CN109369768A - The preparation method of Dexamethasone Intermediate - Google Patents
The preparation method of Dexamethasone Intermediate Download PDFInfo
- Publication number
- CN109369768A CN109369768A CN201811108472.3A CN201811108472A CN109369768A CN 109369768 A CN109369768 A CN 109369768A CN 201811108472 A CN201811108472 A CN 201811108472A CN 109369768 A CN109369768 A CN 109369768A
- Authority
- CN
- China
- Prior art keywords
- reaction
- added
- sodium
- compounds
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
Abstract
The present invention relates to a kind of preparation method of Dexamethasone Intermediate, which is using compound I as starting material, using compound I as raw material, in the presence of a catalyst, Grignard Reagent to be added and sillylation reagent carries out grignard reaction, obtains compound II；Buffer and oxidant is added in compound II, epoxidation reaction is carried out, obtains compound III；Compound III is carried out to ring-opening reaction in acidic environment and obtains compound IV；Compound IV is hydrolyzed to reaction under alkaline environment and obtains Dexamethasone Intermediate V.Raw material of the present invention is easy to get, and preparation method is simple, and each step intermediate can separate without further purification is directly used in the next step, and high income is suitable for industrialized production.
Description
Technical field
The present invention relates to the chemical synthesis process of steroid hormone drug important intermediate, and in particular in a kind of dexamethasone
The preparation method of mesosome.
Background technique
Dexamethasone also known as dexamethasone, fluorine methylprednisolone, Dexamethasone have anti-as other glucocorticoids
Inflammation, antiendotoxin inhibit the pharmacological actions such as immune, Hemorrhagic shock and enhancing stress reaction, and clinic is used to treat a variety of diseases, such as from
Body immunity disease, allergy, inflammation, asthma and dermatology, ophthalmology disease.Decameth even more rescues critically ill
The indispensable first-aid medicine of patient, in recent ten years, clinician treat and prevent in all kinds of using dexamethasone sodium phosphate
The diseases such as fever caused by drug allergy caused by Western medicine and treatment virus flu, increase dexamethasone clinical dosage year by year
Add, China has become maximum dexamethasone market in the world so far.The structural formula of dexamethasone is as follows:
Come in fact currently, the industrialized synthetic route of dexamethasone mainly passes through key intermediate methyltetraene compounds (5ST)
Existing, the structural formula of 5ST is as follows:
Synthetic method in the prior art are as follows: using 5ST as reaction raw materials, it is anti-that grignard reaction, epoxy are successively carried out to 5ST
It answers, fluoride reaction, upper Iod R, replace reaction and hydrolysis, dexamethasone is finally made.
However, there is the above method long preparation route, production cycle length, multistep reaction to cause, product yield is low, reaction is former
The disadvantages of preparation cost of material is higher, product preparation cost is high, the presence of disadvantages mentioned above is unfavorable for the industrialization of dexamethasone
Production.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the deficiencies in the prior art, provide that a kind of step is simple, the production cycle
The preparation method of short, high income, Dexamethasone Intermediate that is low in cost, environmental-friendly and being suitable for industrialized production.
The Dexamethasone Intermediate is dexamethasone epoxy hydrolysate, and structural formula is as follows:
The embodiment of the invention provides a kind of preparation method of Dexamethasone Intermediate, the preparation method includes following step
It is rapid:
Step (1), grignard reaction；
Under inert gas protection, as reaction raw materials, the reaction raw materials are placed in first with compounds of formula I
In organic solvent, Grignard Reagent, sillylation reagent and catalyst are added into first organic solvent, in the catalysis
Under the catalytic action of agent, it is anti-that grignard is carried out to the reaction raw materials using the Grignard Reagent and the sillylation reagent
It answers, terminate liquid quenching reaction is added after reaction and obtains by post-processing operations such as layering, concentration, washings with general formula II
Compound；
Step (2), epoxy reaction；
By described there is compounds of formula II to be placed in the second organic solvent, is added into second organic solvent slow
Electuary and oxidant carry out epoxidation reaction, remove excessive oxidant after reaction, by the post-processing such as being layered, extracting
Operation, obtains with compounds of formula III；
Step (3), ring-opening reaction；
By described there is compounds of formula III to be placed in third organic solvent, is added into the third organic solvent
Acid reagent carries out ring-opening reaction and obtains the chemical combination with general formula IV by post-processing operations such as layering, extraction, washing, concentrations
Object；
Step (4), hydrolysis；
By described there is compounds of formula IV to be placed in the 4th solvent, alkaline reagent be added into the 4th solvent,
So that described there is compounds of formula IV reaction to be hydrolyzed under alkaline environment, pH is adjusted after fully reacting, by decoloration
Removal of impurities (such as using decolorization and impurity removal by active carbon) is concentrated, is filtered, washed, drying post-processing operation, obtains the ground with general formula V
Sai meter Song intermediate.
In the embodiment of the present invention, in step (1), inert gas is the gas not having an effect with reactive material, such as nitrogen
Gas, helium, neon, argon gas, Krypton, xenon or radon gas etc..
In the embodiment of the present invention, in step (1), first organic solvent includes tetrahydrofuran, ether, methyl- tert fourth
At least one of base ether, isopropyl ether, dioxane, toluene, n-hexane, hexamethylphosphoramide and diphenylphosphine amide；
The catalyst includes in copper chloride, propionic acid copper, stannous chloride, cuprous bromide, cuprous iodide and cuprous cyanide
At least one；
The Grignard Reagent includes at least one of methyl-magnesium-chloride, methyl-magnesium-bromide and methylpyridinium iodide magnesium；
The sillylation reagent includes at least one in trim,ethylchlorosilane, Iodotrimethylsilane and tri-methylimidazolium
Kind；
The terminate liquid includes ammonium chloride, ammonium acetate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, sodium carbonate, carbonic acid
At least one of hydrogen sodium and aqueous acetic acid.
In the embodiment of the present invention, in the step (1), the reaction temperature of the grignard reaction is for -20~-60 DEG C and anti-
It is 2~4h between seasonable.
In the embodiment of the present invention, in the step (1), the reaction raw materials, the catalyst, the Grignard Reagent and
Molar ratio between the sillylation reagent is 1:0.02~0.05:1.5~3.5:2.0~4.0.
In the embodiment of the present invention, in the step (2), second organic solvent includes toluene, methanol and dichloromethane
At least one of alkane；
The buffer includes sodium acetate, potassium acetate, ammonium acetate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, phosphorus
At least one of sour potassium, dipotassium hydrogen phosphate and potassium dihydrogen phosphate aqueous solution；
The oxidant includes in hydrogen peroxide, peroxyformic acid, Peracetic acid, metachloroperbenzoic acid and trifluoro peracetic acid
At least one；
It include that sodium thiosulfate solution, sodium sulfite are water-soluble for removing reagent used in the excessive oxidant
At least one of liquid, aqueous solution of sodium bisulfite and metabisulfite solution.
In the embodiment of the present invention, in the step (2), the epoxy reactive reaction temperature is for -25~20 DEG C and anti-
It is 2~15h between seasonable.
