CN107573310A - A kind of preparation method of Ke Linei esterdiols - Google Patents
A kind of preparation method of Ke Linei esterdiols Download PDFInfo
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Abstract
The present invention provides a kind of preparation method of Ke Linei esterdiols, is related to a kind of synthesis technical field of alcohol.The invention comprising following step by being prepared：Cyclopentadiene and dichloroacetyl chloride are raw material, and the pungent ketone of 6 alkene 3 of 2 oxabicyclos [3.3.0] is made through being cyclized, reducing and aoxidizing the reaction of 3 steps；The pungent ketone of 6 alkene 3 of 2 oxabicyclos [3.3.0] is split through basic resolving agent R (+) phenyl ethylamine (PEA), obtains the pungent ketone of 6 alkene 3 of oxabicyclo [3.3.0] of optically active compound (1S, 5R) 2；The pungent ketone of 6 alkene 3 of (1S, 5R) 2 oxabicyclo [3.3.0] has synthesized pungent 3 ketone of oxabicyclo [3.3.0] of 7 hydroxyl of (1S, 5R, 6R, 7R) methylol 2 with paraformaldehyde through regioselectivity Prins reactions, direct hydrolysis.The present invention is simple and easy to do, easily operated, is advantageous to industrialized production.
Description
Technical field
The present invention relates to a kind of synthesis technical field of alcohol, more particularly to a kind of preparation method of Ke Linei esterdiols.
Background technology
Prostaglandin (prostaglandins, PGs) is a kind of important endogenous physiological bioactive natural product, and it is to life
Growing system, nervous system, respiratory system, internal system etc. has effect.Pass through the research to natural prostaglandins and structure
Transformation, has synthesized the quite varied prostanoid medicine of large quantities of purposes, wherein the FP receptor agonisms for treating glaucoma
Agent is one of study hotspot in recent years.The anti-glaucoma medicine listed at present has Latanoprost, travoprost, Bei Meiqian
Arrange element, tafluprost etc..Prostaglandin medicine chiral centre is numerous, and synthetic route is tediously long.Due to natural prostaglandins source
Less, its chemical synthesis is particularly important.Ke Linei esterdiols, chemical name：(1S, 5R, 6R, 7R) -6- methylol -7- hydroxyls
Base -2- oxabicyclos [3.3.0] octyl- 3- ketone, it is the versatile intermediates of synthesis of prostaglandins, obtains in pharmaceuticals industry and extensively should
With.Compound (1S, 5R, 6R, 7R) -6- methylols -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone on domestic market
Main or dependence import, it is expensive.So far, prepare compound (1S, 5R, 6R, 7R) -6- methylol -7- hydroxyls -2-
The literature procedure of oxabicyclo [3.3.0] octyl- 3- ketone mainly has two kinds：(1) with (1S, 5R) -2- oxabicyclos [3.3.0]
Octyl- 6-3- ketone is raw material, hydrolyzes and is made after Prins (Pu Linsi) reactions with paraformaldehyde；(2) using L- fructose as raw material,
It is made by a series of conversions.Prins reactions are classical reactions, and reaction mechanism understands, favorable reproducibility.But compound (1S,
5R) -2- oxabicyclos [3.3.0] octyl- 6-3- ketone is difficult to obtain from domestic market.Document report prepare compound (1S, 5R)-
The method of 2- oxabicyclos [3.3.0] octyl- 6-3- ketone is mainly divided to two classes：(1) racemate resolution method；(2) dissymmetric synthesis.
But the raw material and chiral reagent used in both approaches are expensive, severe reaction conditions, it is difficult to industrialized production.
The content of the invention
Weak point present in topic is watched for above-mentioned, the present invention provides a kind of preparation method of Ke Linei esterdiols, made
Its simple synthetic method is easy, is advantageous to industrialized production Ke Linei esterdiols.
