CN105294800A - Preparation method for hydrocortisone acetate - Google Patents
Preparation method for hydrocortisone acetate Download PDFInfo
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- CN105294800A CN105294800A CN201510787698.0A CN201510787698A CN105294800A CN 105294800 A CN105294800 A CN 105294800A CN 201510787698 A CN201510787698 A CN 201510787698A CN 105294800 A CN105294800 A CN 105294800A
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Abstract
A related preparation method for hydrocortisone acetate comprises taking cortisone acetate as a raw material, successively performing position-3 and position-20 keto protection reaction, position-11 keto reduction reaction, position-21 hydroxyl esterification reaction, and position-3 and position-20 keto deprotection reaction, so as to obtain hydrocortisone acetate. The provided preparation method is a new synthetic route and firstly performs esterification and then performs deprotection, the reaction selectivity is substantially improved, the deprotection reaction product is relatively easily precipitated, the tedious extraction postprocessing manner for a large amount of a solvent in a conventional deprotection reaction technology is avoided, and also side reactions caused by a quenching reaction in a postprocessing process of a conventional technology are avoided. The deprotection reaction postprocessing process is simple, production cost is low, and the preparation method is suitable for industrialized large-scale production.
Description
Technical field
The invention belongs to chemical pharmacy field, be specifically related to a kind of preparation method of hydrocortisone acetate.
Background technology
The structural formula of hydrocortisone acetate (11 β, 17 α, 21-trihydroxy-pregnant steroid-4 alkene-3,20-diketone-21-acetic ester) is:
。
Hydrocortisone acetate belongs to adrenocortical hormone medicine, has the multiple pharmacological effect such as anti-inflammatory, immunosuppression, antitoxin and antishock.11 beta-hydroxies in steroidal compounds structure are the necessary groups of anti-inflammatory drug, and in the preparation process of hydrocortisone acetate, how to introduce the committed step that 11 beta-hydroxies are whole technique, existing technique mainly contains microbe transformation method and chemical method two kinds.The domestic colter that generally adopts is mould for being oxidized bacterial classification, is transformed introduce 11 beta-hydroxies by a step microbial on substrate RSA.The defects such as this technique exists low conversion rate, and by product kind is many, ratio is high, and feed concentrations is low; In contrast, microbial method introduces 11 Alpha-hydroxies, and to have transformation efficiency high, transforms specificity strong, substrate feed concentrations relatively advantages of higher; Because 11 Alpha-hydroxies do not have anti-inflammatory activity, need to change 11 beta-hydroxies into by chemical method.Chemical method mainly contains oxidation-reduction method: first 11 Alpha-hydroxies are oxidized to 11-ketone group, then are obtained by selective reduction; Chemical method mainly also has elimination-halogen addition-reduction method: first 11 Alpha-hydroxies are carried out elimination and obtain △ 9 (11), obtained by upper halogen, dehalogenation, the key of the method needs to control to generate by product △ 11 (12) when eliminative reaction again.
Oxidation-reduction legal system is take cortisone acetate as starting raw material for the prior art of hydrocortisone acetate, and the method bit esterified by 3 and the protection of 20 ketone group semicarbazone, 11 ketone group reduction, 3 and 20 deprotections, 21-is prepared.In wherein 3 and 20 deprotection reactions, the system of traditional technology sodium nitrite solution and hydrochloric acid soln is reacted, use urea as cancellation reagent after reacting completely, chloroform repeatedly extracts (being generally 14 ~ 18 times), separates out hydrocortisone crude crystalline after concentrated; Hydrocortisone crude product through acetic acid esterified, refining obtain hydrocortisone acetate.This operational path deprotection steps has the following disadvantages: deprotection reaction poor selectivity, and reaction produces a large amount of impurity, causes deprotection yield extremely low; Treating processes after the reaction, because reaction product is dissolved in acid solvent system substantially, product crystallization difficulty, needs the operating method adopting a large amount of solvent repeatedly to extract, and solvent-oil ratio is large, concentrates and steams solvent length consuming time, significantly add production cost.Its concrete technology route is:
。
Chinese patent CN102827231 adopts above-mentioned operational path, completes deprotection reaction for the preparation of hydrocortisone acetate intermediate in nonhomogeneous system mode---hydrocortisone crude product.This reactive mode of patent Introduction directly can separate out material, eliminates extraction step, correspondingly improves yield.Present invention applicant gropes according to this patent technique; hydrocortisone crude product can be separated out in deprotection reaction operation; but the hydrocortisone crude product mass yield of directly separating out is only 30% ~ 35%; even if adopt at last handling process and add the mass yield that saturated sodium-chloride water solution mode also cannot improve directly precipitation crude product; only have after adopting and being aided with mode that solvent repeatedly extracts, hydrocortisone crude product quality total recovery is just improved 60% ~ 65%.
