Seventh seed Stefanos Tsitsipas was knocked out in five sets by Dominic Stricker, a qualifier ranked 128 in the world on day three at the US Open.
Then, in the night session, fifth seed and last year’s runner-up Casper Ruud fell foul of China’s world number 67 Zhang Zhizhen.
British qualifier Lily Miyakazi’s run came to and end in the second round.
Chocolate-loving Dominic Stricker caused a major upset at the US Open by knocking out seventh seed Stefanos Tsitsipas.
The chubby-cheeked 21-year-old qualifier from Switzerland, ranked 128 in the world, stunned two-time grand slam finalist Tsitsipas with a 7-5 6-7 (2) 6-7 (5) 7-6 (8) 6-3 victory to reach the third round.
The former French Open junior champion recently admitted his coach had told him to cut down on chocolate and cookies.
Miyazaki’s US Open adventure was ended in the second round by Olympic champion Belinda Bencic.
The 27-year-old came through three matches to qualify at Flushing Meadows for the first time and then picked up a maiden grand slam win against Margarita Betova in round one.
But the world number 198 found 15th seed Bencic, of Switzerland, too tough a nut to crack as she bowed out 6-3 6-3.
Miyazaki still leaves New York with the consolation prize of having virtually doubled her earnings for the year with a £98,000 pay day for winning her first-round match.
There were victories in the doubles for Jamie Murray, with Michael Venus, Joe Salisbury alongside partner Rajeev Ram, Lloyd Glasspool with Harri Heliovaara. and British pair Julian Cash and Henry Patten.
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