CN109761942A - A kind of synthetic method of Ke Linei esterdiol - Google Patents
A kind of synthetic method of Ke Linei esterdiol Download PDFInfo
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- CN109761942A CN109761942A CN201711097494.XA CN201711097494A CN109761942A CN 109761942 A CN109761942 A CN 109761942A CN 201711097494 A CN201711097494 A CN 201711097494A CN 109761942 A CN109761942 A CN 109761942A
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Abstract
The invention discloses the synthetic methods of Ke Linei esterdiol ((-)-Corey lactone diol) a kind of, synthetic method of the invention is to obtain target product through depolymerization, cyclisation, oxidation, dechlorination, open loop, fractionation, Prins reaction, hydrolysis using dicyclopentadiene as raw material.Synthetic route disclosed by the invention, raw material economics split high-efficient, suitable industrial production.
Description
Technical field
The invention belongs to medical synthesis technical fields, are related to the chemical synthesis process of prostaglandin drug key intermediate,
More particularly to the synthetic method of Ke Linei esterdiol ((-)-Corey lactone diol) a kind of.
Background technique
Ke Linei esterdiol is the key intermediate of synthesis of prostaglandins drug, prostaglandin (prostaglandins,
Write a Chinese character in simplified form are as follows: PGs) it is a kind of important there is the active endogenous natural products of multi-biological；Prostanoid is one
Race contains pentacyclic 20 carbon unsaturated hydroxyl fatty acid, its parent is forefront alkanoic acid, to respiratory system, gastrointestinal tract, painstaking effort
The aggregation of guard system and blood platelet has certain influence；Also there is anti-disease, hypnosis, anti-inflammatory and anti-tumor activity.As natural
Endogenous product, PGs is smaller to the toxicity of human body, and various physiological actions can be played when micro.Therefore,
It is attracted wide attention in terms of chemistry, medicine, pharmacy and biology.This is caused widely in biochemistry, pharmaceutical field
Pay attention to.Since natural prostaglandins class compound source is less, chemical synthesis is particularly important, prostaglandin compounds
Contain multiple asymmetric carbon atoms on the five-membered ring of object, controls each chiral centre configuration, stereoselective syntheses difficulty is larger.
Lactones glycol founds in section, is the versatile intermediates of synthesis of prostaglandins class drug, and obtain in pharmaceutical industry
Relatively broad application.Now, section stands the source of lactones glycol mainly or relies on import on domestic market, so price is high
It is expensive.
According to current data it is found that lactones glycol and its derivative preparation method found in section mainly racemic modification Split Method, hand
Property starting material method and dissymmetric synthesis.
For researchers at home and abroad to the study on the synthesis of PGs more than 40 years, there are many synthetic method.Now in industrial production
Or to be synthesized as raw material based on various PGs by Ke Linei esterdiol and its derivative.And it is obtained in industrial production at present
The method of get Ke Linei esterdiol and its derivative is mainly obtained by splitting.
Current existing racemic modification Split Method synthetic method has:
(1) using dicyclopentadiene as raw material, through depolymerization, cyclisation, dechlorination, fractionation, oxidation, Prins reaction, hydrolysis etc.
Step synthesizes Ke Linei esterdiol --- (1S, 5R, 6R, 7R) -6- methylol -7- hydroxyl -2- oxabicyclo [3.3.0] octyl- 3-
Ketone.
Dichloro compound is unstable in the synthetic method, can not carry out large-scale production.
Chiral resolving agent about gamma lactone has the organic-biologicals alkali such as quinine, brucine, ephedrine, but these biologies
Alkali is at high price, it is difficult to promote the use of.
Summary of the invention
The object of the present invention is to provide a kind of synthetic methods of Ke Linei esterdiol.
