Hydrochloric Acid → N-[3-[(4aR,7aS)-4-hydroxy-2-oxo-1-[[3-(trifluoromethyl)phenyl]methyl]-5,6,7,7a-tetrahydro-4aH-cyclopenta[b]pyridin-3-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamide

HRID 731276

반응식

HRID 731276 반응식
CO[C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:4].[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].Cl>CN(C)C=O.C(OCC)(=O)C.C(O)C>[OH:4][C:3]1[C@H:5]2[C@H:6]([CH2:7][CH2:8][CH2:9]2)[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:38](=[O:39])[C:37]=1[C:32]1[NH:31][C:30]2[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=2[S:34](=[O:36])(=[O:35])[N:33]=1

참가 물질

10

반응물 6

HCID 313Hydrochloric AcidHCID 79724-MethylmorpholineHCID 2723922Sodium ethoxideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 248585392H-1,2,4-Benzothiadiazine-3-acetic acid, 7-[(methylsulfonyl)amino]-, 1,1-dioxideHCID 690648942-(3-Trifluoromethyl-benzylamino)-cyclopentanecarboxylic acid methyl ester

생성물 1

HCID 135955930N-[3-[(4aR,7aS)-4-hydroxy-2-oxo-1-[[3-(trifluoromethyl)phenyl]methyl]-5,6,7,7a-tetrahydro-4aH-cyclopenta[b]pyridin-3-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamide수율 46%

시약·촉매·용매 3

HCID 702Ethanol용매2회HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매

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온도
60 °C

실험 절차

2-(3-Trifluoromethyl-benzylamino)-cyclopentanecarboxylic acid methyl ester (0.046 g, 0.15 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.051 g, 0.15 mmol) was added followed by N-methylmorpholine (0.04 mL, 0.33 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.033 g, 0.16 mmol) was added and the mixture was stirred at 25° C. for 3 h. The solution was diluted with ethyl acetate (25 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (4 mL) and a 21% w/w solution of sodium ethoxide in ethanol (0.3 mL, 0.8 mmol) was added, and the reaction mixture was heated to 60° C. for 2 h. Upon cooling to 25° C., the reaction mixture was acidified to pH 2-3 with 2.0 M aqueous hydrochloric acid solution, upon which the product precipitated while stirring. The solid was collected by vacuum filtration and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-95% in 9 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (4aR,7aS)-N-{3-[4-hydroxy-2-oxo-1-(3-trifluoromethyl-benzyl)-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.04 g, 0.068 mmol, 46%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.42-1.64 (3H, m), 1.96-2.18 (3H, m), 3.04 (3H, s), 3.95 (1H, d, J=7.2 Hz), 4.62 (1H, d, J=16.4 Hz), 5.00 (1H, d, J=15.6 Hz), 7.50 (4H, q, J=2.4 Hz), 7.57 (4H, m), 7.68 (2H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C24H23F3N4O6S2 584.10, found 585.0 [M+H+]. [α]D=−47.7083.

후처리

  1. dissolutiondissolved, approximately 5 min
  2. stirringthe mixture was stirred at 25° C. for 3 h
  3. washwashed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL)
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto afford a golden oil
  8. temperatureUpon cooling to 25° C.
  9. customprecipitated
  10. stirringwhile stirring
  11. filtrationThe solid was collected by vacuum filtration
  12. custompurified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-95% in 9 min

출처 및 근거

ORD 기록
ord-8b7ec8a422354a53928307053e68f3c7
출처 데이터셋
uspto-grants-2009_09
특허 번호
US07582626B2

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