Phosphorus oxychloride → HCID 89677206, compound

HRID 589594Notes

Reaction equation

HRID 589594 reaction equation
[F:1][C:2]1([F:29])[CH:10]([F:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[C:3]21[CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:16](=O)[NH:15][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[N:13]2.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:16]1[NH:15][C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:13][C:3]2([C:4]3[C:9](=[CH:8][C:7]([F:12])=[CH:6][CH:5]=3)[CH:10]([F:11])[C:2]2([F:29])[F:1])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]

Participants

3

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 89677716HCID 89677716, compound

Product 1

HCID 89677206HCID 89677206, compound

Conditions

Temperature
110 °C

Procedure

Compound 165 (10.2 g, 23.1 mmol), pyridine-2-carboximidamide hydrochloride (6.37 g, 40.4 mmol), sodium bicarbonate (7.76 g, 92.4 mmol) and dioxane (200 mL) were heated and stirred at 60° C. during 6 hours and stirred further overnight at 40° C. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. The product fractions were combined and concentrated yielding methyl 2,2,3,5-tetrafluoro-6′-oxo-2′-(pyridin-2-yl)-2,3,5′,6′-tetrahydro-1′H-spiro[indene-1,4′-pyrimidine]-5′-carboxylate (6.1 g) as a light yellow amorphous powder. A solution of methyl 2′,2′,3′,5′-tetrafluoro-6-oxo-2-(2-pyridyl)spiro[1,5-dihydropyrimidine-4,1′-indane]-5-carboxylate in phosphorus oxychloride (50 g) equipped with a CaCl2 drying tube was heated at 110° C. during 210 minutes. The reaction mixture was concentrated, the residue dissolved in CH2Cl2 (200 mL), poured in saturated NaHCO3 (200 mL) solution and stirred 30 minutes. The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. methyl 6′-chloro-2,2,3,5-tetrafluoro-2′-(pyridin-2-yl)-2,3-dihydro-1′H-spiro[indene-1,4′-pyrimidine]-5′-carboxylate was isolated as two separate diastereoisomers: and compound 167A (1046 mg after second purification) and compound 167B (1705 mg).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. dissolutionthe residue dissolved in CH2Cl2 (200 mL)
  3. additionpoured in saturated NaHCO3 (200 mL) solution
  4. dry with materialThe organic layer was dried over sodium sulphate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane

Sources & evidence

ORD record
ord-4825ff5a3d154dd38d1e64e74ec6a3b0
Source dataset
uspto-grants-2016_01
Patent number
US09233933B2

Reaction notes

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