CN105061549A - Budesonide preparing method - Google Patents
Budesonide preparing method Download PDFInfo
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Abstract
The invention discloses a budesonide preparing method. Prednisone I and acetic anhydride II react to produce 17,21-diacetoxy-1,4-pregnane diene-3,11,20-triketone III, the III is degreased in an anhydrous solvent to obtain 21-acetoxyl group-1,4,16-pregnane diene-3,11,20-triketone IV, the IV is oxidized to obtain 16alpha,17alpha-dyhydroxy-21-acetoxyl-1,4-pregnane diene-3,11,20-triketone V, the V and n-butyl aldehyde VI are condensed to obtain 16alpha,17alpha-22(R,S) propyl methylenedioxy-21-acetoxyl group-1,4-pregnane diene-3,11,20-triketone VII, the VII is reduced to obtain 16alpha,17alpha-22(R,S) propyl methylenedioxy-11beta-hydroxyl-21-acetoxyl group-1,4-pregnane diene-3,20-diketone VIII, the VIII is subjected to base catalysis to obtain budesonide IX. The budesonide preparing method is suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of medicine, be specifically related to a kind of preparation method of budesonide bulk drug.
Background technology
The chemical name of budesonide is: 16 α, 17 α-22 (R, S) propylmethylene dioxy-11 β, 21-dihydroxyl-Isosorbide-5-Nitrae-pregnen diethylene-3,20-diketone, and its chemical structural formula is:
Budesonide was researched and developed by AstraZeneca pharmaceutical Co. Ltd, in listing in 1981.It is a kind of non-halogenated glucocorticoid medicine with the acetals of very strong antiinflammation, can suppress early stage bronchospasm and the transformation reactions in late period.Its anti-inflammatory activity is 1000 times of hydrocortisone, stronger than beclometasone and other glucocorticosteroids, long action time and seldom produce the systemic side effects of adrenal cortex hormones drug, thus in similar drug, there is higher local/systemic effect ratio, be more suitable for local application, having the advantages that using dosage is little, curative effect is high, side effect is little, the particularly important is and be applicable to children, is inhale human therapy asthma with aerosol and sparge the anaphylactoid first-line drug of nasal cavity therapy.Budesonide has R and S two kinds of configurations, and R configuration drug effect is better than S configuration, and European Pharmacopoeia is that S is configured as 41% ~ 50% to its proportion requirement.
The synthetic route of budesonide and technique is existing a lot of report both at home and abroad.WO8705028, WO9211280, CN103724396, CN103665093, CN103694306, CN102060906 etc. all disclose the method for splitting of preparation R-budesonide, but, do not have in these documents to describe the preparation method meeting the budesonide of European Pharmacopoeia R/S configuration proportion requirement.EP0164636, US3929768, CN103275168, CN101717428 etc. report and prepare the method for budesonide by 16 alpha-hydroxy prednisonlones and n butyraldehyde aldolization through single step reaction, wherein and the preparation method of unexposed budesonide important intermediate 16 alpha-hydroxy prednisonlone.It is raw material that CN101279997 reports with prednisolone acetate; the method of budesonide is prepared through steps such as elimination, oxidation, reduction, transesterify, condensations; CN101863952 discloses with Prednisolone Acetate imperial for raw material, prepares the method for budesonide through steps such as acidylate, elimination, oxidation, transesterify, condensations.When preparing moiety intermediate, there is reaction conditions harsh in above-mentioned two kinds of preparation methods, high to equipment requirements, complex operation, the problems such as man-hour is long, and purity is not high, and yield is low, thus cause that environmental pollution is large, cost is higher, and be unfavorable for suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research and design raw material is easy to get, reaction conditions is gentle, simple to operate, the cycle is short, yield is high, is easy to the preparation method of the budesonide bulk drug of suitability for industrialized production.
The invention provides a kind of preparation method of budesonide, the method comprises the following steps:
(1) prednisone (17,21-dihydroxyl-1,4-pregnen diethylene-3,11,20-triketone) I and aceticanhydride II in a solvent under base catalysis, 17 are generated through acylation reaction, 21-diacetoxy-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketone III, gained crude product III is directly used in next step;
Reaction solvent for use is selected from Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE or pyridine; Described alkali is selected from pyridine, DMAP or DIPEA; Temperature of reaction is 80 DEG C ~ 90 DEG C; Stirring reaction 4h ~ 5h; The mol ratio of aceticanhydride II and prednisone I is 2 ~ 4:1.
