Diisopropylethylamine → 2-cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide

HRID 1753910Notes

Reaction equation

HRID 1753910 reaction equation
[CH:1]1([C:4]2[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:52][CH2:53][CH:54]1[CH2:58][CH2:57][CH2:56][CH:55]1[OH:59]>ClCCl.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]1([C:4]2[C:9]([C:10]([NH:52][CH2:53][CH:54]3[CH2:58][CH2:57][CH2:56][CH:55]3[OH:59])=[O:12])=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:2][CH2:3]1

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 5338872-(Aminomethyl)cyclopentan-1-olHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 672877532-Cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid

Product 1

HCID 708167162-cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolvent

Procedure

To a solution of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized according to the methods described in sections a) to d) of example X1) (0.50 g, 1.91 mmol) in dichloromethane (20 ml) are added N-ethyl-diisopropylamine (0.81 ml, 4.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.42 g, 2.29 mmol), and 1-hydroxybenzotriazole hydrate (0.05 g, 0.38 mmol). The mixture is stirred for 15 min at RT, and then cooled to 0° C., before 2-(aminomethyl)cyclopentanol (0.22 g, 1.91 mmol) is added and stirring is continued for 3 days. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness affording example X4 as crude product. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield the first eluting diastereomer of 2-cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example X4a) (0.34 g, 0.95 mmol, [M+H]+360.2) and the second eluting diastereomer of 2-cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example X4b) (0.27 g, 0.75 mmol, [M+H]+360.2) as white solids.

Workup

  1. additionis added
  2. stirringstirring
  3. waitis continued for 3 days
  4. customAfter completion of the reaction
  5. customThe organic layer is separated
  6. washwashed with saturated sodium hydrogencarbonate solution and brine
  7. dry with materialdried over magnesium sulphate
  8. customevaporated to dryness
  9. customaffording example X4 as crude product
  10. customThe crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane)

Sources & evidence

ORD record
ord-98ce115cea1a43b0ad7c77bf95a5f8f9
Source dataset
uspto-grants-2015_10
Patent number
US09168259B2

Reaction notes

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