Hydrochloric Acid → HCID 67542142, compound

HRID 1809799Notes

Reaction equation

HRID 1809799 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:9]1)=O)(C)(C)C.[CH3:39][O:40][CH2:41][CH2:42][Cl:43].C([O-])([O-])=O.[K+].[K+].Cl>CC(N(C)C)=O>[ClH:43].[CH3:39][O:40][CH2:41][CH2:42][O:26][C:22]1[CH:21]=[C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C@H:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH:15]=2)[CH:25]=[CH:24][CH:23]=1

Participants

6

Reactant 4

HCID 313Hydrochloric Acid2×HCID 11430Potassium Carbonate2×HCID 123162-Chloroethyl methyl ether2×HCID 67543225HCID 67543225, compound

Product 1

HCID 67542142HCID 67542142, compound

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
75 °C

Procedure

A mixture of the title D compound in Example 13, (3R*,4R*)-4-(3′-hydroxy-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester (80 mg, 0.16 mmol), 2-chloroethyl methyl ether (57 μL, 0.62 mmol), K2CO3 (29 mg, 0.21 mmol), Kl (16.6 mg, 0.1 mmol) and dimethylacetamide (1.5 mL) is stirred under argon for 16 h at 75° C. After the addition of a second portion of 2-chloroethyl methyl ether (35 μL, 0.38 mmol) and K2CO3 (44 mg, 0.32 mmol) stirring is continued for 18 h at 75° C. The mixture is filtered and the filtrate evaporated in vacuo. HCl (5M in 2-propanol, 1 mL, 5 mmol) is added to the crude residue and the mixture is stirred for 45 min. at RT. The reaction mixture is evaporated in vacuo and the residue purified using preparative HPLC (H2O/CH3CN). The combined pure fractions are treated with solid K2CO3 and CH3CN is removed in vacuo. The aqueous layer is extracted twice with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. The residue is stirred with HCl (5M in 2-propanol, 1 mL, 5 mmol) for 30 min. at RT. Evaporation of the solvent affords (3R*,4R*)-4-[3′-(2-methoxy-ethoxy)-biphenyl-3-yl]-3-(naphthalen-2-ylmethoxy)-piperidine hydrochloride as a brownish amorphous solid: MS (LC/MS) 468.4 [M+H]+; retention time 5.85 min (HPLC, Nucleosil C18; 5→100% CH3CN in H2O within 8 min).

Workup

  1. stirringstirring
  2. waitis continued for 18 h at 75° C
  3. filtrationThe mixture is filtered
  4. customthe filtrate evaporated in vacuo
  5. stirringthe mixture is stirred for 45 min. at RT
  6. customThe reaction mixture is evaporated in vacuo
  7. customthe residue purified
  8. additionThe combined pure fractions are treated with solid K2CO3 and CH3CN
  9. customis removed in vacuo
  10. extractionThe aqueous layer is extracted twice with CH2Cl2
  11. dry with materialThe combined organic extracts are dried (Na2SO4)
  12. customevaporated in vacuo
  13. customEvaporation of the solvent

Sources & evidence

ORD record
ord-f519ca7f044146cdb6c9b60540f749b8
Source dataset
uspto-grants-2013_01
Patent number
US08362040B2

Reaction notes

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