CN109970834A - A kind of preparation method of hydrocortisone sodium succinate - Google Patents
A kind of preparation method of hydrocortisone sodium succinate Download PDFInfo
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- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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Abstract
The invention discloses a kind of preparation methods of hydrocortisone sodium succinate.Hydrocortisone monomester succinate is prepared using succinic anhydride and hydrocortisone as raw material in this method；It then is that raw material is reacted at low temperature with hydrocortisone monomester succinate etc., -20 DEG C of use or so of acetone handles reaction solution after the reaction was completed, obtains hydrocortisone sodium succinate.The process conditions that this method uses are sodium salt to be generated under low temperature, then reaction solution is added in a large amount of acetone, are refiltered, filter cake acetone band water, it is finally dried in vacuo acetone, the process that high temperature steams water is avoided, stablizes product, high income, Product Status is good, and in reaction, purity can reach 97% or more, after purification, product complies fully with Chinese Pharmacopoeia standard.Acetone can recycle, and also save production cost.So this scheme is suitble to industrialized production, product quality might as well.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation method of hydrocortisone sodium succinate.
Background technique
Hydrocortisone sodium succinate is for rescuing urgent patient, such as Poisoning infection, anaphylactic shock, serious kidney
The anaphylactias such as upper gland cortical hypofunction, connective tissue disease, serious bronchial asthma, and can be used for preventing and treating shifting
Plant a kind of adrenal cortex hormones drug of acute rejection.The drug will not bring tradition to patient in use
The side effects such as Blushing caused by hydrocortisone class alcohol preparation, excited agitation, increased heart rate, and hydrocortisone amber
Sour sodium is water-solubility instant type preparation, absorbs fast, effect rapidly, is well suited for clinical application.Therefore, hydrocortisone sodium succinate
Market be widely used, be in great demand.
Currently, the production method of hydrocortisone sodium succinate is generally divided into two steps: the first step mainly can with hydrogenation
Pine and succinic anhydride be raw material, reacted in the presence of solvent and catalyst, then the obtained product of reaction be added
A large amount of water is simultaneously added hydrochloric acid and adjusts its pH value, makes it that product be precipitated in water.It is generally urged using alkalescent in first step reaction
Agent (faintly alkaline reaction, basic conditions under do not react or formed diester), such as triethylamine, pyridine.It registers if any document:
The pyridine that 5 times are added in raw material is reacted at a certain temperature as solvent and catalyst, is after reaction obtained reaction
Product be added active carbon in cool down filtering, after filter reaction solution be added hydrochloric acid aqueous solution in crystallize.It is added in these techniques big
The pyridine of amount does that solvent is expensive, significantly improves production cost, and pyridine is oxidizable, toxicity is big, in process of production greatly
The use of amount pyridine can be brought greater impact to environment and human body；Need to be added active carbon cooling filtering after reaction, also
It needs to be added other reagents to neutralize excessive pyridine, further results in the waste of a large amount of reagents and the generation of waste.Second step
Then usually using the first step preparation hydrocortisone monomester succinate as raw material, after dissolution in water with sodium carbonate or sodium bicarbonate
Salt is reacted into, is then concentrated under reduced pressure and removes solvent.Described in the application documents of Publication No. " CN101050229 " hydrogenation can
The preparation method of loose sodium succinate, this method is prepared using hydrocortisone monomester succinate as raw material, although this scheme exists
In salt-forming reaction, when organic solvent is not added, but post-processing, it is related to except solvent moisture content, in the case where not having to organic solvent,
It needs to heat decompression, but because shipwreck steams, temperature can only increased and extending in the time weighing apparatus of making even, when either extending
Between or increase temperature (generally cannot be below 40 degree), this product is all unstable in water, gets higher original impurity content, most
Product quality is influenced eventually, and yield is caused to reduce.
Summary of the invention
The present invention for the technical issues of be: when preparing hydrocortisone sodium succinate in the prior art, have ignored hydrogenation
The unstability of cortisone sodium succinate in water causes impurity raising, quality reduce, is unstable, and yield is low.It (can hydrogenating
Loose sodium succinate preparation process in water content it is larger, finally water removal is more thoroughly gone to need higher temperature but existed
Product easily goes bad, generates more impurity under higher temperature；When temperature is lower, water removal effect therein it is bad, product exists
It is also extremely unstable and generate more impurity in water.Cause the product impurity content of preparation high, and post-processing difficulty is big, processing
It is complicated for operation.)
