CN101098867B - Substituted sulfoxide compound and its preparing method and application - Google Patents
Substituted sulfoxide compound and its preparing method and application Download PDFInfo
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- CN101098867B CN101098867B CN200680001258.7A CN200680001258A CN101098867B CN 101098867 B CN101098867 B CN 101098867B CN 200680001258 A CN200680001258 A CN 200680001258A CN 101098867 B CN101098867 B CN 101098867B
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Abstract
The present invention discloses an optical pure compound in Formula I, the salt and the solvate which are acceptable for the medicine of the compound, and the usage of the salt and the solvate in preparing medicine and medicine compound. The present invention also provides the preparation method for the compound defined in the invention.
Description
The cross reference of related application
The application requires the rights and interests of No. the 200510058962.3rd, the Chinese patent application of the same name submitted on March 25th, 2005, and this paper clearly introduces its full content as a reference.
Background of invention
1.
TECHNICAL FIELD OF THE INVENTION
The optical isomer of the sulfoxide class, particularly Omprazole compound that the present invention relates to replace.The invention still further relates to the method for the optical isomer of preparation Omprazole compound, and the purposes in the preparation medicine.
2.
Description of the Prior Art
Usually, peptide ulceration (90% for stomach ulcer and duodenal ulcer) is that the enhancing and/or the weakening of defense factor (as barrier of gastric mucosa, mucosal blood flow, prostaglandin(PG), epithelium regeneration, supercarbonate secretion etc.) of because the interior stomach mucous membrane attack factor of body (as hydrochloric acid in gastric juice, helicobacter pylori (Hp), stomach en-, take NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) etc.) causes.
(Helicobactor pylori, Hp) infecting, take NSAIDs usually is ulcerogenic immediate cause for bad food habits, excessive drinking, stress or various pressure, helicobacter pylori.Wherein hydrochloric acid in gastric juice plays an important role in the process that gastric mucosa injury and ulcer increase the weight of, Hp infect then with seriousness, reactivity and the stubbornness of the morbidity of this disease, pathology more not and recur relevant in early days.Therefore " relieving haperacidity " and " eradication therapy of Hp " (Hp is detected the male patient) become two important indications of peptide ulceration clinical treatment at present.
Have the compound of benzimidazole structure with the class headed by the omeprazole (Omeprazole), can suppress the acid effect of secreting of the parietal cell that caused by any stimulation, promptly gastric acid inhibitory is pumped to the final step of gastral cavity from parietal cell, thereby curative effect is best.Because this step is at H
+, K
+Under the effect of/ATP enzyme, pass through H
+And K
+Exchange transport and realize that therefore, this class can suppress H
+, K
+The compound of/atpase activity be called as proton pump inhibitor (Proton Pump Inhibitor, PPI).Listing at present except that omeprazole, also have lansoprazole (Lansoprazole), pantoprazole (Pantoprazole), rabeprazole (Rabeprazole) and Esso omeprazole (Esomeprazole) the optical purity omeprazole of new listing (calendar year 2001).
Singly clinically can treat various digestive tract ulcers, and treat multiple ulcer due to the gastrin, the medicine source ulcer due to the NSAIDs and bisfentidine (as Cimitidine Type A/AB and Ranitidine HCL) is had chemical sproof intractable ulcer with " drawing azoles " class (being PPI).Its ulcer healing rate two all Nei Keda 80% can reach 100% all around, and recurrence rate also significantly reduces.For the patient of Hp test positive, can with two kinds of antibacterial agents.At this moment, PPI can improve the activity of antiseptic-germicide, can reach more than 90% the Hp clearance rate in two weeks.At present, the triple therapy of PPI and two kinds of antiseptic-germicides has become the basic therapy of treatment Hp male peptide ulceration.Except the treatment peptide ulceration, PPI also can treat gastro oesophageal reflux disease (GORD) (GORD), Zuo-Ai syndrome (ZES) and other disease relevant with hyperchlorhydria.
(the I1-Yang Pharm.Co. of Korea S IL-Yang Pharm. Co., Ltd; Ltd.; Korea) developed 5-(1H-pyrroles-1-the yl)-2-[[(3-methyl-4-methoxyl group-2-pyridyl of racemization)-methyl] sulfinyl]-benzoglyoxaline is as new proton pump inhibitor; in treating GORD and stomach, duodenal ulcer; shown that the antiulcer action more superior than omeprazole (see Korean Patent the 179th, No. 401, United States Patent (USP) the 5th; 703, No. 097).
Above benzimidazoles anti-ulcer medicament all belongs to the sulfoxide of structural similitude, all contains the chiral centre three-dimensional arrangement of a sulfinyl, therefore has a pair of optical isomer, i.e. enantiomer separately.If there is the three-dimensional center of another chirality in the molecule, these compounds exist with paired enantiomorph so.These corresponding thioethers that contained the compound at the three-dimensional center of chirality are not the prochirality compounds, but chipal compounds.Yet the sulphur atom in these compounds does not have asymmetry, and therefore they are called as prochirality thioether class in the present invention.Comprise that a large amount of publications such as patent and patent application disclose the preparation method such as the single enantiomer of benzoglyoxalines such as omeprazole, lansoprazole, rabeprazole, pantoprazole, for example SE 9,500,818, DE 4,035,455, WO 94/27988 and ZL98124029.1 (this paper introduces its full content as a reference).Studies show that optically pure levo-omeprazole (being the Esso omeprazole) is compared with the omeprazole of racemization, have higher physiologically active, better medicament dynamics and lower toxic side effect (Lindberg, P.; Weidolf, No. the 5th, 877,192, L. United States Patent (USP), 1999).
Left-handed (-) that the result of study display optical is pure or dextrorotation (+) 5-(1H-pyrroles-1-yl)-2-[[(3-methyl-4-methoxyl group-2-pyridyl)-methyl] sulfinyl]-benzoglyoxaline to press down the acid effect all strong than its raceme.In view of this optically pure left-handed (-) or dextrorotation (+) body and syntheticly never appear in the newspapers in the literature; therefore; we have made great efforts to study synthetic 5-(1H-pyrroles-1-yl)-2-[[(3-methyl-4-methoxyl group-2-pyridyl)-methyl] sulfinyl]-method of benzoglyoxaline single enantiomer, and as the purposes in the medicine of anti-peptic ulcer and other and gastric acid related disorder.
At notification number is in the Chinese patent of CN 1070489C, discloses by making prochirality thioether generation asymmetric oxidation prepare the method that is rich in enantiomeric form (this paper is introduced into as a reference) of omeprazole.This method is by in organic solvent (being preferably toluene and ethyl acetate), under the condition that organic bases, the Chiral Titanium title complex that is made by titanium compound and chiral alcohol and hydrogen peroxide derivative oxygenant exist, make the prochirality sulfide oxidation, prepare the omeprazole that is rich in enantiomorph.But, when this method being applied to prepare 5-(1H-pyrroles-1-the yl)-2-[[(3-methyl-4-methoxyl group-2-pyridyl that is rich in enantiomorph)-methyl] sulfinyl]-during benzoglyoxaline, there be the enantioselectivity and the lower problem of yield of product.
