Acetonitrile → HCID 57978119、化合物

反応式

C1(C)C=C[C:4]([S:7](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].[OH2:28].ON1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.[C:39](#[N:41])[CH3:40].C(N([CH2:47][CH3:48])CC)C.[C:49]([O:52][CH2:53]C)(=[O:51])C>>[CH2:53]([O:52][C:49]([NH:41][C@@H:39]([CH2:48][CH2:47][S:7][CH3:4])[C:40]([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:28])=[O:51])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1

参加物

反応物 5

HCID 6342Acetonitrile

HCID 8471Triethylamine

HCID 8857Ethyl Acetate

HCID 27960291-Hydroxybenzotriazole hydrate

HCID 57454058HCID 57454058、化合物

生成物 1

HCID 57978119HCID 57978119、化合物

実験手順

Example 1, 2nd Alternative Preparation, Step 1b: 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. Cherney, 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-T-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%).