CN102477065B - Novel 16, 17-ketal intermediate for preparing budesonide - Google Patents
Novel 16, 17-ketal intermediate for preparing budesonide Download PDFInfo
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Abstract
The invention provides a novel 16, 17-ketal intermediate for preparing budesonide and discloses a compound of a formula (III), a method for synthesizing the compound of the formula (III) by a compound of a formula (I) and a method for synthesizing budesonide by the compound of the formula (III).
Description
Technical field:
The present invention relates to a kind of new pregnane compound and this compound in the application of preparing in budesonide.
Background technology:
Budesonide (budesonide, Bud) be a kind of non-halogeno-sugar cortin, there is the effect of anti-inflammatory, antianaphylaxis, antipruritic and exudation resistance, be widely used in clinically bronchial asthma and the asthmatic bronchitis of Corticodependence or dependent/non-dependent.U.S. FDA was ratified its oral enteric preparation and was used for maintaining treatment to relate to ileum and (or) colon ascendens light, moderate Crohn disease be Crohn disease (Crohn ' 5disease) October calendar year 2001.
The chemical name of Bud is 16 α, 17 α-22R, S-butylidene dioxy-11 β, 21-dihydroxyl-Isosorbide-5-Nitrae-pregnen diethylene-3,20-diketone.It is an epimer, and the activity of 22R type isomer is 2 times of 22S type.Bulk drug is the odorless tasteless crystalline powder of white, and water insoluble and heptane, is slightly soluble in ethanol, is soluble in chloroform.
Bud can strengthen the stability of endotheliocyte, smooth muscle cell and lysosome membrane, Immunosuppression reaction and reduction antibody are synthetic, thereby the release of the activity media such as histamine is reduced, activity decreased, and can alleviate antigen-antibody in conjunction with time the enzymic process that excites, suppress the synthetic of bronchoconstriction material and discharge, alleviating the contractile response of unstriated muscle.Experiment in vitro shows, Bud is higher 195 times than hydrocortisone to the avidity of glucocorticoid receptor, higher 15 times than prednisolone.Compared with being usually used in clinically at present the Viarox and fluticasone propionate of Treating Bronchial Asthma, Bud deposition in lung is high, and the residence time is longer, and local anti-inflammatory effect is stronger, eliminate speed fast, and untoward reaction is few.
1961, SeymourBernstein etc. found 16 α, and 17 α-bis-substituted methylene dioxygen structure steroides, think that this compound has higher anti-inflammatory activity, have also introduced 22 building-up processes without stereoselective Hydroxyprednisolone Acetonide simultaneously., under the effect of hydrochloric acid, react with acetone with 16 alpha-hydroxy prednisonlones, generate 16 α, the 17 pregnant steroid ketal compounds of alpha-dihydroxy-(), reaction formula is as follows.
1975, R.Brnasttnad etc. (US3928326,3929768) reported that other aldehydes or ketones replaces acetone to react with 16 alpha-hydroxy prednisonlones, obtains having the adrenocortical hormone of higher anti-inflammatory action.They react with 16 alpha-hydroxy prednisonlones with butyraldehyde-n, have synthesized budesonide, analyze two kinds of isomer proportion 22R: 225=50 with HPLC: 50, and be respectively two kinds of capable signs of isomer with NMR and mass spectrum.Rat is carried out to anti-inflammatory experiment, confirm with respect to fluticasone acetonide, the local anti-inflammatory effect that budesonide is higher, the low 4-7 of its whole body specific activity fluticasone acetonide is doubly simultaneously.Reaction process is that diox is done in solvent, makes catalyzer with 70% perchloric acid, makes butyraldehyde-n at room temperature react 3h with 16 alpha-hydroxy prednisonlones.After completion of the reaction, with methylene dichloride dilution, then by 10% wet chemical adjusting pH value, then with anhydrous magnesium sulfate drying.After underpressure distillation, with methylene dichloride, sherwood oil recrystallization, filter, dry, obtain content and be 94.4% budesonide, HPLC analyzes R, S isomer proportion is 50: 50.
1991, H and .Gerrti etc. improved aforesaid method, had simplified reaction process, made whole reaction feasible more economically.They replace diox to make the solvent reacting with second eyeball, react with Catalyzed by p-Toluenesulfonic Acid 16 alpha-hydroxy prednisonlones with butyraldehyde-n, and temperature of reaction is 25 DEG C, and the reaction times is about 3h, and R, S isomer proportion are 50: 50.
1985, M.Peter etc. (EPO164636) reported the method that can be obtained by Hydroxyprednisolone Acetonide and butyraldehyde-n budesonide through turning aldolization.Having studied Hydroxyprednisolone Acetonide and butyraldehyde-n can react in 70% hydrofluoric acid solution, and temperature of reaction is 0 DEG C, and the reaction times is about 1h, and can obtain two kinds of isomer proportions is 22R: 225=91: 9 budesonide.