Summary of the invention
A first aspect of the present invention relates to the optical pure compound of formula I,
(IUPAC name: 5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline), acceptable salt of its medicine and medicine acceptable solvent thing thereof.
A second aspect of the present invention relates to optical pure compound, the acceptable salt of its medicine or its medicine acceptable solvent thing purposes in preparation medicine or pharmaceutical composition of formula I.
According to the preferred embodiments of the invention, this medicine is used for the treatment of the disease relevant with hyperchlorhydria with pharmaceutical composition, for example stomach ulcer, GORD and Zuo-Ai syndrome.
A third aspect of the present invention relates to pharmaceutical composition, and it comprises the optical pure compound of the formula I that treats effective dose, or the acceptable salt of its medicine or its medicine acceptable solvent thing or its mixture and medicine acceptable carrier.
A fourth aspect of the present invention relates to the method for the treatment of the illness relevant with hyperchlorhydria such as individual stomach ulcer, duodenal ulcer, GORD, Zuo-Ai syndrome, comprises that the optical pure compound with the formula I that treats effective dose carries out administration to individuality.
A fifth aspect of the present invention relates to the method for the optical pure compound of preparation formula I, is included in the trichloromethane prochirality sulfoxide of oxidation-type II (as reacting shown in 1) in the presence of oxygenant.
[reaction 1]
The inventive method is characterised in that the prochirality thioether is single enantiomer or the corresponding sulfoxide that is rich in enantiomorph by asymmetric oxidation.And described method is compared with the method for using other solvent, has more enantioselectivity in trichloromethane.
According to specific embodiments of the present invention, use the hydrogen peroxide derivative as oxygenant, and in the presence of alkali, Chiral Titanium title complex, carry out method of the present invention.According to the preferred embodiment of the inventive method, in reaction system, add
Molecular sieve can improve the yield of the formula I compound that is rich in enantiomorph by this.Preferably, employed
The granularity of molecular sieve is the 4-8 order.
According to another preferred embodiment of the inventive method, be room temperature to 110 ℃ in temperature, be preferably 30 °-80 ℃, carry out reaction of the present invention under more preferably about 31 ℃.
A sixth aspect of the present invention relates to the intermediate shown in the Formula Il I, the IUPAC name: 5-amino-2-[(4-methoxyl group-3-methyl-2-pyridyl)-and methylthio group]-1-hydrogen-benzoglyoxaline.
According to the preferred embodiments of the invention, but at prochirality thioether (IUPAC name: 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl)-methylthio group of acidic conditions Formula Il I compound and formula IV compound reaction preparation formula II]-1-hydrogen-benzoglyoxaline) (shown in reaction formula 2).
[reaction 2]
A seventh aspect of the present invention relates to the formula III intermediates preparation, comprises formula V compound and formula VI compound reaction (shown in reaction formula 3).
[reaction 3]
Animal experiment shows that the optically pure isomer of formula I compound of the present invention is compared with its racemic modification, has more excellent result of treatment in the treatment disease relevant with hyperchlorhydria.
Detailed description of the invention
An aspect of of the present present invention relates to the optical pure compound of formula I, acceptable salt of its medicine and medicine acceptable solvent thing thereof, and their purposes in preparation medicine or pharmaceutical composition:
Unless otherwise indicated; the term that uses among the present invention " optical pure compound of formula I " or " active ingredient " refer to (-)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline or (+)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline.
Term used in the present invention " the acceptable salt of medicine " refers to that medicine is acceptable and has the salt of the The compounds of this invention of required pharmacological activity.This salt includes but not limited to following form: (1) acid-adducting salt, refer to use handle the acceptable acid-adducting salt of the medicine that obtains such as suitable acid such as mineral acid or organic acids, wherein said mineral acid includes but not limited to: haloid acid (example hydrochloric acid, Hydrogen bromide, hydrofluoric acid, hydroiodic acid HI), sulfuric acid, nitric acid, phosphoric acid, perchloric acid, boric acid or the like; Described organic acid includes but not limited to: tartrate, tussol, fumaric acid, succsinic acid, oxysuccinic acid, Whitfield's ointment, toxilic acid, fumaric acid, citric acid, palmitinic acid, styracin, lactic acid, xitix, the hydroxyl naphthoic acid, glyconic acid, L-glutamic acid, acetate, propionic acid, propanedioic acid, Succinic Acid, caproic acid, oxyacetic acid, pyruvic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, cyclohexylamine sulfonic acid, the 2-naphthene sulfonic acid, camphorsulfonic acid, lauryl sulfonic acid, phenylformic acid, Phosphoric acid glycerol esters, ketoisocaproic, stearic acid and the known acid of other those skilled in the art; Or the salt that the acid proton on the benzoglyoxaline substitute to be formed by atoms metal (as basic metal (as Li, Na and K), alkaline-earth metal (as Ca and Mg) or aluminium) in (2) compound, or itself and salt such as the organic bases formation of thanomin, diethanolamine, trolamine and N-methylglucosamine etc.
Term used in the present invention " medicine acceptable solvent thing " can be the hydrate of compound, perhaps can contain the compound that waits other crystallization solvent such as alcohol.
Another aspect of the present invention relates to pharmaceutical composition, and it comprises optical pure compound, the acceptable salt of its medicine or its medicine acceptable solvent thing or its mixture and the medicine acceptable carrier of the formula I that treats effective dose.
In the present invention, when the mixture of the optical pure compound that refers to formula I and/or the acceptable salt of its medicine and/or its medicine acceptable solvent thing, got rid of racemic compound, the acceptable salt of its medicine, its medicine acceptable solvent thing or their mixture of formula I.
Can be used for carrier of the present invention and comprise the acceptable organic or inorganic carrier substance of medicine, these materials are applicable to non-enteron aisle or enteron aisle (oral) administration, and not with active compound generation deleterious effects.Suitable pharmaceutical carrier includes but not limited to: water, salts solution, alcohols, gum arabic, vegetables oil, benzylalcohol, polyoxyethylene glycol, gelatin, sugar (for example lactose), amylose starch or starch, Magnesium Stearate, talcum powder, silicic acid, viscous paraffin, volatile oil, glycerine monofatty ester and two glyceryl ester, pentaerythritol fatty ester, carboxymethyl cellulose, Polyvinylpyrolidone (PVP), Vltra tears, cellulose acetate phthalate, acroleic acid resin, hypromellose phthalate and similar compounds etc.
