Lithium Hydroxide → tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

HRID 521378Notes

Reaction equation

HRID 521378 reaction equation
C([O-])([O-])=O.[Na+].[Na+].[N+](C1C=CC(C([O:16][C@H:17]2[C:21]3[N:22]=[CH:23][N:24]=[C:25](Cl)[C:20]=3[C@H:19]([CH3:27])[CH2:18]2)=O)=CC=1)([O-])=O.B1([C:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH:40]=2)OC(C)(C)C(C)(C)O1.[Li+].[OH-]>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].O>[OH:16][C@H:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([C:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH:40]=3)[C:20]=2[C@H:19]([CH3:27])[CH2:18]1

Participants

8

Reactant 4

HCID 3939Lithium HydroxideHCID 10340Sodium CarbonateHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 86651804(5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate

Product 1

HCID 67438475tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylateYield 67%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A solution of Na2CO3 (2 mL, 2M) was added to a solution of (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (334 mg, 1.00 mmol), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid, pinacol ester (340 mg, 1.10 mmol) in 1,4-dioxane (6 mL). The mixture was sparged with N2 for 2 minutes. The catalyst Pd(dppf)Cl2 (65 mg, 0.08 mmol) was added in one portion. The reaction vial was sealed and heated in microwave to 120° C. for 20 minutes. A solution of LiOH (0.7 mL, 3M) was added. The mixture was stirred at room temperature for 18 hours. Water (30 mL) was added to the mixture, extracted with DCM (3×20 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-5% MeOH/DCM gradient elution) to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate as an oil (221 mg, 67%). 1H NMR (CDCl3, 400 MHz) δ 9.01 (s, 1H), 6.44 (s, 1H), 5.30 (m, 1H), 4.16-4.11 (m, 2H), 3.71-3.55 (m, 3H), 2.83-2.78 (m, 1H), 2.50-2.30 (m, 1H), 2.28-2.24 (m, 2H), 1.50 (s, 9H), 1.28-1.22 (m, 3H).

Workup

  1. customThe mixture was sparged with N2 for 2 minutes
  2. customThe reaction
  3. customvial was sealed
  4. extractionextracted with DCM (3×20 mL)
  5. dry with materialThe combined organics were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by flash chromatography (0-5% MeOH/DCM gradient elution)

Sources & evidence

ORD record
ord-afd40a38b9e54b0391327f71f9f0e8ca
Source dataset
uspto-grants-2016_05
Patent number
US09328091B2

Reaction notes

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