CN107602652A - The method for preparing 6 β methylprednisolones - Google Patents
The method for preparing 6 β methylprednisolones Download PDFInfo
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Abstract
The invention discloses a kind of method for preparing 6 β methylprednisolones, using 6 methyl epoxy materials as raw material, by grignard, hydrolysis, elimination, 6 β methyl of generation eliminate thing, then fermented dehydrogenation, upper iodine, displacement, hydrolysis, prepare liquid phase and purify to obtain 6 β methylprednisolones.Reaction equation is as follows：
Description
Technical field
The present invention relates to a kind of preparation method of chemicals, more particularly to a kind of method for preparing 6 Beta-methyl prednisolones.
Background technology
Methylprednisolone belongs to glucocorticoids medicine, the first aid for critical illness, it may also be used for endocrinopathy,
Rheumatic disease, collagen venereal disease, disease of skin, allergic reaction, ophthalmology disease, enterogastric diseases, hematologic disease, leukaemia, stop
Gram, encephaledema, polyneuritis, myelitis and prevent vomiting etc. caused by cancer chemotherapy.Clinically it is mainly used at present dirty
Device is transplanted.6 Beta-methyl prednisolones are an important impurity in methylprednisolone finished product, without pharmacological activity.In order to more
The quality of good control methylprednisolone, it is necessary to be controlled to impurity therein, therefore prepare the material as reference substance
It is necessary.
Because the synthesis and purifying of 6 Beta-methyl prednisolones have very big technology barrier, so there is presently no special
The method for preparing 6 Beta-methyl prednisolones, it is badly in need of developing a kind of method for preparing 6 Beta-methyl prednisolones, it is high-purity to prepare
6 Beta-methyl prednisolone reference substances of degree, are control effectively to the impurity of methylprednisolone using it, finally improve methyl
The purity and pharmacological activity of prednisolone.
The content of the invention
The purpose of the present invention is to solve that 6 Beta-methyl prednisolone reference substances can not be prepared at present, so as to be difficult to ensure that first
The purity of base prednisolone and the technical problem of pharmacological activity.
In order to solve the above-mentioned technical problem, the present invention provides a kind of method for preparing 6 Beta-methyl prednisolones, and its feature exists
In comprising the following steps：
（1）Grignard, hydrolysis, elimination reaction：Tetrahydrofuran, magnesium sheet are added in dry RMgBr prepares bottle, is passed through a chlorine
Methane boils off tetrahydrofuran after certain time, is passed through nitrogen protection, stand-by；6- methyl epoxy material 1, tetrahydrochysene are added in reaction bulb
Furans, RMgBr is slowly added to, is heated to reflux to reaction completely, being cooled to less than 20 DEG C, obtaining grignard thing 2；In hydrolysis
Glacial acetic acid, ice cube, dichloroethanes are added in bottle, stirring, is slowly added to grignard thing 2, continues stirring to dissolved clarification, under being removed after standing
Layer aqueous phase；Methanol is added in organic phase, aqueous sulfuric acid is added dropwise, stirring at normal temperature obtains hydrolysate 3 to after reacting completely., slowly
Aqueous alkali is added dropwise, adjusts pH value, heating response certain time, while the pH value of regulation in average every 15 minutes, makes system pH
It is maintained at certain value, sampling monitoring HPLC control reaction ends；PH value is adjusted to 6~7 with aqueous acid；The removing that is concentrated under reduced pressure has
Machine phase, add water elutriation, stir, filter, obtaining 6 Beta-methyls in 60 DEG C of baking materials eliminates thing 4；Reaction equation is
；
（2）Dehydrogenation reaction：The first step is seed culture：It is substrate to be added in the fermentation tank of jacketed and eliminate thing 4 with 6 Beta-methyls