It is described have molar ratio between compounds of formula II, the buffer and the oxidant be 1:0.5~
2.0:1.0~4.0.
In the embodiment of the present invention, in the step (3), the third organic solvent includes toluene, methylene chloride, trichlorine
At least one of methane, methanol and ethyl alcohol；
The acid reagent includes at least one of sulfuric acid, hydrochloric acid, acetic acid and phosphoric acid.
In the embodiment of the present invention, in the step (3), reaction temperature -15~25 DEG C of the ring-opening reaction and react
Time is 0.5~5h；The pH of reaction system is 1~5 during the ring-opening reaction carries out.
In the embodiment of the present invention, in the step (4), the 4th solvent includes water, toluene, methylene chloride, trichlorine
At least one of methane, methanol, ethyl alcohol；
The alkaline reagent includes in potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium acetate and sodium sulfite
It is at least one.
In the embodiment of the present invention, in the step (4), reaction temperature -15~65 DEG C of the hydrolysis and react
Time is 0.5~10h；The pH of reaction system is 8.5~14 during the hydrolysis carries out.
The present invention chemically reacts route:
The preparation method of Dexamethasone Intermediate provided in an embodiment of the present invention has the advantages that
1, using with compounds of formula I is starting material for reaction raw materials, reaction raw materials have be easily obtained, cost
Low advantage.
2, preparation method provided in an embodiment of the present invention is with process is simple, process route is short, side reaction is few, feasible
Property high, strong operability the advantages that.
3, the next step is directly used in since the resulting intermediate of step each in this preparation method can separate without further purification
In, therefore greatly improve the yield of product.When experimental data shows to prepare Dexamethasone Intermediate according to this method, institute
In product the purity of Dexamethasone Intermediate be up to 98% or more, the mass yield of Dexamethasone Intermediate is up to 80~
84%, it is seen then that this method has many advantages, such as that preparation efficiency is high.
Detailed description of the invention
Fig. 1 is the preparation method flow chart of the Dexamethasone Intermediate of the embodiment of the present invention.
Specific embodiment:
It is further described below in conjunction with preparation method of the specific preferred embodiment to Dexamethasone Intermediate of the present invention,
But protection scope not thereby limiting the invention.
The embodiment of the invention provides a kind of preparation methods of Dexamethasone Intermediate.Fig. 1 is that the embodiment of the present invention provides
Dexamethasone Intermediate preparation method flow chart, with reference to Fig. 1, the preparation method of the Dexamethasone Intermediate includes:
Step 101, grignard reaction:
Under inert gas protection, as reaction raw materials, the reaction raw materials are placed in first with compounds of formula I
In organic solvent, Grignard Reagent, sillylation reagent and catalyst are added into first organic solvent, in the catalysis
Under the catalytic action of agent, it is anti-that grignard is carried out to the reaction raw materials using the Grignard Reagent and the sillylation reagent
It answers, terminate liquid is added after reaction, obtain with compounds of formula II；
First organic solvent may include tetrahydrofuran, ether, methyl tertiary butyl ether(MTBE), isopropyl ether, dioxane, first
At least one of benzene, n-hexane, hexamethylphosphoramide and diphenylphosphine amide；The catalyst may include copper chloride,
At least one of propionic acid copper, stannous chloride, cuprous bromide, cuprous iodide and cuprous cyanide；The Grignard Reagent may include
At least one of methyl-magnesium-chloride, methyl-magnesium-bromide and methylpyridinium iodide magnesium；The sillylation reagent may include front three
Few one kind in base chlorosilane, Iodotrimethylsilane and tri-methylimidazolium；The terminate liquid may include ammonium chloride, ammonium acetate,
At least one of potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, sodium carbonate, sodium bicarbonate and aqueous acetic acid.
Preferably, the reaction temperature of the grignard reaction is -20~-60 DEG C and the reaction time is 2~4h.
Preferably, between the reaction raw materials, the catalyst, the Grignard Reagent and the sillylation reagent
Molar ratio is 1:0.02~0.05:1.5~3.5:2.0~4.0.
Step 102, epoxy reaction:
By described there is compounds of formula II to be placed in the second organic solvent, is added into second organic solvent slow
Electuary and oxidant carry out epoxidation reaction, remove excessive oxidant after reaction, obtain the chemical combination with general formula III
Object；
Second organic solvent may include at least one of toluene, methanol and methylene chloride；The buffer
May include sodium acetate, potassium acetate, ammonium acetate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate and
At least one of potassium dihydrogen phosphate aqueous solution；The oxidant may include hydrogen peroxide, peroxyformic acid, Peracetic acid, m-chloro
At least one of benzoyl hydroperoxide and trifluoro peracetic acid；It can be with for removing reagent used in the excessive oxidant
Including in sodium thiosulfate solution, sodium sulfite aqueous solution, aqueous solution of sodium bisulfite and metabisulfite solution extremely
Few one kind.
Preferably, the epoxy reactive reaction temperature is -25~20 DEG C and the reaction time is 2~15h.
Preferably, the molar ratio having between compounds of formula II, the buffer and the oxidant is 1:
0.5~2.0:1.0~4.0.
Step 103, ring-opening reaction:
By described there is compounds of formula III to be placed in third organic solvent, is added into the third organic solvent
Acid reagent carries out ring-opening reaction, obtains with compounds of formula IV；
The third organic solvent may include at least one in toluene, methylene chloride, chloroform, methanol and ethyl alcohol
Kind；The acid reagent may include at least one of sulfuric acid, hydrochloric acid, acetic acid and phosphoric acid.
Preferably, reaction temperature -15~25 DEG C of the ring-opening reaction and reaction time are 0.5~5h；The open loop is anti-
The pH of reaction system is 1~5 during should carrying out.
Step 104, hydrolysis:
By described there is compounds of formula IV to be placed in the 4th solvent, alkaline reagent be added into the 4th solvent,
So that described there is compounds of formula IV to be hydrolyzed reaction under alkaline environment, after the hydrolysis, had
There is the Dexamethasone Intermediate of general formula V；
4th solvent may include at least one of water, toluene, methylene chloride, chloroform, methanol, ethyl alcohol；
The alkaline reagent may include in potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium acetate and sodium sulfite at least
It is a kind of.
Preferably, reaction temperature -15~65 DEG C of the hydrolysis and reaction time are 0.5~10h；The hydrolysis is anti-
The pH of reaction system is 8.5~14 during should carrying out.
Based on the mentality of designing that inventive embodiments provide, rice can be filled according to practical control reaction condition and in preparation
The reagent of suitable species is selected during loose intermediate.
It is described in detail below by preparation method of the following embodiment to Dexamethasone Intermediate provided by the present application.
Embodiment 1
Step 1, grignard reaction:
450mL tetrahydrofuran is added into reaction flask, is added with stirring 60g for step 11, under nitrogen protection
(0.156mol) has compounds of formula I I, is cooled to -20~-30 DEG C after dissolved clarification.
