US 12,269,840 B2
Process for the preparation of a cyclic dinucleotide
Michael Anthony Schmidt, Cranbury, NJ (US); Bin Zheng, Kendall Park, NJ (US); Benjamin M. Cohen, Cranford, NJ (US); Amanda J. Rogers, Asbury, NJ (US); Changxia Yuan, Warren, NJ (US); Jason J. Zhu, East Brunswick, NJ (US); Chao Hang, Monmouth Junction, NJ (US); Daniel S. Treitler, Cranford, NJ (US); Adam Joseph Freitag, Hopewell, NJ (US); Geoffrey Eugene Purdum, Freehold, NJ (US); Miao Yu, Malvern, PA (US); Melda Sezen Edmonds, Princeton, NJ (US); and Siwei Guo, Vacaville, CA (US)
Assigned to BRISTOL-MYERS SQUIBB COMPANY, Princeton, NJ (US)
Appl. No. 17/299,087
Filed by Bristol-Myers Squibb Company, Princeton, NJ (US)
PCT Filed Dec. 3, 2019, PCT No. PCT/US2019/064137
§ 371(c)(1), (2) Date Jun. 2, 2021,
PCT Pub. No. WO2020/117739, PCT Pub. Date Jun. 11, 2020.
Claims priority of provisional application 62/775,094, filed on Dec. 4, 2018.
Prior Publication US 2022/0064205 A1, Mar. 3, 2022
Int. Cl. C07H 21/00 (2006.01); C07H 1/00 (2006.01); C07H 19/16 (2006.01); C07H 19/20 (2006.01)
CPC C07H 21/00 (2013.01) [C07H 1/00 (2013.01); C07H 19/16 (2013.01); C07H 19/20 (2013.01)] 17 Claims
 
1. A process for the preparation of Compound I having the formula

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comprising the steps of
a) reacting Compound 1 with TBSCl and Et3N

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to afford Compound 2;
b) reacting Compound 2 with a phosphorus (V) compound consisting of Compound A to afford Compound 3

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c) reacting Compound 3 and Compound 9

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to afford Compound 4;
d) reacting Compound 4 in a solvent, and then adding a base, followed by the addition of a phosphorus (V) compound consisting of Compound B

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 to afford Compound 5 having the formula

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e) selectively deprotecting Compound 5 to afford Compound 6 having the formula

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f) the Compound 6 is cyclized in a suitable solvent under basic conditions to afford Compound 7 having the formula

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g) the Compound 7 is subsequently mixed in a suitable base, stirred and concentrated to afford Compound 8 having the formula

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and h) the Compound 8 is subsequently deprotected to afford Compound I.