Prior art is prepared in the operational path of hydrocortisone acetate by cortisone acetate, and it is poor that deprotection reaction operation ubiquity reaction preference, and product crystallization difficulty, needs solvent repeatedly to extract the drawback ensureing that yield, production cost are high.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of preparation method of hydrocortisone acetate is provided.Present method, by adopting new synthetic route, avoids the operating method that the loaded down with trivial details a large amount of solvents of traditional technology repeatedly extract, improves the yield concentration of deprotection reaction, significantly shorten the production cycle, reduce production cost low, is applicable to industrial scale and produces.
Technical scheme of the present invention adopts following operational path to realize:
。
Method of the present invention specifically comprises the steps:
(1), 3,20-position ketone group protection
With cortisone acetate be starting raw material under the effect of free amine group urea, adopt ethanol as carrying out 3 under solvent, the ketone group protective reaction of 20-position, react complete, concentrating under reduced pressure, elutriation is lowered the temperature, and filters, and water washing is to neutral, and drying obtains condenses;
(2), 11-position ketone group reduction
Condenses step (1) obtained is under the effect of POTASSIUM BOROHYDRIDE, and adopt methyl alcohol to carry out the ketone group reduction reaction of 11-position as solvent, react complete, acid neutralization, concentrating under reduced pressure, elutriation is lowered the temperature, and filter, be washed to neutrality, drying obtains reduzate;
(3), 21-position hydroxy esterification
Reduzate step (2) 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;
(4), 3,20-position ketone group deprotection
Carboxylate step (3) obtained adds in the mixed uniformly solution of hydrochloric acid, water and trichloromethane, stirs clearly molten, drips sodium nitrite in aqueous solution, reacts complete, obtain hydrocortisone acetate through aftertreatment.
Step alkali metal acetate (3) used is sodium acetate or potassium acetate.
The (4) described aftertreatment of step is: left standstill by reacted material, divide dereaction solution, the sticky lumpy solid materials decantation obtained washes three times, divide and remove wash water, in solid materials, add alcoholic solvent, after temperature rising reflux, cooling is filtered, drying obtains hydrocortisone acetate crude product, and crude product recrystallization obtains hydrocortisone acetate.
The alcoholic solvent of step (4) described in aftertreatment is methyl alcohol or ethanol.
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.Like this by changing the substrate structure of deprotection reaction, effectively reducing the solvability of deprotection reaction product at solvent system, contributing to hydrocortisone acetate crude product and isolating with dividing of reaction soln;
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. in deprotection reaction aftertreatment, avoid the operating method that the loaded down with trivial details a large amount of solvents of traditional technology repeatedly extract, shorten the production cycle, reduce production cost;
4. the present invention is by adopting new operational path; deprotection operation leather has gone nitrosification cancellation to react and repeatedly solvent-extracted operating method; significantly simplify technical process; shorten the production cycle; deprotection reaction mass yield has lifting by a relatively large margin compared with prior art level, 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 hydrocortisone acetate intermediate-reduzate be initiator (this initiator with cortisone acetate for raw material, according to J.Am.Chem.Soc., 1956,78 (8), pp1736 – 1738: " 11-OxygenatedSteroids.XVI.ThePreparationofHydrocortisone fromCortisoneAcetate " disclosed method is prepared), carry out following step successively, prepare hydrocortisone acetate.
Embodiment one
In reaction flask, add 900ml acetone, 30g hydrocortisone acetate intermediate reduction thing, 12g sodium acetate, 45ml diacetyl oxide, 9ml acetic acid successively, temperature rising reflux reacts 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 31.3g carboxylate.
By 30g carboxylate drop into by 210ml mass percent concentration be 36% hydrochloric acid, 390ml water, 15ml trichloromethane prepare solution, in 25 DEG C ~ 30 DEG C stir 30 minutes clearly molten.Cooling, drips in 5 DEG C ~ 10 DEG C the solution prepared by 15g Sodium Nitrite and 150ml water.Finish, continue at 5 DEG C ~ 10 DEG C reactions 2 hours.TLC display reacts completely, and reaction system is the state that sticky lumpy solid materials is separated with solvent system, leaves standstill 10 minutes, point dereaction solution, and decantation 200ml water × 3 washing of residual tack blocks of solid material, divides and remove wash water.In residual tack blocks of solid, add 90ml methyl alcohol temperature rising reflux 30 minutes, cooling, stir 0.5 hour in-10 DEG C ~-5 DEG C, leave standstill more than 2 hours, filter, drying obtains 22.2g hydrocortisone acetate crude product.Hydrocortisone acetate crude product again in methyl alcohol decolorizing and refining obtain 18.2g hydrocortisone acetate, HPLC purity 98.6%.
