ChemicalBook CAS DataBase List Retigabine

Retigabine synthesis

13synthesis methods

Product Name:Retigabine
CAS Number:150812-12-7
Molecular formula:C16H18FN3O2
Molecular Weight:303.33

Ezogabine, also known as Retigabine, is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline. Ezogabine works primarily as a potassium channel opener—that is, by activating a certain family of voltage-gated potassium channels in the brain. This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including migraine, tinnitus and neuropathic pain. (Source: http://en.wikipedia.org/wiki/Retigabine). Ezogabine is discontinued (DEA controlled substance).

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

ROUTE 4

ROUTE 5

Zhu, Lei; Wang, Jia-le; Wang, Pu-hai. Improved synthesis of retigabine. Zhongguo Yaowu Huaxue Zazhi. Volume 24. Issue 1. Pages 31-33, 77. Journal. (2014).

{4-[(4-fluorobenzil)aMMino]-2-nitrofenil}carbaMMato di etile

150812-23-0
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150812-12-7
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Yield:150812-12-7 90%

Reaction Conditions:

with hydrogen;1 % platinum and 2% vanadium on carbon in ethanol at 50 - 70; under 1500.15 Torr; for 3 h;Inert atmosphere;Industry scale;

Steps:

3

A pressure vessel was charged with 2-ethyoxycarbonylamino-5-(4-fluorobenzylamino)- nitrobenzene, 1 kg (1 wt), and the catalyst, 1 % Pt + 2 % V/C, 50 g (0.05 wt). The vessel was pressure test with nitrogen to 6 barg. The reactor was charged with denatured ethanol, 10 L (10 vol), and the stir rate was set to > 450 rpm. The vessel was pressure purged 3 times with nitrogen to 2 barg. The reaction mixture was heated to 50 °C under reactor control. Once an internal temperature of 50 °C was achieved, agitation was discontinued and the reactor purged three times with hydrogen to 2 barg. Following the third hydrogen purge and once the vessel reached 2 barg again, hydrogen flow control was initiated and the agitator activated. The reactor contents were aged for 2 hours. The reaction was heated to 70 °C and stirred for an additional 1 hour at 70° C. Once complete, the reaction mixture was filtered. The filtrate was transfer to a second 20 L vessel. The reactor was rinsed with denatured ethanol, 3 L (3 vol) and heated to > 55 °C. The rinse was filtered and the solution transferred to the second 20-L vessel. Once the batch temperature dropped below 30 °C, a vacuum was established, 100 mbar (solution will boil at ~ 29 °C), and the solution concentrated to 7.5 L (7.5 vol). The solution was heated to 65 °C and aged until dissolution has occurred. The batch was cooled to 50 °C and seeded with retigabine (API), 5 g (0.005 wt) slurried in denatured ethanol, 20 ml_ (0.02 vol). After charging the seed, the solution was immediately cooled to 40 °C over 40 minutes, then aged for 60 min. The solution was cooled to 0 °C over 2 hours. The heterogeneous solution was stirred at 0 °C for 1 hour. The batch was milled, isolated and dried. The slurry was transferred to a filter and filtered. The wet cake was transferred to the vacuum oven and dried at 30-40 °C until the LOD indicated < 0.5 % wt. loss (120 °C for 15 minutes).Percent yield range observed: 70-90 %

References:

WO2012/98075,2012,A1 Location in patent:Page/Page column 8