CN109678919A - A kind of preparation method of Methylprednisolone succinate impurity - Google Patents
A kind of preparation method of Methylprednisolone succinate impurity Download PDFInfo
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- CN109678919A CN109678919A CN201811606938.2A CN201811606938A CN109678919A CN 109678919 A CN109678919 A CN 109678919A CN 201811606938 A CN201811606938 A CN 201811606938A CN 109678919 A CN109678919 A CN 109678919A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
Abstract
The invention belongs to chemosynthesis technical fields, are related to a kind of preparation method of Methylprednisolone succinate impurity, it particularly relates to 11 β, 17 α, the pregnant steroid-Isosorbide-5-Nitrae of -6 Beta-methyl of 21- trihydroxy-diene -3,20- diketone -21- succinate preparation method.The present invention is with 11 β, 17 α, the pregnant Gona-4-ene-3 of 21- trihydroxy -6- methylene, 20- diketone is raw material, obtains 11 β, 17 α by a series of reduction reactions, esterification, oxidation reaction, hydrolysis etc., pregnant steroid-the Isosorbide-5-Nitrae of -6 Beta-methyl of 21- trihydroxy-diene -3,20- diketone -21- succinate.The present invention discloses the preparation method of the impurity for the first time, has many advantages, such as that synthesis clear, easy to operate, the obtained product purity in road is higher.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and in particular to 11 β, 17 α, the pregnant steroid-Isosorbide-5-Nitrae-of -6 Beta-methyl of 21- trihydroxy
The preparation method of diene -3,20- diketone -21- succinate.
Background technique
11 β, 17 α, the pregnant steroid-Isosorbide-5-Nitrae of -6 Beta-methyl of 21- trihydroxy-diene -3,20- diketone -21- succinate, is succinic acid
A kind of impurity of methylprednisolone, is recorded, structural formula is as follows according to European Pharmacopoeia:
Methylprednisolone succinate, structural formula are as follows:
Methylprednisolone succinate is artificial synthesized glucocorticoid.Glucocorticoid diffusion penetrates cell membrane, and and born of the same parents
Special receptor combines in slurry.Have anti-inflammatory, immune and antiallergic activity, for rheumatic disease, collagen diseases, skin disease,
The symptomatic treatment of allergic symptom, eye disease, enterogastric diseases, respiratory disease, edematous state etc., as immunosuppressor
And treat tumour, shock etc..
The impurity is of great significance for the research of Methylprednisolone succinate, it can be used for Methylprednisolone succinate production
The qualitative and quantitative analysis of middle impurity provides important to improve the quality standard of Methylprednisolone succinate for safe medication
Directive significance.
In order to preferably control the quality of Methylprednisolone succinate product, guarantee the drug safety of Methylprednisolone succinate
Property, need to do the impurity of Methylprednisolone succinate method validation, but announce 11 β, 17 α, 21- tri- currently without relevant report
Pregnant steroid-the Isosorbide-5-Nitrae of -6 Beta-methyl of hydroxyl-diene -3,20- diketone -21- succinate preparation method, therefore, it is necessary to the impurity
Synthesis technology furtherd investigate.
Summary of the invention
In view of this, the purpose of the present invention is to provide 11 β of one kind, 17 α, the pregnant steroid-Isosorbide-5-Nitrae-of -6 Beta-methyl of 21- trihydroxy
The preparation method of diene -3,20- diketone -21- succinate.
To achieve the above object, the technical solution of the present invention is as follows:
One kind 11 β, 17 α, the pregnant steroid-Isosorbide-5-Nitrae of -6 Beta-methyl of 21- trihydroxy-diene -3,20- diketone -21- succinate system
Preparation Method, this method are original with 11 β, 17 α, 21- trihydroxy -6- methylene pregn-4-ene-3,20-dione (Formula II compound)
Target compound (Formulas I) is made by chemical reactions such as a series of reduction, esterification, oxidation, hydrolysis, compound of formula H in material
It can be hydrolyzed and be made through esterification, mannich reaction and potassium carbonate by hydrocortisone, repeats no more herein.Specific reaction step is such as
Under:
1) Formula II compound obtains formula III compound in a solvent by the raw reduction reaction of catalytic reaction；
2) esterification occurs in a solvent for formula III compound and esterifying reagent, obtains formula IV compound；3)
Oxidation reaction occurs in a solvent and obtains Formula V compound for formula IV compound；
4) Formula V compound and alkali hydrolysis occur in a solvent obtain Formula IV compound；
5) Formula IV compound and esterifying reagent esterification occur in a solvent obtain compound of formula I；
The structural formula of compound and reaction process of reaction are as follows:
In above-mentioned reaction route, Formula II compound is 11 β, 17 α, the pregnant Gona-4-ene-3 of 21- trihydroxy -6- methylene, 20-
Diketone, formula III compound are 11 β, and 17 α, -6 Beta-methyl pregn-4-ene-3,20-dione of 21- trihydroxy, formula IV compound is 11
β, -6 Beta-methyl pregn-4-ene-3,20-dione -21- acetic acid esters of 17 alpha-dihydroxy, Formula V compound are 11 β, 17 alpha-dihydroxys -
Pregnant steroid-the Isosorbide-5-Nitrae of 6 Beta-methyls-diene -3,20- diketone -21- acetic acid esters, Formula IV compound are 11 β, 17 α, -6 β of 21- trihydroxy-first
Pregnant steroid-Isosorbide-5-Nitrae-diene -3, the 20- diketone of base.
