CN105801533B - A kind of key intermediate preparing limaprost and its application - Google Patents
A kind of key intermediate preparing limaprost and its application Download PDFInfo
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- CN105801533B CN105801533B CN201410849448.0A CN201410849448A CN105801533B CN 105801533 B CN105801533 B CN 105801533B CN 201410849448 A CN201410849448 A CN 201410849448A CN 105801533 B CN105801533 B CN 105801533B
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Abstract
The present invention provides compounds shown in the key intermediate formula IV of synthesis limaprost, and utilize the route of the compound synthesis limaprost.The route has the advantages that synthesis step is few, combined coefficient is high, production cost is low etc..
Description
Technical field
The present invention relates to the field of chemical synthesis.Specifically, the present invention relates to a kind of keys for preparing limaprost
The preparation method of intermediate and the intermediate and the intermediate are preparing the application in limaprost.
Background technique
Limaprost (Limaprost) chemical name is (E) -7- [(1R, 2R, 3R) -3- hydroxyl -2- [(3S, 5S) -
(E) -3- hydroxy-5-methyl base -1- nonenyl] -5- oxocyclopentyl] -2- enanthic acid.English language Chemical title: (E) -7- [(1R, 2R,
3R)-3-hydroxy-2-[(3S,5S)-(E)-3-hydroxy-5-methyl-1-noneyl]-5-oxo cyclopentyl]-
2-heptenoic acid, structural formula are as follows:
Limaprost is the derivative of prostaglandin E1, can increase cyclic adenosine monophosphate (cAMP) content, inhibit thrombus
Plain A2 (TXA2) generates, and has the function of blood vessel dilatation, increases blood flow and inhibit platelet aggregation and stick, animal experiments show that
Nerve blood flow can be increased, improve nervous function.Clinically for improving all kinds of ischemics of Buerger's disease initiation
Symptom, such as ulcer, pain, creeping chill；And improve the subjective symptom (pain and feeling of numbness) and row of posteriority lumbar spinal stenosis
Walk ability.
The synthesis of limaprost is started with different chiral starting materials, is synthesized through different paths.Such as
US4294849；JP59128370；Tetrahedron Letters(1993),34(40),6427-30；Chemistry
The preparation method of each route is described in detail in Letters (1992), (10), the documents such as 2095-8.In addition,
CN102875586；The patent documents such as WO2014/040457, which have been made, to be partly improved, and yield is improved.
Process 1
This preparation method originates the supply of chiral raw material commercial-free, and route uses three component couling process, and operating condition is multiple
It is miscellaneous, it is more difficult to control, and three components after reaction dock product, yield is lower, and impurity is more, purifying complex.And every portion is required to
Column chromatographic isolation and purification.Industrialization is relatively difficult to achieve.It is less economical.
Process 2
This preparation process is respectively formed two side chains of α and ω using the two-part reaction of two metal reagents coupling, subsequent
The step of shortened, but the synthesis of starting material and the synthesis of side chain still have a large amount of synthesis step, increase wherein being coupled at two
The synthesis difficulty added to technology controlling and process and operates more demanding.Industrial production amplification is difficult.
Process 3:
It is starting material (having commercial offers) that this route, which is with Coreylactone diol (CAS:32233-40-2), warp
It crosses eight steps to react to obtain intermediate A, reacts to obtain limaprost using ten steps.Obtain during this four it is diastereomeric different
The mixture of structure body composition, the mixture obtain target product by column chromatography separating for several times, and combined coefficient is extremely low and purifying is tired
It is difficult.Process will use two seleno reagent of hexichol being more toxic, and experimental implementation and the feature of environmental protection are poor.
Therefore, this field needs to develop that a kind of production cost is low, and processing efficient is easy to operate, is suitble to industrialized production
Limaprost key intermediate compound, and the synthesis technology of limaprost is prepared accordingly.
Summary of the invention
The object of the present invention is to provide a kind of completely new limaprost key intermediates.
It is a further object of the present invention to provide the methods for preparing limaprost using intermediate of the invention.
In a first aspect, the present invention provides compound shown in formula IV:
In second aspect, the present invention provides the preparation method of compound shown in formula IV, the method such as following formulas institute
Show, compound shown in formula III reacted into compound shown in production IV with ester reducing agent:
In formula,
R1It is selected from: C1–C4Linear or branched alkyl group.
In a preferred embodiment, R1It is methyl.
In a particular embodiment, the ester reducing agent is selected from: diisobutyl aluminium hydride or other aluminum hydride derivatizations
The combination of reagent.
In a preferred embodiment, the ester reducing agent is diisobutyl aluminium hydride.
In a particular embodiment, at -90 DEG C~-70 DEG C, diisobutyl is hydrogenated for the reaction temperature control of the reaction
The dosage molar ratio of compound shown in aluminium and formula III is controlled in 2-4:1, preferably 3:1.
In the third aspect, the present invention provides the purposes of compound shown in formula IV, is used to prepare compound shown in Formula V:
In formula,
R2It is selected from: C1–C8Linear or branched alkyl group, trifluoromethyl, trichloromethyl and allyl.
In fourth aspect, the present invention provides the purposes of compound shown in formula IV, is used to prepare limaprost.
At the 5th aspect, the present invention provides a kind of method for preparing limaprost, the described method comprises the following steps:
(1) compound shown in formula III is reacted into compound shown in production IV with ester reducing agent；
(2) preparation formula V compound is reacted with WITTIG reagent using formula IV compound；
(3) Formula V compound is rearranged and isomery is combined to compound shown in Formula VII
With
(4) limaprost is finally prepared using compound shown in Formula VII；
In formula,
R1As defined above；
R2It is selected from: C1–C8Linear or branched alkyl group, trifluoromethyl, trichloromethyl and allyl.
In a particular embodiment, the ester reducing agent in step (1) is selected from: diisobutyl aluminium hydride or other hydrogenations
The combination of aluminium derivatization reagent.
In a preferred embodiment, the ester reducing agent is diisobutyl aluminium hydride.
In a particular embodiment, at -90 DEG C~-70 DEG C, diisobutyl hydrogenates the reaction temperature control in step (1)
The dosage molar ratio of compound shown in aluminium and formula III is controlled in 2-4:1, preferably 3:1.