Fermentation medium, feed, sterilizing, be cooled to certain temperature, access a certain amount of Arthrobacter simplex and fermented；Fermentation is divided to two
The individual stage：First stage is the thalli growth stage：Inoculation, certain temperature and air mass flow are adjusted, cultivate certain time, bacterium is dense
OD620When reaching certain value, fed intake；Second stage is the microorganism conversion stage：Feed intake, adjust certain temperature and air stream
Amount, converts certain time, and fermentation is completed；Second step is Hydrolysis kinetics：Zymotic fluid is carried out to be filtrated to get fermentation filter cake, to fermentation
Filter cake carries out Hydrolysis kinetics using acetone-water mixed solvent, and extract solution is concentrated under reduced pressure, obtains 6 Beta-methyl dehydrogen substances 5；
Reaction equation is
；
（3）Upper Iod R：Prepare iodine solution：Iodine, anhydrous calcium chloride, methanol input iodine solution are prepared into bottle, stirring；In upper Iod R bottle
In, 6 Beta-methyl dehydrogen substances 5 of input, methanol, stirring add anhydrous calcium chloride, stirring cooling, add calcium oxide, stirring cooling；Keep away
Iodine solution is added dropwise in light, and insulation reaction is complete to reaction；Pour into aqueous acetic acid, stir, elutriation discharging, obtain iodine thing on 6 Beta-methyls
6a and 6b mixture；Reaction equation is
；
（4）Displacement reaction：By acetone, triethylamine input displacement reaction bulb, cooling, acetic acid is added dropwise, insulated and stirred, adds 6 β-first
Iodine thing 6a and 6b mixture on base, agitating and heating, after being incubated 2~3 hours, heating reflux reaction 2~3 hours；Reaction terminates,
It is concentrated to dryness, elutriation discharging, vacuum drying obtains 6 Beta-methyl substitutes 7；Reaction equation is
；
（5）Hydrolysis：The preparation of alkali lye：Methanol is put into Alkali liquid compounding bottle and sodium hydroxide, stirring and dissolving are standby；
Methanol and 6 Beta-methyl substitutes 7 are put into hydrolysis bottle, start to stir, sodium hydroxide-methanol solution is added dropwise, drop finishes after 5
~10 DEG C of insulation reactions 2~3 hours, add glacial acetic acid and be neutralized to pH as 6.0~6.2, concentrate near dry, elutriation discharging, vacuum is dried
Do to obtain 6 Beta-methyl prednisolone crude products 8；Reaction equation is
；
（6）Purified with liquid phase is prepared, obtain 6 Beta-methyl prednisolone fine work.
Further, step（1）Described in elimination reaction, aqueous alkali is sodium hydrate aqueous solution and potassium hydroxide water
One kind or its mixture in solution；The aqueous acid is that the one or more in acetic acid, hydrochloric acid, sulfuric acid and phosphoric acid are mixed
The aqueous solution of compound；
Further, step（1）Described in elimination reaction, the pH value of the aqueous alkali regulation is 8~10, and reaction temperature is
30~65 DEG C, 4~24 hours reaction time.
Further, step（6）Described in prepare liquid phase stationary phase be C18, mobile phase is acetonitrile-water, and flow velocity is
20mL/min。
Further, the step（6）In, flow visualizing is acetonitrile-water, and condition of gradient elution is as follows：
。
Further, the step（6）In, chromatographic column filler is octadecyl silane, Detection wavelength 254nm.
The present invention eliminates thing, then fermented dehydrogenation, upper iodine, displacement, water by grignard, hydrolysis, elimination, 6 Beta-methyls of generation
Solution, preparation liquid phase are purified to obtain 6 Beta-methyl prednisolone high-purity reference substances, and the impurity of methylprednisolone can be entered using it
Row effectively control, finally greatly improve the purity and pharmacological activity of methylprednisolone.
Embodiment
Presently in connection with embodiment, the present invention is further detailed explanation, and application of the invention is not limited to following
Embodiment, any formal accommodation done to the present invention fall within protection scope of the present invention.