Because hydrofluoric acid is wayward, 1987, the use such as J.Edid 70% perchloric acid is made catalyzer, butyraldehyde-n and Hydroxyprednisolone Acetonide react in methylene dichloride, in reaction system, add the inert material particles such as silicon-dioxide, glass, pottery as disperse phase, under room temperature, 16h is carried out in reaction, carries out recrystallization with methylene dichloride and sherwood oil, and the two kinds of isomer proportions of budesonide that obtain are 22R: 22S=95: 5.
1992, U.H.Teresa etc. are taking 21-acetoxyl group-16 alpha-hydroxy prednisonlone as raw material, 75% hydrofluoric acid is made catalyzer, at 0 DEG C, react h3 with butyraldehyde-n, react complete reaction solution is poured in frozen water, with ammonia neutralization, then chloroform extraction, concentrated, concentrated solution, through ethyl alcohol recrystallization, can obtain 21-acetoxyl group budesonide, and two kinds of isomer proportions are 95: 5.Again 21-acetoxyl group budesonide is dissolved in methyl alcohol, adds 10% salt of wormwood, the reaction approximately 1.5 hours that is hydrolyzed at 0 DEG C, after the cruel recrystallization of acetic acid second, two kinds of isomer 22R: 22S=99 of budesonide that obtain: 1.
In aforesaid method, there is a beta-hydroxy freely C11 position, 1998, L.L.FiliPPo etc. adopted Hydrogen bromide or hydroiodic acid HI as catalyzer, taking the compound of different structure as raw material, by acetalation or turn aldolization, can control 22 stereoisomerism selectivity and obtain budesonide.The raw material of reaction can be following various analogue, also can have two keys at C9 and C11 interdigit.Adopt result in this way, two kinds of isomer proportion 22R of budesonide that obtain: 22S can be controlled between 50: 50 to 60: 40.
R
1 is COCH
3 or H
R
2，R
3 are both H or R
2 and R
3，taken together，are-C(CH
3)-
X and Y are chosen from among the following：
A)X and Y，taken together，are an additional bond between C
9 and C
11
B)X is β-OH，and Y is α-Br
C)X and Y，taken together，are-O-
1999, L.L.FiliPPo etc. reported again and adopt Hydrogen bromide or hydroiodic acid HI as catalyzer, taking 9 α-bromine Hydroxyprednisolone Acetonide as raw material, by turning aldolization with butyraldehyde-n, obtain 9 α-bromine budesonide, then obtain budesonide by debrominate or de-iodine, wherein 22R budesonide is greater than 90%.
In the invention CN200810016414.8 of stock company of southern Shandong pharmacy group application in 2008, explanation is taking Prednisone acetate as raw material, by taking off 16-hydroxyl reaction with aceticanhydride, 5-sulphosalicylic acid, again by 16., 17 alkene oxidations, the reduction of 11-ketone, 21-acetic ester hydrolysis, 16,17-contracting butyraldehyde-n obtains budesonide.
In the invention CN200910155058.2 of Zhejiang Polytechnical University in 2009 application, explanation is taking 16 alpha-hydroxy prednisonlones (having another name called 16 Alpha-hydroxy Prednisolone Acetates) as raw material, in acidic ionic liquid by obtaining budesonide with butyraldehyde-n.
In sum, budesonide is to be mainly that raw material synthesizes by 16 alpha-hydroxy prednisonlones, but there is hydroxyl due to 21 in 16 alpha-hydroxy prednisonlones, in acetalation process, can produce impurity and not easily separated, in 21 hydroxyl processes of preparation, often all use iodate, replacing process, hydrolysis process simultaneously, and in iodate technique, use pure iodine as iodinating agent, because pure iodine value lattice are very expensive, so cost is more cheap in the time of the rear end of iodination reaction at synthesis technique.
Summary of the invention:
The invention discloses formula III compound, with formula (I) compou nd synthesis formula III compound method, and the method for formula III compou nd synthesis budesonide.
Formula (I) compound can be prepared by method below by formula II compound.
Wherein the preparation method of formula II compound can obtain in WO9818813.
Preparing a method for formula III compound, is to be reacted with the mixture of butyraldehyde-n, acid, organic solvent or organic solvent and water by formula (I) compound, and reaction is finished, and obtains formula III compound.Acid in described reaction is mineral acid.Be selected from hydrofluoric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, perchloric acid, tosic acid, acetic acid.Described organic solvent is nitrile, ether, the haloalkane of 1-4 carbon, is selected from diox, acetonitrile, tetrahydrofuran (THF), DMF, methylene dichloride, chloroform, preferably acetonitrile, tetrahydrofuran (THF), methylene dichloride, chloroform.
Described preparation method, reaction is finished, and can use mineral alkali to regulate pH value is neutrality.
Described preparation method, reaction is finished, and can obtain formula III compound by dilution, recrystallization.
The invention provides described formula III compound, in the application of preparing in budesonide.
