Dichloromethane → (S)-1-(3-fluoro-4-(6-isopropyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)-3-(2-hydroxyethyl)urea

HRID 1626711Notes

Reaction equation

HRID 1626711 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH2:10][N:9]([CH:11]([CH3:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.[F:21][C:22]1[CH:23]=[C:24]([NH:37][C:38]([NH:40][CH2:41][CH2:42][OH:43])=[O:39])[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].COC1CCCC1>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].CCO.O>[F:21][C:22]1[CH:23]=[C:24]([NH:37][C:38]([NH:40][CH2:41][CH2:42][OH:43])=[O:39])[CH:25]=[CH:26][C:27]=1[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH2:10][N:9]([CH:11]([CH3:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1

Participants

9

Reactant 5

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 138539Cyclopentyl methyl etherHCID 66678959HCID 66678959, compound2×HCID 86663166(S)-4-(2-chloro-6-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine2×

Product 1

HCID 66678817(S)-1-(3-fluoro-4-(6-isopropyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)-3-(2-hydroxyethyl)ureaYield 5%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 962WaterSolvent

Procedure

A solution of (S)-4-(2-chloro-6-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 22) (109 mg, 0.367 mmol), 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 32) (151 mg, 0.466 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (15 mg, 0.018 mmol) and sodium carbonate (117 mg, 1.10 mmol) in 2 ml of a 7:3:1 mixture of CPME:H2O:EtOH respectively was heated in the microwave at 130° C. for 1 hour. The reaction was concentrated in vacuo and the residue redissolved in a mix of MeOH/DCM. It was loaded onto an SCX cartridge and washed with two column volumes of MeOH/DCM before being eluted with 2M NH3 in MeOH and concentrated in vacuo. The sample was then purified via preparative HPLC at high pH to yield the title compound (8 mg, 5%).

Workup

  1. concentrationThe reaction was concentrated in vacuo
  2. dissolutionthe residue redissolved in
  3. additiona mix of MeOH/DCM
  4. washwashed with two column volumes of MeOH/DCM
  5. washbefore being eluted with 2M NH3 in MeOH
  6. concentrationconcentrated in vacuo
  7. customThe sample was then purified via preparative HPLC at high pH

Sources & evidence

ORD record
ord-e2c50abf6922409a9604e96f9bee4510
Source dataset
uspto-grants-2014_07
Patent number
US08785457B2

Reaction notes

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