Cesium carbonate → (3R*,5S*)-5-m-Tolylamino-piperidine-3-carboxylic acid cyclopropyl-[3-methoxy-5-(3-methoxy-Propoxy)-benzyl]-amide

HRID 1698363Notes

Reaction equation

HRID 1698363 reaction equation
C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=O)(C)(C)C.Br[C:37]1[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:31]1([N:15]([CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[C:14]([C@@H:12]2[CH2:11][C@H:10]([NH:35][C:37]3[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=3)[CH2:9][NH:8][CH2:13]2)=[O:34])[CH2:33][CH2:32]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 115603-BromotolueneHCID 634876Binap, (A+-)-HCID 69064081(3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 57870315(3R*,5S*)-5-m-Tolylamino-piperidine-3-carboxylic acid cyclopropyl-[3-methoxy-5-(3-methoxy-Propoxy)-benzyl]-amide

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of (3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.081 mmol), 3-bromotoluene (16 mg, 0.094 mmol), (rac)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (3.8 mg, 0.006 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.8 mg, 0.004 mmol), and cesium carbonate (32 mg, 0.098 mmol) in toluene (0.6 mL) is heated at 110° C. for 36 h. The mixture is purified by RP-HPLC to give the desired amine, which is treated with 4 N HCl-1,4-dioxane (1 mL) at room temperature for 1 h. Concentration under vacuum gives the title compound as a white amorphous solid. MS: 481 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.07 min.

Workup

  1. customThe mixture is purified by RP-HPLC

Sources & evidence

ORD record
ord-f051dea1358044df998f45307b6e9558
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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