CN107629102A - The preparation method of nomegestrol acetate - Google Patents
The preparation method of nomegestrol acetate Download PDFInfo
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Abstract
The preparation method of nomegestrol acetate, using acetic acid Norgesterone as raw material, first acetic acid Norgesterone is dissolved in organic solvent, reacted in the presence of triethyl orthoformate with ethylene glycol under acid catalysis, obtain double Betamethasone Ketal structures；Double Betamethasone Ketal structures are dissolved in organic solvent again, react to obtain epoxy material with hydrogen peroxide under base catalysis：Then epoxy material is dissolved in organic solvent; grignard addition reaction is carried out with methyl halogenated magnesium; hydrolyzed in strong acid solution, be dehydrated to obtain methyl thing; finally methyl thing is dissolved in organic solvent; dehydrogenation reaction occurs with chloranil and obtains nomegestrol acetate; HPLC contents 99.0 99.5%, four step synthetic reaction total recoverys 60 62%.Relative to conventional method, present invention process is easy to operate, economic and environment-friendly, and synthesis total recovery is high, good product quality, cost 35 40% is reduced than conventional method；The recyclable recycled of solvent used in technique, is very beneficial to industrialized production.
Description
Technical field
The invention belongs to the preparation technology of steroid hormone medicine, and in particular to the system of progestational hormone medicine nomegestrol acetate
Preparation Method.
Background technology
Nomegestrol acetate, chemistry are entitled：6- methyl-17 a- acetoxyl groups -19- removes first-pregnant steroid -4,6- diene -3,20-
Diketone, it is a kind of efficient progestational hormone medicine.Clinically it is mainly used in treating womb endometrium ectopia, is also used for producing women
Contraceptive, its 2mg subdermal implants are used for female contraception, are valid up to 6 months, and effective percentage is almost up to 100%.It treats female
The effect of temper Endometriosis is approximately 60 times of progesterone, and due to good effect, side effect is low, and market application foreground is wide.
The conventional production methods of nomegestrol acetate, such as USP4, described in 544,555, using acetic acid Norgesterone as raw material, be etherified through 3 alkene,
The five steps reaction systems such as 6 Wiener reaction formolations, 6 carboxaldehyde radicals reduction, 6 dehydration methines, the catalysis indexing of 6 precedence methyl
, its synthetic route is shown in accompanying drawing 1.Wherein Wiener reaction, it is high to moisture requirement, using POCl3, environment is easily polluted, environmental protection
Processing is difficult.Particularly 6 precedence methyl catalytically rearrangings, the quantity of solvent used is especially big, has reached the 100 of reaction main material inventory
Times, low production efficiency, and side reaction is more, rearrangement reaction yield is low, causes the production cost and the market price of nomegestrol acetate
It is high.
The content of the invention
Present invention aim to address existing nomegestrol acetate productive technical efficiency is low, side reaction is more, and rearrangement reaction is received
Rate is low, and production cost is high, the problem of polluting environment, avoids severe using reaction condition caused by Wiener reaction in traditional processing technology
The shortcomings such as carve, many deficiencies that is especially that of avoiding caused by 6 catalysis translocation reactions that impurity is more, efficiency is low, cost is high etc..
A kind of preparation method of new nomegestrol acetate is provided.
The technical scheme is that：The preparation method of nomegestrol acetate, using acetic acid Norgesterone as raw material, first synthesis is double
Betamethasone Ketal structures, secondary synthesizing epoxy thing, then synthesizing methyl thing, are finally synthesizing nomegestrol acetate, i.e.,：
A, double Betamethasone Ketal structures are synthesized, be by acetic acid Norgesterone under triethyl orthoformate catalysis, in organic solvent with ethylene glycol, acid
Catalytic reaction obtains double Betamethasone Ketal structures：3,20- double ketal group-acetic acid Norgesterones；
B, synthesizing epoxy thing, it is to dissolve in above-mentioned double Betamethasone Ketal structures in organic solvent, under base catalysis, 5 in its molecule, 6 are double
Key reacts with hydrogen peroxide, obtains epoxy material：3,20- double ketal groups -5（6）A- epoxy -17a- acetoxyl groups -19- goes to first-pregnant steroid -3,
20- diketone；
C, synthesizing methyl thing, be by above-mentioned epoxy material in organic solvent, first with methyl-magnesium-halide RMgBr generation grignard it is anti-
Deserved grignard thing, the grignard thing do not take the dish out of the pot, and directly strengthen acid, dehydration occur at 5, while double remove-insurances occur at 3,20
Shield reaction, obtains methyl thing：6- methyl-acetic acid Norgesterone；
D, synthesize nomegestrol acetate, be by above-mentioned methyl thing in organic solvent, with chloranil occur 6 dehydrogenations it is anti-
Should, obtain nomegestrol acetate.
