CN103373947A - Green synthesis method for dinoprostone (prostaglandin PGE2) - Google Patents

Abstract

The invention relates to a synthesis method for dinoprostone (prostaglandin PGE2), and in particular a method for converting prostaglandin F (for example, PGF2 alpha) to prostaglandin E (for example, PGE2). The method comprises the following steps of: oxidizing 11-site and 15-site hydroxy-protected prostaglandin PGF2 alpha to hydroxy-protected PGE2 by environment-friendly pyridine sulphur trioxide, and then hydrolyzing and de-protecting in citric acid aqueous solution to obtain PGE2. The method has the characteristics of being green and environment-friendly, safe to operate, convenient in after-treatment, short in production cycle, low in cost, and high in productivity and purity, as well as is suitable for industrialized production.

Description

A kind of green synthesis method of rostaglin E2

Technical field:

The invention belongs to medical technical field, relate to the preparation method of rostaglin E2 (PGE2).

Technical background:

The active substance with multiple physiological action that prostaglandin(PG) (prostaglandin, PG) is comprised of a class unsaturated fatty acids that is present in animal and human's body.Find the earliest to be present in people's the seminal fluid, thought at that time that this material was discharged by prostate gland, thereby name and be prostaglandin(PG).Now proved prostaglandin(PG) in the seminal fluid mainly from seminal vesicle, the many histocytes of whole body can both produce prostaglandin(PG).Prostaglandin(PG) (PG) is synthesized by arachidonic acid in vivo, and structure is a five rings and two 20 carbon unsaturated fatty acidss that side chain consists of.By its structure, prostaglandin(PG) is divided into the types such as A, B, C, D, E, F, G, H, I.The effect of prostaglandin(PG) is very extensive and complicated, and all types of prostaglandin(PG)s can produce diverse effect to different cells.For example PGE energy vasodilation increases organic blood flow volume, reduces Peripheral resistance, and the effect of row's sodium is arranged, thereby makes blood pressure drops; And PGF effect more complicated can make rabbit, cat blood pressure drops, but makes the elevation of blood pressure of rat, dog.PGE makes the bronchial smooth muscle diastole, reduces aeration resistance; And PGF shrinks bronchial smooth muscle.PGE and PGF have very strong restraining effect to the secretion of gastric juice; But gastrointestinal smooth muscle is strengthened its contraction.They can also make the gravid uterus smooth muscle contraction.In addition, PG is for ovulation, and corpus luteum generates and atrophy, and the reproductive functions such as transportation of ovum and sperm also have substantial connection.

Prostaglandin E2 (PGE2) also claims rostaglin E2 (Dinoprostone), and each phase gravid uterus is all had contraction, and relatively gentleer.Uterine cervix there are conversion and dilating effect, can be used for induction of labor in midpregnancy, full-term pregnancy induced labor and therapeutic(al) abortion, all can use pregnancy induced hypertension syndrome (preeclampsia, hypertension), gestation merging kidney disease patient, postterm pregnancy, the retention of dead fetus, hydatidiform mole, premature rupture of amniotic membrane, elderly primipara.

Because prostaglandin(PG) has multiple extremely important physiological action, so the synthetic of prostaglandin(PG) is the important research field of chemistry and pharmacology always.Early stage E prostanoid (PGE) directly extracts from organism, but output is very limited, and this has brought great difficulty for the research of prostaglandin(PG).In order to obtain for biological activity and the required a large amount of prostaglandin(PG)s of clinical study, scientists has been developed the synthetic and biosynthetic means of number of chemical.The usual method of synthetic PGE is to obtain through polystep reaction after the metal reagent linked reaction of cyclopentanone derivatives and a haloolefin or alkynes again, such as document J.Amer.Chem.Soc., 1969,5675-5677; J.Amer.Chem.Soc., 1970,2586; Tetrahedron Letters, 1970,307; Tetrahedron Letters, 1986,2199-2203 (E.J.Corey etc.), Chemical Communication 1969,304-305; J.Amer.Chem.Soc., 1968,5895-5896 (W.P.Schneider etc.), J.Amer.Chem.Soc., 1975,865-874 (Charles J.Sih etc.) and US Patent No. 5618959, US4031129, US4149007, US4474979 etc. have reported similar synthetic method.The another kind of common method of synthetic PGE is exactly other prostaglandin(PG) to be derived change into the PGE prostanoid, prostaglandin A is transformed into the method for PGE such as US Patent No. 3912725.PGE also can change from prostaglandin F simultaneously, has reported a kind of method that PGF2a is transformed into PGE2 such as US Patent No. 6403817B1.The method is with triethyl silica-based protection, then with sexavalent chrome reagent such as chromium trioxide (CrO with 11,15 hydroxyl among the PGF2a ₃), unprotected 9 hydroxyls of methyl-sulphoxide (Swern reagent, Corey-Kim reagent) oxidation of pyridinium chlorochromate drone salt (PCC), pyridinium dichromate (PDC) or activation become ketone and obtain PGE2.US Patent No. 3892792, Czech patents CS265733B1, J.C.S.CHEM.COMM., 1972,1120-1121 (Ernest W.Yankee etc.), J.Amer.Chem.Soc. have also reported similar method in the documents such as 1969,5675-5677 (E.J.Corey etc.).

