Hydrochloric Acid → 3-amino-N-(4-((3R,4R)-3-amino-4-hydroxy-piperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)picolinamide

HRID 69976

Reaktionsgleichung

Reaktionsgleichung von HRID 69976
NC1C(C(NC2C=NC=CC=2N2CC[C@@H](O[Si](C(C)(C)C)(C)C)[C@H](NC(=O)OC(C)(C)C)C2)=O)=NC(Br)=CC=1.FC1C=CC=C(F)C=1B(O)O.[NH2:51][C:52]1[C:53]([C:66]([NH:68][C:69]2[CH:70]=[N:71][CH:72]=[CH:73][C:74]=2[N:75]2[CH2:80][CH2:79][C@@H:78]([O:81][Si](C(C)(C)C)(C)C)[C@H:77]([NH:89]C(=O)OC(C)(C)C)[CH2:76]2)=[O:67])=[N:54][C:55]([C:58]2[C:63]([F:64])=[CH:62][CH:61]=[CH:60][C:59]=2[F:65])=[CH:56][CH:57]=1.Cl>CO.C1COCC1>[NH2:51][C:52]1[C:53]([C:66]([NH:68][C:69]2[CH:70]=[N:71][CH:72]=[CH:73][C:74]=2[N:75]2[CH2:80][CH2:79][C@@H:78]([OH:81])[C@H:77]([NH2:89])[CH2:76]2)=[O:67])=[N:54][C:55]([C:58]2[C:63]([F:64])=[CH:62][CH:61]=[CH:60][C:59]=2[F:65])=[CH:56][CH:57]=1

Komponenten

7

Edukt 4

HCID 313Hydrochloric AcidHCID 27343362,6-Difluorophenylboronic acidHCID 86669207tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamateHCID 86669208tert-butyl (3R,4R)-1-(3-(3-amino-6-bromo-picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-yl-carbamate

Produkt 1

HCID 690428643-amino-N-(4-((3R,4R)-3-amino-4-hydroxy-piperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)picolinamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

3-amino-6-(2,6-difluorophenyl)picolinic acid and tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate were coupled following method 11 (example 249), to yield tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate after HPLC purification. Alternatively, tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)-piperidin-3-ylcarbamate could be obtained starting with tert-butyl (3R,4R)-1-(3-(3-amino-6-bromo-picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-yl-carbamate and 2,6 difluorophenylboronic acid following the Suzuki procedure outlined in method 14. The TBDMS deprotection of tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-yl-carbamate was performed with 6N HCl, THF, methanol (1:2:1) at room temperature for 2 h. After volatile materials were removed, the crude material was stirred in 30% TFA in dichloromethane for 2 hours. After volatile materials were removed in vacuo, purification and lyophilization yielded 3-amino-N-(4-((3R,4R)-3-amino-4-hydroxy-piperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)picolinamide. HPLC. LCMS (m/z): 441.2 (MH+); LC Rt=2.03 min.

Aufarbeitung

  1. customAfter volatile materials were removed
  2. customAfter volatile materials were removed in vacuo, purification and lyophilization

Quellen und Nachweise

ORD-Eintrag
ord-6f33419dfec74de59ff48e21e9f641ee
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08822497B2

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