Further, the concrete operation step of its synthesis is as follows：
A, the synthesis of double Betamethasone Ketal structures
Acetic acid Norgesterone is dissolved in organic solvent, in the presence of triethyl orthoformate, with ethylene glycol under acid catalysis, in 20
~50 DEG C of stirring reactions 12~16 hours, TLC confirms reaction end, and after react, addition weak base is neutralized to pH 7~7.5, enters
One step post-processes, and obtains double Betamethasone Ketal structures：3,20- double ketal group-acetic acid Norgesterones, its HPLC content 97.5~98.5%, weight are received
Rate 115~120%；
B, the synthesis of epoxy material
Above-mentioned double Betamethasone Ketal structures are dissolved in organic solvent, after adding base catalyst, hydrogen peroxide are slowly added dropwise in 10-50 DEG C, about
1-1.5 hours add, and are then incubated and continue stirring reaction 10-16 hours in 10-50 DEG C again, and TLC confirms reaction end, has reacted
Afterwards, suitable reducing agent is added to destroy remnants hydrogen peroxide, adds acid and system is neutralized to pH7.5-8.0, after further
Processing, obtains epoxy material：3,20- double ketal groups -5（6）A- epoxy -17a- acetoxyl groups -19- removes first-pregnant steroid -3,20- diketone, its
HPLC contents 98.0~99.0%, weight yield 95~100%；
C, the synthesis of methyl thing
Above-mentioned epoxy material is dissolved in organic solvent, wiring solution-forming is standby；In another reaction bulb, organic solvent, magnesium are added
Powder, stirring, temperature control are added dropwise or are passed through methyl halogenated alkane at 10-50 DEG C, prepare RMgBr, after RMgBr is carried out, slowly
Slowly above-mentioned standby epoxy material solution is added dropwise, about 0.5-1.0 hours drip off, after dripping off, in 10~80 DEG C of insulation reaction 8~10 again
Hour, TLC confirms reaction end, and after having reacted, strong acid solution is slowly added dropwise within 1.0-1.5 hours, and in 40-100 DEG C of guarantor
Temperature reaction 4~8 hours, TLC confirms reaction end, after having reacted, first adds alkali lye and is neutralized to system pH6-7, then be concentrated under reduced pressure
Organic solvent about 90-95% is reclaimed, running water is then added, stirring and crystallizing 2-3 hours, filters, wash, dry, it is thick to obtain methyl thing
Product, HPLC content 96.5-98.5%, weight yield 78~82%；Crude product is recrystallized with alcohol, activated carbon decolorizing, obtains methyl thing：6-
Methyl-acetic acid Norgesterone, HPLC contents more than 99.0%, this step reaction weight yield 68~70%；
D, the synthesis of nomegestrol acetate
Above-mentioned methyl thing is dissolved in organic solvent, lower addition chloranil is stirred, then heats at 60~120 DEG C and flow back
Reaction 8~12 hours, TLC confirmation reaction ends, after having reacted, filters out quinhydrones, is washed with liquid caustic soda to organic layer pH 6.8-7.2,
Then organic solvent is reclaimed, cool elutriation, obtains nomegestrol acetate crude product, HPLC content 98.0-99.0%, weight yield 80-
85%；Crude product is recrystallized with below C4 low-carbon alcohols, obtains nomegestrol acetate product, 178~183 DEG C of fusing point, HPLC contents 99.0-
99.5%, this step yield 75-78%；Four-step reaction synthesis total recovery 60-62%.
Further, the reaction condition of above-mentioned synthesis acetic acid Norgesterone is described as follows：
Organic solvent is in dichloromethane, chloroform, toluene, DME, dioxane, THF described in the synthesis of above-mentioned double Betamethasone Ketal structures
One kind；One kind in the reaction optional hydrochloric acid of acid catalyst used, sulfuric acid, phosphoric acid, or select acetic acid, p-methyl benzenesulfonic acid, oxalic acid
In one kind；Weak base used in neutralization selects sodium carbonate or pyridine；20~50 DEG C of reaction temperature；Weight proportion between reactant is,
Acetic acid Norgesterone：Triethyl orthoformate：Ethylene glycol：Acid=1：0.5~1.0：0.3~0.6：0.01~0.05；Reactant and solvent
Between proportioning be acetic acid Norgesterone：Organic solvent=1g：2~8ml；
Organic solvent is in methanol, ethanol, DME, tetrahydrofuran, chloroform, ethyl acetate described in above-mentioned epoxy material synthesis
It is one or two kinds of；Base catalyst used in epoxy reaction is from one kind in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate；Ring
The reaction temperature of oxygen reaction is 10~50 DEG C；Weight proportion between reactant is double Betamethasone Ketal structures：Base catalyst：Hydrogen peroxide=1：
0.2~0.4：0.4~0.6；Proportioning between reactant and solvent is double Betamethasone Ketal structures：Organic solvent=1g：10~15ml；
Organic solvent described in above-mentioned methyl thing synthesis is selected from toluene, chloroform, dichloromethane, ether, DME, ethyl acetate, four
One or both of hydrogen furans, dioxane；RMgBr is from one kind in methyl-magnesium-chloride or magnesium bromide or magnesium iodide；
Grignard acidolysis, deprotection sour water solution are with acid used in dehydration acid catalyst from one kind in hydrochloric acid, sulfuric acid, phosphoric acid, or vinegar
One kind in acid, p-methyl benzenesulfonic acid, oxalic acid；Grignard reaction temperature is 10~80 DEG C, and hydrolysis is 20~80 with dehydration temperature
℃；Weight proportion between reactant is epoxy material：RMgBr：Acid catalyst=1：0.25~0.55：0.5~1.5；Reactant
Proportioning between solvent is epoxy material：Organic solvent=1g：10~20ml；
The one kind of organic solvent in toluene, acetone, dioxane, DME described in above-mentioned nomegestrol acetate synthesis, or often
One kind in the ester such as ethyl acetate seen；40~120 DEG C of reaction temperature；Weight proportion between reactant is methyl thing：Tetrachloro pair
Benzoquinones=1：0.4~0.6；Proportioning between reactant and solvent is methyl thing：Organic solvent=1g：8-15ml.