In order to solve the above problems, the present invention provides a kind of preparation method of Ke Linei esterdiols, wherein, methods described bag
Include following steps：
The synthesis of S10,2- oxabicyclo [3.3.0] oct-6-ene -3- ketone：Cyclopentadiene, dichloroacetyl chloride and n-hexane warp
2- oxabicyclo [3.3.0] oct-6-ene -3- ketone is made in cyclisation, reduction and three steps of oxidation；
The fractionation of S20,2- oxabicyclo [3.3.0] oct-6-ene -3- ketone：Containing 2- oxabicyclos [3.3.0] octyl- 6-
Sodium hydrate aqueous solution is instilled in the there-necked flask of alkene -3- ketone, tetrahydrofuran and distilled water, after stirring, removing tetrahydrofuran under reduced pressure
Ethyl acetate is added, reaction solution acidifying, layering, aqueous layer with ethyl acetate extraction 4 times, the extract solution is scrubbed, is added after drying
R- (+)-phenyl ethylamine, stirring, stands overnight, and filters, filter residue is dissolved in hot ethyl acetate, is filtered to remove oxalates, concentrates, slightly
Salt twice, obtains (1R, the 2s) -2- hydroxyls-amyl- 4- alkene -1- acetic acid R- (+) of ring-phenyl ethylamine salt with re-crystallizing in ethyl acetate, by benzene second
Amine salt is dissolved in sodium hydrate aqueous solution, and with extracted by ether twice, aqueous phase is neutralized with concentration aqueous hydrochloric acid solution, is concentrated under reduced pressure, residual
Excess with extracted by ether twice, dry, and removes solvent under reduced pressure and obtains white solid (1S, 5R) -2- oxabicyclos by anhydrous magnesium sulfate
[3.3.0] oct-6-ene -3- ketone；
The synthesis of S30, (1S, 5R, 6R, 7R)-methylol -7- hydroxyls _ 2- oxabicyclos [3.3.0] octyl- 3- ketone：Water-bath adds
Heat is delayed containing (1S, 5R) -2- oxabicyclos [3.3.0] oct-6-ene -3- ketone, paraformaldehyde, the there-necked flask of glacial acetic acid mixed liquor
It is slow that the concentrated sulfuric acid is added dropwise, heat up, stir, after 24h, cooling, neutralized with natrium carbonicum calcinatum, remove glacial acetic acid under reduced pressure, residue is dissolved in
Dichloromethane, washing, remove solvent under reduced pressure after drying, obtain crude product (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos
[3.3.0] octyl- 3- ketone, by crude product ((1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos [3.3.0] the octyl- 3- ketone
Hydrolysis obtains final product (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone.
Preferably, in the step S10, the process of the cyclisation is：Add cyclopentadiene, dichloroacetyl in three-necked flask
Chlorine and n-hexane, by adding the mixture of triethylamine and n-hexane after stirring, cryosel cooling, filter cake is used after stirring, filtering
N-hexane is rinsed, and merging filtrate and washing lotion, residual liquid is evaporated under reduced pressure after removing solvent under reduced pressure, and collection cut obtains colourless
Liquid 7, bicyclic [3.2.0] hept-2-ene" -6- ketone of 7- dichloros.
Preferably, in the step S10, the reduction process is specially：Dichloro is bicyclic to be added drop-wise to acetic acid mixture
Stirring plus acetic acid in flask containing Zn powder and acetate mixture, after the temperature-fall period again that heats up plus absolute ether stirs, and takes out
Filter out Zn powder, standing is separated after organic phase except acetic acid, regulation ph separate ether layer, be dried, filter, depressurize after be evaporated off it is anhydrous
Ether, in vacuum fractionation, collect its cut and obtain bicyclic [3.2.0] hept-2-ene" -6- ketone of colourless liquid.
Preferably, in the step S30, crude product (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos
[3.3.0] octyl- 3- ketone hydrolytic processes are：52.4g crude products (1S, 5R, 6R, 7R)-methylol -7- is added in 1000mL there-necked flasks
Hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone, 524mL methanol and 20mL concentrated hydrochloric acids, are heated to reflux 4h, reaction solution ice salt bath
After being cooled to 0 DEG C, pH=4.0 is neutralized to saturated sodium bicarbonate solution, is concentrated under reduced pressure, residue is dissolved by heating with chloroform, heat
Filtering, after filtrate lets cool, white crystal is separated out, filtering is dry that (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxa-s are double
Ring [3.3.0] octyl- 3- ketone.