In following embodiments, the grignard of the first step, hydrolysis, the reaction equation of elimination reaction are：
；
The reaction equation of the dehydrogenation reaction of second step is：
；
The reaction equation of the upper Iod R of 3rd step is：
；
4th step displacement reaction reaction equation be：
The reaction equation of the hydrolysis of 5th step is：
。
Embodiment 1
The first step, grignard, hydrolysis, elimination：In 250mL dry reaction bottles, tetrahydrofuran is added（53mL, 5.3V）, add
Magnesium sheet（6.7g, 0.67W）, lead to monochloro methane to being rapidly heated to 55~61 DEG C, cool to reacting balance.By tetrahydrofuran
（80mL, 8V）Reaction bulb is added, is incubated 30~50 DEG C of ventilations to magnesium dissolved clarification, then is ventilated 6~8 hours, is about passed through monochloro methane
（20g, 2W）, closed preservation.Then normal pressure concentration boils off tetrahydrofuran to being warming up to 71~74 DEG C.Protected after being down to room temperature with nitrogen
Shield, it is closed stand-by.Tetrahydrofuran is added in 250mL reaction bulbs（20mL, 2V）, 6- methyl epoxy material 1 (10g, 1W) is added, is stirred
Mix 20~30 minutes, be then slowly added into RMgBr（60mL, 6V）, heat temperature raising flow back 4~5 hours, be cooled to 20 DEG C with
Under；Glacial acetic acid is added in 500mL reaction bulbs（20mL, 2V）, ice cube（66.7g 6.67W）, dichloroethanes（40mL, 4V）, open
Stirring is made into mixed liquor, and then grignard reaction liquid is slowly dropped into reaction bulb, stirring 30 minutes with the complete dissolved clarification of up to system,
1~3 hour is stood again, is extracted, lower aqueous layer is discarded, it is that reaction solution is poured into 500mL reaction bulbs to stay upper organic layer.Add
Enter methanol（60mL, 6V）, the mix acid liquor 7.7mL (water that then will prepare:Sulfuric acid=1V:0.54V）Add in reaction solution, body
System gradually separates out white solid, in 20~30 DEG C of insulation reactions 2~3 hours, starts elimination reaction after reacting completely.It is slowly added dropwise
NaOH solution (NaOH:H2O=1W:3V) tune pH value adjusted a pH value 9, average every 15 minutes, is heated to reflux 6 hours, makes body
It is that pH is maintained at 9, reflux temperature is controlled at 60~65 DEG C, sampling HPLC control reaction ends.With glacial acetic acid adjust pH value to 6~
7.It is concentrated under reduced pressure and removes organic phase, adds water（100mL, 10V）Elutriation, in 5 DEG C of 0.5h stirred below, filter, in 60 DEG C of baking materials, obtain
6 Beta-methyls eliminate thing 4（7.5g, 75%）Product HPLC (254nm, 74%).
Second step, dehydrogenation reaction：Fermentation medium components：Glucose 7g/L, yeast extract 7 g/L, corn steep liquor 11g/L, phosphorus
The g/L of acid dihydride potassium 1, PH=7.3, substrate are that 6 Beta-methyls eliminate thing 4, and during the fermentation, Arthrobacter simplex is by the Beta-methyl of first 6
Eliminate thing 4 and carry out oxidative dehydrogenation, obtain 6 Beta-methyl dehydrogen substances 5.
Fermentation process is as follows：Secondary seed culture, culture medium, coefficient are added in the 10L fermentation tanks of jacketed
0.6, sterilizing, 32 DEG C are cooled to, access Arthrobacter simplex, inoculum concentration 9%, fermentation is in two stages：1. the thalli growth stage：
After inoculation, air mass flow 1.0m3/h is adjusted, 32 DEG C of temperature, cultivates 9h, the dense OD of monitoring bacterium620=36%, fed intake.2. microorganism
Transformation stage：Feed concentrations 1g/L, throw 6 Beta-methyls and eliminate thing 4（7.5g, 1W）, adjust air mass flow 0.5m3/h, temperature 34
DEG C, transformation time 36h, conversion ratio 95%.
Hydrolysis kinetics：Zymotic fluid is filtered, and fermentation filter cake carries out Hydrolysis kinetics using 85% acetone-water mixed solvent, carries
Take liquid to be concentrated under reduced pressure, obtain 6 Beta-methyl dehydrogen substances 5 (6.37g, 84.9%), product HPLC (254nm, 72%).
3rd step, upper Iod R：Prepare iodine solution：By iodine（6.1g, 0.96W）, anhydrous calcium chloride（1.30g 0.2W）, methanol
（25mL3.92V）Put into 50mL iodine solutions and prepare bottle, stir more than 30 minutes.
