CN109734766A - A kind of preparation method of Inflamase intermediate - Google Patents
A kind of preparation method of Inflamase intermediate Download PDFInfo
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- CN109734766A CN109734766A CN201910010072.7A CN201910010072A CN109734766A CN 109734766 A CN109734766 A CN 109734766A CN 201910010072 A CN201910010072 A CN 201910010072A CN 109734766 A CN109734766 A CN 109734766A
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Abstract
A kind of preparation method of Inflamase intermediate; the Inflamase intermediate is prednisolone phosphate shown in formula II; prednisolone is used to react for raw material with pyrophosphoryl chloride; reaction step is as follows: A, under nitrogen protection; chemical compounds I is added in organic solvent MTHP, stirring and dissolving, at -50 DEG C~-60 DEG C; pyrophosphoryl chloride, insulation reaction is slowly added dropwise；B, reaction terminates, and purified water is added and terminates reaction, stratification；Wherein, the stratification time is 2h~4h；C, organic purified water that is added to is extracted twice, and active carbon, heat preservation decoloration are then added in organic phase；Wherein, holding temperature is 30 DEG C~50 DEG C, bleaching time 1h~2h；D, it filters, is concentrated under reduced pressure, cooling discharge, vacuum drying obtains compound ii.This preparation method economy, environmental angle.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, in particular to a kind of Inflamase intermediate sprinkles
The preparation method of Ni Songlong phosphate, belongs to field of medicinal chemistry.
Background technique
Inflamase (Prednisolone Sodium Phosphate), chemical name are 11 β, 17-dihydroxies
Pregnant steroid-the Isosorbide-5-Nitrae of base -3,20- diketone-diene -21- disodium hydrogen phosphate, is one kind of Adrenal Glucocorticoid class drug, is mainly used for
Anti-inflammatory, antiallergy, Hemorrhagic shock, China, the U.S. and European Pharmacopoeia etc. record at present.
The preparation method of traditional Inflamase is with " national bulk pharmaceutical chemicals technique compilation " (country's medicine management
General bureau, 1 zero) in Inflamase technique be with reference to carry out, specifically by Mesylation, iodate, displacement,
It is obtained at salt, wherein in the preparation of prednisolone phosphate, reaction step is cumbersome, and side reaction is more, and has used poisonous reagent
Mesyl chloride and high ammonia nitrogen reagent pyridine, acetic acid piperazine etc., generate a large amount of waste water, environmental pollution is more serious.Chinese patent
CN201510758961.3, CN201410133362.8, CN200710061255.9 are related to analog dexamethasone sodium phosphate
Synthesis have very wherein at ester reaction being carried out with tetrahydrofuran (THF)/pyrophosphoryl chloride system compared to technique above-mentioned
Big improvement, but still remain many problems, including post-processing are complicated, organic solvent THF is unrecovered to be applied, react in produce
The voluminous object of acid there is destruction to cause more than side reaction and the defects of impurity content is high, does not meet energy conservation and environmental protection, Green Development
Theory, be also unfavorable for the raising of bulk pharmaceutical chemicals quality.
Summary of the invention
It is an object of the invention to overcome the above problem existing for current prednisolone phosphate, a kind of prednisone is provided
The preparation method of imperial sodium phosphate intermediate prednisolone phosphate.
To achieve the purpose of the present invention, using following technical solutions: a kind of system of Inflamase intermediate
Preparation Method, the Inflamase intermediate are prednisolone phosphate shown in formula II, using bold and vigorous Buddhist nun shown in formula I
Song Longwei raw material is reacted with pyrophosphoryl chloride, reaction equation are as follows:
Reaction step is as follows:
A, under nitrogen protection, chemical compounds I is added in organic solvent MTHP, stirring and dissolving, at -50 DEG C~-60 DEG C, is delayed
It is slow that pyrophosphoryl chloride, insulation reaction is added dropwise；Wherein, pyrophosphoryl chloride time for adding is 30min~1h, insulation reaction 50min~2h；
B, reaction terminates, and purified water is added and terminates reaction, stratification；Wherein, the stratification time is 2h~4h；
C, organic purified water that is added to is extracted twice, and active carbon, heat preservation decoloration are then added in organic phase；Wherein, heat preservation temperature
Degree is 30 DEG C~50 DEG C, bleaching time 1h~2h；
D, it filters, is concentrated under reduced pressure, cooling discharge, vacuum drying obtains compound ii；In this step, it is 50 DEG C that temperature, which is concentrated under reduced pressure,
~80 DEG C, vacuum drying temperature is 50 DEG C~80 DEG C；
Further；Feed ratio uses chemical compounds I: MTHP: pyrophosphoryl chloride=1:10 ~ 15:0.8~1.0(w/v/v in step A),
Feed ratio uses compound ii: purified water=1:1~2(w/v in step B)；Feed ratio uses compound ii in step C: purifying
Water: active carbon=1:3 ~ 6:0.05~0.1(w/v/w).
