Acetonitrile → HCID 57978119, compound

HRID 554755Notes

Reaction equation

HRID 554755 reaction equation
C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][C@H:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].O.ON1C2C=CC=CC=2N=N1.[C:39]([NH:49][C@H:50]([C:55](O)=[O:56])[CH2:51][CH2:52][S:53][CH3:54])([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40].C(#N)C>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:42]([O:41][C:39]([NH:49][C@@H:50]([CH2:51][CH2:52][S:53][CH3:54])[C:55]([NH:12][C@H:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][C@H:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:56])=[O:40])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 1550857Benzyloxycarbonyl-L-methionineHCID 27960291-Hydroxybenzotriazole hydrateHCID 57454058HCID 57454058, compound

Product 1

HCID 57978119HCID 57978119, compound

Reagents, catalysts & solvents 2

HCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Procedure

Ethyl (7R,8S)-8-amino-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1 (450.1 g; the product of reductive deprotection of a known compound—see R. J. Chemey, WO 2004/098516 and G. V. Delucca & S. S. Ko, WO 2004/110993), was combined with 1-ethyl-3-(3-dimethyl-amino-propyl)carbo-diimide hydrochloride (236.3 g), 1-hydroxy benzotriazole hydrate (171.9 g), N-carbobenzyloxy-L-methionine (333.4 g) and acetonitrile (3.1 L). To the stirred mixture was added triethylamine (249.5 g) below 30° C. Upon reaction completion (HPLC), the mixture was diluted with ethyl acetate (8.2 L) and washed with aqueous 25% potassium bicarbonate solution (2×4.5 L) followed by water (4.5 L). The organic phase was separated and concentrated under reduced pressure to obtain a solution of ethyl (7R,8S)-8-((S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyrylamino)-1,4-dioxa-spiro[4.5]decane-7-carboxylate 2 (1.4 L). Methyl iodide (2.39 kg) was added, the vessel was shielded from light and the mixture was held under slow agitation for approx. 24 h. To the thick yellow precipitate was added methyl tert-butyl ether (2.7 L) and the mixture was held for approx. 1 h. The product was isolated by filtration and the cake was washed with methyl tert-butyl ether (2×1.4 L), then dried under vacuum, yielding [(S)-3-benzyloxy-carbonylamino-3-(7R,8S)-7-ethoxycarbonyl-1,4-dioxa-spiro[4.5]dec-8-ylcarbamoyl)-propyl]-dimethylsulfonium iodide 3 (671.4 g, ˜94% yield) as an off-white solid (HPLC purity 99.9%).

Workup

  1. customUpon reaction completion (HPLC)
  2. washwashed with aqueous 25% potassium bicarbonate solution (2×4.5 L)
  3. customThe organic phase was separated
  4. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-3e90adc1216c440f8048b695b29c303d
Source dataset
uspto-grants-2011_11
Patent number
US08049019B2

Reaction notes

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