HCID 59764747, compound → HCID 59764658, compound

HRID 406467Notes

Reaction equation

HRID 406467 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[Cl:27])[N:23]=[CH:22][N:21]=[C:20]2[NH:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][C:34](=O)[CH2:33]1)=[O:31]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[Cl:27])[N:23]=[CH:22][N:21]=[C:20]2[NH:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH:34]([N:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([OH:15])[CH:9]([CH3:14])[CH2:10]2)[CH2:33]1)=[O:31]

Participants

3

Reactant 2

HCID 59764747HCID 59764747, compoundHCID 68901520HCID 68901520, compound

Product 1

HCID 59764658HCID 59764658, compound

Procedure

2-(6,7-dichloroquinazolin-4-ylamino)-1-(3-(4-(4-fluorophenyl)-4-hydroxy-3-methylpiperidin-1-yl)pyrrolidin-1-yl)ethanone was prepared as a mixture of 4 isomers from (3S,4R)-4-(4-fluorophenyl)-3-methylpiperidin-4-ol (prepared via general procedure O, AA) and 1-(2-(6,7-Dichloroquinazolin-4-ylamino)acetyl)pyrrolidin-3-one (Preparation #32) according to general procedure E then purified via chiral preparative NP-HPLC (isocratic 2.5% methanol:2.5% ethanol:95% heptane:0.1% diethylamine modifier at 16 mL/min, room temperature; UV detection monitored at 265 nm; Daicel AD-H column, 20×250 mm, 5 um particle) to yield two products. Product A eluted at Rt 7.5-11 min. Product B eluted at Rt 11-15 min. Product A has a positive optical rotation and product B has a negative optical rotation. Product A was further separated via chiral preparative NP-HPLC (isocratic 10% methanol:10% ethanol:80% heptane:0.1% diethylamine modifier at 14 mL/min, room temperature; UV detection monitored at 265 nm; Daicel OD-H column, 20×250 mm, 5 um particle) to yield two isomers. Isomer 1 eluted at Rt 14-16.3 min. Isomer 2 eluted at Rt 16.3-19 min. Both isomers have positive optical rotation. The absolute stereochemistry of the isomers was not assigned. Isomers 1 & 2: RP-HPLC (Table 1, Method a) Rt 1.99 min; m/z: (M+H)+ 532. Product B was further separated via chiral preparative NP-HPLC (isocratic 10% methanol:10% ethanol:80% heptane:0.1% diethylamine modifier at 14 mL/min, room temperature; UV detection monitored at 265 nm; Daicel OD-H column, 20×250 mm, 5 um particle) to yield two isomers. Isomer 3 eluted at Rt 13.3-16 min. Isomer 4 eluted at Rt 16.3-19 min. Both isomers have negative optical rotation. The absolute stereochemistry of the isomers was not assigned. Isomers 3 & 4: RP-HPLC (Table 1, Method a) Rt 1.92 min; m/z: (M+H)+ 532.

Workup

  1. customthen purified via chiral preparative NP-HPLC (isocratic 2.5% methanol:2.5% ethanol:95% heptane:0.1% diethylamine modifier at 16 mL/min, room temperature; UV detection monitored at 265 nm; Daicel AD-H column, 20×250 mm, 5 um particle)
  2. customto yield two products
  3. washProduct A eluted at Rt 7.5-11 min
  4. washProduct B eluted at Rt 11-15 min
  5. customProduct A was further separated via chiral preparative NP-HPLC (isocratic 10% methanol:10% ethanol:80% heptane:0.1% diethylamine modifier at 14 mL/min, room temperature; UV detection monitored at 265 nm; Daicel OD-H column, 20×250 mm, 5 um particle)
  6. customto yield two isomers
  7. washIsomer 1 eluted at Rt 14-16.3 min
  8. washIsomer 2 eluted at Rt 16.3-19 min
  9. customProduct B was further separated via chiral preparative NP-HPLC (isocratic 10% methanol:10% ethanol:80% heptane:0.1% diethylamine modifier at 14 mL/min, room temperature; UV detection monitored at 265 nm; Daicel OD-H column, 20×250 mm, 5 um particle)
  10. customto yield two isomers
  11. washIsomer 3 eluted at Rt 13.3-16 min
  12. washIsomer 4 eluted at Rt 16.3-19 min

Sources & evidence

ORD record
ord-c4ab40dd9ad5471b9b5159e3704f3980
Source dataset
uspto-grants-2014_06
Patent number
US08754107B2

Reaction notes

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