Pyridine → HCID 78318764, compound

HRID 1619066Notes

Reaction equation

HRID 1619066 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:24]C(=O)C2C=CC=CC=2)=[N:9]3)[S:6][CH:7]=1)#[N:2].N1C=CC=CC=1.Cl.CON>C(O)C>[NH2:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:5]2[S:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 521874O-Methylhydroxylamine hydrochlorideHCID 89823492HCID 89823492, compound

Product 1

HCID 78318764HCID 78318764, compound

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

Racemic N-[7a-(4-cyano-2-thienyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (1.01 g, 2.17 mmol), pyridine (2.64 mL, 32.6 mmol), and O-methylhydroxylamine hydrochloride (1.82 g, 21.7 mmol) in ethanol (250 mL) are stirred at 60° C. for 24 hours. The mixture is cooled to ambient temperature and concentrated. The mixture is diluted with water and extracted with DCM followed by 3:1 chloroform:isopropyl alcohol. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated. The crude product is purified over silica gel using a gradient of hexane:ethyl acetate (1:0 to 0:1, over 30 min) The product is chirally separated by SFC (Column: Chiralpak AS-H 2.1×15 cm; 5μ; eluent: 30% methyl alcohol with 0.2% isopropylamine) in CO2; flow: 70 mL/minute at 225 nm). The first eluting isomer is the title compound (99% ee). Analysis column: Chiralpak AS-H 4.6×150 mm; eluent: 30% methyl alcohol with 0.2% isopropylamine) in CO2; flow: 5.0 mL/min at UV 225 nm, RT=1.08 minutes). ES/MS (m/e): 361 (M+H).

Workup

  1. concentrationconcentrated
  2. additionThe mixture is diluted with water
  3. extractionextracted with DCM
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product is purified over silica gel using a gradient of hexane:ethyl acetate (1:0 to 0:1, over 30 min) The product
  8. customis chirally separated by SFC (Column: Chiralpak AS-H 2.1×15 cm; 5μ; eluent: 30% methyl alcohol with 0.2% isopropylamine) in CO2

Sources & evidence

ORD record
ord-3e251b49c37b44d4b4d005c792a5377c
Source dataset
uspto-grants-2014_07
Patent number
US08772282B2

Reaction notes

Loading…