Intermediate for preparing lubiprostone, preparation method of intermediate and method for preparing lubiprostone through intermediate

A technology for lubiprostone and compounds, which is applied in the field of preparing lubiprostone, can solve problems such as cumbersome synthesis process operations, and achieve the effects of safe operation, high synthesis efficiency, and significant social and economic benefits

Active Publication Date: 2014-05-14
连云港恒运药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Aiming at the shortcomings of the existing lubiprostone synthesis process that is cumbersome to operate, the present invention provides a new route for synthesizing lubiprostone, which starts from the disclosed compound VI and prepares lubiprostone through a five-step reaction, that is, by The HWE reaction of compound VI constructs the skeleton molecule of the product to obtain the key intermediate shown in formula V, and then through the reduction of two double bonds and selective deprotection of hydroxyl and (or) carboxyl, and selective deprotection of hydroxyl Preparation of Lubiprostone by Oxidation and Hydroxyl Deprotection

Method used

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  • Intermediate for preparing lubiprostone, preparation method of intermediate and method for preparing lubiprostone through intermediate
  • Intermediate for preparing lubiprostone, preparation method of intermediate and method for preparing lubiprostone through intermediate
  • Intermediate for preparing lubiprostone, preparation method of intermediate and method for preparing lubiprostone through intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Preparation of compound VIa (prepared according to the same method as Examples 1 and 2 of Chinese Patent Application 201210338692.1)

[0063] step 1):

[0064] N 2 Under protection, Corey lactone XVII (1.72g, purchased from Taizhou Aoxiang Pharmaceutical Technology Co., Ltd.) was suspended in dichloromethane (60mL), and 4 dimethylaminopyridine (122mg), triethylamine (13.4mL) were added, After cooling to -20°C, a solution of tert-butyldimethylchlorosilane (1.48g) in dichloromethane (20mL) was slowly added dropwise, and then raised to 20°C to react for 24 hours. After the reaction, add methyl tert-butyl ether (50mL) and saturated ammonium chloride (50mL), separate the layers, wash the organic phase with saturated brine, and anhydrous Na 2 SO 4 Dry, filter and concentrate to obtain a white solid. The white solid (2.86 g) was dissolved in dichloromethane (30 mL), PPTS (500 mg), DHP (4.6 mL) were added, and the reaction was carried out at 20°C for 3 hours. After the...

Embodiment 2

[0089] Example 2: Preparation of Compound Va

[0090] Compound Vila (1.7g, synthesized according to patent US4187381) was dissolved in 20mL of methyl tert-butyl ether, protected by nitrogen, added with lithium hydroxide monohydrate (253mg), and reacted at 20°C for 1 hour. A solution of compound Via (1.7 g) in methyl tert-butyl ether (10 mL) was added, and 0.9 mL of water was added. The reaction system was heated to 45° C. for 36 hours. 20 mL of water was added to the reaction system, stirred, and extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.04 g of compound Va, which was directly put into the next step reaction. Yield: 86%.

[0091] Va: 1 H-NMR (400MHz, CDCl 3 )δ=7.13-7.03(m,1H), 6.98-6.90(m,1H), 6.71-6.62(m,1H), 5.81(d,J=16Hz,1H), 5.16(t,J=4.4Hz, 1H), 4.59-4.52(m,1H), 4.15-4.02(m,1H), 3.85-3.70(m,4H), 3.47-3.41(m,1H), 2.83-2.68(m,1H), 2.63 2.56(m,1H),2.17-1.27(m,26H),0.94(...

Embodiment 3

[0092] Example 3: Preparation of Compound Iva

[0093] Compound Va (1.4g) was dissolved in 20mL ethyl acetate, 500mg 10%Pd / C(50%H 2 O), react at normal pressure at 20°C for 2 hours. The palladium carbon was filtered through Celite, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain 1.4 g of compound IVa, which was directly put into the next step reaction. Yield: 100%.

[0094] IVa: 1 H-NMR (400MHz, CDCl 3 )δ=5.09(s,1H), 4.58-4.52(m,1H), 3.97-3.82(m,1H), 3.68(s,3H), 3.50-3.46(m,1H), 2.82(m,1H) ,2.33-2.29(m,3H),2.1-1.2(m,32H),0.94(m,3H)ppm.

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Abstract

The invention relates to an intermediate for preparing lubiprostone, a preparation method of the intermediate and a method for preparing the lubiprostone through the intermediate, in particular to a compound as shown in a formula V for preparing the lubiprostone (as shown in a formula I), a preparation method of the compound and a method for preparing the lubiprostone through the compound. The method comprises the following steps: performing reduction treatment on the compound as shown in the formula V, performing selective deprotection and hydroxyl oxidation to obtain a compound as shown in a formula II, and performing hydroxyl deprotection on the compound as shown in the formula II to prepare the lubiprostone as shown in the formula I. The method is easy and convenient to operate, high in synthetic yield and suitable for large-scale production.

Description

Technical field [0001] The invention relates to an intermediate for preparing lubiprostone, a preparation method thereof and a method for preparing lubiprostone by the intermediate. Background technique [0002] Irritable bowel syndrome (IBS) is a functional disease of the gastrointestinal tract caused by the interaction of digestive tract, mental state and intestinal lumen factors. According to its main symptoms, it is divided into three types: diarrhea, constipation, and alternating (that is, diarrhea and constipation alternately). The prevalence of the disease in Chinese cities is about 10.5%. Although IBS is not life-threatening, due to long-term repeated attacks, it seriously affects the daily life and work of patients. [0003] The symptoms of constipation-type irritable bowel syndrome (IBS-C) are infrequent defecation and defecation discomfort. It is estimated that there are 4-5 million such patients in the United States (about 2% of the total population), which is the most...

Claims

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Application Information

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IPC IPC(8): C07C405/00C07D309/12C07D311/94
CPCY02P20/55
Inventor 张富尧高书三
Owner 连云港恒运药业有限公司
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