US 12,435,042 B2
Process for the preparation of key intermediates for the synthesis of Eltrombopag or salt thereof
Paolo Stabile, Montecchio Maggiore (IT); and Floriana Semeraro, Montecchio Maggiore (IT)
Assigned to F.I.S.—FABBRICA ITALIANA SINTETICI S.P.A., Montecchio Maggiore (IT)
Appl. No. 17/619,383
Filed by F.I.S.—FABBRICA ITALIANA SINTETICI S.P.A., Montecchio Maggiore (IT)
PCT Filed Jul. 4, 2019, PCT No. PCT/EP2019/067968
§ 371(c)(1), (2) Date Dec. 15, 2021,
PCT Pub. No. WO2021/001044, PCT Pub. Date Jan. 7, 2021.
Prior Publication US 2022/0298116 A1, Sep. 22, 2022
Int. Cl. C07D 231/46 (2006.01); B01J 23/44 (2006.01); C07C 65/105 (2006.01); C07C 201/08 (2006.01); C07C 227/04 (2006.01)
CPC C07D 231/46 (2013.01) [B01J 23/44 (2013.01); C07C 65/105 (2013.01); C07C 201/08 (2013.01); C07C 227/04 (2013.01); C07B 2200/13 (2013.01)] 4 Claims
 
1. A process for the preparation of Eltrombopag of formula (I) or salt thereof:

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comprising of the following steps:
A) Palladium catalyzed coupling of 3-carboxyphenylboronic acid of formula (II):

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with the potassium salt of 2-bromo-4-chlorophenol of formula (III):

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to obtain the compound of formula (IV) or a hydrate thereof:

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wherein A is potassium;
B) nitration of the compound of formula (IV) prepared in the step A) in presence of acetic acid and 65% nitric acid to the compound of formula (V):

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C) hydrogenation of compound of formula (V) obtained in the step B) to compound of formula (VI) or its hydrate form:

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D) conversion of compound of formula (VI) obtained in the step C) to Eltrombopag of formula (I) or salt thereof.