CN108033990A - The preparation method of Dexamethasone Intermediate - Google Patents
The preparation method of Dexamethasone Intermediate Download PDFInfo
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- CN108033990A CN108033990A CN201711483575.3A CN201711483575A CN108033990A CN 108033990 A CN108033990 A CN 108033990A CN 201711483575 A CN201711483575 A CN 201711483575A CN 108033990 A CN108033990 A CN 108033990A
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- dexamethasone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
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Abstract
The present invention provides a kind of preparation method of Dexamethasone Intermediate, it is related to bulk pharmaceutical chemicals synthesis field, it is to synthesize 17 α CN through cyanogenation in buffer salt system by chemical compounds I, products therefrom carries out 17 β CN of position rotaring rearrangement reaction synthesis in alkalescent inorganic salt solution, that is compound III, the present invention is compared with traditional handicraft, 17 α CN are synthesized with buffer salt system, again 17 β CN are synthesized through translocation reaction, effectively control the generation of 5 CN impurity in reaction process, reaction yield and purity are improved, reduces production cost, is adapted to large-scale production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, more particularly to a kind of preparation method of Dexamethasone Intermediate.
Background technology
Steroid drugs is a kind of medicine for being widely used in clinic；Dexamethasone, alias Dexamethasone, dexamethasone acetate,
It is mainly used for anaphylactias such as anaphylaxis and auto-immune inflammatory disease, serious bronchial asthma, dermatitis etc., is curing
It is widely used on, market economy is profitable.
Synthesis for dexamethasone and the like, most of difficult point concentrate on the synthesis of 17 side chains；At present, closing
During into 17 side chains of dexamethasone, largely realized by following reaction scheme：
The synthetic route, substrate are made, which receives directly in inorganic weak bases salt system with acetone cyanohydrin reaction
Rate is low, and about 83%, the reason is that because producing 5-CN impurity compounds IV in reaction process, more than 14% is accounted for, causes yield low,
Cost increase, therefore, the generation of control impurity compound IV is particularly critical in reaction process, its structural formula is as follows：
The disclosure of background above technology contents is only used for inventive concept and the technical solution that auxiliary understands the present invention, it is not
The prior art of present patent application is necessarily belonged to, shows the applying date of the above in present patent application in no tangible proof
In the case of disclosed, above-mentioned background technology should not be taken to the novelty and creativeness of evaluation the application.
The content of the invention
It is an object of the invention to propose a kind of preparation method of the high Dexamethasone Intermediate of high income, purity, specifically
Technical solution is as follows：
A kind of preparation method of Dexamethasone Intermediate, including following reactions steps：
(1) cyanogenation
(2) translocation reaction
In formula, ring A and B represent following group：
In formula, R3 is the residue of ether or ester, and when R3 is the residue of ether, R3 is the alkyl of C1-C2, the aryl of C6-C8；When
When R3 represents the residue of ester, it is-COR3；
In formula, n=2 or 3；
In formula, R9 is α-OH or H；
The cyanogenation obtains in buffer salt system using chemical compounds I as raw material with cyano compound through cyanogenation
To compound ii；
Dexamethasone is made through translocation reaction in alkalescent inorganic salt solution for compound ii in the translocation reaction
Intermediate, up to compound III.
Preferably, the preparation method of the Dexamethasone Intermediate, the cyanogenation are in buffer salt system
Organic solvent 1 is added, chemical compounds I is added, stirs evenly, adds cyano compound, the reaction was complete for TLC monitoring, through elutriation, subtracts
Pressure filters, compound ii is made in drying.
Preferably, the preparation method of the Dexamethasone Intermediate, the translocation reaction are in alkalescent inorganic salts
Organic solvent 2, compound ii are sequentially added in aqueous solution, is stirred evenly, insulation reaction finishes, and TLC monitoring adds after the reaction was complete
Water elutriation, the pH for adjusting reaction system are 6.9-7.2, and Dexamethasone Intermediate, i.e. compound III is made in filtering, rinsing, drying.
Preferably, the preparation method of the Dexamethasone Intermediate, the buffer salt for borax-sodium carbonate, boric acid-
One kind in potassium chloride, borax-boric acid.
Preferably, the preparation method of the Dexamethasone Intermediate, the cyano compound is Cymag, potassium cyanide
Or one kind in acetone cyanohydrin.
Preferably, the preparation method of the Dexamethasone Intermediate, the organic solvent 1 is methanol, ethanol, or first
The mixed solvent of alcohol, ethanol and tetrahydrofuran.