Reaction postprocessing method: reactant is poured in the frozen water of solvent 10 times of volumes, leaves standstill solidification 2h ~ 3h, suction filtration, and washing filter cake, is dried to constant weight and obtains compound III, be directly used in next step.
This step molar yield >=98%, chemical purity >=98% of HPLC detection compound III.
(2) under the catalysis of alkali or an alkali metal salt, compound III obtains 21-acetoxyl group-Isosorbide-5-Nitrae through eliminative reaction in anhydrous solvent, 16-pregnant steroid triolefin-3,11,20-triketone IV, and gained crude product IV is directly used in next step;
Described alkali or an alkali metal salt are selected from potassium hydroxide, sodium hydroxide, Potassium ethanoate or sodium-acetate; The mol ratio of alkali or an alkali metal salt and compound III is 1.5 ~ 3.5:1, preferably 2.5 ~ 3:1; Described anhydrous solvent is selected from anhydrous Isosorbide-5-Nitrae-dioxane, anhydrous dimethyl formamide or anhydrous dimethyl sulphoxide; Temperature of reaction is 90 DEG C ~ 100 DEG C; Reaction times is 4h ~ 4.5h.
Post-treating method: reactant is poured in the frozen water of solvent 10 times of volumes, leaves standstill 2h ~ 3h, suction filtration, and washing filter cake, is dried to constant weight and obtains compounds Ⅳ, be directly used in next step.
This step molar yield >=95%, chemical purity >=97% of HPLC detection compound IV.
(3) compounds Ⅳ in solvent under acid catalysis, oxidized dose of oxidation, re-refine to obtain 16 α, 17 alpha-dihydroxy--21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketones V;
Reaction solvent for use is the mixed solvent of organic solvent and water, and the two volume ratio is 10 ~ 5:1, and organic solvent is selected from the trimethyl carbinol, acetone, ether or tetrahydrofuran (THF); Described acid is selected from tosic acid, formic acid, acetic acid or trifluoroacetic acid; Described oxygenant is potassium permanganate; The mol ratio of potassium permanganate and compounds Ⅳ is 1.3 ~ 1.5:1; Temperature of reaction is 0 DEG C ~ 10 DEG C; Reaction times is 5 minutes ~ 10 minutes.
Post-treating method: the reactant sodium sulfite aqueous solution cancellation reaction of 10% ~ 15%, filter, mother liquor steams except organic solvent, and by the solid filtering of separating out, washing filter cake, is dried to the crude product that constant weight obtains compound V.
Process for purification: the solvent adding 10 ~ 15 times of weight in the crude product of compound V, is heated to backflow, steams and desolventizes to residue 1/4 ~ 1/6 amount solvent, 3h ~ 4h is left standstill in 4 DEG C of refrigerators, filter, filter cake obtains the highly finished product of compound V, for next step in 60 DEG C ~ 65 DEG C of drying under reduced pressure.
Refining solvent is selected from methyl alcohol, ethanol, Virahol, acetone, ether, isopropyl ether or methyl tertiary butyl ether.
This step molar yield >=85%, chemical purity >=98.5% of HPLC detection compound V.
(4) under acid catalysis, compound V and butyraldehyde-n VI condensation in a solvent, re-refine to obtain 16 α, 17 α-22 (R, S) propylmethylene dioxy-21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketones VII;
Described acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, tosic acid or methylsulfonic acid, preferred perchloric acid; Solvent for use is ether solvent, preferred Isosorbide-5-Nitrae-dioxane or tetrahydrofuran (THF); Butyraldehyde-n VI is 1.2 ~ 3:1, preferably 2 ~ 2.5:1 with the mol ratio of compound V; Temperature of reaction is 30 DEG C ~ 35 DEG C; Reaction times is 4.5h ~ 5h.