In view of the above-mentioned problems, this method uses the present invention provides a kind of preparation method of hydrocortisone sodium succinate
Be process conditions be sodium salt to be generated under low temperature, then reaction solution is added in a large amount of -20 DEG C or so of acetone, refilter, filter cake
With acetone band water, it is finally dried in vacuo acetone, the process that high temperature steams water is avoided, makes product stabilization, high income, Product Status
Good, in reaction, purity just can exceed that 97%, and after purification, product can comply fully with Chinese Pharmacopoeia standard.Acetone can recycle
It utilizes, also saves production cost.So this scheme is suitble to industrialized production, product quality might as well.Stable production process is kept away
Temperature and time causes product to become qualitative factor when having exempted from water removal, and whole process processing is simple, easy to operate, and can be avoided production
Rotten, the products obtained therefrom high income, purity is high of product.
The present invention is achieved by the following technical solutions
A kind of preparation method of hydrocortisone sodium succinate, method includes the following steps:
(1) it using succinic anhydride and hydrocortisone as raw material, dissolves in a solvent, in the presence of a catalyst, 45~60 DEG C
Under the conditions of react 4~8 hours, obtain reaction solution；
(2) in the reaction solution that step (1) obtains be added stirring solvent uniformly obtain mixed liquor, be cooled to 10 DEG C hereinafter,
Then purified water is added, stirring and crystallizing, filtering is dry to constant weight, obtains hydrocortisone monomester succinate；
(3) under the conditions of 15~25 DEG C, sodium bicarbonate solution is added in hydrocortisone monomester succinate obtained by step (2)
Middle stirring and dissolving, and acetone is added, it is reacted 1.8~2.6 hours under the conditions of 15~25 DEG C；After the reaction was completed, place reaction liquid into-
Crystallization in 15~-30 DEG C of acetone, filtering are dried to get hydrocortisone sodium succinate is arrived.
The preparation method of the hydrocortisone sodium succinate, the solvent are tetrahydrofuran and/or N, N- diformazan
Base formamide；The catalyst is 4-dimethylaminopyridine.
The preparation method of the hydrocortisone sodium succinate, step (1) hydrocortisone and succinic anhydride
Molar ratio is 1:1.5~2.5；The mass ratio of the succinic anhydride and catalyst is 1:0.001~0.1.
The preparation method of the hydrocortisone sodium succinate, the mass body of step (1) succinic anhydride and solvent
Product is than being 1g:(1~10) ml.
The preparation method of the hydrocortisone sodium succinate, solvent described in step (2) are acetone (the dissolution first step
Raw material, while sodium salt is precipitated).
The preparation method of the hydrocortisone sodium succinate, step (2) amount that solvent is added into reaction solution
Volume mass ratio with succinic anhydride used in step (1) is (1.5~7.0) ml:1g；The additional amount and step of the purified water
(1) the volume mass ratio of succinic anhydride used in is (30~100) ml:1g；
The temperature of the purified water is at 5 DEG C or less.
The preparation method of the hydrocortisone sodium succinate, after step (2) the addition purified water when stirring and crystallizing
Temperature be 0~5 DEG C, the stirring and crystallizing time is 2 hours, the drying be drying to constant weight under the conditions of 60~80 DEG C.
The preparation method of the hydrocortisone sodium succinate, the mass fraction of step (3) described sodium bicarbonate solution
It is 5.0%~15.0%；The mass volume ratio of the hydrocortisone sodium succinate monoesters and sodium bicarbonate solution be 1g:(2~
3)ml；The body of the acetone and sodium bicarbonate solution that are added after the sodium bicarbonate solution dissolution hydrocortisone sodium succinate monoesters
Product is than being 1:1.
The preparation method of the hydrocortisone sodium succinate, step (3) described reaction solution are placed in -20 DEG C below third
In ketone when crystallization, the volume ratio of acetone and reaction solution used is 4~10:1.
The preparation method of the hydrocortisone sodium succinate, drying described in step (3) are vacuum drying, 40 DEG C of items
It is 10 hours dry under part.
