CN102850423B - Synthesis method of 16alpha-hydroxy prednisolone - Google Patents
Synthesis method of 16alpha-hydroxy prednisolone Download PDFInfo
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- CN102850423B CN102850423B CN201210364257.6A CN201210364257A CN102850423B CN 102850423 B CN102850423 B CN 102850423B CN 201210364257 A CN201210364257 A CN 201210364257A CN 102850423 B CN102850423 B CN 102850423B
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- 238000001308 synthesis method Methods 0.000 title abstract 5
- SEKYBDYVXDAYPY-ILNISADRSA-N (8s,9s,10r,11s,13s,14s,16r,17s)-11,16,17-trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-3-one Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 SEKYBDYVXDAYPY-ILNISADRSA-N 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- 239000004094 surface-active agent Substances 0.000 claims abstract description 38
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229960005205 prednisolone Drugs 0.000 claims abstract description 27
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 63
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical group C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 claims description 27
- 238000010189 synthetic method Methods 0.000 claims description 23
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000012046 mixed solvent Substances 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000000284 extract Substances 0.000 claims description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 9
- 239000012153 distilled water Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 238000009413 insulation Methods 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 230000008034 disappearance Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 4
- 239000012429 reaction media Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 125000006840 diphenylmethane group Chemical group 0.000 abstract 1
- 239000012847 fine chemical Substances 0.000 abstract 1
- 239000010410 layer Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 101710171243 Peroxidase 10 Proteins 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 101100323029 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) alc-1 gene Proteins 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 238000006277 sulfonation reaction Methods 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- -1 diacetyl compound Chemical class 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Steroid Compounds (AREA)
Abstract
The invention provides a synthesis method of 16alpha-hydroxy prednisolone, belonging to the technical field of fine chemical synthesis method. The synthesis method comprises the following steps: using prednisolone with a structure as shown in formula (I) as a raw material, performing dehydration reaction to generate a double-bond compound under the action of gemini surfactant as shown in formula (II), then adding aqueous hydrogen peroxide solution for further reaction, and adding water to hydrolyze after finishing reaction so as to obtain the target product 16alpha-hydroxy prednisolone, wherein the gemini surfactant is diphenylmethane gemini surfactant. According to the synthesis method, gemini surfactant is simultaneously used as a reaction medium and a catalyst, and can be recovered and reused after reaction finishes, the process is simple, the after-treatment is convenient, the obtained products have the characteristics of high productivity, good efficiency, and less waste, the yield is greater than 85%, and the gemini surfactant can be recycled, and therefore the synthesis method is an economical, practical and environment-friendly technology and is suitable for popularization and application.
Description
Technical field
The invention belongs to fine chemistry industry synthetic method technical field, be specifically related to a kind of synthetic method of 16 alpha-hydroxy prednisonlones.
Background technology
16 alpha-hydroxy prednisonlones are important intermediate of a kind of medicine-ciclesonide for the treatment of asthma.The synthetic method of 16 alpha-hydroxy prednisonlones of report is all take prednisolone as raw material at present; under para-methylbenzenepyridinsulfonate sulfonate katalysis, become ring with triethly orthoacetate; under solutions of weak acidity, selective opening obtains acetylate; under alkaline condition, react with acetic anhydride again and generate after diacetyl compound; the acetic acid that Potassium ethanoate exists lower heating to slough a part obtains (11 β)-hydroxyl-21-acetoxyl group-1; the pregnant steroid of 4,16-triolefin-3,20-dione compounds.By this compound selectivity bishydroxy under potassium permanganate effect, deacetylated product 16 alpha-hydroxy prednisonlones that obtain under the existence of sodium hydroxide.In existing synthetic route, synthesis step is long, product aftertreatment complexity.
Summary of the invention
For the above-mentioned problems in the prior art, the object of the invention is to provide a kind of method of Gemini surface active agent while as reaction medium and synthetic 16 alpha-hydroxy prednisonlones of catalyzer of utilizing, this technology is easy to operate, production capacity is high, excellent in efficiency, the three wastes are few, convenient post-treatment, Gemini surface active agent is reusable, has economical and practical feature.
The synthetic method of described a kind of 16 alpha-hydroxy prednisonlones, its structure is as shown in formula III, it is characterized in that the prednisolone as shown in formula I is raw material take structure, under the Gemini surface active agent effect as shown in formula II, carry out dehydration reaction and generate double bond compound, then add aqueous hydrogen peroxide solution further to react, after reaction finishes, add water and be hydrolyzed again, obtain object product 16 alpha-hydroxy prednisonlones, described Gemini surface active agent is ditane Gemini surface active agent
The synthetic method of described a kind of 16 alpha-hydroxy prednisonlones, it is characterized in that described synthetic method is as follows: prednisolone is added in ditane Gemini surface active agent, at 100～150 ℃, carry out dehydration reaction, TLC tracks to the disappearance of raw material prednisolone point and finishes reaction, and add aqueous hydrogen peroxide solution after being cooled to room temperature, oxidizing reaction 5～50 h at 10～60 ℃, under insulation, add again water to be further hydrolyzed, TLC follows the tracks of reaction process, and reaction finishes rear gained reaction solution and obtains 16 alpha-hydroxy prednisonlone products through aftertreatment.
The synthetic method of described a kind of 16 alpha-hydroxy prednisonlones, is characterized in that described prednisolone and the mass ratio that feeds intake of ditane Gemini surface active agent are 1: 1～20, is preferably 1:8～15, and optimum is 1:10.
The synthetic method of described a kind of 16 alpha-hydroxy prednisonlones, is characterized in that described aqueous hydrogen peroxide solution mass concentration is 30～70%, and the hydrogen peroxide mol ratio in prednisolone and aqueous hydrogen peroxide solution is 1:1～10, is preferably 1:3～5.
The synthetic method of described a kind of 16 alpha-hydroxy prednisonlones, the water add-on that it is characterized in that being hydrolyzed use is 40～60 times of prednisolone quality.
The synthetic method of described a kind of 16 alpha-hydroxy prednisonlones, it is characterized in that aftertreatment adopts following steps: reaction solution first extracts with toluene, the extracting phase obtaining is for subsequent use, extraction phase toluene layer is with using anhydrous magnesium sulfate drying toluene layer after distilled water wash, remove toluene under reduced pressure, obtain 16 alpha-hydroxy prednisonlone products.
The synthetic method of described a kind of 16 alpha-hydroxy prednisonlones, is characterized in that described dehydration reaction temperature is 120～130 ℃, and oxidizing reaction and hydrolysising reacting temperature are 50～60 ℃, and adding the aqueous hydrogen peroxide solution reaction times is 20～40 hours.
The synthetic method of described a kind of 16 alpha-hydroxy prednisonlones, is characterized in that TLC tracking monitor developping agent used is that volume ratio is hexanaphthene and the acetone mixed solvent of 5: 5.
The synthetic method of described a kind of 16 alpha-hydroxy prednisonlones, it is characterized in that extracting phase is the mixed solution containing ditane Gemini surface active agent, can directly add reaction system for reaction, reuse after number of times 3～5 times, wash with water, dichloromethane extraction, dryly reuse again after concentrated.
The synthetic method of described a kind of 16 alpha-hydroxy prednisonlones, is characterized in that described ditane Gemini surface active agent is made by following steps:
1) alkylation adds ditane and the anhydrous AlC1 of catalyzer in the four-hole reaction flask that electric mixer, thermometer, reflux condensing tube, dropping funnel, HCl gas access equipment are housed
3after fully stirring is uniformly dispersed catalyzer, pass into HCl gas, temperature control is to 45-50 ℃, drip alkene at 20-30min, then degree of intensification rises to 70 ℃ gradually, insulation reaction 8h, being washed to neutrality removes after catalyzer again, obtain alkylate chlorsulfonic acid, described alkene and the mol ratio of ditane are 2:1, anhydrous AlC1
3charging capacity is the 8.8-9% of ditane quality;
2) sulfonation is being equipped with the alkylate that adds step 1) to obtain in the four-hole reaction flask of electric mixer, thermometer, reflux condensing tube, dropping funnel, HCl gas absorbing device, under violent stirring, in l hour, dropwise add chlorsulfonic acid, after dripping off, react 2 hours at 20-25 ℃, make after the abundant sulfonation of alkylate, leave standstill the HCl generating is discharged, obtain sulfonated products, described alkylate and the mol ratio of chlorsulfonic acid are 2:1;
3) neutralization reaction
sulfonated products is added in the four-hole reaction flask that electric mixer, thermometer, reflux condensing tube, dropping funnel are housed, by water-bath control temperature of reaction at 35～40 ℃, slowly drip 15% sodium hydroxide solution, regulation system pH value is 7～8, make sulfonic acid all generate sodium sulfonate, obtain ditane Gemini surface active agent.
By adopting above-mentioned technology, compared with prior art, beneficial effect of the present invention is as follows:
1) preparation method for gemini surfactant of the present invention is simple, the present invention its simultaneously as reaction medium and catalyzer, after reaction finishes, can reclaim and reuse, simple operating procedure, and reduced environmental pollution, has reduced cost;
2) reaction solution of the present invention extracts with toluene, toluene layer removes toluene under reduced pressure and obtains 16 alpha-hydroxy prednisonlone products, extracting phase is the mixed solution containing Gemini surface active agent, can directly add reaction system for reaction, reuse after 3～5 times, then wash with water, dichloromethane extraction, reusable again after dry concentrating, active and new Gemini surface active agent is identical;
3) simple, the convenient post-treatment of reaction process of the present invention, the product production capacity that obtains is high, purity is high, excellent in efficiency, the three wastes are few, and yield is up to more than 85%, and Gemini surface active agent is reusable, is economical and practical green environmental protection technique, is suitable for applying;
4) product of the present invention 16 alpha-hydroxy prednisonlone Mp:238～241 ℃, its structure is through hydrogen spectrum authentication: H
1nMR δ: 0.98 (s, 3H) 1.49 (s, 3H), 4.24-4.68 (dd, 2H, J=20.1, Hz), 4.50 (d, 1H, J=2.5Hz), 5.08 (d, 1H, J=8.2Hz), 6.03 (s, 3H), 6.28 (d, 1H, 9.3 Hz), 7.25 (d, 1H, J=10.1 Hz).
Embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this.
16 alpha-hydroxy prednisonlones of the present invention, its synthetic method is as follows: prednisolone is added in ditane Gemini surface active agent, at 100～150 ℃, carry out dehydration reaction, TLC tracks to the disappearance of raw material prednisolone point and finishes reaction, and be cooled to that to add mass concentration after room temperature be the aqueous hydrogen peroxide solution of 30-70%, oxidizing reaction 5～50h at 10～60 ℃, under insulation, add again water to be further hydrolyzed, TLC follows the tracks of reaction process, the reaction solution obtaining after reaction finishes first extracts with toluene, the extracting phase obtaining is for subsequent use, extraction phase toluene layer is with using anhydrous magnesium sulfate drying toluene layer after distilled water wash, remove toluene under reduced pressure, obtain 16 alpha-hydroxy prednisonlone products,
Wherein the mass ratio that feeds intake of prednisolone and ditane Gemini surface active agent is 1: 1～20, is preferably 1:8～15, and optimum is 1:10; Hydrogen peroxide mol ratio in prednisolone and aqueous hydrogen peroxide solution is 1:1～10, is preferably 1:3～5; The water add-on of hydrolysis use is 40～60 times of prednisolone quality;
Dehydration reaction temperature is preferably 120～130 ℃, and the preferred temperature of oxidizing reaction and hydrolysis reaction is 50～60 ℃, adds the aqueous hydrogen peroxide solution reaction times to be preferably 20～40 hours;
TLC tracking monitor developping agent used is that volume ratio is hexanaphthene and the acetone mixed solvent of 5: 5;
When methane extraction product of the present invention, the extracting phase obtaining is the mixed solution containing ditane Gemini surface active agent, can directly add reaction system for reaction, reuse after number of times 3～5 times, wash with water, dichloromethane extraction, dryly reuse again after concentrated.
Hydrogen peroxide used in embodiment below the present invention adds with the form of the aqueous hydrogen peroxide solution of mass concentration 30%, the quality relating in embodiment and amount of substance are all in hydrogen peroxide itself, aqueous hydrogen peroxide solution take mass concentration as the arbitrary concentration of 30%-70% replaces the aqueous hydrogen peroxide solution of mass concentration 30% in theory, all can obtain same technique effect.
Embodiment 1: the preparation of ditane Gemini surface active agent
1) in the four-hole reaction flask that electric mixer, thermometer, reflux condensing tube, dropping funnel, HCl gas access equipment are housed, add 33.6g ditane, add the anhydrous AlC1 of 3g catalyzer
3fully dispersed with stirring is even, passes into HCl gas, and insulation is at 45-50 ℃, dripping amount of substance is the alkene of 2 times of ditanes, is controlled at 20-30min and drips, and then temperature of reaction is risen to 70 ℃ gradually, insulation reaction 8h, is washed to neutrality, and the catalyzer of removing in system obtains alkylate;
2)being equipped with in the four-hole reaction flask of electric mixer, thermometer, reflux condensing tube, dropping funnel, HCl gas absorbing device, the alkylate that adds step 1) to obtain, under violent stirring, dropwise adding mole number is the chlorsulfonic acid of 0.5 times of alkylate, time for adding is lh, temperature control was 20-25 ℃ of reaction 2 hours, make after the abundant sulfonation of alkylate, product is placed to a few hours, the HCl generating is discharged as much as possible;
3) neutralization reaction
by step 2) sulfonated products add in the four-hole reaction flask that electric mixer, thermometer, reflux condensing tube, dropping funnel are housed, by water-bath control temperature of reaction at 35～40 ℃, with dropping funnel, 15% sodium hydroxide solution being slowly added to pH value is 7～8, make sulfonic acid all generate sodium sulfonate, quantitatively obtain ditane Gemini surface active agent, for subsequent use.
The preparation of embodiment 2 16 alpha-hydroxy prednisonlones
By prednisolone 0.1g (2.77 × 10
-4mol) and ditane Gemini surface active agent 1g add in reaction flask, maintain the temperature at 120 ℃ and carry out dehydration reaction, reaction process TLC tracking monitor, using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent, until raw material point disappears, be cooled to room temperature, add hydrogen peroxidase 10 .028g (8.31 × 10
-4mol), at 50 ℃, react 20 hours, add again 5 ml waters, after thin layer plate (using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and is finished, add and extract with 3 × 5mL toluene, raffinate merges to be recycled, combining extraction liquid, with after 3 × 5 mL distilled water washs, separate organic layer, after anhydrous magnesium sulfate drying, underpressure distillation is to constant weight, obtain 16 alpha-hydroxy prednisonlone product 0.093g as shown in formula III, yield is 93%.Mp：238～241 ℃。H
1 NMRδ: 0.98(s, 3H) 1.49 (s, 3H)，4.24-4.68(dd, 2H, J = 20.1，Hz)，4.50 (d, 1H, J = 2.5Hz)，5.08 (d, 1H, J= 8.2Hz)，6.03 (s, 3H)，6.28 (d, 1H, 9.3 Hz)，7.25 (d, 1H, J= 10.1 Hz)。
Embodiment 3 is by prednisolone 0.1g (2.77 × 10
-4mol) and embodiment 2 obtain containing the raffinate of ditane Gemini surface active agent and new ditane Gemini surface active agent altogether 2g add in reaction flask, maintain the temperature at 150 ℃, reaction process TLC tracking monitor, using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent, until raw material point disappears, then, be cooled to room temperature, add hydrogen peroxidase 10 .009g (2.77 × 10
-4mol), at 50 ℃, react 10 hours, add again 6 ml waters, after thin layer plate (using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and is finished, add and extract with 3 × 5mL toluene, raffinate evaporate to dryness reclaims for subsequent use, combining extraction liquid, with after 3 × 5 mL distilled water washs, separate organic layer, after anhydrous magnesium sulfate drying, underpressure distillation is to constant weight, obtain 16 alpha-hydroxy prednisonlone product 0.088g as shown in formula III, yield is 88%.
Embodiment 4 is by prednisolone 0.1g (2.77 × 10
-4mol) and implement 3 obtain add in reaction flask containing the raffinates of ditane Gemini surface active agent 0.1g, maintain the temperature at 130 ℃, reaction process TLC tracking monitor, using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent, until raw material point disappears, then, be cooled to room temperature, add hydrogen peroxidase 10 .09g (27.7 × 10
-4mol), at 10 ℃, react 50 hours, add again 4 ml waters, after thin layer plate (using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and is finished, add and extract with 3 × 5mL toluene, raffinate evaporate to dryness reclaims for subsequent use, combining extraction liquid, with after 3 × 5 mL distilled water washs, separate organic layer, after anhydrous magnesium sulfate drying, underpressure distillation is to constant weight, obtain 16 alpha-hydroxy prednisonlone product 0.085g as shown in formula III, yield is 85%.
Embodiment 5 is by prednisolone 0.1g (2.77 × 10
-4mol) and the ditane Gemini surface active agent 1.5g that obtains of embodiment 2 and embodiment 3 add in reaction flask, maintain the temperature at 100 ℃, reaction process TLC tracking monitor, using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent, until raw material point disappears, then, be cooled to room temperature, add hydrogen peroxidase 10 .045g (13.8 × 10
-4mol), at 10 ℃, react 50 hours, add again 4.5 ml waters, after thin layer plate (using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and is finished, add and extract with 3 × 5mL toluene, raffinate evaporate to dryness reclaims for subsequent use, combining extraction liquid, with after 3 × 5 mL distilled water washs, separate organic layer, after anhydrous magnesium sulfate drying, underpressure distillation is to constant weight, obtain 16 alpha-hydroxy prednisonlone product 0.090g as shown in formula III, yield is 90%.
Embodiment 6 is by prednisolone 0.1g (2.77 × 10
-4mol) and ditane Gemini surface active agent 1.5g add in reaction flask, maintain the temperature at 130 ℃, reaction process TLC tracking monitor, using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent, until raw material point disappears, then, be cooled to room temperature, add hydrogen peroxidase 10 .045g (13.8 × 10
-4mol), at 60 ℃, react 5 hours, add again 5.5 ml waters, after thin layer plate (using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and is finished, add and extract with 3 × 5mL toluene, raffinate reclaims for subsequent use, combining extraction liquid, with after 3 × 5 mL distilled water washs, separate organic layer, after anhydrous magnesium sulfate drying, underpressure distillation is to constant weight, obtain 16 alpha-hydroxy prednisonlone product 0.091g as shown in formula III, yield is 91%.
Embodiment 7 is by prednisolone 0.1g (2.77 × 10
-4mol) and the ditane Gemini surface active agent 0.3g obtaining in embodiment 5 add in reaction flask, maintain the temperature at 140 ℃, reaction process TLC tracking monitor, using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent, until raw material point disappears, then, be cooled to room temperature, add hydrogen peroxidase 10 .045g (13.8 × 10
-4mol), at 55 ℃, react 40 hours, add again 5.5 ml waters, after thin layer plate (using hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is as developping agent) is followed the tracks of reaction and is finished, add and extract with 3 × 5mL toluene, raffinate reclaims for subsequent use, combining extraction liquid, with after 3 × 5 mL distilled water washs, separate organic layer, after anhydrous magnesium sulfate drying, underpressure distillation is to constant weight, obtain 16 alpha-hydroxy prednisonlone product 0.088g as shown in formula III, yield is 88%.
Claims (7)
1. the synthetic method of an alpha-hydroxy prednisonlone, its structure is as shown in formula III, it is characterized in that the prednisolone as shown in formula I is raw material take structure, under the Gemini surface active agent effect as shown in formula II, carry out dehydration reaction and generate double bond compound, then add aqueous hydrogen peroxide solution further to react, after reaction finishes, add water and be hydrolyzed again, obtain object product 16 alpha-hydroxy prednisonlones, described Gemini surface active agent is ditane Gemini surface active agent, concrete steps are as follows: prednisolone is added in ditane Gemini surface active agent, at 100～150 ℃, carry out dehydration reaction, TLC tracks to the disappearance of raw material prednisolone point and finishes reaction, and add aqueous hydrogen peroxide solution after being cooled to room temperature, oxidizing reaction 5～50 h at 10～60 ℃, under insulation, add again water to be further hydrolyzed, TLC follows the tracks of reaction process, reaction finishes rear gained reaction solution and obtains 16 alpha-hydroxy prednisonlone products through aftertreatment, the mass ratio that feeds intake of described prednisolone and ditane Gemini surface active agent is 1:8～15, the water add-on of hydrolysis use is 40～60 times of prednisolone quality, aftertreatment adopts following steps: reaction solution first extracts with toluene, the extracting phase obtaining is for subsequent use, extraction phase toluene layer is with using anhydrous magnesium sulfate drying toluene layer after distilled water wash, remove toluene under reduced pressure, obtain 16 alpha-hydroxy prednisonlone products,
2. the synthetic method of a kind of 16 alpha-hydroxy prednisonlones according to claim 1, is characterized in that described prednisolone and the mass ratio that feeds intake of ditane Gemini surface active agent are 1:10.
3. the synthetic method of a kind of 16 alpha-hydroxy prednisonlones according to claim 1, is characterized in that described aqueous hydrogen peroxide solution mass concentration is 30～70%, and the hydrogen peroxide mol ratio in prednisolone and aqueous hydrogen peroxide solution is 1:1～10.
4. the synthetic method of a kind of 16 alpha-hydroxy prednisonlones according to claim 3, is characterized in that the hydrogen peroxide mol ratio in described prednisolone and aqueous hydrogen peroxide solution is 1:3～5.
5. the synthetic method of a kind of 16 alpha-hydroxy prednisonlones according to claim 1, it is characterized in that described dehydration reaction temperature is 120～130 ℃, oxidizing reaction and hydrolysising reacting temperature are 50～60 ℃, and adding the aqueous hydrogen peroxide solution reaction times is 20～40 hours.
6. the synthetic method of a kind of 16 alpha-hydroxy prednisonlones according to claim 1, is characterized in that TLC tracking monitor developping agent used is that volume ratio is hexanaphthene and the acetone mixed solvent of 5: 5.
7. the synthetic method of a kind of 16 alpha-hydroxy prednisonlones according to claim 1, it is characterized in that extracting phase is the mixed solution containing ditane Gemini surface active agent, can directly add reaction system for reaction, reuse after number of times 3～5 times, wash with water, dichloromethane extraction, dryly reuse again after concentrated.
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| 新型表面活性剂-双烷基双磺酸钠基二苯甲烷的合成与性能;于涛 等;《大庆石油学院学报》;20040228;第28卷(第1期);第35-37、120页 * |
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