N-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}-3-thioxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide → 2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}-3-thioxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

HRID 74736Notes

Reaction equation

HRID 74736 reaction equation
C1C2C(COC([NH:18][C:19]([CH3:69])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:33]([O:63][CH3:64])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:61][CH3:62])[C@@H:43]([CH3:60])[C:44]([NH:46][C@H:47]([C:55]3[S:56][CH:57]=[CH:58][N:59]=3)[CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[S:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl.C(NCC)C>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:33]([O:63][CH3:64])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:61][CH3:62])[C@@H:43]([CH3:60])[C:44]([NH:46][C@H:47]([C:55]1[S:56][CH:57]=[CH:58][N:59]=1)[CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[S:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])([CH3:69])[NH2:18]

Participants

4

Reactant 1

HCID 86685726N-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}-3-thioxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Product 1

HCID 715710182-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}-3-thioxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamideYield 60%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8021DiethylamineSolvent

Procedure

According to general procedure A, from #33 (55 mg, 0.055 mmol, 1 eq.) in dichloromethane (6 mL, 0.009 M) and diethylamine (4 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to give #34 (25 mg, 60%) as a solid. HPLC (Protocol A): m/z 759.4 [M+H+], retention time=7.088 minutes, (purity >75%). 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.54 (br d, J=8 Hz) and 10.81 (br d, J=8 Hz), total 1H], 8.01-8.08 (m, 1H), [7.80 (d, J=3.1 Hz) and 7.83 (d, J=3.3 Hz), total 1H], [7.65 (d, J=3.2 Hz) and 7.69 (d, J=3.2 Hz), total 1H], 7.29-7.33 (m, 2H), 7.20-7.27 (m, 2H), 7.13-7.19 (m, 1H), 6.27-6.35 and 6.40-6.48 (2 m, total 1H), [4.49 (dd, J=9, 8 Hz) and 4.56 (dd, J=9, 8 Hz), total 1H], 3.24 and 3.25 (2 s, total 3H), 3.17 and 3.21 (2 s, total 3H), 2.92 and 2.99 (2 br s, total 3H), 1.20 and 1.21 (2 s, total 3H), 1.12 and 1.13 (2 s, total 3H), 0.75-0.81 (m, 3H).

Workup

  1. customwas purified by silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane)

Sources & evidence

ORD record
ord-a57232a31fa4477aabfb82f2e50a63b6
Source dataset
uspto-grants-2014_09
Patent number
US08828401B2

Reaction notes

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