Compared with prior art, the present invention has following positive beneficial effect
The process conditions that this method uses are sodium salt to be generated under low temperature, then reaction solution is added in a large amount of acetone, are refiltered,
Filter cake acetone band water, is finally dried in vacuo acetone, avoids the process that high temperature steams water, stablize product, high income, product shape
State is good, and in reaction, purity can reach 97% or more, and after purification, product complies fully with Chinese Pharmacopoeia standard.Acetone can recycle
It utilizes, also saves production cost.So this scheme is suitble to industrialized production.Product quality might as well.
It is raw materials used simple and easy to get during the present invention prepares hydrocortisone sodium succinate, it is environmental-friendly, to environment and
Body effect is smaller；Agents useful for same is recyclable in technique recycles；
The present invention carries out at a lower temperature in hydrocortisone sodium succinate preparation process, with the third of -20 DEG C or so
Ketone and reaction solution mixed processing product completely remove moisture therein at a lower temperature, can either efficiently remove therein
Moisture will not impact product due to temperature height, impurity significantly reduces in products obtained therefrom, without the behaviour such as activated carbon adsorption
Make that (product purity is high, high-quality, product colour, in good condition, generates without foreign pigment, operates without decolorizing with activated carbon etc.
The product of high-purity can be obtained) so that last handling process operation is very simple, easily controllable, the direct vacuum of products obtained therefrom is dry
It is dry, and products obtained therefrom purity is high, high income.Yield yield reaches 90% or more.Scheme of the present invention is highly beneficial
In large-scale industrial production, have a good application prospect.
Specific embodiment
The present invention is described in more details below by specific embodiment, but is not intended to restrict the invention
Protection scope.
In one embodiment of the invention, the present invention provides a kind of preparation method of hydrocortisone sodium succinate,
Method includes the following steps:
(1) it using succinic anhydride and hydrocortisone as raw material, dissolves in a solvent, in the presence of a catalyst, 45~60 DEG C
Under the conditions of react 4~8 hours, obtain reaction solution
In the step, the solvent is tetrahydrofuran and/or n,N-Dimethylformamide；The succinic anhydride and solvent
Mass volume ratio 1g:(1.0~10.0) ml；Typical but non-limiting mass volume ratio be 1g:1.0ml, 1g:2.0ml,
1g:3.0ml, 1g:4.0ml, 1g:5.0ml, 1g:6.0ml, 1g:7.0ml, 1g:8.0ml, 1g:9.0ml, 1g:10.0ml.
In the step, the molar ratio of the hydrocortisone and succinic anhydride is 1:1.5~2.5, typical but non-limiting
Molar ratio be 1:1.5,1:2.0,1:2.5；
In the step, the mass ratio of the succinic anhydride and catalyst is 1:0.001~0.1；It is typical but non-limiting
Mass ratio is 1:0.001,1:0.003,1:0.005,1:0.008,1:0.009,1:0.10；
(2) in the reaction solution that step (1) obtains be added stirring solvent uniformly obtain mixed liquor, be cooled to 10 DEG C hereinafter,
Then purified water is added, stirring and crystallizing, filtering is dry to constant weight, obtains hydrocortisone monomester succinate；
In the step, the solvent being added into reaction solution be acetone, the quantity of solvent being added in reaction solution with
The volume mass ratio of succinic anhydride used in step (1) is (1.5~7.0) ml:1g；Singly unrestricted volume mass ratio is typical case
2.5ml:1g, 3.0ml:1g, 4.0ml:1g, 5.0ml:1g, 6.0ml:1g, 7.0ml:1g；
The additional amount of the purified water and the volume mass ratio of step (1) raw materials used succinic anhydride are (30~100) ml:
1g；Typical single unrestricted volume mass ratio is 70ml:1g, 80ml:1g, 90ml:1g, 100ml:1g；The purified water
Temperature is at 5 DEG C or less；Preferably, the temperature of the purified water is 0~5 DEG C.
The temperature of purified water used is 0~5 DEG C, is added after purified water crystallization 2 hours under the conditions of 0~5 DEG C, is filtered,
It dries under the conditions of 60~80 DEG C to constant weight；
(3) under the conditions of 15~25 DEG C, sodium bicarbonate is added portionwise in hydrocortisone monomester succinate obtained by step (2)
Stirring and dissolving in solution, and acetone is added, it is reacted 1.8~2.6 hours under the conditions of 15~25 DEG C；After the reaction was completed, by reaction solution
It is placed in crystallization in -15~-30 DEG C of acetone, is filtered, is dried to get hydrocortisone sodium succinate is arrived；
During being somebody's turn to do, when reaction solution is placed in crystallization in -20 DEG C of acetone below, the volume ratio of acetone and reaction solution used is
4~10:1；Typical but non-limiting volume ratio is 4:1,5:1,6:1,7:1,8:1,9:1,10:1.
