CN107400153A - A kind of preparation method of hydrocortisone acetate - Google Patents
A kind of preparation method of hydrocortisone acetate Download PDFInfo
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- CN107400153A CN107400153A CN201710268441.3A CN201710268441A CN107400153A CN 107400153 A CN107400153 A CN 107400153A CN 201710268441 A CN201710268441 A CN 201710268441A CN 107400153 A CN107400153 A CN 107400153A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- 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 belongs to steroid drugs preparation field, more particularly to a kind of preparation method of hydrocortisone acetate, including reacting synthetic bromide hydroxy compound through bromine hydroxyl using compound C5 as raw material, generating hydrocortisone acetate crude product through debromination again, finally by being refining to obtain hydrocortisone acetate fine work, wherein：Alkali halide is added as catalyst in described bromine hydroxyl reaction, and the quality proportioning that feeds intake is compound C5：Alkali halide=1：0.08‑0.1.Advantage of the invention is that the catalyst reacted using alkali halide as bromine hydroxyl, so as to solve the key that incomplete problem is reacted in bromine hydroxyl reaction process, there is provided the new preparation process that a kind of hydrocortisone acetate product quality is stable, yield is higher.
Description
Technical field
The invention belongs to organic chemical synthesis technical field, it is related to the preparation method of steroid drugs, and in particular to a kind of vinegar
The preparation method of sour hydrocortisone.
Background technology
Hydrocortisone acetate has important physiologically active, such as anti-inflammatory, antiviral, antiallergy, Hemorrhagic shock, reduction inflammatory
The effect of oozing out etc., clinic are usually used in anaphylaxis, non-infectious skin disease and some hyperproliferative skin illness.Such as dermatitis, eczema, god
Through property dermatitis, seborrhea and pruritus etc..
Hydrocortisone acetate has more production technology, common are two kinds of methods of biofermentation and chemical synthesis.It is raw
Typically with his hydroxyl of mould directly upper 11 times of pears head, this method is non-specific, has the generation of RS products, is characterized in technique for thing fermentation
Route is short, but post-processes complexity, and yield is low.Chemical synthesis process, which has, to be made raw material by cortisone acetate and is protected through semicarbazides, potassium boron
Hydrogen reduction, it is deprotected again upper acetate；Also useful Pu Shi through ketal, reduction, hydrolysis, upper iodine, displacement come prepare acetic acid hydrogenation can
Pine；More prepared by hydrocortisone and aceticanhydride reaction, various process routes there are multiple technologies to be improved and improved.
Also have at present and use compound C5 to prepare hydrocortisone acetate through the reaction of bromine hydroxyl, debromination for raw material, but in the technique
The reaction of bromine hydroxyl, which often exists, reacts incomplete problem, causes hydrocortisone acetate final product quality unstable low with yield, therefore,
The technique of the urgent need to resolve problem occurs.
The content of the invention
The technical problem to be solved in the present invention is to provide it is a kind of it is new, be adapted to industrialized production, steady quality high income
Hydrocortisone acetate preparation method.
Particularly, inventor provides following technical scheme：
A kind of preparation method of hydrocortisone acetate, including using the compound C5 of structure as shown in formula I be raw material through bromine
Hydroxyl reaction synthesis the bromine hydroxy compound of structure, cellulose acetate hydrogen again through debromination generation structure as shown in formula III as shown in following formula II
Change cortisone crude product, finally by being refining to obtain hydrocortisone acetate fine work, wherein：Alkali gold is added in described bromine hydroxyl reaction
Belong to halide as catalyst, the quality proportioning that feeds intake is compound C5：Alkali halide=1：0.08-0.1.Its reaction scheme
It is as follows：
In reaction equation：
The compound C5 chemical names of structure shown in formula I be the pregnant steroid -4,9 of 17 Alpha-hydroxies (11)-diene -3,20- diketone -
21- acetates, the chemical name of the bromine hydroxy compound of structure shown in formula II is 9 α-bromo- 11 β, 17 α, the pregnant steroid -4- of 21- trihydroxies
Alkene -3,20- diketone -21- acetates, the compound of structure shown in formula III are target product hydrocortisone acetate.
