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Serena Williams, eyeing a record-equalling 24th grand slam singles title, is the only major winner left in the US Open draw after world No.1 Naomi Osaka's exit.

Top-seeded titleholder Naomi Osaka's fourth-round US Open exit has presented Serena Williams with her best chance yet to match Margaret Court's record of 24 grand slam singles titles.

Osaka will also relinquish the world No.1 ranking to Ashleigh Barty after her 7-5 6-4 loss to Belinda Bencic under the closed roof at Arthur Ashe Stadium on a rainy Monday.

The 21-year-old Osaka found no answer to the accuracy and consistency of the 13th-seeded Swiss as she lost, for the third time this year to Bencic, in one hour and 26 minutes.

"The challenge cannot be bigger playing Naomi," Bencic said.

"She has a lot of power, me not so much. I play like chess and anticipate."

Osaka will slip to third in the rankings after the Open with French Open champion Barty returning to the top ahead of Karolina Pliskova - although both of them are also already out in New York.

Barty aside, Williams shapes as the major beneficiary from Osaka's elimination, which also means the US Open is without both top seeds in the quarter-finals for the first time in the professional era, which started in 1968.

Men's No.1 Novak Djokovic, also the 2018 champion, retired with a shoulder injury in his match against Stan Wawrinka on Sunday.

Williams, who faces Barty's fourth-round conqueror Qiang Wang in the quarter-finals on Tuesday, is now the only grand slam champion left in the women's draw.

The 37-year-old has lost her past three grand slam finals since winning her 23th major while pregnant at the 2017 Australian Open.

While Williams has slipped up against former world No.1s and multiple major winners Angelique Kerber and Simona Halep at Wimbledon in 2018 and 2019 and against Osaka in last year's drama-charged US Open decider, the American is now an overwhelming favourite to finally equal Court's all-time-best tally.

In her second US Open quarter-final on Wednesday, Bencic faces 23rd seed Donna Vekic, who saved a match point while rallying to a first victory in four meetings with German 26th seed Julia Goerges, 6-7 (5-7) 7-5 6-3.

Bencic took the first set against Osaka thanks to an 11th-game break and in the second Bencic broke Osaka to love in the fifth game of the second on a double fault from the Japanese.

Osaka called for the trainer at the following changeover, took a pill she was given, but was not able to turn around the match.

Vekic is enjoying her best run at a major after withstanding 21 aces from Goerges, who committed three of her six double-faults after tightening up while serving for the match at 5-4 in the second set.

The German double faulted again to hand Vekic a crucial 5-3 lead in the final set and the Croatian served out the match after saving two break points.

Belgian 25th seed Elise Mertens cruised into her first US Open quarter-final with a 6-1 6-1 rout of American wildcard Kristie Ahn.

Mertens will play 15th-seeded Bianca Andreescu after the Canadian teenager ended the giant-killing run of American qualifier Taylor Townsend 6-1 4-6 6-2.

US OPEN WOMEN'S QUARTER-FINAL MATCH-UPS

5-Elina Svitolina (UKR) v 16-Joanna Konta (GBR)

8-Serena Williams (USA) v 18-Qiang Wang (CHN)

13-Belinda Bencic (SUI) v 23-Donna Vekic (CRO)

15-Bianca Andreescu (CAN) v 25-Elise Mertens (BEL)