The present invention also provides a kind of method of preparing budesonide, is obtained that (IV), 21 positions are got (V) in return, 21 acetic esters hydrolysis obtain budesonide by 21 iodate of formula III compound.
In described formula IV-I (I
2) illustrate that iodo thing is now two iodine thing-CHI
2or single iodine thing-CH
2i,
A kind of pharmaceutical composition, contains formula III compound and one or more pharmaceutical excipients as activeconstituents.Pharmaceutical excipient can be the pharmaceutical excipient that is applicable to prepare oral preparations, injection formulations, transdermal absorption formulation, sprays, Foradil Aerolizer formoterol fumarate.The synthetic method 1 of formula (I) compound:
Formula II compound 10mmol, acetone 50ml, formic acid 0.5ml adds in there-necked flask, stirs, and ice-water bath, adds KMnO4 solution [1.5g KMnO4 is dissolved in 15mL water], is stirred to red-purple and takes off to the greatest extent, adds 10%Na
2cO
3aqueous solution 12mL, stirs 0.5h, is warming up to 40 DEG C, filtered while hot, and with a small amount of washing with acetone washing leaching cake while hot, filtrate rotary distillation is concentrated into a large amount of crystal and separates out, suction filtration, washing, dry constant weight, obtains formula (I) compound 9.2mmol.
The synthetic method 2 of formula (I) compound:
30molK
3[Fe (CN)
6], 30molK
2cO
3with 0.04mmol K
2osO
2(OH)
4, in the solution of 100ml butanol/water (2: 1), under vigorous stirring, solution is chilled to 0 DEG C, add formula II compound 10mmol in batches, stir 17h, add 8g solid Na
2sO
3, stir 2h.Add 100mL methylene dichloride, separate organic layer.Water layer is used CH again
2cl
2extraction (50mlX3).Merge organic layer, anhydrous MgSO
4dry, concentrating under reduced pressure, by recrystallizing methanol, filters, and vacuum-drying, reclaims part, and the rate of recovery is 97%, obtains the synthetic method 3 of formula (I) compound formula (I) compound:
Acetone-water (10: 1, V/V) 40ml, OsO
40.05mmol, stir after 10min, add N-methyl-N-oxygen beautiful jade (NMO) 13mmol, said mixture is cooled to 0 DEG C, formula II compound 10mmol is dissolved in 20mL acetone, in 2h, slowly drop in reaction flask, 0 DEG C is continued to stir 6h, pressure reducing and steaming acetone, divide and add for three times the chloroform of precooling to amount to 30ml extraction, combined chloroform liquid, recrystallizing methanol, filters to obtain formula (I) compound 9.2mmol.
The invention also discloses the application of acceptable solvated compounds in preparation treatment people or Mammals medicine on described formula III compound and physiology thereof.
The invention also discloses the application of acceptable solvated compounds in preparation treatment people or Mammals anti-inflammatory or Claritin on described formula III compound and physiology thereof.Particularly preferably in preparation treatment people or mammal skin inflammation, as eczema, psoriasis, allergic dermatitis, neurodermatitis, itch and hypersensitivity reaction; Airway inflammation is as bronchial asthma, rhinallergosis, chronic obstructive pulmonary disease, interstitial pneumonia, pulmonary fibrosis; Eye inflammation is as conjunctivitis; Inflammatory bowel is as ulcerative colitis or Crohn disease; Osteoarthropathy is if rheumatic arthritis, rheumatoid arthritis and autoimmune disease are as the application in the medicine of the disease such as lupus erythematosus, pemphigus." treatment " of the present invention can extend to prevention and the diagnosis of disease.
The dosage of formula III compound disclosed by the invention in treatment people or mammalian diseases medicine is 0.2 μ g-50mg/kg/ days, preferably 1 μ g-2mg/kg/ days.During as treatment people's disease, people's body weight is generally calculated according to 50kg, thus people described in the present invention can calculate according to ABW with dosage, also can be according to the calculating of above-mentioned dosage × 50.
The invention also discloses a kind of pharmaceutical composition, it is characterized in that containing as any one or a few compound and one or more the pharmaceutically useful auxiliary materials described in the formula III of activeconstituents.
Pharmaceutical composition taking formula III compound as activeconstituents disclosed in this invention includes but are not limited to the pharmaceutical composition that is applicable to oral administration, drug administration by injection, orally administering, sublingual administration, parenteral admin, part or rectal administration, be preferably the pharmaceutical composition of whole body administration, particularly preferably oral administration, drug administration by injection.
The preparation of oral administration is common has tablet, capsule, oral liquid formulations, suspensoid, aqua etc. by the preparation of gastrointestinal absorption, the common preparation that has injection, infusion solution etc. to absorb by muscle, vein of injecting and administering preparations.
