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A kind of intermediate for preparing lubiprostone, its preparation method and the method for preparing lubiprostone by it

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

Active Publication Date: 2017-02-15
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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  • A kind of intermediate for preparing lubiprostone, its preparation method and the method for preparing lubiprostone by it
  • A kind of intermediate for preparing lubiprostone, its preparation method and the method for preparing lubiprostone by it
  • A kind of intermediate for preparing lubiprostone, its preparation method and the method for preparing lubiprostone by it

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Preparation of Compound VIa (prepared according to the same method as in 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), added 4 dimethylaminopyridine (122mg), triethylamine (13.4mL), 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 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, anhydrous Na 2 SO 4 Dry, filter and concentrate to give a white solid. The white solid (2.86g) was dissolved in dichloromethane (30mL), PPTS (500mg) and DHP (4.6mL) were added and reacted at 20°C for 3 hours. After the reaction, add methyl tert-butyl ethe...

Embodiment 2

[0089] Embodiment 2: the preparation of compound Va

[0090] Compound VIIa (1.7g, synthesized according to patent US4187381) was dissolved in 20mL of methyl tert-butyl ether, under nitrogen protection, lithium hydroxide monohydrate (253mg) was added, 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 then 0.9 mL of water was added, and the temperature of the reaction system was raised to 45° C. for 36 hours. Add 20 mL of water to the reaction system, stir, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 2.04 g of compound Va, which is directly put into the next 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...

Embodiment 3

[0092] Embodiment 3: the preparation of compound Iva

[0093] Compound Va (1.4g) was dissolved in 20mL ethyl acetate, and 500mg 10%Pd / C (50%H 2 O), 20 ℃ normal pressure reaction for 2 hours. Palladium-carbon was filtered out 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 through the intermediate. Background technique [0002] Irritable bowel syndrome (IBS) is a gastrointestinal functional disease caused by the interaction of digestive tract, mental state and intestinal lumen factors. According to its main symptoms, it can be divided into three types: diarrhea type, constipation type, and alternating type (that is, diarrhea and constipation appear alternately). The prevalence rate of the disease in my country's cities is about 10.5%. Although IBS is not life-threatening, it seriously affects the daily life and work of patients due to long-term recurrent attacks. [0003] Irritable bowel syndrome with constipation (IBS-C), characterized by infrequent bowel movements and discomfort with bowel movements, is estimated to affect 4-5 million patients in the United States (approximately 2% ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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