Produce PGE2 and then de-protected method based on chromic acid oxidation PGF2 at present, the average yield of gained PGE2 only has about 15% behind the recrystallization.The method runs into many problems in the technological process of producing at present rostaglin E2, such as:

1), uses chromium trioxide and analogue poisonous and that environmental pollution is serious

2), repeatedly activated carbon treatment and filtration

All very dark being difficult to observes owing to the two-phase color when 3), extracting

4), the production cycle is long

5), repeatedly silica gel column chromatography separates

6), use ether to be recrystallization solvent

Swern reaction process with methyl-sulphoxide/oxalyl chloride oxidation is unstable, condition is harsh need to (78 ℃) carry out under low temperature very, and equipment requirements is high, energy consumption is large, is not suitable for suitability for industrialized production.

Summary of the invention:

In order to overcome the deficiency of above-mentioned technique, the object of the present invention is to provide a kind of preparation method of Prostaglandin PGE2, compare with existing method, successfully avoided the many deficiencies in the existing technique, particularly avoided using severe toxicity and the large chromium reagent of environmental hazard.Equipment requirements of the present invention is simple, easy to operate, the reaction process environmental protection, and easily control is fit to suitability for industrialized production.The present invention is equally applicable to other F type prostaglandin(PG) is changed into E type prostaglandin(PG).For achieving the above object, technical scheme of the present invention is:

A kind of preparation method of Prostaglandin PGE2 may further comprise the steps:

1. the sulphur trioxide pyridine is the PGF2 α of 11,15 hydroxyl protections of oxygenant oxidation, and is can be fast gentle, obtain the PGE2. of 11,15 hydroxyl protections to high yield

2. the PEG2 of hydroxyl protection is hydrolyzed in citric acid and goes protection to obtain PGE2.

Concrete reaction process is as follows:

It is characterized in that:

1), the sulphur trioxide/pyridine of the oxidizing reaction environment for use close friend in the described step 1 replaced the large chromium reagent of hypertoxic environmental hazard, reaction temperature and fast, convenient post-treatment is easy.

2), 11,15 hydroxyl protecting groups of PGF2 α can be the siliceous protecting groups such as trimethyl silicane, triethyl silicon, dimethyl tertiary butyl silicon, also can be the groups of the protection hydroxyl commonly used such as THP trtrahydropyranyl, ether base.Employed oxygenant is sulphur trioxide/pyridine mixture, and solvent is DMSO, and temperature of reaction is between 20 to 25 ℃, and the tertiary amines such as triethylamine are alkali.

3), pyridine/sulphur trioxide is dissolved among a certain amount of DMSO in the storage tank in a reaction, stir until all dissolvings.Another reactor adds respectively the PGF2 of a certain amount of DMSO, protection after vacuum-nitrogen switches deoxygenation, stirring and dissolving also maintains the temperature between 20-25 ℃, then adds quantitative triethylamine and stirs simultaneously and maintain the temperature between 20-25 ℃.The DMSO solution of the sulphur trioxide pyridine that configures is added drop-wise in the reactor, adds rear stirring 15 minutes, whole process remains and stirs and temperature is controlled between 20-25 ℃.The mol ratio of used material is: the PGF2 of protection: the sulphur trioxide pyridine: triethylamine=1: 2～6: 5～10, preferred 1: 3: 6.The amount of solvent for use DMSO is the PGF2 of 3～6 milliliters of every gram protections.