The pharmaceutical composition of described topical includes but are not limited to inhalation as aerosol, powder inhalation, sprays; Nasal formulations comprises as ointment, ointment, gelifying agent, lotion, foaming agent, patch, powder as nasal spray, nasal drop, external preparation; The tablet that orally administering preparation maybe can be sucked as chewed or pill, oral cavity sticking tablet; Local cavity preparation is as suppository, vaginal suppository, enema,retention; Ophthalmic preparation is as eye drops; And liposome or microcapsule formulation.Be preferably inhalation, nasal formulations and external preparation.
The described pharmaceutical composition taking formula III compound as activeconstituents dosage in the time for the treatment of people or mammalian diseases is counted 0.2 μ g-5mg/kg/ days with formula III compound, preferably 1 μ g-2mg/kg/ days.Described pharmaceutical composition is counted 0.2 μ g-5mg/kg/ days at the dosage for the treatment of people or Mammals supersensitivity, diseases associated with inflammation with formula II compound, preferably 1 μ g-2mg/kg/ days, described pharmaceutical composition adopts every day 1 time or more administering mode in use, preferred every day 1～3 time, also can adopt medication in many days administering mode once, dosage is the stack of Dan Tian.
In the time that the described described pharmaceutical composition taking formula III compound as activeconstituents is made oral or injection, described pharmaceutically acceptable auxiliaries is the pharmaceutical excipient of conventional oral or injection, and concrete kind and relevant method for making can be referring to relevant textbook or documents.
In the time that the described described pharmaceutical composition taking formula III compound as activeconstituents is made as the aerosol of inhalation, described pharmaceutically acceptable auxiliaries is propellent and one or more low volatility component.
Described propellent can include but are not limited to fluorochloroparaffins, hydrocarbon polymer, fluorohydrocarbon class, pressurized gas, one or more in ethers, comprise 1, 1, 1, 2-Tetrafluoroethane (HFA134a) and 1, 1, 1.2, 3, 3, 3-heptafluoro-propane (HFA227), Trichloromonofluoromethane (CCl3F), chlorodifluoromethane (CCl2F2), dichloro tetrafluoro ethane (CClF2-CClF2), propane (C3H8, ), Trimethylmethane (III so-C4H10), normal butane (n-C4H10), carbonic acid gas, nitrous oxide, nitrogen, be preferably one or more in fluorohydrocarbon compounds.Be particularly preferably a kind of or its combination in HFA134a and HFA227.
Described low volatility component can include but are not limited to, one or more in solvent, latent solvent, suspending agent, stablizer, correctives, sanitas.And also can be applicable to aerosol or the sprays of non-suction.
Described applicable latent solvent can be but be not limited only to ethanol or oleic acid, and preferably use ethanol, applicable solvent is glycerine, and propylene glycol or polyoxyethylene glycol preferably use glycerine.Solvent and latent solvent also can be referred to as thinner herein.
Described low volatiles can also be but be not limited only to following component, comprise other alcohol and glycol, for example alkanol, as the sugar alcohol of decyl alcohol (decyl alcohol), Sorbitol Powder, mannitol, Saccharum lactis, maltose alcohol, glycofural (tetrahydrofuran base methyl alcohol) and dipropylene glycol, comprise that vegetables oil, organic acid are as comprised the saturated carboxylic acid such as dodecylic acid and tetradecanoic acid and stearic acid; Comprise Sorbic Acid, particularly the unsaturated carboxylic acid such as oleic acid.The known stablizer that is applied to aerosol, sprays, suspending agent, correctives as asccharin, xitix, cyclamic acid, amino acid or aspartame; Alkane is as dodecane and octadecane; Terpenes is as menthol, eucalyptol, limonene; Sugar is as lactose, glucose, sucrose; Polysaccharide is as ethyl cellulose, dextran; Antioxidant is as Yoshinox BHT, Sodium Pyrosulfite, butylated hydroxyanisol; Polymkeric substance is as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone; Amine is as thanomin, diethanolamine, trolamine; Steroid class is as cholesterol, cholesteryl ester.
Should be appreciated that because of known reason, as the retention of activeconstituents in suction apparatus, the amount of every kind of activeconstituents that patient sucks can be different from the amount of metering.Therefore the applicating ratio between activeconstituents can be different from the ratio of metering.The ratio of preferably using is in the described metered proportions indicating.
Pharmaceutical composition taking formula III compound as activeconstituents of the present invention is made as the aerosol of inhalation; described powder inhalation is made up of dried powder; the method that obtains dried powder is for pulverizing activeconstituents of the present invention and pharmaceutical excipient as mechanical disintegration or spray-dired mode with known breaking method; be preferably the micronized dried powder that mid-diameter is less than 10 μ m; powder mass, preferred mid-diameter is from 0.1 to 5 μ m.As one replace, activeconstituents in small, broken bits can with one or more pharmaceutically useful non-active ingredients, as additive, diluent or carrier etc. form specify form of mixtures.The composition using in the present invention can obtain these preferred forms by method known to those skilled in the art.While utilizing spray-drying process to reach median size, in carrier, add nonionogenic tenside to increase mobility, preferred nonionogenic tenside is poloxamer.Activeconstituents: poloxamer weight ratio is 1: (0.01～5).The composition using in the present invention can obtain these preferred forms by method known to those skilled in the art.
