N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide → 3-[(4aR,6R,8aS)-2-amino-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile

HRID 1496772Notes

Reaction equation

HRID 1496772 reaction equation
N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[C:23]([C:25]1[CH:26]=[CH:27][C:28]([F:56])=[C:29]([C@:31]23[CH2:40][O:39][C@@H:38]([C:41]4[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=4)[CH2:37][C@H:36]2[CH2:35][S:34][C:33]([NH:47]C(=O)C2C=CC=CC=2)=[N:32]3)[CH:30]=1)#[N:24]>CO>[NH2:47][C:33]1[S:34][CH2:35][C@@H:36]2[CH2:37][C@H:38]([C:41]3[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=3)[O:39][CH2:40][C@:31]2([C:29]2[CH:30]=[C:25]([CH:26]=[CH:27][C:28]=2[F:56])[C:23]#[N:24])[N:32]=1

Participants

4

Reactant 2

HCID 86762666N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamideHCID 1296629601,8-Diazabicycloundec-7ene

Product 1

HCID 762821133-[(4aR,6R,8aS)-2-amino-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
50 °C

Procedure

1,8-Diazabicycloundec-7-ene (0.298 mL, 1.89 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C47) (1.11 g, 2.71 mmol) in methanol (100 mL). The resulting solution was heated to 50° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) afforded the product as an off-white solid. Yield: 79 mg, 38%. LCMS m/z 372.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.77 (ddd, J=8.5, 4.5, 2.2 Hz, 1H), 7.69 (dd, J=7.2, 2.2 Hz, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.36 (dd, J=12.1, 8.6 Hz, 1H), 4.71 (dd, J=11.6, 2.2 Hz, 1H), 4.24 (dd, J=11.2, 2.3 Hz, 1H), 3.87 (s, 3H), 3.76 (d, J=11.2 Hz, 1H), 3.06-3.11 (m, 1H), 2.89 (dd, J=12.5, 4.1 Hz, 1H), 2.76 (dd, J=12.7, 2.7 Hz, 1H), 2.04-2.14 (m, 1H), 1.82-1.87 (m, 1H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customPurification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane)

Sources & evidence

ORD record
ord-2045543b2bd746e1bc1a7fa5a09f9ca1
Source dataset
uspto-grants-2015_12
Patent number
US09198917B2

Reaction notes

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