During being somebody's turn to do, the drying is to be dried under vacuum conditions, drying condition are as follows: dry 10 under the conditions of 40 DEG C
Hour.
In another embodiment provided by the invention, solvent described in step (1) is tetrahydrofuran and N, N- diformazan
The mixed solvent of base formamide；Preferably, the volume ratio of in the mixed solvent, tetrahydrofuran and n,N-Dimethylformamide is 1:1；
The catalyst is 4-dimethylaminopyridine.
In another embodiment provided by the invention, the mass fraction of the sodium bicarbonate solution is 5.0%~
15.0%；The mass volume ratio of the hydrocortisone monomester succinate and sodium bicarbonate solution is 1g:(2~3) ml；It is typical but
Unrestricted mass volume ratio is 1g:2ml, 1g:2.5ml, 1g:3ml；
In another embodiment provided by the invention, the sodium bicarbonate solution dissolves hydrocortisone sodium succinate list
The volume ratio of the acetone and sodium bicarbonate solution that are added after ester is 1:1.
The preparation of hydrocortisone sodium succinate of the present invention is carried out below by specific preparation embodiment detailed
Illustrate, but is not used to limiting the scope of the invention.
Embodiment 1
(1) sequentially added in clean reaction flask 45g succinic anhydride, 250ml N,N-dimethylformamide (DMF) and
250ml tetrahydrofuran (THF) mixed solvent, 110g hydrocortisone, 10g 4-dimethylaminopyridine (DMAP), heating water bath
To 45 DEG C, magnetic agitation to solution is clarified, and under the conditions of 45 DEG C, is stirred to react the reaction of completion in 4 hours, is obtained reaction solution；
(2) 250ml acetone is added in the reaction solution that step (1) obtains, and (acetone makes precipitation product not agglomerate.Because of acetone
Polarity can even up the polarity of reaction solution and the polarity of water, product is precipitated more preferably between DMF/THF and water, avoid agglomeration and
Product Status) it is uniformly mixing to obtain mixed liquor, by the greenhouse cooling of mixed liquor to 10 DEG C hereinafter, weight is then added in mixed liquor
Amount is equivalent to the purified water (temperature of purified water is 0~5 DEG C) of 35 times of succinic anhydride weight of step (1), in 0~5 DEG C of stirring bar
Crystallization 2 hours under part, filtering, it is to obtain hydrocortisone monomester succinate that by gained crystal, drying to constant weight at 60 DEG C；Through
Detection, gained hydrocortisone monomester succinate fine work 130g, purity 99.4%, yield 92%；
(3) 25g sodium bicarbonate is dissolved in 300ml water and is uniformly mixed；It, will be obtained by step (2) under the conditions of 15~25 DEG C
130g hydrocortisone monomester succinate that (two batches midfeather 30min) mixing is added in sodium bicarbonate solution in two batches is equal
It is even；300ml acetone (every batch of is 150ml, two batches interval 30 minutes) is added in two batches again, after the completion of acetone is added, 15~25 DEG C
Under the conditions of react 2 hours；After the reaction was completed, reaction solution is added in -20 degree 3L ice acetone, product is precipitated, filtering obtains white
It is dried in vacuo under the conditions of solid, then 40 DEG C and obtains within 10 hours white sterling hydrocortisone sodium succinate 125g.After testing: receiving
Rate is that 93%, purity is higher than 99%.
