Water → METHYL (2S,4R)-1-{2-[4-(4-CHLORO-PHENYL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5lambda4-THIENO [3,2-D]PYRIMIDIN-4-YL}-4-HYDROXY-PYRROLIDINE-2-CARBOXYLATE

HRID 70098

Reaction equation

HRID 70098 reaction equation
Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[OH:25][C@H:26]1[CH2:30][NH:29][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27]1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.ClCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([N:29]4[CH2:30][C@H:26]([OH:25])[CH2:27][C@H:28]4[C:31]([O:33][CH3:34])=[O:32])[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1

Participants

7

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 7015125(4R)-4-Hydroxy-L-proline methyl esterHCID 594758954-Chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide

Product 1

HCID 59708424METHYL (2S,4R)-1-{2-[4-(4-CHLORO-PHENYL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5lambda4-THIENO [3,2-D]PYRIMIDIN-4-YL}-4-HYDROXY-PYRROLIDINE-2-CARBOXYLATE

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

500 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 284.19 mg methyl (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylate and 691.65 μl diisopropylethylamine are placed in 8 ml dioxane, heated to 120° C. in the microwave for 0.3 hours. Then the reaction mixture is combined with water and dichloromethane and extracted. The organic phase is separated off using a phase separation cartridge and evaporated to dryness. The diastereomers are separated by preparative HPLC (method B). 200 mg of Diastereomer I (Example 125) and 160 mg of a Diastereomer 2 (Example 126) are obtained as powders. Analytical HPLC-MS (method A): Diastereomer 1, RT=2.51 min, Diastereomer 2, RT=2.57 min.

Workup

  1. extractionextracted
  2. customThe organic phase is separated off
  3. customa phase separation cartridge
  4. customevaporated to dryness
  5. customThe diastereomers are separated by preparative HPLC (method B)
  6. custom200 mg of Diastereomer I (Example 125) and 160 mg of a Diastereomer 2 (Example 126) are obtained as powders

Sources & evidence

ORD record
ord-0985aff65b9b4c70a322c66845821bed
Source dataset
uspto-grants-2014_09
Patent number
US08822474B2

Linked notes

Loading…