Difluoroacetic acid → (S)-1-(4-(7-(2,2-difluoroethyl)-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea

Participants

Role	Name	HCID	Charge
Reactant	Difluoroacetic acid	HCID 9788	—
Reactant	Diisopropylethylamine	HCID 81531	—
Reactant	Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)	HCID 9886157	—
Reactant	(S)-1-(2-chloro-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2,2-difluoroethanone	HCID 59239510	—
Reactant	(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride	HCID 86663157	—
Solvent	Water	HCID 962	—
Solvent	Tetrahydrofuran	HCID 8028	—
Product	(S)-1-(4-(7-(2,2-difluoroethyl)-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea	HCID 59239436	85%

Reaction Steps

Step 1—Synthesis of (S)-1-(2-chloro-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2,2-difluoroethanone (yi): A solution of (S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride (yh) (300 mg, 1.0 mmol), difluoroacetic acid (192 mg, 2.0 mmol), DIPEA (1 mL) and HATU (500 mg, 1.3 mmol) in THF (5 ml) was stirred at r.t. overnight. LC-MS indicated the reaction was completed and the mixture was poured into water, and extracted with EtOAc. The EtOAc layer was dried over anhydrous Na2SO4 and concentrated to give the crude, which was purified by reverse-phase HPLC to give the desired product (280 mg, 85%). 1H NMR (CDCl3, 400 MHz): δ6.23-5.95 (m, 1H), 4.70-4.54 (m, 2H), 4.06-4.04 (m, 1H), 3.90-3.80 (m, 2H), 3.67-3.56 (m, 5H), 3.49-3.35 (m, 1H), 2.66-2.61 (m, 2H), 1.31 (d, J=9.6, 3H). LC-MS: m/z=+496 (M+H)+.

Provenance & Evidence

DOI	10.6084/m9.figshare.5104873.v1
Patent number	US08163763B2
Source dataset	uspto-grants-2012_04
ORD ID	ord-6d3d83ebbd5c49038cf13546950f5a67
Source note	uspto-grants-2012_04