CN105384790A - Preparation method of prednisolone - Google Patents
Preparation method of prednisolone Download PDFInfo
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- CN105384790A CN105384790A CN201510787831.2A CN201510787831A CN105384790A CN 105384790 A CN105384790 A CN 105384790A CN 201510787831 A CN201510787831 A CN 201510787831A CN 105384790 A CN105384790 A CN 105384790A
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- prednisolone
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Abstract
The invention relates to a preparation method of prednisolone. The preparation method comprises the steps of sequentially carrying out 3, 20-keto protective reaction, 11-keto reduction reaction, 21-hydroxyl esterification reaction, 3, 20-keto deprotection reaction and 21-acetic ester hydrolysis reaction by taking prednisone acetate as a raw material to obtain prednisolone. The invention provides a novel synthesis route sequentially comprising the steps of esterifying and deprotecting; nitrosification quenching reaction and resin hydrolysis reaction are omitted in the deprotection process; and ester hydrolysis reaction is finished under the protection of a mixed solvent and inert gases, so that the condition that byproducts are produced by hydrolysis reaction is avoided. The preparation method is novel in process route, simple and rapid in operation process, low in production cost and suitable for large-scale industrial production.
Description
Technical field
The invention belongs to chemical pharmacy field, be specifically related to a kind of preparation method of prednisolone.
Background technology
The structural formula of prednisolone (11 β, 17 α, 21-trihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone) is:
Prednisolone is adrenal cortex hormones drug, be mainly used in supersensitivity and auto-immune inflammatory disease, collagen disease, as rheumatosis, rheumatoid arthritis, lupus erythematosus, serious bronchial asthma, nephrotic syndrome, thrombopenic purpura, granulocytopenia, kemia, various adrenal cortex function not enough disease, exfoliative dermatitis, pemphigus, neurodermatitis, eczema etc.Prednisolone is the important intermediate of the steroid drugss such as synthesis 16 alpha-hydroxy prednisonlone, Triamcinolone Acetonide, and in steroid drugs field, application is very extensive.
The traditional preparation method of prednisolone is divided into bio-transformation and chemosynthesis two clock, is specially:
(1) be, with hydrocortisone conversion of substrate, Arthrobacter fermentation method prepares prednisolone, and conversion reaction formula is:
There is the deficiencies such as substrate hydrocortisone cost is high, substrate feed concentrations is low, the production cycle long, last handling process separation and purification difficulty in this preparation method.
Summary of the invention
(2), with 17 Alpha-hydroxies-Isosorbide-5-Nitrae, 9-triolefin-pregnant steroid-3,20-diketone is raw material, prepares prednisolone through bromination, debrominate, upper iodine, displacement, hydrolysis.Synthesis route is:
Chinese patent CN200710061258.2 adopts above-mentioned operational path to prepare prednisolone.This preparation method exists in debromination and uses chromium metal, easily introduces heavy metal in the product; Upper Iod R needs to use valuable raw material iodine, and upper iodine unstable products, there is the drawbacks such as stock risk in production process.
(3), with 17 Alpha-hydroxies-Isosorbide-5-Nitrae, 9-triolefin-pregnant steroid-3,20-diketone is raw material, prepares prednisolone through bromination, reduction, bromo, hydrolysis.Synthesis route is:
Chinese patent CN201310348285.3 adopts above-mentioned operational path to prepare prednisolone, and this preparation method avoids employing chromium metal and iodine, and intermediate stability is also improved; But in reduction reaction, use metallic zinc, heavy metal can be introduced in the product equally, and need to use the low solvent ether that boils in the polystep reactions such as reduction, bromo, hydrolysis, be unfavorable for that the summer temperature is higher produces, there is larger potential safety hazard.