The concentration of active compound depends on described medicine absorption in vivo, distribution, metabolism and discharge rate in the pharmaceutical composition of the present invention, and the known factor of other those skilled in the art.Should be appreciated that the dose value of composition also can change along with the severity of morbid state to be treated.Be also to be understood that at concrete individuality, should pass in time according to professional's judgement specific dosage is adjusted.
Composition of the present invention can be made into the acceptable various formulations of medicine.Can use the acceptable suitable carrier of medicine when preparing these formulations.These formulations include but not limited to capsule (comprising slow release formulation or delayed release dosage forms), tablet, pulvis, solution, suspension agent, syrup, pill, granule, elixir, tincture, implant (comprising suppository), emulsion and injection, preferred enteric coated capsule or tablet.
For parenterai administration, suitable formulation comprises the sterile solution agent that can inject or freeze-dried preparation and suspension agent, emulsion etc.
For enterally administering, suitable formulation has tablet, drageeing, liquor, drops, capsule, syrup, tincture etc.
Described preparation of the present invention can be individually dosed or with such as other promoting agent Combined Preparation such as antiseptic-germicide.
Another aspect of the present invention relates to the method for the treatment of the illness relevant with hyperchlorhydria such as individual stomach ulcer, duodenal ulcer, GORD and Zuo-Ai syndrome, comprises treating optical pure compound, the acceptable salt of its medicine, its medicine acceptable solvent thing or their mixture of formula I of effective dose to described individual administration.
Among the present invention, term " individuality " is often referred to various animals, is preferably Mammals, more preferably refers to the mankind, and they are objects of treatment, observation or experiment.
For treating any above-mentioned disease, the optical pure compound for the treatment of the formula I of effective dose can be passed through for example administration of oral or non-enteron aisle mode with proper formula (the medicine acceptable carrier that can comprise various routines).In addition, described activeconstituents can be individually dosed, or with such as other promoting agent combination administration such as antiseptic-germicide.Can single administration or multiple dosing.
The solid dosage that is used for oral administration comprises tablet, pill, granula, capsule etc.Described solid dosage can comprise any following ingredients or have the compound of similar characteristics: various vehicle such as Microcrystalline Cellulose, Trisodium Citrate, lime carbonate, Rhodiaphos DKP and glycine; And various disintegrating agents such as starch, more preferably cereal, potato or tapioca (flour), alginic acid, yellow soda ash and some composition silicate; And tackiness agent such as polyvinylpyrrolidone, sucrose, gelatin and kordofan gum; Wetting agent such as glycerine; Solution retarding agent such as paraffin; Absorption enhancer such as quaternary ammonium compound; Wetting agent such as cetyl alcohol and glyceryl monostearate; Absorption agent such as potter's clay, bentonite and clay; Or seasonings such as peppermint, wintergreen oil or orange food flavouring.In addition, also often add Magnesium Stearate, sodium lauryl sulphate, talcum, calcium stearate, solid polyethylene glycol and its mixture as the lubricant in the tablet.For capsule, except that the material of the above-mentioned type, also can comprise liquid vehicle such as lipid acid.Can also use dressing and shell material to prepare solid dosage form such as tablet, capsule, pill and granula, as enteric coating, release control dressing and the known dressing form of other medicines formulation art.When preparation capsule, tablet and pill, can also comprise buffer reagent in the composition that makes up a prescription.Described solid dosage form only can also be made into or the preferential form that discharges its activeconstituents in a part of enteron aisle, selectively discharge in the slowly-releasing mode.In addition, also available one or more the above-mentioned vehicle of described activeconstituents are made microencapsulation form.
The liquid dosage form that is used for oral administration comprises the acceptable emulsion of medicine, microemulsion, solution, suspension liquor, syrup and elixir.Used thinner is selected from water, ethanol, propylene glycol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, phenylamino benzoic acid methyl esters, 1,3-butyleneglycol, dimethyl formamide, oils, as Oleum Gossypii semen, peanut oil, Semen Maydis oil, embryo (bud) oil, sweet oil, Viscotrol C, sesame oil or the like, glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and fatty acid ester, as sorbitanic with and various mixture.For orally using, if desired, can with described activeconstituents with such as combination such as the assistant agent of sweetener, sweetener, tinting material etc.
The formulation that is used for parenterai administration, for example solution or suspension agent etc. can comprise any following component: such as sterile diluent, salt brine solution, expressed oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetic of water for injection; Antiseptic-germicide such as benzylalcohol or methyl parabens; Antioxidant such as xitix or Sodium Metabisulphate 65; Complexing agent such as EDTA; Such as acetate, Citrate trianion or phosphatic buffer reagent and be used to adjust tensile reagent such as sodium-chlor or glucose.If the employing intravenous administration, preferred carrier comprises physiological saline or PBS or auxiliary.Described auxiliary includes but not limited to alum, aluminum phosphate or other oil or aqueous emulsion type auxiliary.
Different according to the state of treat individual body weight and sex, the illness of being treated, the disease of curing the disease and route of administration, The compounds of this invention is used for the dosage of human body and can adjusts according to those skilled in the art's professional judgement.Dosage when usually, being used for adult patient's prevention or treatment gastric duodenal ulcer is preferably 1 to 1000mg/ day, more preferably 3 to 100mg/ days.
Another aspect of the present invention relates to the method for the optical pure compound of preparation formula I, be included in the trichloromethane, in the presence of oxygenant, make formula II 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl)-methylthio group]-the prochirality thioether generation asymmetric oxidation of 1-hydrogen-benzoglyoxaline.
[reaction 1]
Described in CN 1070489C, the used organic solvent of the asymmetric oxidation of formula II thioether can be selected from toluene, p-Xylol, ethyl acetate, methylethylketone, methyl iso-butyl ketone (MIBK), diethyl carbonate, t-butyl methyl ether, tetrahydrofuran (THF), methylene dichloride etc.But adopt trichloromethane as solvent in the methods of the invention, and use other organic solvent to compare the enantioselectivity of asymmetric oxidation is significantly improved.
In the preferred embodiment of the inventive method, in reaction system, add
Molecular sieve, it can improve the yield that is rich in the enantiomorph product.The consumption of described molecular sieve is preferably about 10 times that are no more than substrate weight, and more preferably about 1-5 doubly; The granularity of molecular sieve is preferably the 4-8 order.
In the specific embodiments of the inventive method, described reaction of the present invention is carried out in the presence of alkali and Chiral Titanium title complex.
The alkali that is suitable for the inventive method can be mineral alkali or organic bases.Described mineral alkali includes but not limited to, alkali metal hydroxide, supercarbonate.Described organic bases includes but not limited to guanidine class and amides.Wherein preferred organic bases, more preferably amine, and most preferably triethylamine or N, N-diisopropylethylamine.Institute's alkali charge can be regulated according to the situation of reaction mixture, is preferably about 0.1-1.0 equivalent.
