Methyl iodide → (S)-3-Amino-1-{3-(4-methoxy-phenyl)-1-[2-(4-methoxy-phenyl)-ethyl]-propyl}-1-methyl-piperidinium chloride hydrochloride

HRID 509919Notes

Reaction equation

HRID 509919 reaction equation
C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)(C)(C)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=O)[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1.[BH4-].[Na+].IC.[C:41]([O-])([O-])=O.[K+].[K+].C(Cl)[Cl:48]>CS(C)=O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.CO>[ClH:48].[Cl-:48].[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N@@+:10]([CH:25]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:24][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)([CH3:41])[CH2:9]1

Participants

10

Reactant 6

HCID 6328Methyl iodideHCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 1514171tert-butyl N-[(3S)-piperidin-3-yl]carbamateHCID 2801509HCID 2801509, compoundHCID 4311764Sodium borohydride

Product 1

HCID 117856190(S)-3-Amino-1-{3-(4-methoxy-phenyl)-1-[2-(4-methoxy-phenyl)-ethyl]-propyl}-1-methyl-piperidinium chloride hydrochloride

Reagents, catalysts & solvents 3

HCID 178460666HCID 178460666, compoundCatalystHCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolvent

Procedure

To (S)-piperidin-3-yl-carbamic acid tert-butyl ester (0.10 g) and 1,5-bis-(4-methoxy-phenyl)-pentan-3-one (254 mg, content ca. 88%; obtained by catalytic hydrogenation on platinum oxide pre-catalyst of bis(4-methoxybenzylidene)acetone, Pfaltz-Bauer) in CH2Cl2 is added Ti(OiPr)4 (0.22 mL). The mixture is stirred for 20 h, then NaBH4 (94 mg) is added in several portions. After 20 h MeOH is added and after 30 min volatiles are evaporated, the residue treated with EtOAc and filtered. The filtrate is concentrated in vacuo and purified by column chromatography (SiOH, cHex: EtOAc gradient of increasing polarity). Material thus obtained is allowed to react with iodomethane (2 eq.) in the presence of K2CO3 (1 eq.) in dimethylsulfoxide at 120° C. for 30 min under microwave irradiation. Volatiles are evaporated in vacuo, the residue is purified via preparative reverse phase HPLC. The carbamic acid tert-butyl ester group is removed using HCl in dioxane to give the title compound of content ca. 68%.

Workup

  1. customare evaporated
  2. additionthe residue treated with EtOAc
  3. filtrationfiltered
  4. concentrationThe filtrate is concentrated in vacuo
  5. custompurified by column chromatography (SiOH, cHex: EtOAc gradient of increasing polarity)
  6. customMaterial thus obtained
  7. customVolatiles are evaporated in vacuo
  8. customthe residue is purified via preparative reverse phase HPLC
  9. customThe carbamic acid tert-butyl ester group is removed

Sources & evidence

ORD record
ord-32dc7573be0d4a5ebab7b5a5e6daf504
Source dataset
uspto-grants-2015_08
Patent number
US09096548B2

Reaction notes

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