Thionyl Chloride → HCID 67405110, compound

HRID 913912Notes

Reaction equation

HRID 913912 reaction equation
BrC1C=CC2N(CC3CC3)C([CH2:9][O:10][CH2:11][C:12]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=NC=2C=1.BrC1C=CC2N=C(COCC3(C4C=CC=CC=4)CCN(C(OC(C)(C)C)=O)CC3)N(CC3CC3)C=2C=1.[F:73][C:74]([F:95])([F:94])[C:75]1[CH:76]=[C:77](CO)[C:78]2[N:82]=[CH:81][N:80]([CH2:83][O:84][CH2:85][CH2:86][Si:87]([CH3:90])([CH3:89])[CH3:88])[C:79]=2[CH:91]=1.S(Cl)(Cl)=O.OCC1(C2C=CC=CC=2)CCN(C(OC(C)(C)C)=O)CC1.[H-].[Na+]>O1CCCC1>[C:25]1([C:12]2([CH2:11][O:10][CH2:9][C:77]3[C:78]4[N:82]=[CH:81][N:80]([CH2:83][O:84][CH2:85][CH2:86][Si:87]([CH3:90])([CH3:89])[CH3:88])[C:79]=4[CH:91]=[C:75]([C:74]([F:73])([F:94])[F:95])[CH:76]=3)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14][CH2:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1

Participants

8

Reactant 6

HCID 24386Thionyl ChlorideHCID 24758Sodium hydrideHCID 9994433Tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylateHCID 57545981HCID 57545981, compound2×HCID 57546192HCID 57546192, compound2×HCID 67403042HCID 67403042, compound

Product 1

HCID 67405110HCID 67405110, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

The conversion of the alcohol to chloromethyl derivative and the subsequent alkylation were done using similar procedure as described in the synthesis of tert-butyl 4-(((5-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (5) and tert-butyl 4-(((6-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate. (6-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methanol (25 mg, 0.072 mmol) was converted to chloromethyl derivative as described in the synthesis of tert-butyl 4-(((5-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate and tert-butyl 4-(((6-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate using thionyl chloride (0.030 mL, 5.7 eq) and the crude chloromethyl derivative was alkylated with tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (25.2 mg, 1.2 eq) using sodium hydride (9 equiv) in tetrahydrofuran (3 mL) at ambient temperature for 3 days. The crude product was purified by silica gel chromatography using a gradient of 10%-80% ethyl acetate in dichloromethane. Fractions containing required compound were combined and evaporated in vacuo to give tert-butyl 4-phenyl-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (25 mg) containing required product and piperidinyl alcohol reagent in the ratio of 2:3 by proton NMR. Material used without additional purification. LC/MS (HPLC method 8): tR=3.8 min, 642(MNa)+.

Workup

  1. customat ambient temperature
  2. customfor 3 days
  3. customThe crude product was purified by silica gel chromatography
  4. additionFractions containing required compound
  5. customevaporated in vacuo

Sources & evidence

ORD record
ord-c35918ab2f5147baad958cb7d76c4f88
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

Loading…