Further, in step (1), reaction dissolvent is anhydrous methanol/cyclohexene, dehydrated alcohol/cyclohexene one kind or more
Kind；The ratio of alcohol and cyclohexene is 10v/1v~1v/1v.
As a preference, the solvent reacted in step (1) is dehydrated alcohol/cyclohexene, ratio 5v/1v.
Further, in step (1) catalyst include mass parts be 5% or 10% Pd/C it is one or more；Reaction temperature
Degree is 50 DEG C~80 DEG C.
As a preference, catalyst is the Pd/C that mass parts are 10% in step (1), extent of reaction can be accelerated, contracted
Short reaction time.
Further, in step (2), esterifying reagent be include formic acid, acetic acid, acetic anhydride it is one or more；Reaction temperature
It is 0~50 DEG C；Triethylamine is also added into reaction.
Further, in step (2), the molar ratio of formula III compound and esterifying reagent is 1: 1~1: 1.5.
As a preference, acylating reagent is acetic anhydride in step (2)；The molar ratio of formula III compound and acetic anhydride is
1:1.2；Reaction temperature is 22 DEG C~28 DEG C.
Further, in step (3), reaction oxidant is dichlorocyanobenzoquinone (DDQ), pro-oxidant N, O- bis- (three
Methyl-monosilane base)Trifluoroacetamide(BSTFA), the molar ratio of formula IV compound and DDQ and BSTFA are 1: 1.0: 3.0~1: 2.0
∶6.0。
Further, in step (3), reaction dissolvent is Isosorbide-5-Nitrae-dioxane, and reaction temperature is 70 DEG C~120 DEG C.
As a preference, the molar ratio of formula IV compound and DDQ and BSTFA are 1: 1.1: 4.7 in step (3)；Reaction
Temperature is 100 DEG C~105 DEG C.
Further, in step (4), alkali be include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide it is one or more,
The molar ratio of Formula V compound and alkali is 1: 5~1: 15.
Further, in step (4), reaction dissolvent is methylene chloride and methanol, and volume ratio is 1v/1v~1v/5v；Reaction
Temperature is 0 DEG C~50 DEG C.
As a preference, alkali is potassium carbonate in step (4)；The molar ratio 1: 10 of Formula V compound and alkali；Reaction dissolvent
For methylene chloride/methanol, ratio 1v/2v；Reaction temperature is 25 DEG C~30 DEG C.
Further, in step (5), esterifying reagent is succinic anhydride；The molar ratio of Formula IV compound and succinic anhydride is 1: 1
~1: 5.
Further, in step (5), answering solvent is DMF；Reaction temperature is 0 DEG C~50 DEG C；Three second are also added into reaction
Amine.
As a preference, the molar ratio of Formula IV compound and succinic anhydride is 1: 3 in step (5)；Reaction temperature is 15
DEG C~20 DEG C；Extracted after the reaction was completed, washing, preparation column purification obtains compound of formula I, 95% or more purity.
The beneficial effects of the present invention are:
1) present invention discloses a kind of impurity of preparation Methylprednisolone succinate, 11 β, 17 α, -6 β of 21- trihydroxy-for the first time
Pregnant steroid-the Isosorbide-5-Nitrae of methyl-diene -3,20- diketone -21- succinate method studies meaning for the impurity of Methylprednisolone succinate
Justice is quite great, it can be used for the qualitative and quantitative analysis of impurity in Methylprednisolone succinate production, improves succinic acid first and sprinkles
The quality standard of nylon, to provide important directive significance for safe medication.
