Solketal → 2-(3-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 2,3-dihydroxy-propyl ester

HRID 2110778Notes

Reaction equation

HRID 2110778 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.CC1(C)[O:37][CH:36]([CH2:38]O)[CH2:35][O:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[OH:37][CH:36]([CH2:35][OH:34])[CH2:38][O:28][C:27](=[O:29])[C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)([CH3:31])[CH3:30]

Participants

6

Reactant 4

HCID 7528SolketalHCID 8471TriethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 11669780Pgd2-IN-1

Product 1

HCID 576360262-(3-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 2,3-dihydroxy-propyl esterYield 80.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [145 mg, 0.315 mmol, Example 49(b)] in N,N′-dimethylformamide (4 mL) is added (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol [62 mg, 0.472 mmol] and TBTU (151 mg, 0.472 mmol) followed by triethylamine (1 mL). The reaction mixture is stirred for 16 hours at ambient temperature, quenched with the addition of water (200 mL) and brine (25 mL) and extracted twice with EtOAc (200 mL). The extracts are concentrated in vacuo and the residue is stirred in MeOH (4 mL). 1 N hydrochloric acid is added (4 mL). After one hour the reaction is poured into water (150 mL) and extracted twice with EtOAc (150 mL). The extracts are concentrated and the residue is subjected to flash column chromatography on silica (4 g) eluting with 60 to 80% EtOAc in heptane to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 2,3-dihydroxy-propyl ester (135 mg, Example 89) as an oil. MS: 534 (M+H), 1H NMR [300 MHz, (CD3)2SO]: δ 7.9 (1H, s); 7.8 (1H, s); 7.6 (2H, s); 7.45 (2H, m); 7.35 (2H, s); 6.6 (1H, s); 4.8 (1H, d); 4.55 (1H, t); 4.05 (1H, m); 3.9 (1H, m); 3.85 (3H, s); 3.6 (3H, m); 3.25 (2H, t); 2.95 (2H, t), 1.5 (6H, s). IC50=18 nM

Workup

  1. customquenched with the addition of water (200 mL) and brine (25 mL)
  2. extractionextracted twice with EtOAc (200 mL)
  3. concentrationThe extracts are concentrated in vacuo
  4. stirringthe residue is stirred in MeOH (4 mL)
  5. addition1 N hydrochloric acid is added (4 mL)
  6. additionAfter one hour the reaction is poured into water (150 mL)
  7. extractionextracted twice with EtOAc (150 mL)
  8. concentrationThe extracts are concentrated
  9. washeluting with 60 to 80% EtOAc in heptane

Sources & evidence

ORD record
ord-8886f65093f64749b5311dc1ce28fc4a
Source dataset
uspto-grants-2009_04
Patent number
US07517889B2

Reaction notes

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