Preferably, the preparation method of the Dexamethasone Intermediate, the organic solvent 2 is methanol, ethanol, acetone
Deng one kind in water-soluble solvent.
Preferably, the preparation method of the Dexamethasone Intermediate, the alkalescent inorganic salts are sodium carbonate, carbonic acid
One kind in potassium, sodium acid carbonate, saleratus.
Preferably, mole of the preparation method of the Dexamethasone Intermediate, the chemical compounds I and cyano compound
Than for 1:(3-5).
It is further preferred that the preparation method of the Dexamethasone Intermediate, the condition of the cyanogenation be
15-25h is reacted at 15-50 DEG C, preferable reaction temperature is 25-30 DEG C.
It is further preferred that the preparation method of the Dexamethasone Intermediate, the compound ii and inorganic salts
Molar ratio is 1:(0.18-0.3)；The condition of translocation reaction is that 10-15h, preferable reaction temperature 25- are reacted at 15-50 DEG C
30℃。
Compared with prior art, the present invention advantage have it is following：
(1) present invention compared with traditional handicraft, with buffer salt system synthesize 17 α-CN, then through translocation reaction synthesize 17 β-
CN, effectively controls the generation of 5-CN impurity in reaction process, improves reaction yield and purity, reduces production cost；
(2) reaction stability of the present invention is good, easy to operate, is adapted to large-scale production.
Brief description of the drawings
Fig. 1 is the liquid phase figure of the intermediate of the dexamethasone prepared by 1 translocation reaction of the embodiment of the present invention, i.e. compound III
Spectrum.
Embodiment
A kind of preparation method of Dexamethasone Intermediate, including following reactions steps：
(1) cyanogenation
(2) translocation reaction
In formula, ring A and B represent following group：
In formula, R3 is the residue of ether or ester, and when R3 is the residue of ether, R3 is the alkyl of C1-C2, the aryl of C6-C8；When
When R3 represents the residue of ester, it is-COR3；
In formula, n=2 or 3；
In formula, R9 is α-OH or H；
The cyanogenation obtains in buffer salt system using chemical compounds I as raw material with cyano compound through cyanogenation
To compound ii；
Dexamethasone is made through translocation reaction in alkalescent inorganic salt solution for compound ii in the translocation reaction
Intermediate, up to compound III.
The cyanogenation is that organic solvent 1 is added in buffer salt system, adds chemical compounds I, stirs evenly, adds
Enter cyano compound, the reaction was complete for TLC monitoring, is filtered through crystallization, decompression, compound ii is made in drying.
The translocation reaction is that organic solvent 2, compound ii are sequentially added in inorganic weak bases solution, is stirred evenly,
Insulation reaction finishes, and TLC monitoring adds water elutriation after the reaction was complete, and the pH for adjusting reaction system be 6.9-7.2, filtering, rinse,
Dexamethasone Intermediate, i.e. compound III is made in drying.
The buffer salt is borax-sodium carbonate, one kind in boric acid-potassium chloride, borax-boric acid.
The cyano compound is one kind in Cymag, potassium cyanide or acetone cyanohydrin.
The organic solvent 1 is methanol, ethanol, or its mixed solvent with tetrahydrofuran.
The organic solvent 2 is one kind in the water-soluble solvents such as methanol, ethanol, acetone.
The alkalescent inorganic salts are sodium carbonate, one kind in potassium carbonate, sodium acid carbonate, saleratus.
The chemical compounds I and the molar ratio of cyano compound are 1:(3-5).
The condition of the cyanogenation is to react 15-25h at 15-50 DEG C.
The condition of the translocation reaction is to react 10-15h at 15-50 DEG C.
A kind of preparation method of Dexamethasone Intermediate, specific experimental implementation are as follows：
Embodiment 1
Cyanogenation
At room temperature, the fitting temperature meter toward a clean dried, added in churned mechanically 1000ml three neck round bottom flask
100ml boraxs-borate buffer salt, 75ml methanol, stirs lower addition 50g chemical compounds Is, that is, -16 Alpha-Methyl -4- of the Alpha-hydroxy of androstane -9
Alkene -3,17- diketone, stirs evenly, and adds 43ml acetone cyanohydrins, and being warming up to control in 15 DEG C of insulation reactions 25h, TLC, the reaction was complete
(solvent：Acetone/petroleum ether=1:2) 500ml water elutriations, are added dropwise, stir 0.5h, decompression filters, and filter cake water wash is into
Property, 45 DEG C of drying of solid obtain 51.5g products, yield：103%, purity：96.7%.The detection parameters of purity are：HPLC flows
Phase：Acetonitrile/water=55:45, Detection wavelength 254nm.