Preferably, in the present invention, the reaction of described bromine hydroxyl is：
(1) quality proportioning that feeds intake is compound C5：Catalyst：Acetone：C5H6Br2N2O2：2% perchloric acid=1：0.08-0.1：
24-26：0.6-0.9：2-4,
(2) compound C5 (i.e. type I compound) is put into bromine hydroxyl retort, adds solvent acetone or tetrahydrofuran, stir
Mix cooling, add 2% high chloro acid solution, add catalyst alkali halide, add by several times bromating agent C5H6Br2N2O2 or
NBS, finish continuation and reacted between 0 DEG C -20 DEG C, sampled, TLC detection reaction ends, after completion of the reaction, cooling adds sodium sulfite
The aqueous solution is adjusted to pH value as neutrality, and be then concentrated under reduced pressure solvent, and thickening temperature must not exceed 55 DEG C, and solvent is recovered under reduced pressure and finishes,
Under agitation plus water elutriation, after being cooled to 20 DEG C, stand, centrifugation, washing dry, and dry to obtain bromine hydroxy compound (the i.e. chemical combination of formula II
Thing), in terms of compound C5, the yield of bromine hydroxy compound 120 ± 5%,
As it is further preferred that in the present invention, described catalyst alkali halide includes being not limited to sodium iodide, iodate
Potassium, sodium bromide, KBr etc..
Preferably, in the present invention, described debromination is：
(1) quality proportioning that feeds intake is bromine hydroxy compound：TGA：Reducing agent=1：0.4-0.7：4-6,
(2) dimethylformamide is pumped into reduction reaction can, bromine hydroxy compound stirring and dissolving is put into, adds tetrahydrochysene furan
Then stirring and dissolving of muttering cools, TGA is added under argon gas protection, warm naturally to 20 ± 2 DEG C to complete molten, while will system
In the reducing agent chromous chloride press-in reduction reaction can got ready, between temperature will rise very rapidly up to 40-50 DEG C, carry out violent anti-
Should, 30 DEG C are then cooled to, then react complete to TLC detection reactions, it is concentrated under reduced pressure and removes tetrahydrofuran (less than 60 DEG C), stirring
Add water elutriation, stand overnight, centrifuge dripping, washing, dry drying, obtain hydrocortisone acetate (the i.e. formula III of shallow white crystals
Compound) crude product, in terms of compound C5, the yield of hydrocortisone acetate crude product is 105% or so；Vinegar is obtained after crude product refining
Sour hydrocortisone product,
Cr+HCl→CrCl2
As it is further preferred that reducing agent generates chromous chloride or by chlorine by chromium grain and hydrochloric acid reaction in the debromination of the present invention
Change chromium is with chromous chloride, course of reaction made of zinc powder reaction：In reducing agent chromous chloride preparation tank, one times of amount is first put into
Chromium grain, the deionized water of four times of amounts is added, triplication hydrochloric acid is added under argon gas protection, protochloride is made in stirring temperature reaction
Chromium.Also chromium chloride and chromous chloride made of zinc powder reaction can be used.Reaction finishes survey, and it is active, and method for measuring is：At one
Add about 5ml saturated acetic acid sodium water solution in small test tube, few drops of debrominate agent are added dropwise thereto, just there is substantial amounts of chromous acetate immediately
Brick-red precipitation to be sunken to ttom of pipe as qualified.
As it is further preferred that the whole reaction system of described debromination of the present invention is reacted under argon gas protection.
Preferably, after debromination of the present invention, obtained hydrocortisone acetate crude product is refined, and method is：Vinegar
Sour hydrocortisone crude product dichloromethane, methyl alcohol mixed liquor dissolving add decolorizing with activated carbon filtering, then add toluene to be concentrated into analysis
Go out a large amount of materials, cool, stand, filtering drying obtains hydrocortisone acetate product.
Compared with prior art, the present invention effectively effect is：
Advantage of the invention is that the catalyst reacted using alkali halide as bromine hydroxyl, anti-so as to solve bromine hydroxyl
The key that incomplete problem is reacted in technique is answered, mainly solves in bromine hydroxyl course of reaction that reaction speed is slow, asking more than side reaction
Topic, there is provided the new preparation process that a kind of hydrocortisone acetate product quality is stable, yield is higher, the catalysis that the present invention uses
Agent promotes reaction speed to greatly improve, and side reaction significantly reduces.
Brief description of the drawings
Fig. 1 is raw material C5 of the present invention HPLC collection of illustrative plates.
Fig. 2 is that hydrocortisone acetate differentiates peak and corresponding impurity peak position HPLC collection of illustrative plates.
Fig. 3 is the bromine hydroxyl thing HPLC collection of illustrative plates of the embodiment of the present invention 1.
Fig. 4 is the hydrocortisone acetate HPLC collection of illustrative plates of the embodiment of the present invention 1.
