4,6-Dichloropyrimidine → HCID 87143436, compound

HRID 1645738Notes

Reaction equation

HRID 1645738 reaction equation
Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Li]CCCC.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1>C1COCC1.[Br-].[Zn+2].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:22]=1

Participants

7

Reactant 3

HCID 709434,6-DichloropyrimidineHCID 3279513-Bromoimidazo[1,2-a]pyridineHCID 178418339Butyllithium

Product 1

HCID 87143436HCID 87143436, compound

Reagents, catalysts & solvents 3

HCID 10421208Zinc bromideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 3-bromo-imidazo[1,2-a]pyridine (1 g, 5.1 mmol) in dry THF (25 mL) under N2 at −78° C. was added n-BuLi (1.6 M in hexanes, 3.8 mL, 6.12 mmol) and the reaction mixture was stirred at that temperature for 1 hour. Then freshly dried zinc bromide (1.7 g, 7.65 mmol) in dry THF (15 mL) was added slowly and the reaction mixture was slowly warmed up to room temperature and 4,6-dichloro-pyrimidine (760 mg, 5.1 mmol) and Pd(PPh3)4 (294 mg, 0.26 mmol) was added. After 16 hours at 75° C., the reaction mixture was then concentrated and directly purified by flash chromatography (SiO2, 95:5:0.5/EtOAc:MeOH:TEA) to give 3-(6-chloro-pyrimidin-4-yl)-imidazo[1,2-a]pyridine (Int-1). MS found for C11H7ClN4 as (M+H)+ 231.45. To a solution of Int-1 (100 mg, 0.44 mmol), 4-amino-benzoic acid (72 mg, 0.52 mmol) in dioxane (3 mL) and 2-PrOH (0.5 mL), p-TSA (83 mg, 0.44 mmol) was added and heated in a microwave (Emry's Optimizer) at 130° C. After 20 minutes, the resulting solid was filtered and washed with ether and dried to give 4-(6-imidazo[1,2-a]pyridin-3-yl-pyrimidin-4-ylamino)-benzoic acid (Int-2). MS found for C18H13N5O2 (m/z): 332.39 [M++1]. To Int-2 (75 mg, 0.23 mmol) in DMF (4 mL), was added HATU (129 mg, 0.34 mmol), 1,2-phenylenediamine (49 mg, 0.45 mmol) and DIPEA (0.12 mL, 0.68 mmol) and stirred at room temperature for 45 minutes. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound as tan solid, after lyophilization. MS found for C24H19N7O as (M+H)+ 422.09. 1H NMR (400 MHz, dmso-d6): δ 9.89 (d, J=6.8 Hz, 1H); 8.71 (s, 1H); 8.19 (s, 1H); 7.92 (d, J=8.8 Hz, 2H); 7.80 (d, J=8.8 Hz, 2H); 7.61 (d, J=9.2 Hz, 1H); 7.42 (t, J=7.6 Hz, 1H); 7.13-6.97 (m, 4H); 6.83 (d, J=7.2 Hz, 1H); 6.69 (t, J=7.6 Hz, 1H).

Workup

  1. waitAfter 16 hours at 75° C.
  2. concentrationthe reaction mixture was then concentrated
  3. customdirectly purified by flash chromatography (SiO2, 95:5:0.5/EtOAc:MeOH:TEA)

Sources & evidence

ORD record
ord-61b82766a55f4375a01e6a14c91884b5
Source dataset
uspto-grants-2012_02
Patent number
US08124764B2

Reaction notes

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