Barium hydroxide → 3-(1,3-Dimethyl-10-(4-methylthiazol-2-yl)-2,4-dioxo-1,2,3,4,7,8-hexahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile

HRID 2201187Notes

Reaction equation

HRID 2201187 reaction equation
[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])=[C:6]2[C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34])[CH2:12][CH2:11][CH:10]=[C:9]3B1OC(C)(C)C(C)(C)O1.I[C:36]1[S:37][CH:38]=[C:39]([CH3:41])[N:40]=1.[OH-].[Ba+2].[OH-]>C(#N)C.O.Cl.[Pd+2].ClC1C=C[C-](P(C(C)(C)C)C(C)(C)C)C=1Cl.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])=[C:6]2[C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34])[CH2:12][CH2:11][CH:10]=[C:9]3[C:36]1[S:37][CH:38]=[C:39]([CH3:41])[N:40]=1

Participants

7

Reactant 3

HCID 6093286Barium hydroxideHCID 231545942-Iodo-4-methyl-1,3-thiazole2×HCID 867234303-(1,3-Dimethyl-2,4-dioxo-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,7,8-hexahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile

Product 1

HCID 867234293-(1,3-Dimethyl-10-(4-methylthiazol-2-yl)-2,4-dioxo-1,2,3,4,7,8-hexahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile

Reagents, catalysts & solvents 3

HCID 178454866HCID 178454866, compoundCatalystHCID 313Hydrochloric AcidSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
80 °C

Procedure

A mixture of 3-(1,3-dimethyl-2,4-dioxo-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,7,8-hexahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile (step 9) (202 mg, 0.44 mmol), 2-iodo-4-methylthiazole (Intermediate O) (90 mg, 0.40 mmol), dichloro[1,1′ bis(di-tert-butylphosphino)]ferrocene palladium (11) (13 mg, 0.02 mmol) and barium hydroxide (137 mg, 0.80 mmol) in acetonitrile/water (1:1, 2 mL) was stirred at room temperature for 45 minutes and at 80° C. for 1 hour. The reaction mixture was diluted with 1M HCl (10 mL) and was extracted with DCM (3×10 mL). The combined organic layers were filtered through a hydrophobic frit and the solvent removed under vacuum. Purified by chromatography on silica, eluting with 0.5% MeOH/DCM, 1% MeOH/DCM, 1.5-2.0% MeOH afforded the title product:

Workup

  1. extractionwas extracted with DCM (3×10 mL)
  2. filtrationThe combined organic layers were filtered through a hydrophobic frit
  3. customthe solvent removed under vacuum
  4. customPurified by chromatography on silica
  5. washeluting with 0.5% MeOH/DCM, 1% MeOH/DCM, 1.5-2.0% MeOH

Sources & evidence

ORD record
ord-6737cd798d0e47b7b90314de5efc617c
Source dataset
uspto-grants-2016_06
Patent number
US09359381B2

Reaction notes

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