CN109608511A - The chemical synthesis process of prednisolone valerate acetate - Google Patents
The chemical synthesis process of prednisolone valerate acetate Download PDFInfo
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- prednisolone
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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
Abstract
The invention belongs to chemosynthesis technical fields, disclose a kind of chemical synthesis process of prednisolone valerate acetate, using prednisolone, p-methyl benzenesulfonic acid, original acid methyl ester, dimethyl aminopyridine, pyridine and aceticanhydride as raw material, prednisolone valerate acetate has been synthesized by less processing step, not only simplify production process, significantly reduce production cost, and yield and product purity are high, suitable for the large-scale production of factory, there is good industrial development value and good market application prospect.
Description
Technical field
The invention belongs to chemosynthesis technical fields, specifically, being the change about a kind of prednisolone valerate acetate
Learn synthesis technology.
Background technique
As the prednisolone valerate acetate of cortex hormone of aadrenaline, excellent anti-inflammatory effect is shown in affected part, also
The low activity substance of high security can be converted into vivo, be widely used as eczema, dermatitis, macula, insect bite disease, itch, prickly heat,
The therapeutic agent of nettle rash etc..In existing prednisolone valerate acetate chemical synthesis process method, process flow is not easy to grasp,
The sterling purity of generation is low, production process is complicated, production efficiency is low and cost is high, is not suitable for large-scale production.For
This, needs to research and develop the chemical synthesis process of new prednisolone valerate acetate, to solve the above problems.
Summary of the invention
The object of the present invention is to provide a kind of chemical synthesis process of prednisolone valerate acetate, to overcome the prior art
Present in drawbacks described above.
To achieve the above object, the invention adopts the following technical scheme:
The chemical synthesis process of prednisolone valerate acetate, including following preparation step:
S1: prednisolone (I) q. s. methylene chloride and dimethyl sulfoxide dissolved clarification obtain dissolved clarification system, open nitrogen and protect
Shield；
S2: p-methyl benzenesulfonic acid (PTS) and original acid methyl ester being added into the dissolved clarification system of step S1, control reaction temperature
It is 20~30 DEG C, is stirred to react 1~2 hour, after fully reacting, obtains the reaction system containing cyclic ester object (II)；It is described to first
The additional amount of benzene sulfonic acid is the 2.5~4% of prednisolone quality；The volume mass of the original acid methyl ester and prednisolone ratio
For 1.5~1.75g/ml；
S3: being added appropriate dilute sulfuric acid and organic cosolvent into the reaction system of step S2, and control reaction temperature is 20~
It 30 DEG C, is stirred to react 1~2 hour, after fully reacting, obtains the mixed system containing prednival (III)；
S4: appropriate dimethyl sulfoxide and water are added into the mixed system of step S3, lower layer's organic phase is collected in layering, organic
Mutually decompression distillation and concentration adds suitable methylene chloride entrainment dehydration, obtains prednival crude product；
S5: the prednival crude product of step S4 is cooled to 20~30 DEG C, adds dimethyl aminopyridine, pyrrole
Pyridine, aceticanhydride, insulated and stirred are reacted 1~3 hour, and prednisolone valerate acetate (IV) crude product is obtained；The dimethylamino pyrrole
The additional amount of pyridine is the 0.6~0.75% of prednisolone quality, the volume mass ratio of the pyridine and prednisolone is 0.5~
0.6ml/g；The volume mass of the aceticanhydride and prednisolone ratio is 1.5~1.75ml/g；
S6: the prednisolone valerate acetate crude product of step S5 is added water and stirred, then stratification, circulate operation 1~5
It is secondary, organic phase is collected, organic to be added to appropriate organic cosolvent, and a small amount of bleaching agent bleaching, filtering is added, filter cake is with suitable
Methylene chloride washing, merging filtrate, filtrate air-distillation to material are precipitated, and add organic cosolvent dissolution, concentrated, drop
Temperature stirring, is filtered, is washed, obtaining prednisolone valerate acetate after drying.