Fig. 5 is the bromine hydroxyl thing HPLC collection of illustrative plates of the embodiment of the present invention 2.
Fig. 6 is the hydrocortisone acetate HPLC collection of illustrative plates of the embodiment of the present invention 2.
Embodiment
With reference to embodiment, present disclosure is further illustrated.It should be pointed out that following examples are only the present invention
More representational example.Obviously, technical scheme is not limited to following embodiments, can also there is many deformations.It is every
All deformations for directly exporting or associating from present disclosure, are considered as protection scope of the present invention.
In the present invention, if not refering in particular to, all parts, percentage are unit of weight, and all equipment and raw material etc. are equal
It is commercially available or the industry is conventional.Method in following embodiments, it is the routine of this area unless otherwise instructed
Method.
Embodiment 1
A kind of preparation method of hydrocortisone acetate, including：
(1) bromine hydroxyl reacts：The quality proportioning that feeds intake is compound C5：Catalyst：Solvent：Bromating agent：2% perchloric acid=1：
0.08：25：0.8：3.Process is：Compound C5 (3g) is put into bromine hydroxyl retort, adds acetone (75ml), stirring cooling
During to 0 DEG C, 2% high chloro acid solution (9ml) is added, adds 10% sodium iodide aqueous solution (2.4ml), at 0 DEG C or so point three
It is secondary to put into NBS (2.4g) in retort, about 60 minutes used times, throw Bi Jixu and reacted 4 hours between 0 DEG C -20 DEG C, start to take
Sample, TLC detection reactions are complete, and after completion of the reaction, cooling adds 10% sodium sulfite aqueous solution and is adjusted to pH value about 7, then is subtracted
Acetone is evaporated off in pressure concentration, and thickening temperature must not exceed 55 DEG C, and acetone is recovered under reduced pressure and finishes, and adds water elutriation under agitation, is cooled to
After 20 DEG C, 2 hours are stood, originally water washing blots for filtering, dries to obtain bromine hydroxy compound, in terms of compound C5, bromine hydroxy compound
Yield in 120%, HPLC contents 97.027%.
(2) debromination and refine：The quality proportioning that feeds intake is bromine hydroxy compound：TGA：Reducing agent aqueous solution=1：
0.5：4.Process is：In reducing agent chromous chloride preparation tank, one times of deionized water is first added, adds 0.75 times of chromium block,
First with a small amount of salt acid elution, then with a small amount of washing chromium block, the ionized waters of 1.5 times of amounts are added, under argon gas protection, are added
1.5 times of hydrochloric acid, stirring are warming up to 60 ± 5 DEG C and reacted, about after 30 minutes, can be by 0.35 times of amount when reacting slack-off
Hydrochloric acid be slowly added into.After completion of the reaction, it is necessary to survey chromous chloride activity.The diformazan of quintuple is pumped into reduction reaction can
Base formamide, put into bromine hydroxy compound stirring and dissolving, then add the tetrahydrofurans of four times of amounts, 25 DEG C or so stirring and dissolvings to complete molten,
Then less than 10 DEG C are cooled to, 0.5 times of amount TGA, while the chromous chloride solution that will be prepared are added under argon gas protection
It is pressed into retort, between temperature will rise very rapidly up to 40-50 DEG C, carries out vigorous reaction, then waits to be cooled to 30 DEG C or so, then
Reaction 2 hours, TLC detection reactions are complete, then are concentrated under reduced pressure and remove tetrahydrofuran (less than 60 DEG C), stirring plus water elutriation, stand
Overnight, centrifuge dripping, washing, drying is dried, obtains the hydrocortisone acetate crude product of shallow white crystals, in terms of compound C5, vinegar
The yield of sour hydrocortisone crude product is 105%.Again by hydrocortisone acetate crude product dichloromethane, methyl alcohol mixed liquor dissolved clarification
Add decolorizing with activated carbon to filter, then add toluene to be concentrated into and separate out a large amount of materials, then be cooled to 0 DEG C or so, stand more than 2 hours, mistake
Hydrocortisone acetate product, HPLC contents 99.58% are dried to obtain in filter.
