Cesium carbonate → US9656988, Example 281

HRID 1050589Notes

Reaction equation

HRID 1050589 reaction equation
Cl[C:2]1[C:3]([C:23]#[N:24])=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]3[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[C:15]3=[O:21])[C@H:9]2[CH3:22])[N:7]=1.Cl.[CH:26]1([N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:26]1([N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:43]=[CH:42][C:40]([NH:41][C:2]4[C:3]([C:23]#[N:24])=[N:4][CH:5]=[C:6]([N:8]5[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]6[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[C:15]6=[O:21])[C@H:9]5[CH3:22])[N:7]=4)=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 1181146604-(1-Cyclopentylpiperidin-4-yl)aniline hydrochlorideHCID 1181150663-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile

Product 1

HCID 118114630US9656988, Example 281

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

The mixture of 3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile (405) (60 mg, 0.17 mmol), 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (58 mg, 0.21 mmol), fine-powder cesium carbonate (230 mg, 0.68 mmol), Pd(OAc)2(11 mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol) in 15 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 1 hour. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 10% MeOH in chloroform to isolate 3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile (406). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added one NaOH solid bead (about 100 mg), Et3N (60 μL), and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 30 min, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 150 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, acidified with 0.2 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide (407) as HCl salt (58 mg, 59%). LC-MS (ESI): m/z (M+1) 575.8. UV: λ=268, 277, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.64 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz), 4.93 (1H, m), 4.56-4.30 (3H, m), 3.71 (2H, m), 3.55 (1H, m), 3.38 (3H, m), 3.13 (2H, m), 3.06 (1H, m), 2.97 (3H, s), 2.84 (1H, m), 2.25-1.65 (18H, m), 1.20 (3H, d, J=6.5 Hz) ppm.

Workup

  1. customwas degassed with nitrogen stream for 3 min
  2. temperatureThe mixture was cooled to RT
  3. additiondiluted with 100 mL EtOAc
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-0953cfe6b9ae488cb2b10d25c769e99a
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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