In a preferred embodiment, it the described method comprises the following steps:
(1) compound shown in formula III is reacted into compound shown in production IV with ester reducing agent:
(2) compound shown in synthesis Formula V is reacted with WITTIG reagent using compound shown in formula IV:
(3) compound shown in Formula V is rearranged and isomery is combined to compound shown in Formula VII:
(4) compound shown in Formula VII splits through enzyme, hydrolyzes to form compound shown in Formula VIII:
(5) compound shown in Formula VIII reacts to form compound shown in Formula IX with silane reagent:
(6) compound shown in Formula IX reacts to form compound shown in Formula XI with compound shown in Formula X:
(7) compound shown in Formula XI forms limaprost；
In formula
R1It is selected from: C1–C4Linear or branched alkyl group；
R2It is selected from: C1–C8Linear or branched alkyl group, trifluoromethyl, trichloromethyl, allyl；
R3It is selected from: C1–C4Straight chained alkyl；
R5It is selected from: silylation or THP trtrahydropyranyl；With
R6It is selected from: silylation or THP trtrahydropyranyl.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
Inventor after extensive and in-depth study, it was unexpectedly found that it is a kind of synthesize limaprost key in
Mesosome and the new limaprost synthetic route for utilizing the intermediate, so as to shorten the synthesis of limaprost
Step improves combined coefficient, reduces production cost.The present invention is completed on this basis.
In the new synthesis process research of limaprost, the present inventor has synthesized compound shown in formula IV:
Compound shown in formula IV can react chemical combination shown in production IV with ester reducing agent by compound shown in formula III
Object:
In formula, R1It is selected from: C1–C4Linear or branched alkyl group.
The available ester reducing agent in this field has very much, but inventors have found that is selected from: diisobutyl for the above reaction
The combined ester reducing agent of aluminum hydride or other aluminum hydride derivatization reagents can generate excellent effect.Preferably implementing
In mode, the ester reducing agent is diisobutyl aluminium hydride.
Present inventors have further discovered that although diisobutyl aluminium hydride is the most effective reagent that ester group is reduced to aldehyde,
It is very rambunctious that ester group, which reverts to aldehyde in fact,.It is easy to if reducing condition control is bad excessive reduction of corresponding alcohol, or
Person can rest on aldehyde in the case where cannot get suitable reducing condition sometimes, so that having to first is reoxidised into aldehyde excessive reduction of alcohol.
Therefore different substrate reactions conditions also differs widely, and needs specifically to grope and optimize.
In a preferred embodiment, reaction temperature control is at -90 DEG C~-70 DEG C, diisobutyl aluminium hydride and formula III institute
Show that the dosage molar ratio of compound is controlled in 2-4:1, preferably 3:1.
Further, the present inventor utilizes compound shown in compound synthesis Formula V shown in formula IV:
In formula, R2It is selected from: C1–C8Linear or branched alkyl group, trifluoromethyl, trichloromethyl and allyl.
In view of the structure of compound shown in compound shown in formula IV and Formula V, how sharp those skilled in the art could be aware that
Compound shown in the compound synthesis Formula V shown in formula IV.Such as (but not limited to), compound shown in formula IV and WITTIG reagent are anti-
Compound shown in Formula V should be synthesized, the WITTIG reagent can be selected from phosphonoacetate, phosphinylidyne acetic acid methyl ester diethyl
Ester, phosphinylidyne acetic acid methyl ester diisopropyl ester, phosphoryl allyl acetate diethylester or other phosphinylidyne acetic acid derivatives, preferably phosphorus
Acyl acetic acid methyl esters diethylester, phosphoryl allyl acetate diethylester.
On the basis of compound shown in the compound shown in formula IV and Formula V, the present invention provides a kind of new Lima prostate
Plain synthetic method, this method can shorten the synthesis step of limaprost, improve combined coefficient, reduce production cost.
In a particular embodiment, limaprost synthetic method of the invention includes:
(1) compound shown in formula III is reacted into compound shown in production IV with ester reducing agent；
(2) formula IV preparation of compounds of formula V compound is utilized；
(3) Formula V compound is rearranged and isomery is combined to compound shown in Formula VII；With
(4) limaprost is finally prepared using compound shown in Formula VII.
In view of compound shown in compound shown in formula III and Formula VII, how formula III is obtained as known to those skilled in the art
Shown compound, and how limaprost is made the compound shown in the Formula VII.
For example, in a particular embodiment, the complete side of limaprost is prepared the compound shown in the formula III
Method can comprise the following steps that
(1) compound shown in formula III is reacted into compound shown in production IV with ester reducing agent:
(2) compound shown in synthesis Formula V is reacted with WITTIG reagent using compound shown in formula IV:
(3) compound shown in Formula V is rearranged and isomery is combined to compound shown in Formula VII:
(4) compound shown in Formula VII splits through enzyme, hydrolyzes to form compound shown in Formula VIII:
(5) compound shown in Formula VIII reacts to form compound shown in Formula IX with silane reagent:
(6) compound shown in Formula IX reacts to form compound shown in Formula XI with compound shown in Formula X:
(7) compound shown in Formula XI forms limaprost；
In formula
R1It is selected from: C1–C4Linear or branched alkyl group；
R2It is selected from: C1–C8Linear or branched alkyl group, trifluoromethyl, trichloromethyl, allyl；
R3It is selected from: C1–C4Straight chained alkyl；
R5It is selected from: silylation or THP trtrahydropyranyl；With
R6It is selected from: silylation or THP trtrahydropyranyl.
In a preferred embodiment, rearrangement reaction described in step (3) can be mixed containing 100% water or with organic solvent
It is carried out in the aqueous medium of conjunction, with organic or inorganic acidity or alkaline matter, preferably uses dipotassium hydrogen phosphate/phosphate buffer solution,
The pH of reaction is maintained in the range of about 2.5 to 6.5.Temperature is reset preferably at about 60 DEG C to 200 DEG C, more preferably at about 80 DEG C
It is carried out at a temperature of to 140 DEG C of ranges.And the isomerization reaction can carry out under conditions of chloraldurate and triethylamine.
In a preferred embodiment, enzyme described in step (4) is split and hydrolysis utilizes enantioselectivity lipase, packet
It includes but is not limited to from pig liver, pig pancreas or microorganism, preferably the enantioselectivity lipase of porcine pancreatic lipase (PPL).
The acry radical donor is selected from vinyl acetate, methylvinyl acetate, vinyl valerate, valeric acid isopropyl enester, vinyl butyrate, fourth
The combination of or mixtures thereof sour isopropyl enester, preferably vinyl acetate.Enantioselectivity esterification can carry out in organic solvent, institute
State organic solvent be selected from n-hexane, hexamethylene, toluene, tetrahydrofuran, methyl ethyl ketone, methylisobutylketone, ether, isopropyl ether,
The combination of or mixtures thereof methyl tertiary butyl ether(MTBE).
In a particular embodiment, step (4) includes by the way that there are azodicarboxy acid dialkyl esters and triaryl phosphine
In the case of, make unreacted (S) -ol and formula R4The acyloxy of COOH for precursor reactant and will described in (S) -ol be converted to accordingly
(R) -ester, (R) -ester obtain VIII by hydrolysis.
Above-mentioned azodicarboxy acid dialkyl ester is diethyl azodiformate, diisopropyl azodiformate, azo diformazan
The combination of or mixtures thereof acid benzhydryl ester, preferably diethyl azodiformate.The triaryl phosphine is triphenylphosphine.Wherein R4
For hydrogen or methyl, preferably hydrogen.
