177036-94-1

Basic information

• Product Name: Ambrisentan
• Synonyms: BSF 208075,(+)-(2S)-2-[(4,6-DIMETHYLPYRIMIDIN-2-YL)OXY]-3-METHOXY-3,3-DIPHENYLPROPANOIC ACID;AMBRISENTAN;2-(4,6-Dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-di(phenyl)propanoic acid;(aS)-a-[(4,6-Dimethyl-2-pyrimidinyl)oxy]--methoxy--phenylbenzenepropanoic Acid;BSF 208075;LU 208075;(S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropanoic acid;(+-)-(2S)-2-((4,6-Dimethylpyrimidin-2-yl)oxy)-3-methoxy-3,3-diphenylpropanoic acid,bsf-208075
• CAS NO: 177036-94-1
• Molecular Formula: C22H22N2O4
• Molecular Weight: 378.42
• EINECS: 1308068-626-2
• Product Categories: APIs;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Other APIs
• Mol File: 177036-94-1.mol

Chemical Properties

• Melting Point: >150°C (dec.)
• Boiling Point: 551.1 °C at 760 mmHg
• Flash Point: 287.1 °C
• Appearance: /
• Density: 1.228 g/cm³
• Vapor Pressure: 5.56E-13mmHg at 25°C
• Refractive Index: 1.593
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 0.97±0.10(Predicted)
• Merck: 14,384
• CAS DataBase Reference: Ambrisentan(CAS DataBase Reference)
• NIST Chemistry Reference: Ambrisentan(177036-94-1)
• EPA Substance Registry System: Ambrisentan(177036-94-1)

Safety Data

• Statements: 62/63
• Safety Statements: 53-36/37/39-45
• RTECS: UA2459660
• Hazardous Substances Data: 177036-94-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Ambrisentan is used as an antihypertensive agent for the treatment of pulmonary arterial hypertension (PAH). It works by blocking the ETA receptors, reducing the effects of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that contributes to the acceleration of PAH.
Ambrisentan is used as an endothelin receptor antagonist to improve exercise capacity and delay clinical worsening in patients with PAH. By inhibiting the ETA receptors, it helps to reduce pulmonary vascular resistance and pulmonary arterial pressure, thus preventing right ventricular failure and premature death associated with PAH.
In addition to its primary use in treating PAH, Ambrisentan has shown potential in reducing pulmonary arterial hypertension and PAH-induced right ventricular hypertrophy (RVH) in a rat model of neonatal hyperoxic lung injury. This suggests that Ambrisentan may have broader applications in the treatment of various lung-related conditions.

Clinical Use

Endothelin A (ETA) receptor antagonist: Treatment of pulmonary arterial hypertension

Synthesis

Both the discovery and process routes to the synthesis of ambrisentan have been published and the process route is described as shown in the scheme. Reacting a mixture of benzophenone (14) and sodium methoxide in THF at 0°C with methylchloroacetate over a four hour period provided glycidate 15 which was taken forward without purification to the subsequent step. Addition of ptoluenesulfonic acid monohydrate to a solution of glycidate 15 in methanol was followed by heating at reflux and distilling out the solvent until the temperature reached 66°C. While the solution was still refluxing, 10% potassium hydroxide was added and the remaining organic solvent was distilled out until the temperature reached 94°C, providing complete hydrolysis to acid 16. The reaction was cooled to room temperature and diluted with water and methyl tert-butylether (MTBE) then acidified with 10% sulfuric acid. The MTBE layer was separated and taken to the next step. Additional MTBE and methanol were added to the crude acid 17 and the resulting mixture was heated at reflux. (S)-1-(4-chlorophenyl) ethylamine was added to the refluxing solution and the resulting mixture was allowed to cool to 0-5°C slowly at a rate of 10°C/h which resulted in crystallization of the salt 19 in 33% overall yield from benzophenone and 99% e.e. The chiral hydroxyl acid salt 19 was mixed with sulfone 20 and lithium amide in a toluene/DMF mixture and heated at 45°C for 12 hours to give, after acidic workup and crystallization, ambrisentan (II) in 84% yield as a colorless powder with 99.8% e.e.

Drug interactions

Potentially hazardous interactions with other drugs Ciclosporin: concentration of ambrisentan doubled with an increased risk of side effects; maximum dose 5 mg daily.

Metabolism

Ambrisentan is glucuronidated via several UGT isoenzymes (UGT1A9S, UGT2B7S and UGT1A3S) to form ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism mainly by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19 to form 4-hydroxymethyl ambrisentan (which has little activity) which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide. Ambrisentan is excreted mainly by the liver, although the contribution of hepatic metabolism and biliary excretion is unknown.

references

[1] vatter h, seifert v. ambrisentan, a non-peptide endothelin receptor antagonist. cardiovascular drug reviews, 2006, 24(1): 63-76.[2] barst r j. a review of pulmonary arterial hypertension: role of ambrisentan. vascular health and risk management, 2007, 3(1): 11.