Embodiment 2
A kind of preparation method of hydrocortisone acetate, including：
(1) bromine hydroxyl reacts：The quality proportioning that feeds intake is compound C5：Catalyst：Solvent：Bromating agent：2% perchloric acid=1：
0.09：24：0.9：2.Process is：Compound C5 is put into bromine hydroxyl retort, adds tetrahydrofuran, stirring is cooled to 0 DEG C
When, 2% high chloro acid solution, 10% sodium iodide aqueous solution is added, NBS is put into retort in three times at 0 DEG C or so, used
When about 60 minutes, throw Bi Jixu react 4 hours between 0 DEG C -20 DEG C, start to sample, TLC detection reaction completely, after completion of the reaction,
Cooling adds 10% sodium sulfite aqueous solution and is adjusted to pH value about 7, then be concentrated under reduced pressure and tetrahydrofuran is evaporated off, and thickening temperature must not
More than 55 DEG C, tetrahydrofuran is recovered under reduced pressure and finishes, add water under agitation and be diluted, after being cooled to 20 DEG C, stand 2 hours,
Originally water washing blots for filtering, dries to obtain bromine hydroxy compound, in terms of compound C5, the yield of bromine hydroxy compound is in 119%, HPLC
Content 96.555%.
(2) debromination and refine：The quality proportioning that feeds intake is bromine hydroxy compound：TGA：Reducing agent aqueous solution=1：
0.4：4.Process is：In reducing agent chromous chloride preparation tank, one times of deionized water is first added, adds 0.5 times of chromium block, first
With a small amount of salt acid elution, then with a small amount of washing chromium block, the ionized water of 1 times of amount is added, under argon gas protection, adds 1.0 times
Hydrochloric acid, stirring is warming up to 60 ± 5 DEG C and reacted, about after 30 minutes, can be by the hydrochloric acid of 0.3 times of amount when reacting slack-off
It is slowly added into.After completion of the reaction, it is necessary to survey chromous chloride activity.The dimethyl formyl of quintuple is pumped into reduction reaction can
Amine, bromine hydroxy compound stirring and dissolving is put into, then add the tetrahydrofurans of four times of amounts, then 25 DEG C or so stirring and dissolvings are dropped to complete molten
Temperature adds TGA to less than 10 DEG C under argon gas protection, while the chromous chloride solution prepared is pressed into retort,
Between temperature will rise very rapidly up to 40-50 DEG C, vigorous reaction is carried out, then waits to be cooled to 30 DEG C or so, then reacted two hours,
TLC detection reactions are complete, then are concentrated under reduced pressure and remove tetrahydrofuran (less than 60 DEG C), stirring plus water elutriation, stand overnight, centrifugal drying
It is dry, washing, drying is dried, obtain the hydrocortisone acetate crude product of shallow white crystals, in terms of C5 compounds, hydrocortisone acetate
The yield of crude product is 103%.Hydrocortisone acetate crude product dichloromethane, methyl alcohol mixed liquor dissolved clarification are added into decolorizing with activated carbon again
Filtering, then add toluene to be concentrated into and separate out a large amount of materials, then 0 DEG C or so is cooled to, more than 2 hours are stood, filtering drying obtains acetic acid
Hydrocortisone product, HPLC contents 99.42%.
Embodiment 3
A kind of preparation method of hydrocortisone acetate, including：
(1) bromine hydroxyl reacts：The quality proportioning that feeds intake is compound C5：Catalyst：Solvent：Bromating agent：2% perchloric acid=1：
0.1：25：0.6：3.Process is：Compound C5 (20g) is put into bromine hydroxyl retort, adds acetone (500ml), stirring drop
When temperature is to 0 DEG C, 2% high chloro acid solution (60ml) is added, adds 10% potassium iodide aqueous solution (20ml), at 0 DEG C or so point
C5H6Br2N2O2 (12g) is put into retort three times, about 60 minutes used times, throw Bi Jixu and reacted 4 hours between 0 DEG C -20 DEG C, opened
Begin to sample, TLC detection reactions are complete, and after completion of the reaction, cooling 10% sodium sulfite aqueous solution of addition is adjusted to pH value about 7, then enters
Row, which is concentrated under reduced pressure, is evaporated off acetone, and thickening temperature must not exceed 55 DEG C, and acetone is recovered under reduced pressure and finishes, and adds water elutriation, drop under agitation
After warm to 20 DEG C, 2 hours are stood, originally water washing dries for centrifugation, dries to obtain bromine hydroxy compound, in terms of compound C5, bromine hydroxylation
The yield of compound is in 128%, HPLC contents 95.947%.
