CN104557845B - Preparation method of lubiprostone compound - Google Patents
Preparation method of lubiprostone compound Download PDFInfo
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- CN104557845B CN104557845B CN201510016123.9A CN201510016123A CN104557845B CN 104557845 B CN104557845 B CN 104557845B CN 201510016123 A CN201510016123 A CN 201510016123A CN 104557845 B CN104557845 B CN 104557845B
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a preparation method of lubiprostone, which comprises the steps of carrying out transfer catalytic hydrogenation on an initial raw material in an alcohol solvent by using triethylsilane as a hydrogen source and palladium carbon or palladium hydroxide as a catalyst, and simultaneously removing a protecting group and reducing double bonds to obtain the lubiprostone. Compared with the existing catalytic hydrogenation reaction, the method has the advantages of simple operation, mild reaction conditions, high yield and good purity, obviously shortens the reaction time and the reaction period, greatly improves the production efficiency, reduces the requirements on reaction equipment, and is more suitable for industrial mass production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of lubiprostone.
Background
Lubiprostone (lubiprostone) is jointly developed by Sucampo Pharms (Sucampbo Co.) in combination with Yapei and Wutian, is a selective chloride channel activator marketed in the United states in 2006 and 01 months, promotes secretion of intestinal fluid and intestinal peristalsis by activating a type 2 chloride channel located on a cell membrane of a lumen at the apical end of the gastrointestinal epithelium, has the effects of lubricating the intestinal tract, softening feces and enhancing the peristalsis function of the gastrointestinal tract, and is clinically used for treating adult Chronic Idiopathic Constipation (CIC), irritable bowel syndrome (IBS-C) accompanied with constipation symptoms in adult female patients over 18 years old (inclusive) and constipation (OIC) caused by using opioid drugs in adult chronic non-cancerous pain patients.
The chemical name of lubiprostone is (-) -7- [ (2R,4aR,5R,7aR) -2- (1, 1-difluoropentyl) -2-hydroxy-6-oxooctahydrocyclopentapyran-5-yl ] heptanoic acid, and the drug molecules exist in a hemiketal and ketone equilibrium tautomeric form in bulk drugs and preparations, and have the following structures:
WO9927934, US2013184476A describe the preparation process of lubiprostone, the reaction scheme is as follows:
the methods disclosed in the above patent documents use a catalytic hydrogenation method requiring a certain pressure in both the reduction of the double bond and the removal of the protective group on the carboxyl group, and have disadvantages of high equipment requirements, long reaction time, and low yield due to side reactions such as intramolecular auto-dehydration.
Although US2010056807 adopts p-methoxybenzyl ester as a protecting group for hydroxyl, the subsequent step of preparing lubiprostone cannot avoid catalytic hydrogenation with a certain pressure, and the corresponding disadvantages cannot be avoided.
The CN103180306A adopts a new route, not only does not avoid pressurized catalytic hydrogenation, but also has more complicated reaction steps, and needs to use the dimethyl tert-butyl silyl ether with higher price, so that the route has long reaction period, high cost and low product yield.
Although CN104140410A and CN103787942A disclose the process of preparing lubiprostone intermediate by palladium carbon normal pressure catalytic reaction for 2 hours, the catalytic hydrogenation method using hydrogen as hydrogen source under normal pressure is difficult to completely convert.
Disclosure of Invention
The invention provides a novel method for preparing lubiprostone aiming at the defects of the prior art. Through research, the inventor surprisingly discovers that compared with the existing catalytic hydrogenation reaction, the method has the advantages of simple operation, mild reaction conditions, extremely high reaction rate, high yield and good purity, obviously shortens the reaction time and the reaction period, greatly improves the production efficiency, reduces the requirement on reaction equipment, and is more suitable for industrial large-scale production.
The technical scheme of the invention is as follows:
a method for preparing lubiprostone, comprising the steps of:
(1) adding a compound I into an alcohol solvent, adding a catalyst under the protection of inert gas, adding triethylsilane, and stirring for reaction;
and optionally also (c) a second set of one or more of,
(2) filtering after the reaction is finished, and concentrating the filtrate to obtain lubiprostone;
the reaction route is as follows:
wherein R is1、R2May be independently selected from hydrogen, substituted or unsubstituted benzyl, and R1And R2Not hydrogen at the same time; preferably, in one embodiment of the present invention, R1Is benzyl, R2Is hydrogen;
the alcohol solvent is selected from one or more of methanol, ethanol and isopropanol;
the inert gas is selected from nitrogen, argon, helium, preferably nitrogen;
the catalyst is selected from palladium carbon, palladium hydroxide and palladium chloride, and in the invention, the catalyst can be directly added into the reaction or diluted by using a small amount of alcohol solvent and then added;
the molar ratio of the compound I to the triethylsilane is 1: 2-10; preferably 1: 3-6, most preferably 1: 4;
the reaction temperature is-40 ℃ to the boiling point of the solvent, preferably-20-40 ℃, more preferably 15-30 ℃, and most preferably 20-25 ℃ or 25-30 ℃;
the stirring reaction time in the step (1) is 10-40 minutes, preferably 20-30 minutes.