The optimal conditions of above-mentioned synthesis nomegestrol acetate are as follows：
Organic solvent is dichloromethane or toluene described in above-mentioned double Betamethasone Ketal structures synthesis；Reaction acid catalyst used is to toluene
Sulfonic acid；Weak base used in neutralization is pyridine；25~30 DEG C of reaction temperature；Weight proportion between reactant is acetic acid Norgesterone：Primitive nail
Triethylenetetraminehexaacetic acid ester：Ethylene glycol：Acid=1：0.8：0.5：0.02；Proportioning between reactant and solvent is acetic acid Norgesterone：Organic solvent=
1g：6ml；
Organic solvent is methanol described in above-mentioned epoxy material synthesis；Base catalyst used in epoxy reaction is sodium hydroxide；Epoxy is anti-
20~25 DEG C of the reaction temperature answered；Weight proportion between reactant, double Betamethasone Ketal structures：Base catalyst：Hydrogen peroxide=1：0.30：
0.45；Proportioning between reactant and solvent is：Double Betamethasone Ketal structures：Organic solvent=1g：12ml；
Organic solvent is tetrahydrofuran described in above-mentioned methyl thing synthesis；RMgBr methyl-magnesium-bromide；Grignard acidolysis, remove-insurance
It is hydrochloric acid or sulfuric acid that sour water solution, which is protected, with acid used in dehydration acid catalyst；50~55 DEG C of grignard reaction temperature, hydrolysis and dehydration
60~65 DEG C of reaction temperature；Weight proportion between reactant is epoxy material：RMgBr：Acid catalyst=1：0.40：1.0；Instead
It is epoxy material to answer the proportioning between thing and solvent：Organic solvent=1g：15ml；
Organic solvent is dioxane described in above-mentioned nomegestrol acetate synthesis；90 ~ 95 DEG C of reaction temperature；Weight between reactant
Amount proportioning, methyl thing：Chloranil=1：0.5；Proportioning between reactant and solvent is methyl thing：Organic solvent=1g：
10ml。
The beneficial effects of the invention are as follows：The present invention be methylated through 3,20 double ketalization, 5,6 epoxidations, Grignard 6,
Acid-catalyzed dehydration simultaneously hydrolyzes the four-step reactions such as deprotection, 6 chloranil's dehydrogenations synthesis nomegestrol acetate, relative to acetic acid
The prior synthesizing method of Nomegestrol, have synthetic route short, technological operation is easy, and production economy environmental protection, synthesis total recovery is high,
Good product quality, the plurality of advantages such as production cost is low, avoids and severe reaction conditions needed for Wiener reaction is used in traditional handicraft,
The shortcomings such as environmental protection treatment difficulty, are especially that of avoiding caused by 6 catalysis translocation reactions that impurity is more, efficiency is low, cost is high etc.
Many deficiencies；Production cost reduces 35-40% than conventional production methods；The solvent used in technique, recyclable recycled, both
Economy, but it is environmentally friendly, it is very beneficial to industrialized production.
Brief description of the drawings
Fig. 1 is conventional method nomegestrol acetate synthesis route figure；
Fig. 2 nomegestrol acetate synthesis route figures of the present invention.
Embodiment
In order to which the main points of the present invention and spirit are described in more detail, name three embodiments and be explained：
Embodiment one
A, the preparation of double Betamethasone Ketal structures
In a 1000ml there-necked flask, 100g acetic acid Norgesterone, 600ml dichloromethane, 50g ethylene glycol, 80ml primitive nails are added
Triethylenetetraminehexaacetic acid ester, 2g p-methyl benzenesulfonic acid, it is incubated in 25~30 DEG C of stirring reactions 12~16 hours, TLC detection reaction ends, has reacted
Afterwards, 3ml pyridines are added, stirring 20-25 minutes neutralize acid, then are concentrated under reduced pressure, and reclaim 90-95% dichloromethane, then add
600ml running water, in 10-15 DEG C of stirring and crystallizing 3-4 hour, centrifuge, washing, obtain double Betamethasone Ketal structures crude products, above-mentioned crude product not baking material,
It is added directly into 800ml 50% alcohol, first flows back 1-1.5 hours, then normal pressure steams about 400ml alcohol, it is then that system is cold
But -5-0 DEG C are arrived, stirred crystallization 2~3 hours, is filtered, a small amount of ethanol washs, and is dried below 70 DEG C of filter cake, obtains double Betamethasone Ketal structures
118.6g, HPLC content 99.2%, weight yield 118.6%.Washing lotion and filtrate merge, and recycling design and crude product cover under being used for respectively
Criticize in process for refining；
B, the preparation of epoxy material
In a 2000ml there-necked flask, above-mentioned self-control etherate 100g, methanol 1200ml are added, stirs the burning of lower addition 30%
Aqueous slkali 100g, 20~25 DEG C of temperature control, slowly be added dropwise 30% hydrogen peroxide 150g, 0.5-1.0 hour add, be further continued for after dripping off
Insulated and stirred is reacted 12~16 hours, TLC detection reaction ends, after having reacted, first adds 30g sodium hydrosulfites, stirring reaction 0,5-
1.0 hours, to destroy unnecessary hydrogen peroxide, then 2N hydrochloric acid is slowly added dropwise to pH6.5-7.0, after dripping off, be concentrated under reduced pressure recovery 90-
95% methanol, 500ml running water is then added, stirring and crystallizing 2-3 hours, is filtered, is washed, dries, obtains epoxy material crude product；Again
Above-mentioned epoxy material crude product is added in 600ml alcohol, heating makes its dissolving, adds 5g activated carbons, and backflow decolouring 1~1.5 is small
When, filter while hot, filter cake about 80ml alcohol foam washings, merging filtrate and washing lotion, normal pressure is concentrated into about 85% alcohol of recovery, then will
System is cooled to 0~-5 DEG C, stirring and crystallizing 2~3 hours, filters, and filter cake is washed with 10ml 50% ethanol solution, less than 70 DEG C
Drying, epoxy material 98.8g, HPLC content 99.2%, weight yield 98.8% are obtained, filtrate and washing lotion merge, recovered alcohol and epoxy
Thing mother liquor material covers in lower batch of process for refining respectively.