According to the present invention, it should be understood readily by those skilled in this art, the methylene chloride and dimethyl sulfoxide can add respectively
Enter in prednisolone, then is mixed together, the volume matter of the methylene chloride of addition and the total volume of dimethyl sulfoxide and prednisolone
Amount is than being 20~25ml/g.；It can also mix, be added in the form of mixed solvent in advance.
Preferably, in the step S1, the methylene chloride and dimethyl sulfoxide are added in the form of mixed solvent, described mixed
The volume ratio of methylene chloride and dimethyl sulfoxide is 8~4:1 in bonding solvent；The mixed solvent of addition and the volume matter of prednisolone
Amount is than being 20~25ml/g.
According to the present invention, it in the step S2, detects in the reaction system containing cyclic ester object, reaction raw materials prednisolone
Content≤1wt%, i.e. fully reacting；
In the step S3, detect in the mixed system containing prednival, content≤1wt% of cyclic ester object,
That is fully reacting.
In the step S5, detect in the mixed system containing prednisolone valerate acetate, prednival
Content≤0.5wt%, i.e. fully reacting.
According to the present invention, in the step S3, the dilute sulfuric acid by 98% concentrated sulfuric acid and water according to volume ratio 1:130~
170 is uniformly mixed obtained；The volume mass of the dilute sulfuric acid and prednisolone ratio is 0.15~0.25g/ml.
According to the present invention, it in the step S3, is added before dilute sulfuric acid, will first cool down containing the reaction system of cyclic ester object.
Preferably, the reaction system containing cyclic ester object is cooled to 18~20 DEG C.
According to the present invention, in the step S3, organic cosolvent is selected from one or both of acetone or glacial acetic acid.
According to the present invention, in the step S4, the amount of methylene chloride used and the volume mass ratio of prednisolone are carried secretly
For 5~7.5g/ml.
According to the present invention, in the step S4, methylene chloride is added and carries secretly to system moisture content < 0.3wt%.
According to the present invention, in the step S4, the additional amount of the dimethyl sulfoxide and the volume mass ratio of prednisolone
For 0.4~1.0ml/g.Preferably 0.4~0.5ml/g.
According to the present invention, in the step S4, the volume mass ratio of the additional amount of the water and prednisolone is 15~
20ml/g.Preferably 15~16ml/g.
According to the present invention, in the step S4, the organic phase is evaporated under reduced pressure to 30~60% that volume is stoste volume.
The volume of organic phase after vacuum distillation cannot be too small or too big, otherwise influences the dry step of subsequent methylene chloride band
Rapid and S5 reaction step, the yield and purity for eventually leading to product reduce.
According to a particular embodiment of the invention, described in the step S4 using 20g prednisolone as starting material
It is 190~210ml that organic phase, which is evaporated under reduced pressure to volume,.
According to the present invention, in the step S6, the organic cosolvent is one of methanol, ethyl alcohol and acetone or more
Kind.Preferably, the organic cosolvent is methanol.
Further, in the step S6, if when air-distillation, reaction temperature is not above the boiling point of organic cosolvent,
Organic cosolvent can be continuously added until reaction temperature is greater than the boiling point of organic cosolvent.
When using methanol as preferred organic cosolvent, if be normally set up air-distillation, reaction temperature is without height
In 64.5 DEG C of boiling point of methanol, organic cosolvent can be continuously added until reaction temperature is greater than 64.5 DEG C.
Can 65 DEG C of the preset temperature value terminals as air-distillation, when air-distillation, reaction temperature reaches 65 DEG C, then often
Pressure distillation terminates.
According to the present invention, in the step S6, the bleaching temperature is 40 ± 2 DEG C, and bleaching time is 2~12 hours.