Post-treating method: reactant first uses the dchloromethane of solvent volume 2 ~ 3 times, then react with the alkali lye cancellation of 10% ~ 15%, described alkali is selected from salt of wormwood, sodium carbonate, saleratus or sodium bicarbonate; Washed reaction thing, aqueous phase uses dichloromethane extraction again; Merge all organic phases and be concentrated into dry, a kind of in residue normal heptane, normal hexane or hexanaphthene or the making beating of their mixture, filter, filtration cakes torrefaction to constant weight obtains the crude product of compound VII.
Process for purification: the solvent adding 8 ~ 10 times of weight in the crude product of compound VII, reflux, to dissolving, is steamed and is desolventized to residue 1/3 ~ 1/5 amount solvent, 3h ~ 4h is left standstill in 4 DEG C of refrigerators, filter, filter cake obtains the highly finished product of compound VII, for next step in 60 DEG C ~ 65 DEG C of drying under reduced pressure.
Refining solvent is selected from methyl alcohol, ethanol, Virahol or acetone.
This step molar yield >=88%, chemical purity >=98.5% of HPLC detection compound VII.
(5) compound VII is reduced agent in a solvent and reduces to obtain 16 α, 17 α-22 (R, S) propylmethylene dioxy-11 beta-hydroxy-21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,20-diketone VIII, and gained crude product VIII is directly used in next step;
Reaction solvent for use is selected from methyl alcohol, ethanol, Virahol, the trimethyl carbinol, ether, isopropyl ether or tetrahydrofuran (THF); Described reductive agent is selected from sodium borohydride or Lithium Aluminium Hydride, and the mol ratio of reductive agent and compound VII is 1.1 ~ 2:1; Temperature of reaction is 0 DEG C ~ 5 DEG C; After reacting completely, after adding suitable quantity of water cancellation, by dichloromethane extraction 3-4 time, saturated common salt water washing organic phase, be concentrated into dry compound VIII, be directly used in next step.
This step molar yield >=96%, chemical purity >=97.5% of HPLC detection compound VIII.
(6) compound VIII transesterify under base catalysis, budesonide Ⅸ of re-refining to obtain.
Reaction solvent for use is selected from Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol or the trimethyl carbinol; Described alkali is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide, is mixed with the concentration of 1 ~ 6N with solvent; After alkalization, reaction solution pH is 8 ~ 9; Temperature of reaction is 0 DEG C ~ 5 DEG C; Reaction times is 3h ~ 4h.
Post-treating method: reactant with 20% ~ 30% glacial acetic acid to be neutralized to pH be 7 ~ 7.5, be concentrated into dry, gained residue use water is pulled an oar, and filters, and washing filter cake, is dried to the crude product that constant weight obtains budesonide Ⅸ.
Process for purification: refining solvent is selected from methyl alcohol, ethanol, Virahol or acetone, the solvent of 8 ~ 10 times of weight is added in the crude product of budesonide Ⅸ, reflux is to dissolving, steaming desolventizes to residue 1/3 ~ 1/5 amount solvent, 3h ~ 4h is left standstill in 4 DEG C of refrigerators, filter, filter cake is in 60 DEG C ~ 65 DEG C drying under reduced pressure to constant weight, and the same repetition refines the highly finished product once obtaining budesonide Ⅸ.
Refining solvent is selected from methyl alcohol, ethanol, Virahol or acetone.
This step molar yield >=80%, chemical purity >=99.5% of HPLC detection compound Ⅸ.
Described synthetic route is from total molar yield >=53% of step (1) ~ step (6).
The detection method of promulgating according to China National Drug Surveillance Authority WS-457 (X-405)-2001 is HPLC to budesonide highly finished product and is detected analysis: chemical purity >=99.5%, content 99.5% ~ 101% (SIGMA budesonide standard substance contrast), wherein in R and S two kinds of configurations, S type isomer proportion is 43% ~ 47%, meets above-mentioned quality criteria requirements completely.
The beneficial effect of the inventive method:
The present invention compares with CN101279997 with existing patent of invention CN101863952, after obtaining intermediate 16 alpha-hydroxy prednisonlone both rear, itself and n butyraldehyde aldolization are generated budesonide, and the present invention is oxidizing reaction products therefrom 16 α, 17 alpha-dihydroxy--21-acetoxyl groups-1,4-pregnen diethylene-3,11,20-triketone V and n butyraldehyde aldolization, generate 16 α, 17 α-22 (R, S) propylmethylene dioxy-21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketone VII, then obtain budesonide through reduction and transesterify.Compound VII after experimental result display condensation of the present invention carries out reducing and transesterification reaction, and two reaction yields are all improved, and kind and the total amount of impurity reduce to some extent, thus is conducive to refining purification and raising yield.