Acetic acid copper solution is added in the resulting reaction solution of step 11 by step 12, wherein the acetic acid copper solution be using
It obtains after 400mL tetrahydrofuran dissolution 0.6g (0.003mol) copper acetate (catalyst), at temperature control -20~-30 DEG C, is added
117mL concentration is the methyl magnesium bromide solution and 33.8g (0.314mol) trim,ethylchlorosilane of 2.0mol/L, at -20~-30 DEG C
Insulation reaction 2h, wherein the methyl magnesium bromide solution is Grignard Reagent, methyl-magnesium-bromide in the methyl magnesium bromide solution
Dosage is 0.234mol；
The purity of compound I in the reaction system is monitored using HPLC, when HPLC monitors that compound I is reacting
When purity in system is down to 0.5% or less, the Acetic acid-sodium acetate aqueous solution that 200mL mass fraction is 15% is added and is quenched instead
It answers, the mass ratio of acetic acid and sodium acetate is 1:2 in Acetic acid-sodium acetate aqueous solution, product is obtained, comprising having general formula in the product
The compound II of II.
The resulting product of step 12 is warming up to 20 DEG C or so by step 13, stirs 10min, stratification, obtaining first has
Machine phase and the first water phase extract the organic phase in the first water phase using 50mL toluene, obtain Second Organic Phase and the second water phase, close
And first organic phase and Second Organic Phase, the organic phase after being merged；The organic phase after merging is concentrated under reduced pressure at 40 DEG C, with
The tetrahydrofuran in organic phase after removal merging；600mL toluene is added into remaining concentrate, adds 200mL mass point
The aqueous ammonium chloride solution that number is 20%, stirs 30min, and stratification obtains third organic phase and third water phase, discards third water
Phase, by third organic phase (toluene solution i.e. containing format product, but i.e. containing with compounds of formula II II toluene it is molten
Liquid) it is directly used in and reacts in next step.
Step 2, epoxy reaction:
In the toluene solution containing format product that step 1 obtains, it is added with stirring 20mL sodium acetate aqueous solution,
In, which be dissolved in obtained in 15mL water as 6.5g (0.078mol) sodium acetate, and -25 DEG C of left sides are cooled to
The right side is added the Peracetic acid that 48g (0.156mol) mass fraction is 25%, then heats to 10 DEG C or so, reacts 13~15h；
The purity of compound II in the reaction system is monitored using HPLC, when HPLC monitors compound II anti-
When answering purity in system down to 0.5% or less, 160mL aqueous solution of sodium bisulfite is added, wherein the sodium hydrogensulfite is water-soluble
Liquid is dissolved in obtained in 150mL water as 10g sodium hydrogensulfite, and reaction temperature control is not higher than 25 DEG C, is examined with peroxide test paper
Peroxide is surveyed to terminate completely.30min is stirred, stratification obtains the 4th organic phase and the 4th water phase, is extracted with 50mL toluene
4th water phase obtains the 5th organic phase, merges the 4th organic phase and the 5th organic phase, the organic phase after merging (contain epoxy
The toluene solution of product, and i.e. containing the toluene solution with compounds of formula III III) be directly used in and react in next step.
Step 3, ring-opening reaction:
In the toluene solution containing epoxy product that step 2 is obtained, it is added with stirring 100mL methanol, is cooled to -10 DEG C
Left and right, it is 1~2 that the dilute hydrochloric acid that 8g (0.015mol) concentration is 2mol/L, which is added, and adjusts the pH of reaction system, keeps the temperature -10 DEG C, instead
Answer 1h；
The purity of compound III in the reaction system is monitored using HPLC, when HPLC monitors that compound III exists
When purity in reaction system is down to 1% or less, the sodium bicarbonate aqueous solution that 200mL mass fraction is 10% is added, is warming up to
60 DEG C or so, stratification obtains the 6th organic phase and the 6th water phase, is extracted the 6th water phase 1 time with 50mL toluene, obtains the 7th
Organic phase and the 7th water phase, merge the 6th organic phase and the 7th organic phase, the organic phase after merging are with 200mL mass fraction
5% brine It 1 time, is concentrated under reduced pressure the organic phase after washing, the toluene in removing system, resulting concentrate
(containing open-loop products in concentrate, that is, containing has compounds of formula IV IV) is directly used in next step hydrolysis.
Step 4, hydrolysis:
In the concentrate that step 3 obtains, it is added with stirring 260mL methylene chloride, is cooled to 5 DEG C or so, 350g is added
Methanol solution dissolved with potassium carbonate, wherein the potassium carbonate methanol solution is to be dissolved in 440mL hot methanol to obtain by 5g potassium carbonate
It arrives, keeping the pH of reaction system is 10 or so, and temperature is that 5~15 DEG C of reactions 1h, HPLC monitor compound IV in reactant
Down to after 0.3% or less, it is 6~7 that 2g glacial acetic acid, which is added, and adjusts the pH of reaction system for purity in system.
The pH reaction system for being 6~7 is warming up to 25 DEG C or so, 3g active carbon is added and stirs 30min, filtering.It depressurizes dense
Contracting filtrate is cooled to -10 DEG C to remove the methylene chloride in filtrate, keeps the temperature 3~5h, filters, washing, is dried in vacuo at 35 DEG C,
50g product is obtained, includes that there is compounds of formula V V in the product.Experimental data shows that the mass yield of compound V is
83%, it is detected through HPLC, the purity of compound V is up to 98.5% in product.
Embodiment 2
Step 1, grignard reaction:
450mL tetrahydrofuran is added into reaction flask, is added with stirring 60g for step 11, under nitrogen protection
(0.156mol) has compounds of formula I I, is cooled to -30~-40 DEG C after dissolved clarification.
Propionic acid copper solution is added in the resulting reaction solution of step 11 by step 12, wherein the propionic acid copper solution be using
It obtains after 350mL tetrahydrofuran dissolution 1.2g (0.007mol) propionic acid copper (catalyst), at temperature control -20~-30 DEG C, is added
273mL concentration is the methyl magnesium bromide solution and 67.7g (0.624mol) trim,ethylchlorosilane of 2.0mol/L, at -30~-40 DEG C
Insulation reaction 3h, wherein the methyl magnesium bromide solution is Grignard Reagent, methyl-magnesium-bromide in the methyl magnesium bromide solution
Dosage is 0.546mol；
The purity of compound I in the reaction system is monitored using HPLC, when HPLC monitors that compound I is reacting
When purity in system is down to 0.5% or less, the aqueous ammonium chloride solution quenching reaction that 200mL mass fraction is 20% is added, obtains
To product, comprising having compounds of formula II II in the product.
The resulting product of step 12 is warming up to 20 DEG C or so by step 13, stirs 10min, stratification, obtaining first has
Machine phase and the first water phase extract the organic phase in the first water phase using 50mL methylene chloride, obtain Second Organic Phase and the second water
Phase merges the first organic phase and Second Organic Phase, the organic phase after being merged；It is concentrated under reduced pressure at 40 DEG C organic after merging
Phase, to remove the tetrahydrofuran in the organic phase after merging；400mL methylene chloride is added into remaining concentrate, adds
The aqueous ammonium chloride solution that 200mL mass fraction is 20% stirs 30min, and stratification obtains third organic phase and third water phase,
Discard third water phase, by third organic phase (dichloromethane solution i.e. containing format product, but i.e. containing with general formula II change
Close the dichloromethane solution of object II) it is directly used in and reacts in next step.