The Chiral Titanium title complex that is suitable for catalysis the inventive method can prepare in the presence of the water of any amount by titanium compound and chiral reagent.Preferred titanium compound is the alkoxide of titanium, for example titanium isopropylate or titanium propanolate, more preferably titanium isopropylate.
Preparation use in the titanium complex chiral reagent preferably chiral alcohol, for example chirality dibasic alcohol.Described dibasic alcohol can be branched-chain or straight-chain alkyl dibasic alcohol or aromatic diols.Preferred chirality dibasic alcohol is tartaric ester class, preferred especially (+)-diethyl tartrate or (-)-diethyl tartrate.
The consumption of Chiral Titanium title complex is not crucial among the present invention.Be generally and be no more than about 1 equivalent, and be preferably about 0.05 to about 1 equivalent, more preferably about 0.5 to about 1 equivalent.
In the preferred embodiment of the invention, in the presence of prochirality thioether II, the chirality titanium complex is activated, promptly before adding described chiral coordination compound, in reaction vessel, add described prochirality thioether.Suitable activation temperature is extremely about 115 ℃ of room temperatures, and suitable soak time is about 1-10 hour.
In another embodiment preferred of the present invention, the preparation of described Chiral Titanium title complex is what to carry out simultaneously in the presence of the prochirality thioether of formula II with activation, promptly before adding is used to prepare the component of described Chiral Titanium title complex, in reaction vessel, add described prochirality thioether.Suitable preparation and activation temperature are extremely about 115 ℃ of room temperatures, and the suitable time is about 1-10 hour.
The oxygenant that is suitable for asymmetric oxidation reaction of the present invention can be the hydrogen peroxide derivative, and for example tertbutyl peroxide or cumene hydroperoxide are preferably cumene hydroperoxide.The consumption of described oxygenant is preferably about 1-1.2 equivalent.
Usually, the temperature of asymmetric oxidation reaction is chosen in-40 ℃ to about 115 ℃ approximately, is preferably room temperature to about 115 ℃, more preferably 30 ℃ to about 80 ℃, most preferably is about 31 ℃.
In a preferred embodiment of the invention, after the oxidation, the extraction of gained reaction mixture process, drying, after the evaporation, with the thick product silicagel column purifying of gained, eluent ethyl acetate can obtain the product that optical purity is 76-98%ee.
In another preferred embodiment of the present invention, with optical purity is the further recrystallization in the mixed solvent of organic solvents such as ethyl acetate, acetone, butanone, ether, t-butyl methyl ether, methylene dichloride, trichloromethane or its composition of product of 76-98%ee, be settled out the more product of high antimer content, the optical purity of product can be brought up to more than the 99%ee.
The new compound 5-amino shown in the formula III-2-[(4-methoxyl group-3-methyl-2-pyridyl that relates in one aspect to again of the present invention)-methylthio group]-1-hydrogen-benzoglyoxaline.Wherein the compound shown in the formula III under acidic conditions with formula IV compound 2, but the thioether (as reacting shown in 2) of 5-dimethoxy-tetrahydrofuran reaction preparation formula II.
[reaction 2]
Be adapted at reacting the acid of using in 2 and be preferably organic acid, more preferably Glacial acetic acid.Preferably under the reflux temperature of about 80 ℃-150 ℃ or solvent, carry out described reaction.The mol ratio of formula III compound and formula IV compound is preferably about 1: 1.
In preferred embodiments, the mixture that reacts gained is extracted, drying after the evaporation, obtains crude product, with crude product recrystallization in ether or methyl alcohol, promptly can obtain formula II compound.
The preparation method who relates in one aspect to formula III more of the present invention is included in the solvent and alkali exists and makes formula V compound and formula VI compound react (as reacting shown in 3) down.
[reaction 3]
Be adapted at reacting in 3 the solvent that uses and be preferably polar solvent, more preferably the mixed solvent of methyl alcohol, ethanol, tetrahydrofuran (THF), methylene dichloride, trichloromethane or itself and water.The alkali that is adapted in this reaction using comprises organic bases and mineral alkali, sodium hydroxide for example, potassium hydroxide, salt of wormwood, sodium methylate, sodium bicarbonate, sodium hydride, potassium hydride KH, pyridine, triethylamine, ethyl diisopropyl amine etc., or its mixture.The consumption of described alkali is preferably about 1-2 equivalent.Temperature of reaction is preferably 0 ℃ to about 200 ℃.The mol ratio of formula V and formula VI compound is preferably about 1: 1.
In preferred embodiments, the mixture of filtering reaction gained then with filtrate evaporated under reduced pressure, obtains the thick product of formula III compound to remove solid precipitation, is directly used in the preparation of formula II compound.
In specific embodiments of the present invention, formula V compound 5-amino-2-mercapto phenyl formic-1-hydrogen-benzoglyoxaline can be by reduction following formula VII compound 5-nitro-2-sulfydryl-1-hydrogen benzoglyoxaline preparation (as reacting shown in 4), and used ordinary method and condition are that those skilled in the art are known.
[reaction 4]
In a preferred embodiment of the invention, formula VII compound is dissolved in methyl alcohol, ethanol, methylene dichloride, trichloromethane or the tetrahydrofuran (THF), adds the normal zinc powder of 5-20 then in batches.In mixture, slowly add concentrated hydrochloric acid to described mixture and be colourless.Reaction removes by filter insolubles after finishing, and adds the unsaturated carbonate potassium solution filtrate is adjusted to pH=9-10.Add decolorizing with activated carbon, continued heating reflux reaction 0.5-2 hour, diatomite filtration, drying obtains formula V compound.
Below in conjunction with embodiment above-mentioned aspect of the present invention and others and advantage thereof are illustrated in greater detail.Yet should be appreciated that the present invention is not limited to these specific embodiments and embodiment of the present invention only are illustrative.
Embodiment
Preparation
Synthesizing of 5-amino-2-mercapto phenyl formic-1-hydrogen-benzoglyoxaline (V)
Method 1:
0.5g (2.57mmol) 5-nitro-2-sulfydryl-1-hydrogen-benzoglyoxaline (VII) is dissolved in 50mL methyl alcohol, in this solution, adds 3g (45.8mmol) zinc powder in batches, stir.Then in this mixture slowly Dropwise 5 mL concentrated hydrochloric acid become to it colourless, stirring at room 0.5 hour.Reaction removes by filter insolubles after finishing, and adds 50mL methyl alcohol in filtrate, adds the unsaturated carbonate potassium solution and regulates pH=9-10.The heating reflux reaction mixture is 0.5 hour then, filters, and evaporate to dryness gets 0.27g yellow solid title compound, and yield is 65.0%.
