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1-Hydroxybenzotriazole → 3-{7-[2-(3-aminopyrrolidin-1-yl)-2-oxoethoxy]-1,1-dioxido-4H-1,2,4-benzothiadiazin-3-yl}-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one

HRID 601362
Notes
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Reaction equation

HRID 601362 reaction equation
[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]([OH:31])=O)=[CH:26][C:20]=4[S:19](=[O:33])(=[O:32])[N:18]=3)[C:7]2=[O:34])[CH2:3][CH2:2]1.Cl.C[N:37]([CH3:46])[CH2:38][CH2:39][CH2:40][N:41]=C=NCC.ON1C2C=CC=CC=2N=N1.C(OC(=O)NC1CCNC1)(C)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:41][CH:40]1[CH2:39][CH2:38][N:37]([C:29](=[O:31])[CH2:28][O:27][C:25]2[CH:24]=[CH:23][C:21]3[NH:22][C:17]([C:8]4[C:7](=[O:34])[N:6]([NH:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:15]5[C:10]([C:9]=4[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=5)=[N:18][S:19](=[O:32])(=[O:33])[C:20]=3[CH:26]=2)[CH2:46]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2757234tert-butyl N-(pyrrolidin-3-yl)carbamateHCID 136358499[(3-{1-[(cyclopropylmethyl)amino]-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl}-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl)oxy]acetic acid

Product 1

HCID 136347179
3-{7-[2-(3-aminopyrrolidin-1-yl)-2-oxoethoxy]-1,1-dioxido-4H-1,2,4-benzothiadiazin-3-yl}-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one
Yield 54.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

The product of Example 384B (24 mg, 0,05 mmole), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (16 mg, 0.08 mmol) and 1-hydroxybenzotriazole (14 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL) was added pyrrolidin-3-yl-carbamic acid tert-butyl ester(19 mg, 0.1 mmol). The mixture was stirred for 1 day. The solution was poured into ethyl acetate (40 mL) and washed with saturated aqueous sodium bicarbonate, water, and brine, dried with magnesium sulfate, filtered and concentrated. The residue was triturated with methanol/water and filtered. The solid was treated with hydrochloric acid (1 M in dioxane, 2 mL) and stirred overnight, filtered and washed with ethyl acetate/hexane (1:1) to give title compound (15 mg, 51%). 1H NMR (500 MHz, BENZENE-d6) δ 0.16 (m, 2 H) 0.43 (m, 2 H) 1.01 (m, 1 H) 2.14 (m, 2 H) 2.29 (m, 1 H) 2.89 (d, J=6.84 Hz, 2 H) 3.36 (m, 2 H) 3.81 (m, 2 H) 4.88 (m, 2 H) 7.42 (m, 3 H) 7.61 (m, 1 H) 7.88 (m, 1 H) 8.09 (d, J=8.30 Hz, 1 H) 8.17 (d, J=8.30 Hz, 1 H) 8.28 (s, 3 H) 13.99 (s, 1 H). MS (ESI−) m/z 551 (M−H)−.

Workup

  1. washwashed with saturated aqueous sodium bicarbonate, water, and brine
  2. dry with materialdried with magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was triturated with methanol/water
  6. filtrationfiltered
  7. additionThe solid was treated with hydrochloric acid (1 M in dioxane, 2 mL)
  8. stirringstirred overnight
  9. filtrationfiltered
  10. washwashed with ethyl acetate/hexane (1:1)

Sources & evidence

ORD record
ord-19474a84aa6b47a69ee4ede996f024b9
Source dataset
uspto-grants-2011_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07902203B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes