Methylamine → 1-Methyl-piperidine-2-carboxylic acid [1-({1-[2-hydroxy-2-(4-methylcarbamoyl-thiazol-2-yl)-ethyl]-2-methyl-propyl}-methyl-carbamoyl)-2-methyl-butyl]-amide

HRID 446181Notes

Reaction equation

HRID 446181 reaction equation
[CH3:1][NH2:2].CO[C:5]([C:7]1[N:8]=[C:9]([CH:12]([OH:37])[CH2:13][CH:14]([N:18]([CH3:36])[C:19](=[O:35])[CH:20]([NH:25][C:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH3:34])=[O:27])[CH:21]([CH3:24])[CH2:22][CH3:23])[CH:15]([CH3:17])[CH3:16])[S:10][CH:11]=1)=[O:6]>C1COCC1.CO>[OH:37][CH:12]([C:9]1[S:10][CH:11]=[C:7]([C:5](=[O:6])[NH:2][CH3:1])[N:8]=1)[CH2:13][CH:14]([N:18]([CH3:36])[C:19]([CH:20]([NH:25][C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH3:34])=[O:27])[CH:21]([CH3:24])[CH2:22][CH3:23])=[O:35])[CH:15]([CH3:16])[CH3:17]

Participants

5

Reactant 2

HCID 6329MethylamineHCID 595159712-[1-Hydroxy-4-methyl-3-(methyl-{3-methyl-2-[(1-methyl-piperidine-2-carbonyl)-amino]-pentanoyl}-amino)-pentyl]-thiazole-4-carboxylic acid methyl ester

Product 1

HCID 668396411-Methyl-piperidine-2-carboxylic acid [1-({1-[2-hydroxy-2-(4-methylcarbamoyl-thiazol-2-yl)-ethyl]-2-methyl-propyl}-methyl-carbamoyl)-2-methyl-butyl]-amideYield 52%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

In a sealed tube, 10.0 mL of a 2.0 M solution of methylamine (5.00 mmol) in THF was added to a 0.02 M solution of 23 (27.0 mg, 0.0529 mmol) in MeOH (2.50 mL). The reaction solution was heated to 100° C. for 21 h. After the solution cooled to rt, the solvent was removed under reduced pressure. Reverse-phase HPFC (20:80 to 100:0 MeCN/H2O) followed by lyophilization provided compound 25 (14.0 mg, 52%) as an amorphous solid. The 1H NMR corresponds to a 6:1 mixture of rotamers, with the major isomer reported. [α]D23=−2.9 (c=1.0, MeOH). 1R: 1070, 1499, 1551, 1646, 2876, 2961 cm−1. 1H NMR (500 MHz, MeOD): δ 0.83 (d, 3H, J=6.5 Hz), 0.90 (t, 3H, J=7.5 Hz), 0.966 (d, 3H, J=6.5 Hz), 0.974 (d, 3H, J=6.5 Hz), 1.15-1.25 (m, 1H), 1.25-1.32 (m, 1H), 1.48-1.66 (m, 4H), 1.72 (d, 2H, J=10.5 Hz), 1.81-1.99 (m, 3H), 2.00-2.10 (m, 1H), 2.16 (s, 3H), 2.19-2.37 (m, 1H), 2.53-2.58 (m, 1H), 2.87-2.94 (m, 1H), 2.92 (s, 3H), 3.17 (s, 3H), 4.16-4.58 (br s, 1H), 4.64 (dd, 1H, J=2.3, 10.3 Hz), 4.72 (d, 1H, J=9.0 Hz), 8.06 (s, 1H). 13C NMR (125 MHz, MeOD) δ 11.1, 16.1, 20.5, 20.6, 24.4, 25.9, 26.3, 26.4, 31.3, 31.7, 37.8, 38.8, 44.8, 55.4, 56.7, 70.0, 70.6, 124.2, 151.0, 164.4, 175.3, 175.7, 179.4. HRMS (FAB) calcd for C25H44N5O4S (M+H): 510.3114. Found: 510.3098.

Workup

  1. temperatureAfter the solution cooled to rt
  2. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-17247951e7c148c78deb26a69aec8246
Source dataset
uspto-grants-2013_07
Patent number
US08476451B2

Reaction notes

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