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

HRID 549684Notes

Reaction equation

HRID 549684 reaction equation
[ClH:1].Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[CH2:19][O:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:12])=[CH:6][CH:5]=1.[CH:27](O)=O.[OH-].[Na+]>C=O.O>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:27])[CH2:15][CH:14]2[CH2:19][O:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:12])=[CH:6][CH:5]=1

Participants

6

Reactant 3

HCID 284Formic AcidHCID 14798Sodium HydroxideHCID 66796736N-(4-chlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide dihydrochloride

Product 1

HCID 66796544N-(4-Chlorophenyl)-4-methyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide dihydrochlorideYield 7%

Reagents, catalysts & solvents 2

HCID 712FormaldehydeSolventHCID 962WaterSolvent

Procedure

N-(4-chlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide dihydrochloride (prepared as described in Example 7) (141 mg, 0.335 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 10.3 mg (7%) of the desired product as a white solid. LC-MS: RT=4.48 min, [M+H]+=361.1.

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-b7eaa4edfe8c437e9f178b7532cc9d21
Source dataset
uspto-grants-2011_05
Patent number
US07943622B2

Reaction notes

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