2) present invention provides 11 β, 17 α, the pregnant steroid-Isosorbide-5-Nitrae of -6 Beta-methyl of 21- trihydroxy-diene -3,20- diketone -21- amber
Acid esters preparation method, with 11 β, 17 α, 21- trihydroxy -6- methylene pregn-4-ene-3,20-dione is raw material, anti-by restoring
Answer, esterification, oxidation reaction, hydrolysis and esterification etc. obtain target compound, have that synthesis path is clear, operation
The advantages that product purity easy, obtained is higher.
Detailed description of the invention
Fig. 1 reacting flow chart
Specific embodiment
It detailed description of a preferred embodiment of the present invention will be given below.The reality of actual conditions is not specified in preferred embodiment
Proved recipe method, usually according to normal condition, illustrated embodiment are but not to be to preferably be illustrated to the contents of the present invention
The contents of the present invention are only limitted to illustrated embodiment.Those skilled in the art according to foregoing invention content to embodiment into
The nonessential modifications and adaptations of row, still fall within protection scope of the present invention.
Embodiment 1
Step 1: 11 β, 17 α, the preparation of -6 Beta-methyl pregn-4-ene-3,20-dione (formula III) of 21- trihydroxy
To N2Addition 11 β of 10.0g in the reaction flask of protection, 17 α, the pregnant Gona-4-ene-3 of 21- trihydroxy -6- methylene,
20- diketone, 250ml dehydrated alcohol and 50ml cyclohexene, stirring, add 0.68g triethylamine and 4.0g 10%Pd/C, heat up
To 65~70 DEG C.In 65~70 DEG C of insulation reaction 3h.By reaction solution Filtration of catalyst Pd/C, filtrate decompression is evaporated, and obtains class
White solid 9.4g, yield 93.5%, 6 β-content of isomer 94.7%.
Step 2: 11 β, the system of -6 Beta-methyl pregn-4-ene-3,20-dione -21- acetic acid esters (formula IV) of 17 alpha-dihydroxy
It is standby
To N29.0g11 β, 17 α, the pregnant Gona-4-ene-3 of -6 Beta-methyl of 21- trihydroxy, 20- bis- are added in the reaction flask of protection
Ketone (formula III) and 135ml methylene chloride, stirring, add 3.6g triethylamine and 2.93g acetic anhydride, finish anti-in 25 DEG C of heat preservations
Reaction system should be poured into 180ml ice water to terminating, be stirred, stand liquid separation, water phase is extracted twice with 200ml methylene chloride,
Merge organic phase, then is washed three times with 200ml saturated brine；Organic phase evaporated under reduced pressure obtains 9.8g light yellow solid, yield
98.0%.
Step 3: 11 β, the pregnant steroid-Isosorbide-5-Nitrae of -6 Beta-methyl of 17 alpha-dihydroxy-diene -3,20- diketone -21- acetic acid esters (Formula V)
Preparation
11 β of 9.5g, -6 Beta-methyl pregn-4-ene-3,20-dione of 17 alpha-dihydroxy-is added into reaction flask at room temperature
21- acetic acid esters (formula IV) and 190ml Isosorbide-5-Nitrae-methylene chloride, stirring, add 5.7g DDQ and 27.5g BSTFA, are warming up to
100~105 DEG C, insulation reaction 4 hours.Reaction system is cooled to room temperature, by reaction system pour into 400ml methylene chloride and
The NaHSO of 400ml 1%3In solution, stirring stands liquid separation, and water phase is extracted twice with 400ml methylene chloride, merges organic phase,
It is washed twice again with 300ml saturated brine；Organic phase evaporated under reduced pressure crosses column purification.Eluant, eluent: n-hexane/ethyl acetate=3/
1；Purer product eluent is collected, evaporated under reduced pressure obtains 7.2g light yellow oil, yield 75.4%.
Step 4: 11 β, 17 α, the preparation of the pregnant steroid-Isosorbide-5-Nitrae of -6 Beta-methyl of 21- trihydroxy-diene -3,20- diketone (Formula IV)
To N27.0g11 β, the pregnant steroid-Isosorbide-5-Nitrae-diene -3,20- of -6 Beta-methyl of 17 alpha-dihydroxy are added in the reaction flask of protection
Diketone -21- acetic acid esters (Formula V), 140ml methylene chloride and 280ml methanol, stirring, are added dropwise at 25 DEG C~30 DEG C
23.2gK2CO3The solution that/140ml water is made into, drop finish in 25 DEG C~30 DEG C insulation reaction 1 hour.Reaction solution is poured into 700ml to satisfy
In salt water and 1120ml methylene chloride, stirring stands liquid separation, and water phase is extracted twice with 700ml methylene chloride, merges organic
Phase, then washed twice with 800ml saturated brine；Organic phase evaporated under reduced pressure obtains 6.2g light yellow solid, yield 98.4%.
