Ibiza briefly threatened an upset when Jose Miguel Bernal put them ahead midway through the first half, but Betis reacted strongly after the break, with striker Willian Jose scoring twice, along with Edgar Gonzalez and Nabil Fekir to ease Betis' progress.
Athletic Bilbao cruised past Eldense 6-1 in a game the Basque side took control of after goals in the 35th minute from Nico Williams and in the 40th from Alex Berenguer.
Oier Zaraga, Berenguer again, Iker Muniain and an own goal settled the match in the second half as Athletic produced a display of clinical finishing, reports Xinhua.
Osasuna had to work much harder away to third-tier Gimnastic Taragona, with the home side forcing extra time thanks to Pablo Fernandez cancelling out Kike Garcia's first-half opener for the top-flight side.
Fernandez was then sent off with six minutes of normal time left to play, but it wasn't until a minute before the end of extra time that Eric Montes put the ball into his own net to give Osasuna a 2-1 win.
The draw for the next round is on Saturday, with the games to be played on January 17th, 18th and 19th.
Madrid, Jan 6
Copa del Rey holders Real Betis came back from a goal down away to fourth-tier Ibiza Islas Pitusas to win 4-1 and ensure their place in the last 16 of the tournament on Thursday night.
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