CN101050229A - Method for preparing hydrocortisone sodium succinate - Google Patents
Method for preparing hydrocortisone sodium succinate Download PDFInfo
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- CN101050229A CN101050229A CN 200710057321 CN200710057321A CN101050229A CN 101050229 A CN101050229 A CN 101050229A CN 200710057321 CN200710057321 CN 200710057321 CN 200710057321 A CN200710057321 A CN 200710057321A CN 101050229 A CN101050229 A CN 101050229A
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Abstract
This invention discloses a method for preparing hydrocortisone sodium succinate. The method comprises: (1) reacting hydrocortisone succinate and buffer at 0-80 deg.C for 1-4 h, controlling the pH value at 5-8, and standing the reaction solution for 1-4 h after reaction to below 40 deg.C; (2) stirring, adding an alkaline solution until the pH value is 7.5-11.0, and filtering to obtain white hydrocortisone sodium succinate with a yield higher than 95%. The method has such advantages as no need for organic solvent, no environmental pollution, easy operation, stable product quality, and is suitable for mass production.
Description
Technical field
The present invention relates to the preparation method of Aeroseb-Dex, more precisely is the preparation method who is used for the treatment of the hydrocortisone sodium succinate of asthmatic bronchitis.
Background technology
Trachitis, asthma are one group big to human health risk, and the high respiratory tract chronic disease of sickness rate, and it can have influence on the crowd of all age brackets, and its sickness rate is in rising trend in recent years.Hydrocortisone sodium succinate belongs to the glucocorticosteroid similar drug and has very strong anti-inflammatory action, is mainly used in acute adrenocortical insufficiency and diseases such as asthma acute state and shock, is particularly suitable for critically ill patient and uses.The hydrocortisone that in the past used clinically is the alcohol preparation, Blushing, excited irritated, side effects such as the rhythm of the heart speeds, blood vessel local excitation symptom can appear in the patient, hydrocortisone sodium succinate is a water-solubility instant type preparation now, so absorption is fast, effect is rapid, because hydrocortisone sodium succinate is cheap, be fit to more use clinically.
Hydrocortisone sodium succinate, chemistry is by name: 11 β, 17-dihydroxyl-21-(3-carboxyl-1-propoxyl) pregnant steroid-4-alkene-3,20-diketone ,-sodium salt.
Its structural formula is:
At present, it is to be raw material with intermediate hydrocortisone succinate and sodium hydroxide that traditional hydrocortisone succinate becomes technology of threonates, with acetone is that solvent carries out chemical reaction, under the condition of high temperature, reflux, reaction finishes aftercut to remove acetone, put into an amount of phosphate buffer soln debugging pH value again, filter and obtain hydrocortisone sodium succinate.This technology actual production process exists following defective: (1) acetone with an organic solvent in reaction process, and the toxic substance that produces after this solvent reflux can influence the health of the environment and the person to producing and surrounding enviroment pollute; (2) make that impurity is many in the target product, content is lower, gained hydrocortisone sodium succinate salt is in the requirement that all can not reach clinical application aspect purity and the output; (3) high temperature in the reflux course causes the sweltering heat of Working environment, brings inconvenience to the staff; (4) whole technological process very complicated will carry out vacuum decompression and concentrate, and for the sealing requirements height of equipment, can vacuum tightness be reduced in the production, causes the pollution of finished product, is difficult to guarantee aseptic, no thermal source.
Summary of the invention
The objective of the invention is to overcome the shortcoming of prior art with not enough, provide a kind of hydrocortisone succsinic acid water salifiable preparation method, this water salify preparation cost is lower, and yield height and method for making are simple, prepared product purity height meets the clinical application standard.
Technical scheme of the present invention is as follows:
A kind of preparation method of hydrocortisone sodium succinate is characterized in that, comprises the steps:
(1) in polar solvent, hydrocortisone succinate and buffered soln were reacted 1-4 hour down at 0-80 ℃, control PH5-8 after reaction finishes, leaves standstill 1～4h with reaction solution, and reacting liquid temperature is reached below 40 ℃;
(2) under agitation, basic solution is slowly joined in the above-mentioned reaction solution, reach 7.5-11.0, filter the hydrocortisone sodium succinate that obtains white or off-white color up to pH value.
