Ethanol → N-[3-(4-hydroxy-1-isopentyl-2-oxo-pyrrolo[1,2-b]pyridazin-3-yl)-1,1-dioxo-4H-1$l^{6},4-benzothiazin-7-yl]-N-methyl-methanesulfonamide

HRID 730506Notes

Reaction equation

C(O[C:5]([C:7]1[N:8]([NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1)=[O:6])C=C.[CH3:18][S:19]([N:22]([CH3:39])[C:23]1[CH:38]=[CH:37][C:26]2[NH:27][C:28]([CH2:33][C:34](O)=[O:35])=[CH:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1)(=[O:21])=[O:20].[O-]CC.[Na+].C(O)C>ClCCl.CN(C)C=O>[OH:6][C:5]1[C:7]2[N:8]([CH:9]=[CH:10][CH:11]=2)[N:12]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:34](=[O:35])[C:33]=1[C:28]1[NH:27][C:26]2[CH:37]=[CH:38][C:23]([N:22]([CH3:39])[S:19]([CH3:18])(=[O:21])=[O:20])=[CH:24][C:25]=2[S:30](=[O:31])(=[O:32])[CH:29]=1

Participants

Conditions

Temperature: 25 °C

Procedure

1-(3-Methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 0.112 g, 0.473 mmol) and [7-(methanesulfonyl-methyl-amino)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl]-acetic acid (Example 7e, 0.164 g, 0.473 mmol) were dissolved in a 3:1 mixture of dichloromethane and N,N-dimethylformamide (4 mL) at 25° C. A solution of N,N-dicyclohexylcarbodiimide (0.473 mL, 1.0 M in dichloromethane, 0.473 mmol) was added and the reaction mixture was stirred at 25° C. for 1 h then filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethanol (4 mL) at 25° C. A 21% solution of sodium ethoxide in ethanol (0.368 mL, 1.14 mmol) was added and the reaction mixture was heated at 80° C. for 6 h. After cooling to 25° C., the mixture was partitioned between 0.5 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Sequential purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 5{tilde over (0)}→100% ethyl acetate in hexanes) and preparative HPLC [column=Luna 5μ C18(2) 100 Å Axia 50×21.2 mm Id; eluent=0→100% acetonitrile in water (both containing 0.05% trifluoroacetic acid) over 7.0 min, flow=30 mL/min] afforded the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-N-methyl-methanesulfonamide (0.060 g, 0.119 mmol, 25% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.94 (6H, d, J=6.4 Hz), 1.50-1.54 (2H, m), 1.64-1.70 (1H, m), 2.99 (3H, bs), 3.28 (3H, bs), 4.29-4.32 (2H, m), 5.74 (1H, s), 6.12 (1H, bs), 6.49 (1H, bs), 6.90 (1H, bs), 7.30 (1H, bs), 7.60 (1H, bs), 7.82 (1H, bs). LC-MS (ESI) calcd for C22H26N4O6S2 506.13, found 507.25 [M+H+].

Workup

filtrationthen filtered
concentrationThe filtrate was concentrated in vacuo
dissolutionthe residue was dissolved in ethanol (4 mL) at 25° C
temperaturethe reaction mixture was heated at 80° C. for 6 h
temperatureAfter cooling to 25° C.
customthe mixture was partitioned between 0.5 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL)
dry with materialThe organic layers were dried over sodium sulfate
filtrationfiltered
concentrationconcentrated in vacuo
customSequential purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 5{tilde over (0)}→100% ethyl acetate in hexanes) and preparative HPLC [column=Luna 5μ C18(2) 100 Å Axia 50×21.2 mm Id
waiteluent=0→100% acetonitrile in water (both containing 0.05% trifluoroacetic acid) over 7.0 min

Sources & evidence

ORD record: ord-b9319351eb2044ec9182cc068c94db15
Source dataset: uspto-grants-2009_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07582754B2

Reaction notes

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