In a preferred embodiment, silane reagent described in step (5) is selected from tert-butyl chloro-silicane, tertiary fourth
Base diphenyl chlorosilane, chlorotriethyl silane, trim,ethylchlorosilane or 3,4- dihydropyran, preferably tert-butyldimethylsilyl chloride silicon
Alkane.
In a preferred embodiment, compound shown in Formula IX is obtained with compound shown in Formula X through Isosorbide-5-Nitrae-addition in step (6)
To compound shown in Formula XI
Wherein, R2For C1–C8Linear or branched alkyl group, trifluoromethyl, trichloromethyl, allyl, preferably methyl or allyl
Base；R5For silylation or THP trtrahydropyranyl, preferably t-Butyldimethylsilyl；R6For silylation or THP trtrahydropyranyl, preferably tertiary fourth
Base dimethyl silicon substrate.
In a preferred embodiment, compound shown in Formula XI is removed by hydrolysis of ester group or Pd (0), and hydroxyl is deprotected shape
At limaprost
Wherein, R2To use chemical hydrolysis protecting group, R when methyl2To use HCO when allyl2H-Et3N/Pd (0) is removed
Protecting group；
Alternatively,
Compound shown in Formula XI is deprotected through perhydroxyl radical, and hydrolysis of ester group or Pd (0) removing form limaprost
Wherein R2To use lipase hydrolysis protecting group, R when methyl2To use HCO when allyl2H-Et3N/Pd (0) is clear
Except protecting group.
In a particular embodiment, compound shown in preparation formula III method the following steps are included:
(1) compound shown in anhydride reaction formation Formula II is activated shown in furans and Formulas I
Wherein, R1For C1–C4Linear or branched alkyl group, preferred methyl.The acid anhydrides is selected from chloroacetic anhydride, trifluoroacetic acid
The combination of acid anhydride or other mixed acid anhydrides, preferably trifluoroacetic anhydride；
With
(2) compound shown in Formula II reacts to form compound shown in formula III with reducing agent
Wherein, R1For C1–C4Linear or branched alkyl group, preferred methyl.The reducing agent is selected from sodium borohydride, hydroboration
The combination of or mixtures thereof potassium, lithium borohydride, Li-Al hydrogen, preferably potassium borohydride.
Advantages of the present invention:
1. the present invention provides a kind of new intermediate for synthesizing limaprost；
2. the present invention provides the new limaprost synthetic route for utilizing the intermediate；
3. the synthesis step of the method for synthesis limaprost of the invention is few, combined coefficient is high, production cost is low.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.
The preparation of 1. structure formula (II) of embodiment
Structure formula (I) (80.0g, 0.5mol) is dissolved in toluene (500.0ml), is cooled to 0 DEG C, is maintained at 0 DEG C
Trifluoroacetic anhydride (120.8g, 0.575mol) successively is added dropwise, is added dropwise boron trifluoride ether (12.6ml).Finish, maintain 10 DEG C with
Under, it is added furans (51.0g, 0.75mol), is stirred to react 4 hours, post-process: ice water being added into reaction solution, is extracted with toluene
After 3 times, combining methylbenzene layer is successively washed with saturated sodium bicarbonate solution, washing, saturated salt washing, layering, organic layer anhydrous slufuric acid
Magnesium dries, filters, and filtrate is concentrated to dryness to obtain product: 96.6g (yield 92.0%).
The preparation of 2. structure formula (II) of embodiment
Structure formula (I) (80.0g, 0.5mol) is dissolved in toluene (500.0ml), is cooled to 0 DEG C, monoxone is added
Acid anhydride (98.3g, 0.575mol) is added dropwise boron trifluoride ether (12.6ml).Finish, maintain 10 DEG C hereinafter, be added furans (51.0g,
0.75mol), it is stirred to react 8 hours, post-processes: ice water being added into reaction solution, after being extracted 3 times with toluene, combining methylbenzene layer,
It is successively washed, is washed with saturated sodium bicarbonate solution, saturated salt washing is layered, and organic layer anhydrous magnesium sulfate dries, filters, filtrate
It is concentrated to dryness to obtain product: 88.2g (yield 84.0%).
The preparation of 3. structure formula (III) of embodiment
Structure formula (I) (105.0g, 0.5mol) is dissolved in anhydrous methanol (525.0ml), stirring cools to 0 DEG C, point
It criticizes and potassium borohydride (32.4g, 0.6mol) is added, be maintained at 20 DEG C and be stirred to react completely.Post-processing: glacial acetic acid is added dropwise and adjusts pH
=6, diatomite stirring, filtering is added, filtrate decompression is concentrated into small size, and water is added, and ethyl acetate extracts, organic layer saturated salt
Washing, layering, organic layer anhydrous magnesium sulfate dry, filter, and filtrate is concentrated to dryness to obtain product: 97.0g (yield 91.5%).
The preparation of 4. structure formula (IV) of embodiment
Five reaction flasks are taken, structure formula (III) (1.06g, 0.005mol) is dissolved in dry toluene (10ml), is controlled respectively
Temperature is drop in -110 DEG C~-90 DEG C, -90 DEG C~-70 DEG C, -70 DEG C~-50 DEG C, -50 DEG C~-30 DEG C, -30 DEG C~-10 DEG C
Add diisobutyl aluminium hydride toluene solution (1.0mol/L, 15ml, 0.015mol), heat preservation is added dropwise methanol and quenches down toward fully reacting
It goes out reaction.Post-processing: after diatomite stirring being added in reaction solution 10-20 minutes, filtering, after a small amount of methanol elution of filter cake, filtrate
It is concentrated to dryness to obtain grease.Grease is purified through conventional silicagel column, and target product is collected in elution, and product is concentrated under reduced pressure to obtain,
It is respectively as follows: 0.66g (yield 72%), 0.82g (yield 90%), 0.68g (yield 75%), 0.73g (yield 80%), 0.59g
(yield 62%).
Effect is preferable when experiment discovery reaction temperature is -90 DEG C~-70 DEG C, and yield is higher.
The preparation of 5. structure formula (IV) of embodiment
Four reaction flasks are taken, structure formula (III) (1.06g, 0.005mol) is dissolved in dry toluene (10ml), control temperature
In -90 DEG C~-70 DEG C of degree, diisobutyl aluminium hydride toluene solution 5ml (0.005mol), the 10ml of 1.0mol/L are added dropwise respectively
(0.010mol), 15ml (0.015mol), 20ml (0.020mol), heat preservation are added dropwise down toward fully reacting, control at -50 DEG C or less
Methanol quenching reaction.Post-processing: after diatomite stirring being added in reaction solution 10-20 minutes, filtering, a small amount of methanol elution of filter cake
Afterwards, filtrate decompression is concentrated to dryness to obtain grease.Grease is purified through conventional silicagel column, and target product is collected in elution, is concentrated under reduced pressure
Product is obtained, 0.71g (yield 78%), 0.77g (yield 84%), 0.82g (yield 90%), 0.75g (yield are respectively as follows:
82%).