Step 2, epoxy reaction:
In the dichloromethane solution containing format product that step 1 obtains, it is added with stirring 25mL sodium acetate aqueous solution,
Wherein, which be dissolved in obtained in 15mL water as 10g (0.12mol) sodium acetate, is cooled to 15 DEG C or so,
The metachloroperbenzoic acid that 113g (0.624mol) mass fraction is 85% is added, then heats to 10 DEG C or so, reaction 2~
4h；
The purity of compound II in the reaction system is monitored using HPLC, when HPLC monitors compound II anti-
When answering purity in system down to 0.5% or less, 180mL metabisulfite solution is added, wherein the sodium pyrosulfite is water-soluble
Liquid is dissolved in obtained in 150mL water as 30g sodium pyrosulfite, and reaction temperature control is not higher than 25 DEG C, is examined with peroxide test paper
Peroxide is surveyed to terminate completely.30min is stirred, stratification obtains the 4th organic phase and the 4th water phase, with 50mL methylene chloride
The 4th water phase is extracted, the 5th organic phase is obtained, merges the 4th organic phase and the 5th organic phase, the organic phase after merging (contains
The dichloromethane solution of epoxy product, and i.e. containing the dichloromethane solution with general formula III) be directly used in and react in next step.
Step 3, ring-opening reaction:
In the dichloromethane solution containing epoxy product that step 2 is obtained, it is added with stirring 80mL methanol, be cooled to-
10 DEG C or so, it is 3~4 that the dilute hydrochloric acid that 6g (0.011mol) concentration is 2mol/L, which is added, and adjusts the pH of reaction system, keeps the temperature -5 DEG C,
React 1h；
The purity of compound in the reaction system is monitored using HPLC, when HPLC monitoring compound III is reacting
When purity in system is down to 1% or less, the sodium bicarbonate aqueous solution that 180mL mass fraction is 10% is added, is warming up to 30 DEG C
Left and right, stratification obtain the 6th organic phase and the 6th water phase, are extracted the 6th water phase 1 time with 50mL methylene chloride, obtain the 7th
Organic phase and the 7th water phase, merge the 6th organic phase and the 7th organic phase, the organic phase after merging are with 200mL mass fraction
5% brine It 1 time, is concentrated under reduced pressure the organic phase after washing, and the methylene chloride in removing system, gained is about
300mL concentrate (containing ring-opening product in concentrate, that is, containing has compounds of formula IV IV) is directly used in next one-step hydrolysis
Reaction.
Step 4, hydrolysis:
In the concentrate that step 3 obtains, -10 DEG C or so are cooled to, it is molten that methanol of the 350g dissolved with sodium hydroxide is added
Liquid, wherein the sodium hydrate methanol solution is dissolved in obtained in 440mL hot methanol as 2g sodium hydroxide, and reactant is kept
The pH of system is 12~14, and temperature is -10~-5 DEG C of reaction 2h, HPLC monitor the purity of compound IV in the reaction system down to
After 0.3% or less, it is 6~7 that 2g glacial acetic acid, which is added, and adjusts the pH of reaction system.
The pH reaction system for being 6~7 is warming up to 25 DEG C or so, 3g active carbon is added and stirs 30min, filtering.It depressurizes dense
Contracting filtrate is cooled to -10 DEG C to remove the methylene chloride in filtrate, keeps the temperature 3~5h, filters, washing, is dried in vacuo at 35 DEG C,
50.5g product is obtained, includes that there is compounds of formula V V in the product.Experimental data shows that the mass yield of compound V is
83%, it is detected through HPLC, the purity of compound V is up to 98.7% in product.
Embodiment 3
Step 1, grignard reaction:
450mL tetrahydrofuran is added into reaction flask, is added with stirring 60g for step 11, under nitrogen protection
(0.156mol) has compounds of formula I I, is cooled to -40~-50 DEG C after dissolved clarification.
Cuprous chloride solution is added in the resulting reaction solution of step 11 by step 12, wherein the cuprous chloride solution is
Using what is obtained after 400mL tetrahydrofuran dissolution 0.3g (0.03mol) stannous chloride (catalyst), at temperature control -40~-50 DEG C,
The methyl magnesium bromide solution and 35g (0.322mol) trim,ethylchlorosilane that 170mL concentration is 2.0mol/L is added, -30~-40
DEG C insulation reaction 2h, wherein the methyl magnesium bromide solution is Grignard Reagent, methyl-magnesium-bromide in the methyl magnesium bromide solution
Dosage be 0.34mol；
The purity of compound I in the reaction system is monitored using HPLC, when HPLC monitors that compound I is reacting
When purity in system is down to 0.5% or less, the Acetic acid-sodium acetate aqueous solution that 200mL mass fraction is 15% is added and is quenched instead
It answers, the mass ratio of acetic acid and sodium acetate is 1:2 in Acetic acid-sodium acetate aqueous solution, product is obtained, comprising having general formula in the product
The compound II of II.
The resulting product of step 12 is warming up to 20 DEG C or so by step 13, stirs 10min, stratification, obtaining first has
Machine phase and the first water phase extract the organic phase in the first water phase using 50mL toluene, obtain Second Organic Phase and the second water phase, close
And first organic phase and Second Organic Phase, the organic phase after being merged；The organic phase after merging is concentrated under reduced pressure at 40 DEG C, with
Tetrahydrofuran after removal merges in organic phase；600mL toluene is added to remaining concentrate, adding 200mL mass fraction is
20% aqueous ammonium chloride solution stirs 30min, and stratification obtains third organic phase and third water phase, discards third water phase,
By third organic phase (toluene solution i.e. containing format product, and i.e. containing the toluene solution with compounds of formula II II)
It is directly used in and reacts in next step.
Step 2, epoxy reaction:
In the toluene solution containing format product that step 1 obtains, it is added with stirring 20mL sodium acetate aqueous solution,
In, which be dissolved in obtained in 25mL water as 15g (0.183mol) sodium acetate, is cooled to 0 DEG C or so, is added
Enter the metachloroperbenzoic acid that 45g (0.221mol) mass fraction is 85%, then heat to 10 DEG C or so, reacts 2~3h；
The purity of compound II in the reaction system is monitored using HPLC, when HPLC monitors compound II anti-
When answering purity in system down to 0.5% or less, 160mL aqueous solution of sodium bisulfite is added, wherein the sodium hydrogensulfite is water-soluble
Liquid is dissolved in obtained in 150mL water as 10g sodium hydrogensulfite, and reaction temperature control is not higher than 25 DEG C, is examined with peroxide test paper
Peroxide is surveyed to terminate completely.30min is stirred, stratification obtains the 4th organic phase and the 4th water phase, is extracted with 50mL toluene
4th water phase obtains the 5th organic phase, merges the 4th organic phase and the 5th organic phase, the organic phase after merging (contain epoxy
The toluene solution of product, and i.e. containing the toluene solution with compounds of formula III III) be directly used in and react in next step.
