Hydrochloric Acid → N-[3-[(4aR,7aS)-4-hydroxy-2-oxo-1-[[4-(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 731274Notes

Reaction equation

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][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][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:13]=[CH:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=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

Participants

Conditions

Temperature: 60 °C

Procedure

2-(4-Trifluoromethyl-benzylamino)-cyclopentanecarboxylic acid methyl ester (0.1 g, 0.33 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 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, 0.108 g, 0.33 mmol) was added followed by N-methylmorpholine (0.087 mL, 0.66 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.069 g, 0.36 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 (1.3 mL, 3.6 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, 50%-70% in 8 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-(4-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 (0.1 g, 0.171 mmol, 52%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.42-1.62 (3H, m), 1.96-2.15 (3H, m), 3.06 (3H, s), 3.90 (1H, d, J=7.2 Hz), 4.58 (1H, d, J=14.8 Hz), 5.00 (1H, d, J=15.6 Hz), 7.49 (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 585.1 [M+H+]. [α]D=−50.6863.

Workup

dissolutiondissolved, approximately 5 min
stirringthe mixture was stirred at 25° C. for 3 h
washwashed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL)
dry with materialdried over magnesium sulfate
filtrationfiltered
concentrationconcentrated in vacuo
customto afford a golden oil
temperatureUpon cooling to 25° C.
customprecipitated
stirringwhile stirring
filtrationThe solid was collected by vacuum filtration
custompurified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 50%-70% in 8 min

Sources & evidence

ORD record: ord-6fc17f6b643348d3b01a8a91a69b00c6
Source dataset: uspto-grants-2009_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07582626B2

Reaction notes

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