Formic Acid → HCID 25160968, compound

HRID 914030Notes

Reaction equation

HRID 914030 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:43]=[CH:42][C:12]3[N:13]([CH2:38][CH:39]4[CH2:41][CH2:40]4)[C:14]([CH2:16][O:17][CH2:18][C:19]4([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C=O.C(O)=O>C(OCC)(=O)C>[CH:39]1([CH2:38][N:13]2[C:12]3[CH:42]=[CH:43][C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)=[CH:10][C:11]=3[N:15]=[C:14]2[CH2:16][O:17][CH2:18][C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:41][CH2:40]1

Participants

5

Reactant 3

HCID 284Formic AcidHCID 712FormaldehydeHCID 67403049HCID 67403049, compound

Product 1

HCID 25160968HCID 25160968, compoundYield 50%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

tert-Butyl 4-(((5-(4-cyanophenyl)-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (23 mg, 0.04 mmol) was combined with aqueous formaldehyde (37%, 0.5 mL, 168 equiv) and formic acid (0.5 mL, 329 equiv) and heated at 70° C. for 64 h. At the end, after adjusting the pH of the reaction mixture to 6.0 extractive work up with ethyl acetate followed by evaporation of the organic layer in vacuo gave the crude product. The crude product was purified by preparative HPLC (HPLC method 12). Fractions containing the required product were combined and evaporated in vacuo. The residue obtained was purified by silica gel chromatography using a linear gradient of 1.2%-20% methanol in dichloromethane to obtain 12 mg (50% yield) as a TFA salt. 1H-NMR (500 MHz, CD3OD) δ 7.92 (s, 1H), 7.86 (d, JAB=8.5 Hz, 2 H), 7.81 (d, JAB=8.5 Hz, 2 H), 7.67-7.65 (m, 1 H), 7.63 (d, J=8.2 Hz, 1 H), 7.39-7.32 (m, 4 H), 7.24 (m, 1 H), 4.75 (s, 2 H), 3.84 (d, J=6.7 Hz, 2 H), 3.60 (s, 2 H), 3.08 (m, 2 H), 2.67 (m, 2 H), 2.55 (s, 3 H), 2.42 (m, 2 H), 2.12 (m, 2 H), 1.05 (m, 1 H), 0.51-0.48 (m, 2 H), 0.35-0.32 (m, 2 H). 13C NMR (126 MHz, CD3OD) δ 151.8, 146.5, 142.2, 136.1, 134.4, 132.8, 128.8, 128.0, 127.2, 126.8, 123.0, 118.9, 117.6, 111.6, 110.4, 65.5, 51.5, 43.7, 40.4, 30.6, 11.0, 3.6. Mass Spec.: 491(MH)+.

Workup

  1. customfollowed by evaporation of the organic layer in vacuo
  2. customgave the crude product
  3. customThe crude product was purified by preparative HPLC (HPLC method 12)
  4. additionFractions containing the required product
  5. customevaporated in vacuo
  6. customThe residue obtained
  7. customwas purified by silica gel chromatography

Sources & evidence

ORD record
ord-1d0b60dfec1f475ab7483000e50309fb
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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