Step 3, ring-opening reaction:
In the toluene solution containing epoxy product that step 2 is obtained, it is added with stirring 100mL methanol, is cooled to -10 DEG C
Left and right, it is 1~2 that the dilute hydrochloric acid that 8g (0.015mol) concentration is 2mol/L, which is added, and adjusts the pH of reaction system, keeps the temperature -10 DEG C, instead
Answer 1h；
The purity of compound III in the reaction system is monitored using HPLC, when HPLC monitoring compound III is anti-
When answering purity in system down to 1% or less, the sodium bicarbonate aqueous solution that 200mL mass fraction is 10% is added, is warming up to 60
DEG C or so, stratification obtains the 6th organic phase and the 6th water phase, is extracted the 6th water phase 1 time with 50mL toluene, obtaining the 7th has
Machine phase and the 7th water phase, merge the 6th organic phase and the 7th organic phase, the organic phase after merging share 200mL mass fraction and be
5% brine It 1 time, is concentrated under reduced pressure the organic phase after washing, the toluene in removing system, resulting concentrate
(containing open-loop products in concentrate, that is, containing has compounds of formula IV IV) is directly used in next step hydrolysis.
Step 4, hydrolysis:
In the concentrate that step 3 obtains, it is added with stirring 260mL methylene chloride, is cooled to 5 DEG C or so, 350g is added
Methanol solution dissolved with potassium carbonate, wherein the potassium carbonate methanol solution is to be dissolved in 440mL hot methanol to obtain by 5g potassium carbonate
It arrives, keeping the pH of reaction system is 10 or so, and temperature is that 5~15 DEG C of reactions 1h, HPLC monitor compound IV in reactant
Down to after 0.3% or less, it is 6~7 that 2g glacial acetic acid, which is added, and adjusts the pH of reaction system for purity in system.
The pH reaction system for being 6~7 is warming up to 25 DEG C or so, 3g active carbon is added and stirs 30min, filtering.It depressurizes dense
Contracting filtrate is cooled to -10 DEG C to remove the methylene chloride in filtrate, keeps the temperature 3~5h, filters, washing, is dried in vacuo at 35 DEG C,
50g product is obtained, includes that there is compounds of formula V V in the product.Experimental data shows that the mass yield of compound V is
83%, it is detected through HPLC, the purity of compound V is up to 98.5% in product.
Embodiment 4
Step 1, grignard reaction:
450mL tetrahydrofuran is added into reaction flask, is added with stirring 60g for step 11, under nitrogen protection
(0.156mol) has compounds of formula I I, is cooled to -40~-50 DEG C after dissolved clarification.
Propionic acid copper solution is added in the resulting reaction solution of step 11 by step 12, wherein the propionic acid copper solution be using
It obtains after 350mL tetrahydrofuran dissolution 1.2g (0.007mol) propionic acid copper (catalyst), at temperature control -40~-50 DEG C, is added
180mL concentration is the methyl magnesium bromide solution and 35g (0.322mol) trim,ethylchlorosilane of 2.0mol/L, is protected at -30~-40 DEG C
Temperature reaction 2h, wherein the methyl magnesium bromide solution is Grignard Reagent, the use of methyl-magnesium-bromide in the methyl magnesium bromide solution
Amount is 0.36mol；
The purity of compound I in the reaction system is monitored using HPLC, when HPLC monitors that compound I is reacting
When purity in system is down to 0.5% or less, the aqueous ammonium chloride solution quenching reaction that 200mL mass fraction is 20% is added, obtains
To product, comprising having compounds of formula II II in the product.
The resulting product of step 12 is warming up to 20 DEG C or so by step 13, stirs 10min, stratification, obtaining first has
Machine phase and the first water phase extract the organic phase in the first water phase using 50mL methylene chloride, obtain Second Organic Phase and the second water
Phase merges the first organic phase and Second Organic Phase, the organic phase after being merged；It is concentrated under reduced pressure at 40 DEG C organic after merging
Phase, to remove the tetrahydrofuran in the organic phase after merging；400mL methylene chloride is added into remaining concentrate, adds
The aqueous ammonium chloride solution that 200mL mass fraction is 20%, stirs 30min, and stratification obtains third organic phase and third water
Phase discards third water phase, by third organic phase (dichloromethane solution i.e. containing format product, but i.e. containing have general formula II
Compound II dichloromethane solution) be directly used in next step react.
Step 2, epoxy reaction:
In the dichloromethane solution containing format product that step 1 obtains, it is added with stirring 20mL sodium acetate aqueous solution,
Wherein, which be dissolved in obtained in 15mL water as 5g (0.061mol) sodium acetate, is cooled to -15 DEG C of left sides
The right side is added the metachloroperbenzoic acid that 40g (0.197mol) mass fraction is 85%, then heats to 10 DEG C or so, and reaction 2~
3h；
The purity of compound II in the reaction system is monitored using HPLC, when the compound II that HPLC is monitored exists
When purity in reaction system is down to 0.5% or less, 160mL metabisulfite solution is added, wherein the sodium pyrosulfite water
Solution is dissolved in obtained in 150mL water as 10g sodium pyrosulfite, and reaction temperature control is not higher than 25 DEG C, with peroxide test paper
Peroxide is detected to terminate completely.30min is stirred, stratification obtains the 4th organic phase and the 4th water phase, with 50mL dichloromethane
Alkane extracts the 4th water phase, obtains the 5th organic phase, merges the 4th organic phase and the 5th organic phase, the organic phase after merging (contain
Have the dichloromethane solution of epoxy product, and i.e. containing the dichloromethane solution with compounds of formula III III) directly use
It is reacted in next step.
Step 3, ring-opening reaction:
In the dichloromethane solution containing epoxy product that step 2 is obtained, it is added with stirring 80mL methanol, is cooled to 0
DEG C or so, it is 4~5 that the dilute hydrochloric acid that 5g (0.009mol) concentration is 2mol/L, which is added, and adjusts the pH of reaction system, keeps the temperature 5 DEG C, instead
Answer 3h；
The purity of compound III in the reaction system is monitored using HPLC, when HPLC monitoring compound III is anti-
When answering purity in system down to 1% or less, the sodium bicarbonate aqueous solution that 180mL mass fraction is 10% is added, is warming up to 30
DEG C or so, stratification obtains the 6th organic phase and the 6th water phase, is extracted the 6th water phase 1 time with 50mL methylene chloride, obtains the
Seven organic phases and the 7th water phase, merge the 6th organic phase and the 7th organic phase, the organic phase after merging are with 200mL mass fraction
5% brine It 1 time, is concentrated under reduced pressure the organic phase after washing, and the methylene chloride in removing system, gained is about
300mL concentrate (containing open-loop products in concentrate, that is, containing has compounds of formula IV IV) is directly used in next step water
Solution reaction.
