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Preparation process of lubiprostone intermediate

A lubiprostone and preparation technology, applied in the field of sewage treatment and environmental protection, can solve the problems of complex and cumbersome synthesis, and achieve the effects of high yield, high economic benefit, and fast and convenient synthesis route

Inactive Publication Date: 2019-02-22
EMEISHAN HONGSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-[(tetrahydro-2H-pyran- 2-yl)oxyl]cyclopentyl]-5-benzyl heptanoate is a lubiprostone intermediate, and there is no relatively easy route to synthesize at present, that is, there are problems such as complex synthesis and cumbersome synthesis in the prior art

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of Intermediate 1:

[0025] Dissolve 1 mol of the starting material in anhydrous toluene, lower the temperature to -25~-15°C under the protection of nitrogen, add diisobutylaluminum hydride, stir and react for 3 hours, TLC detects that the reaction is complete, add saturated potassium sodium tartrate aqueous solution, Separate the liquid, add ethyl acetate to extract the aqueous phase until TCL shows that the aqueous layer has no intermediate 1, combine the organic layers, concentrate to obtain the crude product, and purify by silica gel column chromatography (eluent: petroleum ether / ethyl acetate=3 / 1) , to obtain intermediate 1.

[0026] Preparation of Intermediate 2:

[0027] Dissolve 1 mol of triphenylphosphine bromide butyric acid in anhydrous ether, add 3.5 mol of triethylamine at room temperature, add the anhydrous ether solution of intermediate 1, wherein intermediate 1 is 1 mol, and react at -10°C for 4 hours. TLC detected that the reaction was com...

Embodiment 2

[0032] Similar to Example 1, the difference is:

[0033] Preparation of Intermediate 2:

[0034] Dissolve 1 mol of triphenylphosphine bromide butyric acid in anhydrous ether, add 3 mol of triethylamine at room temperature, add the anhydrous ether solution of intermediate 1, in which intermediate 1 is 1 mol, react at -10°C for 4 hours, TLC Check that the reaction is complete, add hydrochloric acid dropwise, adjust to pH 6.0, add ethyl acetate, extract, extract the aqueous phase with ethyl acetate, combine the organic layers, concentrate and dry under reduced pressure to obtain the crude intermediate 2, the yield is 91.3%, the purity 93%. Go straight to the next step.

[0035] Preparation of intermediate 3:

[0036] Add 1 mol of intermediate 2, acetonitrile, diisopropylethylamine and 1 mol of benzyl bromide to the single-necked bottle, keep the temperature for reaction, TLC detects that the reaction is complete, concentrate and dry under reduced pressure, add ethyl acetate, w...

Embodiment 3

[0039] Similar to Example 1, the difference is:

[0040] Preparation of intermediate 2:

[0041] Dissolve 1 mol of triphenylphosphine bromide butyric acid in anhydrous ether, add 5 mol of triethylamine at room temperature, add the anhydrous ether solution of intermediate 1, in which intermediate 1 is 1 mol, react at -10°C for 4 hours, TLC Check that the reaction is complete, add hydrochloric acid dropwise, adjust to pH 6.0, add ethyl acetate, extract, extract the aqueous phase with ethyl acetate, combine the organic layers, concentrate and dry under reduced pressure to obtain the crude intermediate 2, the yield is 90%, the purity 92%. Go straight to the next step.

[0042] Preparation of intermediate 3:

[0043] Add 1 mol of intermediate 2 to the single-necked flask, then add acetonitrile, diisopropylethylamine and 1 mol of benzyl bromide, keep warm for reaction, TLC detects that the reaction is complete, concentrate and dry under reduced pressure, add ethyl acetate, wash w...

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Abstract

The invention discloses a preparation process of a lubiprostone intermediate. The preparation process comprises the following steps: firstly, carrying out reduction reaction on a lubi-initiator to obtain an intermediate 1; secondly, adding excessive weak base into a mixed solution of triphenylphosphonic acid bromide and absolute ether, then adding the intermediate 1 for complete reaction, then adjusting a pH value to 5 to 6, adding ethyl acetate for extracting, combining organic layers to obtain an organic phase, and carrying out vacuum concentration and drying on the organic phase to obtain an intermediate 2; thirdly, adding acetonitrile, diisopropylethylamine and benzyl bromide into the intermediate 2 for complete reaction, then carrying out vacuum concentration and drying, and adding the ethyl acetate and water for extracting and separating liquid; carrying out vacuum concentration and drying on the organic phase to obtain a crude product of an intermediate 3. The preparation process disclosed by the invention has the advantages of rapid and convenient synthesis route, high yield and relatively high economic value; the preparation process is quite suitable for scale production and provides another synthesis route with high economic benefits and high production efficiency for producing lubiprostone.

Description

technical field [0001] The invention relates to the field of sewage treatment and environmental protection, in particular to a preparation process of a lubiprostone intermediate. Background technique [0002] Lubiprostone is a chemical constipation treatment drug. It is the only prescription drug approved in Switzerland for the treatment of long-term chronic idiopathic constipation. Compared with other laxatives, it not only has a good constipation treatment effect, but also has long-term drug resistance The incidence of sex is low, and it also has the advantages of small doses. [0003] The structure of lubiprostone is primarily a 20-carbon acid with a five-membered aliphatic ring with two side chains. Among them, the five-membered ring contains multiple chiral carbon atoms and two side chains. These chiral carbon atoms respectively control the configuration of each chiral center, making the stereoselective synthesis difficult. [0004] (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluor...

Claims

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Application Information

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IPC IPC(8): C07D309/06
CPCC07D309/06
Inventor 鲁成宪谯在银田健宏车尚泽
Owner EMEISHAN HONGSHENG PHARMA
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