When the described pharmaceutical composition taking formula III compound as activeconstituents is made nasal formulations, described pharmaceutically acceptable auxiliaries can include but are not limited to pH adjusting agent, carrier, osmotic pressure regulator, viscosity modifier,, one or more in all pharmaceutical excipients that are applicable to local nose administration such as suspending agent, antioxidant, tensio-active agent, stablizer, antibacterial sanitas.
Described carrier can include but are not limited to one or more in water, propylene glycol, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, whiteruss, vegetables oil, Vaseline, lanolin, CP.In the time that described pharmaceutical composition is made gelifying agent, described carrier contains water and crosslinked acrylic resin, and the CP using is preferably carbomer resin, is particularly preferably carbomer 934, consumption is 0.1%～1% of pharmaceutical composition weight, preferably 0.2% to 0.5%.The consumption of water is 90% to 99% of pharmaceutical composition weight.
Described pH adjusting agent can be enumerated but be not limited only to phosphoric acid and salt, boric acid and salt thereof, Citric Acid and salt thereof, acetic acid and salt thereof, tartrate and salt thereof, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, tromethane etc.
Described suspending agent can include but are not limited to, asccharin, xitix, cyclamic acid, amino acid or aspartame; Alkane is as dodecane and octadecane; Terpenes is as menthol, eucalyptol, limonene; Sugar is as lactose, glucose, sucrose; Polysaccharide is as one or more in ethyl cellulose, dextran.
Described antioxidant can include but are not limited to Yoshinox BHT, Sodium Pyrosulfite, butylated hydroxyanisol; Amine is as thanomin, diethanolamine, trolamine; Steroid class is as cholesterol, cholesteryl ester.
Described osmotic pressure regulator to include but are not limited to osmotic pressure regulator and can enumerate but be not limited only to glycerine, propylene glycol, sodium-chlor, Repone K, Sorbitol Powder, N.F,USP MANNITOL one or more etc.
Described viscosity modifier can be enumerated but be not limited only to one or more of polyvinyl alcohol, carboxy vinyl polymer, Polyvinylpyrolidone (PVP), foregoing CP, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, also can be used as viscosity modifier.
Described stablizer can include but are not limited to ethylenediamine tetraacetic acid (EDTA) and alkaline metal salt thereof, preferably disodium ethylene diamine tetraacetate.
Described tensio-active agent can be enumerated but be not limited only to tween-80, HCO60, polyoxyethylene glycol-stearate, Macrogol 4000, Yelkin TTS, sucrose ester, Voranol EP 2001, polyoxy stearate, one or more in polyoxyethylene, polyoxypropylene diols and analogue thereof.
Described antibacterial sanitas can include but are not limited to, one or more in benzalkonium chloride, benzethonium chloride, Sorbic Acid, potassium sorbate, methyl p-hydroxybenzoate (Tegosept M), nipagin A (ethyl p-hydroxybenzoate) propylparaben (propylben), chlorobutanol.
Propylene glycol, glycerine in described pharmaceutically useful auxiliary material can also replace with other alcohols, available alcohols can include but are not limited to other alcohols and glycols, for example alkanol, as decyl alcohol (decyl alcohol), the sugar alcohol that comprises Sorbitol Powder, mannitol, Saccharum lactis, maltose alcohol, glycofural (tetrahydrofuran base methyl alcohol) and dipropylene glycol.
When the described pharmaceutical composition taking formula III compound as activeconstituents is made external preparation, preferably make ointment, described pharmaceutically acceptable auxiliaries includes but are not limited to the antioxidant for pharmaceutical composition described in preservation, pH buffer reagent, wetting Agent for Printing Inks, oil-phase component, antibiotic antiseptic, the in addition water of surplus.
Described oil-phase component comprises one or more in solid in oil-phase component, consistency modifiers, emulsifying agent.
Solid in described oil-phase component includes but are not limited to one or more of stearic acid, paraffin, beeswax, higher alcohols, described higher alcohols is the monohydroxy-alcohol of 16～22 carbon atoms, preferably hexadecanol and/or stearyl alcohol, described consistency modifiers includes but are not limited to one or more in Vaseline, whiteruss, vegetables oil, preferably Vaseline and/or Liquid Paraffin, described emulsifying agent, include but are not limited to the derivative of soap class emulsifying agent, Soxylat A 25-7, described higher alcohols also plays the effect of tensio-active agent in emulsifiable paste simultaneously.
The composition of the above pharmaceutical composition is not limited only to described in technical solution of the present invention, also comprise any can be for the composition of the pharmaceutical excipient of above-mentioned preparation, the composition of described pharmaceutical excipient can be with reference to " pharmaceutics " (the 5th edition, Cui Fude, 2003 publish) in disclosed scheme.