Step 4, hydrolysis:
In the concentrate that step 3 obtains, -10 DEG C or so are cooled to, the methanol solution of 350g sodium hydroxide is added,
In, which is that the pH that reaction system is kept obtained in 440mL hot methanol is dissolved in as 2g sodium hydroxide
It is 12~14, temperature is that -10~-5 DEG C of reactions 2h, HPLC monitor the purity of compound IV in the reaction system down to 0.3%
After below, it is 6~7 that 2g glacial acetic acid, which is added, and adjusts the pH of reaction system.
The pH reaction system for being 6~7 is warming up to 25 DEG C or so, 3g active carbon is added and stirs 30min, filtering.It depressurizes dense
Contracting filtrate is cooled to -10 DEG C to remove the methylene chloride in filtrate, keeps the temperature 3~5h, filters, washing, is dried in vacuo at 35 DEG C,
50.5g product is obtained, includes that there is compounds of formula V V in the product.Experimental data shows that the mass yield of compound V is
84%, it is detected through HPLC, the purity of compound V is up to 98.7% in product.
Embodiment 5
Step 1, grignard reaction:
450mL tetrahydrofuran is added into reaction flask, is added with stirring 60g for step 11, under nitrogen protection
(0.156mol) has compounds of formula I I, is cooled to -50~-60 DEG C after dissolved clarification.
Propionic acid copper solution is added in the resulting reaction solution of step 11 by step 12, wherein the propionic acid copper solution be using
It obtains after 350mL tetrahydrofuran dissolution 1.5g (0.007mol) propionic acid copper (catalyst), at temperature control -50~-60 DEG C, is added
180mL concentration is the methyl magnesium bromide solution and 35g (0.322mol) trim,ethylchlorosilane of 2.0mol/L, is protected at -50~-60 DEG C
Temperature reaction 2h, wherein the methyl magnesium bromide solution is Grignard Reagent, the use of methyl-magnesium-bromide in the methyl magnesium bromide solution
Amount is 0.36mol；
The purity of compound I in the reaction system is monitored using HPLC, when HPLC monitors that compound I is reacting
When purity in system is down to 0.5% or less, the aqueous ammonium chloride solution quenching reaction that 200mL mass fraction is 20% is added, obtains
To product, comprising having compounds of formula II II in the product.
The resulting product of step 12 is warming up to 20 DEG C or so by step 13, stirs 10min, stratification, obtaining first has
Machine phase and the first water phase extract the organic phase in the first water phase using 50mL methylene chloride, obtain Second Organic Phase and the second water
Phase merges the first organic phase and Second Organic Phase, the organic phase after being merged；It is concentrated under reduced pressure at 40 DEG C organic after merging
Phase, the tetrahydrofuran after being merged with removal in organic phase；400mL methylene chloride is added into remaining concentrate, adds 200mL
The aqueous ammonium chloride solution that mass fraction is 20%, stirs 30min, and stratification obtains third organic phase and third water phase, discards
Third water phase, by third organic phase (dichloromethane solution i.e. containing format product, but i.e. containing have compounds of formula II
The dichloromethane solution of II) it is directly used in and reacts in next step.
Step 2, epoxy reaction:
In the dichloromethane solution containing format product that step 1 obtains, it is added with stirring 20mL sodium acetate aqueous solution,
Wherein, which be dissolved in obtained in 15mL water as 5g sodium acetate, is cooled to -15 DEG C or so, and 63.5g is added
The metachloroperbenzoic acid that (0.312mol) mass fraction is 85% then heats to 10 DEG C or so, reacts 2~3h；
The purity of compound II in the reaction system is monitored using HPLC, when HPLC monitors compound II anti-
When answering purity in system down to 0.5% or less, 160mL metabisulfite solution is added, wherein the sodium pyrosulfite is water-soluble
Liquid is dissolved in obtained in 150mL water as 10g sodium pyrosulfite, and reaction temperature control is not higher than 25 DEG C, is examined with peroxide test paper
Peroxide is surveyed to terminate completely.30min is stirred, stratification obtains the 4th organic phase and the 4th water phase, with 50mL methylene chloride
The 4th water phase is extracted, the 5th organic phase is obtained, merges the 4th organic phase and the 5th organic phase, the organic phase after merging (contains
The dichloromethane solution of epoxy product, and i.e. containing the dichloromethane solution with compounds of formula III III) be directly used in
It reacts in next step.
Step 3, ring-opening reaction:
In the dichloromethane solution containing epoxy product that step 2 is obtained, it is added with stirring 80mL methanol, be cooled to-
10 DEG C or so, it is 1~2 that the dilute hydrochloric acid that 6g (0.011mol) concentration is 2mol/L, which is added, and adjusts the pH of reaction system, keeps the temperature -5 DEG C,
React 1h；
The purity of compound III in the reaction system is monitored using HPLC, when HPLC monitoring compound III is anti-
When answering purity in system down to 1% or less, addition 180mL mass fraction is 10% sodium bicarbonate aqueous solution, is warming up to 30 DEG C
Left and right, stratification obtain the 6th organic phase and the 6th water phase, are extracted the 6th water phase 1 time with 50mL methylene chloride, obtain the 7th
Organic phase and the 7th water phase, merge the 6th organic phase and the 7th organic phase, the organic phase after merging are with 200mL mass fraction
5% brine It 1 time, is concentrated under reduced pressure the organic phase after washing, and the methylene chloride in removing system, gained is about
300mL concentrate (containing open-loop products in concentrate, that is, containing has compounds of formula IV IV) is directly used in next step water
Solution reaction.
Step 4, hydrolysis:
In the concentrate that step 3 obtains, -10 DEG C or so are cooled to, the methanol solution of 350g sodium hydroxide is added,
In, which is that the pH that reaction system is kept obtained in 440mL hot methanol is dissolved in as 2g sodium hydroxide
It is 12~14, temperature is that -10~-5 DEG C of reactions 2h, HPLC monitor the purity of compound IV in the reaction system down to 0.3%
After below, it is 6~7 that 2g glacial acetic acid, which is added, and adjusts the pH of reaction system.
The pH reaction system for being 6~7 is warming up to 25 DEG C or so, 3g active carbon is added and stirs 30min, filtering.It depressurizes dense
Contracting filtrate is cooled to -10 DEG C of 3~5h of heat preservation to remove the methylene chloride in filtrate, filters, washing, is dried in vacuo, obtains at 35 DEG C
50.5g product, comprising having compounds of formula V V in the product.Experimental data shows that the mass yield of compound V is
84%, it is detected through HPLC, the purity of compound V is up to 98.7% in product.
Embodiment 6
Step 1, grignard reaction:
450mL tetrahydrofuran is added into reaction flask, is added with stirring 60g for step 11, under nitrogen protection
(0.156mol) has compounds of formula I I, is cooled to -50~-60 DEG C after dissolved clarification.