Synthetic method of the invention with compound 1 (dicyclopentadiene) be raw material, through depolymerization, cyclisation, oxidation, dechlorination,
Open loop, fractionation, Prins reaction, hydrolysis obtain target product Ke Linei esterdiol.The following reaction route (A) of reaction
It is shown:
Specifically includes the following steps:
1) 1 dicyclopentadiene of compound collects fraction, obtains (1, the 3- ring of compound 2 by being heated to depolymerization, rectifying
Pentadiene)；
2) compound 2 is added in solvent, adds dichloroacetyl chloride, and catalyst is added dropwise, chemical combination is obtained after cyclization
Object 3；
3) compound 3 is added in solvent, after being added dropwise to hydrogen peroxide, then sodium hydroxide is added dropwise, obtains chemical combination through oxidation reaction
Object 4；
4) compound 4 is dissolved in solvent, and zinc powder, ammonium chloride is added, and dechlorinated reaction obtains compound 5；
5) compound 5 is added in solvent, after addition sodium hydroxide sufficiently reacts, then is adjusted under acid condition, is added dropwise chiral
Amine resolving agent, fractionation obtain compound 6；
6) paraformaldehyde and sulfuric acid are added in solvent, are heated to solid and all dissolve, then instill compound 6, carries out
After Prins reaction, sodium acetate is added, acetic anhydride back flow reaction obtains compound 7；
7) compound 7 is added in solvent, adds ion exchange resin or hydrochloric acid, obtains compound 8 through hydrolysis.
In step 1), the temperature of the heating is 175~210 DEG C；It preferably, is 180~185 DEG C.
In step 1), the heating preferably carries out under normal pressure.
In step 1), the fraction is preferably 38~42 DEG C of fractions.
In step 2), the temperature of the cyclization is 0~35 DEG C；It preferably, is 20~25 DEG C.
In step 2), time of the cyclization is 12~for 24 hours；It preferably, is 14~16h.
In step 2), the solvent is selected from one of pentane, n-hexane, normal heptane, petroleum ether etc. or a variety of；It is excellent
Selection of land is normal heptane.
In step 2), the catalyst is triethylamine.
In step 2), the compound 2, dichloroacetyl chloride, catalyst molar ratio be 1:(1~5): (1~5)；It is preferred that
Ground is 1:(1~2): (2~3).
In step 2), it is preferable that distill after cyclization, 80 DEG C of temperature, pressure: -0.095Mpa collects fraction and obtains
Compound 3；The fraction is preferably 50~54 DEG C of fractions.
In step 3), the temperature of the oxidation reaction is -30~-5 DEG C；It preferably, is -10~-5 DEG C.
In step 3), the time of the oxidation reaction is 10~16h；It preferably, is 12-14h.
In step 3), the solvent is selected from one of methanol, ethyl alcohol, propyl alcohol etc. or a variety of；It preferably, is methanol.
In step 3), the hydrogen peroxide is preferably 30% hydrogen peroxide.
In step 3), the concentration of the sodium hydroxide is preferably 5N.
In step 3), the compound 3, hydrogen peroxide, sodium hydroxide molar ratio be 1:(1~5): (1~5)；It is preferred that
Ground is 1:(1.5~3): (1~2).
In step 4), the temperature of the dechlorination reaction is 60~100 DEG C；It preferably, is 70~80 DEG C.
In step 4), the time of the dechlorination reaction is 2-6h；It preferably, is 4-5h.
In step 4), the solvent is selected from one of methanol, ethyl alcohol, propyl alcohol etc. or a variety of；It preferably, is methanol.
In step 4), the compound 4, zinc powder, ammonium chloride molar ratio be 1:(2~10): (2~10)；Preferably,
For 1:(4~6): (4~6).
In step 5), the solvent is water.
In step 5), the concentration of the sodium hydroxide is 1~4N；It preferably, is 2N.
In step 5), the acid condition is PH=3~5；It preferably, is 3.5~4.
In step 5), the temperature that the addition sodium hydroxide sufficiently reacts is 0-50 DEG C；It preferably, is 20-40 DEG C.
It is described that the time that sodium hydroxide sufficiently reacts is added as 1-3h in step 5)；It preferably, is 2h.
In step 5), the Chiral Amine includes R- (+)-α-phenylethylamine, (R)-(+)-α -1- naphthalene ethylamine, (R)-(+)-two
Luxuriant iron ethamine, one of (R)-(+)-ferrocene methylamine etc. or a variety of；It preferably, is R- (+)-α-phenylethylamine.
In step 5), the compound 5, sodium hydroxide, Chiral Amine molar ratio be 1:(1~5): (1~2)；It is preferred that
Ground is 1:(1.5~3): (1~1.5).
In step 6), the solvent is selected from acetic acid.
In step 6), compound 6 is preferably added at room temperature.
In step 6), the temperature of the Prins reaction is 60~100 DEG C；It preferably, is 70~90 DEG C.
In step 6), the time of the Prins reaction is 18~32h；Preferably, for for 24 hours.
In step 6), the temperature of the back flow reaction is 90~120 DEG C；It preferably, is 110~120 DEG C.