The dosage molar ratio of experiment discovery diisobutyl aluminium hydride is at 2-4:1 (diisobutyl aluminium hydride: formula III compound)
When, effect is preferable when more preferable 3:1 (diisobutyl aluminium hydride: formula III compound), and yield is higher.
From embodiment 4 and 5 as can be seen that although diisobutyl aluminium hydride is the most effective reagent that ester group is reduced to aldehyde,
It is easy to but if reducing condition control is bad excessive reduction of corresponding alcohol；And sometimes because cannot get suitable reducing condition
And aldehyde is rested on, so that it is first reoxidized at aldehyde again excessive reduction of alcohol to have to, it can be seen that ester group is also in the method for the present invention
Original is that substrate reactions condition very rambunctious, different also differs widely to aldehyde, needs specifically to grope and optimize.
Embodiment 4 and 5 proves by the way that reaction temperature control effect at -90 DEG C~-70 DEG C is preferable, and will feed intake mole
It is preferable than controlling the effect at 3:1 (diisobutyl aluminium hydride: III).Following embodiment is in the reaction temperature and molar ratio
Lower progress.
The preparation of 6. structure formula (IV) of embodiment
Structure formula (III) (106.0g, 0.5mol) is dissolved in dry toluene (1060.0ml), stirring is cooled to -80 DEG C, drop
Add diisobutyl aluminium hydride toluene solution (1.0mol/L, 1500.0ml, 1.5mol), is maintained at -80 DEG C down toward fully reacting, control
Methanol quenching reaction is added dropwise at -50 DEG C in system.Post-processing: after diatomite stirring being added in reaction solution 10-20 minutes, filtering, filter cake
After a small amount of methanol elution, filtrate decompression is concentrated to dryness to obtain grease.Grease is purified through conventional silicagel column, and elution is collected target and produced
Product: 82.0g (yield 90.1%) is concentrated under reduced pressure to obtain in object.
MS(ES+):182。
1H-NMR(CDCl3): δ 1.34-2.11 (m, 6H), 2.43-2.47 (m, 2H), 4.66-2.4.69 (m, 1H), 6.23
(s,1H),6.33(s,1H),7.37(s,1H),9.75(s,1H)。
Preparation (the R of 7. structure formula (V) of embodiment2For methyl)
Structure formula (IV) (91.0g, 0.5mol) is dissolved in methylene chloride (910.0ml), stirring is cooled to 0 DEG C, is added dropwise
30% sodium hydroxide solution (86.7ml), finishes, and controls -5 DEG C of temperature, continues the dichloro that phosphinylidyne acetic acid methyl ester diethylester is added dropwise
Dichloromethane [phosphinylidyne acetic acid methyl ester diethylester (136.6g, 0.65mol), methylene chloride (546.0ml)], it is small to be stirred to react 2
Up to fully reacting.Post-processing: 10% aqueous citric acid solution is added into reaction solution and adjusts pH=3, stirring after twenty minutes, divides
Layer, water layer methylene chloride extract 2-3 times, merge dichloromethane layer, and saturated salt washing, layering, organic layer anhydrous magnesium sulfate is dry,
Filtering, filtrate decompression are concentrated to give grease.Silica gel column purification on grease, elution collect target product, product are concentrated under reduced pressure to obtain:
103.0g (yield 87.7%).
MS(ESI+):239(M+1)+。
1H-NMR(CDCl3): δ 1.33-1.52 (m, 4H), 1.83-1.88 (m, 2H), 2.09 (s, 1H), 2.18-2.23 (m,
2H), 3.69 (s, 3H), 4.65-4.68 (m, 1H), 5.82-5.83 (d, 1H, J=1.2), 6.22 (m, 1H), 6.32 (m, 1H),
6.91-6.99(m,1H),7.37(s,1H)。
Preparation (the R of 8. structure formula (V) of embodiment2For allyl)
Structure formula (IV) (91.0g, 0.5mol) is dissolved in methylene chloride (910.0ml), stirring is cooled to 0 DEG C, is added dropwise
30% sodium hydroxide solution (86.7ml), finishes, and controls -5 DEG C of temperature, continues to be added dropwise the two of phosphoryl allyl acetate diethylester
Chloromethanes solution [phosphoryl allyl acetate diethylester (153.0g, 0.65mol), methylene chloride (546.0ml)], is stirred to react
2 hours to fully reacting.Post-processing: 10% aqueous citric acid solution being added into reaction solution and adjusts pH=3, stirs after twenty minutes,
Layering, water layer methylene chloride extract 2-3 times, merge dichloromethane layer, and saturated salt washing is layered, and organic layer anhydrous magnesium sulfate is dry
Dry, filtering, filtrate decompression is concentrated to give grease.Target product is collected in silica gel column purification on grease, elution, is concentrated under reduced pressure to produce
Object: 118.0g (yield 90.0%).
MS(ESI+):265(M+1)+。
Preparation (the R of 9. structure formula (VII) of embodiment2For methyl)
Structure formula (V) (119.0g, 0.5mol) is added in water (2380.0ml), stirring 0.5mol/L dipotassium hydrogen phosphate
PH of mixed=4.0 are adjusted, hydroquinone (50.5mg, 0.5mmol) temperature rising reflux is added and reacts 18 hours, fully reacting.Drop
To room temperature.Post-processing: reaction solution is extracted with ethyl acetate 2 times, and organic layer merges, and successively uses saturated sodium bicarbonate solution, saturation
Salt washing.Layering, organic layer anhydrous magnesium sulfate dry, filter, and filtrate is concentrated to dryness to obtain grease (containing VI and VII).By oily
Object is transferred in reaction flask, is added toluene (1190.0ml), and stirring is added triethylamine (30.4g, 0.3mol), chloraldurate
(4.96g, 0.03mol) is stirred at room temperature 12 hours, fully reacting.Post-processing: reaction solution is washed with water 2 times, saturated salt washing 1
Secondary, layering, organic layer anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated to give grease.Silica gel column purification on grease, is washed
It is de- to collect target product, product: 83.4g (yield 70.0%) is concentrated under reduced pressure to obtain.
