CN104557845A - Method for preparing lubiprostone compound - Google Patents

Method for preparing lubiprostone compound Download PDF

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Publication number
CN104557845A
CN104557845A CN201510016123.9A CN201510016123A CN104557845A CN 104557845 A CN104557845 A CN 104557845A CN 201510016123 A CN201510016123 A CN 201510016123A CN 104557845 A CN104557845 A CN 104557845A
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Prior art keywords
reaction
preparation
lubiprostone
triethyl silicane
compound
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CN104557845B (en
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田振平
潘雷
高源�
周晓东
张贵岭
范传文
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Qilu Pharmaceutical Co Ltd
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Qilu Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a method for preparing lubiprostone. The method comprises the following steps: by taking triethyl silicane as a hydrogen source, and taking palladium carbon or palladium hydroxide as a catalyst, performing catalytic transfer hydrogenation, removing the protecting groups, and reducing double bonds, thereby obtaining the product. Compared with a conventional catalytic hydrogenation reaction at present, the method has the advantages of simplicity in operation, mild reaction conditions, high yield and high purity, the reaction time and reaction period are obviously shortened, the production efficiency is greatly improved, the requirements on reaction equipment are reduced, and the method is suitable for industrial production.

Description

A kind of preparation method of Lubiprostone 1 compound
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to a kind of preparation method of Lubiprostone 1.
Background technology
Lubiprostone 1 (lubiprostone) is by Sucampo Pharms (Sucampo AG) associating Abbott Laboratories, military field joint development, in the selective chloride ion channel activator that 2006 01 month goes on the market in the U.S., the 2 type chloride channels be positioned on the most advanced and sophisticated tube chamber cytolemma of GI epithelium by activation promote the secretion of intestinal juice and the wriggling of enteron aisle, there is lubrication enteron aisle, softer stool, strengthen the effect of gastrointestinal motility function, be used for the treatment of Adult chronic idiopathic constipation (CIC) clinically, more than 18 one full year of life (contain) constipation (OIC) that adult female patient causes because using opioid drug with the irritable bowel syndrome (IBS-C) of constipation symptom and Adult chronic's Non-cancerous pain patient.
The chemical name of Lubiprostone 1 is (-)-7-[(2R, 4aR, 5R, 7aR)-2-(1,1-difluoro amyl group)-2-hydroxyl-6-oxo octahydro pentamethylene pyrans-5-base] enanthic acid, in bulk drug and preparation, this drug molecule exists with the balance tautomeric form of hemiketal and ketone, and structure is as follows:
Describe the preparation technology of Lubiprostone 1 in WO9927934, US2013184476A, reaction scheme is as follows:
Method disclosed in above-mentioned patent documentation is in reduction double bond and to remove on carboxyl when protecting group; all have employed the catalytic hydrogenation needing certain pressure; the shortcoming of this method is, long reaction time high to equipment requirements, thus causes the side reaction such as automatic dehydration in molecule, and yield is low.
Although US2010056807 have employed the protecting group of methoxy benzyl ester as hydroxyl, the follow-up step preparing Lubiprostone 1 still cannot avoid the catalytic hydrogenation needing to use certain pressure, also just cannot avoid corresponding shortcoming.
Have employed new route in CN103180306A, not only do not avoid pressurized catalysis hydrogenation, and reactions steps is more loaded down with trivial details, also need to use price dimethyl tertiary butyl silicon ether costly, cause this route reaction cycle long, cost is high, and product yield is low.
Although CN104140410A, CN103787942A disclose the process adopting palladium carbon normal pressure catalyzed reaction to prepare Lubiprostone 1 intermediate for 2 hours, the method for carrying out shortening under normal pressure using hydrogen as hydrogen source is difficult to transform completely.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of method preparing Lubiprostone 1 is newly provided.The present inventor is through research, surprising discovery, this method has simple to operate, that reaction conditions is gentle, speed of reaction is high, yield is high, purity is good advantage relative to current existing catalytic hydrogenation, not only obvious Reaction time shorten and reaction time, substantially increase production efficiency, and the requirement reduced conversion unit, be more suitable for industrialization scale operation.