On 250mL in Iod R bottle, 6 Beta-methyl dehydrogen substances 5 are put into（6.37g 1W）, methanol（64mL, 10V）, stirring
30 minutes.Add anhydrous calcium chloride（0.77g, 0.12W）, stir and be cooled to about 10 DEG C, add calcium oxide（3.20g 0.50W）,
Stirring is cooled to 0~6 DEG C.Iodine solution is added dropwise in lucifuge, adjusts rate of addition with colour fading speed, 0~6 DEG C of keeping temperature, drips within about 1 hour
Add complete.0~6 DEG C of insulation reaction is continued at after dripping off about 3 hours.On 1000mL in iodine elutriation reaction bulb, drinking water is added
（637mL, 10V）With glacial acetic acid（6.25mL 0.98V）, be cooled to less than 10 DEG C it is standby.Upper Iod R liquid is poured into upper iodine elutriation
Bottle carries out acid out, stir about 30 minutes, stands more than 1 hour, below 10 DEG C of temperature.Filtering, drain overnight, directly cast step and put
Change reaction.Sampling detection, obtains (the 8.69g of iodine thing 6 on 6 Beta-methyls（It is wet）, 136%), product 6a HPLC (254nm, 65%),
6bHPLC (254nm,5%).Avoid light place.
4th step, displacement reaction：Acetone (79mL, 9V), triethylamine (9.48mL, 1.1V) input 250mL displacement reaction bulbs,
0~10 DEG C is cooled to, acetic acid (6.32mL, 0.73V) is added dropwise.Temperature is controlled below 10 DEG C.Stirring insulation 30 minutes after dripping off.
Add iodine thing 6a and 6b mixtures on 6 Beta-methyls（8.69g 1W）, 20~25 DEG C of agitating and heating, 2~3 hours are incubated, rear heating
To 56~60 DEG C of back flow reactions 2~3 hours.Reaction terminates, and normal pressure concentrates 0.5 hour, is concentrated under reduced pressure（Vacuum 0.04~
0.09MPa）, 60 DEG C or so are heated to, then rush plus water 100mL, are concentrated into untill the basic no liquid of condenser flows down.Addition is drunk
Water (50mL, 5.75V) elutriation, is cooled to 0~5 DEG C.Filtering, filter cake are rinsed with drinking water, are filtered dry.In heated-air circulation oven 55 ~
65 DEG C of dryings 12 hours.Obtain 6 Beta-methyl substitutes 7（7g, 80%）Product HPLC (254nm, 65%).
5th step, hydrolysis：The preparation of alkali lye：Methanol (14mL, 2V) and sodium hydroxide are put into Alkali liquid compounding bottle
(0.29g, 0.41), stir about dissolves for 1 hour, standby.Methanol (175mL, 25V) and 6 Beta-methyls are put into hydrolysis bottle
Substitute 7 (7g, 1W), opens stirring, is passed through nitrogen, and flow is controlled in 0.5~0.7m3/ h, 5~10 DEG C are cooled to, hydrogen-oxygen is added dropwise
Change sodium-methanol solution, dropping temperature is 5~10 DEG C, time for adding 10~15 minutes.Drop finish after 5~10 DEG C of insulation reactions 2~
3 hours, it was 6.0~6.2 to add glacial acetic acid (0.56mL, 0.08V) and be neutralized to pH, closes nitrogen.It is concentrated under reduced pressure near dry（Vacuum
0.04~0.09MPa）, with water (35mL, 5V) elutriation, it is cooled to 0~5 DEG C.Filtering, it is dry in 55~65 DEG C of heated-air circulation oven
Dry 12 hours.Obtain 6 Beta-methyl prednisolone crude products 8（6.23g 89%）Product HPLC (254nm, 60%).
6th step, purified with liquid phase is prepared:The stationary phase for preparing liquid phase is C18, and mobile phase is to be containing acetonitrile-water, flow velocity
20mL/min, isolate and purify 6 Beta-methyl prednisolone crude products 8（6.23g）, purity HPLC (254nm, 60%).
