4-Oxobutanoic acid → N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(morpholin-4-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

HRID 882602Notes

Reaction equation

HRID 882602 reaction equation
C(OC([N:8]([CH3:59])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:25]([O:53][CH3:54])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:51][CH3:52])[C@@H:35]([CH3:50])[C:36]([NH:38][C@H:39]([C:47]([OH:49])=O)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])C(C)C)=O)(C)(C)C.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1.[CH:66]1[CH:67]=CC2N(O)N=NC=2[CH:71]=1.F[C:77](F)(F)[C:78]([OH:80])=[O:79].F[C:84](F)(F)[C:85]([O-])=O.O=CCCC(O)=O.C([BH3-])#N.[Na+]>C(Cl)CCl>[C:78]([CH2:77][CH2:84][CH2:85][N:8]([CH3:59])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:25]([O:53][CH3:54])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:51][CH3:52])[C@@H:35]([CH3:50])[C:36]([NH:38][C@@H:39]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:47]([N:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1)=[O:49])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:66]([CH3:67])[CH3:71])([OH:80])=[O:79]

Participants

9

Reactant 7

HCID 11124-Oxobutanoic acidHCID 6422Trifluoroacetic acidHCID 8083MorpholineHCID 757711-HydroxybenzotriazoleHCID 84468TrifluoroacetateHCID 5003444Sodium cyanoborohydrideHCID 71111548t-Boc-N-MMAF2×

Product 1

HCID 56952699N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(morpholin-4-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

First, in analogy to the synthesis described in Intermediate 79, by coupling of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 46) and morpholine in the presence of EDC and HOBT and subsequent detachment of the Boc protecting group by means of trifluoroacetic acid, the amine compound N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(morpholin-4-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was prepared as the trifluoroacetate. 30 mg (0.033 mmol) of this compound were then used, in analogy to the preparation of Intermediate 61, by reaction with 4-oxobutanoic acid in the presence of sodium cyanoborohydride, to obtain 22 mg (76% of theory) of the title compound.

Sources & evidence

ORD record
ord-5834f6e5001548d19e0a186f36585eb1
Source dataset
uspto-grants-2015_03
Patent number
US08992932B2

Reaction notes

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