Technical solution of the present invention is as follows:
A preparation method for Lubiprostone 1, the method comprises following steps:
(1) Compound I is joined in alcoholic solvent, and under protection of inert gas, add catalyzer, then add triethyl silicane stirring reaction;
And optionally,
(2) filter after completion of the reaction, filtrate is concentrated obtains Lubiprostone 1;
Reaction scheme is as follows:
Wherein, R 1, R 2independently can be selected from hydrogen, substituted or unsubstituted benzyl, and R 1and R 2be asynchronously hydrogen; Preferably, in a technical scheme of the present invention, R 1for benzyl, R 2for hydrogen;
Described alcoholic solvent be selected from methyl alcohol, ethanol, Virahol one or more;
Institute's rare gas element is selected from nitrogen, argon gas, helium, preferred nitrogen;
Described catalyzer is selected from palladium carbon, palladium hydroxide, Palladous chloride, and in invention, catalyzer can directly add in reaction, adds after a small amount of alcoholic solvent also can be used to dilute;
The mol ratio of described Compound I and triethyl silicane is 1:2 ~ 10; Be preferably 1:3 ~ 6, most preferably 1:4;
Described temperature of reaction be-40 DEG C to solvent boiling point, preferably-20 ~ 40 DEG C, more preferably 15 ~ 30 DEG C, most preferably 20 ~ 25 DEG C or 25 ~ 30 DEG C;
The stirring reaction time of step (1) is 10 ~ 40 minutes, preferably 20 ~ 30 minutes.
In a technical scheme of the present invention, the preparation method of Lubiprostone 1 comprises the following steps:
(1) Compound I is joined in alcoholic solvent, and stirring reaction add catalyzer, triethyl silicane under protection of inert gas after;
(2) filter after completion of the reaction, filtrate concentrates, and adds acetic acid ethyl dissolution condensate residue, and one or both selecting in saturated sodium carbonate solution, saturated nacl aqueous solution wash, and after dry, concentrated evaporate to dryness obtains Lubiprostone 1.
In the present invention, the application of triethyl silicane makes reaction efficiency greatly promote, and does not need to carry out pressure hydration again, but make use of triethyl silicane as hydrogen source, and its boiling point is at 108 DEG C, active high, improves reaction yield.
It is as follows that triethyl silicane carries out transfer catalysis Germane:
First be reaction substrate in conjunction with two protons, obtain intermediate state, proton by system water extraction supply.Then triethyl silicane provides two negative hydrogen, and middle figure is converted into product, and triethyl silicane becomes triethyl silanol.
Present invention utilizes the difference of catalytic hydrogenation and transfer catalysis hydrogenation, employ different hydrogen sources, make product reaction efficiency and purity have large increase.Catalytic hydrogenation is generally be that hydrogen source carries out catalytic hydrogenation with hydrogen in autoclave, and transfer catalysis hydrogenation carries out catalytic hydrogenation using other hydrogen donors containing negative hydrogen as hydrogen source at ambient pressure.The advantage of transfer catalysis hydrogenation is without high pressure hydrogen, safety; Simultaneously not high to equipment requirements, and the hydrogen source used is cheap and easy to get.
It is pointed out that in the present invention, Compound I refers to the compound shown in formula I.As do not made specified otherwise, the consumption of described reaction solvent and related reagent is the conventional amount used of reaction, and those skilled in the art can determine according to prior art; The reagent that the present invention uses is conventional reagent, can be bought by market and obtain, starting raw material used and reactant all can be prepared by prior art or disclosed existing document, compound (Z)-7-[(1R, 2R, 3R)-2-(4,4-bis-fluoro-3-oxo octyl group)-3-hydroxyl-5-oxocyclopentyl] enanthic acid-5-alkene benzyl ester can from Shanghai Tianwei Biological Pharmaceutical Corp. buy obtain, triethyl silicane can from Zhejiang Hutu Silicon Co., Ltd buy obtain.