Raw material of the present invention is easy to get, reaction conditions is gentle, simple to operate, the cycle is short, yield is high, is suitable for suitability for industrialized production, has larger using value.
Embodiment
Enumerate embodiment below to be described in detail the present invention, embodiment provides by way of example, is not construed as limiting the invention.
The preparation of embodiment 1:17,21-diacetoxy-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketone III
The pyridine of prednisone 200g (0.56mol) and 1L is added in 3L tri-mouthfuls of round-bottomed flasks, stir clearly molten, add aceticanhydride 150mL, in 85 DEG C ~ 90 DEG C reaction 2.5h, TLC monitoring reactions to reacting completely.Poured into by reactant in the frozen water of 10L, leave standstill solidification 2.5h, suction filtration, washing filter cake, be dried to constant weight and obtain midbody compound III 243g, white solid, is directly used in next step.Yield 98.4%, HPLC detects chemical purity 98.2%.
Embodiment 2:21-acetoxyl group-Isosorbide-5-Nitrae, the preparation of 16-pregnant steroid triolefin-3,11,20-triketone IV
By 17,21-diacetoxy-Isosorbide-5-Nitrae-pregnen diethylene-3; the DMF of 11,20-triketone III 240g (0.54mol) and anhydrous sodium acetate 120g and 1.5L adds in 3L tri-mouthfuls of round-bottomed flasks, under nitrogen protection; in 95 DEG C ~ 100 DEG C reaction 4.5h, TLC monitoring reactions to reacting completely.Poured into by reactant in the frozen water of 15L, leave standstill solidification 3h, suction filtration, washing filter cake, be dried to constant weight and obtain midbody compound IV 200g, khaki color solid, is directly used in next step.Yield 96.4%, HPLC detects chemical purity 97.8%.
Embodiment 3:16 α, the preparation of 17 alpha-dihydroxy--21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketones V
By 21-acetoxyl group-Isosorbide-5-Nitrae, the acetone of 16-pregnant steroid triolefin-3,11,20-triketone IV 200g (0.52mol) and 6L adds in the stainless steel reaction bucket of 10L, stirs clearly molten, temperature 0 DEG C ~ 5 DEG C in ice-water bath control; Potassium permanganate 115g first uses that 800mL's is clearly water-soluble, and ice-water bath adds freezing acetone 800mL and freezing formic acid 50mL when interior temperature 0 DEG C ~ 5 DEG C, stirs; Above-mentioned potassium permanganate solution is added in the acetone soln of midbody compound IV, at 0 DEG C ~ 5 DEG C, rapid stirring reacts 7 minutes, with the sodium sulfite aqueous solution 600mL cancellation reaction of 15%, suction filtration, washing with acetone filter cake, mother liquor concentrations steams except acetone, solid is had to separate out, filter, filter cake is washed, and is dried to the crude product that constant weight obtains midbody compound V.In the crude product of compound V, add 3L acetone, be heated to backflow, remove solvent under reduced pressure to residue 1/4 amount solvent, leave standstill 3h in 4 DEG C of refrigerators, filter, filter cake obtains the highly finished product 193g of compound V in 60 DEG C ~ 65 DEG C drying under reduced pressure, white solid.Yield 88.6%, HPLC detects chemical purity 98.6%.