Compared with glucocorticosteroid of the prior art, new formula III compound 21 provided by the invention is not for there is no hydroxyl, but when anti-inflammatory, still produce curative effect, with similar compound comparison, curative effect does not reduce, but the long-time skin atrophy situation causing that uses has had obvious improvement, uses and has better effect in long-term or general.
Embodiment:
Embodiment 1
Formula (I) compound 10mmol, acetonitrile 50ml, perchloric acid (70%) 30mmol adds in there-necked flask, stirs, and in 25 DEG C, adds butyraldehyde-n 12mmol, stirs after 3h, adds 10%Na
2cO
3the aqueous solution regulates pH value to 7, and rotary distillation is concentrated into a large amount of crystal and separates out, suction filtration, and washing, dry constant weight, obtains formula III compound 9.4mmol, 22R: 22S=58: 42.
Ultimate analysis: C, 72.31; H, 8.30; O, 19.39
Embodiment 2
Formula (I) compound 10mmol, tetrahydrofuran (THF) 30ml, HF aqueous solution 20mmol adds in there-necked flask, stir, in 25 DEG C, slowly drip butyraldehyde-n 12mmol, stir after 3h, add the 10%NaHCO3 aqueous solution to regulate pH value to 7, rotary distillation is concentrated into a large amount of crystal and separates out, suction filtration, washing, dry constant weight, obtains formula III compound 9.3mmol, 22R: 22S=51: 49.
Embodiment 3
Formula (I) compound 10mmol, tetrahydrofuran (THF) 5ml, chloroform 20ml, tosic acid 25mmol adds in there-necked flask, stir, in 25 DEG C, add butyraldehyde-n 12mmol, stir after 3h, with 10%NaHCO3 aqueous solution adjusting pH value to 7, add 20ml water, stratification, water layer divides three extractions with chloroform, each 10ml, after combined chloroform, rotary distillation is concentrated, by recrystallizing methanol, and suction filtration, dry constant weight, obtains formula III compound 9.2mmol, 22R: 22S=56: 44.
Embodiment 4 formula III compounds are prepared the synthetic method of budesonide
The technique of being prepared budesonide by (III) compound is existing common process, specifically can be referring to CN 200510122250.3, CN 200510122249.0.
The preparation of formula IV compound
Add 10mL methyl alcohol, (III) compound, then add chloroform that (III) compound 10mmol is dissolved, be cooled to 10 DEG C after clear and add below 0.3g calcium oxide until molten, continue to be down to 0 DEG C ± 2 DEG C, drip iodine liquid 12mmol, drip Bi Jixu insulated and stirred 1 hour.Be down to 0 DEG C again and add below static 30 minutes, chloroform layer is filtered, water layer 12mL, adds the chloroform of precooling to divide four extractions, combined chloroform liquid, and recrystallizing methanol, filters to obtain light yellow solid formula IV compound.
Formula (V) compound
Formula IV compound, 13mmol Potassium ethanoate that upper step is obtained are placed on 25mlN, in dinethylformamide (DMF), slowly be warming up to 50 DEG C with three hours, be incubated after 1 hour, cool to 0 DEG C, be diluted in frozen water, obtain formula (V) compound 9.1mmol.
The preparation of budesonide
Formula (V) compound 10mmol continues to add methyl alcohol to entirely molten under stirring, lower the temperature in 0-5 DEG C of dropping NaOH-MeOH solution, reacts after 2 hours, stops stirring, drip acetic acid to PH neutrality, filter, the concentrated white solid of separating out of filtrate, filter, dry, make budesonide.Mp：223-228℃
Example of formulations 1
Activeconstituents
Formula III compound 100.0g
Auxiliary material:
Pregelatinized Starch 100g
Microcrystalline Cellulose 130g
Lactose 200g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is appropriate
Make altogether 1000
Take activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross respectively 60-100 mesh sieve, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particle processed, dry, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes the applicable punch die of rear employing and is pressed into tablet.Every contains formula III compound 100mg.
Example of formulations 2
Activeconstituents:
Formula III compound 5.0g
Auxiliary material:
Microcrystalline Cellulose 130g
Lactose 200g
Magnesium Stearate 3g
Make altogether 1000
Activeconstituents, Microcrystalline Cellulose, lactose are crossed respectively to 80 mesh sieves, after mixing, add the Magnesium Stearate of recipe quantity, after mixing, pack in suitable capsule and get final product.Every contains formula III compound 5mg.
Example of formulations 3
Formula III compound 100.0g
Auxiliary material:
Pregelatinized Starch 100g
Microcrystalline Cellulose 130g
Lactose 200g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is appropriate
Make altogether 1000
Take activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross respectively 60-100 mesh sieve, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particle processed, dry, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes the applicable punch die of rear employing and is pressed into tablet.Every contains formula III compound 100mg.