In step 6), the time of the back flow reaction is 4-6h；It preferably, is 5h.
In step 6), the compound 6, paraformaldehyde, acetic anhydride, sodium acetate mass ratio be 1:(0.5~5): (0.5
~5): (0.5~5)；Preferably, it is 1:(1~5): (1~5): (1~5)；It is further preferred that being 1:(0.8~2): (0.8
~2): (0.8~2).
In step 7), the temperature of the hydrolysis is 60~100 DEG C；It preferably, is 85-95 DEG C.
In step 7), the time of the hydrolysis is 2-6h；It preferably, is 4h.
In step 7), the solvent is selected from one of methanol, ethyl alcohol etc. or a variety of；It preferably, is methanol.
In step 7), the ion exchange resin refers to cationic sulfonate resin Amberlyst-15.
In step 7), the concentration of the hydrochloric acid is 12N.
In step 7), the compound 7, ion exchange resin mass ratio 1:(0.5-3)；It preferably, is 1:(1~3)；Into one
Step is 1:(0.8-1.5 preferably).Or the mass ratio of the compound 7, hydrochloric acid is 1:(1~7)；It preferably, is 1:(1-
5)；It is further preferred that being 1:(1-3).
The invention also provides the Ke Linei esterdiols as shown in compound 8 being prepared as above-mentioned synthetic method.
The beneficial effects of the present invention are: the synthetic route reaction time of the invention is short, raw material economics, and when oxidation avoids
The generation of isomer, splits high-efficient, is suitble to industrial production.
Specific embodiment
In conjunction with following specific embodiments, the present invention is described in further detail.Implement process of the invention, condition,
Experimental method etc. is among the general principles and common general knowledge in the art in addition to what is specifically mentioned below, and the present invention does not have
There is especially limitation content.
The present invention is explained in detail below with reference to specific example, so that those skilled in the art more fully Xie Benfa
Bright, specific example is only used to illustrate the technical scheme of the present invention, and does not limit the present invention in any way.
The synthesis of embodiment 1, compound 2
200g dicyclopentadiene is added in 500ml eggplant type bottle, is heated to being completely dissolved clarification under stirring, with essence
Fractional distillation column carries out rectifying, collects 38~42 DEG C of fractions and obtains 192g compound 2 (1,3- cyclopentadiene), yield 96%.
The synthesis of embodiment 2, compound 3
By 100g dichloroacetyl chloride, 103g compound 2 (1,3- cyclopentadiene) and 0.68L normal heptane are added to tetra- mouthfuls of 2L
In bottle, under mechanical stirring, it is slowly dropped into the hexane solution of triethylamine (72.4g), drop finishes, is stirred overnight at room temperature.It filters out and filters
Slag, filtrate saturated common salt water washing, anhydrous sodium sulfate is dry, low-temperature reduced-pressure distillation removal solvent, residue vacuum distillation,
50~54 DEG C of fractions are collected, 104g product Compound 3, yield 86% are obtained.
1H NMR(500MHz,CHLOROFORM-d)ppm2.58(m,1H,CH),2.82(m,1H,CH),4.07 (m,1H,
CH),4.27(m,1H,CH),6.05(m,1H,CH)。
The synthesis of embodiment 3, compound 4
100g compound 3 is added into 1L there-necked flask, methanol 150ml, water 150ml are placed in ice salt bath under stirring, are controlled
30% hydrogen peroxide 110ml is slowly added dropwise at Nei Wen -5 DEG C processed, drop finishes, then is slowly dropped into 5N sodium hydrate aqueous solution, controls interior temperature
Not higher than 30 DEG C, drop finishes, and is stirred overnight at room temperature.
Sodium sulfite is added, excessive hydrogen peroxide is quenched, hydrochloric acid tune acidity is sufficiently added after reaction, filters out in system
Salt, ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, is evaporated under reduced pressure out solvent, and residue is used
Methanol dissolution clarification, adds pentane crystallization, after sufficiently cleaning, filters out solid, obtain 479g white compound 4, yield
57%.
The synthesis of embodiment 4, compound 5
75g compound 4,1L methanol are added into 2L there-necked flask, stirring to dissolution clarification is placed in ice salt bath and cools down,
127g zinc powder and 104g ammonium chloride is added portionwise, finishes, is heated to flowing back, room temperature is down in reaction to no starting material left, is filtered
Waste residue out, mother liquor are evaporated under reduced pressure out solvent, and residue is dissolved by heating with methylene chloride, extract insoluble matter out, and filtrate decompression distills out
Solvent obtains 47g compound 5, yield 97%.