(4) be raw material with Prednisone acetate, the method through 3 and 20 ketone group semicarbazone protections, 11 ketone group reduction, 3 and 20 deprotections prepares prednisolone.Synthesis route is:
Chinese patent CN00136583.5 adopts above-mentioned operational path to prepare prednisolone intermediate reduzate; this preparation technology adopts semicarbazone to protect and reduction two-step reaction completes in " one kettle way " mode, but the committed step deprotection reaction of the not mentioned whole operational path of patented method.In critical process 3 and 20 deprotection reactions, conventional fabrication techniques carries out being obtained by reacting nitrous compound prior to the system of sodium nitrite solution and hydrochloric acid soln, then carry out obtaining prednisolone after resin hydrolyzing is further purified removal impurity.Why adopt the deprotection reaction mode that nitrosification and resin hydrolyzing combine; due to comparatively strong to the destruction of steroidal ring structure under strong acidic condition, a large amount of impurity needing the reactive mode by adding resin hydrolyzing to remove to produce in nitrosation reaction process and improve product appearance.Deprotection operation reaction product certainly will affect the yield concentration of this operation in the resin hydrolyzing step of the larger solubleness of acid solvent system and increase; nitrosification and the resin hydrolyzing two-step reaction quality total recovery of deprotection operation are only 55% ~ 60%, and the yield short slab of this operation makes the production cost of prednisolone remain high.
The present invention is directed to the deficiencies in the prior art, a kind of preparation method of prednisolone is provided.Present method take Prednisone acetate as initial feed; by adopting new synthetic route; eliminate cancellation reaction and the resin hydrolyzing reaction of deprotection operation; simplify technical process; shorten the production cycle; improve the yield concentration of critical process, reduce production cost low, be applicable to industrial scale and produce.
Technical scheme of the present invention adopts following operational path to realize:
Method of the present invention specifically comprises the steps:
(1), 3, the protection of 20-position ketone group and 11-position ketone group reduction
Take Prednisone acetate as starting raw material under the effect of semicarbazide hydrochloride and Lithium Aluminium Hydride, adopt methyl alcohol as carrying out 3 under solvent, the ketone group protective reaction of 20-position and the reaction of 11-position ketone group reduction, react complete, filter, concentrating under reduced pressure, elutriation is lowered the temperature, and filters, water washing is to neutral, and drying obtains reduzate;
(2), 21-position hydroxy esterification
Reduzate step (1) obtained is under the effect of diacetyl oxide, and adopt alkali metal acetate to carry out the bit esterified reaction of 21-as catalyzer, react complete, steam and desolventize cooling, filter, drying obtains carboxylate;
(3), 3,20-position ketone group deprotection
Carboxylate step (2) obtained adds in the mixed uniformly solution of hydrochloric acid, water and trichloromethane, stir clearly molten, drip sodium nitrite in aqueous solution, react complete, cooling, filter, water washing, to neutral, adds alcoholic solvent, after temperature rising reflux in gained filter cake, cooling is filtered, and drying obtains prednisolone acetate crude product.
(4), 21-position acid ester hydrolysis
Prednisolone acetate crude product step (3) obtained adds in mixed solvent, drips the methyl alcohol of alkali, the aqueous solution under the protection of rare gas element, reacts complete; drip glacial acetic acid and be neutralized to pH6 ~ 7, concentrated solvent evaporated, freezing; filtration obtains prednisolone crude product, and crude product recrystallization obtains prednisolone.
Step alkali metal acetate (2) used is sodium acetate or potassium acetate.
The (3) described alcoholic solvent of step is methyl alcohol or ethanol.
The (4) described mixed solvent of step is methanol dichloromethane.
The (4) described rare gas element of step is nitrogen or argon gas.