It should be understood readily by those skilled in this art, the decolorising agent can for active carbon, carclazyte, absorption resin, molecular sieve,
One of diatomite, neutral alumina, silmag are a variety of.
Preferably, in the step S6, the decolorising agent is active carbon.
According to the present invention, in the step S6, in the concentration step, the boiling point of organic cosolvent is greater than with reaction temperature
For striking point.
According to the present invention, it should be understood readily by those skilled in this art, air-distillation or decompression can be used in the concentration step
Distillation.It is preferably air-distillation in this step.
According to the present invention, in the step S6, the cooling step uses substep cool-down method, is first cooled down with conventional method
To reaction temperature less than 40 DEG C, then frozen cooling is to 0~5 DEG C.
According to the present invention, it in the step S6, in the whipping step, stirs 1~8 hour.
According to the present invention, 5~10 hours dry under 40~60 DEG C of vacuum in the drying steps in the step S6.
The yield of prednisolone valerate acetate prepared by the present invention is 95.0%~115.0%, the purity of finished product >=
99.5%.
Further, the purity of finished product is 99.5~99.8%.
Compared with prior art, the present invention has following advantageous effects:
The chemical synthesis process of prednisolone valerate acetate of the invention, with prednisolone, p-methyl benzenesulfonic acid, orthovaleric acid
Trimethyl, dimethyl aminopyridine, pyridine and aceticanhydride are raw material, have synthesized prednisolone acetic acid penta by less processing step
Acid esters not only simplifies production process, production cost is significantly reduced, and yield and product purity are high, suitable for the big of factory
Large-scale production has good industrial development value and good market application prospect.
Detailed description of the invention
Fig. 1 is prednisolone valerate acetate chemical synthesis process route map of the invention.
Specific embodiment
Below in conjunction with specific embodiment, the invention will be further described.It should be understood that following embodiment is merely to illustrate this
Invention is not for limiting the scope of the invention.
In the following example, raw material used is commercially available.
Definition yield=[raw material that S6 finally dries resulting prednisolone valerate acetate product quality/investment sprinkles Buddhist nun
The quality of Song Long] × 100%
The prednisolone valerate acetate of the preparation of following embodiment, weight be 19~23g, yield be 95.0%~
115.0%, the purity of the purity finished product of finished product is 99.5~99.8%.
The detection of content is carried out to the sample of each step using high performance liquid chromatography.
1 prednisolone valerate acetate chemical synthesis process of embodiment
Prednisolone valerate acetate chemical synthesis process, the specific steps are as follows:
S1: 20g prednisolone being added into reaction flask, controls reaction temperature at 25 DEG C, and 25ml volume ratio is then added and is
The methylene chloride of 4:1 and the mixed solvent of dimethyl sulfoxide, stirring to material dissolved clarification obtain dissolved clarification system, open nitrogen protection.
S2: 0.5g p-methyl benzenesulfonic acid being added into the dissolved clarification system of step S1, adds 30mL original acid methyl ester, controls
Reaction temperature is 25 DEG C, is stirred to react 1 hour, content≤1wt% of prednisolone in detection reaction system, i.e. fully reacting,
Obtain the reaction system containing cyclic ester object.
S3: the temperature of the reaction system of step S2 is reduced to 20 ± 2 DEG C, 3mL dilution heat of sulfuric acid is added, adds 20mL third
Ketone controls reaction temperature at 25 DEG C, is stirred to react 2 hours, detects content≤1wt% of cyclic ester object in reaction system, that is, react
Completely, the mixed system of prednival is obtained.In this step, dilute sulfuric acid is by 98% concentrated sulfuric acid and water according to volume ratio
1:150, which is uniformly mixed, to be made.
S4: 8mL dimethyl sulfoxide and 300mL water being added into the mixed system of step S3, and stirring stands 15 points after five minutes
Clock, then layering is collected in organic phase to another reaction flask, and vacuum distillation to volume is 200mL, and 100mL dichloro is then added
Methane entrainment dehydration, until moisture content < 0.3wt% in reaction system, obtain prednival crude product.
S5: being cooled to 25 DEG C for the prednival crude product of step S4, and 0.12g diformazan is then added in reaction flask
Base aminopyridine, 10mL pyridine, 10mL aceticanhydride, control reaction temperature are 25 DEG C, and insulated and stirred is reacted 2 hours, and reactant is detected
Content≤0.5wt% of prednival, i.e. fully reacting obtain prednisolone valerate acetate crude product in system.
S6: 100mL water being added into the prednisolone valerate acetate crude product of step S5, stirs 5 minutes, stratification,
Circulate operation 3 times, collection is organic to be added to 100mL methanol and a small amount of active carbon, is warming up to 40 ± 2 DEG C, and stirring is decolourized 2 hours,
Filtering washs filter cake, merging filtrate with 20mL methylene chloride, and air-distillation to material is precipitated, and it is molten that 240mL methanol is then added
Solution continues air-distillation to reaction temperature and is greater than 64.5 DEG C, then concentration terminates.Then, reaction temperature first is cooled to tap water
Less than 40 DEG C, then ice water frozen cooling, to 0~5 DEG C, stirring filters after 2 hours, and filter cake is eluted with 20mL ice methanol, drained, received
Collect filter cake, collection material is weighed after drying 6 hours under 60 DEG C of vacuum.
Prednisolone valerate acetate finished weight obtained is 20g, and yield 100% detects through HPLC, finished product it is pure
Degree is 99.5%.
Embodiment 2, prednisolone valerate acetate chemical synthesis process
Prednisolone valerate acetate chemical synthesis process, the specific steps are as follows:
S1: 20g prednisolone being added into reaction flask, controls reaction temperature at 30 DEG C, and 20ml volume ratio is then added and is
The methylene chloride and dimethyl sulfoxide of 8:1, stirring to material dissolved clarification obtain dissolved clarification system, open nitrogen protection.
S2: 0.6g p-methyl benzenesulfonic acid being added into the dissolved clarification system of step S1, adds 32mL original acid methyl ester, controls
Reaction temperature is 30 DEG C, is stirred to react 1 hour, detects content≤1wt% of prednisolone in reaction system at this time, that is, reacted
Entirely, the reaction system containing cyclic ester object (II) is obtained.
S3: the reaction temperature of the reaction system of step S2 is reduced to 20 ± 2 DEG C, 4mL dilution heat of sulfuric acid is added, adds
22mL acetone controls reaction temperature at 20 DEG C, is stirred to react 2 hours, detects content≤1wt% of cyclic ester object in reaction system,
That is fully reacting obtains prednival mixed system.In this step, dilute sulfuric acid is by 98% concentrated sulfuric acid and water according to body
Product is uniformly mixed than 1:150 and is made.
S4: 9mL dimethyl sulfoxide and 310mL water being added into the mixed system of step S3, and stirring stands 15 points after five minutes
Clock, then layering is collected in organic phase to another reaction flask, and vacuum distillation to volume is 200mL, and 150mL dichloro is then added
Methane entrainment dehydration, until moisture content < 0.3wt% in reaction system, obtains prednival crude product；
S5: being cooled to 30 DEG C for the prednival crude product of step S4, and 0.13g diformazan is then added in reaction flask
Base aminopyridine, 11mL pyridine, 11mL aceticanhydride, control reaction temperature are 30 DEG C, and insulated and stirred is reacted 2 hours, and reactant is detected
Content≤0.5wt% of prednival, i.e. fully reacting obtain prednisolone valerate acetate crude product in system.
S6: 100mL water being added into the prednisolone valerate acetate crude product of step S5, stirs 5 minutes, stratification,
Circulate operation 3 times, collection is organic to be added to 100mL methanol and a small amount of active carbon, is warming up to 40 ± 2 DEG C, and stirring is decolourized 6 hours,
Filtering washs filter cake, merging filtrate with 20mL methylene chloride, and air-distillation to material is precipitated, and the dissolution of 240mL methanol is added, after
Continuous air-distillation to reaction temperature is greater than 65 DEG C, then concentration terminates.Then, reaction temperature first is cooled to less than 40 with tap water
DEG C, then brine ice frozen cooling, to 0~5 DEG C, stirring filters after 2 hours, and filter cake is eluted with 20mL ice methanol, drains, collects filter
Cake, collection material is weighed after drying 6 hours under 60 DEG C of vacuum.
Prednisolone valerate acetate finished weight obtained is 23g, and yield 115% detects through HPLC, finished product it is pure
Degree is 99.6%.
Embodiment 3, prednisolone valerate acetate chemical synthesis process
Prednisolone valerate acetate chemical synthesis process, the specific steps are as follows:
S1: 20g prednisolone being added into reaction flask, controls reaction temperature at 20 DEG C, and 22ml volume ratio is then added and is
The methylene chloride and dimethyl sulfoxide of 6:1, stirring to material dissolved clarification obtain dissolved clarification system, open nitrogen protection.
S2: 0.8g p-methyl benzenesulfonic acid being added into the dissolved clarification system of step S1, adds 35mL original acid methyl ester, controls
Reaction temperature is 20 DEG C, is stirred to react 2 hours, content≤1wt% of prednisolone in detection reaction system, i.e. fully reacting,
Obtain the reaction system containing cyclic ester object.
S3: the reaction temperature of the reaction system of step S2 is reduced to 20 ± 2 DEG C, 5mL dilution heat of sulfuric acid is added, adds
25mL acetone controls reaction temperature at 30 DEG C, is stirred to react 1 hour, detects content≤1wt% of cyclic ester object in reaction system,
That is fully reacting obtains the mixed system containing prednival.In this step, dilute sulfuric acid passes through 98% concentrated sulfuric acid and water
It is uniformly mixed and is made according to volume ratio 1:150.
S4: 10mL dimethyl sulfoxide and 320mL water being added into the mixed system of step S3, and stirring stands 15 after five minutes
Minute, then layering is collected in organic phase to another reaction flask, and vacuum distillation to volume is 200mL, and 120mL bis- is then added
Chloromethanes entrainment dehydration, until moisture content < 0.3wt% in reaction system, obtains prednival crude product.
S5: being cooled to 20 DEG C for the prednival crude product of step S4, and 0.15g diformazan is then added in reaction flask
Base aminopyridine, 12mL pyridine, 12mL aceticanhydride, control reaction temperature are 20 DEG C, and insulated and stirred is reacted 2 hours, and prednisone is detected
Content≤0.5wt% of imperial valerate, i.e. fully reacting obtain prednisolone valerate acetate crude product.
S6: 100mL water being added into the prednisolone valerate acetate crude product of step S5, stirs 5 minutes, stratification,
Circulate operation 3 times, collection is organic to be added to 100mL methanol and a small amount of active carbon, is warming up to 40 ± 2 DEG C, and stirring is decolourized 12 hours,
Filtering washs filter cake, merging filtrate with 20mL methylene chloride, and air-distillation to material is precipitated, and the dissolution of 240mL methanol is added, after
Continuous air-distillation to reaction temperature is greater than 65 DEG C, then concentration terminates.Then, reaction temperature first is cooled to less than 40 with tap water
DEG C, then ice water frozen cooling, to 0~5 DEG C, stirring filters after 2 hours, and filter cake is eluted with 20mL ice methanol, drains, collects filter cake,
Collection material is weighed after drying 6 hours under 60 DEG C of vacuum.
Prednisolone valerate acetate finished weight obtained is 19g, and yield 95% detects through HPLC, finished product it is pure
Degree is 99.7%.