Prepare Lubiprostone 1 by technical solution of the present invention, there is following advantage: (1) reaction times is short, within tens minutes, just complete reaction; (2) reaction yield is high, can reach 95 ~ 100%; (3) reaction conditions is gentle, does not need pressurized catalysis hydrogenation, low for equipment requirements.
Embodiment
Below by way of concrete embodiment, foregoing of the present invention is described in further detail, but this should be interpreted as any restriction the present invention being protected to theme.All technical schemes realized based on foregoing of the present invention all belong to scope of the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.It will be apparent to those skilled in the art that hereinafter, if not specified, the operation that the present invention carries out carries out under the room temperature condition of this area routine, and described room temperature has art-recognized meanings well known in the art, generally refers to 20 ~ 35 DEG C, preferably 20 ~ 30 DEG C.
Instrument of the present invention and method:
(1) high resolution mass spectrum
INSTRUMENT MODEL: Q-Tofmicro mass spectrograph.
Test condition: ESI (electron spray(ES)).
Embodiment 1:
Under room temperature condition; 0.5g (Z)-7-[(1R is added in reaction flask; 2R; 3R)-2-(4; 4-bis-fluoro-3-oxo octyl group)-3-hydroxyl-5-oxocyclopentyl] enanthic acid-5-alkene benzyl ester and 10ml methyl alcohol, add the 10%Pd/C (50%H of 0.1g under nitrogen protection 2o), use 10ml methanol dilution 0.7g triethyl silicane wiring solution-forming again, by in its slowly instillation reaction flask, dropwise, keep 15 ~ 25 DEG C of thermotonuses 10 minutes, cross and filter palladium carbon, 20ml ethyl acetate is added after concentration of reaction solution, with the washing of 20ml saturated sodium-chloride, anhydrous sodium sulfate drying organic layer, it is oily matter that filtrate concentrates evaporate to dryness, obtains Lubiprostone 1.Weigh 0.39g, yield 97.5%, product purity 98.12%.
MS(m/z):389.46(M-1).
Embodiment 2:
Under room temperature condition; 0.5g (Z)-7-[(1R is added in reaction flask; 2R; 3R)-2-(4; 4-bis-fluoro-3-oxo octyl group)-3-hydroxyl-5-oxocyclopentyl] enanthic acid-5-alkene benzyl ester and 10ml ethanol, add the 10%Pd/C (50%H of 0.1g under nitrogen protection 2o), then use 10ml alcohol dilution 0.7g triethyl silicane wiring solution-forming, by its slowly instillation reaction flask, dropwise, react 30 minutes at keeping 15 ~ 25 DEG C, cross and filter palladium carbon, 20ml ethyl acetate is added after concentration of reaction solution, with the washing of 20ml saturated sodium-chloride, anhydrous sodium sulfate drying organic layer, filters, removing siccative, filtrate concentrates the oily matter of evaporate to dryness, and weigh 0.39g, yield 97.5%.Product purity 98.05%.
Embodiment 3:
By 0.5g (Z)-7-[(1R, 2R, 3R)-2-(4, 4-bis-fluoro-3-oxo octyl group)-3-hydroxyl-5-oxocyclopentyl] enanthic acid-5-alkene benzyl ester joins in methyl alcohol, stir entirely molten, palladium hydroxide is added under nitrogen protection, 0.7g triethyl silicane is joined in 10mL and dilutes in methyl alcohol, then drop in above-mentioned solution, within 10 ~ 15 minutes, drip and finish, then react 30 minutes at 20 ~ 25 DEG C, cross and filter palladium hydroxide, 20mL ethyl acetate is added after concentration of reaction solution, the saturated sodium bicarbonate solution of 20mL and 20mL saturated sodium-chloride is used to wash once, anhydrous sodium sulfate drying.Filter, after removing siccative, filtrate is concentrated obtains Lubiprostone 1, and weigh 0.375g, yield 93.8%, product purity 97.93%.
Embodiment 4:
By 0.8g (Z)-7-[(1R, 2R, 3R)-2-(4, 4-bis-fluoro-3-oxo octyl group)-3-hydroxyl-5-oxocyclopentyl] enanthic acid-5-alkene benzyl ester joins in methyl alcohol, stirring and dissolving, palladium hydroxide is added under nitrogen protection, 1g triethyl silicane is joined in 10mL methyl alcohol and dilutes, then drop in above-mentioned solution, within 10 ~ 15 minutes, drip and finish, then react 20 minutes at 25 ~ 30 DEG C, filter, removing palladium hydroxide, 30mL ethyl acetate is added after concentration of reaction solution, the saturated sodium bicarbonate of 20mL and 20mL saturated nacl aqueous solution is used to wash once successively, anhydrous sodium sulfate drying.Filter, after removing siccative, filtrate is concentrated obtains Lubiprostone 1, and weigh 0.631g, yield 96.6%, product purity 97.54%.
Embodiment 5:
