Sage 50 Accounts does not directly interact with, or have knowledge of, low level networking so would be blissfully unaware of whether you have IPv6 enabled or not and there are no settings in the software that would directly affect any networking options. There is no good reason why it cannot work with IPv6 enabled, which you have already proven given you have been running like this for a good while as you say "I've been running IPv6 for a couple of years, and Sage50 with Office 365 integration on since May 2021".

Jeremy Curtis said:

Something has changed over the last week or so that kills it.

The key thing here would be to identify what has changed, which may not be straightforward. There have been no updates released recently for Sage 50 Accounts so there will be no change there. Something else must have changed but hard to say what. Possibly a Windows or Office update or a change or update to Anti-virus/security software but that is really just guessing.

The machine this is installed on is my main workstation, which runs various CAD and development software. I block updates until I’ve checked them out, so there should have been none over the last few days.

It could be a cloud service now has an IPv6 dns entry but isn’t up and running on IPv6 yet. I may have a tinker today with a packet sniffer and see if I can track down the issue.

There is one other query on here with IPv6 on here from a few weeks ago. Where remote data access was failing with IPv6 enabled. So there must be something going on, I suspect in the backend somewhere.  

Hmm, I wonder if any of the Sage backend is hosted in Azure?
It seems with IPv6 the traffic manager that sits in front of Azure can't resolve something, but using IPv4 it can.  Should be fun to track down...

Jeremy Curtis said:

I wonder if any of the Sage backend is hosted in Azure?

No, there is no Sage backend involved and if there were most of our services are currently hosted in AWS. Of course Azure is what Microsoft will be using for their Office 365 backend so perhaps it's something there?

By backend, I meant the Sharepoint created by Sage for the Office 365 integration.  I can see lots of traffic to the Amazon eu-west-1 compute service, which I presume is Sage data.  
I only need it to automatically drop created documents into OneDrive (Invoices, purchase orders, etc.).  So that I can free text search the text within those documents.  If there were a full free text search in Sage I'd drop the Office integration.  Print to file is laborious when OneDrive saves files neatly and names the documents for me. 

I know it has been working fine since May 2021, and I've been using IPv6 long before I moved to Sage.  Then in the last week or so, it stopped working under IPv6.  Every other Microsoft based service I use has shown no interruption.  It's just this single Sage<->Office 365 thing that is broken.  So I guess it's down to who manages the Azure instances hosting the Sage generated Sharepoint site, any idea who that is?