Pyridine → (S)-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-yl)propanamide

HRID 1054488Notes

Reaction equation

HRID 1054488 reaction equation
[F:1][C:2]([F:22])([F:21])[C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[N:16][CH:15]=2)=[CH:10][N:9]=1.[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35](O)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40].C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>C(Cl)Cl>[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35]([NH:20][C:18]3[CH:17]=[N:16][CH:15]=[C:14]([C:11]4[CH:10]=[N:9][C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@H:3]5[C:2]([F:21])([F:1])[F:22])=[N:13][CH:12]=4)[N:19]=3)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40]

Participants

6

Reactant 4

HCID 1049PyridineHCID 10868DicyclohexylcarbodiimideHCID 86727121HCID 86727121, compound2×HCID 86727123(S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine

Product 1

HCID 76685061(S)-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-yl)propanamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A round bottom flask was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine (5.097 g, 16.43 mmol) and (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoic acid (Intermediate 8) (4.97 g, 19.71 mmol). The reagents were suspended in DCM (Volume: 36.5 ml, Ratio: 4), sonicated and allowed to stir for 5 minutes. To the yellow heterogenous mixture was added DCC (5.76 g, 27.9 mmol) and finally pyridine (Volume: 18.25 ml, Ratio: 2) was added and the mixture was allowed to stir for 3 hours. The reaction mixture was diluted with CH2Cl2 and filtered over Celite®. The filtrate was then concentrated and redissolved in a minimal amount of and added dropwise to stirring hexanes to precipitate out crude 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-yl)propanamide, which was dried overnight. The mixture of diasteromers was resolved using SFC purification to give the (S,S)-isomer in 2.58 g (retention time: 2.5 min, de: 98%); and the (R,S)-isomer in 0.208 g (retention time: 2.2 min, de: 99%); 1H NMR, (S,S)-isomer (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.16 (d, J=3.5 Hz, 3H), 8.97 (s, 1H), 8.36 (s, 1H), 5.86 (d, J=7.3 Hz, 1H), 5.20-5.03 (m, 1H), 3.73 (t, J=6.5 Hz, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.29-2.04 (m, 4H), 1.89 (d, J=7.3 Hz, 3H); m/z found [M+H]+=545.19

Workup

  1. customsonicated
  2. additionwas added
  3. stirringto stir for 3 hours
  4. filtrationfiltered over Celite®
  5. concentrationThe filtrate was then concentrated
  6. dissolutionredissolved in a minimal amount of and
  7. additionadded dropwise
  8. stirringto stirring hexanes
  9. customto precipitate out crude 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-yl)propanamide, which
  10. customwas dried overnight
  11. additionThe mixture of diasteromers
  12. customSFC purification
  13. customto give the (S,S)-isomer in 2.58 g (retention time: 2.5 min, de: 98%)

Sources & evidence

ORD record
ord-5f0418160a6d4653bee914bbf99c755b
Source dataset
uspto-grants-2016_07
Patent number
US09394308B2

Reaction notes

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