(2) debromination and refine：The quality proportioning that feeds intake is bromine hydroxy compound：TGA：Reducing agent aqueous solution=1：
0.5：4.Process is：In reducing agent chromous chloride preparation tank, one times of deionized water is first added, adds 0.5 times of chromium block, first
With a small amount of salt acid elution, then with a small amount of washing chromium block, the ionized water of 1 times of amount is added, under argon gas protection, adds 1.0 times
Hydrochloric acid, stirring is warming up to 60 ± 5 DEG C and reacted, about after 30 minutes, can be by the hydrochloric acid of 0.3 times of amount when reacting slack-off
It is slowly added into.After completion of the reaction, it is necessary to survey chromous chloride activity.Dimethylformamide is pumped into reduction reaction can, is put into
Then bromine hydroxy compound stirring and dissolving, then add tetrahydrofuran, 25 DEG C or so stirring and dissolvings are cooled to less than 10 DEG C to complete molten,
Argon gas protection is lower to add TGA, while the chromous chloride solution prepared is pressed into retort, and temperature will rise rapidly
To between 40-50 DEG C, vigorous reaction is carried out, then waits to be cooled to 30 DEG C, then reacted two hours, TLC detection reactions are complete, then subtract
Pressure concentration removes tetrahydrofuran (less than 60 DEG C), stirring plus water elutriation, stands overnight, centrifuge dripping, washs, and dries drying, obtains
The hydrocortisone acetate crude product of shallow white crystals, in terms of C5 compounds, the yield of hydrocortisone acetate crude product is 105%.
Add decolorizing with activated carbon to filter with dichloromethane, methyl alcohol mixed liquor dissolved clarification hydrocortisone acetate crude product again, then add toluene concentration
To a large amount of materials of precipitation, then 0 DEG C or so being cooled to, stand more than 2 hours, filtering drying obtains hydrocortisone acetate product,
HPLC contents 99.227%..
Embodiment 4
A kind of preparation method of hydrocortisone acetate, including：
(1) bromine hydroxyl reacts：The quality proportioning that feeds intake is compound C5：Catalyst：Solvent：Bromating agent：2% perchloric acid=1：
0.08：23：0.7：3.Process is：Compound C5 is put into bromine hydroxyl retort, adds tetrahydrofuran, stirring is cooled to 0 DEG C
When, 2% high chloro acid solution is added, adds 10% potassium iodide aqueous solution, is in three times put into C5H6Br2N2O2 at 0 DEG C or so anti-
Answer in tank, about 60 minutes used times, throw Bi Jixu and reacted 4 hours between 0 DEG C -20 DEG C, start to sample, TLC detection reactions are complete, instead
After answering, cooling adds 10% sodium sulfite aqueous solution and is adjusted to pH value about 7, then be concentrated under reduced pressure and tetrahydrofuran is evaporated off, dense
Contracting temperature must not exceed 55 DEG C, and tetrahydrofuran is recovered under reduced pressure and finishes, and adds water under agitation and is diluted, after being cooled to 20 DEG C,
2 hours are stood, originally water washing dries for centrifugation, dries to obtain bromine hydroxy compound, in terms of compound C5, the yield of bromine hydroxy compound exists
126%, HPLC content 95.003%.
(2) debromination and refine：The quality proportioning that feeds intake is bromine hydroxy compound：TGA：Reducing agent aqueous solution=1：
0.7：6.Process is：In reducing agent chromous chloride preparation tank, one times of deionized water is first added, adds 0.5 times of chromium block, first
With a small amount of salt acid elution, then with a small amount of washing chromium block, the ionized water of 1 times of amount is added, under argon gas protection, adds 1.0 times
Hydrochloric acid, stirring is warming up to 60 ± 5 DEG C and reacted, about after 30 minutes, can be by the hydrochloric acid of 0.3 times of amount when reacting slack-off
It is slowly added into.After completion of the reaction, it is necessary to survey chromous chloride activity.Dimethylformamide is pumped into reduction reaction can, is put into
Then bromine hydroxy compound stirring and dissolving, then add tetrahydrofuran, 25 DEG C or so stirring and dissolvings are cooled to less than 10 DEG C to complete molten,
Argon gas protection is lower to add TGA, while the chromous chloride solution prepared is pressed into retort, and temperature will rise rapidly
To between 40-50 DEG C, vigorous reaction being carried out, then waits to be cooled to 30 DEG C or so, then reacted two hours, TLC detection reactions are complete,
It is concentrated under reduced pressure again and removes tetrahydrofuran (less than 60 DEG C), stirring plus water elutriation, stands overnight, centrifuge dripping, wash, dry and dry
It is dry, the hydrocortisone acetate crude product of shallow white crystals is obtained, in terms of C5 compounds, the yield of hydrocortisone acetate crude product exists
103%.Add decolorizing with activated carbon to filter with dichloromethane, methyl alcohol mixed liquor dissolved clarification hydrocortisone acetate crude product again, then add first
Benzene, which is concentrated into, separates out a large amount of materials, then is cooled to 0 DEG C or so, stands more than 2 hours, and filtering drying obtains hydrocortisone acetate production
Product, HPLC contents 99.548%.