MS(ESI+):261(M+Na)。
Preparation (the R of 10. structure formula (VII) of embodiment2For ethyl)
Structure formula (V) (126.0g, 0.5mol) is added in water (2380.0ml), stirring 0.5mol/L dipotassium hydrogen phosphate
PH of mixed=4.0 are adjusted, hydroquinone (50.5mg, 0.5mmol) temperature rising reflux is added and reacts 18 hours, fully reacting.Drop
To room temperature.Post-processing: reaction solution is extracted with ethyl acetate 2 times, and organic layer merges, and successively uses saturated sodium bicarbonate solution, saturation
Salt washing.Layering, organic layer anhydrous magnesium sulfate dry, filter, and filtrate is concentrated to dryness to obtain grease (containing VI and VII).By oily
Object is transferred in reaction flask, is added toluene (1190.0ml), and stirring is added triethylamine (30.4g, 0.3mol), chloraldurate
(4.96g, 0.03mol) is stirred at room temperature 12 hours, fully reacting.Post-processing: reaction solution is washed with water 2 times, saturated salt washing 1
Secondary, layering, organic layer anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated to give grease.Silica gel column purification on grease, is washed
It is de- to collect target product, product: 93.3g (yield 74.0%) is concentrated under reduced pressure to obtain.
MS(ESI+):275(M+Na)。
1H-NMR(CDCl3): δ 1.26-1.29 (m, 3H), 1.49-1.58 (m, 4H) 2.19-2.33 (m, 6H), 2.77-
2.83(dm,1H),4.16-4.22(m,2H),4.952(s,1H),5.793-5.839(d,1H),6.897-6.971(m,1H),
7.152-7.165(s,1H)。
Preparation (the R of 11. structure formula (VII) of embodiment2For allyl)
Structure formula (V) (132.0g, 0.5mol) is added in water (2640.0ml), stirring 0.5mol/L dipotassium hydrogen phosphate
PH of mixed=4.0 are adjusted, hydroquinone (50.5mg, 0.5mmol) temperature rising reflux is added and reacts 18 hours, fully reacting.Drop
To room temperature.Post-processing: reaction solution is extracted with ethyl acetate 2 times, and organic layer merges, and successively uses saturated sodium bicarbonate solution, saturation
Salt washing.Layering, organic layer anhydrous magnesium sulfate dry, filter, and filtrate is concentrated to dryness to obtain grease (containing VI and VII).By oily
Object is transferred in reaction flask, is added toluene (1320.0ml), and stirring is added triethylamine (30.4g, 0.3mol), chloraldurate
(4.96g, 0.03mol) is stirred at room temperature 12 hours, fully reacting.Post-processing: reaction solution is washed with water 2 times, saturated salt washing 1
Secondary, layering, organic layer anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated to give grease.Silica gel column purification on grease, is washed
It is de- to collect target product, product: 95.0g (yield 72.0%) is concentrated under reduced pressure to obtain.
MS(ESI+):287(M+Na)。
Preparation (the R of 12. structure formula (VIII) of embodiment2For methyl, R3For methyl)
It by structure formula (VII) (238.0g, 1.0mol), is dissolved in vinyl acetate (2380.0ml), pig pancreas rouge is added in stirring
Fat enzyme PPL (238.0g) is reacted at room temperature 7 days, and diatomite (200.0g) is added in reaction solution, filtering, the elution of filter cake ethyl acetate,
Filtrate decompression is concentrated to give grease.Silica gel column purification on grease, elution are collected the lesser target product of polarity, are concentrated under reduced pressure
Grease (R3CO-VIII).The biggish target product of polarity is collected afterwards, and grease (VIII ') is concentrated under reduced pressure to obtain.By grease
(R3CO-VIII it) is dissolved in anhydrous methanol (2800.0ml), is added Anhydrous potassium carbonate (172.8g, 1.25mol), room temperature reaction 1
Hour, fully reacting.Post-processing: reaction solution filtering, the elution of filter cake anhydrous methanol.Filtrate adjusts pH=7 with glacial acetic acid, and water is added
(5600.0ml), ethyl acetate (5600.0ml), stratification after stirring, water layer ethyl acetate extract 2 times, merge organic layer,
After saturated salt is washed 2 times, organic layer anhydrous magnesium sulfate is dried, filtered, and filtrate decompression is concentrated to give product: 96.0g (yield
99.0%) 40.3%, ee value are greater than.
Preparation (the R of 13. structure formula (VIII) of embodiment2For methyl, R4For hydrogen) (VIII is prepared by VIII ' (S))
The grease (VIII ') (125.0g) obtained in example 9 is dissolved in tetrahydrofuran (1250.0ml), stirring is lower to be added
Enter triphenylphosphine (157.4g, 0.6mol), water beetle acid (27.6g, 0.6mol), reaction solution is cooled to -5 DEG C, and azodicarboxy is added
Diethyl phthalate (209.0g, 1.2mol) reacts at room temperature fully reacting in 12 hours, grease is concentrated under reduced pressure to obtain, grease is dissolved in
It in anhydrous ether (600.0ml), is added n-hexane (400.0ml), stirring is filtered after 30 minutes, and filtrate decompression is concentrated to give oily
Grease is dissolved in anhydrous methanol (2800.0ml) by object, is cooled to 0 DEG C, and the methanol solution of 0.5mol/L guanidine is added
(300.0ml) after being stirred at room temperature 30 minutes, adjusts pH=7 with glacial acetic acid, grease is concentrated under reduced pressure to obtain, grease is dissolved in acetic acid
Ethyl ester (5600.0ml), water (5600.0ml), stratification after stirring, water layer ethyl acetate extract 2 times, merge organic layer, satisfy
After washing 2 times with salt, organic layer anhydrous magnesium sulfate is dried, filtered, and filtrate decompression is concentrated to give product: 98.0g (yield 41.1%,
94.0%) ee value is greater than.
The preparation of 14. structure formula (VIII) of embodiment
It by structure formula (VII) (238.0g, 1.0mol), is dissolved in vinyl acetate (2380.0ml), pig pancreas rouge is added in stirring
Fat enzyme PPL (238.0g) is reacted at room temperature 7 days, and diatomite (200.0g) is added in reaction solution, filtering, the elution of filter cake ethyl acetate,
Filtrate decompression is concentrated to give grease (containing R3CO-VIII and VIII ').Grease is dissolved in tetrahydrofuran (1250.0ml), is stirred
Lower addition triphenylphosphine (157.4g, 0.6mol), anhydrous formic acid (27.6g, 0.6mol) are mixed, reaction solution is cooled to -5 DEG C, is added
Diethylazodicarboxylate (209.0g, 1.2mol) reacts at room temperature fully reacting in 12 hours, grease is concentrated under reduced pressure to obtain, will be oily
Shape object is dissolved in anhydrous ether (600.0ml), is added n-hexane (400.0ml), and stirring is filtered after 30 minutes, filtrate decompression concentration
Grease is obtained, grease is dissolved in anhydrous methanol (2800.0ml), is cooled to 0 DEG C, the methanol solution of 0.5mol/L guanidine is added
(600.0ml) after being stirred at room temperature 30 minutes, adjusts pH=7 with glacial acetic acid, grease is concentrated under reduced pressure to obtain, grease is dissolved in acetic acid
Ethyl ester (5600.0ml), water (5600.0ml), stratification after stirring, water layer ethyl acetate extract 2 times, merge organic layer, satisfy
After washing 2 times with salt, organic layer anhydrous magnesium sulfate is dried, filtered, and filtrate decompression is concentrated to give product: 168.0g (yield 70.6%,
96.0%) ee value is greater than.