1H-NMR(300MHz，DMSO-d
6)：δ(ppm)：4.96(s，2H)，6.37(s，1H)，6.39(d，J＝9Hz，1H)，6.81(d，J＝9Hz，1H)。
Method 2:
5g (25.7mmol) 5-nitro-2-sulfydryl-1-hydrogen-benzoglyoxaline (VII) is dissolved in the 300mL dehydrated alcohol, in this solution, adds 16.8g (257mmol) zinc powder in batches, stir.In this mixture, slowly drip then the 30mL concentrated hydrochloric acid become to it colourless, stirring at room 1 hour.Reaction removes by filter insolubles after finishing, and adds 100mL ethanol in filtrate, adds the unsaturated carbonate potassium solution and regulates pH=9-10.The heating reflux reaction mixture is 1 hour then, filters, and evaporate to dryness obtains 2.5g yellow solid title compound, and yield is 60.2%.
Method 3:
50g (0.257mol) 5-nitro-2-sulfydryl-1-hydrogen-benzoglyoxaline (VII) is dissolved in the 2000mL methyl alcohol, in this solution, adds 168g (2.57mol) zinc powder in batches, stir.In this mixture, slowly drip then the 320mL concentrated hydrochloric acid become to it colourless, stirring at room 2 hours.Reaction removes by filter insolubles after finishing, and adds the unsaturated carbonate potassium solution and regulates pH=9-10.The heating reflux reaction mixture is 1 hour then, filters, and evaporate to dryness obtains 28g yellow solid title compound, and yield is 67.4%.
5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl)-methylthio group]
Synthesizing of-1-hydrogen-benzoglyoxaline (II)
Method 1:
Under the room temperature, 4.95g (0.030mol) 5-amino-2-mercapto phenyl formic-1-hydrogen-benzoglyoxaline (V) and 2.88g (0.072mol) sodium hydroxide are dissolved in the 30mL water, drip the methanol solution 150mL of 2-chloromethyl-3-methyl-4-methoxypyridine hydrochloride of 8.09g (0.039mol) then.After 3 hours, filter reaction mixture and reduction vaporization obtain thick product (III).
1H-NMR(300MHz，DMSO-d
6)：δ(ppm)：2.16(s，3H)，3.84(s，3H)，4.58(s，2H)，6.43(d，J＝7.8Hz，1H)，6.54(s，1H)，6.93(d，J＝5.7Hz，1H)，7.15(d，J＝7.8Hz，1H)，8.23(d，J＝5.7Hz，1H)。
Then, described thick product is dissolved in the 60mL acetate, stirs, add 4.65mL (0.036mol) 2,5-dimethoxy-tetrahydrofuran (THF) (IV) was 120 ℃ of reflux products therefroms 5 minutes.Reaction is poured reaction mixture in the 200mL water into after finishing, with methylene dichloride (100mL * 3) extraction.Merge organic phase, anhydrous sodium sulfate drying, reduction vaporization desolvates to remove.Resistates obtains the title compound of 3.45g with ether or recrystallizing methanol, and yield is 38.1%.
Fusing point 194.8-196.0 ℃.
1H-NMR(300MHz，CDCl3)：δ(ppm)：2.27(s，3H)，3.91(s，3H)，4.38(s，2H)，6.34(t，J＝2.1Hz，2H)，6.78(d，J＝6.0Hz，1H)，7.09(t，J＝2.1Hz，2H)，7.23-7.27(m，1H)，7.53-7.56(m，2H)，8.37(d，J＝6.0Hz，1H)。
Method 2:
Under the room temperature, 29.7g (0.18mol) 5-amino-2-mercapto phenyl formic-1-hydrogen-benzoglyoxaline (V) and 14.4g (0.36mol) sodium hydroxide are dissolved in 200mL water and the 250mL ethanol composition mixed solvent, drip the ethanolic soln 200mL of 2-chloromethyl-3-methyl-4-methoxypyridine hydrochloride of 37.34g (0.18mol) then.After 3 hours, filter reaction mixture and reduction vaporization obtain thick product (III).Then described thick product is dissolved in the 300mL acetate, stirs, be added dropwise to 27.9mL (0.216mol) 2,5-dimethoxy-tetrahydrofuran (THF) (IV) is in this solution.120 ℃ of reflux products therefroms 5 minutes.Reaction is poured reaction mixture in the 1000mL water into after finishing, with methylene dichloride (500mL * 3) extraction.Merge organic phase, anhydrous sodium sulfate drying, reduction vaporization desolvates to remove.Resistates 30mL recrystallizing methanol obtains the title compound of 15.75g, and yield is 29%.
Asymmetric synthesis
(-)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl]
Sulfinyl]-1-hydrogen-benzoglyoxaline
Embodiment 1
With 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl)-methylthio group]-1-hydrogen-benzoglyoxaline (II) (50mg, 0.143mmol) be dissolved in the 1mL trichloromethane, add (-)-diethyl tartrate of 49 μ L (0.286mmol) and the titanium isopropylate of 43 μ L (0.143mmol), and stirred 5 minutes.The water that in this solution, adds 2.6 μ L (143mmol).After the stirring at room one hour, add the N of 25 μ L (0.143mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 31 μ L (0.172mmol).Room temperature reaction 18 hours, termination reaction.Reaction mixture is through extraction, and drying obtains thick product after the evaporation.Then with the thick product silicagel column purifying of gained, eluent ethyl acetate, can obtain yield is 37.7%, it is the title compound of 76.4%ee that HPLC measures enantioselectivity.
1H-NMR(300MHz，CDCl
3)：δ(ppm)：2.21(s，3H)，3.85(s，3H)，4.72-4.91(AB-system，J＝13.5Hz，2H)，6.37(t，J＝2.1Hz，2H)，6.72(d，J＝5.7Hz，1H)，7.10(t，J＝2.1Hz，2H)，7.38(d，J＝8.7，1H)，7.56(s，1H)，7.66(d，J＝8.7Hz，1H)，8.29(d，J＝5.7Hz，1H)。
Measure the HPLC analysis condition of enantioselectivity: Chiralpak OJ-H post, moving phase are 35% Virahol-normal hexane, and flow velocity is 1ml/min, and the detection wavelength is 254nm, RT
(+)=9.588min, RT
(-)=18.614min.
Embodiment 2
Under 31 ℃, 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl with 50mg (0.143mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL trichloromethane, adds (-)-diethyl tartrate of 49 μ L (0.286mmol) and the titanium isopropylate of 43 μ L (0.143mmol).After the stirring at room one hour, add the N of 25 μ L (0.143mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 31 μ L (0.172mmol).31 ℃ were reacted termination reaction 18 hours.Reaction mixture is through extraction, and drying obtains thick product after the evaporation.With the thick product silicagel column purifying of gained, eluent ethyl acetate, can obtain yield is 49.7%, it is the title compound of 88.0%ee that HPLC measures enantioselectivity.