Embodiment 4, prednisolone valerate acetate chemical synthesis process
Preparation method is substantially the same manner as Example 1, and difference is,
S5: being cooled to 25 DEG C for the prednival crude product of step S4, and 0.12g diformazan is then added in reaction flask
Base aminopyridine, 10mL pyridine, 10mL aceticanhydride, control reaction temperature are 25 DEG C, and insulated and stirred is reacted 1 hour, and reactant is detected
Content≤0.5wt% of prednival, i.e. fully reacting obtain prednisolone valerate acetate crude product in system.
S6: 100mL water being added into the prednisolone valerate acetate crude product of step S5, stirs 5 minutes, stratification,
Circulate operation 1 time, collection is organic to be added to 100mL ethyl alcohol and a small amount of diatomite, is warming up to 40 ± 2 DEG C, and stirring is decolourized 2 hours,
Filtering washs filter cake, merging filtrate with 20mL methylene chloride, and air-distillation to material is precipitated, and the dissolution of 240mL ethyl alcohol is added, after
Continuous air-distillation to reaction temperature is greater than 78 DEG C, then concentration terminates.First reaction temperature is cooled to less than 40 DEG C, then ice with tap water
Brine freezing is cooled to 0~5 DEG C, and stirring filters after 2 hours, and filter cake is eluted with 20mL ice methanol, drains, collects filter cake, 40
Under DEG C vacuum it is 10 hours dry after collection material weigh.
Prednisolone valerate acetate finished weight obtained is 21g, and yield 105% detects through HPLC, finished product it is pure
Degree is 99.5%.
Embodiment 5, prednisolone valerate acetate chemical synthesis process
Preparation method is substantially the same manner as Example 1, and difference is,
S5: being cooled to 20 DEG C for the prednival crude product of step S4, and 0.12g diformazan is then added in reaction flask
Base aminopyridine, 10mL pyridine, 10mL aceticanhydride, control reaction temperature are 20 DEG C, and insulated and stirred is reacted 8 hours, and reactant is detected
Content≤0.5wt% of prednival, i.e. fully reacting obtain prednisolone valerate acetate crude product in system.
S6: 100mL water being added into the prednisolone valerate acetate crude product of step S5, stirs 5 minutes, stratification,
Circulate operation 5 times, collection is organic to be added to 100mL acetone and a small amount of active carbon, is warming up to 40 ± 2 DEG C, and stirring is decolourized 2 hours,
Filtering washs filter cake, merging filtrate with 20mL methylene chloride, and air-distillation to material is precipitated, and 240mL acetone solution is added, after
Continuous air-distillation to reaction temperature is greater than 58.5 DEG C, then concentration terminates.Then reaction temperature first is cooled to less than 40 with tap water
DEG C, then ice water frozen cooling, to 0~5 DEG C, stirring filters after 2 hours, and filter cake is eluted with 20mL ice methanol, drains, collects filter cake,
Collection material is weighed after drying 6 hours under 60 DEG C of vacuum.
Prednisolone valerate acetate finished weight obtained is 20g, and yield 100% detects through HPLC, finished product it is pure
Degree is 99.8%.
Embodiment 6, prednisolone valerate acetate chemical synthesis process
Preparation method is substantially the same manner as Example 1, and difference is,
Step S3: dilute sulfuric acid is uniformly mixed according to volume ratio 1:130 with water by 98% concentrated sulfuric acid and is made.
Prednisolone valerate acetate finished weight obtained is 22g, and yield 110% detects through HPLC, finished product it is pure
Degree is 99.5%.
Embodiment 7, prednisolone valerate acetate chemical synthesis process
Preparation method is substantially the same manner as Example 1, and difference is,
Step S3: dilute sulfuric acid is uniformly mixed according to volume ratio 1:170 with water by 98% concentrated sulfuric acid and is made.
Prednisolone valerate acetate finished weight obtained is 19, and yield 95% is detected through HPLC, the purity of finished product
It is 99.5%.
