Conservative MP Nick Boles resigned from his party's whip on the floor of the House of Commons, seconds after MPs rejected alternatives to Theresa May's EU withdrawal deal.
"My party refuses to compromise," he said. "I regret therefore that I can no longer sit for this party."
He later tweeted that he would "sit as an Independent Progressive Conservative."
His resignation came after MPs rejected all four alternatives to the prime minister's EU withdrawal deal after Parliament took control of the Brexit process for the second time in the space of a week.
They rejected Mr Boles' proposal for a Norway-style deal put forward by 21.
A proposal from Europhile Tory grandee Kenneth Clarke for a customs union arrangement with the EU was rejected by only three votes, while a demand for a second referendum was defeated by 12.
SNP MP Joanna Cherry's proposal to give MPs the power to block a no-deal Brexit by voting to revoke Article 50 was rejected by a margin of 101 votes.
Brexit Secretary Stephen Barclay told MPs that the default outcome was now a no-deal Brexit on 12 April, but said it was still possible to leave with a deal - and avoid holding European Parliament elections in May - if the Commons approves an agreement this week.
The cabinet will meet on Tuesday for five hours to thrash out a way forward.
Mr Barclay told MPs: "This House has continuously rejected leaving without a deal, just as it has rejected not leaving at all. Therefore the only option is to find a way through which allows the UK to leave with a deal. The Government continues to believe that the best course to take is to do so as soon as possible."
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