4), a certain amount of citric acid is dissolved in the quantitative water is mixed with aqueous citric acid solution.After thin-layer chromatography detection oxidizing reaction is finished, slowly aqueous citric acid solution is joined in the reactor take the cancellation reaction until pH, remains simultaneously that temperature is between 20 to 25 ℃ as about 3.Add subsequently a certain amount of ethyl acetate and fully stirring.The consumption of citric acid and ethyl acetate roughly is respectively: the PGF2 of every gram protection adds 6 gram citric acids, 5 milliliters of ethyl acetate.After telling organic phase, water boils off the PGE2 crude product that is protected after the ethyl acetate with quantitative ethyl acetate extraction twice.

5), the hydrolysis protective reaction of described step 2 is clean fast.Primary column chromatography is only used in aftertreatment, once decolouring, and primary crystallization just can reach satisfied result, and the crystallization solvent for use is ethyl acetate/normal hexane, avoids the ether solvent that uses lower boiling inflammable.Brought up to the 65%-70% from average about 15% to the PGE2 overall yield from the PGF2 of protection.

6), to go to protect employed acid be citric acid, solvent is tetrahydrofuran (THF)/water, so citric acid is 50% aqueous solution, temperature is between 20～60 ℃, preferred 50 ℃, about 1-2 of reaction times hour.

7), reaction drip after finishing the sodium bicarbonate aqueous solution cancellation react to pH between 3.6-4.0, the control temperature adds ethyl acetate extraction between 20-25 ℃.Tell organic layer, last product dissolves in and transfers to silica gel column chromatography behind a small amount of methylene dichloride and carry out separation and purification after the distillation desolventizing.All moving phases of column chromatography are respectively methyl alcohol-dichloromethane solution of 3%, 4.5%, 9%.

8), the column chromatography purification products therefrom is dissolved in ethyl acetate, add activated carbon decolorizing, filter, in filtrate, add normal hexane, temperature control crystallization between 16-18 ℃.The amount of agents useful for same is: every gram PGE2 restrains 6 milliliters of normal hexanes with 3 milliliters of ethyl acetate, gac 0.1.Crystallization time is 2-3 hour.If necessary, can use the same method and carry out recrystallization.

Embodiment

Key point of the present invention is that to have replaced toxicity chromium reagent with the sulphur trioxide pyridine be that oxygenant is oxidized to PGE with PGF, environmental friendliness; Disposable charcoal is processed and has been replaced repeatedly activated carbon decolorizing-filtration treatment; The layering difficulty of having taken an advanced study very much owing to the two-phase color in the last handling process when having avoided with chromium reagent; Avoid using ether to shorten the production cycle simultaneously.Whole process is simple, safety, low cost.The following examples can more specifically be understood the present invention.

Embodiment 1:11, the oxidation of the PGF2 α of 15 hydroxyl protections

The sulphur trioxide pyridine that in a flask, adds 12 grams (0.075 mole), 50 milliliters of DMSO, induction stirring makes its dissolving.To the PGF2 α that adds respectively 12.5 gram (0.025mol) protections during another is equipped with the four-hole bottle of mechanical stirrer, thermometer, constant pressure funnel; 25 milliliters of DMSO, 23 milliliters of triethylamines, whole process system nitrogen protection; keep stirring, temperature is controlled between the 20-25 ℃ of degree.Then transfer to the sulphur trioxide pyridine for preparing first-DMSO solution in the dropping funnel and slowly splash in the reaction flask, the control temperature is between 20-25 ℃.Stirred 15 minutes between 20-25 ℃ after adding, TLC follows the tracks of reaction process until raw material point disappears, and reaction generally finished within 30 minutes.In another beaker, add 75 gram citric acids, 180 ml waters preparation citric acid quencher.After question response is finished, aqueous citric acid solution is slowly joined in the reaction solution until reaction mixture pH arrives 3 with the cancellation reaction, the cancellation process temperature is controlled between 20-25 ℃.Add subsequently 60 milliliters of ethyl acetate, standing demix after fully stirring, tell organic layer after water use again ethyl acetate extraction twice, use 25 milliliters of ethyl acetate at every turn.Underpressure distillation is removed ethyl acetate gained residue and is the PGE2 crude product of protection, can be directly used in lower one-step hydrolysis and go protection, or save backup in refrigerator under the nitrogen protection.