C, the preparation of methyl thing
In a 1000ml there-necked flask, the above-mentioned self-control epoxy materials of 100g, 800mlTHF are added, stirring is warming up to 40~45 DEG C,
It is completely dissolved, then is slowly cooled down standby；700mlTHF is added in another 2000ml reaction bulb, 10g metal magnesium powders, is put
After ventilating, start slowly to be passed through bromomethane at 30-35 DEG C, until magnesium metal total overall reaction is complete, stops logical bromomethane, continue
Insulated and stirred is reacted 1~1.5 hour, is continuously heating to 50-55 DEG C, is started that above-mentioned standby epoxy material solution, 1.0-1.5 is added dropwise
Hour drips off, and after dripping off, continues at 50-55 DEG C of insulation reaction 8-10 hour, TLC detection reaction ends, after having reacted, then slowly
Hydrochloric acid 300ml, the 1.5-2.0 hour of dropwise addition 30% drips off, and drips off follow-up continuation of insurance warm 60-65 DEG C of stirring reaction 6-8 hours, TLC inspections
Reaction end is surveyed, after having reacted, is first concentrated under reduced pressure, reclaims 90-95% THF, add 800ml running water, be cooled to 10-15
DEG C, stirring and crystallizing 3-4 hours, filter, wash, dry, obtain methyl thing crude product, filtrate and washing lotion merge, and the recovery that is concentrated under reduced pressure is residual
Purification tank for liquid waste is discharged into after remaining solvent；Then above-mentioned crude product is recrystallized by well-established law alcohol, activated carbon decolorizing, obtains methyl thing
69.5g, HPLC content 99.2%, weight yield 69.5%.
D, the preparation of nomegestrol acetate
In a 2000ml there-necked flask, the above-mentioned self-control methyl things of 100g, 1000ml dioxane are added, stirs lower addition 50g
Chloranil, then 90~95 DEG C are slowly ramped to, insulated and stirred reaction response 8~12 hours, TLC confirms reaction end, instead
After having answered, quinhydrones is filtered out, is washed to organic layer pH6.8-7.2 with 400ml 30% liquid caustic soda, is then concentrated under reduced pressure at twice, is returned
90-85% dioxane is received, then adds 600 ml running water, 10~15 DEG C is cooled to, stirring and crystallizing 2-3 hours, filters,
Neutrality is washed to, is dried below 70 DEG C of filter cake, obtains nomegestrol acetate crude product 84.2g, HPLC content 98.8%, weight yield
84.2%；Filtrate and washing lotion merge, and purification tank for liquid waste is discharged into after reclaiming residual solvent；Crude product is taken off by well-established law with alcohol and activated carbon
Color recrystallizes, and obtains nomegestrol acetate 77.8g, 178~183 DEG C of fusing point, HPLC contains 99.5%, yield 77.8%.
