Preparation method for treprostinil intermediate

Abstract

The invention relates to a preparation method for a treprostinil intermediate (I). The preparation method comprises the steps that: a compound of a formula (II) and a compound of a formula (III) or acidic salt thereof react in the presence of a condensing agent to obtain a compound of a formula (IV); the compound of the formula (IV) and a compound of a formula (V) react to obtain a compound of a formula (I). According to the preparation method for the treprostinil intermediate, weinreb amide and alkyne negative ions react to directly obtain a ketone compound (I), so that environment pollution caused by heavy metal (a PCC oxidant) is avoided, and the adoption of a butyl lithium low-temperature reaction method is also avoided. The preparation method for the treprostinil intermediate has the advantages that reaction conditions are mild, the yield is high, the purity of products is high, and the industrial application prospect is wide. (Formulae (I), (II), (III), (IV) and (V) are shown in the specification)

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a preparation method of a treprostinil intermediate. Background technique [0002] Pulmonary arterial hypertension (PAH) is a kind of disease or pathophysiological syndrome caused by known or unknown causes of abnormally elevated pressure in the pulmonary arteries, characterized by vasospasm, intimal hyperplasia, medial hypertrophy, adventitial hyperplasia, It is characterized by thrombosis, different degrees of inflammation, and plexiform changes. The clinical manifestations are progressive increase in pulmonary arterial pressure and eventually lead to right heart failure. Pulmonary arterial hypertension is a cardiovascular disease with a poor prognosis and a low incidence rate. In Europe and the United States, 1 to 2 people per million people develop each year. It is a rare disease. The diagnostic criteria for PAH defined by WHO are: resting state The mean pulmon...

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Problems solved by technology

[0010] 1. Since all intermediates are oily substances during the preparation of compound 8, product purification is difficult, column chromatography needs to be performed many times, and solvent consumption is large, resulting in increased costs and high pressure on environmental protection

[0011] 2. The Claisen rearrangement reaction is a high-temperature reaction. The instability of the aldehyde compound itself and the long-term reaction at high temperature will produce a large amount of by-product polymer oil. The oil must be removed by column chromatography, which is cumbersome to operate.

[0012] 3. The heavy metals used in the oxidation of PCC cause serious environmental pollution, and it is easy to cause heavy metals in the product to exceed the standard

[0013] 4. In the preparation of compound 6, on the one hand, n-butyllithium is used, and it needs to be reacted at -40°C--50°C. In addition, the more expensive trimethylsilylpropyne is used, which leads to the high cost of compound 6 and harsh reaction conditions , low industrial application value

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