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Crystalline (S)-Ethyl2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-4- morpholinobutanoate oxalate Disclosure Number: IPCOM000244720D
Publication Date: 2016-Jan-06
Document File: 2 page(s) / 29K

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Crystalline (S)-Ethyl2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-4- morpholinobutanoate oxalate

     Provided herein is a process for the preparing of crystalline (S)-Ethyl2-(3-((2- isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanoate oxalate, referred herein as Compound I. The process is described in Example 1.

    Compound I may be used for the preparing of 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2- [(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4- yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate.

Example 1: A process for the preparing of crystalline (S)-Ethyl2-(3-((2-isopropylthiazol-4-yl) methyl)-3-methylureido)-4-morpholinobutanoate oxalate

    Into 250ml reactor were loaded under stream of nitrogen: (S)-3-aminodihydrofuran-2(3H)- one hydrochloride  (10g), N,N'-carbonyldiimidazole (11.79g) and DCM (70ml). The mixture was cooled down to -7 oC and N,N-diisopropylethylamine (15.2mL) was added dropwise. The reaction was stirred 2.5h followed by addition of 2-Isopropyl-4(((N-Methyl) amino)Methyl)thiazole dihydrochloride (16.79g). N,N-diisopropylethylamine (29.12mL) was added dropwise and the reaction was stirred 40 min at -7 oC followed by heating to 25 oC and stirring for 5h. The organic phase was extracted with water and 20% citric acid. The combined aqueous phases were extracted with DCM. The combined organic phases were extracted with water and dried over Na2SO4.

    The DCM solution was cooled to 0 oC, followed by addition of Lithium bromide (24.75 g) and ethanol (20mL). Trimethylsilyl chloride (TMSCl) (36.2mL) was added drop-wise over 60 min, after which the reaction mixture was heated to 35 °C. Stirring was continued for 24 h until completion of the reaction and then the reaction mixture was cooled to -10 °C and morpholine
(52.4mL) was added drop-wi...