Trifluoroacetic acid → (R)-1-(4-((6-(3-aminopiperidin-1-yl)pyridin-3-yl)amino)-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl)propan-1-one trichloride

HRID 526233Notes

Reaction equation

[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:23])[CH2:21][CH3:22])=[C:13]3[NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:36][CH2:35][CH2:34][C@@H:33]([NH:37]C(=O)OC(C)(C)C)[CH2:32]3)=[N:29][CH:30]=2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[Cl-:1].[Cl-:1].[Cl-:1].[NH2:37][C@@H:33]1[CH2:34][CH2:35][CH2:36][N:31]([C:28]2[N:29]=[CH:30][C:25]([NH:24][C:13]3[C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:4]5[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=5)[N:11]=4)[N:16]=[CH:15][C:14]=3[C:20](=[O:23])[CH2:21][CH3:22])=[CH:26][CH:27]=2)[CH2:32]1

Participants

Reactant 2

HCID 6422Trifluoroacetic acid

HCID 136981877(R)-tert-butyl (1-(5-((6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate

Product 1

HCID 137231125(R)-1-(4-((6-(3-aminopiperidin-1-yl)pyridin-3-yl)amino)-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-3-yl)propan-1-one trichlorideYield 261.8%

Procedure

Following general procedure IV-2, (R)-tert-butyl (1-(5-((6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (120 mg, 0.19 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (78 mg, 65%) as a orange-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.38 (s, 1H), 8.48 (d, J=9.0 Hz, 1H), 8.41 (d, J=9.0 Hz, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.90 (dd, J=9.5, 2.5 Hz, 1H), 7.56-7.30 (m, 2H), 7.27 (d, J=9.5 Hz, 1H), 4.43-4.32 (m, 1H), 4.08-3.96 (m, 1H), 3.53-3.38 (m, 3H), 3.29-3.20 (m, 2H), 2.29-2.20 (m, 1H), 2.09-1.98 (m, 1H), 1.88-1.74 (m, 2H), 1.38-1.21 (m, 3H); ESI MS m/z 521 [M+H]+; HPLC 97.6% (AUC), tR=9.86 min.

Sources & evidence

ORD record: ord-fea7a38325764d2aa8faf557b86b5d34
Source dataset: uspto-grants-2016_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09345709B2

Reaction notes

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