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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
ノート
印刷プレビュー

反応式

HRID 2285365 の反応式
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
参加物実験手順後処理出典と根拠反応ノート

参加物

8

反応物 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、化合物

生成物 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]-amide
収率 35%

試薬・触媒・溶媒 2

HCID 6342Acetonitrile溶媒HCID 6344Dichloromethane溶媒

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-9ecc954e538346cb8fa6fda1bd206eb1
出典データセット
uspto-grants-2015_09
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US09145441B2

反応ノート

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このページの内容参加物実験手順後処理出典と根拠反応ノート