Flow visualizing is acetonitrile-water, and condition of gradient elution is as follows：
Chromatographic column filler is octadecyl silane, Detection wavelength 254nm.
Obtained preparation solution concentration removes organic solvent, and water freezes.Obtain 6 Beta-methyl prednisolone fine work（2.5g
40%）, product HPLC (254nm, 99.8%).
Embodiment 2
The first step, grignard, hydrolysis, elimination：In 250mL dry reaction bottles, tetrahydrofuran is added（53mL, 5.3V）, add
Magnesium sheet（6.7g, 0.67W）, lead to monochloro methane to being rapidly heated to 55~61 DEG C, cool to reacting balance.By tetrahydrofuran
（80mL, 8V）Reaction bulb is added, is incubated 30~50 DEG C of ventilations to magnesium dissolved clarification, then is ventilated 6~8 hours, is about passed through monochloro methane
（20g, 2W）, closed preservation.Then normal pressure concentration boils off tetrahydrofuran to being warming up to 71~74 DEG C.Protected after being down to room temperature with nitrogen
Shield, it is closed stand-by.Tetrahydrofuran is added in 250mL reaction bulbs（20mL, 2V）, 6- methyl epoxy material 1 (10g, 1W) is added, is stirred
Mix 20~30 minutes, be then slowly added into RMgBr（60mL, 6V）, heat temperature raising flow back 4~5 hours, be cooled to 20 DEG C with
Under；Glacial acetic acid is added in 500mL reaction bulbs（20mL, 2V）, ice cube（66.7g 6.67W）, dichloroethanes（40mL, 4V）, open
Stirring is made into mixed liquor, and then grignard reaction liquid is slowly dropped into reaction bulb, stirring 30 minutes with the complete dissolved clarification of up to system,
1~3 hour is stood again, is extracted, lower aqueous layer is discarded, it is that reaction solution is poured into 500mL reaction bulbs to stay upper organic layer.Add
Enter methanol（60mL, 6V）, the mix acid liquor 7.7mL (water that then will prepare:Sulfuric acid=1V:0.54V）Add in reaction solution, body
System gradually separates out white solid, in 20~30 DEG C of insulation reactions 2~3 hours, starts elimination reaction after reacting completely.It is slowly added dropwise
KOH solution (KOH:H2O=1W:3V) tune pH value adjusted a pH value 8, average every 15 minutes, is heated to reaction 24 hours, makes
System pH is maintained at 8, and temperature control is at 30~40 DEG C, sampling HPLC control reaction ends.PH value is adjusted to 6 with aqueous hydrochloric acid solution
~7.It is concentrated under reduced pressure and removes organic phase, adds water（100mL, 10V）Elutriation, in 5 DEG C of 0.5h stirred below, filter, in 60 DEG C of baking materials,
Obtain 6 Beta-methyls and eliminate thing 4（6.6g, 66%）Product HPLC (254nm, 60%).
Other steps are the same as embodiment 1.