Alkali in the methyl alcohol of the alkali that step is (4) described, the aqueous solution is sodium hydroxide or potassium hydroxide
Compared with prior art, the present invention has the following advantages:
1., before deprotection reaction, after first 21-position hydroxyl being carried out esterification, carry out deprotection reaction again.Which increase deprotection reaction substrate and the reaction product stability in acid solvent system; By changing the substrate structure of deprotection reaction, effectively reducing deprotection reaction product in the solvability of solvent system, helping lend some impetus to the precipitation of prednisolone acetate crude crystalline;
2. in deprotection reaction aftertreatment, expeled the very large urea of usage quantity and alkali, not only reduced production cost, and avoid drip aqueous solution of urea produce foam flashes phenomenon generation, decrease because the generation of the by product caused is reacted in cancellation simultaneously;
3. eliminate resin hydrolyzing reaction in deprotection operation, shorten the production cycle, reduce production cost;
4. adopt the mode of mixed solvent and protection of inert gas to carry out at ester hydrolysis reaction, effectively prevent the generation of side reaction, ensure that product quality and the yield concentration of hydrolysis reaction;
5. the present invention passes through to adopt new operational path, and deprotection reaction product is easy to divide with reaction solvent isolate, and has gone nitrosification cancellation to react and has reacted with resin hydrolyzing, significantly simplify post-processing operation flow process at deprotection operation leather; Ester hydrolysis reaction completes under mixed solvent and protection of inert gas, avoids producing by product at hydrolysis reaction.Present invention process route is novel, and operating process is simple and direct, production cost is low, is applicable to industrial scale and produces.
Embodiment
In order to simple and clearly object, hereafter eliminate the description of known conventional production process rightly, in order to avoid the description of those unnecessary details impact to the technical program.
Illustrate the present invention with example below, these examples are intended to help to understand technique means of the present invention.But should be understood that these embodiments are exemplary, the present invention is not limited thereto.
With prednisolone intermediate-reduzate be initiator (this initiator with Prednisone acetate for raw material, according to Chinese patent CN00136583.5: " producing and manufacturing technique of prednisolone Acetate condensating reduced product " disclosed method obtains), carry out following step successively, prepare prednisolone.
Embodiment one
In reaction flask, add 750ml acetone, 30g prednisolone intermediate reduzate, 12g sodium acetate, 50ml diacetyl oxide, 8ml acetic acid successively, temperature rising reflux reacts 4 hours.TLC display reacts completely, and most of solvent is reclaimed in air distillation, then evaporated under reduced pressure solvent, is cooled to less than 5 DEG C, stirs after 30 minutes, leaves standstill more than 2 hours, and filter, drying obtains 32.0g carboxylate.
By 30g carboxylate drop into by 150ml mass percent concentration be 36% hydrochloric acid, 240ml water, 15ml trichloromethane prepare solution, in 25 DEG C ~ 30 DEG C stir 30 minutes clearly molten.Cooling, drips in 18 DEG C ~ 22 DEG C the solution prepared by 30g Sodium Nitrite and 1050ml water.Finish, continue at 18 DEG C ~ 22 DEG C reactions 3 hours.TLC display reacts completely, be cooled to 0 DEG C, stir 0.5 hour in 0 DEG C ~ 5 DEG C, leave standstill more than 2 hours, filter, be washed to neutrality, in gained filter cake, add 30ml methyl alcohol temperature rising reflux 30 minutes, cooling, stir 0.5 hour in-5 DEG C ~ 0 DEG C, leave standstill more than 2 hours, filter, drying obtains 21.8g prednisolone acetate crude product.
20g prednisolone acetate crude product is added the solution prepared by 240ml methyl alcohol and 24ml methylene dichloride; stir 30 minutes in 25 DEG C ~ 30 DEG C; be cooled to less than 5 DEG C; pass into nitrogen protection; control temperature 0 DEG C ~ 5 DEG C dripped the solution prepared by 2g sodium hydroxide, 4ml water, 40ml methyl alcohol, in 0 DEG C ~ 5 DEG C insulation reaction 2 hours.Control temperature 0 DEG C ~ 5 DEG C drips glacial acetic acid and is neutralized to pH6 ~ 7.Stop logical nitrogen, concentrated solvent evaporated, adds 30ml methyl alcohol temperature rising reflux 30 minutes, and cooling is stirred 0.5 hour in-12 DEG C ~-10 DEG C, leaves standstill more than 2 hours, and filter, drying obtains 17.5g prednisolone crude product.Prednisolone crude product again in methyl alcohol decolorizing and refining obtain 15.8g prednisolone, HPLC purity 99.3%.
