ChemicalBook CAS DataBase List Valsartan

Valsartan synthesis

8synthesis methods

Product Name:Valsartan
CAS Number:137862-53-4
Molecular formula:C24H29N5O3
Molecular Weight:435.52

Valsartan is an angiotensin II receptor antagonist (commonly called an ARB, or angiotensin receptor blocker), that is selective for the type I (AT1) angiotensin receptor. Valsartan is mainly used for treatment of high blood pressure, congestive heart failure, and to increase the chances of living longer after a heart attack. Valsartan is used to treat high blood pressure, congestive heart failure, and to reduce death for people with left ventricular dysfunction after having had a heart attack. Synthetic Description Reference: Seki, Masahiko; Nagahama, Masaki. Synthesis of Angiotensin II Receptor Blockers by Means of a Catalytic System for C-H Activation. Journal of Organic Chemistry. Volume 76. Issue 24. Pages 10198-10206. Journal; Online Computer File. (2011) Synthetic Description Reference: Goossen, Lukas J.; Melzer, Bettina. Synthesis of Valsartan via Decarboxylative Biaryl Coupling. Journal of Organic Chemistry. Volume 72. Issue 19. Pages 7473-7476. Journal. (2007) Synthetic Description Reference: Nagaki, Aiichiro; Hirose, Katsuyuki; Tonomura, Osamu; Taniguchi, Satoshi; Taga, Toshiki; Hasebe, Shinji; Ishizuka, Norio; Yoshida, Jun-ichi. Design of a Numbering-up System of Monolithic Microreactors and Its Application to Synthesis of a Key Intermediate of Valsartan. Organic Process Research & Development. Volume 20. Issue 3. Pages 687-691. Journal; Online Computer File. (2016) Synthetic Description Reference: Ghosh, Samir; Kumar, A. Sanjeev; Mehta, G. N. Convenient synthesis of Valsartan via a Suzuki reaction. Journal of Chemical Research. Volume 34. Issue 4. Pages 191-193. Journal. (2010) Synthetic Description Reference: Ambati, Srinivas; Penikelapati, Hanumantha Rao; Maruthikumar, T. V.; Ambati, Narahari Babu. Alternative synthesis of valsartan via Negishi coupling. Pharma Chemica. Volume 3. Issue 4. Pages 13-17. Journal; Online Computer File. (2011) Synthetic Description Reference: Gano, Kyle W. Preparation of pyrido[2,1-a]isoquinoline derivatives for treating hyperkinetic disorders. Assignee Neurocrine Biosciences, Inc., USA. WO 2008058261. (2008).

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

ROUTE 4

ROUTE 5

ROUTE 6

ROUTE 7

ROUTE 8

ROUTE 9

Reference: Seki, Masahiko; Nagahama, Masaki. Synthesis of Angiotensin II Receptor Blockers by Means of a Catalytic System for C-H Activation. Journal of Organic Chemistry. Volume 76. Issue 24. Pages 10198-10206. Journal; Online Computer File. (2011)

781664-81-1 Synthesis

(S)-Methyl 3-methyl-2-(N-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)pentanamido

781664-81-1
14 suppliers
$466.51/1g

137862-53-4
891 suppliers
$9.00/10g

Yield:137862-53-4 95%

Reaction Conditions:

Stage #1: N-[[2'-(1-triphenylmethyltetrazol-5yl)biphenyl-4-yl]methyl]-N-valeryl-L-valine methyl esterwith methanol;potassium hydroxide for 4 h;Heating / reflux;
Stage #2: with water for 5 h;Heating / reflux;

Steps:

3 Preparation of crude valsartan (I)

1.2 g of methyl (S)-3-methyl-2-(pentanoyl-(2'-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl-4-ylmethyl)amino) butanoate, prepared as in example 2, are dissolved in 10.7 ml of methanol and 0.16 g (2.9 mmol) of pulverized KOH are added. The mixture is first heated under reflux for 4 h, and then 2.5 ml 2M KOH are added. The mixture is then heated for another 5h under reflux. After the completion of the reaction the evaporable components are distilled off and the water phase is acidified to pH 1 and extracted with tert-butyl methyl ether (2 * 12 ml). The organic phase is washed twice with 16 ml of water, dried over Na₂SO₄ and evaporated to leave a dry residue. 0.72 g of crude valsartan are isolated (HPLC Area %: 98.0 %, yield: 95 %, yield based on compound (II): 92 %). By contrast, the yield in the deprotection step (Example 3 of WO 2004/094391) is only 81%.

References:

EP1661891,2006,A1 Location in patent:Page/Page column 13