Embodiment 5
A kind of preparation method of hydrocortisone acetate, including：
(1) bromine hydroxyl reacts：The quality proportioning that feeds intake is compound C5：Catalyst：Solvent：Bromating agent：2% perchloric acid=1：
0.1：26：0.8：4.Process is：Compound C5 is put into bromine hydroxyl retort, acetone is added, when stirring is cooled to 0 DEG C, adds
Enter 2% high chloro acid solution, add 10% aqueous sodium bromide, C5H6Br2N2O2 is put into retort in three times at 0 DEG C or so
In, about 60 minutes used times, throw Bi Jixu and reacted 4 hours between 0 DEG C -20 DEG C, start to sample, TLC detection reactions are complete, reacted
Bi Hou, cooling adds 10% sodium sulfite aqueous solution and is adjusted to pH value about 7, then be concentrated under reduced pressure and acetone is evaporated off, and thickening temperature is not
Acetone must be recovered under reduced pressure and finish more than 55 DEG C, add water under agitation and be diluted, after being cooled to 20 DEG C, stand 2 hours, from
Originally water washing dries the heart, dries to obtain bromine hydroxy compound, in terms of compound C5, the yield of bromine hydroxy compound contains in 125%, HPLC
Amount 95.782%.
(2) debromination and refine：The quality proportioning that feeds intake is bromine hydroxy compound：TGA：Reducing agent aqueous solution=1：
0.5：5.Process is：In reducing agent chromous chloride preparation tank, one times of deionized water is first added, adds 0.5 times of chromium block, first
With a small amount of salt acid elution, then with a small amount of washing chromium block, the ionized water of 1 times of amount is added, under argon gas protection, adds 1.0 times
Hydrochloric acid, stirring is warming up to 60 ± 5 DEG C and reacted, about after 30 minutes, can be by the hydrochloric acid of 0.3 times of amount when reacting slack-off
It is slowly added into.After completion of the reaction, it is necessary to survey chromous chloride activity.Dimethylformamide is pumped into reduction reaction can, is put into
Then bromine hydroxy compound stirring and dissolving, then add tetrahydrofuran, 25 DEG C or so stirring and dissolvings are cooled to less than 10 DEG C to complete molten,
Argon gas protection is lower to add TGA, while the chromous chloride solution prepared is pressed into retort, and temperature will rise rapidly
To between 40-50 DEG C, vigorous reaction is carried out, then waits to be cooled to 30 DEG C, then reacted two hours, TLC detection reactions are complete, then subtract
Pressure concentration removes tetrahydrofuran (less than 60 DEG C), stirring plus water elutriation, stands overnight, centrifuge dripping, washs, and dries drying, obtains
The hydrocortisone acetate crude product of shallow white crystals, in terms of C5 compounds, the yield of hydrocortisone acetate crude product is 106%.
Add decolorizing with activated carbon to filter with dichloromethane, methyl alcohol mixed liquor dissolved clarification hydrocortisone acetate crude product again, then add toluene concentration
To a large amount of materials of precipitation, then 0 DEG C or so being cooled to, stand more than 2 hours, filtering drying obtains hydrocortisone acetate product,
HPLC contents 99.16%.
Embodiment 6
A kind of preparation method of hydrocortisone acetate, including：
(1) bromine hydroxyl reacts：The quality proportioning that feeds intake is compound C5：Catalyst：Solvent：Bromating agent：2% perchloric acid=1：
0.08：26：0.9：4.Process is：Compound C5 is put into bromine hydroxyl retort, adds tetrahydrofuran, stirring is cooled to 0 DEG C
When, 2% high chloro acid solution is added, adds 10% kbr aqueous solution, is in three times put into C5H6Br2N2O2 at 0 DEG C or so anti-
Answer in tank, about 60 minutes used times, throw Bi Jixu and reacted 4 hours between 0 DEG C -20 DEG C, start to sample, TLC detection reactions are complete, instead
After answering, cooling adds 10% sodium sulfite aqueous solution and is adjusted to pH value about 7, then be concentrated under reduced pressure and tetrahydrofuran is evaporated off, dense
Contracting temperature must not exceed 55 DEG C, and tetrahydrofuran is recovered under reduced pressure and finishes, and adds water under agitation and is diluted, after being cooled to 20 DEG C,
2 hours are stood, originally water washing dries for centrifugation, dries to obtain bromine hydroxy compound, in terms of compound C5, the yield of bromine hydroxy compound exists
123%, HPLC content 95.223%.