Embodiment 4:16 α, the preparation of 17 α-22 (R, S) propylmethylene dioxy-21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketones VII
1 is added in 3L tri-mouthfuls of round-bottomed flasks, 4-dioxane 2L, add perchloric acid 20mL and butyraldehyde-n 75g successively, stir 10 minutes, finally add 16 α, 17 alpha-dihydroxy--21-acetoxyl groups-1,4-pregnen diethylene-3,11,20-triketone V 190g (0.46mol), in 30 DEG C ~ 35 DEG C stirring reaction 5h, TLC monitoring reaction to reacting completely.The methylene dichloride of 4L to be added in reactant rapid stirring 5 minutes, pH ≈ 7-8 is adjusted to react with cancellation with 15% solution of potassium carbonate, washed reaction thing 3 times, each 1L, separates organic phase for subsequent use, merges aqueous phase, with methylene dichloride back extraction 2 times, each 750mL, merges the organic phase that separates of secondary, is evaporated to the crude product of dry midbody compound VII.In the crude product of compound VII, add 1.5L methyl alcohol, reflux, to dissolving, is steamed and is desolventized to residue 1/3 amount solvent, leave standstill 4h in 4 DEG C of refrigerators, and filter, filter cake obtains the highly finished product 190g of compound VII in 60 DEG C ~ 65 DEG C drying under reduced pressure, white solid.Yield 88.5%, HPLC detects chemical purity 98.9%.
Embodiment 5:16 α, the preparation of 17 α-22 (R, S) propylmethylene dioxy-11 beta-hydroxy-21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,20-diketone VIII
Add midbody compound VII 190g (0.40mol) in 3L tri-mouthfuls of round-bottomed flasks and add methyl alcohol 2L, stir clearly molten, add sodium borohydride 27.5g in batches at 0 DEG C ~ 5 DEG C, TLC monitoring reaction is to reacting completely.In reactant, add 500mL water, with dichloromethane extraction 4 times, each 1.5L, merge organic phase, by saturated common salt water washing organic phase, concentrating under reduced pressure does organic phase, and be dried to constant weight and obtain midbody compound VIII 187g, white solid, is directly used in next step.Yield 98%, HPLC detects chemical purity 98.4%.
Embodiment 6: the preparation of budesonide Ⅸ
Add midbody compound VIII 185g (0.39mol) in 3L tri-mouthfuls of round-bottomed flasks and add ethanol 2L, the ethanolic soln of the sodium hydroxide of 3N adjusts pH to be 8 ~ 9, in 0 DEG C ~ 5 DEG C stirring reaction 3.5h, glacial acetic acid with 20% adjusts pH to be 6 ~ 7, reactant is evaporated to dry at 45 DEG C, and residue use water 900mL pulls an oar, and filters, washing filter cake, is dried to the crude product that constant weight obtains budesonide Ⅸ.In the crude product of budesonide Ⅸ, add 1.8L ethanol, reflux, to dissolving, is steamed and is desolventized to residue 1/3 amount solvent, leave standstill 4h in 4 DEG C of refrigerators, filter, filter cake is in 60 DEG C ~ 65 DEG C drying under reduced pressure to constant weight, repeat the refining highly finished product 140g once obtaining budesonide Ⅸ, white solid.Yield 83.1%, HPLC detects chemical purity 99.6%.The preparation of embodiment 7:17,21-diacetoxy-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketone III
By prednisone (17,21-dihydroxyl-1,4-pregnen diethylene-3,11,20-triketone) dimethyl formamide of 200g (0.56mol) and 1L adds in 3L tri-mouthfuls of round-bottomed flasks, stirs clearly molten, add N successively, N-diisopropylethylamine 300mL and aceticanhydride 150mL, in 88 DEG C ~ 90 DEG C reactions, TLC monitoring reaction is to reacting completely.Poured into by reactant in the frozen water of 10L, leave standstill solidification 3h, suction filtration, washing filter cake, be dried to constant weight and obtain midbody compound III 242g, white solid, is directly used in next step.Yield 98%, HPLC detects chemical purity 98.5%.Embodiment 8:16 α, the preparation of 17 alpha-dihydroxy--21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketones V
By 21-acetoxyl group-Isosorbide-5-Nitrae, the tetrahydrofuran (THF) of 16-pregnant steroid triolefin-3,11,20-triketone IV 200g (0.52mol) and 5L adds in the stainless steel reaction bucket of 10L, stirs clearly molten, temperature 0 DEG C ~ 5 DEG C in ice-water bath control; Potassium permanganate 115g first uses that 800mL's is clearly water-soluble, and ice-water bath adds freezing tetrahydrofuran (THF) 800mL and freezing trifluoroacetic acid 50mL when interior temperature 0 DEG C ~ 5 DEG C, stirs; Above-mentioned potassium permanganate solution is added in the tetrahydrofuran solution of midbody compound IV, at 0 DEG C ~ 5 DEG C, rapid stirring reacts 7 minutes, with the sodium sulfite aqueous solution 600mL cancellation reaction of 15%, suction filtration, tetrahydrofuran (THF) washing leaching cake, mother liquor concentrations steams except tetrahydrofuran (THF), solid is had to separate out, filter, filter cake is washed, and is dried to the crude product that constant weight obtains midbody compound V.Process for purification, with embodiment 3, obtains the highly finished product 190g of midbody compound V, white solid.Yield 87.2%, HPLC detects chemical purity 98.5%.