Embodiment 2
(1) sequentially added in clean reaction flask 60g succinic anhydride, 300ml N,N-dimethylformamide (DMF) and
300ml tetrahydrofuran (THF) mixed solvent, 110g hydrocortisone, 10g 4-dimethylaminopyridine (DMAP), heating water bath
To 45 DEG C, magnetic agitation to solution is clarified, and under the conditions of 45 DEG C, is stirred to react the reaction of completion in 4 hours, is obtained reaction solution；
(2) 300ml acetone is added in the reaction solution that step (1) obtains and is uniformly mixing to obtain mixed liquor, by mixed liquor
Greenhouse cooling is to 10 DEG C hereinafter, the purifying that weight is equivalent to 35 times of succinic anhydride weight of step (1) is then added in mixed liquor
Water (temperature of purified water is 0~5 DEG C), crystallization 2 hours under 0~5 DEG C of stirring condition, filtering, by gained crystal at 60 DEG C
Drying to constant weight obtains hydrocortisone monomester succinate；Through detecting, gained hydrocortisone monomester succinate fine work 125g,
Purity 99.7%, yield 89%；
(3) 24g sodium bicarbonate is dissolved in 300ml water and is uniformly mixed；It, will be obtained by step (2) under the conditions of 15~25 DEG C
125g hydrocortisone monomester succinate be added in sodium bicarbonate solution in two batches (every batch of be added half monoesters, middle ware
Every 30min) it is uniformly mixed；300ml acetone (every batch of is 150ml, midfeather 30min) is added in two batches again, acetone has been added
Cheng Hou reacts 2 hours under the conditions of 15~25 DEG C；After the reaction was completed, reaction solution is added in -20 degree 3L ice acetone, is precipitated and produces
Product, filtering obtain obtaining white sterling hydrocortisone sodium succinate within vacuum dry 10 hours under the conditions of white solid, then 40 DEG C
123g.After testing: yield 94%, purity are higher than 97%.
Embodiment 3
(1) sequentially added in clean reaction flask 60g succinic anhydride, 500ml N,N-dimethylformamide (DMF) and
500ml tetrahydrofuran (THF) mixed solvent, 110g hydrocortisone, 10g 4-dimethylaminopyridine (DMAP), heating water bath
To 45 DEG C, magnetic agitation to solution is clarified；Under the conditions of 45 DEG C, it is stirred to react the reaction of completion in 4 hours, obtains reaction solution；
(2) 300ml acetone is added in the reaction solution that step (1) obtains and is uniformly mixing to obtain mixed liquor, by mixed liquor
Greenhouse cooling is to 10 DEG C hereinafter, the purifying that weight is equivalent to 35 times of succinic anhydride weight of step (1) is then added in mixed liquor
Water (temperature of purified water is 0~5 DEG C), crystallization 2 hours under 0~5 DEG C of stirring condition, filtering, by gained crystal at 80 DEG C
Drying to constant weight obtains hydrocortisone monomester succinate；Through detecting, gained hydrocortisone monomester succinate fine work 125g,
Purity 99.3%, yield 89%；
(3) 24g sodium bicarbonate is dissolved in 300ml water and is uniformly mixed；It, will be obtained by step (2) under the conditions of 15~25 DEG C
125g hydrocortisone monomester succinate be added in sodium bicarbonate solution in two batches (every batch of be added half monoesters, interval
30min) it is uniformly mixed；300ml acetone (every batch of 150ml, two batches interval 30min) is added in two batches again, after the completion of acetone is added,
It is reacted 2 hours under the conditions of 15~25 DEG C；After the reaction was completed, reaction solution is added in -20 degree 5L ice acetone, product, mistake is precipitated
Filter obtains being dried in vacuo under the conditions of white solid, then 40 DEG C obtaining within 10 hours white sterling hydrocortisone sodium succinate 127g.
After testing: yield 97%, purity 99.9%.
Embodiment 4
(1) sequentially added in clean reaction flask 60g succinic anhydride, 300ml N,N-dimethylformamide (DMF) and
300ml tetrahydrofuran (THF) mixed solvent, 110g hydrocortisone, 10g 4-dimethylaminopyridine (DMAP), heating water bath
To 45 DEG C, magnetic agitation to solution is clarified, and is warming up to 60 DEG C, is stirred to react the reaction of completion in 8 hours, is obtained reaction solution；
(2) 300ml acetone is added in the reaction solution that step (1) obtains and is uniformly mixing to obtain mixed liquor, by mixed liquor
Greenhouse cooling is to 10 DEG C hereinafter, the purifying that weight is equivalent to 35 times of succinic anhydride weight of step (1) is then added in mixed liquor
Water (temperature of purified water is 0~5 DEG C), crystallization 2 hours under 0~5 DEG C of stirring condition, filtering, by gained crystal at 70 DEG C
Drying to constant weight obtains hydrocortisone monomester succinate；Through detecting, gained hydrocortisone monomester succinate fine work 120g,
Purity 99%, yield 85%；
(3) 25g sodium bicarbonate is dissolved in 300ml water and is uniformly mixed；Under the conditions of 15~25 DEG C, by sodium bicarbonate solution
It is equal that mixing is added in step (2) resulting 120g hydrocortisone monomester succinate and (be added in two batches, be spaced 30min) in two batches
It is even；300ml acetone (every batch of is 150ml, two batches interval 30min) is added in two batches again, after the completion of acetone is added, -20~-10
It is reacted 2 hours under the conditions of DEG C；After the reaction was completed, reaction solution is added in -20 degree 5L ice acetone, product is precipitated, filtering obtains white
It is dried in vacuo under the conditions of color solid, then 40 DEG C and obtains within 10 hours white sterling hydrocortisone sodium succinate 120g.After testing:
Yield is 95%, purity 99.7%.