Embodiment two
In reaction flask, add 750ml acetone, 30g prednisolone intermediate reduzate, 15g potassium acetate, 51ml diacetyl oxide, 9ml acetic acid successively, temperature rising reflux reacts 4.5 hours.TLC display reacts completely, and most of solvent is reclaimed in air distillation, then evaporated under reduced pressure solvent, is cooled to less than 5 DEG C, stirs after 30 minutes, leaves standstill more than 2 hours, and filter, drying obtains 31.9g carboxylate.
By 30g carboxylate drop into by 150ml mass percent concentration be 36% hydrochloric acid, 240ml water, 15ml trichloromethane prepare solution, in 25 DEG C ~ 30 DEG C stir 30 minutes clearly molten.Cooling, drips in 18 DEG C ~ 22 DEG C the solution prepared by 30g Sodium Nitrite and 1050ml water.Finish, continue at 18 DEG C ~ 22 DEG C reactions 3 hours.TLC display reacts completely, be cooled to 0 DEG C, stir 0.5 hour in 0 DEG C ~ 5 DEG C, leave standstill more than 2 hours, filter, be washed to neutrality, in gained filter cake, add 30ml ethanol temperature rising reflux 30 minutes, cooling, stir 0.5 hour in-5 DEG C ~ 0 DEG C, leave standstill more than 2 hours, filter, drying obtains 21.6g prednisolone acetate crude product.
20g prednisolone acetate crude product is added the solution prepared by 240ml methyl alcohol and 24ml methylene dichloride; stir 30 minutes in 25 DEG C ~ 30 DEG C; be cooled to less than 5 DEG C; pass into nitrogen protection; control temperature 0 DEG C ~ 5 DEG C dripped the solution prepared by 2g potassium hydroxide, 4ml water, 40ml methyl alcohol, in 0 DEG C ~ 5 DEG C insulation reaction 2 hours.Control temperature 0 DEG C ~ 5 DEG C drips glacial acetic acid and is neutralized to pH6 ~ 7.Stop logical nitrogen, concentrated solvent evaporated, adds 30ml methyl alcohol temperature rising reflux 30 minutes, and cooling is stirred 0.5 hour in-12 DEG C ~-10 DEG C, leaves standstill more than 2 hours, and filter, drying obtains 17.3g prednisolone crude product.Prednisolone crude product again in methyl alcohol decolorizing and refining obtain 15.6g prednisolone, HPLC purity 99.1%.
Claims (6)
1. a preparation method for prednisolone, comprises the steps:
this operational path is made up of following reactions steps:
(1), 3, the protection of 20-position ketone group and 11-position ketone group reduction
Take Prednisone acetate as starting raw material under the effect of semicarbazide hydrochloride and Lithium Aluminium Hydride, adopt methyl alcohol as carrying out 3 under solvent, the ketone group protective reaction of 20-position and the reaction of 11-position ketone group reduction, react complete, filter, concentrating under reduced pressure, elutriation is lowered the temperature, and filters, water washing is to neutral, and drying obtains reduzate;
(2), 21-position hydroxy esterification
Reduzate step (1) obtained is under the effect of diacetyl oxide, and adopt alkali metal acetate to carry out the bit esterified reaction of 21-as catalyzer, react complete, steam and desolventize cooling, filter, drying obtains carboxylate;
(3), 3,20-position ketone group deprotection
Carboxylate step (2) obtained adds in the mixed uniformly solution of hydrochloric acid, water and trichloromethane, stir clearly molten, drip sodium nitrite in aqueous solution, react complete, cooling, filter, water washing, to neutral, adds alcoholic solvent, after temperature rising reflux in gained filter cake, cooling is filtered, and drying obtains prednisolone acetate crude product;
(4), 21-position acid ester hydrolysis
Prednisolone acetate crude product step (3) obtained adds in mixed solvent, drips the methyl alcohol of alkali, the aqueous solution under the protection of rare gas element, reacts complete; drip glacial acetic acid and be neutralized to pH6 ~ 7, concentrated solvent evaporated, freezing; filtration obtains prednisolone crude product, and crude product recrystallization obtains prednisolone.
