US 12,187,757 B2
2′-deoxy-2′,2′-difluorotetrahydrouridines with high purity and methods of making the same
Gemma Zuend, Haywood, CA (US); Ian Scott, Niwot, CO (US); Nipun Davar, Pleasanton, CA (US); Kimiyoshi Annaka, Osaka (JP); Masahiro Miyake, Osaka (JP); and Motoshi Matsui, Osaka (JP)
Assigned to Otsuka Pharmaceutical Co., Ltd., Tokyo (JP)
Appl. No. 17/766,074
Filed by OTSUKA PHARMACEUTICAL CO., LTD., Tokyo (JP)
PCT Filed Oct. 7, 2020, PCT No. PCT/US2020/054500
§ 371(c)(1), (2) Date Apr. 1, 2022,
PCT Pub. No. WO2021/071890, PCT Pub. Date Apr. 15, 2021.
Claims priority of provisional application 62/912,317, filed on Oct. 8, 2019.
Prior Publication US 2022/0411457 A1, Dec. 29, 2022
Int. Cl. C07H 19/06 (2006.01); C07H 1/00 (2006.01)
CPC C07H 19/06 (2013.01) [C07H 1/00 (2013.01)] 20 Claims
 
1. A method of producing compound 1:

OG Complex Work Unit Chemistry
or a salt thereof;
comprising the steps of:
(a) hydrogenating a compound of Formula IV:

OG Complex Work Unit Chemistry
wherein R is a hydroxyl protecting group,
to produce a compound of Formula IIa:

OG Complex Work Unit Chemistry
(b) reducing the compound of Formula IIa to produce a compound of Formula IIIa:

OG Complex Work Unit Chemistry
(c) deprotecting the compound of Formula IIIa to produce compound 2:

OG Complex Work Unit Chemistry
 and
(d) precipitating or crystallizing compound 2 in the presence of a catalyst to produce compound 1:

OG Complex Work Unit Chemistry
or a salt thereof;
wherein the method comprises the following steps:
(i) wherein the hydrogenating step (a) is performed under hydrogen atmosphere with a palladium catalyst;
(ii) wherein the reducing step (b) is performed at a temperature of about −12° C. to about −5° C.;
(iii) wherein the deprotecting step (c) is performed in the presence of an organic base; and
(iv) wherein the work-up of the deprotected compound from deprotecting step (c) is performed under non-aqueous conditions.