Preparation (the R of 15. structure formula (IX) of embodiment2For methyl)
Structure formula (VIII) (238.0g, 1.0mol) is dissolved in anhydrous DMF (1190.0ml), addition imidazoles (170.0g,
2.5mol), stirring clarification is cooled to 0 DEG C, and tert-butyl chloro-silicane (226.0g, 1.5mol) is added portionwise, adds nature
It is warming up to room temperature reaction 2 hours, TLC detects fully reacting, reaction solution is poured into 10 liters of ice water, stirs 10 minutes, uses acetic acid
Ethyl ester 3000ml is extracted 3 times, is merged organic layer, is washed with 1N hydrochloric acid 3000ml, saturated brine 3000ml is washed 3 times, and organic layer is anhydrous
Magnesium sulfate, which dries, filters, is concentrated to give grease.Target product is collected in silica gel column purification on grease, elution, is concentrated under reduced pressure to produce
Object: 334.0g (yield 94.9%).
Preparation (the R of 16. structure formula (IX) of embodiment2For allyl)
[reaction equation is with embodiment 15]
Structure formula (VIII) (264.0g, 1.0mol) is dissolved in anhydrous DMF (1190.0ml), addition imidazoles (170.0g,
2.5mol), stirring clarification is cooled to 0 DEG C, and tert-butyl chloro-silicane (226.0g, 1.5mol) is added portionwise, adds nature
It is warming up to room temperature reaction 2 hours, TLC detects fully reacting, reaction solution is poured into 10 liters of ice water, stirs 10 minutes, uses acetic acid
Ethyl ester 3000ml is extracted 3 times, is merged organic layer, is washed with 1N hydrochloric acid 3000ml, saturated brine 3000ml is washed 3 times, and organic layer is anhydrous
Magnesium sulfate, which dries, filters, is concentrated to give grease.Target product is collected in silica gel column purification on grease, elution, is concentrated under reduced pressure to produce
Object: 363.0g (yield 96.0%).
Preparation (the R of 17. structure formula (IX) of embodiment2For methyl)
Structure formula (VIII) (238.0g, 1.0mol) is dissolved in anhydrous DMF (1190.0ml), addition imidazoles (170.0g,
2.5mol), stirring clarification is cooled to 0 DEG C, is added dropwise chlorotriethyl silane (226.0g, 1.5mol), adds and warm naturally to room temperature
Reaction 2 hours, TLC detect fully reacting, reaction solution are poured into 10 liters of ice water, stir 10 minutes, with ethyl acetate 3000ml
It extracting 3 times, merges organic layer, washed with 1N hydrochloric acid 3000ml, saturated brine 3000ml is washed 3 times, and organic layer anhydrous magnesium sulfate is dry,
Filtering and concentrating obtains grease.Target product is collected in silica gel column purification on grease, elution, and product is concentrated under reduced pressure to obtain: 328.0g (is received
Rate 93.2%).
Preparation (the R of 18. structure formula (IX) of embodiment2For allyl)
[reaction equation is with embodiment 17]
Structure formula (VIII) (264.0g, 1.0mol) is dissolved in anhydrous DMF (1190.0ml), addition imidazoles (170.0g,
2.5mol), stirring clarification is cooled to 0 DEG C, is added dropwise chlorotriethyl silane (226.0g, 1.5mol), adds and warm naturally to room temperature
Reaction 2 hours, TLC detect fully reacting, reaction solution are poured into 10 liters of ice water, stir 10 minutes, with ethyl acetate 3000ml
It extracting 3 times, merges organic layer, washed with 1N hydrochloric acid 3000ml, saturated brine 3000ml is washed 3 times, and organic layer anhydrous magnesium sulfate is dry,
Filtering and concentrating obtains grease.Target product is collected in silica gel column purification on grease, elution, and product is concentrated under reduced pressure to obtain: 366.7g (is received
Rate 97.0%).
Preparation (the R of 19. structural formula of embodiment (XI)2For methyl)
Under argon gas protection, structure formula (X) (396.0g, 1.0mol) is added in reaction flask, anhydrous ether is added
(2640.0ml), stirring are cooled to -78 DEG C, are added dropwise 1.3mol/L tert-butyl lithium (1538.0ml, 2.0mol), and -78 DEG C of holding anti-
It answers 2 hours, the diethyl ether solution * of benzene sulphur copper is added dropwise, the THF of structure formula (IX) is added dropwise after -78 DEG C are reacted 1 hour in drop Bi Jixu
Solution [structure formula (IX) (176.0g, 0.5mol), THF (5280.0ml)] is warming up to -40 after keeping -78 DEG C of reactions 1 hour
DEG C reaction 1 hour, TLC detect fully reacting.Post-processing: reaction solution is poured into saturated ammonium chloride solution, is stirred, and petroleum is added
Ether extracts 2 times, merges organic layer, and the stirring of 10% aqueous citric acid solution is added, and filters insoluble matter, layering, water layer petroleum ether is counter to mention 2
It is secondary, merge organic layer, washing, saturated salt washing is layered, and organic layer anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated to give oil
Shape object.
Silica gel column purification on grease, elution collect target product, product: 218.0g (yield are concentrated under reduced pressure to obtain
70.1%).
* the diethyl ether solution of benzene sulphur copper is prepared: under argon gas protection, anhydrous ether (2640.0ml) is added in reaction flask,
(Me2N)3P (324.0g, 2.0mol), stirring is added benzene sulphur copper (173.0g, 1.0mol), is stirred at room temperature 1 hour, spare.
Preparation (the R of 20. structural formula of embodiment (XI)2For allyl)
[reaction equation is with embodiment 19]
Under argon gas protection, structure formula (X) (396.0g, 1.0mol) is added in reaction flask, anhydrous ether is added
(2640.0ml), stirring are cooled to -78 DEG C, are added dropwise 1.3mol/L tert-butyl lithium (1538.0ml, 2.0mol), and -78 DEG C of holding anti-
It answers 2 hours, the diethyl ether solution * of benzene sulphur copper is added dropwise, the THF of structure formula (IX) is added dropwise after -78 DEG C are reacted 1 hour in drop Bi Jixu
Solution [structure formula (IX) (189.0g, 0.5mol), THF (5280.0ml)] is warming up to -40 after keeping -78 DEG C of reactions 1 hour
DEG C reaction 1 hour, TLC detect fully reacting.Post-processing: reaction solution is poured into saturated ammonium chloride solution, is stirred, and petroleum is added
Ether extracts 2 times, merges organic layer, and the stirring of 10% aqueous citric acid solution is added, and filters insoluble matter, layering, water layer petroleum ether is counter to mention 2
It is secondary, merge organic layer, washing, saturated salt washing is layered, and organic layer anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated to give oil
Shape object.