Translocation reaction
At room temperature, toward the fitting temperature meter of a clean dried, add in churned mechanically 1000ml three neck round bottom flask
2.85g sodium carbonate, 76ml water, stirring is molten to ask, and adds 103ml methanol, 51.5g compound iis, that is,-17 β of the Alpha-hydroxy of androstane-9-hydroxyl
- 17 alpha-cyano -4- alkene -3- ketone (i.e. above-mentioned cyaniding product) of the Alpha-Methyl of base -16, stirs evenly, is warming up to 15 DEG C of insulation reactions
Control the reaction was complete (solvent in 15h, TLC：Ethyl acetate/n-hexane=1:2) 10~15 DEG C, are cooled to, 500ml water water is added dropwise
Analysis, stirs 0.5h, and 10% hydrochloric acid regulation system PH=7 is added dropwise, and decompression filters, and filter cake wet feed adds 150ml acetone, rises to 40 DEG C and stirs
0.5h is mixed, 50ml water is added dropwise, is down to 25 DEG C of suction filtrations, the acetone elution of filter cake ice, 40 DEG C of drying of solid, obtain the production of 49.4g targets
Thing, yield：96.0%, purity 98.5%.The detection parameters of purity are：HPLC mobile phases：Acetonitrile/water=55:45, Detection wavelength
For 254nm.
Embodiment 2
Cyanogenation
At room temperature, the fitting temperature meter toward a clean dried, added in churned mechanically 1000ml three neck round bottom flask
100ml boraxs-sodium carbonate buffer salt, 75ml ethanol, lower addition 50g chemical compounds Is, that is, -9 Alpha-hydroxy of androstane -3- methoxyl groups of stirring -
16 Alpha-Methyl -3,5- diene -17- ketone, stir evenly, and add 36.62g Cymags, are warming up in 25 DEG C of insulation reactions 22h, TLC
Control the reaction was complete (solvent：Acetone/petroleum ether=1:2) 500ml water elutriations, are added dropwise, stir 0.5h, decompression filters, and filter cake is used
For water wash to neutrality, 45 DEG C of drying of solid, obtain 51.0g products, yield：102%, purity：96.8%.The detection parameters of purity
It is：HPLC mobile phases：Acetonitrile/water=55:45, Detection wavelength 254nm.
Translocation reaction
At room temperature, toward the fitting temperature meter of a clean dried, add in churned mechanically 1000ml three neck round bottom flask
12.31g potassium carbonate, 76ml water, stirring is molten to ask, and adds 103ml ethanol, 51.0g compound iis, that is, -9 α of androstane -3- methoxyl groups-hydroxyl
- 17 alpha-cyano -3,5- diene of -16 Alpha-Methyl of the beta-hydroxy of base -17 (i.e. above-mentioned cyaniding product), stirs evenly, is warming up to 25 DEG C of guarantors
Temperature reaction 14h, control the reaction was complete (solvent in TLC：Ethyl acetate/n-hexane=1:2) 10~15 DEG C, are cooled to, is added dropwise
30% hydrochloric acid regulation system PH=2~3, insulation reaction 0.5h is complete to methoxy hydrolysis, and 500ml water elutriations are added dropwise, stir 0.5h,
Decompression filters, and filter cake is washed to neutrality, and wet feed adds 150ml acetone, rises to 40 DEG C of stirring 0.5h, 50ml water is added dropwise, is down to 25
DEG C filter, the elution of the acetone of filter cake ice, 40 DEG C of drying of solid, obtain 46.0g target products, yield：90.2%, purity
98.5%.The detection parameters of purity are：HPLC mobile phases：Acetonitrile/water=55:45, Detection wavelength 254nm.