Embodiment 3
The first step, grignard, hydrolysis, elimination：In 250mL dry reaction bottles, tetrahydrofuran is added（53mL, 5.3V）, add
Magnesium sheet（6.7g, 0.67W）, lead to monochloro methane to being rapidly heated to 55~61 DEG C, cool to reacting balance.By tetrahydrofuran
（80mL, 8V）Reaction bulb is added, is incubated 30~50 DEG C of ventilations to magnesium dissolved clarification, then is ventilated 6~8 hours, is about passed through monochloro methane
（20g, 2W）, closed preservation.Then normal pressure concentration boils off tetrahydrofuran to being warming up to 71~74 DEG C.Protected after being down to room temperature with nitrogen
Shield, it is closed stand-by.Tetrahydrofuran is added in 250mL reaction bulbs（20mL, 2V）, 6- methyl epoxy material 1 (10g, 1W) is added, is stirred
Mix 20~30 minutes, be then slowly added into RMgBr（60mL, 6V）, heat temperature raising flow back 4~5 hours, be cooled to 20 DEG C with
Under；Glacial acetic acid is added in 500mL reaction bulbs（20mL, 2V）, ice cube（66.7g 6.67W）, dichloroethanes（40mL, 4V）, open
Stirring is made into mixed liquor, and then grignard reaction liquid is slowly dropped into reaction bulb, stirring 30 minutes with the complete dissolved clarification of up to system,
1~3 hour is stood again, is extracted, lower aqueous layer is discarded, it is that reaction solution is poured into 500mL reaction bulbs to stay upper organic layer.Add
Enter methanol（60mL, 6V）, the mix acid liquor 7.7mL (water that then will prepare:Sulfuric acid=1V:0.54V）Add in reaction solution, body
System gradually separates out white solid, in 20~30 DEG C of insulation reactions 2~3 hours, starts elimination reaction after reacting completely.It is slowly added dropwise
NaOH solution (NaOH:H2O=1W:3V) tune pH value adjusted a pH value 10, average every 15 minutes, heating response 4 hours, made
System pH is maintained at 10, and temperature control is at 40~45 DEG C, sampling HPLC control reaction ends.Arrived with aqueous sulfuric acid regulation pH value
6~7.It is concentrated under reduced pressure and removes organic phase, adds water（100mL, 10V）Elutriation, in 5 DEG C of 0.5h stirred below, filter, in 60 DEG C of bakings
Material, obtain 6 Beta-methyls and eliminate thing 4（6.0g, 60%）Product HPLC (254nm, 58%).
Other steps are the same as embodiment 1.
Embodiment 4
The first step, grignard, hydrolysis, elimination：In 250mL dry reaction bottles, tetrahydrofuran is added（53mL, 5.3V）, add
Magnesium sheet（6.7g, 0.67W）, lead to monochloro methane to being rapidly heated to 55~61 DEG C, cool to reacting balance.By tetrahydrofuran
（80mL, 8V）Reaction bulb is added, is incubated 30~50 DEG C of ventilations to magnesium dissolved clarification, then is ventilated 6~8 hours, is about passed through monochloro methane
（20g, 2W）, closed preservation.Then normal pressure concentration boils off tetrahydrofuran to being warming up to 71~74 DEG C.Protected after being down to room temperature with nitrogen
Shield, it is closed stand-by.Tetrahydrofuran is added in 250mL reaction bulbs（20mL, 2V）, 6- methyl epoxy material 1 (10g, 1W) is added, is stirred
Mix 20~30 minutes, be then slowly added into RMgBr（60mL, 6V）, heat temperature raising flow back 4~5 hours, be cooled to 20 DEG C with
Under；Glacial acetic acid is added in 500mL reaction bulbs（20mL, 2V）, ice cube（66.7g 6.67W）, dichloroethanes（40mL, 4V）, open
Stirring is made into mixed liquor, and then grignard reaction liquid is slowly dropped into reaction bulb, stirring 30 minutes with the complete dissolved clarification of up to system,
1~3 hour is stood again, is extracted, lower aqueous layer is discarded, it is that reaction solution is poured into 500mL reaction bulbs to stay upper organic layer.Add
Enter methanol（60mL, 6V）, the mix acid liquor 7.7mL (water that then will prepare:Sulfuric acid=1V:0.54V）Add in reaction solution, body
System gradually separates out white solid, in 20~30 DEG C of insulation reactions 2~3 hours, starts elimination reaction after reacting completely.It is slowly added dropwise
NaOH solution (NaOH:H2O=1W:3V) tune pH value adjusted a pH value 9, average every 15 minutes, is heated to reflux 6 hours, makes body
It is that pH is maintained at 9, reflux temperature is controlled at 60~65 DEG C, sampling HPLC control reaction ends.PH value is adjusted with phosphate aqueous solution
To 6~7.It is concentrated under reduced pressure and removes organic phase, adds water（100mL, 10V）Elutriation, in 5 DEG C of 0.5h stirred below, filter, in 60 DEG C of bakings
Material, obtain 6 Beta-methyls and eliminate thing 4（7.4g, 74%）Product HPLC (254nm, 72%).
Other steps are the same as embodiment 1.
