1,2-Dichloroethane → 6-Fluoro-2-methyl-3-[(3R,9aR)-8-{[2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile

HRID 2175930노트

반응식

HRID 2175930 반응식
ON1C2C=CC=CC=2N=N1.[N:11]1([C:16]2[N:17]=[CH:18][C:19]3[CH:24]([C:25]([OH:27])=O)[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:15]=[N:14][N:13]=[N:12]1.C(Cl)CCl.[F:32][C:33]1[C:38]([C:39]#[N:40])=[C:37]([CH3:41])[C:36]([C@H:42]2[O:47][CH2:46][C@H:45]3[CH2:48][NH:49][CH2:50][CH2:51][N:44]3[CH2:43]2)=[CH:35][CH:34]=1.C(N(CC)CC)C>ClCCl.CCOC(C)=O>[F:32][C:33]1[C:38]([C:39]#[N:40])=[C:37]([CH3:41])[C:36]([C@H:42]2[O:47][CH2:46][C@H:45]3[CH2:48][N:49]([C:25]([CH:24]4[C:19]5[CH:18]=[N:17][C:16]([N:11]6[CH:15]=[N:14][N:13]=[N:12]6)=[N:21][C:20]=5[CH2:22][CH2:23]4)=[O:27])[CH2:50][CH2:51][N:44]3[CH2:43]2)=[CH:35][CH:34]=1

참가 물질

8

반응물 5

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 712735846-fluoro-2-methyl-3-((3R,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrileHCID 712737752-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid

생성물 1

HCID 867271146-Fluoro-2-methyl-3-[(3R,9aR)-8-{[2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile

시약·촉매·용매 2

HCID 6344Dichloromethane용매HCID 8857Ethyl Acetate용매

실험 절차

1-Hydroxybenzotriazole (173 mg, 1.280 mmol) was added to a suspension of 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid [I-67] (200 mg, 0.861 mmol) in dichloromethane (2 mL) followed by EDC (331 mg, 1.73 mmol), 6-fluoro-2-methyl-3-[(3R,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile [I-40D] (551 mg, 1.095 mmol) and triethylamine (0.70 mL, 5.0 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution, water and brine, dried (MgSO4), filtered, and the solvent evaporated to afford the title compound as a mixture of two diastereomers. The crude product was purified by MPLC on silica (24 g cartridge) using CH2Cl2 (A) and CH2Cl2:MeOH 90:10 (B) with gradient elution from 100% A to 100% B over 12 CV's to afford the title compound as a mixture of 2 diastereomers. LC/MS 490 (M+H). The mixture of diastereomers was purified by preparative chiral HPLC (SFC) on a Chiralcel AS column, 100 bar, 40% MeOH (0.2% DEA)/CO2, 35° C. to afford the two separated aza-indane diastereomers of the title compound: Isomer 2C (faster eluting) and Isomer 2D (slower eluting). Each isomer was dissolved separately in 1 mL of dichloromethane and 1 eq. 1 M HCl in ether was added. The solvent was evaporated to yield the hydrochloride salts of each isomer. Isomer 2C HCl salt: NMR 600 MHz (CD3OD) (mixture amide rotamers) 9.988 (s, 0.6H); 9.975 (s, 0.4H); 8.73 (s, 0.6H); 8.67 (s, 0.4H); 7.94 (dd, 1H); 7.31 (app t, 1H); 5.15 (d, 1H); 4.80 (t, 0.5H); 4.75 (d, 0.5H); 4.65-4.70 (m, 1H); 4.47 (d, 0.5H); 4.32-4.38 (m, 1H); 4.19-4.29 (m, 2H); 3.84-3.98 (m, 2H 3.57-3.72 (m, 2H); 3.44-3.54 (m, 2H); 3.31-3.38 (m, 0.5H); 3.23 (t, 2H); 2.69-2.86 (m, 1H); 2.62 (s, 3H); 2.33-2.42 (m, 0.5H); 2.20-2.28 (m, 0.5H). LC/MS 531 (M+H+CH3CN). Isomer 2D HCl salt: NMR 500 MHz (CD3OD) (mixture amide rotamers) 9.98 (s, 1H); 8.72 (s, 0.6H)); 8.69 (s, 0.4H); 7.91-7.96 (m, 1H); 7.30 (q, 1H); 5.14-5.18 (m, 1H); 472-4.78 (m, 1.5H); 4.65 (d, 0.5H); 4.49 (d, 0.5H); 4.35 (d, 1H); 4.21-4.30 (m, 2H); 3.32-3.95 (m, 6.5H); 3.18-3.27 (m, 2H); 2.71-2.79 (m, 1H); 2.62 (s, 3H); 2.35-2.42 (m, 0.5H); 2.18-2.26 (m, 0.5H). LC/MS 531 (M+H+CH3CN).

후처리

  1. washwashed with saturated NaHCO3 solution, water and brine
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered
  4. customthe solvent evaporated

출처 및 근거

ORD 기록
ord-a65748f06274477ab9af8378e3376fb2
출처 데이터셋
uspto-grants-2015_06
특허 번호
US09062070B2

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