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Synthesis method of Emricasan intermediate tert-butyl 3-amino-5-bromo-4-oxovalerate
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A technology of tert-butyl oxopentanoate and tert-butyl hydroxyvalerate, which is applied in the synthesis field of Enricason intermediate 3-amino-5-bromo-4-tert-butyl oxopentanoate, can solve the problem of Restricted operation, explosiveness, increased production cost and other problems, to achieve the effect of easy operation, high yield, avoiding low temperature and high temperature reactions
Inactive Publication Date: 2017-06-13
CHINA PHARM UNIV
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[0007] Because diazomethane gas is highly toxic, explosive and prone to safety accidents, and it is difficult to store it when it is ready for use, and the reaction requires strict control of moisture, which makes the industrialization of tert-butyl 3-amino-5-bromo-4-oxopentanoate Increased production costs and restricted operations
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Embodiment 1
[0030] (1) The preparation of tert-butyl 3-nitro-4-hydroxyvalerate: add tert-butyl 3-nitropropionate (17.51g, 0.1mol) in the 500ml reaction flask, 100ml dichloromethane, triethylamine ( 10.00g, 0.1mol), under nitrogen protection, the mixture was stirred at 0°C for 0.5h, acetaldehyde (5.28g, 0.12mol) was dissolved in 50ml of dichloromethane, slowly added dropwise to the above mixture, stirred at 0°C for 3h, the reaction Complete, add 100ml 1mol / L dilute hydrochloric acid solution, separate layers, wash the organic phase with water, wash with saturated brine, dry over anhydroussodiumsulfate, filter, and concentrate to obtain 19.37g of light yellow liquid (yield: 88.4%).
[0031] (2) Preparation of tert-butyl 3-amino-4-hydroxyvalerate: add tert-butyl 3-nitro-4-hydroxyvalerate (15.34g, 0.07mol) in 250ml reaction flask, 150ml methyl alcohol, palladium carbon ( 10%) (1.0g), ammoniumformate (17.64g, 0.28mol), under nitrogen protection, stirred at 50°C for 3h, filtered, concentrate...
Embodiment 2
[0035] (1) Preparation of tert-butyl 3-nitro-4-hydroxyvalerate: add tert-butyl 3-nitropropionate (30.00g, 0.17mol), 200ml toluene, triethylamine (17.33g , 0.17mol), under nitrogen protection, the mixture was stirred at 50°C for 0.5h, acetaldehyde (8.98g, 0.204mol) was dissolved in 50ml of toluene, slowly added dropwise to the above mixture, stirred at 50°C for 3h, the reaction was complete, and 180ml 1mol / L dilute hydrochloric acid solution, separated, washed the organic phase with water, washed with saturated brine, dried over anhydroussodiumsulfate, filtered, and concentrated to obtain 31.18 g of light yellow liquid (yield: 83.7%).
[0036] (2) Preparation of tert-butyl 3-amino-4-hydroxyvalerate: add tert-butyl 3-nitro-4-hydroxyvalerate (30.00g, 0.137mol) in the 500ml reaction flask, 250ml ethanol, palladium carbon ( 10%) (2.0g), ammoniumformate (34.5g, 0.548mol), under nitrogen protection, stirred at 80°C for 2h, filtered, concentrated, added 200ml of water to the residu...
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Abstract
The invention discloses a synthesis method of an Emricasan intermediate tert-butyl 3-amino-5-bromo-4-oxovalerate and belongs to the technical field of chemical synthesis. The synthesis method is characterized by comprising the following steps: (1) carrying out reaction on tert-butyl 3-nitropropionate and acetaldehyde under the alkaline condition to obtain tert-butyl 3-nitryl-4-hydroxyvalerate; (2) carrying out Pd-C catalytic hydrogenation reduction on the tert-butyl 3-nitryl-4-hydroxyvalerate to obtain tert-butyl 3-amino-4-hydroxyvalerate; (3) carrying out catalytic oxidation on the tert-butyl 3-amino-4-hydroxyvalerate with TEMPO and PhI(OAc)2 to obtain tert-butyl 3-amino-4-oxovalerate; and (4) carrying out substitution on the tert-butyl 3-amino-4-oxovalerate and Br2 through acid catalysis, so that the product is obtained. The synthesis method disclosed by the invention has the advantages of cheap and easily available raw materials, high reaction yield, high product purity and the like and is applicable to industrial production.
Description
[0001] Technical field: [0002] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for synthesizing 3-amino-5-bromo-4-oxopentanoic acid tert-butyl ester, an enlikasen intermediate. [0003] Background technique: [0004] 3-Amino-5-bromo-4-oxopentanoic acid tert-butyl ester is an important pharmaceutical intermediate and has a wide range of uses in drug synthesis. For example, peptide compounds synthesized with tert-butyl 3-amino-5-bromo-4-oxopentanoate and peptides can be used to inhibit caspase and play a therapeutic role in mediating apoptosis and various types of inflammation. For example, Enlikasen, an effective and oral caspase inhibitor invented by Conarus Pharmaceutical Company of the United States, provides a new treatment for patients with severe liver function. The intermediate 3-amino-5 is required for its synthesis. - Involvement of tert-butyl bromo-4-oxopentanoate. [0005] At present, the synthetic method ...
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