Cesium carbonate → 3-{3,5-Dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-phenyl}-azetidine-1-carboxylic acid tert-butyl ester

HRID 2366252Notes

Reaction equation

HRID 2366252 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([C:19]3[S:20][C:21]4[C:22](Cl)=[N:23][CH:24]=[CH:25][C:26]=4[N:27]=3)=[C:14]([Cl:29])[CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1[N:36]=[CH:35][N:34]=[C:33]([NH2:37])[CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([Cl:29])[C:15]([C:19]3[S:20][C:21]4[C:22]([NH:37][C:33]5[CH:32]=[C:31]([CH3:30])[N:36]=[CH:35][N:34]=5)=[N:23][CH:24]=[CH:25][C:26]=4[N:27]=3)=[C:16]([Cl:18])[CH:17]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 5728526-Methylpyrimidin-4-amineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866690043-[3,5-Dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-azetidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 668016723-{3,5-Dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-phenyl}-azetidine-1-carboxylic acid tert-butyl esterYield 52.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 3-[3,5-dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-azetidine-1-carboxylic acid tert-butyl ester (0.106 g, 0.225 mmol), 6-methylpyrimidin-4-ylamine (0.024 g, 0.248 mmol), XantPhos (0.013 g, 0.023 mmol), Pd2(dba)3 (0.010 g, 0.0113 mmol) and Cs2CO3 (0.147 g, 0.45 mmol) in dioxane (2 mL) was degassed with a stream of argon. The reaction mixture was heated at 85° C. for 18 hours. Additional Pd2(dba)3 (0.005 g), XantPhos (0.007 g) and 6-methylpyrimidin-4-ylamine (0.006 g) were added and the mixture was heated at 85° C. for 18 hours. After cooling to room temperature, the crude reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-90% EtOAc in petroleum ether to afford the title compound as a pale yellow glass (64 mg, 52% yield). 1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 8.45 (d, J=5.7 Hz, 1H), 8.15 (s, 1H), 7.76 (d, J=5.6 Hz, 1H), 7.51-7.41 (m, 3H), 4.39 (t, J=8.7 Hz, 2H), 4.02-3.92 (m, 2H), 3.80-3.70 (m, 1H), 2.56 (s, 3H), 1.48 (s, 9H).

Workup

  1. customwas degassed with a stream of argon
  2. additionAdditional Pd2(dba)3 (0.005 g), XantPhos (0.007 g) and 6-methylpyrimidin-4-ylamine (0.006 g) were added
  3. temperaturethe mixture was heated at 85° C. for 18 hours
  4. temperatureAfter cooling to room temperature
  5. customthe crude reaction mixture
  6. filtrationwas filtered through Celite®
  7. concentrationthe filtrate was concentrated under reduced pressure
  8. customThe resultant residue was purified by column chromatography on silica gel eluting with 0-90% EtOAc in petroleum ether

Sources & evidence

ORD record
ord-f4466b15393d4bda92110b434b39af4c
Source dataset
uspto-grants-2014_04
Patent number
US08697708B2

Reaction notes

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