Compared with prior art, the present invention has advantages below：
The invention provides a kind of preparation method that is simple and easy to do, being advantageous to industrialized production Ke Linei esterdiols.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, the present invention is made with reference to example
It is further described, but example is not as a limitation of the invention.
Embodiments of the invention comprise the following steps：
The synthesis of S10,2- oxabicyclo [3.3.0] oct-6-ene -3- ketone：Cyclopentadiene, dichloroacetyl chloride and n-hexane warp
2- oxabicyclo [3.3.0] oct-6-ene -3- ketone is made in cyclisation, reduction and three steps of oxidation；
S101, cyclisation：Add cyclopentadiene, dichloroacetyl chloride and n-hexane in three-necked flask, after stirring, cryosel cooling
Add the mixture of triethylamine and n-hexane, filter cake is rinsed with n-hexane after stirring, filtering, merging filtrate and washing lotion, decompression
Residual liquid is evaporated under reduced pressure after solvent is evaporated off, and is collected cut and is obtained colourless liquid 7, bicyclic [3.2.0] the hept- 2- of 7- dichloros
Alkene -6- ketone；
S102, reduction：Bicyclic be added drop-wise to acetic acid mixture in the flask containing Zn powder and acetate mixture of dichloro is stirred
Add acetic acid, by heating up again after temperature-fall period plus absolute ether stirring, suction filtration remove Zn powder, standing separate remove after organic phase acetic acid,
Regulation ph separate ether layer, be dried, filter, depressurize after absolute ether is evaporated off, in vacuum fractionation, collect its cut and obtain nothing
Bicyclic [3.2.0] hept-2-ene" -6- ketone of color liquid；
It is S103, bicyclic：[3.2.0] hept-2-ene" -6- ketone is by aoxidizing generation 2- oxabicyclo [3.3.0] oct-6-enes -3-
Ketone
The fractionation of S20,2- oxabicyclo [3.3.0] oct-6-ene -3- ketone：124.1g is added in 5000mL there-necked flasks
(1.0mol) 2- oxabicyclos [3.3.0] oct-6-ene -3- ketone, 720mL tetrahydrofurans, 510mL distilled water, are slowly instilled at 0 DEG C
750mL concentration is 2.0mol/L (1.5mol) sodium hydrate aqueous solution.4h is stirred at room temperature in reaction solution, removes tetrahydrochysene furan under reduced pressure
Mutter.Add 1200mL ethyl acetate.Reactant mixture is acidified to H=3.0 with the saturated oxalic acid aqueous solution, layering, water layer acetic acid
Ethyl ester extracts 4 times.Mixing acetic acid ethyl acetate extract is washed with saturated sodium-chloride water solution, and anhydrous magnesium sulfate is dried.To acetic acid second
160mL (150.4g, 1.24mol) R- (+)-phenyl ethylamine is added in ester extract solution, 30min is stirred, stands overnight, is filtered.Will filter
Slag is dissolved in 10L hot ethyl acetates, is filtered to remove oxalates, concentration.Crude salt twice, obtained with re-crystallizing in ethyl acetate (1R, 2s)-
The amyl- 4- alkene -1- acetic acid R- (+) of 2- hydroxyls-ring-phenyl ethylamine salt 94.5g.It is 1.0mol/L that phenyl ethylamine salt is dissolved in into 430mL concentration
In the sodium hydrate aqueous solution of (0.43mol), with extracted by ether twice.In the aqueous hydrochloric acid solution that aqueous phase is 2.0mol/L with concentration
With to pH=3.0, it is concentrated under reduced pressure, residue with 200mL extracted by ether twice, dry, and removes solvent under reduced pressure and obtains by anhydrous magnesium sulfate
White solid (1S, 5R) -2- oxabicyclos [3.3.0] oct-6-ene -3- ketone 42.6g.
