4-Methylmorpholine → CCR2 antagonist 3

HRID 1808820노트

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HRID 1808820 반응식
[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]

참가 물질

10

반응물 5

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

생성물 1

HCID 57345449CCR2 antagonist 3수율 68%

시약·촉매·용매 4

HCID 679Dimethyl Sulfoxide용매HCID 962Water용매2회HCID 6228Dimethylformamide용매HCID 312751,4-Dioxane용매

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온도
0 °C

실험 절차

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).

후처리

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

출처 및 근거

ORD 기록
ord-44993275046643df967997fb3696bb80
출처 데이터셋
uspto-grants-2013_01
특허 번호
US08361998B2

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