Cuprous chloride solution is added in the resulting reaction solution of step 11 by step 12, wherein the cuprous chloride solution is
Using what is obtained after 400mL tetrahydrofuran dissolution 0.3g (0.03mol) stannous chloride (catalyst), at temperature control -50~-60 DEG C,
The methyl magnesium bromide solution and 35g (0.322mol) trim,ethylchlorosilane that 170mL concentration is 2.0mol/L is added, -50~-60
DEG C insulation reaction 2h, wherein the methyl magnesium bromide solution is Grignard Reagent, methyl-magnesium-bromide in the methyl magnesium bromide solution
Dosage be 0.34mol；
The purity of compound I in the reaction system is monitored using HPLC, when HPLC monitors that compound I is reacting
When purity in system is to 0.5% or less, the Acetic acid-sodium acetate aqueous solution quenching reaction that 200mL mass fraction is 15% is added,
The mass ratio of acetic acid and sodium acetate is 1:2 in Acetic acid-sodium acetate aqueous solution, obtains product, comprising having general formula II in the product
Compound II.
The resulting product of step 12 is warming up to 20 DEG C or so by step 13, stirs 10min, stratification, obtaining first has
Machine phase and the first water phase extract the organic phase in the first water phase using 50mL toluene, obtain Second Organic Phase and the second water phase, close
And first organic phase and Second Organic Phase, the organic phase after being merged；The organic phase after merging is concentrated under reduced pressure at 40 DEG C, with
The tetrahydrofuran in organic phase after removal merging；600mL toluene is added into remaining concentrate, adds 200mL mass point
The aqueous ammonium chloride solution that number is 20%, stirs 30min, and stratification obtains third organic phase and third water phase, discards third water
Phase, by third organic phase (toluene solution i.e. containing format product, but i.e. containing with compounds of formula II II toluene it is molten
Liquid) it is directly used in and reacts in next step.
Step 2, epoxy reaction:
In the toluene solution containing format product that step 1 obtains, it is added with stirring 20mL sodium acetate aqueous solution,
In, which be dissolved in obtained in 15mL water as 5g (0.061mol) sodium acetate, -25 DEG C or so are cooled to,
The metachloroperbenzoic acid that 63.5g (0.312mol) mass fraction is 85% is added, then heats to 10 DEG C or so, reaction 2~
3h；
The purity of compound II in the reaction system is monitored using HPLC, when HPLC monitors compound II anti-
When answering purity in system down to 0.5% or less, 160mL aqueous solution of sodium bisulfite is added, wherein the sodium hydrogensulfite is water-soluble
Liquid is dissolved in obtained in 150mL water as 10g sodium hydrogensulfite, and reaction temperature control is not higher than 25 DEG C, is examined with peroxide test paper
Peroxide is surveyed to terminate completely.30min is stirred, stratification obtains the 4th organic phase and the 4th water phase, is extracted with 50mL toluene
4th water phase obtains the 5th organic phase, merges the 4th organic phase and the 5th organic phase, the organic phase after merging (contain epoxy
The toluene solution of product, and i.e. containing the toluene solution with compounds of formula III III) be directly used in and react in next step.
Step 3, ring-opening reaction:
In the toluene solution containing epoxy product that step 2 is obtained, it is added with stirring 100mL methanol, is cooled to -10 DEG C
Left and right, it is 1~2 that the dilute hydrochloric acid that 8g (0.015mol) concentration is 2mol/L, which is added, and adjusts the pH of reaction system, keeps the temperature -10 DEG C, instead
Answer 1h；
The purity of compound III in the reaction system is monitored using HPLC, when HPLC monitors that compound III exists
When purity in reaction system is down to 1% or less, addition 200mL mass fraction is 10% sodium bicarbonate aqueous solution, is warming up to 60
DEG C or so, stratification obtains the 6th organic phase and the 6th water phase, is extracted the 6th water phase 1 time with 50mL toluene, obtaining the 7th has
Machine phase and the 7th water phase merge the 6th organic phase and the 7th organic phase, and the 200mL mass fraction of the organic phase after merging is 5%
Brine It 1 time, the organic phase after washing is concentrated under reduced pressure, the toluene in removing system, resulting concentrate is (dense
Contain open-loop products in contracting liquid, that is, containing has compounds of formula IV IV) it is directly used in next step hydrolysis.
Step 4, hydrolysis:
In the concentrate that step 3 obtains, it is added with stirring 260mL methylene chloride, is cooled to 5 DEG C or so, 350g is added
The methanol solution of potassium carbonate, wherein the potassium carbonate methanol solution is dissolved in obtained in 440mL hot methanol as 5g potassium carbonate,
Keeping the pH of reaction system is 10 or so, temperature is 5~15 DEG C of reaction 1h, and HPLC monitors compound IV in the reaction system
Purity is 6~7 down to 2g glacial acetic acid after 0.3% or less, is added to adjust the pH of reaction system.
The pH reaction system for being 6~7 is warming up to 25 DEG C or so, 3g active carbon is added and stirs 30min, filtering.It depressurizes dense
Contracting filtrate is cooled to -10 DEG C to remove the methylene chloride in filtrate, keeps the temperature 3~5h, filters, washing, is dried in vacuo at 35 DEG C,
50g product is obtained, includes that there is compounds of formula V V in the product.Experimental data shows that the mass yield of compound V is
83%, it is detected through HPLC, the purity of compound V is up to 98.5% in product.
The foregoing is merely preferred embodiments of the invention, are not intended to limit the invention, any to be familiar with this technology neck
In the technical scope disclosed by the present invention, any changes or substitutions that can be easily thought of by the technical staff in domain, should all cover in this hair
In bright protection scope.
Claims (10)
1. a kind of preparation method of Dexamethasone Intermediate, which is characterized in that the preparation method comprises the following steps:
Step (1), grignard reaction；
Under inert gas protection, as reaction raw materials, it is organic that the reaction raw materials are placed in first with compounds of formula I
In solvent, Grignard Reagent, sillylation reagent and catalyst are added into first organic solvent, in the catalyst
Under catalytic action, grignard reaction is carried out to the reaction raw materials using the Grignard Reagent and the sillylation reagent, instead
Terminate liquid is added after answering, obtains with compounds of formula II；
Step (2), epoxy reaction；
By described there is compounds of formula II to be placed in the second organic solvent, buffer is added into second organic solvent
And oxidant, epoxidation reaction is carried out, excessive oxidant is removed after reaction, obtains with compounds of formula III；
Step (3), ring-opening reaction；
By described there is compounds of formula III to be placed in third organic solvent, is added into the third organic solvent acid
Reagent carries out ring-opening reaction, obtains with compounds of formula IV；
Step (4), hydrolysis；
By described there is compounds of formula IV to be placed in the 4th solvent, alkaline reagent is added into the 4th solvent, so that
It is described that there is compounds of formula IV to be hydrolyzed reaction under alkaline environment, after the hydrolysis, obtains having and lead to
The Dexamethasone Intermediate of Formula V；
2. preparation method according to claim 1, which is characterized in that in step (1), first organic solvent includes
Tetrahydrofuran, ether, methyl tertiary butyl ether(MTBE), isopropyl ether, dioxane, toluene, n-hexane, hexamethylphosphoramide and diphenyl
At least one of phosphamide；
The catalyst include in copper chloride, propionic acid copper, stannous chloride, cuprous bromide, cuprous iodide and cuprous cyanide extremely
Few one kind；
The Grignard Reagent includes at least one of methyl-magnesium-chloride, methyl-magnesium-bromide and methylpyridinium iodide magnesium；
The sillylation reagent includes few one kind in trim,ethylchlorosilane, Iodotrimethylsilane and tri-methylimidazolium；
The terminate liquid includes ammonium chloride, ammonium acetate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, sodium carbonate, sodium bicarbonate
At least one of with aqueous acetic acid.