2. the preparation method of a kind of prednisolone according to claim 1, is characterized in that: reactions steps (2) in, alkali metal acetate used is sodium acetate or potassium acetate.
3. the preparation method of a kind of prednisolone according to claim 1, is characterized in that: reactions steps (3) in, alcoholic solvent used is methyl alcohol or ethanol.
4. the preparation method of a kind of prednisolone according to claim 1, is characterized in that: reactions steps (4) in,
Described mixed solvent is methanol dichloromethane.
5. the preparation method of a kind of prednisolone according to claim 1, is characterized in that: reactions steps (4) in, described rare gas element is nitrogen or argon gas.
6. the preparation method of a kind of prednisolone according to claim 1, is characterized in that: reactions steps (4) in, the alkali in the methyl alcohol of described alkali, the aqueous solution is sodium hydroxide or potassium hydroxide.
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| CN201510787831.2A CN105384790A (en) | 2015-11-17 | 2015-11-17 | Preparation method of prednisolone |
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| CN201510787831.2A CN105384790A (en) | 2015-11-17 | 2015-11-17 | Preparation method of prednisolone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113563402A (en) * | 2021-06-11 | 2021-10-29 | 佳尔科生物科技南通有限公司 | Synthetic method for preparing prednisolone by one-pot method |
| CN113801183A (en) * | 2021-09-13 | 2021-12-17 | 丽江映华生物药业有限公司 | Prednisolone refining method |
| CN114195847A (en) * | 2021-12-15 | 2022-03-18 | 河南利华制药有限公司 | Prednisolone and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB817176A (en) * | 1955-07-25 | 1959-07-29 | Chimiotherapie Lab Franc | Improvements in or relating to cyclopentanophenanthrene compounds |
| CN102146113A (en) * | 2010-02-08 | 2011-08-10 | 仙居县力天化工有限公司 | Method for synthesizing 16 alpha-hydroxy prednisolone |
| CN102827231A (en) * | 2012-09-25 | 2012-12-19 | 河南利华制药有限公司 | Process for preparing hydrocortisone |
-
2015
- 2015-11-17 CN CN201510787831.2A patent/CN105384790A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB817176A (en) * | 1955-07-25 | 1959-07-29 | Chimiotherapie Lab Franc | Improvements in or relating to cyclopentanophenanthrene compounds |
| CN102146113A (en) * | 2010-02-08 | 2011-08-10 | 仙居县力天化工有限公司 | Method for synthesizing 16 alpha-hydroxy prednisolone |
| CN102827231A (en) * | 2012-09-25 | 2012-12-19 | 河南利华制药有限公司 | Process for preparing hydrocortisone |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113563402A (en) * | 2021-06-11 | 2021-10-29 | 佳尔科生物科技南通有限公司 | Synthetic method for preparing prednisolone by one-pot method |
| CN113801183A (en) * | 2021-09-13 | 2021-12-17 | 丽江映华生物药业有限公司 | Prednisolone refining method |
| CN114195847A (en) * | 2021-12-15 | 2022-03-18 | 河南利华制药有限公司 | Prednisolone and preparation method thereof |
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Inventor after: Liao Jun Inventor after: Liu Yuting Inventor after: Zhao Chengan Inventor after: Fu Lin Inventor after: Zeng Jianhua Inventor after: Li Guilian Inventor before: Liao Jun Inventor before: Fu Lin Inventor before: Zeng Jianhua Inventor before: Li Guilian Inventor before: Zhao Chengan |
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