Embodiment 9:16 α, the preparation of 17 α-22 (R, S) propylmethylene dioxy-21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketones VII
Tetrahydrofuran (THF) 2L is added in 3L tri-mouthfuls of round-bottomed flasks, add perchloric acid 20mL and butyraldehyde-n 75g successively, stir 10 minutes, finally add 16 α, 17 alpha-dihydroxy--21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylenes-3,11,20-triketone V 190g (0.46mol), in 30 DEG C ~ 35 DEG C stirring reactions, TLC monitoring reaction is to reacting completely.The methylene dichloride of 6L to be added in reactant rapid stirring 5 minutes, pH ≈ 7-8 is adjusted to react with cancellation with 15% solution of potassium carbonate, washed reaction thing 3 times, each 1.5L, separates organic phase, merges all aqueous phases, with methylene dichloride back extraction 2 times, each 1.1L, merges the organic phase that separates of secondary, is evaporated to the crude product of dry midbody compound VII.With acetone refining, process for purification, with embodiment 4, obtains the highly finished product 189g of midbody compound VII, white solid.Yield 88%, HPLC detects chemical purity 98.7%.
Embodiment 10:16 α, the preparation of 17 α-22 (R, S) propylmethylene dioxy-11 beta-hydroxy-21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,20-diketone VIII
Add midbody compound VII 190g (0.40mol) in 3L tri-mouthfuls of round-bottomed flasks and add tetrahydrofuran (THF) 2L, stir clearly molten at 0 DEG C ~ 5 DEG C, under nitrogen protection, add Lithium Aluminium Hydride 4.6g in three batches, TLC monitoring reaction is to reacting completely.Post-treating method is with embodiment 5, and obtain midbody compound VIII 184g, white solid, is directly used in next step.Yield 96.4%, HPLC detects chemical purity 98%.
Embodiment 11: the preparation of budesonide Ⅸ
Add midbody compound VIII 185g (0.39mol) in 3L tri-mouthfuls of round-bottomed flasks and add tetrahydrofuran (THF) 2L, the tetrahydrofuran solution of the sodium hydroxide of 1N adjusts pH to be 8 ~ 9, in 0 DEG C ~ 5 DEG C stirring reaction 3h ~ 3.5h, glacial acetic acid with 30% adjusts pH to be 6 ~ 7, be evaporated to dry at reactant 45 DEG C, residue use water 900mL pulls an oar, and filters, washing filter cake, is dried to the crude product that constant weight obtains budesonide Ⅸ.With acetone refining 2 times, process for purification, with embodiment 6, obtains the highly finished product 136g of budesonide Ⅸ, white solid.Yield 80.7%, HPLC detects chemical purity 99.6%.
Embodiment 12: difficulties of the present invention:
(1) in the inventive method, because the eliminative reaction of compound III needs comparatively high temps, reaction conditions is violent, the side reaction such as cracking, rearrangement easily occurs and causes the quantity of impurity and the increase of total amount, and product yield reduces.For investigating temperature to the impact of eliminative reaction, the present inventor has done a lot of design and test, now enumerates:
The present inventor is parallel under three temperature condition respectively carries out eliminative reaction, and comparative result is as follows:
So the present invention adopts 90 DEG C ~ 100 DEG C relatively gentle reaction conditionss, slightly extend the reaction times to 4h ~ 4.5h, such condition can reduce the generation of side reaction and reduce by product, and is conducive to follow-up process for refining.
(2) in the oxidizing reaction of step (3), the present invention's potassium permanganate oxidation, within 5 minutes ~ 10 minutes, complete reaction is got final product in 0 DEG C ~ 10 DEG C reactions, be swift in response, easy control of reaction conditions, and the reaction conditions of subzero less than 5 degrees Celsius requires higher to appointed condition, be unfavorable for reducing costs.