Positive advantageous effects of the invention are: this preparation method uses a kind of novel agent MTHP(4- methyl-four
Hydrogen pyrans) replace tetrahydrofuran to be reacted, taking full advantage of MTHP, to have the highly dissoluble for the THF that matches in excellence or beauty, high stability etc. excellent
Point, and it is miscible compared to THF and water, and MTHP and water mutual solubility are smaller, excessive after reaction terminates plus water quenches reaction
Pyrophosphoryl chloride and the acid that generates of water reaction enter water phase, realize efficiently separating for target product and acid, keep away
Exempt from destruction of the strong acid system to prednisolone phosphate, reduce the generation of side reaction, avoids the generation of impurity in product, instead
Should after can be realized the recovery of MTHP simultaneously, and existing THF system patented technology cannot achieve due to miscible with water
The efficient recovery of THF；From reaction step it is also apparent that.Post-reaction treatment of the present invention is simple, efficient, avoids
Numerous cumbersome post-processings, mass yield are more secure.The product HPLC content of this preparation method is not less than 99.4% after tested,
110% or more yield；The discharge of waste water is also reduced simultaneously, reaches energy-saving and environment-friendly purpose, no matter is imitated from technology, economy, generation
Rate or environmental angle suffer from unrivaled advantage.
Specific embodiment
In order to more fully explain implementation of the invention, embodiment of the invention is provided.These embodiments are only
Elaboration to the technique, does not limit the scope of the invention.
Raw material prednisolone used in the present invention can be directly obtained from market, and solid material metering is in the present invention with g(grams
Number) metering, indicated with material (g), liquid material is measured with ml(milliliters) metering, indicate that the ratio between material w/v refers to material (ml)
G:ml, w/w refer to that g:g, TLC refer to thin-layered chromatography, and HPLC refers to high performance liquid chromatography.In the present invention, MTHP refers to 4- methyl-tetrahydro
Pyrans, cas:4717-96-8.
Embodiment 1:
A, in reaction flask, prednisolone 50g, MTHP500ml is added under nitrogen protection, is cooled to -55~-60 under stirring
DEG C, pyrophosphoryl chloride 40ml is slowly added dropwise in 40min, finishes, insulation reaction 1h, TLC detection is without raw material point；
B, plus the quenching reaction of 100ml purified water, standing 2h are layered；
C, organic phase is extracted twice with 150ml purified water every time, and it is de- that 30 DEG C of 2.5g active carbon heat preservations are then added in organic phase
Color 1h；
D, it filters, 60 DEG C are concentrated under reduced pressure into paste, are cooled to 0 DEG C with bottom discharge, and 60 DEG C are dried under vacuum to constant weight, HPLC99.5%,
Largest single impurity 0.2%, yield 115.2%.
Embodiment 2:
A, in reaction flask, prednisolone 100g, MTHP1000ml is added under nitrogen protection, is cooled to -55~-60 under stirring
DEG C, pyrophosphoryl chloride 80ml is slowly added dropwise in 1h, finishes, insulation reaction 80min, TLC detection is without raw material point；
B, plus the quenching reaction of 200ml purified water, standing 3h are layered；
C, organic phase is extracted twice with 300ml purified water every time, and the 40 DEG C of heat preservation decolorations of 5g active carbon are then added in organic phase
1.5h；
D, it filters, 60 DEG C are concentrated under reduced pressure into paste, are cooled to 0 DEG C with bottom discharge, and 70 DEG C are dried under vacuum to constant weight, HPLC99.4%,
Largest single impurity 0.25%, yield 116.3%, wherein recycling MTHP800ml.
Embodiment 3:
A, in reaction flask, prednisolone 50g, recycling MTHP500ml are added under nitrogen protection, it is cooled to -55 under stirring~-
60 DEG C, pyrophosphoryl chloride 50ml is slowly added dropwise in 45min, finishes, insulation reaction 1h, TLC detection is without raw material point；
B, plus the quenching reaction of 75ml purified water, standing 3h are layered；
C, organic phase is extracted twice with 200ml purified water every time, and the 40 DEG C of heat preservation decolorations of 3g active carbon are then added in organic phase
1.5h；
D, it filters, 60 DEG C are concentrated under reduced pressure into paste, are cooled to 0 DEG C with bottom discharge, and 60 DEG C are dried under vacuum to constant weight, HPLC99.5%,
Largest single impurity 0.21%, yield 116.5%.
Embodiment 4:
A, in reaction flask, prednisolone 50g, MTHP500ml is added under nitrogen protection, is cooled to -55~-60 under stirring
DEG C, pyrophosphoryl chloride 45ml is slowly added dropwise in 40min, finishes, insulation reaction 1h, TLC detection is without raw material point；
B, plus the quenching reaction of 100ml purified water, standing 2h are layered；
C, organic phase is extracted twice with 150ml purified water every time, and it is de- that 50 DEG C of 2.5g active carbon heat preservations are then added in organic phase
Color 1h；
D, it filters, 60 DEG C are concentrated under reduced pressure into paste, are cooled to 0 DEG C with bottom discharge, and 65 DEG C are dried under vacuum to constant weight, HPLC99.6%,
Largest single impurity 0.24%, yield 116.7%.