The preparation method of the preferred hydrocortisone sodium succinate of the present invention comprises the steps:
(1) with the hydrocortisone succinate, reacted 1-4 hour down at 5-70 ℃ with phosphate buffer soln, control PH6.5-7.5 after reaction finishes, leaves standstill 1～4h with reaction solution reacting liquid temperature is reached below 40 ℃;
(2) under agitation, basic solution is slowly joined in the above-mentioned reaction solution, reach 8.0-10.0, finish reaction, filter the hydrocortisone sodium succinate that obtains white or off-white color up to pH value.
Buffered soln of the present invention, it generally is a pair of concentration conjugate acid-base pair about equally, for example about equally HAc-NaAc of concentration, carbonic acid-sodium bicarbonate, Citric Acid-Sodium Citrate, SODIUM PHOSPHATE, MONOBASIC-Sodium phosphate dibasic, potassium primary phosphate-dipotassium hydrogen phosphate or the like, preferably phosphoric acid sodium dihydrogen-Sodium phosphate dibasic, potassium primary phosphate-dipotassium hydrogen phosphate.Acidic component in the phosphate buffer soln can be SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate.
Polar solvent of the present invention is water, methyl alcohol or ethanol, preferably water.
The present invention can adopt ordinary method to prepare phosphate buffer soln.For example Sodium phosphate dibasic (Na2HPO412H2O) 6.02g and SODIUM PHOSPHATE, MONOBASIC (NaH2PO42H2O) 0.5g being settled to 1000mL with dissolved in distilled water makes.For example Sodium phosphate dibasic (Na2HPO412H2O) 6.02g and potassium primary phosphate (KH2PO42H2O) 0.5g are settled to 1000mL with dissolved in distilled water again and make phosphate buffer soln.
Alkaline matter of the present invention is the composition of a kind of of sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash, sodium bicarbonate, Sodium phosphate dibasic, dipotassium hydrogen phosphate or two kinds.Preferred sodium bicarbonate or yellow soda ash, the preferred yellow soda ash of mixing solutions, sodium bicarbonate mixing solutions, its concentration is generally 25～80% alkaline aqueous solution.Preferred 30～75%, be more preferably the alkaline aqueous solution of 40-70%.
The positive technique effect that the present invention is compared with prior art had is: preparation method of the present invention is not with an organic solvent, directly in water, react, avoided environmental pollution, improved productive rate simultaneously, the productive rate of hydrocortisone sodium succinate reaches more than 95%, reaction process steadily, have continuity and adopt one-step synthesis, simple to operate, constant product quality has reduced production cost simultaneously and more has been applicable to large-scale industrial production.
Embodiment
In order to explain enforcement of the present invention more fully, provide preparation method's embodiment of following hydrocortisone succinate.These embodiments only are to explain rather than limit the scope of the invention.
Embodiment 1
The preparation of hydrocortisone succinate: hydrocortisone (1kg), succinyl oxide (1kg), pyridine (3L), DMAP (100g) in ethyl acetate, room temperature reaction 4h, reclaim under reduced pressure solvent.Add in the dilute hydrochloric acid (100L) [36% concentrated hydrochloric acid-ice-water (8: 50: 40)], analyse crystallization, filter, be washed to PH7.0.In 80 ℃ of dry crude product hydrocortisone succinates (1.3kg) that get.Add acetone (7L) and gac (130g), reflux decolour 15min filters, and washs with small amount of acetone.Filtrate is poured in the distilled water (100L), leaves standstill 1h and makes crystallization complete, filter, and washing, in 80 ℃ of dry highly finished product hydrocortisone succinates (1.21kg) that get, highly finished product are white powder.Yield is 94.8%.