Silica gel column purification on grease, elution collect target product, product: 243.0g (yield are concentrated under reduced pressure to obtain
75.0%).
Preparation (the R of 21. structural formula of embodiment (XI)2For methyl)
Under argon gas protection, structure formula (X) (396.0g, 1.0mol) is added in reaction flask, anhydrous ether is added
(2640.0ml), stirring are cooled to -78 DEG C, are added dropwise 1.3mol/L tert-butyl lithium (1538.0ml, 2.0mol), and -78 DEG C of holding anti-
It answers 2 hours, the diethyl ether solution * of benzene sulphur copper is added dropwise, the THF of structure formula (IX) is added dropwise after -78 DEG C are reacted 1 hour in drop Bi Jixu
Solution [structure formula (IX) (176.0g, 0.5mol), THF (5280.0ml)] is warming up to -40 after keeping -78 DEG C of reactions 1 hour
DEG C reaction 1 hour, TLC detect fully reacting.Post-processing: reaction solution is poured into saturated ammonium chloride solution, is stirred, and petroleum is added
Ether extracts 2 times, merges organic layer, and the stirring of 10% aqueous citric acid solution is added, and filters insoluble matter, layering, water layer petroleum ether is counter to mention 2
It is secondary, merge organic layer, washing, saturated salt washing is layered, and organic layer anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated to give oil
Shape object.
Silica gel column purification on grease, elution collect target product, product: 206.0g (yield are concentrated under reduced pressure to obtain
66.2%).
* the diethyl ether solution configuration of benzene sulphur copper: under argon gas protection, being added anhydrous ether (2640.0ml) in reaction flask,
(Me2N)3P (324.0g, 2.0mol), stirring is added benzene sulphur copper (173.0g, 1.0mol), is stirred at room temperature 1 hour, spare.
Preparation (the R of 22. structural formula of embodiment (XI)2For allyl)
[reaction equation is with embodiment 21]
Under argon gas protection, structure formula (X) (396.0g, 1.0mol) is added in reaction flask, anhydrous ether is added
(2640.0ml), stirring are cooled to -78 DEG C, are added dropwise 1.3mol/L tert-butyl lithium (1538.0ml, 2.0mol), and -78 DEG C of holding anti-
It answers 2 hours, the diethyl ether solution * of benzene sulphur copper is added dropwise, the THF of structure formula (IX) is added dropwise after -78 DEG C are reacted 1 hour in drop Bi Jixu
Solution [structure formula (IX) (189.0g, 0.5mol), THF (5280.0ml)] is warming up to -40 after keeping -78 DEG C of reactions 1 hour
DEG C reaction 1 hour, TLC detect fully reacting.Post-processing: reaction solution is poured into saturated ammonium chloride solution, is stirred, and petroleum is added
Ether extracts 2 times, merges organic layer, and the stirring of 10% aqueous citric acid solution is added, and filters insoluble matter, layering, water layer petroleum ether is counter to mention 2
It is secondary, merge organic layer, washing, saturated salt washing is layered, and organic layer anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated to give oil
Shape object.
Silica gel column purification on grease, elution collect target product, product: 224.0g (yield are concentrated under reduced pressure to obtain
69.1%).
Preparation (the R of 23. limaprost of embodiment2For methyl)
Structural formula (XI) (311.0g, 0.5mol) is dissolved in dehydrated alcohol (3110.0ml), stirring is cooled to 5 DEG C, is added dropwise
0.5mol/L potassium hydroxide aqueous solution (1500.0ml) is kept for 15-20 DEG C to fully reacting, 5 DEG C is cooled to, with 1.0mol/L salt
Acid solution adjusts pH=5, and methyl tertiary butyl ether(MTBE) is added and extracts 2 times, merges organic layer, washes, saturated salt washing, and layering is organic
Layer anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated to give grease.Grease is dissolved in acetonitrile (6220.0ml), pyrrole is added
Pyridine (933.0ml) is cooled to 0 DEG C, is added dropwise 55%HF.Py (1866.0ml), is stirred at room temperature to TLC and detects fully reacting.After
Reason: reaction solution is added to the water, methyl tertiary butyl ether(MTBE) extract, layering, organic layer washing, saturated salt washing, layering, organic layer without
Water magnesium sulfate dries, filters, and filtrate decompression is concentrated to give grease, silica gel column purification on grease, successively uses petroleum ether: acetic acid second
Ester=2:1, petroleum ether: ethyl acetate=1:1, ethyl acetate, elution collect target product, crude product, crude product second are concentrated under reduced pressure to obtain
Acetoacetic ester/petroleum ether recrystallizes to obtain finished product: 72.0g (yield 37.9%).
Preparation (the R of 24. limaprost of embodiment2For allyl)
[reaction equation is with embodiment 23]
THF (5000.0ml) is added in reaction flask, 88% formic acid (91.5g, 1.75mol), three second are sequentially added under stirring
Amine (151.8g, 1.5mol), Pd2(dba)3-CHCl3(51.8g, 0.05mol), n-Bu3P (40.5g, 0.2mol), is stirred at room temperature
After 30 minutes, THF (1000.0ml) solution of structural formula (XI) (311.0g, 0.5mol) is added, is warming up to 40 DEG C of reaction TLC inspections
Survey fully reacting.Post-processing: reaction solution is added in the mixed liquor of salt water and petroleum ether and stirs layering, water layer petroleum ether is counter to be mentioned
Afterwards, merge organic layer anhydrous magnesium sulfate to dry, filter, filtrate is concentrated to give grease.Silicagel column rapidly purifies on grease, elution
Target product is collected, grease is concentrated under reduced pressure to obtain.Grease is dissolved in acetonitrile (6220.0ml), is added pyridine (933.0ml), drop
Temperature is added dropwise 55%HF.Py (1866.0ml) to 0 DEG C, is stirred at room temperature to TLC and detects fully reacting.Post-processing: reaction solution is added
In water, methyl tertiary butyl ether(MTBE) is extracted, layering, and organic layer washing, saturated salt washing, layering, organic layer anhydrous magnesium sulfate is dry, mistake
Filter, filtrate decompression are concentrated to give grease, silica gel column purification on grease, successively use petroleum ether: ethyl acetate=2:1, petroleum ether:
Ethyl acetate=1:1, ethyl acetate, elution collect target product, crude product, crude product ethyl acetate/petroleum ether weight are concentrated under reduced pressure to obtain
Crystallize to obtain finished product: 122.0g (yield 64.2%).