Embodiment 3
Under 31 ℃, 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl with 50mg (0.143mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL trichloromethane, and add the titanium isopropylate of (-)-diethyl tartrate of 49 μ L (0.286mmol) and 43 μ L (0.143mmol) and stirred 5 minutes.The water that in this solution, adds 2.6 μ L (0.143mmol).Stir after one hour, add the N of 25 μ L (0.143mmol) successively, N-diisopropylethylamine and 31 μ L (0.172mmol) cumene hydroperoxides (80%).Under 31 ℃, react 18 hours termination reactions.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 32.5%, it is the title compound of 92.1%ee that HPLC measures enantioselectivity.
Embodiment 4
Under 80 ℃, 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl with 50mg (0.143mol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL trichloromethane, add (-)-diethyl tartrate of 49 μ μ L (0.286mmol) and the titanium isopropylate of 43 μ μ L (0.143mmol), and stirred 5 minutes.The water that in this solution, adds 2.6 μ μ L (0.143mmol).Stir after one hour, add the N of 25 μ μ L (0.143mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 31 μ L (0.172mmol).Under 80 ℃, react 18 hours termination reactions.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 24.7%, it is the title compound of 93.7%ee that HPLC measures enantioselectivity.
Embodiment 5
5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl with 50mg (0.143mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL toluene, add (-)-diethyl tartrate of 49 μ L (0.286mmol) and the titanium isopropylate of 43 μ L (0.143mmol), and stirred 5 minutes.The water that in this solution, adds 2.6 μ L (0.143mmol).After the stirring at room one hour, add the N of 25 μ L (0.143mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 31 μ L (0.172mmol).Under 30 ℃, react 1 hour termination reaction.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 32.7%, it is the title compound of 64.1%ee that HPLC measures enantioselectivity.
Embodiment 6
Under the room temperature, with 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl of 50mg (0.143mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL trichloromethane, adds 100mg's
(-)-diethyl tartrate of molecular sieve (4-8 order), 49 μ L (0.286mmol) and the titanium isopropylate of 43 μ L (0.143mmol) stirred 5 minutes.The water that in this solution, adds 2.6 μ L (0.143mmol).Stir after one hour, add the N of 25 μ L (0.143mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 31 μ L (0.172mmol).Under the room temperature, react 16 hours termination reactions.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 39.9%, it is the title compound of 89.4%ee that HPLC measures enantioselectivity.
Embodiment 7
Under 31 ℃, with 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl of 50mg (0.143mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL trichloromethane, adds 100mg's
(-)-diethyl tartrate of molecular sieve (4-8 order), 49 μ L (0.286mmol) and the titanium isopropylate of 43 μ L (0.143mmol) stirred 5 minutes.The water that in this solution, adds 2.6 μ L (0.143mmol).Stir after one hour, add the N of 25 μ L (0.143mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 31 μ L (0.172mmol).Under 31 ℃, react 18 hours termination reactions.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 76.5%, it is the title compound of 92.8%ee that HPLC measures enantioselectivity.
Embodiment 8
Under 80 ℃, with 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl of 50mg (0.143mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL trichloromethane, adds 200mg's
(-)-diethyl tartrate of molecular sieve (4-8 order), 49 μ L (0.286mmol) and the titanium isopropylate of 43 μ L (0.143mmol) stirred 5 minutes.The water that in this solution, adds 2.6 μ L (0.143mmol).Stir after one hour, add the N of 25 μ L (0.143mmol) successively, under (80%) 80 ℃ of the cumene hydroperoxide of N-diisopropylethylamine and 31 μ L (0.172mmol), react 18 hours termination reactions.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 35.5%, it is the title compound of 96.2%ee that HPLC measures enantioselectivity.
The comparative example
Following is (-)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl that the described method of Chinese patent of CN 1070489C is rich in enantiomeric form according to notification number)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline synthetic.
The comparative example 1
5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl with 20mg (0.057mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL methylene dichloride, add (-)-diethyl tartrate of 19.6 μ L (0.114mmol) and the titanium isopropylate of 17.2 μ L (0.057mmol), stirred 5 minutes.The water that in this solution, adds 1.0 μ L (0.057mmol).After the stirring at room one hour, add the N of 10.0 μ L (0.057mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 12.4 μ L (0.069mmol).22 hours termination reactions of room temperature reaction.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 37.7%, it is the title compound of 11.1%ee that HPLC measures enantioselectivity.
The comparative example 2
5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl with 20mg (0.057mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL toluene, add (-)-diethyl tartrate of 19.6 μ μ L (0.114mmol) and the titanium isopropylate of 17.2 μ L (0.057mmol), stirred 5 minutes.The water that in this solution, adds 1.0 μ μ L (0.057mmol).After the stirring at room one hour, add the N of 10.0 μ μ L (0.057mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 12.4 μ L (0.069mmol).Under 30 ℃, react 16 hours termination reactions.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 5.2%, it is the title compound of 23.3%ee that HPLC measures enantioselectivity.
The comparative example 3
Under 54 ℃, 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl with 20mg (0.057mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL toluene, add (-)-diethyl tartrate of 19.6 μ μ L (0.114mmol) and the titanium isopropylate of 17.2 μ μ L (0.057mmol), stirred 5 minutes.The water that in this solution, adds 1.0 μ L (0.057mmol).54 ℃ are stirred after one hour down, add the N of 10.0 μ L (0.057mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 12.4 μ L (0.069mmol).Under 54 ℃, react 1 hour termination reaction.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 33.3%, it is the title compound of 36.5%ee that HPLC measures enantioselectivity.
The comparative example 4
Under 110 ℃, 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl with 20mg (0.057mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL toluene, add (-)-diethyl tartrate of 19.6 μ L (0.114mmol) and the titanium isopropylate of 17.2 μ L (0.057mmol), stirred 5 minutes.The water that in this solution, adds 1.0 μ L (0.057mmol).110 ℃ are stirred after one hour down, add the N of 10.0 μ L (0.057mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 12.4 μ L (0.069mmol).Under 110 ℃, react 1 hour termination reaction.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 35.4%, it is the title compound of 53.1%ee that HPLC measures enantioselectivity.
The comparative example 5
Under 110 ℃, 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl with 20mg (0.057mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL toluene, add (-)-diethyl tartrate of 19.6 μ L (0.114mmol) and the titanium isopropylate of 17.2 μ L (0.057mmol), stirred 5 minutes.The water that in this solution, adds 1.0 μ L (0.057mmol).110 ℃ are stirred after one hour down, add the N of 10.0 μ L (0.057mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 12.4 μ L (0.069mmol).Under 110 ℃, react 16 hours termination reactions.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 21.4%, it is the title compound of 29.2%ee that HPLC measures enantioselectivity.