Step 5: 11 β, 17 α, the pregnant steroid-Isosorbide-5-Nitrae of -6 Beta-methyl of 21- trihydroxy-diene -3,20- diketone -21- succinate
The preparation of (Formulas I)
To N2Addition 11 β of 6.0g in the reaction flask of protection, 17 α, the pregnant steroid-Isosorbide-5-Nitrae-diene -3 of -6 Beta-methyl of 21- trihydroxy,
20- diketone (Formula IV) and 120ml DMF, stirring, add 1.9g triethylamine and 4.8g succinic anhydride, anti-in 15~20 DEG C of heat preservations
Answer 1.5h.Reaction solution is poured into 600ml ice water, is stirred, then be extracted twice with 900ml methylene chloride, organic phase is merged, is used
700ml saturated brine washes twice；Organic phase evaporated under reduced pressure, excessively preparation column purification, the purer eluent of collection, evaporated under reduced pressure,
Obtain off-white powder 4.3g, yield 56.6%.
It is 95.4% that HPLC, which detects purity,.
MS (ESI): [M+H]+=475.4, [2M+H]+=949.8.
IR:3520,3482,2957~2839,1746~1653,1610~1595,1458~1238,1172~1136.
Embodiment 2
11 β, 17a, the preparation of -6 Beta-methyl pregn-4-ene-3,20-dione (formula III) of 21- trihydroxy
To N2Addition 11 β of 10.0g in the reaction flask of protection, 17a, the pregnant Gona-4-ene-3 of 21- trihydroxy -6- methylene,
20- diketone, 250ml dehydrated alcohol and 50ml cyclohexene, stirring, add 0.68g triethylamine and 4.0g 10%Pd/C, heat up
To 65~70 DEG C.In 65~70 DEG C of insulation reaction 3h.By reaction solution Filtration of catalyst Pd/C, filtrate decompression is evaporated, and obtains class
White solid 9.4g, yield 93.5%, 6 β-content of isomer 94.7%.
Embodiment 3
11 β, the preparation of -6 Beta-methyl pregn-4-ene-3,20-dione -21- acetic acid esters (formula IV) of 17 alpha-dihydroxy
To N29.0g11 β, 17 α, the pregnant Gona-4-ene-3 of -6 Beta-methyl of 21- trihydroxy, 20- bis- are added in the reaction flask of protection
Ketone (formula III) and 135ml methylene chloride, stirring, add 3.6g triethylamine and 2.93g acetic anhydride, finish anti-in 25 DEG C of heat preservations
Reaction system should be poured into 180ml ice water to terminating, be stirred, stand liquid separation, water phase is extracted twice with 200ml methylene chloride,
Merge organic phase, then is washed three times with 200ml saturated brine；Organic phase evaporated under reduced pressure obtains 9.8g light yellow solid, yield
98.0%.
Embodiment 4
11 β, the pregnant steroid-Isosorbide-5-Nitrae of -6 Beta-methyl of 17 alpha-dihydroxy-diene -3,20- diketone -21- acetic acid esters (Formula V) preparation room
11 β of 9.5g, -6 Beta-methyl pregn-4-ene-3,20-dione -21- acetic acid esters (formula of 17 alpha-dihydroxy is added under temperature into reaction flask
IV) and 190ml Isosorbide-5-Nitrae-methylene chloride, stirring add 5.7g DDQ and 27.5g BSTFA, are warming up to 100~105 DEG C, protect
Temperature reaction 4 hours.Reaction system is cooled to room temperature, reaction system is poured into 400ml methylene chloride and 400ml1%
NaHS03In solution, stirring stands liquid separation, and water phase is extracted twice with 400ml methylene chloride, merges organic phase, then full with 300ml
It is washed twice with salt water；Organic phase evaporated under reduced pressure crosses column purification.Eluant, eluent: n-hexane/ethyl acetate=3/1；It collects purer
Product eluent, evaporated under reduced pressure obtain 7.2g light yellow oil, yield 75.4%.