1H NMR(400MHz,CHLOROFORM-d)ppm2.68-2.79(m,2H,CH),3.30-3.37(m,1H, CH),
3.46-3.51 (m, 1H, CH), 3.86-3.92 (m, 1H, CH), 5.31 (m, 1H, CH), 5.79-5.81 (m, 1H, CH), 5.85-
5.88(m,1H,CH)。
The synthesis of embodiment 5, compound 6
50ml water is added into 500ml there-necked flask, 20g compound 5 stirs lower dropwise addition sodium hydroxide (5g) aqueous solution, drop
Finish, is warming up to 30 DEG C and continues after stirring 2h, be cooled to room temperature, with hydrochloric acid tune pH faintly acid, then be slowly added dropwise into 13g R- (+)-
α-phenylethylamine drips and finishes stirring 1h, is evaporated under reduced pressure out solvent, obtains benzylamine salt.
Benzylamine salt is added in ethyl acetate, is heated to being completely dissolved, is naturally cooling to room temperature, white solid is precipitated.
White solid is soluble in water, lower instillation dilute sodium hydroxide aqueous solution is stirred, adjusts PH alkalescent, then adjust PH strong acid
Property, ethyl acetate extraction, organic phase anhydrous sodium sulfate is dry, vacuum distillation removal solvent, obtains 7.6g compound 6, yield
38%, ee > 99.0%.
1H NMR(400MHz,CHLOROFORM-d)ppm 2.45(1H,d-d,J1=1.6Hz, J2=18HZ,CH),
2.71-2.81(m,3H,CH),3.49-3.54(m,1H,CH),5.12-5.15(m,1H,CH),5.57-5.60(m, 1H,CH),
5.79-5.81(m,1H,CH)。
The synthesis of embodiment 6, compound 7
5g paraformaldehyde, the 1ml concentrated sulfuric acid are added into 100ml there-necked flask, 30ml acetic acid is heated to solid and all dissolves,
After being cooled to room temperature, the acetic acid solution of compound 6 (5g) is added dropwise, drop finishes, and weak back flow reaction is for 24 hours.Add 5g sodium acetate, 5g
Acetic anhydride, back flow reaction 5h.It is down to room temperature, wet chemical tune PH=5, ethyl acetate extraction, organic phase saturated salt solution
Washing, anhydrous sodium sulfate is dry, and column chromatographs to obtain 8.694g compound 7, yield 83.7%.
The synthesis of embodiment 7, compound 8
By 2g compound 7,30ml methanol is added in 100ml there-necked flask, under stirring, hydrochloric acid 3mL is added, is heated to reflux
After 4h, reaction solution is cooled to 0 DEG C with ice salt bath, is neutralized to PH=4 with saturated sodium bicarbonate solution, and decompression distillation removes solvent,
Residue is dissolved with methylene chloride, and heat filtering goes out insoluble matter, and after filtrate is cooling, 1.1g compound as white solid 8, yield is precipitated
82.1%.
1H NMR (400MHz, DMSO) ppm 1.71-1.79 (m, 2H, CH), 2.16 (t-d, Jt=6.4Hz, Jd=
14.6Hz,1H,CH),2.38(d-d,J1=18Hz, J2=2.6Hz, 1H, CH), 2.58-2.64 (m, 1H, CH), 2.78 (d-d,
J1=18Hz, J2=10.4Hz, 1H, CH), 3.25-3.31 (m, 1H, CH), 3.36-3.42 (m, 1H, CH), 4.86 (t-d, J1
=7Hz, J4=2.3Hz, 1H, CH).
1H NMR(400MHz,DMSO+D2O) ppm 1.73-1.81 (m, 2H, CH), 2.18 (t-d, Jt=6.4Hz, J4=
14.6Hz,1H,CH),2.39(d-d,J1=18Hz, J2=2.6Hz, 1H, CH), 2.59-2.66 (m, 1H, CH), 2.80 (d-d,
J1=18Hz, J2=10.4Hz, 1H, CH), 3.27-3.33 (m, 1H, CH), 3.37-3.41 (m, 1H, CH), 3.89-3.93 (m,
1H,CH),4.89(t-d,J1=7Hz, J4=2.3Hz, 1H, CH).
Protection content of the invention is not limited to above embodiments.Without departing from the spirit and scope of the invention, originally
Field technical staff it is conceivable that variation and advantage be all included in the present invention, and be with appended claims
Protection scope.