InChI:InChI=1/C22H22N2O4/c1-15-14-16(2)24-21(23-15)28-19(20(25)26)22(27-3,17-10-6-4-7-11-17)18-12-8-5-9-13-18/h4-14,19H,1-3H3,(H,25,26)/t19-/m1/s1

Upstream product

• 1240470-84-1 (S)-methyl-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate 
• 76527-25-8 3,3-diphenyloxirane-2-carboxylic acid methyl ester 
• 35144-22-0 4,6-dimethyl-2-methylsulfonylpyrimidine 
• 178306-52-0 (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid 
• 1106685-61-3 (S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid methyl ester 
• 1231755-41-1 (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid monomethylamine salt 
• 1231755-49-9 (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid tertiary butylamine salt 
• 178306-51-9 (S)-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid 
• 1260633-84-8 (S)-1-(3-methoxyphenyl)ethylammonium (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate 
• 1260633-70-2 (R)-1-(2,4-dichlorophenyl)ethylammonium (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate 
• 1334552-80-5 (+)-2(S)-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid S-(-)-4-nitro-phenyl ethylamine salt 
• 1334552-81-6 (S)-1-phenylethan-1-aminium (S)-2-((4,6-dimethyl-pyrimidin-2-yl)oxy)-3-methoxy-3,3-diphenylpropanoate 
• 119-61-9 benzophenone 
• 178306-47-3 2-hydroxy-3-methoxy-3,3-diphenylpropionicacid methyl ester 

Downstream Products

• 1334552-81-6 (S)-1-phenylethan-1-aminium (S)-2-((4,6-dimethyl-pyrimidin-2-yl)oxy)-3-methoxy-3,3-diphenylpropanoate 
• 178306-51-9 (S)-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid 
• 1007358-76-0 ambrisentan 

Relevant articles and documents

Enantioselective epoxidation by the chiral auxiliary approach: Asymmetric total synthesis of (+)-Ambrisentan

Enantioselective and a highly concise total synthesis of Ambrisentan are described. The chiral auxiliary controlled enantioselective epoxidation (Azerad protocol), photochemical regioselective epoxide opening, and base mediated ester hydrolysis reactions

Preparation method of ambrisentan

The invention belongs to the field of medicine synthesis and particularly relates to a preparation method of ambrisentan, wherein the ambrisentan is prepared through a benzyl protection reaction, a condensation reaction, and a benzyl protection group removal reaction in the method. A benzyl-protected intermediate is delivered to the next step of the condensation reaction without post-treatment. The debenzylation reaction is carried out through catalytic hydrogenation, which is green and environment-friendly and is simple in reaction operations and post-treatment. A reaction liquid is treated and pulped in an ether solvent, so that residual raw materials and intermediate in the solid are removed effectively. When an ambrisentan crude product is prepared, a recrystallization step with a methanol/water mixed solvent is carried out to obtain high-purity ambrisentan. The method is fewer in steps and high in yield, has short production cycle, simple operation, good reproducibility and mild conditions, and is suitable for industrial production.

An improved method of preparing Anritsu tezosentan

The invention belongs to the field of chemical synthesis, and discloses an improved method used for preparing ambrisentan. According to the improved method, 2-hydroxy-3-methoxy-3,3-diphenylpropionic ester and 4,6-dimethyl-2-methylsulfonylpyrimidine are su

Process Research for (+)-Ambrisentan, an Endothelin-A Receptor Antagonist

An efficient and robust synthetic route to (+)-ambrisentan ((+)-AMB) was designed by recycling the unwanted isomer from the resolution mother liquors. The racemization of AMB in the absence of either acid or base in the given solvents was reported. The recovery process was developed to produce racemates with purities over 99.5%. The mechanism of the formation of the process-related impurities of (+)-AMB is also discussed in detail. (+)-AMB was obtained in 47% overall yield with >99.5% purity and 99.8% e.e. by chiral resolution with only one recycling of the mother liquors on a 100-g scale without column purification.

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

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

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.

Method for Preparing Optically Pure (+)-Ambrisentan and (+)-Darusentan

Disclosed is a method for preparing optically pure (+)-ambrisentan and (+)-darusentan, comprising: firstly catalyzing the asymmetric epoxidation of a β-unsaturated alkene using a chiral ketone derived from fructose or a hydrate thereof as a catalyst, and then subjecting the product to an epoxy compound ring-opening reaction and substitution reaction successively to obtain optically pure (+)-ambrisentan and (+)-darusentan.

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.