(2) debromination and refine：The quality proportioning that feeds intake is bromine hydroxy compound：TGA：Reducing agent aqueous solution=1：
0.6：6.Process is：In reducing agent chromous chloride preparation tank, one times of deionized water is first added, adds 0.5 times of chromium block, first
With a small amount of salt acid elution, then with a small amount of washing chromium block, the ionized water of 1 times of amount is added, under argon gas protection, adds 1.0 times
Hydrochloric acid, stirring is warming up to 60 ± 5 DEG C and reacted, about after 30 minutes, can be by the hydrochloric acid of 0.3 times of amount when reacting slack-off
It is slowly added into.After completion of the reaction, it is necessary to survey chromous chloride activity.Dimethylformamide is pumped into reduction reaction can, is put into
Then bromine hydroxy compound stirring and dissolving, then add tetrahydrofuran, 25 DEG C or so stirring and dissolvings are cooled to less than 10 DEG C to complete molten,
Argon gas protection is lower to add TGA, while the chromous chloride solution prepared is pressed into retort, and temperature will rise rapidly
To between 40-50 DEG C, vigorous reaction being carried out, then waits to be cooled to 30 DEG C or so, then reacted two hours, TLC detection reactions are complete,
It is concentrated under reduced pressure again and removes tetrahydrofuran (less than 60 DEG C), stirring plus water elutriation, stands overnight, centrifuge dripping, wash, dry and dry
It is dry, the hydrocortisone acetate crude product of shallow white crystals is obtained, in terms of C5 compounds, the yield of hydrocortisone acetate crude product exists
111%.Add decolorizing with activated carbon to filter with dichloromethane, methyl alcohol mixed liquor dissolved clarification hydrocortisone acetate crude product again, then add first
Benzene, which is concentrated into, separates out a large amount of materials, then is cooled to 0 DEG C or so, stands more than 2 hours, and filtering drying obtains hydrocortisone acetate production
Product, HPLC contents 99.403%.
The detection data of hydrocortisone acetate product of the present invention
Comparative example 1
Bromine hydroxyl reacts：Compound C5 (3g) is put into bromine hydroxyl retort, adds acetone (75ml), stirring is cooled to 0 DEG C
When, 2% high chloro acid solution (16ml) is added, is in three times put into NBS (2.4g) in retort at 0 DEG C or so, the used time about 60
Minute, throw Bi Jixu and reacted 4 hours between 0 DEG C -20 DEG C, start to sample, TLC detection reactions are incomplete, then react 2 hours and take
Sample, reaction get nowhere, and cooling adds 10% sodium sulfite aqueous solution and is adjusted to pH value about 7, is concentrated under reduced pressure and acetone is evaporated off, thickening temperature
55 DEG C are must not exceed, acetone is recovered under reduced pressure and finishes, adds water elutriation under agitation, after being cooled to 20 DEG C, stands 2 hours, filtering is certainly
Carry out water washing to blot, dry to obtain bromine hydroxy compound, in terms of compound C5, the yield of bromine hydroxy compound is in 112%, HPLC contents
68.056%.Raw material C5 unreacted 21.267%.
Comparative example 2
Bromine hydroxyl reacts：Compound C5 (3g) is put into bromine hydroxyl retort, adds acetone (75ml), stirring is cooled to 0
DEG C when, add 2% high chloro acid solution (16ml), 0 DEG C or so in three times by NBS (2.4g) put into retort in, the used time is about
60 minutes, throw Bi Jixu and reacted 4 hours between 0 DEG C -20 DEG C, start to sample, TLC detection reactions are incomplete, then react 2 hours and take
Sample reaction gets nowhere, and it is unchanged to add NBS, adds that perchloric acid reaction is same unchanged, and reaction is incomplete all the time, and cooling adds
10% sodium sulfite aqueous solution is adjusted to pH value about 7, is concentrated under reduced pressure and acetone is evaporated off, and thickening temperature must not exceed 55 DEG C, be recovered under reduced pressure
Acetone finishes, and adds water elutriation under agitation, after being cooled to 20 DEG C, stands 2 hours, and originally water washing blots for filtering, dries to obtain bromine
Hydroxy compound, in terms of compound C5, the yield of bromine hydroxy compound is in 113%, HPLC contents 80.175%.Raw material C5 is unreacted
10.312%.