Embodiment 8, prednisolone valerate acetate chemical synthesis process
Preparation method is substantially the same manner as Example 1, and difference is,
Step S6: in the cooling step, the reaction system that concentration terminates directly is cooled to 0~5 DEG C.
Prednisolone valerate acetate finished weight obtained be 20, yield 100% is detected through HPLC, finished product it is pure
Degree is 99.6%.
Embodiment 9, prednisolone valerate acetate chemical synthesis process
Preparation method is substantially the same manner as Example 1, and difference is,
Step S4: the additional amount of dimethyl sulfoxide is 20ml, and the additional amount of water is 400ml, and organic phase is evaporated under reduced pressure to body
Product 210ml.
Prednisolone valerate acetate finished weight obtained is 19g, and yield 95% detects through HPLC, finished product it is pure
Degree is 99.7%.
Embodiment 10, prednisolone valerate acetate chemical synthesis process
Preparation method is substantially the same manner as Example 1, and difference is,
Step S4: organic phase is evaporated under reduced pressure to volume 190ml.
Prednisolone valerate acetate finished weight obtained is 20g, and yield 100% detects through HPLC, finished product it is pure
Degree is 99.6%.
Specific embodiments of the present invention are described in detail above, but it is only used as example, the present invention is not intended to limit
In particular embodiments described above.To those skilled in the art, it any equivalent modifications to the practical progress and replaces
In generation, is also all among scope of the invention.Therefore, without departing from the spirit and scope of the invention made by equal transformation and repair
Change, all should be contained within the scope of the invention.
Claims (12)
1. the chemical synthesis process of prednisolone valerate acetate, which is characterized in that including following preparation step:
S1: prednisolone q. s. methylene chloride and dimethyl sulfoxide dissolved clarification obtain dissolved clarification system, open nitrogen protection；
S2: p-methyl benzenesulfonic acid and original acid methyl ester being added into the dissolved clarification system of step S1, and control reaction temperature is 20~30
DEG C, it is stirred to react 1~2 hour, after fully reacting, obtains the reaction system containing cyclic ester object；The addition of the p-methyl benzenesulfonic acid
Amount is the 2.5~4% of prednisolone quality；The volume mass of the original acid methyl ester and prednisolone ratio be 1.5~
1.75ml/g；
S3: appropriate dilute sulfuric acid and organic cosolvent being added into the reaction system of step S2, and control reaction temperature is 20~30 DEG C,
It is stirred to react 1~2 hour, after fully reacting, obtains the mixed system containing prednival；
S4: appropriate dimethyl sulfoxide and water are added into the mixed system of step S3, lower layer's organic phase is collected in layering, organic to subtract each other
Distillation and concentration is pressed, suitable methylene chloride entrainment dehydration is added, obtains prednival crude product；
S5: being cooled to 20~30 DEG C for the prednival crude product of step S4, add dimethyl aminopyridine, pyridine,
Aceticanhydride, insulated and stirred are reacted 1~3 hour, after fully reacting, obtain prednisolone valerate acetate crude product；The dimethylamino
The additional amount of yl pyridines is the 0.6~0.75% of prednisolone quality；The volume mass of the pyridine and prednisolone ratio is 0.5
~0.6ml/g；The volume mass of the aceticanhydride and prednisolone ratio is 1.5~1.75ml/g；
S6: the prednisolone valerate acetate crude product of step S5 is added into suitable quantity of water stirring, layering, circulate operation 1~5 time, is collected
Organic phase, it is organic to be added to appropriate organic cosolvent, and a small amount of bleaching agent bleaching, filtering is added, the suitable dichloromethane of filter cake
Alkane washing, merging filtrate, filtrate air-distillation to material are precipitated, and add appropriate organic cosolvent dissolved matter, concentrated, drop
Temperature stirring, filters, washing, drying, obtains prednisolone valerate acetate.