Obtained 6 Beta-methyl prednisolones in various embodiments above are detected, mass spectrum：m/z 375 (M+H+), melt
Point：240-244oC, compareed with 6 Beta-methyl prednisolone reference materials, comply fully with the characteristic of 6 Beta-methyl prednisolones.
It is complete by above-mentioned description, relevant staff using the above-mentioned desirable embodiment according to the present invention as enlightenment
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property scope is not limited to the content on specification, it is necessary to determines its technical scope according to right.
Claims (6)
1. prepare the method for 6 Beta-methyl prednisolones, it is characterised in that comprise the following steps：
（1）Grignard, hydrolysis, elimination reaction：Tetrahydrofuran, magnesium sheet are added in dry RMgBr prepares bottle, is passed through a chlorine
Methane boils off tetrahydrofuran after certain time, is passed through nitrogen protection, stand-by；6- methyl epoxy material 1, tetrahydrochysene are added in reaction bulb
Furans, RMgBr is slowly added to, is heated to reflux to reaction completely, being cooled to less than 20 DEG C, obtaining grignard thing 2；In hydrolysis
Glacial acetic acid, ice cube, dichloroethanes are added in bottle, stirring, is slowly added to grignard thing 2, continues stirring to dissolved clarification, under being removed after standing
Layer aqueous phase；Methanol is added in organic phase, aqueous sulfuric acid is added dropwise, stirring at normal temperature obtains hydrolysate 3 to after reacting completely；
Aqueous alkali is slowly added dropwise, adjusts pH value, heating response certain time, while the pH value of regulation in average every 15 minutes,
System pH is set to be maintained at certain value, sampling monitoring HPLC control reaction ends；PH value is adjusted to 6~7 with aqueous acid；Depressurize dense
Contracting removes organic phase, adds water elutriation, stirs, and filters, and obtaining 6 Beta-methyls in 60 DEG C of baking materials eliminates thing 4；Reaction equation is
；
（2）Dehydrogenation reaction：The first step is seed culture：It is substrate to be added in the fermentation tank of jacketed and eliminate thing 4 with 6 Beta-methyls
Fermentation medium, feed, sterilizing, be cooled to certain temperature, access a certain amount of Arthrobacter simplex and fermented；Fermentation is divided to two
The individual stage：First stage is the thalli growth stage：Inoculation, certain temperature and air mass flow are adjusted, cultivate certain time, bacterium is dense
OD620When reaching certain value, fed intake；Second stage is the microorganism conversion stage：Feed intake, adjust certain temperature and air stream
Amount, converts certain time, and fermentation is completed；Second step is Hydrolysis kinetics：Zymotic fluid is carried out to be filtrated to get fermentation filter cake, to fermentation
Filter cake carries out Hydrolysis kinetics using acetone-water mixed solvent, and extract solution is concentrated under reduced pressure, obtains 6 Beta-methyl dehydrogen substances 5；
Reaction equation is
；
（3）Upper Iod R：Prepare iodine solution：Iodine, anhydrous calcium chloride, methanol input iodine solution are prepared into bottle, stirring；In upper Iod R bottle
In, 6 Beta-methyl dehydrogen substances 5 of input, methanol, stirring add anhydrous calcium chloride, stirring cooling, add calcium oxide, stirring cooling；Keep away
Iodine solution is added dropwise in light, and insulation reaction is complete to reaction；Pour into aqueous acetic acid, stir, elutriation discharging, obtain iodine thing on 6 Beta-methyls
6a and 6b mixture；Reaction equation is
；
（4）Displacement reaction：By acetone, triethylamine input displacement reaction bulb, cooling, acetic acid is added dropwise, insulated and stirred, adds 6 β-first
Iodine thing 6a and 6b mixture on base, agitating and heating, after being incubated 2~3 hours, heating reflux reaction 2~3 hours；Reaction terminates,
It is concentrated to dryness, elutriation discharging, vacuum drying obtains 6 Beta-methyl substitutes 7；Reaction equation is
；
（5）Hydrolysis：The preparation of alkali lye：Methanol is put into Alkali liquid compounding bottle and sodium hydroxide, stirring and dissolving are standby；
Methanol and 6 Beta-methyl substitutes 7 are put into hydrolysis bottle, start to stir, sodium hydroxide-methanol solution is added dropwise, drop finishes after 5
~10 DEG C of insulation reactions 2~3 hours, add glacial acetic acid and be neutralized to pH as 6.0~6.2, concentrate near dry, elutriation discharging, vacuum is dried
Do to obtain 6 Beta-methyl prednisolone crude products 8；Reaction equation is
；
（6）Purified with liquid phase is prepared, obtain 6 Beta-methyl prednisolone fine work.
