Alex de Minaur will find himself in the all too familiar position of being the last Australian man standing in a big ATP tournament before he even takes the court at the Madrid Open.

De Minaur has been waiting patiently to launch his title bid on Saturday, but the rest of the five-strong Australian men's contingent at the Spanish capital's Caja Magica have left him having to play another lone hand following the second-round exits of Alexei Popyrin and Chris O'Connell on Friday.

The 25th seed Popyrin's hopes of a deep run crumbled in his first match of the week as he suffered a disappointing 6-4 7-6 (7-4) loss to the unpredictable Kazakh Alexander Bublik, who conjured up one of his more impressive days in the 'Magic Box'.

Then O'Connell, who'd won his opening match on Wednesday, proved no match for third seed Taylor Fritz, with the US Open finalist outplaying the Sydneysider 6-1 6-4.

The biggest disappointment for the Australian challenge was Popyrin's defeat at the hands of world no.75 Bublik, which meant the Sydneysider was unable to build on his encouraging start to the clay-court season in Monte Carlo where he reached the quarters.

This time, he was chasing from the moment he got broken by the Kazakh in the fifth game of the opening set.

Popyrin looked to have put the poor opening stanza behind him when he raced into a 3-0 lead in the second and he later had three set points to level the match only for Bublik to hang tough and pounce in the tiebreak to prevail in an hour and 52 minutes.

Any thoughts that world No.4 Fritz might then prove vulnerable after his early-season abdominal problems were quickly extinguished as he looked sharp enough in working over O'Connell with 22 winners in a one-sided hour-and-a-quarter.

It all leaves world No.7 de Minaur to save the day again on Saturday when he faces Italian world No.43 Lorenzo Sonego, over whom he holds a 3-0 career advantage, on the main Manolo Santana Stadium court.

On Santana on Thursday, top seed Alexander Zverev looked the pick of the big names as he cruised to a 6-2 6-2 win over veteran home favourite Roberto Bautista Agut, extending his winning streak to six matches after victory in last week's Bavarian Championships in Munich propelled him to No.2 in the world.

"This is my favourite centre court in the world, I only lost twice here in my entire life," said the German. "I hope that stays the way throughout the next 10 days."

Czech teenager Jakub Mensik earned his first win since winning the Miami Open last month as he beat American qualifier Ethan Quinn 7-6 (7-4) 6-1 and he'll next face 12th seed Ben Shelton, who fought back to beat Argentine Mariano Navone 4-6 7-6 (7-5) 6-3.

Casper Ruud, seeking to get back into the world top 10, beat Frenchman Arthur Rinderknech 6-3 6-4, while Daniil Medvedev advanced to the third round after his Serbian opponent Laslo Djere withdrew before their match with a shoulder injury.