2. the chemical synthesis process of prednisolone valerate acetate according to claim 1, which is characterized in that the step
In S1, the methylene chloride and dimethyl sulfoxide are added in the form of mixed solvent, the in the mixed solvent methylene chloride and diformazan
The volume ratio of base sulfoxide is (4~8): 1；The mixed solvent of addition and the volume mass ratio of prednisolone are 20~25ml/g.
3. the chemical synthesis process of prednisolone valerate acetate according to claim 1, which is characterized in that
In the step S2, detect in the reaction system containing cyclic ester object, content≤wt1% of reaction raw materials prednisolone, i.e.,
Fully reacting；
In the step S3, detect in the mixed system containing prednival, content≤1wt% of cyclic ester object, i.e., instead
It should be complete.
In the step S5, detect in the mixed system containing prednisolone valerate acetate, the content of prednival
≤ 0.5wt%, i.e. fully reacting.
4. the chemical synthesis process of prednisolone valerate acetate according to claim 1, which is characterized in that the step
In S3, the dilute sulfuric acid, according to volume ratio 1:130~170, is uniformly mixed and is made by 98% concentrated sulfuric acid and water；The dilute sulfuric acid
Volume mass ratio with prednisolone is 0.15~0.25ml/g.
5. the chemical synthesis process of prednisolone valerate acetate according to claim 1, which is characterized in that the step
It in S3, is added before dilute sulfuric acid, will first cool down containing the reaction system of cyclic ester object.
6. the chemical synthesis process of prednisolone valerate acetate according to claim 1, which is characterized in that the step
In S4, the volume mass ratio for carrying methylene chloride and prednisolone used secretly is 5~7.5ml/g.
7. the chemical synthesis process of prednisolone valerate acetate according to claim 6, which is characterized in that the step
In S4, methylene chloride is added and carries secretly to system moisture < 0.3wt%.
8. the chemical synthesis process of prednisolone valerate acetate according to claim 1, which is characterized in that the step
In S3, organic cosolvent is acetone or glacial acetic acid；In the step S6, the organic cosolvent is in methanol, ethyl alcohol and acetone
It is one or more.
9. the chemical synthesis process of prednisolone valerate acetate according to claim 1, which is characterized in that the step
In S6, the bleaching temperature is 40 ± 2 DEG C, and bleaching time is 2~12 hours.
10. the chemical synthesis process of prednisolone valerate acetate according to claim 1, which is characterized in that the step
In rapid S6, the cooling step uses substep cool-down method, is first cooled to reaction temperature less than 40 DEG C, then frozen cooling is to 0~5
℃。
11. the chemical synthesis process of prednisolone valerate acetate according to claim 1, which is characterized in that the step
In rapid S6, the concentration step is more than or equal to the boiling point of organic cosolvent as striking point using system temperature.
12. the chemical synthesis process of prednisolone valerate acetate according to claim 1, which is characterized in that the step
In rapid S6, the suitable quantity of water of addition and the volume mass ratio of starting material prednisolone are 4~6ml/g；The appropriate organic co-solvent being added
The volume mass ratio of agent and starting material prednisolone is 4~6ml/g.
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| US3147249A (en) * | 1961-06-13 | 1964-09-01 | Vismara Francesco Spa | 17alpha, 21-substituted methylenedioxy steroids and methods therefor |
| US4113680A (en) * | 1975-03-31 | 1978-09-12 | Taisho Pharmaceutical Co., Ltd. | Method for preparing 17 α-ester-21-halo pregnanes |
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| CN112851734A (en) * | 2019-11-27 | 2021-05-28 | 重庆华邦胜凯制药有限公司 | Preparation method of betamethasone dipropionate |
| CN112851734B (en) * | 2019-11-27 | 2024-02-06 | 重庆华邦胜凯制药有限公司 | Preparation method of betamethasone dipropionate |
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