-hydroxyl-3-methoxyl-3-diphenyl propionic acid. According to the method, the resolution reagent which is cheap, easy to obtainand good in safety is used, the mass yield is 45% or above while the cost is reduced, the method can be amplified to large-scale industrial production, and the method has very good industrial prospects.
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Paragraph 0042-0078

(2020/05/14)

Preparation method ambrisentan key intermediate
The invention relates to a preparation method ambrisentan key intermediate (S)-2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid. According to the preparation method, 2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid containing R configuration is subjected to hydroxy protection and hydroxy substitution reaction to change the R configuration into S configuration. The preparation method is capable of realizing high efficiency configuration change, recycling of (R)-2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid after splitting, improving atom economical performance, and reducing ambrisentan cost greatly.
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Paragraph 0020; 0022; 0023; 0025; 0026; 0028

(2019/11/20)

Method for preparing 2-hydroxy-3-methoxy-3,3,-diphenyl propionate racemate
The invention provides a method for preparing racemate 2-hydroxy-3-methoxy-3,3,-diphenyl propionate. The method comprises the following steps: 1) dissolving R-2-hydroxy-3-methoxy-3,3,-diphenyl propionate-L-proline methylester salt in a mixed solvent to obtain a solution; 2) adding a first acid solid or a solution into the solution of the step 1), and performing backflowing; 3) after the reaction is completed, adding a solution of a second acid, performing liquid separation, and collecting an organic phase; 4) concentrating the organic phase, dissolving a residue obtained after desolvation into ethanol or methanol, adding a hydroxide solution, separating out racemate 2-hydroxy-3-methoxy-3,3,-diphenyl propionate, drying, and filtering, thereby obtaining the racemate 2-hydroxy-3-methoxy-3,3,-diphenyl propionate. The invention further provides a process for preparing S-2-hydroxy-3-methoxy-3,3,-diphenyl propionate. The yield can be increased to about 40% from 30%, meanwhile wastes can be reduced, and good economic benefits and social benefits can be achieved.
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Paragraph 0035; 0038; 0039; 0040; 0041

(2017/08/29)

METHOD FOR PRODUCING (S)-2-HYDROXYPROPANOIC ACID DERIVATIVE
PROBLEM TO BE SOLVED: To provide a method for producing an (S)-2-hydroxypropanoic acid derivative and ambrisentan having high optical purity in an industrially advantageous manner. SOLUTION: There is provided a method for producing an (S)-2-hydroxypropanoic acid derivative represented by the formula (1a) by reacting an (RS)-2-hydroxypropanoic acid derivative represented by the formula (1) with (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine to form a diastereomer salt, followed by desalting. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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(2017/12/15)

2 - Hydroxy - 3 - methoxy - 3, 3 - diphenyl-propionic acid racemate resolution method
The invention relates to a resolution method of 2-hydroxy-3-methoxy-3,3-dibenzylpropionic acid racemate. The method comprises the following steps: reacting racemic acid with an optical alkali, and separating non-enantiomeric salts of acid and alkali. L-proline methyl ester hydrochloride and R-(+)-alpha-phenylethylamine are used as optically active alkalis. Highly pure target compounds can be obtained in a high yield mode by using an efficient and cheap resolution reagent, and the method has good reappearance in industrial production and has a wide industrial application prospect.
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Paragraph 0009; 0028; 0029; 0031

(2017/12/04)

Process for Preparing Ambrisentan
The present invention relates to a method of preparing high purity ambrisentan in a cost-effective and efficient way, and a novel intermediate product used for the method. According to the present invention, optical resolution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid can be cost-effectively and efficiently performed using L-prolinamide, and thus crystalline ambrisentan having 99.9% or more of purity and optical purity can be prepared on an industrial scale using the same.COPYRIGHT KIPO 2016
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Paragraph 0111; 0112

(2017/02/28)

S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid and preparation method thereof
The invention provides S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid and a preparation method thereof. The preparation method comprises 1, dissolving 2, 3-epoxy-3, 3-dibenzylpropionate in methanol, carrying out acid-catalyzed ring-opening, alkali metal hydroxide hydrolysis and reaction solution condensation, adding water into the condensed solution, filtering the solution after solids are separated, and carrying out solvent washing and purification to obtain refined 2-hydroxy-3-methoxy-3, 3-dibenzylpropionate, and 2, carrying out a reaction process on the refined 2-hydroxy-3-methoxy-3, 3-dibenzylpropionate and methyl L-prolinate, carrying out splitting to obtain methyl S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid-L-prolinate, adding an acid into the methyl S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid-L-prolinate so that the methyl S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid-L-prolinate is free and carrying out extraction, drying, condensation and recrystallization to obtain S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid. The preparation method has simple processes, can produce high purity S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid, can guarantee ambrisentan reaching the standard, can shorten a synthesis period, is free of an acid binding agent in a splitting stage and reduces a cost.
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Paragraph 0021; 0022; 0023

(2017/01/02)

