Synthetic route to 2′-deoxy-2′,2′-difluorotetrahydrouridines
The present invention relates to methods and intermediates for synthesizing 2′-deoxy-2′,2′-difluorotetrahydrouridine compounds.
1. A method of producing compound 1:
or a salt thereof;
comprising precipitating or crystallizing compound 1 from a solution of compound 2:
in the presence of a catalyst,
wherein the solution comprises acetonitrile, and
wherein the catalyst is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).
2. The method of claim 1 , wherein the catalyst is about 1 mol % to about 20 mol % DBU.
3. The method of claim 1 , wherein the catalyst is about 5 mol % to about 10 mol % DBU.
4. The method of claim 3 , wherein the catalyst is about 5 mol % DBU.
5. A method of producing compound 1:
or a salt thereof;
comprising the steps of:
(a) hydrogenating a compound of Formula IV:
wherein R is a hydroxyl protecting group,
to produce a compound of Formula IIa:
(b) reducing the compound of Formula IIa to produce a compound of Formula IIIa:
(c) deprotecting the compound of Formula IIIa to produce compound 2:
and
(d) precipitating or crystallizing compound 2 in the presence of a catalyst to produce compound 1:
or a salt thereof,
wherein the catalyst is DBU.
6. The method of claim 5 , wherein the catalyst is about 1 mol % to about 20 mol % DBU.
7. The method of claim 6 , wherein the catalyst is about 5 mol % to about 10 mol % DBU.
8. The method of claim 7 , wherein the catalyst is about 5 mol % DBU.
9. The method of claim 5 , wherein the final product is recrystallized or slurrified.
10. The method of claim 5 , wherein step (d) is carried out in the presence of a solution comprising acetonitrile.
11. The method, of claim 5 , wherein step (b) is carried out in the presence of CeCl 3 .
12. The method of claim 5 , further comprising a step of reducing the particle size of compound 1.
13. The method of claim 12 , wherein the particle size is reduced to about 50 μm or less.