By 0.279g (Z)-7-[(1R, 2R, 3R)-2-(4, 4-bis-fluoro-3-oxo octyl group)-3-hydroxyl-5-oxocyclopentyl] enanthic acid-5-alkene benzyl ester joins in 5mL ethanol, stirring and dissolving, palladium hydroxide is added under nitrogen protection, after 0.33g triethyl silicane being added the alcohol dilution of 5mL, drop in above-mentioned solution, within 10 ~ 15 minutes, drip and finish, then react 30 minutes at 20 ~ 25 DEG C, filter, removing palladium hydroxide, 10mL ethyl acetate is added after concentration of reaction solution, the saturated sodium bicarbonate solution of 10mL and the saturated nacl aqueous solution of 10mL is used to wash once successively, anhydrous sodium sulfate drying.Filter, after removing siccative, filtrate is concentrated obtains Lubiprostone 1, and weigh 0.219g, yield 96.0%, product purity 97.93%.
Embodiment 6:
By 0.5g (Z)-7-[(1R; 2R; 3R)-2-(4; 4-bis-fluoro-3-oxo octyl group)-3-benzyloxy-5-oxocyclopentyl] enanthic acid-5-alkene benzyl ester joins in the ethanol of 4mL; stirring and dissolving; palladium hydroxide is added under nitrogen protection; 0.51g triethyl silicane is joined in the ethanol of 5mL, drops in above-mentioned solution after dilution, within 15 minutes, drip and finish; drip after finishing and react 30 minutes at 20 ~ 25 DEG C; remove palladium hydroxide after filtration, filtrate is concentrated obtains Lubiprostone 1, and weigh 0.32g; yield 94.1%, product purity 96.54%.
Embodiment 7:
By 1.0g (Z)-7-[(1R; 2R; 3R)-2-(4; 4-bis-fluoro-3-oxo octyl group)-3-benzyloxy-5-oxocyclopentyl] enanthic acid-5-alkene benzyl ester joins in the Virahol of 10mL; stirring and dissolving; palladium hydroxide is added under nitrogen protection; 1.02g triethyl silicane is joined in the Virahol of 10mL, drops in above-mentioned solution after dilution, within 15 minutes, drip and finish; drip after finishing and react 40 minutes at 20 ~ 25 DEG C; remove palladium hydroxide after filtration, filtrate is concentrated obtains Lubiprostone 1 crude product, and weigh 0.68g; yield 97.1%, product purity 97.26%.
Comparative example 1: carry out with reference to US2010056807
By 0.814g (Z)-7-[(1R, 2R, 3R)-2-(4; 4-bis-fluoro-3-oxo octyl group)-3-hydroxyl-5-oxocyclopentyl] enanthic acid-5-alkene benzyl ester joins in 90% ethanol of 50mL, and stirring and dissolving, under nitrogen protection; add 0.2g palladium hydroxide, after nitrogen replacement, pass into hydrogen, after compressive reaction 8h; filter; removing palladium hydroxide charcoal, filtrate is concentrated obtains Lubiprostone 1 crude product, and weigh 0.642g; yield 86.1%, purity 89.08%.
Can find out, adopt alcoholic solvent, with hydrogen as hydrogen source, catalysis pressure hydration, long reaction time, products obtained therefrom purity is low, and impurity is many, causes product yield to reduce.
Comparative example 2: adopt tetrahydrofuran (THF) as solvent
By 0.243g (Z)-7-[(1R, 2R, 3R)-2-(4, 4-bis-fluoro-3-oxo octyl group)-3-hydroxyl-5-oxocyclopentyl] enanthic acid-5-alkene benzyl ester joins in 5L tetrahydrofuran (THF), stirring and dissolving, palladium hydroxide is added under nitrogen protection, 0.3g triethyl silicane is joined in the tetrahydrofuran (THF) of 5mL, drop in above-mentioned solution after dilution, within 10 minutes, drip and finish, dropping process produces a large amount of bubble, drip after finishing and react 30 minutes at 20 ~ 25 DEG C, cross and filter palladium hydroxide charcoal, 10mL ethyl acetate is added after concentration of reaction solution, the saturated sodium bicarbonate solution of 10mL and the saturated nacl aqueous solution of 10mL is used to wash once successively, anhydrous sodium sulfate drying.Filter, after removing siccative, filtrate is concentrated obtains Lubiprostone 1, and weigh 0.172g, yield 86.9%, product purity 67.91%.
Can find out, although still adopt triethyl silicane as hydrogen source, the hydrogenation of normal pressure transfer catalysis, solvent have employed tetrahydrofuran (THF), makes yield and purity all lower, infers in radical reduction process, create other side reactions.
The present invention adopts alcoholic solvent, and provide two negative hydrogen in conjunction with triethyl silicane as hydrogen source, palladium carbon or palladium hydroxide are as catalyzer normal pressure hydrogenation, the reaction times is made to shorten to 10 ~ 40 minutes by more than 2 hours of prior art, product purity has had large increase, low for equipment requirements, simple to operate, be very applicable to large-scale industrial production.