Example of formulations 4
Formula III compound 40.0g
Auxiliary material:
Pregelatinized Starch 100g
Microcrystalline Cellulose 130g
Lactose 200g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is appropriate
Make altogether 1000
Take activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross respectively 60-100 mesh sieve, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particle processed, dry, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes the applicable punch die of rear employing and is pressed into tablet.Every contains formula III compound 40mg.
Example of formulations 5
Formula III compound 5.0g
Auxiliary material:
Lactose 100g
Magnesium Stearate 3g
Make altogether 1000
Activeconstituents, lactose are crossed respectively to 80 mesh sieves, after mixing, add the Magnesium Stearate of recipe quantity, after mixing, pack in suitable capsule and get final product.Every contains formula III compound 5mg.
Example of formulations 6
Formula III compound 10.0g
Auxiliary material:
Pregelatinized Starch 100g
Microcrystalline Cellulose 130g
Lactose 200g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is appropriate
Make altogether 1000
Take activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross respectively 60-100 mesh sieve, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particle processed, dry, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes the applicable punch die of rear employing and is pressed into tablet.Every contains formula III compound 10mg.
Example of formulations 7
Formula III compound 200.0g
Auxiliary material:
Pregelatinized Starch 100g
Microcrystalline Cellulose 80g
Lactose 180g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is appropriate
Make altogether 1000
Take activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross respectively 60-100 mesh sieve, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particle processed, dry, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes the applicable punch die of rear employing and is pressed into tablet.Every contains formula III compound 200mg.
Example of formulations 8
Formula III compound 50.0g
Auxiliary material:
Pregelatinized Starch 100g
Microcrystalline Cellulose 130g
Lactose 200g
Carboxymethylstach sodium 4g
Micropowder silica gel 5g
Magnesium Stearate 3g
The polyvidone aqueous solution is appropriate
Make altogether 1000
Take activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose according to recipe quantity, cross respectively 60-100 mesh sieve, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particle processed, dry, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes the applicable punch die of rear employing and is pressed into tablet.Every contains formula III compound 50mg.
Example of formulations 9
Activeconstituents: formula III compound 5g
Pharmaceutical excipient:
Hydroxypropylβ-cyclodextrin 30g
Carboxymethyl cellulose 50g
Propylene glycol 200g
Ethyl p-hydroxybenzoate 5g
Distilled water adds to 1000ml
Preparation technology:
Activeconstituents and hydroxypropylβ-cyclodextrin are crossed respectively to 100 mesh sieves, take according to recipe quantity, mix, add appropriate sterile distilled water fully to grind; Carboxymethyl cellulose and propylene glycol are mixed, then add appropriate hot distilled water, place after being swelled into gel, then add the activeconstituents that contains after grinding and the aqueous solution of hydroxypropylβ-cyclodextrin and urea and ethyl p-hydroxybenzoate, add water to 1000ml, by 10ml packing.Every ml contains formula III compound 5mg.
Pharmacology embodiment 1
Laboratory animal: 60 of CXA-1 recombinant inbred strain small white mouses (Bengbu Medical College's animal center provides), body weight 18～22g, divide control group, experimental group A, B, it is activeconstituents that experimental group A, B group adopts respectively hydrocortisone, formula III compound, the external preparation coating experiment mice auris dextra inner side that the active component content making according to example of formulations 9 methods is 0.5%, it is identical that each group is coated with dose, and in contrast at the emulsifiable paste matrix of left ear coating same amount simultaneously.All coating substrates of control group two ears.
The making of chronic dermatitis eczema animal model: adopt 7%DNCB (dinitrotoluene (DNT)) acetone soln 100 μ L to be coated with mouse back sensitization outward, within 5 days, being coated with afterwards 0.1%DNCB acetone soln 5 μ L outward excites in mouse right ear inner side, excite once every 72h, experimental group 24h after exciting first starts coating, every day, coating twice was coated with dose identical at every turn.Excite rear 72h to put to death mouse in the 5th, measure swelling and the incrustation rate of mouse right ear.Swelling=(auris dextra weight-left ear weight)/(left ear weight) × 100%.
Experimental data adopts spss to process and carries out t inspection
Experimental data sees the following form
| Group | Swelling % | Incrustation rate % |
| Contrast | 152.2±11.3 | 50 |
| A | 110.4±8.9 | 20 |
| B | 113.9±9.8 | 20 |
Show through experiment, experimental group A-B is compared with control group, in the time of the swelling for the treatment of mouse ear, all there is significant difference (P < 0.05), especially, compared with hydrocortisone, compound provided by the invention is in to the treatment of mouse chronic dermatitis Eczema Model, there were significant differences for the swelling of mouse ear (P < 0.05), and the incrustation rate of mouse ear is also identical, show compound provided by the invention in the time being used for the treatment of Mammals local inflammation and hydrocortisone has similar curative effect.
Pharmacology embodiment 2 local actions cause atrophy effect contrast
Laboratory animal: 40 of white Baby guinea pigs, body weight 300g ± 20g, is divided into experiment A, B group, and respectively with hydrocortisone, formula III compound is activeconstituents, and 0.5% external preparation making by embodiment 9 methods is the medication of experiment A, B group.