Discuss
As shown in table 1, each embodiment and comparative example's reaction conditions and product yield and enantioselectivity are compared
Table 1
| Add water | Add molecular sieve | Solvent | Temperature (℃) | Yield (%) | Enantioselectivity (%ee) | |
| Embodiment | ||||||
| 1 | Be | Not | Trichloromethane | Room temperature | 37.7 | 76.4 |
| 2 | Not | Not | Trichloromethane | 31 | 49.7 | 88.0 |
| 3 | Be | Not | Trichloromethane | 31 | 32.5 | 92.1 |
| 4 | Be | Not | Trichloromethane | 80 | 24.7 | 93.7 |
| Add water | Add molecular sieve | Solvent | Temperature (℃) | Yield (%) | Enantioselectivity (%ee) | |
| 5 | Be | Be | Toluene | 30 | 32.7 | 64.1 |
| 6 | Be | Be | Trichloromethane | Room temperature | 39.9 | 89.4 |
| 7 | Be | Be | Trichloromethane | 31 | 76.5 | 92.8 |
| 8 | Be | Be | Trichloromethane | 80 | 35.5 | 96.2 |
| The comparative example | ||||||
| 1 | Be | Not | Methylene dichloride | Room temperature | 37.7 | 11.1 |
| 2 | Be | Not | Toluene | 30 | 5.2 | 23.3 |
| 3 | Be | Not | Toluene | 54 | 33.3 | 36.5 |
| 4 | Be | Not | Toluene | 110 | 35.4 | 53.1 |
| 5 | Be | Not | Toluene | 110 | 21.4 | 29.2 |
As can be seen from Table 1:
1. do not add
During molecular sieve, adopt methylene dichloride or toluene as solvent, the enantioselectivity of product lower (＜55%ee); And when using trichloromethane as solvent, the enantioselectivity of product significantly improve (＞75%ee).
2. add
Molecular sieve is compared with not adding molecular sieve, when keeping or improving enantioselectivity, the yield of product is risen.
(+)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl]
Sulfinyl]-1-hydrogen-benzoglyoxaline
Embodiment 9
Under 31 ℃, 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl with 50mg (0.143mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL trichloromethane, add (+)-diethyl tartrate of 49 μ L (0.286mmol) and the titanium isopropylate of 43 μ L (0.143mmol), stirred 5 minutes.The water that in this solution, adds 2.6 μ L (0.143mmol).Holding temperature is 31 ℃, stirs after one hour, adds the N of 25 μ L (0.143mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 31 μ L (0.172mmol).Under 31 ℃, react 18 hours termination reactions.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with the thick product silicagel column purifying of gained, and eluent ethyl acetate, can obtain yield is 34.4%, it is the title compound of 94.9%ee that HPLC measures enantioselectivity.
1H-NMR(300MHz，CDCl
3)：δ(ppm)：2.21(s，3H)，3.85(s，3H)，4.72-4.91(AB-system，J＝13.5Hz，2H)，6.37(t，J＝2.1Hz，2H)，6.72(d，J＝5.7Hz，1H)，7.10(t，J＝2.1Hz，2H)，7.38(d，J＝8.7，1H)，7.56(s，1H)，7.66(d，J＝8.7Hz，1H)，8.29(d，J＝5.7Hz，1H)。
Measure the HPLC analysis condition of enantioselectivity: Chiralpak OJ-H post, moving phase are 35% Virahol-normal hexane, and flow velocity is 1ml/min, and the detection wavelength is 254nm, RT
(+)=9.588min, RT
(-)=18.614min.
Embodiment 10
Under 31 ℃, with 5-(1H-pyrroles-1-yl)-2-[(4-methoxyl group-3-methyl-2-pyridyl of 50mg (0.143mmol))-methylthio group]-1-hydrogen-benzoglyoxaline (II) is dissolved in the 1mL trichloromethane, adds 100mg's
(+)-diethyl tartrate of molecular sieve (4-8 order), 49 μ L (0.286mmol) and the titanium isopropylate of 43 μ L (0.143mmol).Stir after one hour, add the N of 25 μ L (0.143mmol) successively, the cumene hydroperoxide (80%) of N-diisopropylethylamine and 31 μ L (0.172mmol).Under 31 ℃, react 18 hours termination reactions.Reaction mixture is through extraction, and drying obtains thick product after the evaporation, with product silicagel column purifying, and eluent ethyl acetate, can obtain yield is 40.2%, it is the mixture of 92.6%ee that HPLC measures enantioselectivity.
The purifying of asymmetric synthesis product
(-)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl]
Sulfinyl]-purifying of 1-hydrogen-benzoglyoxaline
Method 1:
With 100mg (-)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline (90.2%ee) is dissolved in 0.5mL CH
2Cl
2In, stirring at room, decolorizing with activated carbon.Filter, in filtrate, add the 1.5mL ether.Stirring at room mixture half an hour, refrigerator is placed and is spent the night, filter, 42mg white solid title compound, yield: 42%, ee:93.2%.
Method 2:
With 100mg (-)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline (90.2%ee) is dissolved in the 10mL acetone, still has small amount of solid not molten.Filter, mother liquor filters with the decolouring of activated carbon room temperature, evaporation.Resistates is dissolved in 2mL acetone, and stirring at room half an hour, refrigerator is placed and is spent the night, and filters, and obtains 36mg white solid title compound, yield 36%, ee:93.7%.
Method 3:
With 100mg (-)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline (87.3%ee) is dissolved in the 10mL acetone, has a large amount of solids insoluble.Filter, the decolouring of activated carbon room temperature is filtered, evaporation.Resistates is dissolved in the mixture of 2mL acetone and 4mL ethyl acetate, stirring at room one day, refrigerator is placed and is spent the night, and filters, and obtains 32mg faint yellow solid title compound, yield: 32%, ee:96.2%.
Method 4:
With 20mg (-)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline (96.2%ee) is dissolved in 0.2mL CH
2Cl
2In, stirring at room is molten clear.Decolorizing with activated carbon filters.Add the 1.0mL ether in filtrate, stirring at room half an hour, refrigerator is placed and is spent the night, filter, 12mg white solid title compound, yield is 60%, ee:＞99%.
[α]
D 23=-207.8 (c=1, pyridines).
(+)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl]
Sulfinyl]-purifying of 1-hydrogen-benzoglyoxaline
Method 1:
With 100mg (+)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline (87.3%ee) is dissolved in the 10mL methylene dichloride, obtains settled solution.The decolouring of activated carbon room temperature is filtered, evaporation.Resistates is dissolved in the mixture of 2mL methylene dichloride and 4mL butanone, stirring at room two days, refrigerator is placed and is spent the night, and filters, and obtains 35mg white solid title compound, yield: 35%, ee:96.8%.