S30, (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone synthesis：
Added in 500mL there-necked flasks 19.3g paraformaldehydes, 24.8g (0.2mol) (1S, 5R) -2- oxabicyclos [3.3.0] oct-6-ene -
The 6.5mL concentrated sulfuric acids are slowly added dropwise to 50 DEG C in 3- ketone, 193mL glacial acetic acid, heating water bath, and control rate of addition makes reacting liquid temperature
Below 60 DEG C.Finish, be warming up to 75~80 DEG C and continue to stir 24h.Room temperature is cooled to, pH=is neutralized to natrium carbonicum calcinatum
5.0.Removing glacial acetic acid under reduced pressure, residue is dissolved in 300mL dichloromethane, and successively with saturated sodium bicarbonate aqueous solution, saturation
Sodium-chloride water solution and distillation water washing, are dried with anhydrous magnesium sulfate.Remove solvent under reduced pressure, obtain crude product (1S, 5R, 6R, 7R)-hydroxyl
Methyl -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone 52.4g.Added in 1000mL there-necked flasks 52.4g crude products (1S,
5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone, 524mL methanol and 20mL concentrated hydrochloric acids, are heated back
Flow 4h.After reaction solution is cooled to 0 DEG C with ice salt bath, pH=4.0 is neutralized to saturated sodium bicarbonate solution, is concentrated under reduced pressure.It is remaining
Thing is dissolved by heating with chloroform, heat filtering, after filtrate lets cool, separates out white crystal, filtering, dry (1S, 5R, 6R, 7R)-hydroxyl first
Base -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone 26.3g, yield 76.5%.
The foregoing description of the disclosed embodiments, professional and technical personnel in the field are enable to realize or using the present invention.
A variety of modifications to these embodiments will be apparent for those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, it is of the invention
The embodiments shown herein is not intended to be limited to, and is to fit to and principles disclosed herein and features of novelty phase one
The most wide scope caused.
Claims (4)
1. a kind of preparation method of Ke Linei esterdiols, it is characterised in that the described method comprises the following steps：
The synthesis of S10,2- oxabicyclo [3.3.0] oct-6-ene -3- ketone：Cyclopentadiene, dichloroacetyl chloride and n-hexane are through ring
Change, 2- oxabicyclo [3.3.0] oct-6-ene -3- ketone is made in reduction and three steps of oxidation；
The fractionation of S20,2- oxabicyclo [3.3.0] oct-6-ene -3- ketone：Containing 2- oxabicyclos [3.3.0] oct-6-ene -3-
Instill sodium hydrate aqueous solution in the there-necked flask of ketone, tetrahydrofuran and distilled water, stir, remove tetrahydrofuran under reduced pressure after add second
Acetoacetic ester, reaction solution acidifying, layering, aqueous layer with ethyl acetate extract 4 times, the extract solution is scrubbed, dry after add R- (+)-
Phenyl ethylamine, stirring, stands overnight, and filters, filter residue is dissolved in hot ethyl acetate, is filtered to remove oxalates, concentrates, crude salt second
Acetoacetic ester recrystallizes twice, obtains (1R, the 2s) -2- hydroxyls-amyl- 4- alkene -1- acetic acid R- (+) of ring-phenyl ethylamine salt, and phenyl ethylamine salt is molten
In sodium hydrate aqueous solution, with extracted by ether twice, aqueous phase is neutralized with concentration aqueous hydrochloric acid solution, is concentrated under reduced pressure, and residue is used
Extracted by ether twice, dry, and removes solvent under reduced pressure and obtains white solid (1S, 5R) -2- oxabicyclos [3.3.0] by anhydrous magnesium sulfate
Oct-6-ene -3- ketone；
S30, (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone synthesis：Heating water bath contains
There are (1S, 5R) -2- oxabicyclos [3.3.0] oct-6-ene -3- ketone, paraformaldehyde, the there-necked flask of glacial acetic acid mixed liquor, slowly drop
Enriching sulfuric acid, heat up, stir, after 24h, cooling, neutralized with natrium carbonicum calcinatum, remove glacial acetic acid under reduced pressure, residue is dissolved in dichloro
Methane, washing, remove solvent under reduced pressure after drying, obtain crude product (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos
[3.3.0] octyl- 3- ketone, by the crude product (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone water
Solution obtains final product (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone.