In one technical scheme of the invention, the preparation method of lubiprostone comprises the following steps:
(1) adding a compound I into an alcohol solvent, adding a catalyst and triethylsilane under the protection of inert gas, and stirring for reaction;
(2) filtering after the reaction is finished, concentrating the filtrate, adding ethyl acetate to dissolve and concentrate the residue, selecting one or two of saturated sodium carbonate solution and saturated sodium chloride solution to wash, drying, concentrating and evaporating to dryness to obtain the lubiprostone.
In the invention, the application of the triethylsilane greatly improves the reaction efficiency, does not need pressurized hydrogenation, but utilizes the triethylsilane as a hydrogen source, the boiling point of the triethylsilane is 108 ℃, the activity is high, and the reaction yield is improved.
The transfer catalytic hydrogenation reaction mechanism of triethylsilane is as follows:
first, the reaction substrate combines two protons, which are provided by the water in the system, to obtain an intermediate state. Triethylsilane then provides two negative hydrogens, converting the intermediate state to the product, triethylsilane becoming triethylsilanol.
The invention utilizes the difference between catalytic hydrogenation and transfer catalytic hydrogenation and uses different hydrogen sources, thereby greatly improving the reaction efficiency and purity of the product. Catalytic hydrogenation is generally carried out in an autoclave by using hydrogen as a hydrogen source, and transfer catalytic hydrogenation is carried out under normal pressure by using other hydrogen donors containing negative hydrogen as the hydrogen source. The transfer catalytic hydrogenation has the advantages of no high-pressure hydrogen and safety; meanwhile, the requirement on equipment is not high, and the used hydrogen source is cheap and easy to obtain.
It should be noted that, in the present invention, the compound I refers to a compound represented by formula I. If not otherwise stated, the amounts of the reaction solvent and the reagents are conventional and can be determined by one skilled in the art in light of the prior art; the reagents used in the present invention are conventional reagents, commercially available, and the starting materials and reactants used can be prepared by the prior art or published prior art documents, and the compound (Z) -7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl ] hept-5-enebenzyl ester can be purchased from Shanghai Wei biopharmaceutical Co., Ltd, and triethylsilane can be purchased from Wako Si Hutu Si Co., Ltd.
The lubiprostone prepared by the technical scheme of the invention has the following advantages: (1) the reaction time is short, and the reaction can be completed in more than ten minutes; (2) the reaction yield is high and can reach 95-100%; (3) the reaction condition is mild, pressure catalytic hydrogenation is not needed, and the requirement on equipment is low.
Detailed Description
The foregoing and other aspects of the present invention are achieved by the following detailed description, which should not be construed to limit the claimed subject matter in any way. All technical solutions realized based on the above contents of the present invention belong to the scope of the present invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. It is clear to those skilled in the art that, unless otherwise specified, the operation of the present invention is carried out under ambient temperature conditions conventional in the art, said ambient temperature having technical meaning well known in the art, generally 20 to 35 ℃, preferably 20 to 30 ℃.
The apparatus and method used in the present invention:
(1) high resolution mass spectrometry
The instrument model is as follows: Q-Tofmicro mass spectrometer.
And (3) testing conditions are as follows: ESI (electrospray).
Example 1:
to the reaction flask was added 0.5g of (Z) -7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl at room temperature]Heptalein-5-ene benzyl ester and 10ml methanol, 0.1g 10% Pd/C (50% H) was added under nitrogen2O), diluting 0.7g of triethylsilane by 10ml of methanol to prepare a solution, slowly dripping the solution into a reaction bottle, keeping the temperature of 15-25 ℃ for reaction for 10 minutes after dripping is finished, filtering to remove palladium carbon, concentrating the reaction solution, adding 20ml of ethyl acetate, washing by 20ml of saturated sodium chloride, and drying by anhydrous sodium sulfateAnd concentrating the organic layer, and evaporating the filtrate to obtain an oily substance to obtain the lubiprostone. Weigh 0.39g, yield 97.5%, product purity 98.12%.
MS(m/z):389.46(M-1).