Although inventor has done more detailed elaboration to technical solution of the present invention and has enumerated, it should be understood that right
For the those skilled in the art of this field one, modifications to the embodiments described above may be made, the flexible or equivalent alternative of use
Case be it is obvious, cannot all be detached from the essence of spirit of that invention, the term occurred in the present invention is used for inventive technique scheme
It illustrates and understands, can not be construed as limiting the invention.
Claims (2)
1. a kind of preparation method of Inflamase intermediate, the Inflamase intermediate is shown in formula II
Prednisolone phosphate, use prednisolone shown in formula I to react for raw material with pyrophosphoryl chloride, it is characterised in that: reaction equation
Are as follows:
Reaction step is as follows:
A, under nitrogen protection, chemical compounds I is added in organic solvent MTHP, stirring and dissolving, at -50 DEG C~-60 DEG C, is delayed
It is slow that pyrophosphoryl chloride, insulation reaction is added dropwise；Wherein, pyrophosphoryl chloride time for adding is 30min~1h, insulation reaction 50min~2h；
B, reaction terminates, and purified water is added and terminates reaction, stratification；Wherein, the stratification time is 2h~4h；
C, organic purified water that is added to is extracted twice, and active carbon, heat preservation decoloration are then added in organic phase；Wherein, heat preservation temperature
Degree is 30 DEG C~50 DEG C, bleaching time 1h~2h；
D, it filters, is concentrated under reduced pressure, cooling discharge, vacuum drying obtains compound ii；In this step, it is 50 DEG C that temperature, which is concentrated under reduced pressure,
~80 DEG C, vacuum drying temperature is 50 DEG C~80 DEG C.
2. a kind of preparation method of Inflamase intermediate according to claim 1, it is characterised in that: step A
Middle feed ratio is using chemical compounds I: MTHP: pyrophosphoryl chloride=1:10 ~ 15:0.8~1.0(w/v/v), feed ratio useization in step B
Close object II: purified water=1:1~2(w/v)；Feed ratio uses compound ii: purified water: active carbon=1:3 ~ 6:0.05 in step C
~0.1(w/v/w).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112094311A (en) * | 2020-10-16 | 2020-12-18 | 西安国康瑞金制药有限公司 | Process for preparing dexamethasone sodium phosphate by one-step method |
| CN112358525A (en) * | 2019-10-15 | 2021-02-12 | 河南利华制药有限公司 | Production process for synthesizing prednisolone phosphate by using tangential flow tubular reactor |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3764616A (en) * | 1968-10-14 | 1973-10-09 | Glaxo Lab Ltd | 21-phosphate esters of 17{60 -acyloxy-21 hydroxy steroids of the pregnane series |
| JP2015017071A (en) * | 2013-07-12 | 2015-01-29 | 株式会社クラレ | Method for producing ester by using 4-methyltetrahydrofuran as solvent |
| JP2015017074A (en) * | 2013-07-12 | 2015-01-29 | 株式会社クラレ | 4-methyltetrahydropyran composition |
| CN104744543A (en) * | 2013-12-26 | 2015-07-01 | 重庆华邦制药有限公司 | Preparation method of pregnenolone phosphate derivatives and their salts |
| CN105801650A (en) * | 2016-04-13 | 2016-07-27 | 浙江仙琚制药股份有限公司 | Method for preparing prednisolone |
-
2019
- 2019-01-07 CN CN201910010072.7A patent/CN109734766B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3764616A (en) * | 1968-10-14 | 1973-10-09 | Glaxo Lab Ltd | 21-phosphate esters of 17{60 -acyloxy-21 hydroxy steroids of the pregnane series |
| JP2015017071A (en) * | 2013-07-12 | 2015-01-29 | 株式会社クラレ | Method for producing ester by using 4-methyltetrahydrofuran as solvent |
| JP2015017074A (en) * | 2013-07-12 | 2015-01-29 | 株式会社クラレ | 4-methyltetrahydropyran composition |
| CN104744543A (en) * | 2013-12-26 | 2015-07-01 | 重庆华邦制药有限公司 | Preparation method of pregnenolone phosphate derivatives and their salts |
| CN105801650A (en) * | 2016-04-13 | 2016-07-27 | 浙江仙琚制药股份有限公司 | Method for preparing prednisolone |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358525A (en) * | 2019-10-15 | 2021-02-12 | 河南利华制药有限公司 | Production process for synthesizing prednisolone phosphate by using tangential flow tubular reactor |
| CN112358525B (en) * | 2019-10-15 | 2022-02-01 | 河南利华制药有限公司 | Preparation method of prednisolone sodium phosphate intermediate prednisolone phosphate |
| CN112094311A (en) * | 2020-10-16 | 2020-12-18 | 西安国康瑞金制药有限公司 | Process for preparing dexamethasone sodium phosphate by one-step method |
| CN112094311B (en) * | 2020-10-16 | 2022-04-08 | 西安国康瑞金制药有限公司 | Process for preparing dexamethasone sodium phosphate by one-step method |
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