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Tributylphosphine → methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate

HRID 2278686
Notes
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Reaction equation

HRID 2278686 reaction equation
[Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([O-:31])=[O:30])[C@H:26]([CH3:32])[C:25]([C:33]([F:36])([F:35])[F:34])=[N:24]4)=[CH:19][CH:18]=3)[C@H:12]([CH3:37])[CH2:11]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O[C:39]1C=CC(N2[C@@H](CC(OC)=O)[C@H](C)C(C(F)(F)F)=N2)=CC=1.ClC1C(N2CC[C@H](O)[C@H](C)C2)=CC(OC)=NC=1.C(P(CCCC)CCCC)CCC.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([O:31][CH3:39])=[O:30])[C@H:26]([CH3:32])[C:25]([C:33]([F:36])([F:34])[F:35])=[N:24]4)=[CH:21][CH:22]=3)[C@H:12]([CH3:37])[CH2:11]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 13831TributylphosphineHCID 5702657diazenedicarboxylic acid bis(N,N-piperidide)HCID 867194222-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetateHCID 86719423methyl 2-((4S,5S)-1-(4-hydroxyphenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate
HCID 86719424
(3R,4S)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol

Product 1

HCID 86719421methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetateYield 64%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
50 °C

Procedure

2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a solution of methyl 2-((4S,5S)-1-(4-hydroxyphenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (1J, 4.6 g, 15 mmol) and (3R,4S)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol (3.4 g, 13 mmol) in toluene (166 mL) was added tributylphosphine (5.5 mL, 21 mmol). While stirring, (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (5.4 g, 21 mmol) was added portionwise to the reaction mixture, and the resulting mixture was heated at 50° C. for 120 min. The mixture was cooled to rt and 150 mL of hexanes was added to the mixture and a white precipitate formed. The mixture was filtered, and the filtrate was concentrated and was purified via silica gel chromatography to give methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (4.7 g, 8.5 mmol, 64% yield). LC-MS Anal. Calc'd for C26H30ClF3N4O4 554.19. found [M+H] 555.2. 1H NMR (400 MHz, CDCl3) δ ppm 8.00 (s, 1H), 7.15-7.04 (m, 2H), 7.01-6.89 (m, 2H), 6.30 (s, 1H), 4.49-4.36 (m, 1H), 3.91 (s, 4H), 3.73 (s, 3H), 3.62-3.49 (m, 2H), 3.28-3.15 (m, 1H), 2.95-2.85 (m, 1H), 2.82 (dd, J=16.2, 3.2 Hz, 1H), 2.67 (dd, J=12.3, 9.0 Hz, 1H), 2.43 (dd, J=16.1, 10.3 Hz, 1H), 2.26-2.12 (m, 2H), 1.91-1.78 (m, 1H), 1.36 (d, J=7.0 Hz, 3H), 1.16 (d, J=6.6 Hz, 3H).

Workup

  1. temperatureThe mixture was cooled to rt
  2. customa white precipitate formed
  3. filtrationThe mixture was filtered
  4. concentrationthe filtrate was concentrated
  5. customwas purified via silica gel chromatography

Sources & evidence

ORD record
ord-371321e345c1431aa90d9d11e9af3457
Source dataset
uspto-grants-2015_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09133163B2

Reaction notes

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