Embodiment 5
11 β, 17 α, the preparation of the pregnant steroid-Isosorbide-5-Nitrae of -6 Beta-methyl of 21- trihydroxy-diene -3,20- diketone (Formula IV)
To N27.0g11 β, the pregnant steroid-Isosorbide-5-Nitrae-diene -3,20- of -6 Beta-methyl of 17 alpha-dihydroxy are added in the reaction flask of protection
Diketone -21- acetic acid esters (Formula V), 140ml methylene chloride and 280ml methanol, stirring, are added dropwise at 25 DEG C~30 DEG C
23.2gK2CO3The solution that/140ml water is made into, drop finish in 25 DEG C~30 DEG C insulation reaction 1 hour.Reaction solution is poured into 700ml to satisfy
In salt water and 1120ml methylene chloride, stirring stands liquid separation, and water phase is extracted twice with 700ml methylene chloride, merges organic
Phase, then washed twice with 800ml saturated brine；Organic phase evaporated under reduced pressure obtains 6.2g light yellow solid, yield 98.4%.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to excellent
Embodiment is selected to describe the invention in detail, those skilled in the art should understand that, it can be to skill of the invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the scope of the claims of invention.
Claims (14)
1. a kind of preparation method of Methylprednisolone succinate impurity, which is characterized in that the impurity is 11 β, tri- hydroxyl of 17 α, 21-
Pregnant steroid -1,4- diene -3,20- diketone -21- the succinate of -6 Beta-methyl of base；The method is with 11 β of Formula II compound, 17 α, 21-
Trihydroxy -6- methylene pregn-4-ene-3,20-dione is raw material, by by the raw reduction reaction of catalytic reaction, obtaining formula in a solvent
III compound；
2. preparation method according to claim 1, which is characterized in that the formula III compound and esterifying reagent are in solvent
Middle generation esterification, obtains formula IV compound；
3. preparation method according to claim 2, which is characterized in that it is anti-that oxidation occurs in a solvent for the formula IV compound
Deserved Formula V compound；
4. preparation method according to claim 3, which is characterized in that water occurs in a solvent for the Formula V compound and alkali
Solution reacts to obtain Formula IV compound；
5. the preparation method according to claim 4, which is characterized in that the Formula IV compound and esterifying reagent are in a solvent
Esterification occurs and obtains 11 β of compound of formula I, 17 α, the pregnant steroid -1,4- diene -3,20- diketone -21- amber of -6 Beta-methyl of 21- trihydroxy
Amber acid esters；
6. preparation method according to claim 1, which is characterized in that the solvent is anhydrous methanol/cyclohexene, anhydrous second
Alcohol/cyclohexene is one or more, and the volume ratio of alcohol and cyclohexene is 10v/1v~1v/1v；Catalyst includes that mass parts are 5%
Or 10% Pd/C it is one or more；Reaction temperature is 50 DEG C~80 DEG C.
7. preparation method according to claim 2, which is characterized in that the esterifying reagent be include formic acid, acetic acid, acetic acid
Acid anhydride it is one or more；The solvent of reaction is methylene chloride；Reaction temperature is 0~50 DEG C；Triethylamine is also added into reaction.
8. the preparation method according to claim 2 or 7, which is characterized in that the molar ratio of formula III compound and esterifying reagent
For 1:1~1:1.5.
9. preparation method according to claim 3, which is characterized in that oxidant DDQ, pro-oxidant BSTFA；Formula IV
The molar ratio of compound and DDQ and BSTFA are 1:1.0:3.0~1:2.0:6.0.
10. preparation method according to claim 3 or 9, which is characterized in that reaction dissolvent is Isosorbide-5-Nitrae-dioxane, reaction
Temperature is 70 DEG C~120 DEG C.
11. the preparation method according to claim 4, which is characterized in that the alkali be include sodium carbonate, potassium carbonate, hydrogen-oxygen
Change sodium, potassium hydroxide it is one or more；The molar ratio of Formula V compound and alkali is 1:5~1:15.
12. the preparation method according to claim 4 or 11, which is characterized in that the reaction dissolvent is methylene chloride and first
Alcohol, volume ratio are 1v/1v~1v/5v；Reaction temperature is 0 DEG C~50 DEG C.
13. preparation method according to claim 5, which is characterized in that the esterifying reagent is succinic anhydride；Formula IV chemical combination
The molar ratio of object and succinic anhydride is 1:1~1:5.
14. the preparation method according to claim 5 or 13, which is characterized in that reaction dissolvent DMF；Reaction temperature is 0 DEG C
~50 DEG C；Triethylamine is also added into reaction.
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