1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-3-[4-[[3-[(S)-phenyl-[[(3R)-quinuclidin-3-yl]oxycarbonylamino]methyl]phenoxy]methyl]benzoyl]thiazolidine-2-carboxylate

HRID 2284844Notes

Reaction equation

HRID 2284844 reaction equation
[C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:38]1([CH2:41][O:42][C:43]2[CH:44]=[C:45]([C@@H:53]([O:64][C:65]([C@H:67]3[NH:71][CH2:70][CH2:69][S:68]3)=[O:66])[CH2:54][C:55]3[C:60]([Cl:61])=[CH:59][N+:58]([O-:62])=[CH:57][C:56]=3[Cl:63])[CH:46]=[CH:47][C:48]=2[O:49][CH:50]([F:52])[F:51])[CH2:40][CH2:39]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:38]1([CH2:41][O:42][C:43]2[CH:44]=[C:45]([C@@H:53]([O:64][C:65]([C@H:67]3[N:71]([C:17](=[O:18])[C:16]4[CH:20]=[CH:21][C:13]([CH2:12][O:11][C:10]5[CH:22]=[CH:23][CH:24]=[C:8]([C@H:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[NH:25][C:26]([O:28][C@@H:29]6[CH:34]7[CH2:33][CH2:32][N:31]([CH2:36][CH2:35]7)[CH2:30]6)=[O:27])[CH:9]=5)=[CH:14][CH:15]=4)[CH2:70][CH2:69][S:68]3)=[O:66])[CH2:54][C:55]3[C:60]([Cl:61])=[CH:59][N+:58]([O-:62])=[CH:57][C:56]=3[Cl:63])[CH:46]=[CH:47][C:48]=2[O:49][CH:50]([F:52])[F:51])[CH2:40][CH2:39]1

Participants

6

Reactant 3

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 710925203,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochlorideHCID 867208154-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoic acid

Product 1

HCID 118114277[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-3-[4-[[3-[(S)-phenyl-[[(3R)-quinuclidin-3-yl]oxycarbonylamino]methyl]phenoxy]methyl]benzoyl]thiazolidine-2-carboxylateYield 34.3%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 4-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoic acid (I17, 61 mg, 0.125 mmol) in DMF (2 mL) was added [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-thiazolidine-2-carboxylate hydrochloride (I5, 71 mg, 0.125 mmol) followed by DMAP (8 mg, 0.06 mmol) and EDC.HCl (48 mg, 0.25 mmol). The mixture was allowed to stir at room temperature for 18 h and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (43 mg, 34%). 1H NMR (400 MHz, DMSO): δ 8.57 (s, 2 H), 8.23 (d, J=9.4 Hz, 1 H), 7.58-7.42 (m, 4 H), 7.37-6.87 (m, 12 H), 7.10 (t, J=74.4 Hz, 1 H), 6.08-5.97 (m, 1 H), 5.84 (d, J=9.1 Hz, 1 H), 5.58-5.48 (m, 1 H), 5.16 (s, 2 H), 4.60-4.53 (m, 1 H), 4.00-3.88 (m, 1 H), 3.88 (d, J=7.0 Hz, 2 H), 3.83-3.73 (m, 1 H), 3.55-2.92 (m, 5 H), 2.79-2.31 (m, 5 H), 1.93-1.13 (m, 6 H), 0.58-0.52 (m, 2 H), 0.32-0.26 (m, 2 H). LCMS (Method 1): [MH+]=1003 at 3.16 min.

Workup

  1. customthe solvent was removed in vacuo
  2. customThe residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL)
  3. customthe solvent was removed in vacuo
  4. customPurification

Sources & evidence

ORD record
ord-e2e41d9d68754a28a95422a4af4060eb
Source dataset
uspto-grants-2015_09
Patent number
US09145409B2

Reaction notes

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