The contrast of embodiment 13 the present invention and each parameter of prior art is as following table:
Claims (8)
1. a preparation method for budesonide, is characterized in that, the method comprises the following steps:
(1) prednisone I and aceticanhydride II are in a solvent under base catalysis, and generate 17,21-diacetoxy-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketone III through acylation reaction, gained crude product III is directly used in next step;
(2) under the catalysis of alkali or an alkali metal salt, compound III in anhydrous solvent through eliminative reaction, after degreasing 21-acetoxyl group-Isosorbide-5-Nitrae, 16-pregnant steroid triolefin-3,11,20-triketone IV, gained crude product IV is directly used in next step;
(3) compounds Ⅳ in solvent under acid catalysis, oxidized dose of oxidation, re-refine to obtain 16 α, 17 alpha-dihydroxy--21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketones V;
(4) under acid catalysis, compound V and butyraldehyde-n VI condensation in a solvent, re-refine to obtain 16 α, 17 α-22 (R, S) propylmethylene dioxy-21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,11,20-triketones VII;
(5) compound VII is reduced agent in a solvent and reduces to obtain 16 α, 17 α-22 (R, S) propylmethylene dioxy-11 beta-hydroxy-21-acetoxyl group-Isosorbide-5-Nitrae-pregnen diethylene-3,20-diketone VIII, and gained crude product VIII is directly used in next step;
(6) compound VIII transesterify under base catalysis, budesonide Ⅸ of re-refining to obtain
2. the preparation method of a kind of budesonide according to claim 1, is characterized in that, described step (1) reaction solvent for use is selected from Isosorbide-5-Nitrae-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE or pyridine; Described alkali is selected from pyridine, DMAP or DIPEA; Temperature of reaction is 80 DEG C ~ 90 DEG C; Reaction times is 4h ~ 5h; The mol ratio of aceticanhydride II and prednisone I is 2 ~ 4:1; React complete, reactant is poured in the frozen water of solvent 10 times of volumes, leaves standstill solidification 2h ~ 3h, suction filtration, and washing filter cake, is dried to constant weight and obtains compound III.
3. the preparation method of a kind of budesonide according to claim 1, is characterized in that, step (2) described alkali or an alkali metal salt are selected from potassium hydroxide, sodium hydroxide, Potassium ethanoate or sodium-acetate; The mol ratio of alkali or an alkali metal salt and compound III is 1.5 ~ 3.5:1, preferably 2.5 ~ 3:1; Described anhydrous solvent is selected from anhydrous Isosorbide-5-Nitrae-dioxane, anhydrous dimethyl formamide or anhydrous dimethyl sulphoxide; Temperature of reaction is 90 DEG C ~ 100 DEG C; Reaction times is 4h ~ 4.5h; React complete, reactant is poured in the frozen water of solvent 10 times of volumes, leaves standstill 2h ~ 3h, suction filtration, and washing filter cake, is dried to constant weight and obtains compounds Ⅳ.
4. the preparation method of a kind of budesonide according to claim 1, it is characterized in that, described step (3) reaction solvent for use is the mixed solvent of organic solvent and water, and the two volume ratio is 10 ~ 5:1, and organic solvent is selected from the trimethyl carbinol, acetone, ether or tetrahydrofuran (THF); Described acid is selected from tosic acid, formic acid, acetic acid or trifluoroacetic acid; Described oxygenant is potassium permanganate; The mol ratio of potassium permanganate and compounds Ⅳ is 1.3 ~ 1.5:1; Temperature of reaction is 0 DEG C ~ 10 DEG C; Reaction times is 5 minutes ~ 10 minutes; React complete, the reactant sodium sulfite aqueous solution cancellation reaction of 10% ~ 15%, filter, mother liquor steams except organic solvent, and by the solid filtering of separating out, washing filter cake, is dried to the crude product that constant weight obtains compound V; The highly finished product obtaining compound V are refined with methyl alcohol, ethanol, Virahol, acetone, ether, isopropyl ether or methyl tertiary butyl ether.