Example 2:
to the reaction flask was added 0.5g of (Z) -7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl at room temperature]5-Enobenzyl heptanoate and 10ml ethanol, 0.1g of 10% Pd/C (50% H) was added under nitrogen2O), diluting 0.7g of triethylsilane by 10ml of ethanol to prepare a solution, slowly dripping the solution into a reaction bottle, keeping the temperature of 15-25 ℃ for reaction for 30 minutes after dripping is finished, filtering to remove palladium carbon, concentrating the reaction solution, adding 20ml of ethyl acetate, washing by 20ml of saturated sodium chloride, drying an organic layer by anhydrous sodium sulfate, filtering, removing a drying agent, concentrating the filtrate to obtain an oily substance by evaporation, weighing 0.39g, and obtaining the yield of 97.5%. The purity of the product is 98.05%.
Example 3:
adding 0.5g of (Z) -7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl ] hept-5-enebenzyl ester into methanol, stirring to dissolve completely, adding palladium hydroxide under the protection of nitrogen, adding 0.7g of triethylsilane into 10mL of methanol for dilution, then dropwise adding into the solution, reacting at 20-25 ℃ for 30 minutes after dropwise adding for 10-15 minutes, filtering to remove palladium hydroxide, concentrating the reaction solution, adding 20mL of ethyl acetate, washing once with 20mL of saturated sodium bicarbonate solution and 20mL of saturated sodium chloride, and drying with anhydrous sodium sulfate. After filtration and removal of the drying agent, the filtrate was concentrated to give lubiprostone weighing 0.375g, yield 93.8% and product purity 97.93%.
Example 4:
adding 0.8g of (Z) -7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl ] hept-5-enebenzyl ester into methanol, stirring and dissolving, adding palladium hydroxide under the protection of nitrogen, adding 1g of triethylsilane into 10mL of methanol for dilution, then dropwise adding into the solution for 10-15 minutes, then reacting at 25-30 ℃ for 20 minutes, filtering, removing palladium hydroxide, concentrating the reaction solution, adding 30mL of ethyl acetate, washing once by using 20mL of saturated sodium bicarbonate and 20mL of saturated sodium chloride solution in turn, and drying by using anhydrous sodium sulfate. After filtration and removal of the drying agent, the filtrate was concentrated to give lubiprostone weighing 0.631g, yield 96.6% and product purity 97.54%.
Example 5:
0.279g of (Z) -7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl ] hept-5-enebenzyl ester is added into 5mL of ethanol, stirred and dissolved, palladium hydroxide is added under the protection of nitrogen, 0.33g of triethylsilane is added into 5mL of ethanol for dilution, the solution is added dropwise into the solution for 10-15 minutes, then the reaction is carried out for 30 minutes at 20-25 ℃, the palladium hydroxide is removed by filtration, 10mL of ethyl acetate is added after the reaction solution is concentrated, and the solution is washed once with 10mL of saturated sodium bicarbonate solution and 10mL of saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. After filtration and removal of the drying agent, the filtrate was concentrated to give lubiprostone weighing 0.219g, yield 96.0% and product purity 97.93%.
Example 6:
adding 0.5g of (Z) -7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxooctyl) -3-benzyloxy-5-oxocyclopentyl ] heptanoic acid-5-alkene benzyl ester into 4mL of ethanol, stirring and dissolving, adding palladium hydroxide under the protection of nitrogen, adding 0.51g of triethylsilane into 5mL of ethanol, diluting and dropwise adding into the solution, reacting at 20-25 ℃ for 30 minutes after 15 minutes of dropwise adding is finished, filtering and removing palladium hydroxide, concentrating the filtrate to obtain lubiprostone, weighing 0.32g, obtaining the yield of 94.1%, and obtaining the product with the purity of 96.54%.
Example 7:
adding 1.0g of (Z) -7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxooctyl) -3-benzyloxy-5-oxocyclopentyl ] heptanoic acid-5-alkene benzyl ester into 10mL of isopropanol, stirring for dissolving, adding palladium hydroxide under the protection of nitrogen, adding 1.02g of triethylsilane into 10mL of isopropanol, diluting, dropwise adding into the solution, reacting at 20-25 ℃ for 40 minutes after 15 minutes of dropwise adding, filtering, removing palladium hydroxide, concentrating the filtrate to obtain a lubiprostone crude product, weighing 0.68g, the yield being 97.1% and the product purity being 97.26%.