Embodiment 2
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone succinate 63.8g, and the phosphate solution (SODIUM PHOSPHATE, MONOBASIC-Sodium phosphate dibasic) that adds 800ml reacted 1 hour, and temperature of reaction is 1-5 ℃.Control PH 5, after reaction finishes, reaction solution is left standstill 4h, the 11.59g sodium bicarbonate is mixed with 150ml water, prepare sodium hydrogen carbonate solution, slowly join then in the reaction solution, evenly stir 4min after the solution pH value reach 7.5, filtration obtains hydrocortisone sodium succinate 44.78g, and color is white or off-white powder.Yield is 67%, 169.5 ℃ of fusing points.
Embodiment 3
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone succinate 63.8g, the phosphate solution (potassium primary phosphate-dipotassium hydrogen phosphate) that adds 800ml reacts, 2 hours reaction times, when temperature of reaction is 40 ℃, control PH6.5, after reaction finishes, reaction solution is left standstill 2h, reacting liquid temperature is reached below 40 ℃; The 11.59g sodium bicarbonate joined in the 150ml water mixes, draw sodium hydrogen carbonate solution and slowly be added drop-wise in the reaction solution, evenly stir 8min after the solution pH value reach 10.0, filtration obtains hydrocortisone sodium succinate 63.49g, color is white or off-white powder, yield 95%, 171 ℃ of fusing points.
Embodiment 4
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone succinate 53.4g, the phosphate solution (potassium primary phosphate-dipotassium hydrogen phosphate) that adds 800ml reacted 4 hours, when temperature is 75 ℃, control PH 5, after reaction finishes, reaction solution is left standstill 4h, reacting liquid temperature is reached below 40 ℃; 12.23g yellow soda ash joined in the 100ml water mixes, sodium carbonate solution slowly is added drop-wise in the reaction solution, evenly stir 15min after the solution pH value reach 8.5, filtration obtains hydrocortisone sodium succinate 48.1g, color is white or off-white powder, yield 86%, 170.5 ℃ of fusing points.
Embodiment 5
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone succinate 53.4g, the phosphate solution (SODIUM PHOSPHATE, MONOBASIC-Sodium phosphate dibasic) that adds 800ml reacted 2 hours, when temperature is 70 ℃, control PH 8, after reaction finishes, reaction solution is left standstill 3h, reacting liquid temperature is reached below 40 ℃; 4.62g sodium hydroxide joined in the 50ml water mixes, draw sodium hydroxide solution and slowly be added drop-wise in the reaction solution, evenly stir 15min after the solution pH value reach 8, filtration obtains hydrocortisone sodium succinate 44.19g, color is white or off-white powder, yield 79%, 170.5 ℃ of fusing points.
Embodiment 6
Synthesizing of hydrocortisone sodium succinate: the method with embodiment 1 obtains hydrocortisone succinate 53.4g, the ethanolic soln that adds Citric Acid-Sodium Citrate of 800ml reacted 3 hours, when reacting liquid temperature is 25 ℃, control PH 7, after reaction finishes, reaction solution is left standstill 1h, with 75% yellow soda ash, sodium bicarbonate mixing solutions (yellow soda ash and sodium bicarbonate ratio of weight and number are 1: 1) slowly is added drop-wise in the reaction solution, the solution pH value reaches 9.0 after evenly stirring 15min, filtration obtains hydrocortisone sodium succinate 52.02g, and color is white or off-white powder.Yield 93%, 171 ℃ of fusing points.
After the preferred embodiment that describes in detail, being familiar with this technology personage can be well understood to, can carry out various variations and modification not breaking away under above-mentioned claim and the spirit, all foundations technical spirit of the present invention all belongs to the scope of technical solution of the present invention to any simple modification, equivalent variations and modification that above embodiment did.And the embodiment that the present invention also is not subject in the specification sheets to be given an actual example.
Claims (7)
1, a kind of preparation method of hydrocortisone sodium succinate is characterized in that, comprises the steps:
(1) in polar solvent, hydrocortisone succinate and buffered soln were reacted 1-4 hour down at 0-80 ℃, control PH 5-8 after reaction finishes, leaves standstill 1～4h with reaction solution, and reacting liquid temperature is reached below 40 ℃;
(2) under agitation, basic solution is slowly joined in the above-mentioned reaction solution, reach 7.5-11.0, filter the hydrocortisone sodium succinate that obtains white or off-white color up to pH value.