Embodiment two
A, the preparation of double Betamethasone Ketal structures
In a 1000ml there-necked flask, 100g acetic acid Norgesterone, 600ml toluene, 50g ethylene glycol, 80ml orthoformic acid three are added
The sulfuric acid of ethyl ester, 2g 98%, it is incubated in 25~30 DEG C of stirring reactions 12~16 hours, TLC detection reaction ends, after having reacted,
3ml pyridines are added, stirring 20-25 minutes neutralize acid, then are concentrated under reduced pressure, and reclaim 90-95% toluene, then add 600ml certainly
Water, in 10-15 DEG C of stirring and crystallizing 3-4 hour, centrifuge, washing, obtain double Betamethasone Ketal structures crude products.Above-mentioned crude product not baking material, directly plus
Enter into 800ml 50% alcohol, first flow back 1-1.5 hours, then normal pressure steams about 400ml alcohol, be then cooled to system-
5-0 DEG C, stirred crystallization 2~3 hours, filter, a small amount of ethanol washing, dried below 70 DEG C of filter cake, obtain double Betamethasone Ketal structures 116.8g,
HPLC contents 99.5%, weight yield 116.8%.Washing lotion and filtrate merge, and recycling design and crude product cover refined for lower batch respectively
In technique；
The preparation of B epoxy materials
In a 2000ml there-necked flask, above-mentioned self-control etherate 100g, ethanol 1200ml are added, stirs the burning of lower addition 30%
30% hydrogen peroxide 150g is slowly added dropwise in 20~25 DEG C in aqueous slkali 100g, temperature control, and about 0.5-1.0 hours add, after dripping off again
Continue insulated and stirred to react 12~16 hours, TLC detection reaction ends, after having reacted, first add 30g sodium hydrogensulfites, stirring
0.5-1.0 hours are reacted, to destroy unnecessary hydrogen peroxide, then 2N hydrochloric acid are slowly added dropwise to pH6.5-7.0, after dripping off, decompression is dense
Retract and receive 90-95% methanol, then add 500ml running water, stirring and crystallizing 2-3 hours, filter, wash, dry, obtain epoxy
Thing crude product；Above-mentioned epoxy material crude product is added in 600ml alcohol again, heating makes its dissolving, adds 5g activated carbons, and backflow is decolourized
1~1.5 hour, filter while hot, filter cake about 80ml alcohol foam washings, merging filtrate and washing lotion, normal pressure is concentrated into about 85% wine of recovery
Essence, then system is cooled to 0~-5 DEG C, stirring and crystallizing 2~3 hours, filtering, filter cake is washed with 10ml 50% ethanol solution,
Less than 70 DEG C drying, epoxy material 97.6g, HPLC content 99.4%, weight yield 97.6% are obtained, filtrate and washing lotion merge, and reclaim wine
Essence and epoxy material mother liquor material cover in lower batch of process for refining respectively.
The preparation of C methyl things
In a 1000ml there-necked flask, the above-mentioned self-control epoxy materials of 100g, 800ml toluene are added, stirring is warming up to 40~45 DEG C,
It is completely dissolved, then is slowly cooled down standby；700mlTHF is added in another 2000ml reaction bulb, 10g metal magnesium powders, is put
After ventilating, start slowly to be passed through chloromethanes at 30-35 DEG C, until magnesium metal total overall reaction is complete, stops logical chloromethanes, continue
Insulated and stirred is reacted 1~1.5 hour, then is warming up to 50-55 DEG C, starts that above-mentioned standby epoxy material solution is added dropwise, 1.0-1.5 is small
When drip off, after dripping off, continue at 50-55 DEG C of insulation reaction 8-10 hour, TLC detection reaction ends, after having reacted, then slowly drip
Add 200ml 50% sulfuric acid, 1.5-2.0 hours drip off, and drip off follow-up continuation of insurance temperature in 60-65 DEG C of stirring reaction 6-8 hour, TLC
Reaction end is detected, after having reacted, is first concentrated under reduced pressure, reclaims 90-95% THF and toluene, add 800ml running water, is cooled down
To 10-15 DEG C, stirring and crystallizing 3-4 hours, filter, wash, dry, obtain methyl thing crude product, filtrate and washing lotion merge, be concentrated under reduced pressure
Purification tank for liquid waste is discharged into after recovery residual solvent；Then above-mentioned crude product is recrystallized by well-established law alcohol, activated carbon decolorizing, obtains first
Substratess 68.9g, HPLC content 99.5%, weight yield 68.9%.
The preparation of D nomegestrol acetates
In a 2000ml there-necked flask, the above-mentioned self-control methyl things of 100g, 1000ml ethyl acetate are added, stirs lower addition 50g
Chloranil, then 75~80 DEG C are slowly ramped to, insulated and stirred is reacted 8~12 hours, and TLC confirms reaction end, has reacted
Afterwards, quinhydrones is filtered out, is washed to organic layer pH6.8-7.2 with 400ml 30% liquid caustic soda, is then concentrated under reduced pressure at twice, reclaims 90-
85% ethyl acetate, 600 ml running water are then added, be cooled to 10~15 DEG C, stirring and crystallizing 2-3 hours, filtering, be washed to
Neutrality, dry below 70 DEG C of filter cake, obtain nomegestrol acetate crude product 82.6g, HPLC content 98.5%, weight yield 82.6%；Filter
Liquid and washing lotion merge, and purification tank for liquid waste is discharged into after reclaiming residual solvent；Crude product is recrystallized by well-established law with alcohol and activated carbon decolorizing,
Obtain nomegestrol acetate 76.9g, 178~182 DEG C of fusing point, HPLC contents 99.4%, yield 76.9%.
Embodiment three
A, the preparation of double Betamethasone Ketal structures
In a 1000ml there-necked flask, 100g acetic acid Norgesterone, 600ml dichloromethane, 50g ethylene glycol, 80ml primitive nails are added
The ethanol solution of triethylenetetraminehexaacetic acid ester, 10g hydrochloric acids, it is incubated in 25~30 DEG C of stirring reactions 12~16 hours, TLC detections reaction is eventually
Point, after having reacted, 3ml pyridines being added, stirring 20-25 minutes neutralize acid, then are concentrated under reduced pressure, and reclaim 90-95% dichloromethane,
Then 600ml running water is added, in 10-15 DEG C of stirring and crystallizing 3-4 hour, is centrifuged, washing, obtains double Betamethasone Ketal structures crude products.It is above-mentioned thick
Product not baking material, is added directly into 800ml50% alcohol, first flows back 1-1.5 hours, then normal pressure steams about 400ml alcohol, so
System is cooled to -5-0 DEG C afterwards, stirred crystallization 2~3 hours, filtered, a small amount of ethanol washs, and is dried below 70 DEG C of filter cake, obtains double
Betamethasone Ketal structures 116.2g, HPLC content 99.6%, weight yield 116.2%.Washing lotion and filtrate merge, and recycling design and crude product cover respectively
For in lower batch of process for refining.
