Ambrisentan, a potent selective endothelin receptor antagonist, is utilized for the treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis. It blocks the endothelin receptor on vascular smooth muscle cells and cardiac myocytes, preventing vasoconstriction and smooth muscle proliferation.
Ambrisentan is marketed under the trade name Letairis™ or Volibris®. Ambrisentan is chemically known as (S)-2-((4,6-dimethylpyrimidin-2-yl)oxy)-3-methoxy-3,3-diphenyl propanoic acid and has the structural formula as shown in formula (I).

U.S. Pat. No. 5,703,017 broadly discloses several molecules generally, which are 3-(Het) aryl carboxylic acid derivatives. The compounds disclosed also include Ambrisentan. In the specification, synthetic schemes for preparation of the molecules and for their intermediates are disclosed. The general methods of preparation involve coupling the epoxide of formula III (for example, with R═COOR) with alcohols or thiols of formula IV according to the following scheme:

U.S. Pat. No. 7,109,205 discloses and claims Ambrisentan. The patent also discloses the process for the preparation of Ambrisentan as per a similar scheme as in the above patent. This specification also discloses the preparation of Ambrisentan according to the above process.
This patent also describes the preparation in laboratory scale of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid (compound V) by resolution of the corresponding racemate using L-proline methyl ester and (S)-1-(4-nitrophenyl)ethylamine. By this resolution, yield of 35% based on the racemate and an optical purity of 99.8% were achieved.
U.S. Pat. No. 6,559,338 describe a process of resolution of 2-hydroxypropanoic acid by using an optically active base (S)-1-(4-chlorophenyl)ethylamine and then one of the diastereomeric salts formed is separated off. However the optically active base used here is very expensive and would not be preferable for large-scale production. Additionally, the objective of this resolution has not been clearly defined.
However, the U.S. Pat. No. 6,559,338 also state that, it has been found that when this described reaction step was scaled up (several kg to 100 kg), additional working steps became necessary in order to ensure a high optical purity. The diastereomeric salt of (S)-2-hydroxypropanoic acid and (S)-1-(4-nitrophenyl)ethylamine crystallizes with difficulty and therefore cannot be filtered off readily either, so that some of the mother liquor remains in the crystals together with the enantiomer to be separated off. Only when the crystals were additionally stirred in the tank together with fresh solvent, and when the crystals that had been filtered off are copiously rewashed, the required optical purity was obtained.
Therefore, the present invention provides a process for resolution of racemic 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid (VIII) that does not have the above-mentioned disadvantages but can readily be carried out on an industrial scale.
In addition, the inventors of the present invention surprisingly found the improved resolution of the racemate compound (VIII) by reacting the racemic acid with a suitable optically active amine and subsequently separating off the diastereomeric salt with high chiral purity. Additionally the same diastereomeric salt can further be utilized for the preparation of Ambrisentan.
Thus, the present invention discloses an improved process for preparing Ambrisentan. The present invention discloses an improved process for preparing Ambrisentan wherein the chiral amine base used as resolving agent, provides a novel intermediate that is used in preparation of Ambrisentan of high enantiomeric purity.
WO2010017918 disclosed the amorphous form of Ambrisentan and process for the preparation of thereof. It is well known that amorphous forms have several limitations in terms of stability, processability etc. thereby making the crystalline form of any compound more preferable. The present inventors have surprisingly found a new crystalline form of Ambrisentan which is stable, easily processable & can be used to obtain the commercial form of Ambrisentan in chirally and chemically pure form.