New carboxylic acid derivative, its production and its use
Heterocyclyl-substd. propanoic acids and their derivs., of formula (I), are new. R = formyl, tetrazolyl, nitrile, COOH or a gp. that can be hydrolysed to COOH; X = N or CR14; R2 = H, OH, NH2, alkylamino, dialkylamino, halo, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio; R14 = H or 1-5 C alkyl; R3 = R2 or alkoxyimino; or CR3 + CR14 = 5 or 6 membered alkylene or alkenyl ring (opt. substd. by 1-2 alkyl) in which a methylene can be replaced by O, S, NH or alkylamino; R4, R5 = phenyl or naphthyl (both opt. substd. by one or more halo, NO2, CN, OH, alkyl, haloalkyl, alkoxy, haloalkyloxy, phenoxy, alkylthio, NH2, alkylamine or dialkylamino) or 3-7 C cycloalkyl; or the phenyl or naphthyl gps. are opt. bonded at the O- position (by a bond, CH2, O, S, SO2, ethylene, ethenylene or opt. alkylated amino); R6 = H, 1-8 C alkyl, 2-6 C alkenyl, 3-6 C alkynyl, 3-8 C cycloalkyl (all opt. substd. by 1 or more halo, NO2, CN, alkoxy 3-6 C alkenyloxy, 3-6 C alkynyloxy, alkylthio, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, 3-8 C alkylcarbonylalkyl, alkylamino, dialkylamino, phenyl, Ph or OPh), Ar or Het; Y = S, O or bond; Q = S, O, SO, SO2 or bond; Ph = substd. phenyl, where substits. are halo, NO2, CN, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio; Ar = phenyl or naphthyl (both opt. substd. by 1 or more halo, NO2, CN, OH, NH2, alkylamino, dialkylamino or OCH2CH2O); Het = 5 or 6 membered heteroaromatic with 1-3 N atoms and/or one S or O (opt. substd. by 1-4 halo and/or 1 or 2 alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, phenyl, phenoxy or phenyl carbonyl (where the phenyl is opt. substd. by 1-5 halo and/or 1-3 alkyl, haloalkyl, alkoxy, haloalkoxy and/or alkylthio)); alkyl and alkoxy have 1-4 C unless otherwise stated; provided that R6 is not H when Q = bond.
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Paragraph 0071; 0072

(2018/11/22)

PREPARATION PROCESS OF CARBOXYLIC ACID DERIVATIVES AND INTERMEDIATES THEREOF
A cocrystal of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid and an amino acid, in particular L-valine or L-2-aminobutyric acid, their preparation processes, as well as the preparation process of Ambrisentan or Darusentan using any of the cocrystals of the invention.
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Page/Page column 24

(2014/01/17)

Process for the Preparation of an Endothelin Receptor Antagonist
The present invention relates to a novel process for the preparation of a compound of formula (I) wherein R is a methyl or methoxy group; to certain novel intermediates prepared in such a process and their use.
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Page/Page column

(2014/09/29)

PROCESS FOR THE PREPARATION OF AN ENDOTHELIN RECEPTOR ANTAGONIST
The present invention relates to a novel process for the preparation of a compound of formula (I) wherein R is a methyl or methoxy group; to certain novel intermediates prepared in such a process and their use.
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Page/Page column 23-24

(2013/05/09)

IMPROVED PROCESS TO PREPARE S-2-HYDROXY-3-METHOXY-3,3-DIPHENYL PROPIONIC ACID
Disclosed is a process for the preparation of S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (I) the key intermediate for the preparation of Ambrisentan [(+)-2(S)-(4,6-Dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid]. Ambrisentan of the formula (IA) is approved under the trademark "Letairis " by the US Food and Drug Administration for the treatment of Pulmonary artery hypertension(PAH).
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(2012/02/15)

Improved Process For The Preparation Of Endothelin Receptor Antagonists
The present invention relates to improved processes for the preparation of Endothelin receptor antagonists, their salts and intermediates.
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(2011/11/06)

IMPROVED PROCESS FOR THE PREPARATION OF ENDOTHELIN RECEPTOR ANTAGONISTS
The present invention relates to improved processes for the preparation of Endothelin receptor antagonists, their salts and intermediates.
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Page/Page column 19

(2010/08/05)

Carboxylic acid derivatives, their preparation and use in treating cancer
This invention provides a method for treating cancer in an individual, wherein the cancer is a tumor in which endothelin is upregulated (e.g. tumors of the prostate, lung, liver, breast, brain, stomach, colon, endometrium, testicle, thyroid, pituatary, bladder, kidney, pancreas and meninges) by administering to the individual an effective amount of a compound of Formula I or Formula Ia, as describe herein.
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(2008/06/13)

Carboxylic acid derivatives, their preparation and use
Carboxylic acid derivatives STR1 where R-R6, X, Y and Z have the meanings stated in the description, and the preparation thereof, are described. The novel compounds are suitable for controlling diseases.
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(2008/06/13)

Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2(4,6- dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ET(A)/ET(B) receptor antagonist
Structural variation of the endothelin A-selective antagonist (S)-3- methoxy-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 135252) led to analogues which retain ETA affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2- (3,4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)-3,3- diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ETA receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.
Amberg, Willi,Hergenr?der, Stefan,Hillen, Heinz,Jansen, Rolf,Kettschau, Georg,Kling, Andreas,Klinge, Dagmar,Raschack, Manfred,Riechers, Hartmut,Unger, Liliane
p. 3026 - 3032
(2007/10/03)