Fusing point: 167.1-167.3 ℃.
Method 2:
With 100mg (+)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline (87.3%ee) is dissolved in the 10mL acetone, has a large amount of solids insoluble.Add the 2mL aqueous methylamine solution, the solution becomes clarification.The decolouring of activated carbon room temperature is filtered, evaporation.Resistates is dissolved in the mixture of 2mL acetone and 4mL butanone, stirring at room one day, refrigerator is placed and is spent the night, and filters, and obtains 43mg white solid title compound, yield: 43%, ee:97.7%.
[α]
D 23=+207.6 (c=1, pyridines).
Method 3:
With 100mg (+)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline (98.3%ee) is dissolved in the 10mL acetone, has a large amount of solids insoluble.Add the 2mL aqueous methylamine solution, the solution becomes clarification.The decolouring of activated carbon room temperature is filtered, evaporation.Resistates is dissolved in the mixture of 2mL acetone and 4mL butanone, stirring at room one day, refrigerator is placed and is spent the night, and filters, and obtains 51mg white solid title compound, yield: 51%, ee:＞99%.
Pharmacology test
Effect (pylorus ligature law) to rat acute stomach ulcer
Method
With pylorus ligature law (Shay method) research optical purity (+)/(-)-5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline is to the effect of rat acute stomach ulcer, and the result is contrasted with normal control group and raceme group.Concrete test method is as follows:
With 26 healthy SD is female adult rat fasting 24 hours, but can drink water, and is divided into 4 groups at random.Use the vetanarcol of 30mg/kg that every rat is anaesthetized then and carry out pylorus ligation.After this; 3 groups of rats (treatment group) by duodenum respectively with 5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline raceme, levo form and the direct administration of dextrorotatory form; dosage is 3mg/kg, and the solvent that uses equal volume is to other group (control group) administration.
Then whole rat fasting were prohibited water 6 hours, put to death then.Stomach-tissue is taken out in the ligation spray behind the door, collects gastric juice.Be immersed in 10% formalin solution, dissect the appetizing tissue along greater gastric curvature then, open coat of the stomach, the degree and the quantity of visual inspection stomach mucous membrane ulcer.With the summation of the long diameter of each ulcer as ulcer index.Be housed in the metabolic cage the whole rats of duration of test.
The result
The results are shown in Table 2.
The effect of table 2 pair rat acute stomach ulcer
| Rat quantity | Dosage (mg/kg) | Average hydrochloric acid in gastric juice volume (ml), (inhibiting rate %) | Ulcer index (mm), (inhibiting rate %) | |
| Control group | 8 | 4.6±2.6 | 25±16 | |
| Raceme | 6 | 3 | 3.2±2.3 (30.8％) | 14±8(41.8％) |
| Levo form | 4 ** | 3 | 1.4±1.0 (68.3％) | 6±6 *(75.6％) |
| Dextrorotatory form | 6 | 3 | 2.6±1.1 (43.2％) | 6±7 *(75.6％) |
Annotate:
1. "
*" compare with control group, use the t check, P＜0.05.
2. "
*" 6 rats are at first in this group test, but at 1 rats death of duration of test, the data exception of 1 rat is got rid of it according to statistics.
3.
4.
As can be seen from Table 2, after test showed (1) pylorus ligation, control rats obviously showed acute gastric ulcer, and the gastric acid secretion that for example increases also stomach mucous membrane ulcer occurs; (2) compare with control group, in whole treatment groups, the volume of hydrochloric acid in gastric juice reduces and stomach mucous membrane ulcer is eased; And (3) and 5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-raceme of 1-hydrogen-benzoglyoxaline compares, and its levo form and dextrorotatory form be gastric acid inhibitory secretion and ulcer more effectively.
Although the present invention has used and has stated bright and specific embodiment and be described in detail.But those skilled in the art obviously can be by disclosed instruction of the present invention, and the present invention is further changed and modifies, and these do not break away from the variation of marrow of the present invention and modify and should belong to scope of the present invention.
Claims (6)
1. the optical pure compound method of preparation formula I, it is included in the trichloromethane, in the presence of oxygenant, the prochirality thioether of oxidation-type II:
Wherein said oxygenant is hydroperoxide, and carries out described method in the presence of alkali and Chiral Titanium title complex.
2. the method for claim 1 also comprises adding 4
Molecular sieve.
3. method as claimed in claim 2, wherein said 4
The granularity of molecular sieve is the 4-8 order.
4. as the described method of arbitrary claim among the claim 1-3, wherein under room temperature to 110 ℃, carry out described method.
5. method as claimed in claim 4 is wherein carried out described method under 30 ° to 80 ℃.
6. method as claimed in claim 5 is wherein carried out described method under 31 ℃.
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| PCT/CN2006/000490 WO2006099810A1 (en) | 2005-03-25 | 2006-03-24 | Substituted sulfoxide compounds, methods for preparing the same and use thereof |
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| CN102140092B (en) * | 2010-02-03 | 2013-05-29 | 丽珠医药集团股份有限公司 | Hydrate of ilaprazole salt, preparation method thereof and application thereof |
| CN105218522B (en) * | 2014-06-25 | 2019-04-02 | 江苏奥赛康药业股份有限公司 | A kind of dextrorotation Iprazole compound and its pharmaceutical composition |
| CN105566294B (en) * | 2014-10-08 | 2018-04-24 | 江苏奥赛康药业股份有限公司 | A kind of dextrorotation Iprazole sodium compound and its pharmaceutical composition |
| CN108794451A (en) * | 2017-04-26 | 2018-11-13 | 深圳市华先医药科技有限公司 | A kind of synthesis of chiral Iprazole method |
| CN107141281B (en) * | 2017-06-28 | 2020-04-14 | 珠海赛隆药业股份有限公司 | Levalprazole sodium compound and pharmaceutical composition and preparation method thereof |
| CN107311984B (en) * | 2017-07-19 | 2020-04-14 | 珠海赛隆药业股份有限公司 | Dextro-ilaprazole sodium compound, and pharmaceutical composition and preparation method thereof |
| CN107468659A (en) * | 2017-09-26 | 2017-12-15 | 丽珠医药集团股份有限公司 | A kind of lactinated powder-injection and preparation method thereof |
| CN113880817A (en) * | 2021-12-07 | 2022-01-04 | 嘉实（湖南）医药科技有限公司 | Avanafil impurity D and synthesis method and application thereof |
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| CN1157614A (en) * | 1994-07-15 | 1997-08-20 | 阿斯特拉公司 | Process for synthesis of substituted sulphoxides |
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| US5703097A (en) * | 1994-02-28 | 1997-12-30 | Il-Yang Pharm. Co., Ltd. | 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole derivatives |
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