Dicyclohexylcarbodiimide → (S)-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-((methylthio)methyl)-N-(6 (2 (2 (trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-yl)acetamide

HRID 1054482Notes

Reaction equation

HRID 1054482 reaction equation
[CH3:1][S:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[C:22]([F:25])([F:24])[F:23])=[N:15][CH:16]=2)[N:6]=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:41]1([C:52](=[O:53])[C:51]2[N:50]([CH2:54][C:55](O)=[O:56])[CH:49]=[N:48][C:47]=2[N:45]([CH3:46])[C:43]1=[O:44])[CH3:42]>N1C=CC=CC=1.C(Cl)Cl>[CH3:42][N:41]1[C:52](=[O:53])[C:51]2[N:50]([CH2:54][C:55]([N:4]([CH2:3][S:2][CH3:1])[C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]4[CH:16]=[N:15][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C@H:18]5[C:22]([F:25])([F:23])[F:24])=[N:13][CH:12]=4)[N:6]=3)=[O:56])[CH:49]=[N:48][C:47]=2[N:45]([CH3:46])[C:43]1=[O:44]

Participants

6

Reactant 3

HCID 10868Dicyclohexylcarbodiimide2×HCID 69550Acefylline2×HCID 86727119(S)-N-((methylthio)methyl)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine

Product 1

HCID 86727120(S)-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-((methylthio)methyl)-N-(6 (2 (2 (trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-yl)acetamideYield 68.3%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

A solution of (S)—N-((methylthio)methyl)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 4.17 g, 46.0 mmol) and DCC (18.99 g, 92 mmol) in pyridine (230 mL) was heated for 30 minutes at 60° C. before theophylline 7-acetic acid (21.92 g, 92 mmol) was added in one portion. The reaction mixture was stirred at 60° C. and monitored by LCMS. After 2 hours, additional theophylline 7-acetic acid (21.92 g, 92 mmol) and DCC (18.99 g, 92 mmol) were added to drive the reaction to completion. The reaction mixture was diluted with CH2Cl2. The resulting precipitate (DCC urea) was filtered over Celite® and washed with CH2Cl2 (3×). The mixture was diluted with water and adjusted to pH 3 with aqueous 3M HCl. The organic and aqueous layers were separated and the aqueous layer was extracted with additional CH2Cl2 (3×). The combined organic layers were washed with aqueous 1M HCl (2×), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified using silica gel chromatography, eluting with EtOAc:Hex (70:30) to yield 18.5 g (31.4 mmol, 68%) of the title product as a thick oil; 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.16-8.03 (m, 2H), 7.99 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 5.33 (s, 2H), 5.12 (m, 3H), 3.82-3.65 (m, 2H), 3.43 (s, 3H), 3.18 (s, 3H), 2.31-2.09 (m, 4H), 2.06 (s, 3H); m/z found [M+H]+=590.37.

Workup

  1. additionwas added in one portion
  2. customthe reaction to completion
  3. filtrationThe resulting precipitate (DCC urea) was filtered over Celite®
  4. washwashed with CH2Cl2 (3×)
  5. additionThe mixture was diluted with water
  6. customThe organic and aqueous layers were separated
  7. extractionthe aqueous layer was extracted with additional CH2Cl2 (3×)
  8. washThe combined organic layers were washed with aqueous 1M HCl (2×)
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe crude material was purified
  13. washeluting with EtOAc

Sources & evidence

ORD record
ord-d563b37b9d214ca7894d3a74054825d4
Source dataset
uspto-grants-2016_07
Patent number
US09394308B2

Reaction notes

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