4-Methylmorpholine → CCR2 antagonist 3

HRID 1808820ノート

反応式

HRID 1808820 の反応式
[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH3:41][CH:42]([CH3:52])[C@H:43]([NH:50][CH3:51])[CH2:44][N:45]1[CH2:48][CH:47]([OH:49])[CH2:46]1.[OH-].[Na+]>CN(C=O)C.CS(C)=O.O.O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:50]([C@@H:43]([CH:42]([CH3:52])[CH3:41])[CH2:44][N:45]2[CH2:46][CH:47]([OH:49])[CH2:48]2)[CH3:51])=[O:8])=[CH:4][C:3]=1[CH3:11]

参加物

10

反応物 5

HCID 79724-MethylmorpholineHCID 14798Sodium HydroxideHCID 2428284-Fluoro-3-methylbenzoic acidHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 67772249HCID 67772249、化合物

生成物 1

HCID 57345449CCR2 antagonist 3収率 68%

試薬・触媒・溶媒 4

HCID 679Dimethyl Sulfoxide溶媒HCID 962Water溶媒2 回HCID 6228Dimethylformamide溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
0 °C

実験手順

4-Fluoro-3-methylbenzoic acid (0.089 g, 0.58 mmol) and TBTU (0.196 g, 0.61 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to 0° C. and NMM (0.070 mL, 0.64 mmol) was dropwise added. After 40 min at 0° C. was (S)-1-(3-methyl-2-(methylamino)butyl)azetidin-3-ol (Compound K2) (0.1 g, 0.58 mmol) added. The resultant mixture was stirred at 0° C. for 30 min and at rt for 16 h. NaOH (aq., 3.8 M, 0.5 mL), water (0.5 mL) and dioxane (1 mL) was added and the resultant mixture was stirred at rt overnight. To the mixture was water (2 mL) and DMSO (4 mL) added. The residue was purified by preparative HPLC to give the title compound (121 mg, 68%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.80-0.87, 0.94, 1.05, 1.68-1.93, 2.25-2.34, 2.54-3.00, 3.26-3.34, 3.39-3.46, 3.55-3.61, 3.62-3.75, 4.19-4.43, 7.02-7.49. Ratio major:minor:1:0.5. Total no of protons: 24. HRMS (M+H)+: calculated 309.1978. found 309.1949. XRPD pattern d (Å) 9.3 (vw), 7.8 (w), 7.6 (w), 6.5 (med), 5.7 (vs), 5.3 (str), 4.71 (str), 4.52 (str), 4.40 (med), 4.31 (med), 3.83 (med), 3.30 (med), 3.22 (med). The compound was found to be a hydrate (most likely a monohydrate).

後処理

  1. additionadded
  2. customThe residue was purified by preparative HPLC

出典と根拠

ORDレコード
ord-44993275046643df967997fb3696bb80
出典データセット
uspto-grants-2013_01
特許番号
US08361998B2

反応ノート

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