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 the steps of:
(a) hydrogenating the starting compound of Formula IV:
wherein R is a hydroxyl protecting group,
to produce the compound of Formula IIa:
(b) reducing the compound of Formula IIa to produce the 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 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), acetic acid, trifluoroacetic acid, diisopropylethylamine, or ammonium hydroxide; and
wherein the hydrogenating in step (a) is carried out in the presence of a palladium catalyst.
2. The method of claim 1 , wherein the catalyst is about 1 mol % to about 20 mol % DBU.
3. The method of claim 2 , 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. The method of claim 1 , wherein the catalyst is acetic acid, trifluoroacetic acid, diisopropylethylamine, or ammonium hydroxide.
6. The method of claim 1 , wherein the final product is recrystallized or slurrified.
7. The method of claim 1 , wherein step (d) is carried out in the presence of a solution comprising acetonitrile.
8. The method of claim 1 , wherein step (d) is carried out in the presence of a solution comprising acetone or tetrahydrofuran.
9. The method of claim 1 , wherein step (b) is carried out in the presence of CeCl 3 .
10. The method of claim 1 , further comprising a step of reducing the particle size of compound 1.
11. The method of claim 10 , wherein the particle size is reduced to about 50 μm or less.
12. The method of claim 1 , wherein the palladium catalyst is palladium on charcoal.