Formic Acid → N-(4-methoxyphenyl)-4-methyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide dihydrochloride

HRID 1487724Notes

Reaction equation

HRID 1487724 reaction equation
[ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:20][O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:13])=[CH:7][CH:6]=1.[CH:28](O)=O.[OH-].[Na+]>C=O.O>[ClH:1].[ClH:1].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:28])[CH2:16][CH:15]2[CH2:20][O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:13])=[CH:9][CH:10]=1

Participants

6

Reactant 3

HCID 284Formic AcidHCID 14798Sodium HydroxideHCID 66796687N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide dihydrochloride

Product 1

HCID 66796582N-(4-methoxyphenyl)-4-methyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide dihydrochlorideYield 13%

Reagents, catalysts & solvents 2

HCID 712FormaldehydeSolventHCID 962WaterSolvent

Procedure

N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide dihydrochloride (prepared as described in Example 10) (123 mg, 0.295 mmol), was dissolved in formaldehyde (37% aqueous solution, 1 mL) and formic acid (1 mL) and heated to 60° C. After 16 h, the reaction mixture was brought to pH 12 with 1 N NaOH in water and was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by HPLC (5 to 30% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL) and treated with 4M HCl in 1,4-dioxane. The mixture was concentrated under reduced pressure, yielding 16.2 mg (13%) of the desired product as an off-white solid. LC-MS: RT=3.59 min, [M+H]+=357.1.

Workup

  1. extractionwas extracted with CH2Cl2 (3×10 mL)
  2. dry with materialThe combined organics were dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe material was purified by HPLC (5 to 30% MeCN/0.1% TFA in H2O/0.1% TFA gradient)
  6. concentrationThe desired fractions were concentrated under reduced pressure
  7. dissolutiondissolved in MeOH (1 mL)
  8. additiontreated with 4M HCl in 1,4-dioxane
  9. concentrationThe mixture was concentrated under reduced pressure

Sources & evidence

ORD record
ord-20cfb3576dce4c7ba2ce64f9f4c564c5
Source dataset
uspto-grants-2016_08
Patent number
US09428522B2

Reaction notes

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