Comparative example 1: reference is made to US2010056807
0.814g of (Z) -7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl ] hept-5-enebenzyl ester is added into 50mL of 90% ethanol, stirred and dissolved, 0.2g of palladium hydroxide is added under the protection of nitrogen, hydrogen is introduced after nitrogen replacement, pressurized reaction is carried out for 8h, filtration is carried out, palladium hydroxide charcoal is removed, and the filtrate is concentrated to obtain the crude rubiprostone, the weight is 0.642g, the yield is 86.1%, and the purity is 89.08%.
It can be seen that the alcohol solvent and the hydrogen are used as hydrogen sources to catalyze, pressurize and hydrogenate, the reaction time is long, the purity of the obtained product is low, the impurities are more, and the product yield is reduced.
Comparative example 2: tetrahydrofuran is used as solvent
Adding 0.243g of (Z) -7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl ] hept-5-ene benzyl ester into 5L tetrahydrofuran, stirring and dissolving, adding palladium hydroxide under the protection of nitrogen, adding 0.3g of triethylsilane into 5mL of tetrahydrofuran, diluting, dropwise adding into the solution, dropwise adding for 10 minutes, generating a large amount of bubbles in the dropwise adding process, reacting at 20-25 ℃ for 30 minutes after dropwise adding, filtering to remove palladium-carbon hydroxide, concentrating the reaction solution, adding 10mL of ethyl acetate, washing once by using 10mL of saturated sodium bicarbonate solution and 10mL of saturated sodium chloride solution in turn, and drying by using anhydrous sodium sulfate. After filtration and removal of the drying agent, the filtrate was concentrated to give lubiprostone weighing 0.172g, yield 86.9% and product purity 67.91%.
It can be seen that although triethylsilane is still used as hydrogen source for atmospheric transfer catalytic hydrogenation, tetrahydrofuran is used as solvent, resulting in lower yield and purity, presumably due to other side reactions during radical reduction.
According to the invention, an alcohol solvent is adopted, triethylsilane is combined as a hydrogen source to provide two negative hydrogens, palladium carbon or palladium hydroxide is used as a catalyst for normal pressure hydrogenation, so that the reaction time is shortened to 10-40 minutes from more than 2 hours in the prior art, the product purity is greatly improved, the requirement on equipment is low, the operation is simple, and the method is very suitable for large-scale industrial production.
Claims (4)
1. A method for preparing lubiprostone, comprising the steps of: adding a compound I into an alcohol solvent, adding a catalyst under the protection of inert gas, adding triethylsilane, and stirring for reaction; the reaction route is as follows:
wherein R is1、R2May be independently selected from unsubstituted benzyl;
the alcohol solvent is selected from one or more of methanol, ethanol and isopropanol;
the inert gas is selected from nitrogen, argon and helium;
the catalyst is palladium hydroxide;
the molar ratio of the compound I to the triethylsilane is 1: 3-6;
the reaction temperature is 15-30 ℃;
the stirring reaction time is 20-30 minutes.
2. The method according to claim 1, wherein the molar ratio of the compound I to triethylsilane is 1: 4.
3. The method according to claim 1, wherein the reaction temperature is 20 to 25 ℃ or 25 to 30 ℃.
4. The method of claim 1, comprising the steps of: (1) adding a compound I into an alcohol solvent, adding a catalyst and triethylsilane under the protection of inert gas, and stirring for reaction;
(2) filtering after the reaction is finished, concentrating the filtrate, adding ethyl acetate to dissolve and concentrate the residue, selecting one or two of saturated sodium carbonate solution and saturated sodium chloride solution to wash, drying, concentrating and evaporating to dryness to obtain the lubiprostone.
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| CN105753867B (en) * | 2016-03-24 | 2018-03-27 | 齐鲁制药有限公司 | A kind of preparation method of improved AVM hereinafter Batan sodium midbody compound |
| US10253011B1 (en) * | 2018-07-13 | 2019-04-09 | Chirogate International Inc. | Lubiprostone crystals and methods for preparing the same |
| US10457623B1 (en) * | 2018-07-13 | 2019-10-29 | Chirogate International Inc. | Process for the preparation of Lubiprostone and intermediates thereof |
| CN111943950B (en) * | 2020-09-10 | 2022-03-29 | 山东安信制药有限公司 | Preparation method of rilibatan |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1206997C (en) * | 1997-11-28 | 2005-06-22 | 株式会社·R-技术上野 | Endothelin antagonist |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1206997C (en) * | 1997-11-28 | 2005-06-22 | 株式会社·R-技术上野 | Endothelin antagonist |
Non-Patent Citations (1)
| Title |
|---|
| Pd-C-Induced Catalytic Transfer Hydrogenation with Triethylsilane;Pijus K. Mandal et al.;《J. Org. Chem.》;20070714;第72卷;6599-6601 * |
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