Embodiment 3
Cyanogenation
At room temperature, the fitting temperature meter toward a clean dried, added in churned mechanically 1000ml three neck round bottom flask
100ml boraxs-potassium chloride buffer salt, 75ml methanol, the lower addition 50g chemical compounds Is, that is, Alpha-Methyl -4,9 of androstane -16 (11) of stirring -
Diene -3,17- diketone, stirs evenly, and adds 28.21g potassium cyanide, is warming up to control in 30 DEG C of insulation reactions 20h, TLC and has reacted
(solvent entirely：Acetone/petroleum ether=1:2), be added dropwise 500ml water elutriations, stir 0.5h, decompression filter, filter cake with water wash extremely
Neutrality, 45 DEG C of drying of solid, obtains 48.6g products, yield：97.2%, purity：97.4%.The detection parameters of purity are：HPLC flows
Dynamic phase：Acetonitrile/water=55:45, Detection wavelength 254nm.
Translocation reaction
At room temperature, toward the fitting temperature meter of a clean dried, add in churned mechanically 1000ml three neck round bottom flask
3.6g sodium acid carbonates, 76ml water, stirring is molten to ask, addition 103ml acetone, and 48.6g compound iis, that is,-16 α of the beta-hydroxy of androstane-17-
Methyl-17 alpha-cyano -4,9 (11)-diene -3- ketone (i.e. above-mentioned cyaniding product), stirs evenly, is warming up to 30 DEG C of insulation reactions
Control the reaction was complete (solvent in 13h, TLC：Ethyl acetate/n-hexane=1:2) 10~15 DEG C, are cooled to, 500ml water water is added dropwise
Analysis, stirs 0.5h, and 10% hydrochloric acid regulation system PH=7 is added dropwise, and decompression filters, and filter cake wet feed adds 150ml acetone, rises to 40 DEG C and stirs
0.5h is mixed, 50ml water is added dropwise, is down to 25 DEG C of suction filtrations, the acetone elution of filter cake ice, 40 DEG C of drying of solid, obtain the production of 46.4g targets
Thing, yield：95.5%, purity 97.9%.The detection parameters of purity are：HPLC mobile phases：Acetonitrile/water=55:45, Detection wavelength
For 254nm.
Embodiment 4
Cyanogenation
At room temperature, toward the fitting temperature meter of a clean dried, 50ml is added in churned mechanically 500ml three neck round bottom flask
Borax-borate buffer salt, 25ml methanol and 12.5ml tetrahydrofurans, the lower addition 25g chemical compounds Is, that is, Alpha-Methyl of androstane -16 of stirring -
5- alkene -17- ketone -3- ketone contracting ring 3- (1,2- ethylene glycol), stir evenly, and add 26.5ml acetone cyanohydrins, are warming up to 50 DEG C of insulations
15h is reacted, control the reaction was complete (solvent in TLC：Acetone/petroleum ether=1:2) 10-15 DEG C, is cooled to, 200ml water water is added dropwise
Analysis, stirs 0.5h, and decompression filters, filter cake water wash to neutrality, and 45 DEG C of drying of solid, obtain 24.0g products, yield：96.0%,
Purity：97.5%.The detection parameters of purity are：HPLC mobile phases：Acetonitrile/water=55:45, Detection wavelength 254nm.
Translocation reaction
At room temperature, toward the fitting temperature meter of a clean dried, 1.9g is added in churned mechanically 500ml three neck round bottom flask
Sodium carbonate, 25ml water, stirring is molten to ask, and adds 50ml acetone, stirs evenly, adds 24.0g compound iis, that is, beta-hydroxy of androstane-17-16
Alpha-cyano -5- alkene -3- ketone contracting ring the 3- of Alpha-Methyl -17 (1,2- ethylene glycol) (i.e. above-mentioned cyaniding product), stir evenly, are warming up to 50
Control the reaction was complete (solvent in DEG C insulation reaction 10h, TLC：Ethyl acetate/n-hexane=1:2) 10~15 DEG C, are cooled to, drop
Add 30% hydrochloric acid regulation system PH=2~3, insulation reaction 0.5h is complete to ketal protection hydrolysis, and 500ml water elutriations are added dropwise, stir
0.5h, decompression filter, and filter cake is washed to neutrality, and filter cake wet feed adds 100ml acetone, rise to 40 DEG C of stirring 0.5h, 25ml is added dropwise
Water, is down to 25 DEG C of suction filtrations, the acetone elution of filter cake ice, 40 DEG C of drying of solid, obtain 20.45g target products, yield：85.2%,
Purity 98.2%.The detection parameters of purity are：HPLC mobile phases：Acetonitrile/water=55:45, Detection wavelength 254nm.