3. preparation method according to claim 1, which is characterized in that in the step (1), the grignard reaction it is anti-
Answer that temperature is -20~-60 DEG C and the reaction time is 2~4h.
4. preparation method according to claim 1, which is characterized in that in the step (1), the reaction raw materials, institute
The molar ratio stated between catalyst, the Grignard Reagent and the sillylation reagent is 1:0.02~0.05:1.5~3.5:
2.0~4.0.
5. preparation method according to claim 1, which is characterized in that in the step (2), second organic solvent
Including at least one of toluene, methanol and methylene chloride；
The buffer include sodium acetate, potassium acetate, ammonium acetate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate,
At least one of dipotassium hydrogen phosphate and potassium dihydrogen phosphate aqueous solution；
The oxidant include in hydrogen peroxide, peroxyformic acid, Peracetic acid, metachloroperbenzoic acid and trifluoro peracetic acid extremely
Few one kind；
For remove reagent used in the excessive oxidant include sodium thiosulfate solution, sodium sulfite aqueous solution,
At least one of aqueous solution of sodium bisulfite and metabisulfite solution.
6. preparation method according to claim 1, which is characterized in that described epoxy reactive anti-in the step (2)
Answer that temperature is -25~20 DEG C and the reaction time is 2~15h.
The molar ratio having between compounds of formula II, the buffer and the oxidant is 1:0.5~2.0:1.0
~4.0.
7. preparation method according to claim 1, which is characterized in that in the step (3), the third organic solvent
Including at least one of toluene, methylene chloride, chloroform, methanol and ethyl alcohol；
The acid reagent includes at least one of sulfuric acid, hydrochloric acid, acetic acid and phosphoric acid.
8. preparation method according to claim 1, which is characterized in that in the step (3), the ring-opening reaction it is anti-
It answers temperature -15~25 DEG C and the reaction time is 0.5~5h；The pH of reaction system is 1~5 during the ring-opening reaction carries out.
9. preparation method according to claim 1, which is characterized in that in the step (4), the 4th solvent includes
At least one of water, toluene, methylene chloride, chloroform, methanol, ethyl alcohol；
The alkaline reagent include in potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium acetate and sodium sulfite at least
It is a kind of.
10. preparation method according to claim 1, which is characterized in that in the step (4), the hydrolysis
Reaction temperature -15~65 DEG C and reaction time are 0.5~10h；The pH of reaction system is 8.5 during the hydrolysis carries out
~14.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811108472.3A CN109369768A (en) | 2018-09-21 | 2018-09-21 | The preparation method of Dexamethasone Intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811108472.3A CN109369768A (en) | 2018-09-21 | 2018-09-21 | The preparation method of Dexamethasone Intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109369768A true CN109369768A (en) | 2019-02-22 |
Family
ID=65401712
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811108472.3A Pending CN109369768A (en) | 2018-09-21 | 2018-09-21 | The preparation method of Dexamethasone Intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109369768A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276406A (en) * | 2022-01-06 | 2022-04-05 | 江苏远大仙乐药业有限公司 | Preparation method of desoximetasone intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4891426A (en) * | 1984-06-11 | 1990-01-02 | The Upjohn Company | 16α-methyl-17α 20-epoxysteroid and process |
-
2018
- 2018-09-21 CN CN201811108472.3A patent/CN109369768A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4891426A (en) * | 1984-06-11 | 1990-01-02 | The Upjohn Company | 16α-methyl-17α 20-epoxysteroid and process |
Non-Patent Citations (2)
| Title |
|---|
| DAVID G. HULCOOP ETAL: "Expedient synthesis of 17a,21-dihydroxy-9b,11b-Epoxy -16a-methylpregna-1,4-diene-3,20-dione 21-acetate from prednislone utilising a novel Mattox rearrangement", 《STEROIDS》 * |
| 张正之译: "《有机金属络合物化学》", 30 April 1990, 化学工业出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276406A (en) * | 2022-01-06 | 2022-04-05 | 江苏远大仙乐药业有限公司 | Preparation method of desoximetasone intermediate |
| CN114276406B (en) * | 2022-01-06 | 2023-12-19 | 江苏远大仙乐药业有限公司 | Preparation method of intermediate of deoxomilpine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105348412B (en) | A kind of purification process for the more glucose sodium that relaxes | |
| CN104961715B (en) | A kind of preparation method of Dapagliflozin | |
| CN103342663B (en) | A kind of preparation method of Anastrozole key intermediate | |
| CN106431993B (en) | A kind of preparation method of LCZ-696 key intermediates | |
| CN109369768A (en) | The preparation method of Dexamethasone Intermediate | |
| CN104356111B (en) | A kind of method for preparing dabigatran etcxilate mesylate hydrolysis impurity | |
| CN103214421B (en) | The industrialized preparing process of 2-sulfydryl-1-Methylimidazole | |
| CN104844593A (en) | Synthetic method for Apixaban drug intermediate | |
| CN108997377B (en) | Preparation method of E-type 7-ATCA | |
| CN109369487B (en) | Preparation method of high-purity cantharis yellow | |
| CN103664739B (en) | A kind of preparation method of Telaprevir intermediate | |
| CN106749457A (en) | A kind of preparation method of tylonolide | |
| CN114014863B (en) | Preparation method of bone marrow protective agent traasiril | |
| CN110498744A (en) | A kind of preparation method of 1- ethyl -3- nitrobenzene | |
| CN104761442A (en) | Method for preparing 1-(2, 6, 6-trimethyl-3-cyclohexenyl)-1, 3-butanedione | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN107383066A (en) | A kind of method of latamoxef acid deprotection base | |
| CN110684019B (en) | Preparation method of ticagrelor intermediate oxide impurity | |
| CN106518812A (en) | Preparation method of medetomidine and intermediate thereof | |
| CN106749055A (en) | A kind of preparation method of Fluconazole | |
| CN106083971A (en) | A kind of preparation method of (E) 3 α hydroxyl 6 ethylidene 7 ketone 5 β cholane 24 acid | |
| CN110790690A (en) | Synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid | |
| CN105481831B (en) | A kind of method for preparing dabigatran etexilate intermediate | |
| CN104496900A (en) | Method for preparing 2-methoxy-6-one-5,7,8-trihydro-quinoline | |
| CN115322118B (en) | Preparation method of benidipine hydrochloride intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: Southward dongwaihuan road 274100 in Shandong province Heze city Dingtao District Applicant after: Shandong srui Pharmaceutical Co., Ltd Applicant after: SHANDONG SAITUO BIOTECHNOLOGY CO., LTD. Address before: Southward dongwaihuan road 274100 in Shandong province Heze city Dingtao District Applicant before: Shandong Sirui Biomedical Co., Ltd. Applicant before: SHANDONG SAITUO BIOTECHNOLOGY CO., LTD. |
|
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190222 |