The preparation of B epoxy materials
In a 2000ml there-necked flask, above-mentioned self-control etherate 100g, 1200ml DME is added, stirs the carbon of lower addition 30%
Acid sodium solution 100g, temperature control in 20~25 DEG C, slowly be added dropwise 30% hydrogen peroxide 150g, 0.5-1.0 hour add, after dripping off again
Continue insulated and stirred to react 12~16 hours, TLC detection reaction ends, after having reacted, first add 30g sodium thiosulfate, stirring
0.5-1.0 hours are reacted, to destroy unnecessary hydrogen peroxide, then 2N sulfuric acid are slowly added dropwise to pH6.5-7.0, after dripping off, decompression is dense
Retract and receive 90-95% DME, then add 500ml running water, stirring and crystallizing 2-3 hours, filter, wash, dry, obtain epoxy material
Crude product；Above-mentioned epoxy material crude product is added in 600ml alcohol again, heating makes its dissolving, adds 5g activated carbons, backflow decolouring 1
~1.5 hours, filter while hot, filter cake about 80ml alcohol foam washings, merging filtrate and washing lotion, normal pressure is concentrated into about 85% wine of recovery
Essence, then system is cooled to 0~-5 DEG C, stirring and crystallizing 2~3 hours, filtering, filter cake is washed with 10ml 50% ethanol solution,
Less than 70 DEG C drying, epoxy material 96.5g, HPLC content 99.4%, weight yield 96.5% are obtained, filtrate and washing lotion merge, and reclaim wine
Essence and epoxy material mother liquor material cover in lower batch of process for refining respectively.
The preparation of C methyl things
In a 1000ml there-necked flask, the above-mentioned self-control epoxy materials of 100g, 800ml chloroforms are added, stirring is warming up to 40~45 DEG C,
It is completely dissolved, then is slowly cooled down standby；The addition 700ml ether in another 2000ml reaction bulb, 10g metal magnesium powders,
After displaced air, start that iodomethane is slowly added dropwise at 35-40 DEG C, until magnesium metal total overall reaction is complete, stop adding iodomethane,
Continue insulated and stirred to react 1~1.5 hour, be continuously heating to 50-55 DEG C, start that above-mentioned standby epoxy material solution is added dropwise,
1.0-1.5 hours drip off, and after dripping off, continue at 50-55 DEG C of insulation reaction 8-10 hour, TLC detection reaction ends, have reacted
Afterwards, then slowly being added dropwise 30% hydrochloric acid 300ml, 1.5-2.0 hour drips off, and drips off follow-up continuation of insurance temperature in 60-65 DEG C of stirring reaction 6-
8 hours, TLC detection reaction ends, after having reacted, first it is concentrated under reduced pressure, reclaims 90-95% ether and chloroform, add 800ml
Running water, 10-15 DEG C is cooled to, stirring and crystallizing 3-4 hours, is filtered, is washed, is dried, obtain methyl thing crude product, filtrate and washing lotion are closed
And it is discharged into purification tank for liquid waste after the recovery residual solvent that is concentrated under reduced pressure；Then by above-mentioned crude product by well-established law alcohol, activated carbon decolorizing
Recrystallization, obtains methyl thing 68.7g, HPLC content 99.3%, weight yield 68.7%.
The preparation of D nomegestrol acetates
In a 2000ml there-necked flask, the above-mentioned self-control methyl things of 100g, 1000ml toluene are added, stirs lower addition 50g tetrachloros
1,4-benzoquinone, then 105~110 DEG C are slowly ramped to, insulated and stirred is reacted 8~12 hours, and TLC confirms reaction end, after having reacted,
Quinhydrones is filtered out, is washed to organic layer pH 6.8-7.2 with 400ml 30% liquid caustic soda, is then concentrated under reduced pressure at twice, reclaims 90-
85% dioxane, 600 ml running water are then added, be cooled to 10~15 DEG C, stirring and crystallizing 2-3 hours, filtering, be washed to
Neutrality, dry below 70 DEG C of filter cake, obtain nomegestrol acetate crude product 82.8g, HPLC content 98.6%, weight yield 82.8%；Filter
Liquid and washing lotion merge, and purification tank for liquid waste is discharged into after reclaiming residual solvent；Crude product is recrystallized by well-established law with alcohol and activated carbon decolorizing,
Nomegestrol acetate 76.2g, 179~183 DEG C of fusing point are obtained, HPLC contains 99.5%, yield 76.2%.
