Cesium carbonate → US9656988, Example 250

HRID 1050573Notes

Reaction equation

HRID 1050573 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2[CH3:20])[CH:5]=[N:4][C:3]=1[C:21]#[N:22].Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:42]#[N:43])[CH2:36][CH2:35][N:34]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=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]>[C:21]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2[CH3:20])=[N:7][C:2]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:42]#[N:43])[CH2:36][CH2:35][N:34]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)#[N:22]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 1181145264-(4-Aminophenyl)-1-cyclopentylpiperidine-4-carbonitrile hydrochlorideHCID 118115647US9656988, Example 237

Product 1

HCID 118146425US9656988, Example 250

Reagents, catalysts & solvents 2

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

Conditions

Temperature
115 °C

Procedure

The mixture of 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (100 mg, 0.31 mmol), 4-(4-aminophenyl)-1-cyclopentylpiperidine-4-carbonitrile hydrochloride (350) (114 mg, 0.37 mmol), fine-powder cesium carbonate (400 mg, 1.24 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), BINAP (62 mg, 0.1 mmol) in 20 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2.5 hours. 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-((2R,3R)-1-(5-cyano-6-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (351). It was dissolved in 10 mL MeOH and 1 mL DMSO. To it were added one NaOH solid bead (about 100 mg), DIEA (60 μL), and then 1 mL 30% H2O2. The mixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was acidified with TFA (0.5 mL) and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide (352) as HCl salt (22 mg). LC-MS (ESI): adz (M+1) 574.6. UV: λ=270, 281, 309, 336, 371 nm. Proton NMR (CD3OD): δ 7.78 (2H, d, J=9.0 Hz), 7.67 (1H, s), 7.49 (2H, d, J=8.5 Hz), 5.09 (1H, m), 4.28 (1H, m), 3.88 (3H, m), 3.69 (1H, m), 3.36 (2H, m), 3.09 (1H, m), 2.97 (6H, s), 2.51 (2H, m), 2.40 (2H, m), 2.26 (2H, m), 1.89 (4H, m), 1.86-1.66 (6H, m), 1.17 (3H, d, J=6.5 Hz) ppm. Compound 353, 3-(4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide, was also found and isolated as a major by-product in the final step.

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-3a7c541dcb4445389c62db305d289e6f
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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