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Treprostinil intermediate and preparation process thereof

A compound and selected technology, applied in the field of medicine, can solve problems such as environmental pollution, instability of aldehyde-based compounds, harsh reaction conditions, etc., and achieve the effects of broad industrial application prospects, easy recrystallization and purification, and mild reaction conditions

Active Publication Date: 2020-05-08
JIANGSU HANSOH PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] 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
[0012] 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.
[0013] 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
[0014] 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

Method used

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  • Treprostinil intermediate and preparation process thereof
  • Treprostinil intermediate and preparation process thereof
  • Treprostinil intermediate and preparation process thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110]

[0111] Under the protection of nitrogen, add 1000ml of methanol to the reaction flask, and then add the compound 3-hydroxy-benzoic acid methyl ester 200.0g (1.314mol), potassium carbonate 218.0g (1.580mol), sodium iodide 20.0g (0.133mol) 191.0 g (1.579 mol) of bromopropylene, heated to reflux; after stirring for 7-9 hours, TLC detected that the reaction of raw materials was complete (developing agent: petroleum ether: ethyl acetate = 4:1), cooled to 25 ° C, and reacted 500ml of methyl tert-butyl ether was added to the residue, filtered, the filtrate was washed once with 300ml of 15% aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain Light yellow oil 3-allyloxy-benzoic acid methyl ester 243.5g (1.267mol, molar yield: 96.4%, HPLC purity 96.5%).

Embodiment 2

[0113]

[0114] Put 243.5g (1.267mol) of 3-allyloxy-benzoic acid methyl ester in the reaction flask, raise the temperature to 220°C for 1.0-3.0 hours, then cool down to 60°C; add 500ml of methyl tert-butyl ether and 844ml 1mol / L lithium hydroxide aqueous solution, adjust the temperature to 30-40°C and stir the reaction overnight, cool down to 0-5°C, add 117ml concentrated hydrochloric acid dropwise to adjust the pH of the reaction solution to 1-2, and use 700ml formazan extracted with tert-butyl ether, the organic phase was washed successively with saturated aqueous sodium bicarbonate solution (700ml×2), saturated aqueous sodium chloride solution (500ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain light yellow half Solid 2-allyl-3-hydroxy-benzoic acid methyl ester 193.8g (1.008mol, molar yield 79.6%, HPLC purity 96.4%).

Embodiment 3

[0116]

[0117] 193.8g (1.008mol) of 2-allyl-3-hydroxyl-benzoic acid methyl ester was placed in the reaction flask, 3000ml of acetone was added, and then 14.8g (0.099mol) of sodium iodide and 393.4g of cesium carbonate ( 1.207mol), benzyl bromide 190.6g (1.112mol), and the temperature was raised to reflux. Stir the reaction for 1-2 hours, TLC analysis of the raw material reaction is complete (developer: petroleum ether: ethyl acetate = 4:1), cool down to room temperature, filter, concentrate to dryness under reduced pressure; add 300mL of n-hexane, water (200ml*3 ) washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give light yellow oily matter 2-allyl-3-benzyloxy-methyl benzoate 279.8g (0.991mol, molar yield 98.3% , HPLC purity 91.1%).

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Abstract

The invention relates to a treprostinil intermediate and a preparation process thereof. The preparation process comprises the following steps: reacting a compound as shown in a formula (II) with a compound as shown in a formula (III) or an acidic salt thereof in the presence of a condensing agent to obtain a compound as shown in a formula (IV); and reacting the compound as shown in the formula (IV) with a compound as shown in a formula (V) to obtain a compound as shown in a formula (I). According to the invention, the ketone compound (I) is directly obtained by a reaction of Weber amide and alkyne anions, environmental pollution caused by use of a heavy metal (a PCC oxidant) is avoided, and a low-temperature reaction method adopting butyl lithium is also avoided; and the method is mild inreaction conditions, high in yield, good in product purity and wide in industrial application prospects.

Description

[0001] This application is a divisional application of the Chinese patent application with the application number 201510093682.X, the application date is March 2, 2015, and the invention title is "Preparation Method of Treprostinil Intermediate". technical field [0002] The invention belongs to the technical field of medicines, and in particular relates to a treprostinil intermediate and a preparation process thereof. Background technique [0003] 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 c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C259/10C07D309/12
CPCC07C259/10C07D309/12Y02P20/55
Inventor 王听中苏熠东冯卫东王宝珠成明吕爱锋
Owner JIANGSU HANSOH PHARMA CO LTD
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