Embodiment two
In reaction flask, add 900ml acetone, 30g hydrocortisone acetate intermediate reduction thing, 15g potassium acetate, 51ml diacetyl oxide, 9ml acetic acid successively, temperature rising reflux reacts 6 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 31.5g carboxylate.
By 30g carboxylate drop into by 210ml mass percent concentration be 36% hydrochloric acid, 390ml water, 15ml trichloromethane prepare solution, in 25 DEG C ~ 30 DEG C stir 30 minutes clearly molten.Cooling, drips in 5 DEG C ~ 10 DEG C the solution prepared by 15g Sodium Nitrite and 150ml water.Finish, continue at 5 DEG C ~ 10 DEG C reactions 2 hours.TLC display reacts completely, and reaction system is the state that sticky lumpy solid materials is separated with solvent system, leaves standstill 10 minutes, point dereaction solution, and decantation 200ml water × 3 washing of residual tack blocks of solid material, divides and remove wash water.In residual tack blocks of solid, add 75ml ethanol temperature rising reflux 30 minutes, cooling, stir 0.5 hour in-10 DEG C ~-5 DEG C, leave standstill more than 2 hours, filter, drying obtains 22.0g hydrocortisone acetate crude product.Hydrocortisone acetate crude product again in methyl alcohol decolorizing and refining obtain 18.1g hydrocortisone acetate, HPLC purity 98.7%.
Claims (4)
1. a preparation method for hydrocortisone acetate, comprises the steps:
This operational path is made up of following reactions steps:
(1), 3,20-position ketone group protection
With cortisone acetate be starting raw material under the effect of free amine group urea, adopt ethanol as carrying out 3 under solvent, the ketone group protective reaction of 20-position, react complete, concentrating under reduced pressure, elutriation is lowered the temperature, and filters, and water washing is to neutral, and drying obtains condenses;
(2), 11-position ketone group reduction
Condenses step (1) obtained is under the effect of POTASSIUM BOROHYDRIDE, and adopt methyl alcohol to carry out the ketone group reduction reaction of 11-position as solvent, react complete, acid neutralization, concentrating under reduced pressure, elutriation is lowered the temperature, and filter, be washed to neutrality, drying obtains reduzate;
(3), 21-position hydroxy esterification
Reduzate step (2) 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;
(4), 3,20-position ketone group deprotection
Carboxylate step (3) obtained adds in the mixed uniformly solution of hydrochloric acid, water and trichloromethane, stirs clearly molten, drips sodium nitrite in aqueous solution, reacts complete, obtain hydrocortisone acetate through aftertreatment.
2. the preparation method of a kind of hydrocortisone acetate according to claim 1, is characterized in that: reactions steps (3) in, alkali metal acetate used is sodium acetate or potassium acetate.
3. the preparation method of a kind of hydrocortisone acetate according to claim 1, it is characterized in that: the (4) described aftertreatment of step is: left standstill by reacted material, divide dereaction solution, the sticky lumpy solid materials decantation obtained washes three times, divides and removes wash water, in solid materials, add alcoholic solvent, after temperature rising reflux, cooling is filtered, and drying obtains hydrocortisone acetate crude product, and crude product recrystallization obtains hydrocortisone acetate.
4. the preparation method of a kind of hydrocortisone acetate according to claim 3, is characterized in that: the alcoholic solvent of step (4) described in aftertreatment is methyl alcohol or ethanol.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114195847A (en) * | 2021-12-15 | 2022-03-18 | 河南利华制药有限公司 | Prednisolone and preparation method thereof |
Citations (2)
| 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 |
| 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 CN201510787698.0A patent/CN105294800A/en active Pending
Patent Citations (2)
| 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 |
| CN102827231A (en) * | 2012-09-25 | 2012-12-19 | 河南利华制药有限公司 | Process for preparing hydrocortisone |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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: Wei Xuli Inventor after: Xu Mingqin Inventor before: Liao Jun Inventor before: Fu Lin Inventor before: Zeng Jianhua Inventor before: Wei Xuli Inventor before: Xu Mingqin Inventor before: Zhao Chengan |
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