Ammonia → (2S)-3-{4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-methoxy-6-methyl-phenoxy}-propane-1,2-diol

HRID 1685788Notes

Reaction equation

[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[CH3:16][C:17]1([CH3:37])[O:21][C@H:20]([CH2:22][O:23][C:24]2[C:33]([CH3:34])=[CH:32][C:27]([C:28]([NH:30][OH:31])=[NH:29])=[CH:26][C:25]=2[O:35][CH3:36])[CH2:19][O:18]1.Cl.N>>[CH3:16][C:17]1([CH3:37])[O:21][C@H:20]([CH2:22][O:23][C:24]2[C:33]([CH3:34])=[CH:32][C:27]([C:28]3[N:30]=[C:12]([C:10]4[S:11][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([CH3:15])[CH:9]=4)[O:14][N:29]=3)=[CH:26][C:25]=2[O:35][CH3:36])[CH2:19][O:18]1.[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:31][N:30]=[C:28]([C:27]3[CH:32]=[C:33]([CH3:34])[C:24]([O:23][CH2:22][C@@H:20]([OH:21])[CH2:19][OH:18])=[C:25]([O:35][CH3:36])[CH:26]=3)[N:29]=2)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2]

Participants

Reactant 4

HCID 222Ammonia

HCID 313Hydrochloric Acid

HCID 672654805-Diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid

HCID 178492424HCID 178492424, compound

Product 2

HCID 67265281(2S)-3-{4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-methoxy-6-methyl-phenoxy}-propane-1,2-diolYield 114.8%

HCID 67265934(R)-(5-{3-[4-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-methoxy-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-3-methyl-thiophen-2-ylmethyl)-diethyl-amine

Procedure

(R)-(5-{3-[4-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-methoxy-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-3-methyl-thiophen-2-ylmethyl)-diethyl-amine is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3-methoxy-5-methyl-benzamidine (36 mg, 117 μmol) according to Method A. After the coupling and cyclisation step, the reaction mixture is acidified by adding 35% aq. HCl and the reaction mixture is stirred at rt for 40 min. The mixture is neutralised by adding 25% aq. NH3 solution before it is separated by prep. HPLC to give the title compound (31 mg) as a resin; LC-MS: tR=0.52 min; [M+1]+=462.21; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 2.22 (s, 3H), 2.32 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 3.41-3.50 (m, 2H), 3.73 (s, 2H), 3.74-3.81 (m, 1H), 3.84-3.89 (m, 1H), 3.89 (s, 3H), 4.03 (dd, J=9.8, 4.3 Hz, 1H), 4.59 (t, J=5.8 Hz, 1H), 4.84 (d, J=5.3 Hz, 1H), 7.44-7.47 (m, 1H), 7.49-7.52 (m, 1H), 7.81 (s, 1H).

Workup

customis separated by prep

Sources & evidence

ORD record: ord-f18740ac3e144dd98c7ea5394fa1ff4a
Source dataset: uspto-grants-2012_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08148410B2

Reaction notes

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