Claims (8)

1. a preparation method for Lubiprostone 1, the method comprises following steps:
(1) Compound I is joined in alcoholic solvent, and under protection of inert gas, add catalyzer, then add triethyl silicane stirring reaction; And optionally,
(2) filter after completion of the reaction, filtrate is concentrated obtains Lubiprostone 1;
Reaction scheme is as follows:
Wherein, R 1, R 2independently can be selected from hydrogen, substituted or unsubstituted benzyl, and R 1and R 2be asynchronously hydrogen;
Described alcoholic solvent be selected from methyl alcohol, ethanol, Virahol one or more;
Institute's rare gas element is selected from nitrogen, argon gas, helium;
Described catalyzer is selected from palladium carbon, palladium hydroxide, Palladous chloride;
The mol ratio of described Compound I and triethyl silicane is 1:2 ~ 10;
Described temperature of reaction be-40 DEG C to solvent boiling point;
The described stirring reaction time is 10 ~ 40 minutes.
2. preparation method according to claim 1, the mol ratio of described Compound I and triethyl silicane is 1:3 ~ 6.
3. preparation method according to claim 1, described temperature of reaction is-20 ~ 40 DEG C.
4. preparation method according to claim 1, the described stirring reaction time is 20 ~ 30 minutes.
5. the preparation method according to claim 1 or 2 or 3 or 4, the mol ratio of described Compound I and triethyl silicane is 1:4.
6. the preparation method according to claim 1 or 2 or 3 or 4, described temperature of reaction is 15 ~ 30 DEG C.
7. the preparation method according to claim 1 or 2 or 3 or 4, described temperature of reaction is 20 ~ 25 DEG C or 25 ~ 30 DEG C.
8. preparation method according to claim 1, comprises the steps:
(1) Compound I is joined in alcoholic solvent, and stirring reaction add catalyzer, triethyl silicane under protection of inert gas after;
(2) filter after completion of the reaction, filtrate concentrates, and adds acetic acid ethyl dissolution condensate residue, and one or both selecting in saturated sodium carbonate solution, saturated nacl aqueous solution wash, and after dry, concentrated evaporate to dryness obtains Lubiprostone 1.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105753867A (en) * 2016-03-24 2016-07-13 齐鲁制药有限公司 Preparation method of improved avibactam sodium intermediate compound
CN110713477A (en) * 2018-07-13 2020-01-21 佳和桂科技股份有限公司 Process for preparing LUBIPROSTONE (lubiprosone) and intermediates thereof
CN110713478A (en) * 2018-07-13 2020-01-21 佳和桂科技股份有限公司 Lubiprostone (lubiprosone) crystal and preparation method thereof
CN111943950A (en) * 2020-09-10 2020-11-17 山东安信制药有限公司 Preparation method of rilibatan

Citations (1)

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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

Patent Citations (1)

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CN1206997C (en) * 1997-11-28 2005-06-22 株式会社·R-技术上野 Endothelin antagonist

Non-Patent Citations (1)

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Title
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105753867A (en) * 2016-03-24 2016-07-13 齐鲁制药有限公司 Preparation method of improved avibactam sodium intermediate compound
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
CN110713477A (en) * 2018-07-13 2020-01-21 佳和桂科技股份有限公司 Process for preparing LUBIPROSTONE (lubiprosone) and intermediates thereof
CN110713478A (en) * 2018-07-13 2020-01-21 佳和桂科技股份有限公司 Lubiprostone (lubiprosone) crystal and preparation method thereof
CN110713477B (en) * 2018-07-13 2023-06-02 佳和桂科技股份有限公司 Preparation method of LUBIPROSTONE (LUBIPROSTONE) and intermediate thereof
CN111943950A (en) * 2020-09-10 2020-11-17 山东安信制药有限公司 Preparation method of rilibatan

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