Tri-o-tolylphosphine → (S)-1-[(S)-2-((S)-2-{(E)-2-Cyano-4-[2-((R)-1-hydroxy-ethyl)-quinolin-7-yl]-2-methyl-but-3-enoylamino}-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

HRID 2285370Notes

Reaction equation

HRID 2285370 reaction equation
[Cl:1][C:2]([Cl:34])([Cl:33])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:32])[C@@H:14]([NH:16][C:17](=[O:31])[C@@H:18]([NH:22][C:23](=[O:30])[C:24]([C:28]#[N:29])([CH3:27])[CH:25]=[CH2:26])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].Br[C:36]1[CH:45]=[C:44]2[C:39]([CH:40]=[CH:41][C:42]([C@H:46]([OH:48])[CH3:47])=[N:43]2)=[CH:38][CH:37]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(CNCC2CCCCC2)CCCCC1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:34][C:2]([Cl:33])([Cl:1])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:32])[C@@H:14]([NH:16][C:17](=[O:31])[C@@H:18]([NH:22][C:23](=[O:30])[C:24]([C:28]#[N:29])([CH3:27])/[CH:25]=[CH:26]/[C:36]2[CH:45]=[C:44]3[C:39]([CH:40]=[CH:41][C:42]([C@H:46]([OH:48])[CH3:47])=[N:43]3)=[CH:38][CH:37]=2)[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6]

Participants

7

Reactant 4

HCID 80271Tri-o-tolylphosphineHCID 4594378Bis(cyclohexylmethyl)amineHCID 86706048(R)-1-(7-Bromoquinolin-2-yl)ethanolHCID 86709665(S)-1-{(S)-2-[(S)-2-(2-Cyano-2-methyl-but-3-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

Product 1

HCID 86709664(S)-1-[(S)-2-((S)-2-{(E)-2-Cyano-4-[2-((R)-1-hydroxy-ethyl)-quinolin-7-yl]-2-methyl-but-3-enoylamino}-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl esterYield 39%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
120 °C

Procedure

(S)-1-{(S)-2-[(S)-2-(2-Cyano-2-methyl-but-3-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (283 mg, 0.527 mmol), (R)-1-(7-bromo-quinolin-2-yl)-ethanol (146 mg, 0.580 mmol), palladium(II) acetate (24 mg, 0.105 mmol) and tri(o-tolyl)phosphine (32 mg, 0.105 mmol) were suspended in anhydrous acetonitrile and N,N-dicyclohexylmethylamine (113 mg, 124 μL, 0.580 mmol) added. The vessel was sealed and heated in a microwave reactor at 120° C. for 40 minutes. The mixture was evaporated and the residue dissolved in ethyl acetate and washed with saturated ammonium chloride solution (2×), water then saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 0:1 to give the title compound (68 mg, 39%) as a yellow solid as a mixture of diastereoisomers. 1H NMR (300 MHz, CD3OD) δ 0.92-0.98 (m, 3H) 1.01 (d, J=6.9 Hz, 3H), 1.27 (app t, J=7.1 Hz, 3H), 1.59 (d, J=5.5 Hz, 3H), 1.68-1.81 (m, 2H), 1.86 (s, 3H), 1.88-1.99 (m, 1H), 2.10-2.25 (m, 2H), 2.86-3.05 (m, 1H), 3.60-3.75 (m, 1H), 3.85 (t, J=8.7 Hz, 1H), 4.22-4.38 (m, 2H), 4.69 (dd, J=12.0, 8.6 Hz, 1H), 4.95 (dd, J=12.0, 7.2 Hz, 1H), 4.98-5.09 (m, 2H), 5.26-5.42 (m, 1H), 6.48 (dd, J=16.1, 13.8 Hz, 1H), 6.62-6.68 (m, 1H), 6.96 (dd, J=15.5, 8.2 Hz, 1H), 7.16 (dd, J=16.1, 4.9 Hz, 1H), 7.35 (dd, J=8.5, 2.0 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.81 (dd, J=8.5, 2.7 Hz, 1H), 8.09 (d, J=5.4 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H). LCMS (m/z) 709.1, 711.1, 713.2 [M+H], Tr=2.38 min.

Workup

  1. customThe vessel was sealed
  2. customThe mixture was evaporated
  3. dissolutionthe residue dissolved in ethyl acetate
  4. washwashed with saturated ammonium chloride solution (2×), water
  5. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-bc3300775e97487f8117bc45e1c76dc0
Source dataset
uspto-grants-2015_09
Patent number
US09145441B2

Reaction notes

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