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)pyridin-2-yl)propanamide

HRID 1054485Notes

Reaction equation

HRID 1054485 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]=[CH: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].C1C=NC2N(O)N=NC=2C=1.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]=[CH: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:1])([F:21])[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

7

Reactant 5

HCID 1049PyridineHCID 10868DicyclohexylcarbodiimideHCID 181649HOAtHCID 86727117(S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine2×HCID 86727121HCID 86727121, compound2×

Product 1

HCID 86727122(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)pyridin-2-yl)propanamideYield 50%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

A flask was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 3, 5.44 g, 17.59 mmol) and (S)-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propanoic acid (Intermediate 8, 5.10 g, 20.23 mmol, ee: 99%), CH2Cl2 (58.6 mL) and the resulting mixture was stirred at 25° C. for 5 minutes. To the resulting yellow heterogeneous mixture was added HOAt (2.394 g, 17.59 mmol) and DCC (6.90 g, 33.4 mmol). The reaction mixture was cooled to 0° C. and pyridine (2.85 mL, 35.2 mmol) was added slowly around the edges of the flask. The reaction mixture was kept at 0° C. for 5 minutes before it was removed from the ice bath, and was then stirred at 25° C. for 3 hours. The reaction mixture was diluted with CH2Cl2 and filtered over Celite® to remove urea byproduct. The filtrate was then quickly concentrated to an oil, taken up in minimal CH2Cl2 and added dropwise to stirring hexanes to precipitate out crude (S,S)-product which was dried overnight. The product was recrystallized from CH2Cl2:MeOH (4:1) to obtain the title product (4.78 g, 8.79 mmol, 50%, de>99%); 1H NMR; 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.12 (s, 2H), 8.34 (s, 1H), 7.88 (dt, J=15.7, 8.1 Hz, 2H), 7.68 (d, J=8.2 Hz, 1H), 5.84 (d, J=6.7 Hz, 1H), 5.11 (p, J=7.4, 7.0 Hz, 1H), 3.83-3.61 (m, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.33-1.96 (m, 4H), 1.87 (d, J=7.3 Hz, 3H); m/z [M+H]+=544.20.

Workup

  1. temperatureThe reaction mixture was cooled to 0° C.
  2. waitThe reaction mixture was kept at 0° C. for 5 minutes before it
  3. customwas removed from the ice bath
  4. stirringwas then stirred at 25° C. for 3 hours
  5. additionThe reaction mixture was diluted with CH2Cl2
  6. filtrationfiltered over Celite®
  7. customto remove urea byproduct
  8. concentrationThe filtrate was then quickly concentrated to an oil
  9. additionadded dropwise
  10. stirringto stirring hexanes
  11. customto precipitate out crude (S,S)-product which
  12. customwas dried overnight
  13. customThe product was recrystallized from CH2Cl2:MeOH (4:1)

Sources & evidence

ORD record
ord-579c64073b3f405487ba9d004d083a4c
Source dataset
uspto-grants-2016_07
Patent number
US09394308B2

Reaction notes

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