Preparation (the R of 25. limaprost of embodiment2For methyl)
Structural formula (XI) (311.0,0.5mol) is dissolved in acetonitrile (6220.0ml), is stirred, pyridine is added
(933.0ml) is cooled to 0 DEG C, is added dropwise 55%HF.Py (1866.0ml), is stirred at room temperature to TLC and detects fully reacting.Post-processing:
Reaction solution is added to the water, methyl tertiary butyl ether(MTBE) extracts, layering, organic layer washing, saturated salt washing, layering, and organic layer is anhydrous
Magnesium sulfate dries, filters, and filtrate decompression is concentrated to give grease.Silicagel column rapidly purifies on grease, collects target product decompression
It is concentrated to give Lima methyl esters.Lima methyl esters is dissolved with acetone (3110.0ml), is added 0.1mol/L phosphate buffer (pH=8)
(31100.0ml) is stirred at room temperature and porcine pancreatic lipase PPL (622.0g) is added, 1.0mol/L sodium hydroxide solution is added dropwise, and remains anti-
Process pH=8 is answered, is reacted 48 hours, TLC detects fully reacting.Post-processing: reaction solution adjusts pH=4 with saturation sodium bisulfate,
Diatomite filtering is added, filtrate methyl tertiary butyl ether(MTBE) extracts 2 times, merges methyl tertiary butyl ether layer, it washes, saturated salt washing, layering,
Organic layer anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated to give grease.Silica gel column purification on grease, successively uses petroleum
Ether: ethyl acetate=2:1, petroleum ether: ethyl acetate=1:1, ethyl acetate, elution collect target product, are concentrated under reduced pressure slightly
Product, crude product recrystallization from ethyl acetate/petroleum ether obtain finished product: 78.0g (yield 41.1%).
Preparation (the R of 26. limaprost of embodiment2For methyl)
Structural formula (XI) (311.0,0.5mol) is dissolved in acetonitrile (6220.0ml), is stirred, pyridine is added
(933.0ml) is cooled to 0 DEG C, is added dropwise 55%HF.Py (1866.0ml), is stirred at room temperature to TLC and detects fully reacting.Post-processing:
Reaction solution is added to the water, methyl tertiary butyl ether(MTBE) extracts, layering, organic layer washing, saturated salt washing, layering, and organic layer is anhydrous
Magnesium sulfate dries, filters, and filtrate decompression is concentrated to give grease.Silicagel column rapidly purifies on grease, collects target product decompression
It is concentrated to give Lima methyl esters.Lima methyl esters is dissolved with acetone (3110.0ml), is added 0.1mol/L phosphate buffer (pH=8)
(31100.0ml) is stirred at room temperature and porcine pancreatic lipase PPL (622.0g) is added, 1.0mol/L sodium hydroxide solution is added dropwise, and remains anti-
Process pH=8 is answered, is reacted 48 hours, TLC detects fully reacting.Post-processing: reaction solution adjusts pH=4 with saturation sodium bisulfate,
Diatomite filtering is added, filtrate methyl tertiary butyl ether(MTBE) extracts 2 times, merges methyl tertiary butyl ether layer, it washes, saturated salt washing, layering,
Organic layer anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated to give grease.Silica gel column purification on grease, successively uses petroleum
Ether: ethyl acetate=2:1, petroleum ether: ethyl acetate=1:1, ethyl acetate, elution collect target product, are concentrated under reduced pressure slightly
Product, crude product recrystallization from ethyl acetate/petroleum ether obtain finished product: 81.0g (yield 42.6%).
MS(ES+):380。
1H-NMR(CDCl3): δ 0.87-0.91 (m, 6H), 1.14-1.62 (m, 16H), 1.97-2.02 (m, 1H), 2.19-
2.26(m,3H),2.32-2.39(m,1H),2.70-2.77(m,1H),4.03-4.09(m,1H)4.19-4.25(m,1H),
5.54-5.70(m,2H),5.78-5.83(m,1H),6.98-7.05(m,1H)。
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (9)
1. the preparation method of compound shown in formula IV, the method is as shown in following formulas, by compound shown in formula III and ester
Reducing agent reacts compound shown in production IV:
In formula,
R1It is selected from: C1–C4Linear or branched alkyl group.
2. the method as described in claim 1, which is characterized in that R1For methyl.
3. the method as described in claim 1, which is characterized in that the ester reducing agent is diisobutyl aluminium hydride.
4. method as claimed in claim 3, which is characterized in that the reaction temperature of the reaction is controlled at -90 DEG C~-70 DEG C,
The dosage molar ratio of compound shown in diisobutyl aluminium hydride and formula III is controlled in 2-4:1.
5. method as claimed in claim 4, which is characterized in that the dosage of compound shown in diisobutyl aluminium hydride and formula III
Molar ratio is controlled in 3:1.
6. a kind of method for preparing limaprost, the described method comprises the following steps:
(1) compound shown in formula III is reacted into compound shown in production IV with ester reducing agent；
(2) preparation formula V compound is reacted with WITTIG reagent using formula IV compound；
(3) Formula V compound is rearranged and isomery is combined to compound shown in Formula VII
With
(4) limaprost is finally prepared using compound shown in Formula VII；
In formula,
R1As defined in claim 1；
R2It is selected from: C1–C8Linear or branched alkyl group, trifluoromethyl and trichloromethyl.
7. method as claimed in claim 6, which is characterized in that the ester reducing agent is diisobutyl aluminium hydride.
8. the method for claim 7, which is characterized in that in step (1), the control of the reaction temperature of the reaction-
90 DEG C~-70 DEG C, the dosage molar ratio of compound shown in diisobutyl aluminium hydride and formula III is controlled in 2-4:1.
9. method as claimed in claim 6, which is characterized in that the dosage of compound shown in diisobutyl aluminium hydride and formula III
Molar ratio is controlled in 3:1.
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|---|---|---|---|---|
| US20110039893A1 (en) * | 2006-10-11 | 2011-02-17 | Takeda Pharmaceutical Company Limited | Gsk-3beta inhibitor |
| CN102056887A (en) * | 2008-04-09 | 2011-05-11 | 台湾神隆股份有限公司 | Process for the preparation of prostaglandin analogues and intermediates thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110039893A1 (en) * | 2006-10-11 | 2011-02-17 | Takeda Pharmaceutical Company Limited | Gsk-3beta inhibitor |
| CN102056887A (en) * | 2008-04-09 | 2011-05-11 | 台湾神隆股份有限公司 | Process for the preparation of prostaglandin analogues and intermediates thereof |
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| Title |
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| An Efficient Synthesis of the Antisecretory Prostaglandin Enisoprost;John H. Dygos等;《J. Org. Chem.》;19911231;第56卷(第7期);第2549-2552页 |
| The Manufacture of a Homochiral 4-Silyoxycyclopentenone Intermediate for the Synthesis of Prostaglandin Analogues;Julian P. Henschke等;《Organic Process Research & Development》;20121115;第16卷;第1905-1916页 |
| 前列腺素类药物全合成的研究进展;葛渊源等;《中国医药工业杂志》;20131231;第44卷(第7期);第720-728页 |
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