Experimental technique: the region of every guinea pig back left and right sides antimere being selected to 3cm × 3cm, shave hair, left side is used experimental group to be coated with pastille emulsifiable paste, right side coating emulsifiable paste matrix, medication every day 2 times is coated with same amount at every turn, continuous use, after medication the 20th day by every group of cavy drug withdrawal, cavy is put to death and gets respectively medication district, back and check plot skin, measure medication district skin thickness with the ratio of check plot skin thickness to determine skin atrophy degree.The results are shown in following table
Upper table data declaration, compared with existing hydrocortisone, compound provided by the invention causes skin atrophy effect in the time of local application remarkable reduction (P < 0.05).Can draw thus, use the treatment of compound provided by the invention for local inflammation, side effect is less, and medication is safer.
Claims (19)
1. a formula III compound
2. preparing a method for formula III compound, is to be reacted with the mixture of butyraldehyde-n, acid, organic solvent or organic solvent and water by formula (I) compound, and reaction is finished, and obtains formula III compound
（
）。
3. preparation method as claimed in claim 2, is characterized in that in reaction, acid is mineral acid.
4. preparation method as claimed in claim 2, is characterized in that acid is for hydrofluoric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, perchloric acid, tosic acid, acetic acid.
5. preparation method as claimed in claim 2, is characterized in that organic solvent is nitrile, ether, the haloalkane of 1-4 carbon.
6. preparation method as claimed in claim 2, is characterized in that organic solvent Wei diox, acetonitrile, tetrahydrofuran (THF), DMF, methylene dichloride, chloroform.
7. preparation method as claimed in claim 2, is characterized in that organic solvent is acetonitrile, tetrahydrofuran (THF), methylene dichloride, chloroform.
8. preparation method as claimed in claim 2, is characterized in that reaction is complete, and using mineral alkali to regulate pH value is neutrality.
9. preparation method as claimed in claim 2, is characterized in that reaction is complete, obtains formula III compound by dilution, recrystallization.
10. prepare a method for budesonide, obtained by 21 iodate of formula III compound that (IV), 21 positions are got (V) in return, 21 acetic esters hydrolysis obtain budesonide
11. 1 kinds of formula III compounds as claimed in claim 1 are in the application of preparing in budesonide.
12. 1 kinds of formula III compounds as claimed in claim 1 are in the application of preparing in people or Mammals anti-inflammatory or Claritin.
13. 1 kinds of formula III compounds as claimed in claim 1 are treated the application in airway inflammation medicine in preparation.
14. 1 kinds of formula III compounds as claimed in claim 1 are treated the application in eye inflammation medicine in preparation.
15. 1 kinds of formula III compounds as claimed in claim 1 are treated the application in skin inflammation medicine in preparation.
16. 1 kinds of formula III compounds as claimed in claim 1 are treated the application in osteoarthropathy medicine in preparation.
17. 1 kinds of formula III compounds as claimed in claim 1 are treated the application in autoimmune disorders medicine in preparation.
18. 1 kinds of pharmaceutical compositions, is characterized in that containing formula III compound and one or more pharmaceutical excipients as activeconstituents
(III).
19. pharmaceutical compositions as claimed in claim 18, is characterized in that pharmaceutical excipient is the pharmaceutical excipient that is applicable to prepare oral preparations, injection formulations, external preparation, nasal formulations, aerosol, powder inhalation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010556798.XA CN102477065B (en) | 2010-11-23 | 2010-11-23 | Novel 16, 17-ketal intermediate for preparing budesonide |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010556798.XA CN102477065B (en) | 2010-11-23 | 2010-11-23 | Novel 16, 17-ketal intermediate for preparing budesonide |
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| CN102477065B true CN102477065B (en) | 2014-06-11 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2990401A (en) * | 1958-06-18 | 1961-06-27 | American Cyanamid Co | 11-substituted 16alpha, 17alpha-substituted methylenedioxy steroids |
| CN1810824A (en) * | 2005-12-09 | 2006-08-02 | 天津理工大学 | Momertasone furoate intermediate 21-ester and its prepn |
| CN101279997A (en) * | 2008-05-29 | 2008-10-08 | 鲁南制药集团股份有限公司 | Novel preparation of budesonide |
-
2010
- 2010-11-23 CN CN201010556798.XA patent/CN102477065B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2990401A (en) * | 1958-06-18 | 1961-06-27 | American Cyanamid Co | 11-substituted 16alpha, 17alpha-substituted methylenedioxy steroids |
| CN1810824A (en) * | 2005-12-09 | 2006-08-02 | 天津理工大学 | Momertasone furoate intermediate 21-ester and its prepn |
| CN101279997A (en) * | 2008-05-29 | 2008-10-08 | 鲁南制药集团股份有限公司 | Novel preparation of budesonide |
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| CN102477065A (en) | 2012-05-30 |
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