Sodium Carbonate → HCID 71283555, compound

HRID 1752437Notes

Reaction equation

HRID 1752437 reaction equation
[C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]([NH2:18])=[O:17])[CH:10]=1)(=[O:3])[NH2:2].[Cl:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[C:22]([F:42])[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C:23]3[CH:40]=[CH:41][C:20]([Cl:19])=[CH:21][C:22]=3[F:42])=[CH:30][CH:29]=2)[N:12]=[C:11]([C:16]([NH2:18])=[O:17])[CH:10]=1)(=[O:3])[NH2:2]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 71285772HCID 71285772, compoundHCID 90399257HCID 90399257, compound

Product 1

HCID 71283555HCID 71283555, compoundYield 33%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of (S)-6-(2-carbamoylpyrrolidin-1-yl)-2-chloropyrimidine-4-carboxamide (0.272 g, 1.01 mmol) in dioxane (5 mL) was added 2-(4-(4-chloro-2-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.387 g, 1.11 mmol), 2M aqueous Na2CO3 (1.0 mL, 2.0 mmol) and PdCl2(dppf) (0.044 g, 0.054 mmol). The reaction vessel was flushed with argon, sealed, and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 25-100% acetone in hexanes. The product fractions were evaporated in vacuo and the residue further chromatographed using reverse-phase chromatography with a 40-70% acetonitrile in water (+0.1% TFA) gradient. The product fractions were pooled and lyophilized. The residue was triturated with acetonitrile (3 mL). The solid was filtered off, washed with acetonitrile (1×1 mL), and dried under vacuum at 40° C. to give (S)-6-(2-carbamoylpyrrolidin-1-yl)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as an off-white powder (0.152 g, 0.333 mmol, 33% yield). 1H NMR (400 MHz, DMSO-d6): Exists as a ˜70:30 ratio of rotamers: 8.60-8.52 (2H, m), 8.35 (1H, s), 7.80 (1H, s), 7.73-7.67 (1.3H, m), 7.51 (0.7H, s), 7.38-7.28 (2H, m), 7.23 (0.3H, s), 7.09 (0.6H, d, J=8.3 Hz), 7.04 (1.4H, d, J=8.8 Hz), 7.00-6.94 (1.4H, m), 6.77 (0.3H, s), 4.58-4.52 (0.7H, m), 4.33-4.27 (0.3H, m), 3.90-3.81 (0.3H, m), 3.79-3.70 (0.3H, m), 3.70-3.62 (0.7H, m), 3.56-3.47 (0.7H, m), 2.38-2.17 (1H, m), 2.11-1.91 (3H, m). LC/MS: m/z=456.1 [M+H]+.

Workup

  1. customThe reaction vessel was flushed with argon
  2. customsealed
  3. temperatureAfter cooling
  4. customthe reaction mixture was evaporated in vacuo
  5. customthe residue chromatographed over silica gel with 25-100% acetone in hexanes
  6. customThe product fractions were evaporated in vacuo
  7. customthe residue further chromatographed
  8. customThe residue was triturated with acetonitrile (3 mL)
  9. filtrationThe solid was filtered off
  10. washwashed with acetonitrile (1×1 mL)
  11. customdried under vacuum at 40° C.

Sources & evidence

ORD record
ord-5c7eadb61b3c47c09c638c2ee98ed33e
Source dataset
uspto-grants-2015_10
Patent number
US09163008B2

Reaction notes

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