Ethyl 2-bromo-1,3-thiazole-4-carboxylate → [6-Chloro-7-(2-chloro-5-methoxy-phenyl)-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine

HRID 449240Notes

Reaction equation

HRID 449240 reaction equation
[Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[Cl:21])=[CH:4][C:5]2[N:10]=[N:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:12]=1.CC1[C:28]2[N:29]=[C:30](NC3SC=C(C(OCC)=O)N=3)N=N[C:27]=2[CH:26]=[C:25](C2C(C)=CC=CC=2C)C=1.BrC1SC=C(C(OCC)=O)N=1.Cl[C:64]1[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][C:65]=1B(O)O>>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=1[C:3]1[C:2]([Cl:1])=[CH:12][C:6]2[N:7]=[C:8]([NH:11][C:64]3[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:30][N:29]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:66][CH:65]=3)[N:9]=[N:10][C:5]=2[CH:4]=1.[Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[Cl:21])=[CH:4][C:5]2[N:10]=[N:9][C:8]([NH:11][C:64]3[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:30][N:29]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:66][CH:65]=3)=[N:7][C:6]=2[CH:12]=1

Participants

6

Reactant 4

HCID 353965Ethyl 2-bromo-1,3-thiazole-4-carboxylateHCID 17750233(2-Chloro-5-methoxyphenyl)boronic acidHCID 59837651Ethyl 2-(5-methyl-7-(2,6-dimethylphenyl)benzo[e][1,2,4]triazin-3-ylamino)thiazole-4-carboxylateHCID 598377296-Chloro-7-(2-chloro-5-methoxy-phenyl)benzo[1,2,4]triazin-3-ylamine

Product 2

HCID 116202224-Chloro-3-{6-chloro-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-benzo[1,2,4]triazin-7-yl}-phenolHCID 68983850[6-Chloro-7-(2-chloro-5-methoxy-phenyl)-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amineYield 27%

Procedure

6-chloro-7-(2-chloro-5-methoxy-phenyl)benzo[1,2,4]triazin-3-ylamine designated on the reaction scheme (CCLXXVI) as compound 19 (54 mg, 68%) was prepared from compound 18 and 2-chloro-5-methoxyphenylboronic acid according to the above-described coupling procedure. The crude product was purified by silica gel column chromatography (Rf=0.41, EtOAc/hexanes 50:50). The title compound (CCLXXV) was prepared from compound 19 and 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine following the above-described coupling procedure, followed by demethylation. The coupling product was purified by reverse phase preparative HPLC to give [6-chloro-7-(2-chloro-5-methoxy-phenyl)-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (28.7 mg, 27%). Deprotection of the methoxy group with BBr3 (22 μl, 0.23 mmol) in 2 mL CH2Cl2 at room temperature yielded 4-chloro-3-{6-chloro-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-benzo[1,2,4]triazin-7-yl}-phenol, which was purified by reverse phase preparative HPLC and converted to the free amine to give a brown solid (13 mg, 57%). 1H NMR DMSO-d6: δ 1.68 (m, 4H), 2.50-2.55 (m, 4H), 2.79 (t, J=5.9 Hz, 2H), 4.07 (t, J=5.9, 2H), 7.07 (d, J=9.0 Hz, 1H), 6.77 (d, J=2.8, 1H), 6.84 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 6.98 (d, J=9.0 Hz, 2H), 7.32 (d, J=8.8, 1H), 7.85 (d, J=9.0 Hz, 2H), 7.90 (s, 1H), 8.22 (s, 1H), 10.90 (br s, 1H). MS (ESI+) m/z=496.

Workup

  1. customThe crude product was purified by silica gel column chromatography (Rf=0.41, EtOAc/hexanes 50:50)
  2. customThe coupling product was purified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-eb32e69306d74b319e16d8c79d625b8b
Source dataset
uspto-grants-2013_07
Patent number
US08481536B2

Reaction notes

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