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

HRID 1698051Notes

Reaction equation

HRID 1698051 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[C:5]2[CH2:11][CH2:10][N:9]([C:12](=O)[CH:13]([F:15])[F:14])[CH2:8][C:6]=2[N:7]=1.Cl.Cl[C:26]1[N:27]=[C:28](N2CCOC[C@@H]2C)[C:29]2[CH2:35][CH2:34]N[CH2:32][C:30]=2[N:31]=1.F[CH:44](F)[C:45](O)=O.CCN(C(C)C)C(C)C.CN(C([O:65]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[F:14][CH:13]([F:15])[CH2:12][N:9]1[CH2:10][CH2:11][C:5]2[C:4]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]3[CH3:23])=[N:3][C:2]([C:34]3[CH:35]=[CH:29][C:28]([NH:27][C:26]([NH:31][CH2:30][CH3:32])=[O:65])=[CH:45][CH:44]=3)=[N:7][C:6]=2[CH2:8]1

Participants

8

Reactant 5

HCID 9788Difluoroacetic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59239510(S)-1-(2-chloro-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2,2-difluoroethanoneHCID 86663157(S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride

Product 1

HCID 59239436(S)-1-(4-(7-(2,2-difluoroethyl)-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylureaYield 85%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

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)+.

Workup

  1. extractionextracted with EtOAc
  2. dry with materialThe EtOAc layer was dried over anhydrous Na2SO4
  3. concentrationconcentrated
  4. customto give the crude, which
  5. customwas purified by reverse-phase HPLC

Sources & evidence

ORD record
ord-6d3d83ebbd5c49038cf13546950f5a67
Source dataset
uspto-grants-2012_04
Patent number
US08163763B2

Reaction notes

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