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4,6-Dichloropyrimidine → (3R*,5S*)-5-(6-Chloro-pyrimidin-4-ylamino)-piperidine-3-carboxylic acid cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-amide

HRID 1698364
Notes
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Reaction equation

HRID 1698364 reaction equation
C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:51]=[C:50](Cl)[N:49]=[CH:48][N:47]=1>CN(C=O)C>[CH:31]1([N:15]([CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[C:14]([C@@H:12]2[CH2:11][C@H:10]([NH:35][C:50]3[CH:51]=[C:46]([Cl:45])[N:47]=[CH:48][N:49]=3)[CH2:9][NH:8][CH2:13]2)=[O:34])[CH2:32][CH2:33]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 709434,6-DichloropyrimidineHCID 81531DiisopropylethylamineHCID 69064081(3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 57870291(3R*,5S*)-5-(6-Chloro-pyrimidin-4-ylamino)-piperidine-3-carboxylic acid cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-amide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) in DMF (0.5 mL) are added i-Pr2NEt (26 uL, 0.15 mmol) and 4,6-dichloropyrimidine (23 mg, 0.15 mmol). After stirring for 16 h, the reaction mixture is quenched by H2O (30 mL) and extracted with EtOAc/Et2O (c.a. 1:1, 60 mL). The organic phase is successively washed with 5% KHSO4aq, 5% NaHCO3aq, H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo. The residue is purified by silica gel column chromatography to give Boc protected title compound. MS: 604 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.88 min. The Boc protected compound is treated with 4N HCl-1,4-dioxane to give the title compound as a white amorphous solid. MS: 504 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.66 min.

Workup

  1. customthe reaction mixture is quenched by H2O (30 mL)
  2. extractionextracted with EtOAc/Et2O (c.a. 1:1, 60 mL)
  3. washThe organic phase is successively washed with 5% KHSO4aq, 5% NaHCO3aq, H2O, and brine
  4. dry with materialdried over Na2SO4
  5. filtrationThe solution is filtered
  6. customthe solvent is evaporated in vacuo
  7. customThe residue is purified by silica gel column chromatography
  8. customto give Boc

Sources & evidence

ORD record
ord-3ff5546d74ef4a879a0d8bfba3bca1a7
Source dataset
uspto-grants-2012_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08163773B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes