CN107619846A - A kind of preparation method of triamcinolone - Google Patents
A kind of preparation method of triamcinolone Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of steroidal compounds, more particularly, to the preparation of triamcinolone.The present invention is using chloride as starting material, and successively by 9,11 epoxies, 1,2 dehydrogenation, 17 are dehydrated, fluorine on 9, and the upper double hydroxyls of 16,17 double bonds oxidations, 21 is bit esterified, and 16,17 condensations, 21 hydrolysis obtain triamcinolone.The invention new technology has more industrialization value, can effectively control side reaction, improves reaction yield and quality；High-risk reaction it is not related in technological design, it is easy to accomplish industrialization；Reacted in the absence of high pollution, alleviate environmental protection treatment pressure.
Description
Technical field
The present invention relates to new technology prepared by a kind of triamcinolone, belong to pharmaceutical technology field.
Background technology
Triamcinolone (9 α-fluoro- 11 β, 16 α, 17 α, pregnant steroid-Isosorbide-5-Nitrae-diene -3, the 20- diketone of 21- tetrahydroxys), is adrenal gland skin
Matter amcinonide, antiinflammatory action are strong compared with hydrocortisone, metacortandracin.Water-sodium retention effect is then slighter.It is oral easily to absorb.It is suitable
For rheumatoid arthritis, other connective tissue diseases, bronchial astehma, allergic dermatitis, neurodermatitis, eczema etc.,
The arthritic with hypertension or edema being particularly suitable for use in cortin taboo.
The production process route of early stage triamcinolone is older, and is using saponin as initiation material, and saponin supply at present becomes
Tightly, therefore, new natural resources are developed, are undoubtedly had very important significance for steroidal industry.
There are many countries just actively to seek its substitute products always in five sixties or using artificial synthesized in the world
Method solves imbalance between supply and demand.American-European a few countries achieve important breakthrough, Ta Menli in the exploitation of hormone pharmacy new raw material
With the phytosterol extracted in caused accessory substance during vegetable oil refining, the androstenedione by biodegradation production produces
Cortin, solves the problem that corticosteroid drug production relies on saponin.
Realized compared to saponin route for starting material production corticoid medicine with androstenedione (AD) and once leaped
The technological revolution of formula, all achieves very big improvement from Social benefit and economic benefit, but androstenedione route there is also
One defect.Many clinical effective corticoid medicines 11 have β hydroxyl structures, or are re-introduced into halogen on 9
To strengthen drug effect, however it is industrial at present, it can only obtain 11 α hydroxylic species using bioanalysis.In order to obtain 11 β hydroxyls, at present
The method of generally use be using Jones reagent aoxidize 11 α hydroxyls be 11 carbonyls, reselection is reduced to 11 β hydroxyls,
Heavy metal chromium is inevitably used in transfer process, on the one hand increases entreprise cost in environmental protection treatment, on the other hand a huge sum of money
Category chromium is the metalloid that possible cause genotoxicity, and the limit required in finished product residual is very low, is the quality of finished product
Research brings very big hidden danger.In addition, in the corticoid drug products of 9 halogens of preparation, five are generally utilized in production
Phosphorus chloride is dehydrated to obtain 9,11 double bond things, then obtains corresponding product to double bond addition.Substantial amounts of acid can be produced in dewatering process
Water, higher environmental protection treatment expense is caused to enterprise.
The problem of existing for above-mentioned route, new natural resources and synthetic route are developed, for steroidal industry undoubtedly
Have very important significance.
The content of the invention：
The present invention relates to a kind of preparation method of triamcinolone, devises a brand-new process route for synthesizing triamcinolone：
Using chloride as starting material, aoxidized successively by 9,11- epoxies, 1,2- dehydrogenation, 17- dehydrations, the upper fluorine of 9-, 16,17 double bonds
Double hydroxyls, 21 is bit esterified, 16,17 condensations, 21 hydrolysis, obtains triamcinolone.Route map is as follows：
A kind of preparation method of described triamcinolone, it is characterised in that：
(1) epoxy：Chloride first reacts with halide reagent and acid catalyst, adds alkali reaction, obtains epoxy material；
(2) dehydrogenation：Dehydrogen substance is obtained using the method for Arthrobacter simplex biological dehydrogenation using epoxy material as substrate；
(3) it is dehydrated：Dehydrogen substance is reacted in basic solvent with dehydrating agent, obtains dehydrate；
(4) fluorine on：Dehydrate and hydrogen fluoride reaction are obtained into fluoride；
(5) aoxidize：Fluoride obtains oxide with oxidant reaction；
(6) it is esterified：Oxide obtains carboxylate with acetic acid reactant salt；
(7) it is condensed：Carboxylate obtains triamcinolone with condensation of acetone；
(8) hydrolyze：Triamcinolone hydrolyzes to obtain triamcinolone in the basic conditions.
A kind of preparation method of described triamcinolone, it is characterised in that：
(1) epoxy：One or more of the described acidic catalyst in organic acid or inorganic acid, described halogenation
Reagent is selected from bromide reagent or chlorine reagent, and described alkali is selected from inorganic base；
(2) dehydrogenation：The Arthrobacter simplex is selected from AS1.754* or AS1.94*；
(3) it is dehydrated：The basic solvent is selected from one or both of pyridine or triethylamine, and the dehydrating agent is selected from three
Chlorethoxyfos, mesyl chloride or to the one or more in tosylate chloride；
(4) fluorine on：Dehydrate and hydrogen fluoride reaction are obtained into fluoride；
(5) aoxidize：The oxidant is selected from potassium permanganate, hydrogen peroxide or osmium tetroxide；
(6) it is esterified：Oxide obtains carboxylate with acetic acid nak response；
(7) it is condensed：Carboxylate obtains triamcinolone with condensation of acetone；
(8) hydrolyze：Alkali is selected from alkali carbonate or alkali metal hydrogencarbonate.
A kind of preparation method of described triamcinolone, it is characterised in that：
(1) epoxy：Described acid catalyst is selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, formic acid or acetic acid；It is described
Halide reagent be selected from DBNPA, dibromo cyano propionamide, C5H6Br2N2O2, N- bromo acetamides, N- bromo neighbour's benzene
Diformamide, N-bromosuccinimide or N-chlorosuccinimide；Described alkali is selected from sodium hydroxide, potassium hydroxide, carbon
Sour sodium or potassium carbonate；
(2) dehydrogenation：The Arthrobacter simplex is selected from AS1.754* or AS1.94*；
(3) it is dehydrated：The basic solvent is selected from one or both of pyridine or triethylamine, and the dehydrating agent is selected from three
Chlorethoxyfos, mesyl chloride or to the one or more in tosylate chloride；
(4) fluorine on：Dehydrate and hydrogen fluoride reaction are obtained into fluoride；
(5) aoxidize：The oxidant is selected from potassium permanganate, hydrogen peroxide or osmium tetroxide；
(6) it is esterified：Oxide obtains carboxylate with acetic acid nak response；
(7) it is condensed：Carboxylate obtains triamcinolone with condensation of acetone；
(8) hydrolyze：Alkali is selected from sodium carbonate, potassium carbonate, sodium acid carbonate or saleratus.
A kind of preparation method of described triamcinolone, it is characterised in that：
(1) epoxy：Acid catalyst is perchloric acid；Halide reagent is selected from DBNPA or N- bromos succinyl is sub-
Amine；Alkali is sodium hydroxide；
(2) dehydrogenation：The Arthrobacter simplex is selected from AS1.754* or AS1.94*；
(3) it is dehydrated：The basic solvent is selected from one or both of pyridine or triethylamine, and the dehydrating agent is selected from three
Chlorethoxyfos, mesyl chloride or to the one or more in tosylate chloride；
(4) fluorine on：Dehydrate and hydrogen fluoride reaction are obtained into fluoride；
(5) aoxidize：The oxidant is potassium permanganate；
(6) it is esterified：Oxide obtains carboxylate with acetic acid nak response；
(7) it is condensed：Carboxylate obtains triamcinolone with condensation of acetone；
(8) hydrolyze：Alkali is selected from sodium carbonate or potassium carbonate.
A kind of preparation method of described triamcinolone, it is characterised in that：
(1) epoxy：The reaction temperature in halogenation stage is selected from -10-30 DEG C；Alkali epoxidation stage reaction temperature is selected from -10-
40℃；
(2) dehydrogenation：Fermentation temperature is selected from 30-34 DEG C；
(3) it is dehydrated：Reaction temperature is selected from 25-120 DEG C；
(4) fluorine on：Reaction temperature is selected from -5-10 DEG C；
(6) it is esterified：Reaction temperature is selected from 60-100 DEG C；
(7) it is condensed：Reaction temperature is in the range of 0 DEG C to solvent boiling point；
(8) hydrolyze：Reaction temperature is selected from -10-40 DEG C.
A kind of preparation method of described triamcinolone, it is characterised in that：
(1) epoxy：The reaction temperature in halogenation stage is selected from 0-20 DEG C；Alkali epoxidation stage reaction temperature is selected from -5-30
℃；
(2) dehydrogenation：Fermentation temperature is selected from 30-34 DEG C；
(3) it is dehydrated：Reaction temperature is selected from 70-90 DEG C；
(4) fluorine on：Reaction temperature is selected from -5-10 DEG C；
(6) it is esterified：Reaction temperature is selected from 60-100 DEG C；
(7) it is condensed：Reaction temperature is selected from 10-30 DEG C；
(8) hydrolyze：Reaction temperature is selected from 15-30 DEG C.
A kind of preparation method of described triamcinolone, it is characterised in that：
(1) epoxy：Reaction dissolvent be selected from methanol, ethanol, acetone, ether, tetrahydrofuran, dioxane, dichloromethane,
One or more in chloroform；
(2) dehydrogenation：The one kind of reaction dissolvent in methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide
It is or a variety of；
(3) it is dehydrated：The basic solvent is selected from one or both of pyridine or triethylamine；
(4) fluorine on：Reaction dissolvent is selected from dimethylformamide or tetrahydrofuran；
(5) aoxidize：One or more of the reaction dissolvent in lower aliphatic alcohols, ketone, ether organic solvent；
(6) it is esterified：Reaction dissolvent is dimethylformamide；
(7) it is condensed：Reaction dissolvent is acetone；
(8) hydrolyze：Reaction dissolvent in methanol, chloroform, dichloromethane, ether, tetrahydrofuran, dioxane one
Kind is a variety of.
A kind of preparation method of described triamcinolone, it is characterised in that：
(2) dehydrogenation：Described biological dehydrogenation concrete technology is：Epoxy material is crushed or complete molten or semi-soluble with solvent, put into
Progress biological dehydrogenation reaction in the fermentation tank of arthrobacterium or Arthrobacter simplex has been cultivated, has been extracted after conversion and obtains dehydrogen substance；
Described biological dehydrogenation reaction uses following zymotechnique：
Inclined-plane culture → one-level culture → two level culture → addition epoxy material fermentation progress biological dehydrogenation reaction → termination is anti-
Should.
A kind of preparation method of described triamcinolone, it is characterised in that：
(2) dehydrogenation：The epoxy material to feed intake that crushes is selected from the particulate that micro mist turns to D90≤100 μm；The throwing of epoxy material
Expect that concentration is selected from 1~4%.
A kind of preparation method of described triamcinolone, it is characterised in that：
(2) dehydrogenation：Chaotropic agent is added when crushing feeds intake into zymotic fluid, described chaotropic agent is Tween-80.
A kind of new steroidal intermediate：
The starting material chloride of the present invention, it is using 9 Alpha-hydroxy-AD as starting material, be dehydrated by 17 cyanidings, 9 (11) positions,
17 silicon etherificates, 17 substitution-hydrolysis are prepared.9 Alpha-hydroxies-androstenedione (9 Alpha-hydroxy-AD) are a kind of lifes newly developed
The important source material of corticoid medicine is produced, can be degraded to obtain by phytosterol bio.In phytosterol bio degradation process
9 Alpha-hydroxies are introduced simultaneously, equivalent to effect (the phytosterol first biodegradation of two steps biology in androstenedione (4AD) technique
4AD is obtained, rear bioanalysis introduces 11 Alpha-hydroxies), 9 Alpha-hydroxy-AD and 4AD, the two industrial cost is suitable, thus 9 Alpha-hydroxy-AD
There is cost advantage compared to 4AD.
The present invention is mainly using 9 Alpha-hydroxy-AD derivative --- and chloride passes through a series of synthetic reactions as starting material
Prepare triamcinolone.The invention new technology has more industrialization value, can effectively control side reaction, improves reaction yield and quality；
High-risk reaction it is not related in technological design, it is easy to accomplish industrialization；Reacted in the absence of high pollution, alleviate environmental protection treatment pressure.
The present invention realizes prepares steroidal compounds using 9 Alpha-hydroxy-AD derivative-chloride as starting material, effectively keeps away
The defects of AD routes are present is exempted from, has realized once rapid technological revolution, all obtained from Social benefit and economic benefit
Very big improvement.
Embodiment：
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Identical reagent and reagent use same lot number in following examples.Chloride is limited purchased from Tianjin day medicine share
Company.
The epoxy reaction of inventive embodiments 1
Embodiment 1-1
10g chloride is added in reaction bulb, 2ml perchloric acid, 50ml tetrahydrofuran, stirring, cools to 0 DEG C,
NCS 9g were added in 30 minutes, is maintained at 5-10 DEG C and reacts, is terminated with thin-layer chromatography monitoring reaction process to reaction, diluted
Yu Shuizhong, it is filtrated to get halide wet product solid and is directly dissolved in 100ml acetone, be warming up to 20 ± 2 DEG C, added in 1 hour
10% potassium hydroxide aqueous solution 15ml, 20-25 DEG C of reaction of temperature control, terminated with thin-layer chromatography monitoring reaction process to reaction, acetic acid
PH=7 is neutralized, being concentrated under reduced pressure into does not have acetone taste, is diluted in frozen water, filters, and dries, obtains 9,11- epoxy materials 10.9g.
Embodiment 1-2
10g chloride is added in reaction bulb, 2ml perchloric acid, 120ml acetone, stirring, 0 DEG C is cooled to, 30
NBS 9g are added in minute, is maintained at 5-10 DEG C and reacts, is terminated with thin-layer chromatography monitoring reaction process to reaction, adds 10%
Aqueous sodium carbonate neutralizes and arrives pH=6.5, is warming up to 20 ± 2 DEG C, in adding 10% sodium hydrate aqueous solution 15ml in 1 hour,
20-25 DEG C of reaction of temperature control, terminated with thin-layer chromatography monitoring reaction process to reaction, acetic acid neutralizes and arrives pH=7, is concentrated under reduced pressure into not
There is acetone taste, be diluted in frozen water, filter, dry, obtain 9,11- epoxy materials 11.2g.
Embodiment 1-3
11.1g chloride is added in reaction bulb, 2ml perchloric acid, 50ml tetrahydrofuran, stirring, cools to 0
DEG C, DBNPA 6.5g was added in 30 minutes, is maintained at 5-10 DEG C and reacts, reaction process is monitored with thin-layer chromatography
Terminate to reaction, be diluted in water, be filtrated to get halide wet product solid and be directly dissolved in 40ml methanol and 30ml dichloromethane,
20 ± 2 DEG C are warming up to, in adding 10% potassium hydroxide aqueous solution 15ml in 1 hour, 20-25 DEG C of reaction of temperature control, uses thin-layer chromatography
Monitoring reaction process to reaction terminates, and hydrochloric acid neutralizes and arrives pH=7, and being concentrated under reduced pressure into does not have methanol taste, is diluted in frozen water, mistake
Filter, dry, obtain 9,11- epoxy materials 11.3g.
The dehydrogenation reaction of inventive embodiments 2
Slant medium (%)：Glucose 1.3, yeast extract 1.3, agar 2.0, and the distilled water of surplus, pH7.0-
7.2, for inclined-plane culture.
Fermentation medium (%)：Glucose 1.0, yeast extract 0.16, KH2PO40.25, corn steep liquor 0.1, and the steaming of surplus
Distilled water, pH 7.0-7.2, in being reacted for one-level, two level culture and final biological dehydrogenation.
Inclined-plane culture：Slant medium is sub-packed in 15mL test tube, inclined-plane is put into after the 30min that sterilizes.Inclined-plane is in 37
2d is placed in DEG C incubator, observing no microbiological contamination situation can be inoculated with.Inoculation back bevel cultivates 2d at 30 DEG C, is subsequently placed in
Preserved in 4 DEG C of refrigerators.
One-level culture：Thalline, 250mL of the access equipped with 30ml culture mediums are taken from well-grown Arthrobacter simplex inclined-plane
In triangular flask, 30~34 DEG C, 180r/min shaken cultivations 24 hours.
Two level culture：Zymotic fluid after completion one-level culture is equipped with 150ml culture mediums with the access of 5% inoculum concentration
In 1000mL secondary seed culture triangular flasks, two level culture is carried out with same condition, two level incubation time is 24 hours.
The measure of substrate conversion efficiency：Conversion ratio accounts for the total matter of initial substrate with the substrate quality that product is converted into course of reaction
The percentage of amount represents.Determined using HPLC, splitter is C18 posts, and Detection wavelength 240nm, mobile phase is acetonitrile: water
The flow velocity that is dissolved in of (volume ratio)=60: 40 is 1.5mL/min.Substrate conversion efficiency is calculated using area normalization method.
Embodiment 2-1
Arthrobacter simplex (AS1.94*) is subjected to inclined-plane culture, one-level culture and two level culture, cultivation temperature 30 successively
DEG C, (D90=90 μm) of the epoxy material substrate of micronizing is put into 5L fermentation tanks, and add 150ml Tween-80s as dissolution
Agent, feed concentrations 4%, reaction temperature are 30 DEG C.Reaction time is 36 hours, and 70 DEG C are warming up to after the completion of reaction and is terminated instead
Should, filtering, mycelia is extracted with ethyl acetate, organic phase is concentrated, and measures substrate conversion efficiency as 76.2%.
Embodiment 2-2
Arthrobacter simplex (AS1.94*) is subjected to inclined-plane culture, one-level culture and two level culture, cultivation temperature 31 successively
DEG C, it will be dissolved in DMF epoxy material input 5L fermentation tanks, feed concentrations 1%, reaction temperature is 31 DEG C.Reaction time is 60
Hour, 70 DEG C of terminating reactions are warming up to after the completion of reaction, are filtered, mycelia is extracted with ethyl acetate, organic phase is concentrated, and measures bottom
Thing conversion ratio is 73.5%.
Embodiment 2-3
Arthrobacter simplex (AS1.94*) is subjected to inclined-plane culture, one-level culture and two level culture, cultivation temperature 32 successively
DEG C, it will be dissolved in the epoxy material input 5L fermentation tanks of 5 times of methanol, feed concentrations 2%, reaction temperature is 32 DEG C.Reaction time
For 38 hours, 70 DEG C of terminating reactions are warming up to after the completion of reaction, are filtered, mycelia is extracted with ethyl acetate, organic phase is concentrated, and is surveyed
It is 81.4% to obtain substrate conversion efficiency.
Embodiment 2-4
Arthrobacter simplex (AS1.94*) is subjected to inclined-plane culture, one-level culture and two level culture, cultivation temperature 32 successively
DEG C, it will be dissolved in the epoxy material input 5L fermentation tanks of 5 times of tetrahydrofurans, feed concentrations 2%, adding 80ml when feeding intake tells
Temperature -80 is used as chaotropic agent, and the reaction time shorten to 32 hours, and reaction temperature is 32 DEG C, and 70 DEG C of terminations are warming up to after the completion of reaction
Reaction, filtering, mycelia are extracted with ethyl acetate, organic phase are concentrated, and measure substrate conversion efficiency as 87.6%.
Embodiment 2-5
Arthrobacter simplex (AS1.754) is subjected to inclined-plane culture, one-level culture and two level culture, cultivation temperature 33 successively
DEG C, it will be dissolved in the epoxy material input 5L fermentation tanks of 3 times of ethanol, feed concentrations 1.5%, reaction temperature is 33 DEG C.During reaction
Between be 40 hours, 70 DEG C of terminating reactions are warming up to after the completion of reaction, are filtered, mycelia extracted with ethyl acetate, organic phase concentrated,
Substrate conversion efficiency is measured as 86.7%.
Embodiment 2-6
Arthrobacter simplex (AS1.754) is subjected to inclined-plane culture, one-level culture and two level culture, cultivation temperature 34 successively
DEG C, by (D90=100 μm) input 5L fermentation tank of epoxy material of micronizing, feed concentrations 3%, reaction temperature is 34 DEG C.Instead
It is 60 hours between seasonable, 70 DEG C of terminating reactions is warming up to after the completion of reaction, filters, mycelia is extracted with ethyl acetate, by organic phase
Concentration, substrate conversion efficiency is measured as 80.1%.
Embodiment 2-7
Arthrobacter simplex (AS1.94*) is subjected to inclined-plane culture, one-level culture and two level culture, cultivation temperature 34 successively
DEG C, it will be dissolved in the epoxy material input 5L fermentation tanks of dioxane, feed concentrations 2.5%, reaction temperature is 34 DEG C.Reaction
Time is 36 hours, and 70 DEG C of terminating reactions are warming up to after the completion of reaction, is filtered, mycelia is extracted with ethyl acetate, and organic phase is dense
Contracting, substrate conversion efficiency is measured as 82.1%.
The dehydration of inventive embodiments 3
Embodiment 3-1
10g dehydrogen substances are dissolved in the in the mixed solvent of 60ml pyridines and 20ml triethylamines, are added dropwise to 9ml tolysulfonyl
Chlorine, reaction solution are heated to 70 DEG C of clock reactions, and 800ml frozen water is diluted in after being terminated with thin-layer chromatography monitoring reaction process to reaction
In.Filtering and discharging after placing two hours, obtains 7.4g dehydrates.
Embodiment 3-2
10g dehydrogen substances are dissolved in 80ml triethylamines, are added dropwise to 4ml POCl3s and 5ml mesyl chlorides, reaction solution heating
To 90 DEG C of clock reactions, it is diluted in after being terminated with thin-layer chromatography monitoring reaction process to reaction in 800ml frozen water.Place two hours
Filtering and discharging afterwards, obtain 7.3g dehydrates.
The fluoride reaction of inventive embodiments 4
Embodiment 4-1
Hydrogen fluoride/dimethyl formamide solution that dehydrate 12g is added to 60g 54% carries out fluoride reaction, and reaction finishes
Afterwards, it is diluted in 1200ml frozen water, ammoniacal liquor neutralizes, filters, dries；Recrystallizing and refining is carried out again, uses chloroform:Methanol (7: 3)
Solvent dissolves；Concentration, later stage pour methanol；Recrystallized, filtered in methyl alcohol, dry fluoride 8.9g.
Embodiment 4-2
With dehydrate 12g；Hydrogen fluoride/the dimethyl formamide solution for adding 60g 58% carries out fluoride reaction, has reacted
Bi Hou, it is diluted in 1200mL frozen water, ammoniacal liquor neutralizes, filters, dries；Recrystallizing and refining is carried out again, with chloroform: methanol (7: 3)
Solvent dissolved；Concentration, later stage pour methanol；Recrystallized, filtered in methyl alcohol, dry fluoride 9g.
Embodiment 4-3
With dehydrate 12g；Hydrogen fluoride/the dimethyl formamide solution for adding 60g 62% carries out fluoride reaction, has reacted
Bi Hou, it is diluted in 1200L frozen water, ammoniacal liquor neutralizes, filters, dries；Recrystallizing and refining is carried out again, with chloroform: methanol (7: 3)
Solvent is dissolved；Concentration, later stage pour methanol；Recrystallized, filtered in methyl alcohol, dry fluoride 8.9g.
The oxidation reaction of inventive embodiments 5
By 4g potassium permanganate cold cut in acetone and water (12ml：Mixed solution 6ml) is standby.5.7g is added in reaction bulb
Fluoride and 300ml acetone, stirring and dissolving, -5 DEG C are cooled to, 0.5ml formic acid are added, under quick stirring, by ready Gao Meng
Sour potassium solution is added in reaction bulb, is reacted under the conditions of 10 DEG C, is terminated with thin-layer chromatography monitoring reaction process to reaction, added
The sodium sulfite aqueous solutions of 40ml 10%, 40 DEG C are warming up under stirring, static, filtering, removing manganese dioxide, is repeatedly washed with acetone
Wash, merging filtrate and washing lotion, be concentrated under reduced pressure into no acetone taste, add 15 times of water, stand, filter, drying, obtain 5.8g oxidations
Thing.
The esterification of inventive embodiments 6
1.0g oxide is added in reaction bulb, 20ml dimethylformamides is added, 80 DEG C is warming up under stirring condition,
1.0g acetic acid nak responses are added, is terminated with thin-layer chromatography monitoring reaction process to reaction, reaction solution is diluted in frozen water, mistake
Filter, dry, 0.94g carboxylate is recrystallized to give in ethyl acetate.
The condensation reaction of inventive embodiments 7
Embodiment 7-1
The 5.8g carboxylates and 200ml acetone that upper step is obtained are added in reaction vessel, are passed through N2, stirring and dissolving, 20
3.7ml concentrated hydrochloric acids are added at DEG C, stirring, is terminated with thin-layer chromatography monitoring reaction process to reaction, adds 10% sodium acid carbonate
Solution is neutralized to neutrality, and decompression steams acetone, cools down, and filters, and washing, obtains 6.3g crude product triamcinolones, is recrystallized in methanol
Obtain 5.6g fine work triamcinolones.
Embodiment 7-2
6.3g carboxylates and 200ml acetone are added in reaction vessel, are passed through N2, stirring and dissolving, 1ml is added at 20 DEG C
Perchloric acid, stirring, terminated with thin-layer chromatography monitoring reaction process to reaction, add 10% sodium bicarbonate solution and be neutralized to
Property, decompression steams acetone, cools down, filter, and washing obtains crude product, wash with methanol and dry obtains fine work triamcinolone to constant weight
6.5g。
Embodiment 7-3
6.3g carboxylates and 200ml acetone are added in reaction vessel, are passed through N2, stirring and dissolving, 3ml is added at 35 DEG C
P-methyl benzenesulfonic acid, stirring, terminated with thin-layer chromatography monitoring reaction process to reaction, add 10% sodium bicarbonate solution and be neutralized to
Neutrality, decompression steam acetone, cool down, and filter, and washing, obtain crude product, washs with methanol and dry obtain 6.9g triamcinolones to constant weight.
The hydrolysis of inventive embodiments 8
25ml methanol and 25ml dichloromethane are added in reaction bulb, adds 2.0g triamcinolone and 0.83g potassium carbonate,
It is passed through N2,Room temperature reaction, terminated with thin-layer chromatography monitoring reaction process to reaction, be concentrated under reduced pressure, recrystallized in ethyl acetate, obtained
To 1.30g product triamcinolone.
Claims (10)
- A kind of 1. preparation method of triamcinolone, it is characterised in that using chloride as starting material, successively by epoxy, dehydrogenation, dehydration, Upper fluorine, oxidation, esterification, condensation, hydrolysis, obtain triamcinolone, and specific route is as follows：
- A kind of 2. preparation method of triamcinolone as claimed in claim 1, it is characterised in that：(1) epoxy：Chloride first reacts with halide reagent and acid catalyst, adds alkali reaction, obtains epoxy material；(2) dehydrogenation：Dehydrogen substance is obtained using the method for Arthrobacter simplex biological dehydrogenation using epoxy material as substrate；(3) it is dehydrated：Dehydrogen substance is reacted in basic solvent with dehydrating agent, obtains dehydrate；(4) fluorine on：Dehydrate and hydrogen fluoride reaction are obtained into fluoride；(5) aoxidize：Fluoride obtains oxide with oxidant reaction；(6) it is esterified：Oxide obtains carboxylate with acetic acid reactant salt；(7) it is condensed：Carboxylate obtains triamcinolone with condensation of acetone；(8) hydrolyze：Triamcinolone hydrolyzes to obtain triamcinolone in the basic conditions.
- A kind of 3. preparation method of triamcinolone as claimed in claim 2, it is characterised in that：(1) epoxy：One or more of the described acidic catalyst in organic acid or inorganic acid, described halide reagent Selected from bromide reagent or chlorine reagent, described alkali is selected from inorganic base；(2) dehydrogenation：The Arthrobacter simplex is selected from AS1.754* or AS1.94*；(3) it is dehydrated：The basic solvent is selected from one or both of pyridine or triethylamine, and the dehydrating agent is selected from trichlorine oxygen Phosphorus, mesyl chloride or to the one or more in tosylate chloride；(4) fluorine on：Dehydrate and hydrogen fluoride reaction are obtained into fluoride；(5) aoxidize：The oxidant is selected from potassium permanganate, hydrogen peroxide or osmium tetroxide；(6) it is esterified：Oxide obtains carboxylate with acetic acid nak response；(7) it is condensed：Carboxylate obtains triamcinolone with condensation of acetone；(8) hydrolyze：Alkali is selected from alkali carbonate or alkali metal hydrogencarbonate.
- A kind of 4. preparation method of triamcinolone as claimed in claim 3, it is characterised in that：(1) epoxy：Described acid catalyst is selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, formic acid or acetic acid；Described halogen Change reagent and be selected from DBNPA, dibromo cyano propionamide, C5H6Br2N2O2, N- bromo acetamides, N- bromo O-phthalics Acid amides, N-bromosuccinimide or N-chlorosuccinimide；Described alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate Or potassium carbonate；(2) dehydrogenation：The Arthrobacter simplex is selected from AS1.754* or AS1.94*；(3) it is dehydrated：The basic solvent is selected from one or both of pyridine or triethylamine, and the dehydrating agent is selected from trichlorine oxygen Phosphorus, mesyl chloride or to the one or more in tosylate chloride；(4) fluorine on：Dehydrate and hydrogen fluoride reaction are obtained into fluoride；(5) aoxidize：The oxidant is selected from potassium permanganate, hydrogen peroxide or osmium tetroxide；(6) it is esterified：Oxide obtains carboxylate with acetic acid nak response；(7) it is condensed：Carboxylate obtains triamcinolone with condensation of acetone；(8) hydrolyze：Alkali is selected from sodium carbonate, potassium carbonate, sodium acid carbonate or saleratus.
- A kind of 5. preparation method of triamcinolone as claimed in claim 4, it is characterised in that：(1) epoxy：Acid catalyst is perchloric acid；Halide reagent is selected from DBNPA or N-bromosuccinimide；Alkali For sodium hydroxide；(2) dehydrogenation：The Arthrobacter simplex is selected from AS1.754* or AS1.94*；(3) it is dehydrated：The basic solvent is selected from one or both of pyridine or triethylamine, and the dehydrating agent is selected from trichlorine oxygen Phosphorus, mesyl chloride or to the one or more in tosylate chloride；(4) fluorine on：Dehydrate and hydrogen fluoride reaction are obtained into fluoride；(5) aoxidize：The oxidant is potassium permanganate；(6) it is esterified：Oxide obtains carboxylate with acetic acid nak response；(7) it is condensed：Carboxylate obtains triamcinolone with condensation of acetone；(8) hydrolyze：Alkali is selected from sodium carbonate or potassium carbonate.
- A kind of 6. preparation method of triamcinolone as described in claim 1-5 is any, it is characterised in that：(1) epoxy：The reaction temperature in halogenation stage is selected from -10-30 DEG C；Alkali epoxidation stage reaction temperature is selected from -10-40 DEG C；(2) dehydrogenation：Fermentation temperature is selected from 30-34 DEG C；(3) it is dehydrated：Reaction temperature is selected from 25-120 DEG C；(4) fluorine on：Reaction temperature is selected from -5-10 DEG C；(6) it is esterified：Reaction temperature is selected from 60-100 DEG C；(7) it is condensed：Reaction temperature is in the range of 0 DEG C to solvent boiling point；(8) hydrolyze：Reaction temperature is selected from -10-40 DEG C.
- A kind of 7. preparation method of triamcinolone as claimed in claim 6, it is characterised in that：(1) epoxy：The reaction temperature in halogenation stage is selected from 0-20 DEG C；Alkali epoxidation stage reaction temperature is selected from -5-30 DEG C；(2) dehydrogenation：Fermentation temperature is selected from 30-34 DEG C；(3) it is dehydrated：Reaction temperature is selected from 70-90 DEG C；(4) fluorine on：Reaction temperature is selected from -5-10 DEG C；(6) it is esterified：Reaction temperature is selected from 60-100 DEG C；(7) it is condensed：Reaction temperature is selected from 10-30 DEG C；(8) hydrolyze：Reaction temperature is selected from 15-30 DEG C.
- 8. claim 1-5,7 it is any as described in a kind of triamcinolone preparation method, it is characterised in that：(1) epoxy：Reaction dissolvent is selected from methanol, ethanol, acetone, ether, tetrahydrofuran, dioxane, dichloromethane, chloroform In one or more；(2) dehydrogenation：The one kind or more of reaction dissolvent in methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide Kind；(3) it is dehydrated：The basic solvent is selected from one or both of pyridine or triethylamine；(4) fluorine on：Reaction dissolvent is selected from dimethylformamide or tetrahydrofuran；(5) aoxidize：One or more of the reaction dissolvent in lower aliphatic alcohols, ketone, ether organic solvent；(6) it is esterified：Reaction dissolvent is dimethylformamide；(7) it is condensed：Reaction dissolvent is acetone；(8) hydrolyze：One kind in methanol, chloroform, dichloromethane, ether, tetrahydrofuran, dioxane of reaction dissolvent or It is a variety of.
- 9. claim 1-5,7 it is any as described in a kind of triamcinolone preparation method, it is characterised in that：(2) dehydrogenation：Described biological dehydrogenation concrete technology is：Epoxy material is crushed or complete molten or semi-soluble with solvent, input has been trained Support and biological dehydrogenation reaction is carried out in the fermentation tank of good arthrobacterium or Arthrobacter simplex, extracted after conversion and obtain dehydrogen substance；Described biological dehydrogenation reaction uses following zymotechnique：Inclined-plane culture → one-level culture → two level culture → addition epoxy material fermentation carries out biological dehydrogenation reaction → terminating reaction.
- A kind of 10. new steroidal intermediate：
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|---|---|---|---|---|
| US3210341A (en) * | 1963-03-29 | 1965-10-05 | Upjohn Co | 9, 11-epoxy-6-fluoro-delta4, 16-pregnadienes and products produced therefrom |
| CN104231031A (en) * | 2014-09-10 | 2014-12-24 | 江西赣亮医药原料有限公司 | Preparation method of triamcinolone acetonide |
| CN104311625A (en) * | 2014-11-06 | 2015-01-28 | 江西赣亮医药原料有限公司 | Preparation method for fluocinolone acetonide midbody |
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- 2016-07-15 CN CN201610555864.9A patent/CN107619846A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3210341A (en) * | 1963-03-29 | 1965-10-05 | Upjohn Co | 9, 11-epoxy-6-fluoro-delta4, 16-pregnadienes and products produced therefrom |
| CN104231031A (en) * | 2014-09-10 | 2014-12-24 | 江西赣亮医药原料有限公司 | Preparation method of triamcinolone acetonide |
| CN104311625A (en) * | 2014-11-06 | 2015-01-28 | 江西赣亮医药原料有限公司 | Preparation method for fluocinolone acetonide midbody |
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