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Hydrochloric Acid → (S)-1-((S)-2-{(S)-2-[2-(2-Hydroxy-ethyl)-2-methyl-but-3-enoylamino]-3-methyl-butyrylamino}-propionyl)-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide

HRID 2285365
Notes
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Reaction equation

HRID 2285365 reaction equation
C([O:5][C:6](=O)[NH:7][C@@H:8]([CH3:33])[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[O:32])[NH:18][C@@H:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Br:31])=[CH:26][CH:27]=3)[N:22]=2)[CH3:20])[NH:12]1)=[O:10])(C)(C)C.Cl.[OH:36][CH2:37][CH2:38][C:39]([CH3:52])([CH:50]=[CH2:51])[C:40]([NH:42][C@@H:43]([CH:47]([CH3:49])[CH3:48])C(O)=O)=[O:41].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>ClCCl.C(#N)C>[Br:31][C:25]1[CH:24]=[C:23]2[C:28]([CH:29]=[CH:30][C:21]([C@H:19]([NH:18][C:17]([C@@H:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@@H:8]([NH:7][C:6](=[O:5])[C@@H:43]([NH:42][C:40](=[O:41])[C:39]([CH2:38][CH2:37][OH:36])([CH3:52])[CH:50]=[CH2:51])[CH:47]([CH3:49])[CH3:48])[CH3:33])[NH:12]3)=[O:32])[CH3:20])=[N:22]2)=[CH:27][CH:26]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 86706107((S)-2-{(S)-3-[(R)-1-(7-bromo-quinolin-2-yl)-ethylcarbamoyl]-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl esterHCID 86709660(S)-2-[2-(2-hydroxy-ethyl)-2-methyl-but-3-enoylamino]-3-methyl-butyric acidHCID 178484293HCID 178484293, compound

Product 1

HCID 86709659(S)-1-((S)-2-{(S)-2-[2-(2-Hydroxy-ethyl)-2-methyl-but-3-enoylamino]-3-methyl-butyrylamino}-propionyl)-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amideYield 35%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

A cooled (0° C.) solution of ((S)-2-{(S)-3-[(R)-1-(7-bromo-quinolin-2-yl)-ethylcarbamoyl]-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (432.0 mg, 0.808 mmol) in dichloromethane (30 mL) was treated with a solution of hydrochloric acid (2.4 mL, 9.699 mmol, 4 M in 1,4-dioxane). After stirring for 2 h at room temperature the volatiles were removed in vacuo. Residual water was azeotroped off with toluene to provide a white solid that was combined with (S)-2-[2-(2-hydroxy-ethyl)-2-methyl-but-3-enoylamino]-3-methyl-butyric acid (196.6 mg, 0.808 mmol) and anhydrous acetonitrile (30 mL). This mixture was cooled to 0° C. and subsequently treated with N,N-diisopropylethylamine (0.71 mL, 4.04 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (430.1 mg, 1.131 mmol). The reaction was slowly warmed to room temperature. After stirring at room temperature for 20 h, the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 1:1 to afford the title compound (186.4 mg, 35%) as a yellow foam and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 659.2, 661.1 [M+H], Tr=2.21 min.

Workup

  1. customwere removed in vacuo
  2. customResidual water was azeotroped off with toluene
  3. customto provide a white solid
  4. temperatureThis mixture was cooled to 0° C.
  5. temperatureThe reaction was slowly warmed to room temperature
  6. stirringAfter stirring at room temperature for 20 h
  7. customthe volatiles were removed in vacuo
  8. customthe residue was purified by silica gel chromatography
  9. washeluted with a continuous gradient of iso-hexanes/acetone 1:0 to 1:1

Sources & evidence

ORD record
ord-9ecc954e538346cb8fa6fda1bd206eb1
Source dataset
uspto-grants-2015_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09145441B2

Reaction notes

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