Claims (10)
1. a kind of synthetic method of Ke Linei esterdiol, which is characterized in that using dicyclopentadiene as raw material, through depolymerization, cyclisation,
Oxidation, dechlorination, open loop, fractionation, Prins reaction, hydrolysis obtain the compound Ke Linei esterdiol.
2. a kind of synthetic method of Ke Linei esterdiol, which is characterized in that shown in the following reaction route (A) of reaction:
Specifically includes the following steps:
1) 1 dicyclopentadiene of compound collects fraction, obtains 21,3 cyclopentadiene of compound by being heated to depolymerization, rectifying；
2) compound 2 is added in solvent, adds dichloroacetyl chloride, and catalyst is added dropwise, compound 3 is obtained after cyclization；
3) compound 3 is added in solvent, after being added dropwise to hydrogen peroxide, then sodium hydroxide is added dropwise, obtains compound 4 through oxidation reaction；
4) compound 4 is dissolved in solvent, and zinc powder, ammonium chloride is added, and dechlorinated reaction obtains compound 5；
5) compound 5 is added in solvent, after addition sodium hydroxide sufficiently reacts, then is adjusted under acid condition, and Chiral Amine is added dropwise and tears open
Divide agent, fractionation obtains compound 6；
6) paraformaldehyde and sulfuric acid are added in solvent, are heated to solid and all dissolve, then instill compound 6, it is anti-carries out Prins
Ying Hou adds sodium acetate, acetic anhydride back flow reaction obtains compound 7；
7) compound 7 is added in solvent, adds ion exchange resin or hydrochloric acid, obtains compound 8 through hydrolysis.
3. synthetic method as claimed in claim 2, which is characterized in that in step 1), the temperature of the heating is 175~210
℃；The heating carries out under normal pressure；The fraction is 38~42 DEG C of fractions.
4. synthetic method as claimed in claim 2, which is characterized in that in step 2), the temperature of the cyclization is 0~35
℃；The catalyst is triethylamine；The compound 2, dichloroacetyl chloride, catalyst molar ratio be 1:(1~5): (1~5).
5. synthetic method as claimed in claim 2, which is characterized in that in step 3), the temperature of the oxidation reaction is -30
~-5 DEG C；The solvent is selected from one of methanol, ethyl alcohol, propyl alcohol or a variety of；The compound 3, hydrogen peroxide, sodium hydroxide
Molar ratio is 1:(1~5): (1~5).
6. synthetic method as claimed in claim 2, which is characterized in that in step 4), the temperature of the dechlorination reaction is 60~
100℃；The solvent is selected from one of methanol, ethyl alcohol, propyl alcohol or a variety of；The compound 4, zinc powder, ammonium chloride mole
Than for 1:(2~10): (2~10).
7. synthetic method as claimed in claim 2, which is characterized in that in step 5), the solvent is water；The addition hydrogen-oxygen
Changing the temperature that sodium sufficiently reacts is 0-50 DEG C.
8. synthetic method as claimed in claim 2, which is characterized in that in step 5), the Chiral Amine includes R- (+)-α-benzene
Ethamine, (R)-(+)-α -1- naphthalene ethylamine, (R)-(+)-ferrocene ethamine, one of (R)-(+)-ferrocene methylamine or a variety of；
The compound 5, sodium hydroxide, Chiral Amine molar ratio be 1:(1~5): (1~2).
9. synthetic method as claimed in claim 2, which is characterized in that in step 6), the temperature of Prins reaction is 60~
100℃；The temperature of the back flow reaction is 90~120 DEG C；The quality of the compound 6, paraformaldehyde, acetic anhydride, sodium acetate
Than for 1:(0.5~5): (0.5~5): (0.5~5).
10. synthetic method as claimed in claim 2, which is characterized in that in step 7), the temperature of the hydrolysis is 60~
100℃；The compound 7 and ion exchange resin mass ratio 1:(0.5~3), or with the mass ratio of hydrochloric acid be 1:(1~7).
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| CN112939911A (en) * | 2019-12-11 | 2021-06-11 | 常州工程职业技术学院 | Chiral resolution process for preparing key intermediate of levo-Corey lactone |
| 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 |
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| CN112939911A (en) * | 2019-12-11 | 2021-06-11 | 常州工程职业技术学院 | Chiral resolution process for preparing key intermediate of levo-Corey lactone |
| 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 |
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Application publication date: 20190517 |