Claims (10)
1. a kind of preparation method of hydrocortisone sodium succinate, which is characterized in that method includes the following steps:
(1) it using succinic anhydride and hydrocortisone as raw material, dissolves in a solvent, in the presence of a catalyst, 45~60 DEG C of conditions
Lower reaction 4~8 hours, obtains reaction solution；
(2) stirring solvent is added in the reaction solution that step (1) obtains and uniformly obtains mixed liquor, be cooled to 10 DEG C hereinafter, then
Purified water is added, stirring and crystallizing, filtering is dry to constant weight, obtains hydrocortisone monomester succinate；
(3) under the conditions of 15~25 DEG C, hydrocortisone monomester succinate obtained by step (2) is added in sodium bicarbonate solution
Stirring and dissolving, and acetone is added, it is reacted 1.8~2.6 hours under the conditions of 15~25 DEG C；After the reaction was completed, -15 are placed reaction liquid into
Crystallization in~-30 DEG C of acetone, filtering are dried to get hydrocortisone sodium succinate is arrived.
2. the preparation method of hydrocortisone sodium succinate according to claim 1, which is characterized in that the solvent is
Tetrahydrofuran and/or N,N-dimethylformamide；The catalyst is 4-dimethylaminopyridine.
3. the preparation method of hydrocortisone sodium succinate according to claim 1 or 2, which is characterized in that step (1) institute
The molar ratio for stating hydrocortisone and succinic anhydride is 1:1.5~2.5；The mass ratio of the succinic anhydride and catalyst is 1:
0.001~0.1.
4. the preparation method of hydrocortisone sodium succinate according to claim 1 or 2, which is characterized in that step (1) institute
The mass volume ratio for stating succinic anhydride and solvent is 1g:(1~10) ml.
5. the preparation method of hydrocortisone sodium succinate according to claim 1, which is characterized in that step (2) is described
Solvent be acetone.
6. the preparation method of hydrocortisone sodium succinate according to claim 1 or 5, which is characterized in that step (2) institute
The volume mass ratio for stating succinic anhydride used in the amount that solvent is added into reaction solution and step (1) is (1.5~7.0) ml:1g；Institute
The volume mass ratio of succinic anhydride used in the additional amount for the purified water stated and step (1) is (30~100) ml:1g；
The temperature of the purified water is at 5 DEG C or less.
7. the preparation method of hydrocortisone sodium succinate according to claim 1, which is characterized in that step (2) is described
Temperature after addition purified water when stirring and crystallizing is 0~5 DEG C, the stirring and crystallizing time is 2 hours, and the drying is 60~80
Drying to constant weight under the conditions of DEG C.
8. the preparation method of hydrocortisone sodium succinate according to claim 1, which is characterized in that step (3) is described
The mass fraction of sodium bicarbonate solution is 5.0%~15.0%；The hydrocortisone sodium succinate monoesters and sodium bicarbonate are molten
The mass volume ratio of liquid is 1g:(2~3) ml；It is added after the sodium bicarbonate solution dissolution hydrocortisone sodium succinate monoesters
Acetone and sodium bicarbonate solution volume ratio be 1:1.
9. the preparation method of hydrocortisone sodium succinate according to claim 1, which is characterized in that step (3) is described
When reaction solution is placed in crystallization in -20 DEG C of acetone below, the volume ratio of acetone and reaction solution used is 4~10:1.
10. the preparation method of hydrocortisone sodium succinate according to claim 1, which is characterized in that step (3) is described
Drying be vacuum drying, it is 10 hours dry under the conditions of 40 DEG C.
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| CN101613392A (en) * | 2009-07-14 | 2009-12-30 | 河南利华制药有限公司 | A kind of preparation method of 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 |
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| 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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