Potassium Acetate → tert-butyl (3S)-4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate

HRID 1621882Notes

Reaction equation

HRID 1621882 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:16]2[CH:17]=[C:18](B(O)O)[C:19]([F:22])=[N:20][CH:21]=2)[CH3:15])[C@@H:10]([CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]1[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH:29]=1.CC([O-])=O.[K+]>>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:35]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:28]([C:18]3[CH:17]=[C:16]([C@H:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH3:26])[CH3:15])[CH:21]=[N:20][C:19]=3[F:22])[CH:29]=2)=[CH:51][CH:50]=1

Participants

4

Reactant 3

HCID 517044Potassium AcetateHCID 59548404HCID 59548404, compoundHCID 685129855-((R)-1-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid

Product 1

HCID 68517227tert-butyl (3S)-4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylateYield 24.8%

Conditions

Temperature
120 °C

Procedure

A glass microwave reaction vessel was charged with (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (Example 272, Step 2) (0.530 g, 1.443 mmol), 6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (Example 177) (0.554 g, 1.443 mmol), PdCl2 (AmPhos)2 (0.102 g, 0.144 mmol) and KOAc (0.425 g, 4.33 mmol). The tube was sealed and evacuated under vacuum and back-filled with nitrogen. Dioxane (3.75 mL) and water (0.375 mL) was added and Ar (g) was bubbled through the mixture for 5 minutes. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 minutes. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl (3S)-4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (0.240 g, 0.358 mmol, 24.79% yield) as a yellow oil. m/z (ESI, +ve) 671.3 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.40 (dd, J=9.39, 2.54 Hz, 1H); 8.13 (d, J=1.37 Hz, 1H); 7.18 (d, J=8.02Hz, 4H); 6.80-6.90 (m, 5H); 4.50-5.03 (m, 4H); 4.03 (d, J=5.28 Hz, 1H); 3.73-3.84 (m, 6H); 3.24-3.57 (m, 3H); 3.08-3.22 (m, 1H); 2.69-2.81 (m, 1H); 2.61 (s, 3H); 2.29-2.51 (m, 2H); 1.37-1.48 (m, 12H); 1.02 (d, J=6.26 Hz, 3H).

Workup

  1. customA glass microwave reaction vessel
  2. customThe tube was sealed
  3. customevacuated under vacuum
  4. additionback-filled with nitrogen
  5. additionDioxane (3.75 mL) and water (0.375 mL) was added
  6. customAr (g) was bubbled through the mixture for 5 minutes
  7. custompurified by chromatography through a silica gel column (40 g)
  8. washeluting with a gradient of 0% to 100% EtOAc in hexane

Sources & evidence

ORD record
ord-a669775a389c4e41b68efe29b5245300
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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