2. according to the method for claim 1, it is characterised in that step（1）Described in elimination reaction, aqueous alkali is hydrogen
One kind or its mixture in aqueous solution of sodium oxide and potassium hydroxide aqueous solution；The aqueous acid be acetic acid, hydrochloric acid, sulfuric acid and
The aqueous solution of one or more kinds of mixtures in phosphoric acid.
3. according to the method for claim 1, it is characterised in that step（1）Described in elimination reaction, the aqueous alkali
The pH value of regulation is 8~10, and reaction temperature is 30~65 DEG C, 4~24 hours reaction time.
4. according to the method for claim 1, it is characterised in that step（6）Described in prepare liquid phase stationary phase be C18,
Mobile phase is acetonitrile-water, flow velocity 20mL/min.
5. according to the method for claim 4, it is characterised in that the step（6）In, flow visualizing is acetonitrile-water, ladder
It is as follows to spend elution requirement：
。
6. according to the method for claim 5, it is characterised in that the step（6）In, chromatographic column filler is octadecyl key
Close silica gel, Detection wavelength 254nm.
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| CN201710940269.1A Pending CN107602652A (en) | 2017-10-11 | 2017-10-11 | The method for preparing 6 β methylprednisolones |
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| CN108299533A (en) * | 2018-03-13 | 2018-07-20 | 岳阳环宇药业有限公司 | A kind of methylprednisolone synthesis technology |
| CN109678919A (en) * | 2018-12-27 | 2019-04-26 | 重庆华邦胜凯制药有限公司 | A kind of preparation method of Methylprednisolone succinate impurity |
| CN110655549A (en) * | 2018-06-29 | 2020-01-07 | 天津药业研究院有限公司 | Preparation method of 6 beta-methylprednisolone |
| CN114195848A (en) * | 2021-12-20 | 2022-03-18 | 河南利华制药有限公司 | Preparation method of 11-deoxyprednisolone |
| CN114350737A (en) * | 2022-01-14 | 2022-04-15 | 台州仙琚药业有限公司 | Preparation method of 5 alpha, 6 alpha-epoxy-11 beta, 17 alpha-dihydroxypregn-3, 20-diethylene glycol ketal |
| CN114380878A (en) * | 2021-12-15 | 2022-04-22 | 河南利华制药有限公司 | Synthetic method of flumethasone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108299533A (en) * | 2018-03-13 | 2018-07-20 | 岳阳环宇药业有限公司 | A kind of methylprednisolone synthesis technology |
| CN110655549A (en) * | 2018-06-29 | 2020-01-07 | 天津药业研究院有限公司 | Preparation method of 6 beta-methylprednisolone |
| CN110655549B (en) * | 2018-06-29 | 2022-06-14 | 天津药业研究院股份有限公司 | Preparation method of 6 beta-methylprednisolone |
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| CN114380878A (en) * | 2021-12-15 | 2022-04-22 | 河南利华制药有限公司 | Synthetic method of flumethasone |
| CN114195848A (en) * | 2021-12-20 | 2022-03-18 | 河南利华制药有限公司 | Preparation method of 11-deoxyprednisolone |
| CN114350737A (en) * | 2022-01-14 | 2022-04-15 | 台州仙琚药业有限公司 | Preparation method of 5 alpha, 6 alpha-epoxy-11 beta, 17 alpha-dihydroxypregn-3, 20-diethylene glycol ketal |
| CN114350737B (en) * | 2022-01-14 | 2023-09-15 | 台州仙琚药业有限公司 | Preparation method of 5 alpha, 6 alpha-epoxy-11 beta, 17 alpha-dihydroxypregna-3, 20-diethylene glycol ketal |
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