Proton sponge → (S)-3-isopropyl-6-((1-(o-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione

HRID 709438Notes

Reaction equation

HRID 709438 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH2:10])[CH3:9].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:28]1[NH:33][C:32](=[O:34])[N:31]([CH:35]([CH3:37])[CH3:36])[C:30](=[O:38])[CH:29]=1>CN1C(=O)CCC1.CS(C)=O>[CH:35]([N:31]1[C:30](=[O:38])[CH:29]=[C:28]([NH:10][C@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH3:9])[NH:33][C:32]1=[O:34])([CH3:37])[CH3:36]

Participants

6

Reactant 3

HCID 88675Proton spongeHCID 197800(alphaS)-alpha,2-DimethylbenzenemethanamineHCID 8201076-Chloro-3-(propan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione

Product 1

HCID 117764102(S)-3-isopropyl-6-((1-(o-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dioneYield 8.1%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
130 °C

Procedure

To a stirred solution of (1S)-1-(2-methylphenyl)ethan-1-amine (310 mg, 2.29 mmol, 1.50 equiv) in NMP (1 mL) was added proton sponge (491.4 mg, 2.30 mmol, 1.50 equiv) and 1.3 (288 mg, 1.53 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 130° C. in an oil bath, cooled to room temperature, and then diluted with DMSO (2 mL). The solids were filtered and the filtrate was purified by Flash-Prep-HPLC with the following conditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: H2O/0.05% TFA, Mobile Phase B: CH3CN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min. This afforded 50 mg of crude product which was subsequently separated by chiral preparative HPLC with the following conditions: Column, Chiralpak IC, 2*25 cm, Sum; mobile phase, hexanes and ethanol (9:1, 15 min). This resulted in 35.6 mg (8%) of the title compound as a white solid. LC/MS: m/z (ES+) 288 (M+H)+. 1H-NMR (300 MHz, DMSO-d6): δ ppm 9.76 (br s, 1H), 7.28 (d, J=7.2 Hz, 1H) 7.24-7.14 (m, 3H), 6.48 (d, J=6.3 Hz, 1H), 4.95-4.86 (m, 1H), 4.60 (quin, J=6.9 Hz, 1H), 4.19 (s, 1H), 2.34 (s, 3H), 1.37 (d, J=6.6 Hz, 3H), 1.27 (d, J=6.9 Hz, 6H).

Workup

  1. temperaturecooled to room temperature
  2. filtrationThe solids were filtered
  3. customthe filtrate was purified by Flash-Prep-HPLC with the following conditions
  4. waitGradient: 30% B to 70% B in 10 min
  5. customThis afforded 50 mg of crude product which was subsequently separated by chiral preparative HPLC with the following conditions
  6. custommobile phase, hexanes and ethanol (9:1, 15 min)

Sources & evidence

ORD record
ord-8daa09b225c0443fb61c802a6d203ab6
Source dataset
uspto-grants-2015_11
Patent number
US09181200B2

Reaction notes

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