Bromine hydroxy compound detection data compare
Comparative example and embodiment are more more intuitively found out, the reaction of bromine hydroxyl reacts non-in the presence of alkali metal-free halide
Often slowly, impurity is more, raw material reaction is incomplete, yield is low, of poor quality.Reacted in the presence of having alkali halide it is very fast,
Impurity is few, raw material reaction is complete, high income, quality are good, is therefrom not difficult to show that the present invention has very big advantage.
Claims (7)
- A kind of 1. preparation method of hydrocortisone acetate, it is characterised in that including using the compound C5 of the structure as shown in formula I as Raw material, the bromine hydroxy compound through bromine hydroxyl reaction synthesis structure as shown in formula II, then through debromination generation structure as shown in formula III Hydrocortisone acetate crude product, finally by being refining to obtain hydrocortisone acetate fine work, wherein：In described bromine hydroxyl reaction Alkali halide is added as catalyst, the mass ratio that feeds intake is compound C5：Alkali halide=1：0.08-0.1,
- A kind of 2. preparation method of hydrocortisone acetate as claimed in claim 1, it is characterised in that described bromine hydroxyl reaction For：(1) quality proportioning that feeds intake is compound C5：Catalyst：Solvent：Bromating agent：2% perchloric acid=1：0.08-0.1：24-26： 0.6-0.9：2-4,(2) compound C5 is put into bromine hydroxyl retort, adds solvent acetone or tetrahydrofuran, stirring cooling, add perchloric acid The aqueous solution, catalyst alkali halide is added, adds bromating agent C5H6Br2N2O2 or NBS by several times, finish continuation at 0 DEG C -20 React, sample between DEG C, TLC detection reaction ends, after completion of the reaction, cooling add sodium sulfite aqueous solution and be adjusted to during pH value is Property, be then concentrated under reduced pressure solvent, and thickening temperature must not exceed 55 DEG C, and solvent is recovered under reduced pressure and finishes, and adds water elutriation under agitation, drop After warm to 20 DEG C, stand, centrifugation, washing dry, and dry to obtain bromine hydroxy compound.
- A kind of 3. preparation method of hydrocortisone acetate as claimed in claim 1 or 2, it is characterised in that described alkali gold Belonging to halide includes sodium iodide, KI, sodium bromide, KBr.
- A kind of 4. preparation method of hydrocortisone acetate as claimed in claim 1, it is characterised in that described debromination For：(1) quality proportioning that feeds intake is bromine hydroxy compound：TGA：Reducing agent aqueous solution=1：0.4-0.7：4-6(2) dimethylformamide of quintuple is pumped into reduction reaction can, bromine hydroxy compound stirring and dissolving is put into, adds four times Then the tetrahydrofuran stirring and dissolving of amount cools, adds TGA under argon gas protection, warm naturally to 20 ± 2 to complete molten DEG C, while reducing agent chromous chloride is pressed into reduction reaction can, between temperature will rise very rapidly up to 40-50 DEG C, carry out violent Reaction, then wait to be cooled to 30 DEG C, then react complete to TLC detection reactions, be then concentrated under reduced pressure and remove tetrahydrofuran, stirring Add water elutriation, stand overnight, centrifuge, wash, dry, dry, obtain the hydrocortisone acetate crude product of shallow white crystals.
- 5. a kind of preparation method of hydrocortisone acetate as claimed in claim 4, it is characterised in that described reducing agent is anti- The process is answered to be：In reducing agent chromous chloride preparation tank, one times of amount chromium grain is first put into, adds the deionized water of four times of amounts, Argon gas protection is lower to add triplication hydrochloric acid, and chromous chloride is made in stirring temperature reaction.
- A kind of 6. preparation method of hydrocortisone acetate as claimed in claim 4, it is characterised in that described debromination Whole reaction system is reacted under argon gas protection.
- 7. a kind of preparation method of hydrocortisone acetate as claimed in claim 1, it is characterised in that described process refines Hydrocortisone acetate fine work is obtained, by following operation：Hydrocortisone acetate crude product methylene chloride-methanol mixed liquor dissolves Decolorizing with activated carbon filtering is added, then adds toluene to be concentrated into and separates out a large amount of materials, cools, stands, filtering drying obtains acetic acid hydrogenation can Loose product.
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