5. the preparation method of a kind of budesonide according to claim 1, is characterized in that, step (4) described acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, tosic acid or methylsulfonic acid; Solvent for use is ether solvent; Butyraldehyde-n VI is 1.2 ~ 3:1 with the mol ratio of compound V; Temperature of reaction is 30 DEG C ~ 35 DEG C; Reaction times is 4.5h ~ 5h; React complete, reactant first uses the dchloromethane of solvent volume 2 ~ 3 times, then reacts with the alkali lye cancellation of 10% ~ 15%, and described alkali is selected from salt of wormwood, sodium carbonate, saleratus or sodium bicarbonate; Washed reaction thing, aqueous phase uses dichloromethane extraction again; Merge all organic phases and be concentrated into dry, a kind of in residue normal heptane, normal hexane or hexanaphthene or the making beating of their mixture, filter, filtration cakes torrefaction to constant weight obtains the crude product of compound VII; The highly finished product of compound VII are obtained with methyl alcohol, ethanol, Virahol or acetone refining.
6. the preparation method of a kind of budesonide according to claim 1, is characterized in that, described step (5) reaction solvent for use is selected from methyl alcohol, ethanol, Virahol, the trimethyl carbinol, ether, isopropyl ether or tetrahydrofuran (THF); Described reductive agent is selected from sodium borohydride or Lithium Aluminium Hydride, and the mol ratio of reductive agent and compound VII is 1.1 ~ 2:1; Temperature of reaction is 0 DEG C ~ 5 DEG C; After reacting completely, after adding suitable quantity of water cancellation, by dichloromethane extraction 3-4 time, saturated common salt water washing organic phase, be concentrated into dry compound VIII.
7. the preparation method of a kind of budesonide according to claim 1, it is characterized in that, described step (6) reaction solvent for use is selected from Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol or the trimethyl carbinol; Described alkali is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide, is mixed with the concentration of 1 ~ 6N with solvent; After alkalization, reaction solution pH is 8 ~ 9; Temperature of reaction is 0 DEG C ~ 5 DEG C; Reaction times is 3h ~ 4h; React complete, reactant with 20% ~ 30% glacial acetic acid to be neutralized to pH be 7 ~ 7.5, be concentrated into dry, gained residue use water is pulled an oar, and filters, and washing filter cake, is dried to the crude product that constant weight obtains budesonide Ⅸ; The highly finished product of budesonide Ⅸ are obtained for 1-2 time with methyl alcohol, ethanol, Virahol or acetone refining.
8. the preparation method of a kind of budesonide according to claim 5, is characterized in that, step (4) described acid is perchloric acid; Solvent for use be 1,4 ?dioxane or tetrahydrofuran (THF); Butyraldehyde-n VI is 2 ~ 2.5:1 with the mol ratio of compound V.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107778344A (en) * | 2016-08-30 | 2018-03-09 | 天津太平洋制药有限公司 | A kind of preparation method of budesonide |
| CN107840865A (en) * | 2016-09-20 | 2018-03-27 | 天津金耀集团有限公司 | A kind of preparation method of methylprednisolone |
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| CN107778344A (en) * | 2016-08-30 | 2018-03-09 | 天津太平洋制药有限公司 | A kind of preparation method of budesonide |
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| CN109485689B (en) * | 2019-01-08 | 2020-03-27 | 黑龙江中医药大学 | Preparation method of budesonide for treating infantile asthma |
| CN109485689A (en) * | 2019-01-08 | 2019-03-19 | 黑龙江中医药大学 | The preparation method of asthma in children stype desonide |
| CN109575097A (en) * | 2019-01-20 | 2019-04-05 | 湖南科瑞生物制药股份有限公司 | A kind of new preparation method of 16a- hydroxy prednisonlone product |
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| CN109734763A (en) * | 2019-01-20 | 2019-05-10 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of 16a- hydroxacetic acid prednisolone product |
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| CN109705182B (en) * | 2019-01-24 | 2021-08-31 | 上海新华联制药有限公司 | Preparation method of nilestriol |
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| CN110078784B (en) * | 2019-06-04 | 2020-04-28 | 博诺康源(北京)药业科技有限公司 | Synthesis method of budesonide impurity USP-Z1 |
| CN110407902A (en) * | 2019-07-15 | 2019-11-05 | 浙江工业大学 | A kind of method of steroidal compounds removing 17- acetoxyl group |
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