Embodiment 2: protection preparation PGE2 is removed in hydrolysis

In 500 milliliters of four-hole bottles that mechanical stirrer, reflux condensing tube, thermometer vacuum/nitrogen switching deoxygenation are housed, add respectively 12.4 gram (0.025 mole), 65 milliliters of tetrahydrofuran (THF)s, after the stirring and dissolving, add 26 milliliter of 50% aqueous citric acid solution.Reaction solution is hydrolyzed 1-2 hour 50 ℃ of lower stirrings.Sampling in per 30 minutes, TLC detects until raw material point disappears.Reaction is cooled to 20-25 ℃ after finishing, and adds behind 90 ml waters with 10% sodium bicarbonate aqueous solution (about 84 grams) accent pH between the 3.6-4.0.Then add 95 milliliters of ethyl acetate, after fully stirring, standing demix.Water layer merges organic phase with 50 milliliters of ethyl acetate extraction after telling upper organic phase.Last oily matter is dissolved in 8 milliliters of methylene dichloride after the underpressure distillation desolventizing, and transfers to and carry out separation and purification on the silicagel column.Moving phase is respectively methyl alcohol-dichloromethane solution of 3%, 4.5%, 9%.Collection contains the PEG2 cut, gets the PGE2 crude product after the distillation desolventizing.

The crystallization of embodiment 3:PGE2 and recrystallizing and refining

Add 12.5 gram PGE2 crude products in 250 milliliters of four-hole bottles, 50 milliliters of ethyl acetate, and control 20-25 ℃ of temperature, and add 1.25 gram gacs, stirred 1 hour.Filter, the filtrate decompression distillation, the oily residuum after the desolventizing is dissolved in 35 milliliters of ethyl acetate again, and whipping temp is controlled between 20-25 ℃.After having dissolved, add 35 ml n-hexanes, stirred 1 hour at 16-18 ℃.Should there be crystal to separate out around here, when having a large amount of crystal to separate out, slowly adds other 35 ml n-hexanes in one hour, maintain the temperature between 16-18 ℃.After adding normal hexane, continue to stir material 2-3 hour, keep 15-16 ℃ of temperature.Filter, filter cake is washed twice with 15 milliliters of cold normal hexanes.Filter cake 20-25 ℃ of lower vacuum-drying to constant weight.Total recovery is about 70%, purity 98.5%.

Claims (7)

1. method for preparing rostaglin E2 (being prostaglandin E2), it is characterized in that: the method is 11,15 hydroxyl protections with Prostaglandin PGF2 alpha, and 9 hydroxyls of oxidation become the ketone carbonyl, goes to obtain Prostaglandin PGE2 after the protection.

2. described preparation method according to claim 1, it is characterized in that: prostaglandin F can be that PGF2 α also can be other F prostanoid, thereby to other PGEs.11,15 hydroxyl selectivity of prostaglandin F are protected, protecting group can be siliceous group such as trimethyl silicon based, triethyl is silica-based, the dimethyl tertiary butyl is silica-based, also can use ethers protecting group such as THP trtrahydropyranyl, ether base etc.

3. described preparation method according to claim 1, it is characterized in that: used oxygenant is sulfur trioxide pyridine complex, solvent is DMSO, DMF isopolarity aprotic solvent, temperature of reaction is between the 20-25 degree, the tertiary amines such as triethylamine are alkali.The molar weight ratio of used material is: the PGF of protection: sulphur trioxide: triethylamine=1: 2～6: 5～10, preferred 1: 3: 6, quantity of solvent was 3～6 ml/gs of PGF.

4. method for oxidation according to claim 3 is characterized in that: after reaction was finished, adding aqueous citric acid solution was 3 cancellation reactions to pH, and aftertreatment ethyl acetate extraction product, ethyl acetate consumption are that every gram PGF is with 5～10 milliliters.

5. described preparation method according to claim 1 is characterized in that hydrolysis goes protective to be: tetrahydrofuran (THF)-50% aqueous citric acid solution.Temperature of reaction is between the 20-60 degree, and preferred 50 spend, and the reaction times is 1-2 hour.After finishing, reaction transfers pH to 3.6-4.3, ethyl acetate extraction product with sodium bicarbonate aqueous solution.

6. described preparation method according to claim 5, it is characterized in that: the thick product purification by silica gel column chromatography of gained PGE after the hydrolysis, used moving phase is respectively methyl alcohol-dichloromethane solution of 3%, 4.5%, 9%.

7. described preparation method according to claim 6 is characterized in that: product is further purified recrystallization behind the available activated carbon decolorizing behind column chromatography purification.The amount of used gac is 10% of crude product, and recrystallization solvent is that volume ratio is ethyl acetate-normal hexane of 1: 2, and Tc is between the 16-18 degree, and the time is 2-3 hour.The amount of solvent for use is 9 milliliters of every gram crude products.