2, preparation method as claimed in claim 1, wherein said buffered soln is acetic acid-sodium-acetate, carbonic acid-sodium bicarbonate, Citric Acid-Sodium Citrate, SODIUM PHOSPHATE, MONOBASIC-Sodium phosphate dibasic or potassium primary phosphate-dipotassium hydrogen phosphate.
3, preparation method as claimed in claim 1, acidic component is acetic acid, carbonic acid, Citric Acid, SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate in the wherein said buffered soln.
4, preparation method as claimed in claim 1 or 2, wherein said buffered soln is SODIUM PHOSPHATE, MONOBASIC-Sodium phosphate dibasic or potassium primary phosphate-dipotassium hydrogen phosphate.
5, preparation method as claimed in claim 1, wherein said basic solution concentration is 25～80%.
6, preparation method as claimed in claim 1, wherein said alkaline matter is the mixture of a kind of of sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash, sodium bicarbonate, Sodium phosphate dibasic, dipotassium hydrogen phosphate or two kinds.
7, preparation method as claimed in claim 1, wherein said polar solvent is water, methyl alcohol or ethanol.
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| CN 200710057321 CN101050229A (en) | 2007-05-11 | 2007-05-11 | Method for preparing hydrocortisone sodium succinate |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101559287B (en) * | 2009-05-15 | 2010-10-13 | 天津生物化学制药有限公司 | Method for drying hydrocortisone sodium succinate asepsis powder |
| CN102293755A (en) * | 2011-08-24 | 2011-12-28 | 天津金耀集团有限公司 | Two lyophilized powder injections of methylprednisolone sodium succinate and preparation methods thereof |
| CN102293754A (en) * | 2011-08-24 | 2011-12-28 | 天津金耀集团有限公司 | Methylprednisolone sodium succinate freeze-dried powder injection and preparation method thereof |
| CN101613392B (en) * | 2009-07-14 | 2012-01-04 | 河南利华制药有限公司 | Method for preparing hydrocortisone sodium succinate |
| CN102718825A (en) * | 2012-06-28 | 2012-10-10 | 天津生物化学制药有限公司 | Preparation method of hydrocortisone hemisuccinat |
| CN103724383A (en) * | 2012-10-10 | 2014-04-16 | 河南利华制药有限公司 | Drying technology of production of hydrocortisone sodium succinate |
| CN112220761A (en) * | 2020-10-20 | 2021-01-15 | 安徽海洋药业有限公司 | Preparation method of hydrocortisone sodium succinate for injection |
-
2007
- 2007-05-11 CN CN 200710057321 patent/CN101050229A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101559287B (en) * | 2009-05-15 | 2010-10-13 | 天津生物化学制药有限公司 | Method for drying hydrocortisone sodium succinate asepsis powder |
| CN101613392B (en) * | 2009-07-14 | 2012-01-04 | 河南利华制药有限公司 | Method for preparing hydrocortisone sodium succinate |
| CN102293755A (en) * | 2011-08-24 | 2011-12-28 | 天津金耀集团有限公司 | Two lyophilized powder injections of methylprednisolone sodium succinate and preparation methods thereof |
| CN102293754A (en) * | 2011-08-24 | 2011-12-28 | 天津金耀集团有限公司 | Methylprednisolone sodium succinate freeze-dried powder injection and preparation method thereof |
| CN102718825A (en) * | 2012-06-28 | 2012-10-10 | 天津生物化学制药有限公司 | Preparation method of hydrocortisone hemisuccinat |
| CN103724383A (en) * | 2012-10-10 | 2014-04-16 | 河南利华制药有限公司 | Drying technology of production of hydrocortisone sodium succinate |
| CN112220761A (en) * | 2020-10-20 | 2021-01-15 | 安徽海洋药业有限公司 | Preparation method of hydrocortisone sodium succinate for injection |
| CN112220761B (en) * | 2020-10-20 | 2022-08-05 | 安徽海洋药业有限公司 | Preparation method of hydrocortisone sodium succinate for injection |
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Application publication date: 20071010 |