Claims (4)
1. the preparation method of nomegestrol acetate, using acetic acid Norgesterone as raw material, it is characterised in that double Betamethasone Ketal structures are first synthesized, it is secondary
Synthesizing epoxy thing, then synthesizing methyl thing, are finally synthesizing nomegestrol acetate, i.e.,：
A, double Betamethasone Ketal structures are synthesized, be by acetic acid Norgesterone under triethyl orthoformate catalysis, exist in organic solvent with ethylene glycol
Double Betamethasone Ketal structures are reacted to obtain under acid catalysis：3,20- double ketal group-acetic acid Norgesterones；
B, synthesizing epoxy thing, it is to dissolve in above-mentioned double Betamethasone Ketal structures in organic solvent, under base catalysis, 5 in its molecule, 6 are double
Key reacts with hydrogen peroxide, obtains epoxy material：3,20- double ketal groups -5（6）A- epoxy -17a- acetoxyl groups -19- goes to first-pregnant steroid -3,
20- diketone；
C, synthesizing methyl thing, be by above-mentioned epoxy material in organic solvent, first with methyl-magnesium-halide RMgBr generation grignard it is anti-
Deserved grignard thing, the grignard thing, which does not take the dish out of the pot, directly strengthens acid, dehydration occurs at 5, while double remove-insurances occur at 3,20
Shield reaction, obtains methyl thing：6- methyl-acetic acid Norgesterone；
D, synthesize nomegestrol acetate, be by above-mentioned methyl thing in organic solvent, with chloranil occur 6 dehydrogenations it is anti-
Should, obtain nomegestrol acetate.
2. the preparation method of nomegestrol acetate as claimed in claim 1, it is characterized in that, concrete operation step is as follows：
A, the synthesis of double Betamethasone Ketal structures
Acetic acid Norgesterone is dissolved in organic solvent, in the presence of triethyl orthoformate, with ethylene glycol under acid catalysis, in 20
~50 DEG C of stirring reactions 12~16 hours, TLC confirms reaction end, and after react, addition weak base is neutralized to pH 7~7.5, enters
One step post-processes to obtain double Betamethasone Ketal structures：3,20- double ketal group-acetic acid Norgesterones, its HPLC content 97.5~98.5%, weight yield
115~120%；
B, the synthesis of epoxy material
Above-mentioned double Betamethasone Ketal structures are dissolved in organic solvent, after adding base catalyst, hydrogen peroxide, 1- are slowly added dropwise in 10-50 DEG C
Add within 1.5 hours, then be incubated and continue stirring reaction 10-16 hours in 10-50 DEG C, TLC confirms reaction end, after having reacted, adds
Enter reducing agent to destroy remnants hydrogen peroxide, add acid and system is neutralized to pH7.5-8.0, further work-up obtains epoxy
Thing：3,20- double ketal groups -5（6）A- epoxy -17a- acetoxyl groups -19- removes first-pregnant steroid -3,20- diketone, its HPLC content
98.0~99.0%, weight yield 95~100%；
C, the synthesis of methyl thing
Above-mentioned epoxy material is dissolved in organic solvent, wiring solution-forming is standby；In another reaction bulb, organic solvent, magnesium are added
Powder, stirring, temperature control are added dropwise or are passed through methyl halogenated alkane at 10-50 DEG C, prepare RMgBr, after RMgBr is carried out, slowly
Slowly above-mentioned standby epoxy material solution is added dropwise, 0.5-1.0 hours drip off, drip off after 10~80 DEG C again insulation reaction 8~10 it is small
When, TLC confirms reaction end, and after having reacted, strong acid solution is slowly added dropwise within 1.0-1.5 hours, and in 40-100 DEG C of insulation
Reaction 4~8 hours, TLC confirm reaction end, and adding alkali lye after having reacted is neutralized to system pH6-7, then the recovery that is concentrated under reduced pressure has
Solvent about 90-95%, running water is then added, stirring and crystallizing 2-3 hours, is filtered, is washed, dries, obtains methyl thing crude product,
HPLC content 96.5-98.5%, weight yield 78~82%；Crude product is recrystallized with alcohol, activated carbon decolorizing, obtains methyl thing：6- first
Base-acetic acid Norgesterone, HPLC contents more than 99.0%, this step reaction weight yield 68~70%；
D, the synthesis of nomegestrol acetate
Above-mentioned methyl thing is dissolved in organic solvent, lower addition chloranil is stirred, then heats at 60~120 DEG C and flow back
Reaction 8~12 hours, TLC confirmation reaction ends, after having reacted, filters out quinhydrones, is washed with liquid caustic soda to organic layer pH 6.8-7.2,
Then organic solvent is reclaimed, cool elutriation, obtains nomegestrol acetate crude product, HPLC content 98.0-99.0%, weight yield 80-
85%；Crude product is recrystallized with below C4 low-carbon alcohols, obtains nomegestrol acetate product, 178~183 DEG C of fusing point, HPLC contents 99.0-
99.5%, this step yield 75-78%；Four-step reaction synthesis total recovery 60-62%.