Above content is to combine specific/preferred embodiment further description made for the present invention, it is impossible to
Assert that the specific implementation of the present invention is confined to these explanations.Come for general technical staff of the technical field of the invention
Say, without departing from the inventive concept of the premise, it can also make some replacements or modification to the embodiment that these have been described,
And these are substituted or variant should all be considered as belonging to protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Dexamethasone Intermediate, it is characterised in that including following reactions steps：
(1) cyanogenation
(2) translocation reaction
In formula, ring A and B represent following group：
In formula, R3 is the residue of ether or ester, and when R3 is the residue of ether, R3 is the alkyl of C1-C2, the aryl of C6-C8；When R3 generations
During the residue of table ester, it is-COR3；
In formula, n=2 or 3；
In formula, R9 is α-OH or H；
The cyanogenation is using chemical compounds I as raw material, and in buffer salt system and cyano compound is through cyanogenation
Compound II；
The translocation reaction is made among dexamethasone for compound ii in alkalescent inorganic salt solution through translocation reaction
Body, up to compound III.
2. the preparation method of Dexamethasone Intermediate as claimed in claim 1, it is characterised in that：The cyanogenation be
Organic solvent 1 is added in buffer salt system, chemical compounds I is added, stirs evenly, adds cyano compound, TLC monitoring has been reacted
Entirely, filtered through elutriation, decompression, compound ii is made in drying.
3. the preparation method of Dexamethasone Intermediate as claimed in claim 1, it is characterised in that：The translocation reaction be
Organic solvent 2, compound ii are sequentially added in alkalescent inorganic salt solution, is stirred evenly, insulation reaction finishes, TLC monitoring
After the reaction was complete, add water elutriation, Dexamethasone Intermediate, i.e. compound III is made in filtering, rinsing, drying.
4. such as the preparation method of claim 1-2 any one of them Dexamethasone Intermediates, it is characterised in that：The buffering
Salt is borax-sodium carbonate, one kind in boric acid-potassium chloride, borax-boric acid.
5. such as the preparation method of claim 1-2 any one of them Dexamethasone Intermediates, it is characterised in that：The cyano group
Compound is one kind in Cymag, potassium cyanide or acetone cyanohydrin.
6. the preparation method of Dexamethasone Intermediate as claimed in claim 2, it is characterised in that：The organic solvent 1 is
Methanol, ethanol, or the mixed solvent of methanol, ethanol and tetrahydrofuran；The organic solvent 2 is methanol, ethanol, the one of acetone
Kind.
7. such as the preparation method of claim 1-3 any one of them Dexamethasone Intermediates, it is characterised in that：The weak base
Property inorganic salts be sodium carbonate, potassium carbonate, sodium acid carbonate, one kind in saleratus.
8. the preparation method of Dexamethasone Intermediate as claimed in claim 2, it is characterised in that：The chemical compounds I and cyanogen
The molar ratio of based compound is 1:(3-5).
9. such as the preparation method of claim 1-2 any one of them Dexamethasone Intermediates, it is characterised in that：The cyaniding
The condition of reaction is to react 15-25h at 15-50 DEG C.
10. the preparation method of Dexamethasone Intermediate as claimed in claim 3, it is characterised in that：The compound ii and
The molar ratio of inorganic salts is 1:(0.18-0.3)；The condition of translocation reaction is to react 10-15h at 15-50 DEG C.
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| CN201711483575.3A CN108033990A (en) | 2017-12-29 | 2017-12-29 | The preparation method of Dexamethasone Intermediate |
| PCT/CN2019/076373 WO2019129309A1 (en) | 2017-12-29 | 2019-02-27 | Preparation method for dexamethasone intermediate |
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| CN201711483575.3A CN108033990A (en) | 2017-12-29 | 2017-12-29 | The preparation method of Dexamethasone Intermediate |
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Cited By (2)
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| CN109734762A (en) * | 2018-12-05 | 2019-05-10 | 郑良彬 | The method of one pot process 16- β methyl steroidal compound |
| WO2019129309A1 (en) * | 2017-12-29 | 2019-07-04 | 广西万德药业有限公司 | Preparation method for dexamethasone intermediate |
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Cited By (2)
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| WO2019129309A1 (en) * | 2017-12-29 | 2019-07-04 | 广西万德药业有限公司 | Preparation method for dexamethasone intermediate |
| CN109734762A (en) * | 2018-12-05 | 2019-05-10 | 郑良彬 | The method of one pot process 16- β methyl steroidal compound |
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| WO2019129309A1 (en) | 2019-07-04 |
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