2. the preparation method of Ke Linei esterdiols as claimed in claim 1, it is characterised in that described in the step S10
The process of cyclisation is：Add cyclopentadiene, dichloroacetyl chloride and n-hexane in three-necked flask, by adding three after stirring, cryosel cooling
The mixture of ethamine and n-hexane, filter cake is rinsed with n-hexane after stirring, filtering, and merging filtrate and washing lotion, is removed under reduced pressure
Residual liquid is evaporated under reduced pressure after solvent, is collected cut and is obtained colourless liquid 7, bicyclic [3.2.0] hept-2-ene" -6- of 7- dichloros
Ketone.
3. the preparation method of Ke Linei esterdiols as claimed in claim 1, it is characterised in that described in the step S10
Reduction process is specially：Dichloro is bicyclic to be added drop-wise to stirring plus second in the flask containing Zn powder and acetate mixture with acetic acid mixture
Acid, after heating again temperature-fall period plus absolute ether stirring, suction filtration remove Zn powder, and standing removes acetic acid, regulation after separating organic phase
Ph separates ether layer, be dried, filter, depressurize after absolute ether is evaporated off, in vacuum fractionation, collect its cut and obtain colourless liquid
Bicyclic [3.2.0] hept-2-ene" -6- ketone of body.
4. the preparation method of Ke Linei esterdiols as claimed in claim 1, it is characterised in that in the step S30, crude product
(1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone hydrolytic processes are：In 1000mL there-necked flasks
Middle addition 52.4g crude products (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone, 524mL methanol
With 20mL concentrated hydrochloric acids, 4h is heated to reflux, after reaction solution is cooled to 0 degree with ice salt bath, pH is neutralized to saturated sodium bicarbonate solution
=4.0, it is concentrated under reduced pressure, residue is dissolved by heating with chloroform, heat filtering, after filtrate lets cool, is separated out white crystal, is filtered, dries
Obtain (1S, 5R, 6R, 7R)-methylol -7- hydroxyl -2- oxabicyclos [3.3.0] octyl- 3- ketone.
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Cited By (4)
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| CN108546258A (en) * | 2018-04-10 | 2018-09-18 | 厦门欧瑞捷生物科技有限公司 | A kind of method that simple and effective synthesizes esterdiol in Corey |
| CN113480506A (en) * | 2021-06-23 | 2021-10-08 | 四川大学 | Preparation method of corey lactone diol |
| CN115010686A (en) * | 2022-05-30 | 2022-09-06 | 南京工业大学 | Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-ene-3-ketone |
| CN115745764A (en) * | 2022-12-08 | 2023-03-07 | 重庆华森制药股份有限公司 | Preparation method of milobalin intermediate |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108546258A (en) * | 2018-04-10 | 2018-09-18 | 厦门欧瑞捷生物科技有限公司 | A kind of method that simple and effective synthesizes esterdiol in Corey |
| CN108546258B (en) * | 2018-04-10 | 2019-02-26 | 厦门欧瑞捷生物科技有限公司 | A kind of method that simple and effective synthesizes esterdiol in Corey |
| CN113480506A (en) * | 2021-06-23 | 2021-10-08 | 四川大学 | Preparation method of corey lactone diol |
| CN115010686A (en) * | 2022-05-30 | 2022-09-06 | 南京工业大学 | Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-ene-3-ketone |
| CN115745764A (en) * | 2022-12-08 | 2023-03-07 | 重庆华森制药股份有限公司 | Preparation method of milobalin intermediate |
| CN115745764B (en) * | 2022-12-08 | 2024-03-12 | 重庆华森制药股份有限公司 | Preparation method of milbelin intermediate |
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Application publication date: 20180112 |