Dimethylcarbamoyl Chloride → HCID 118115004, compound

HRID 1050595Notes

Reaction equation

HRID 1050595 reaction equation
[NH:1]1[C@H:10]2[C@H:5]([NH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[C:22]([C:28]#[N:29])=[N:23][CH:24]=[C:25](Cl)[N:26]=1.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>CN1C(=O)CCC1.CCOC(C)=O>[Cl:20][C:21]1[N:26]=[C:25]([N:1]2[CH2:2][CH2:3][CH2:4][C@@H:5]3[C@H:10]2[CH2:9][CH2:8][CH2:7][N:6]3[C:32]([N:31]([CH3:35])[CH3:30])=[O:33])[CH:24]=[N:23][C:22]=1[C:28]#[N:29]

Participants

7

Reactant 4

HCID 6598Dimethylcarbamoyl ChlorideHCID 81531Diisopropylethylamine2×HCID 11083982rel-(4aR,8aR)-Decahydro-1,5-naphthyridineHCID 529877443,5-Dichloropyrazine-2-carbonitrile

Product 1

HCID 118115004HCID 118115004, compoundYield 19%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

Commercial (4aR,8aR)-decahydro-1,5-naphthyridine (423, 120 mg, 0.86 mmol) was dissolved in 2 mL NMP. To it were added DIEA (150 μL, 0.86 mmol) and then 3,5-dichloropyrazine-2-carbonitrile (150 mg, 0.86 mmol). The mixture was stirred at RT for 1.5 hour, and to it were added DIEA (450 μL, 2.58 mmol) and dimethylcarbamoyl chloride (240 μL, 2.58 mmol). The mixture was stirred at RT for overnight. It was diluted with 100 mL EtOAc, washed with water ×2, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 3% MeOH in DCM to isolate (4aR,8aR)-5-(6-chloro-5-cyanopyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide (424, 56 mg, 19%). It was mixed with 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (90 mg, 0.32 mmol), fine-powder cesium carbonate (210 mg, 0.64 mmol), Pd(OAc)2(11 mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol) in 15 mL dioxane. The mixture was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 1.5 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 11% MeOH in DCM to isolate (4aR,8aR)-5-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide (425). 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, acidified with 0.3 mL TFA, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (4aR,8aR)-5-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide (426) as HCl salt (23 mg). LC-MS (ESI): m/z (M+1) 575.8. UV: λ=269, 276, 305, 335, 372 nm.

Workup

  1. stirringThe mixture was stirred at RT for overnight
  2. washwashed with water ×2
  3. customdried
  4. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-1e1fcd54b1ba4e0b8a923f382afa080f
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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