3. the preparation method of nomegestrol acetate as claimed in claim 1 or 2, it is characterized in that, synthesize the reaction of acetic acid Norgesterone
Condition is as follows：
A, organic solvent described in the synthesis of double Betamethasone Ketal structures is in dichloromethane, chloroform, toluene, DME, dioxane, THF
It is a kind of；One kind in the reaction optional hydrochloric acid of acid catalyst used, sulfuric acid, phosphoric acid, or select in acetic acid, p-methyl benzenesulfonic acid, oxalic acid
One kind；Weak base used in neutralization selects sodium carbonate or pyridine；20~50 DEG C of reaction temperature；Weight proportion between reactant is vinegar
Sour Norgesterone：Triethyl orthoformate：Ethylene glycol：Acid=1：0.5~1.0：0.3~0.6：0.01~0.05；Between reactant and solvent
Proportioning be acetic acid Norgesterone：Organic solvent=1g：2~8ml；
B, epoxy material synthesis described in organic solvent in methanol, ethanol, DME, tetrahydrofuran, chloroform, ethyl acetate one
Kind or two kinds；Base catalyst used in epoxy reaction is from one kind in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate；Reaction
Temperature is 10~50 DEG C；Weight proportion between reactant is double Betamethasone Ketal structures：Base catalyst：Hydrogen peroxide=1：0.2~0.4：0.4~
0.6；Proportioning between reactant and solvent is double Betamethasone Ketal structures：Organic solvent=1g：10~15ml；
C, the organic solvent described in the synthesis of methyl thing is selected from toluene, chloroform, dichloromethane, ether, DME, ethyl acetate, tetrahydrochysene
One or both of furans, dioxane；RMgBr is from one kind in methyl-magnesium-chloride or magnesium bromide or magnesium iodide；Lattice
One kind that family name's acidolysis, deprotection sour water solution are selected in hydrochloric acid, sulfuric acid, phosphoric acid with acid used in dehydration acid catalyst, or acetic acid,
One kind in p-methyl benzenesulfonic acid, oxalic acid；Grignard reaction temperature is 10~80 DEG C, and hydrolysis is 20~80 DEG C with dehydration temperature；
Weight proportion between reactant is epoxy material：RMgBr：Acid catalyst=1：0.25~0.55：0.5~1.5；Reactant with it is molten
Proportioning between agent is epoxy material：Organic solvent=1g：10~20ml；
D, nomegestrol acetate synthesis described in organic solvent in toluene, acetone, dioxane, DME, ethyl acetate one
Kind；40~120 DEG C of reaction temperature；Weight proportion between reactant is methyl thing：Chloranil=1：0.4~0.6；Reactant
Proportioning between solvent is methyl thing：Organic solvent=1g：8-15ml.
4. the preparation method of nomegestrol acetate as claimed in claim 1 or 2, it is characterized in that, synthesize the optimization of acetic acid Norgesterone
Condition is as follows：
A, organic solvent is dichloromethane or toluene described in double Betamethasone Ketal structures synthesis；Reaction acid catalyst used is to toluene sulphur
Acid；Weak base used in neutralization is pyridine；25~30 DEG C of reaction temperature；Weight proportion between reactant is acetic acid Norgesterone：Orthoformic acid
Triethyl：Ethylene glycol：Acid=1：0.8：0.5：0.02；Proportioning between reactant and solvent is acetic acid Norgesterone：Organic solvent=1g：
6ml；
B, organic solvent is methanol described in epoxy material synthesis；Base catalyst used is sodium hydroxide；20~25 DEG C of reaction temperature；
Weight proportion between reactant, double Betamethasone Ketal structures：Base catalyst：Hydrogen peroxide=1：0.30：0.45；Proportioning between reactant and solvent
It is：Double Betamethasone Ketal structures：Organic solvent=1g：12ml；
C, organic solvent is tetrahydrofuran described in the synthesis of methyl thing；RMgBr methyl-magnesium-bromide；Grignard acidolysis, deprotection
Sour water solution is hydrochloric acid or sulfuric acid with acid used in dehydration acid catalyst；50~55 DEG C of grignard reaction temperature, hydrolysis are anti-with dehydration
Answer 60~65 DEG C of temperature；Weight proportion between reactant is epoxy material：RMgBr：Acid catalyst=1：0.40：1.0；Reaction
Proportioning between thing and solvent is epoxy material：Organic solvent=1g：15ml；
D, organic solvent is dioxane described in nomegestrol acetate synthesis；90 ~ 95 DEG C of reaction temperature；Weight between reactant
Proportioning, methyl thing：Chloranil=1：0.5；Proportioning between reactant and solvent is methyl thing：Organic solvent=1g：10ml.
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| CN108299533A (en) * | 2018-03-13 | 2018-07-20 | 岳阳环宇药业有限公司 | A kind of methylprednisolone synthesis technology |
| CN108467420A (en) * | 2018-04-24 | 2018-08-31 | 国家卫生计生委科学技术研究所 | A kind of Nomegestrol acetate crystal form II and preparation method thereof |
| CN108623648A (en) * | 2018-04-24 | 2018-10-09 | 国家卫生计生委科学技术研究所 | Nomegestrol acetate crystal form I and its preparation method and application |
| CN114380878A (en) * | 2021-12-15 | 2022-04-22 | 河南利华制药有限公司 | Synthetic method of flumethasone |
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| CN106518944A (en) * | 2016-10-27 | 2017-03-22 | 湖南科瑞生物制药股份有限公司 | Preparation method of methylprednisone |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299533A (en) * | 2018-03-13 | 2018-07-20 | 岳阳环宇药业有限公司 | A kind of methylprednisolone synthesis technology |
| CN108467420A (en) * | 2018-04-24 | 2018-08-31 | 国家卫生计生委科学技术研究所 | A kind of Nomegestrol acetate crystal form II and preparation method thereof |
| CN108623648A (en) * | 2018-04-24 | 2018-10-09 | 国家卫生计生委科学技术研究所 | Nomegestrol acetate crystal form I and its preparation method and application |
| CN114380878A (en) * | 2021-12-15 | 2022-04-22 | 河南利华制药有限公司 | Synthetic method of flumethasone |
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