CN109293723A - The preparation method of female steroid -4,9- diene -3,17- diketone - Google Patents
The preparation method of female steroid -4,9- diene -3,17- diketone Download PDFInfo
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- CN109293723A CN109293723A CN201811108789.7A CN201811108789A CN109293723A CN 109293723 A CN109293723 A CN 109293723A CN 201811108789 A CN201811108789 A CN 201811108789A CN 109293723 A CN109293723 A CN 109293723A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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Abstract
The present invention provides a kind of female steroids -4,9- diene -3, the preparation method of 17- diketone, the described method includes: using with compounds of formula I as reaction raw materials, mixed acid anhydride preparation, grignard reaction, ring-closure reaction, hydrolysis and ring-closure reaction are successively carried out to the reaction raw materials, the compound with structural formula V is made；The synthetic route of the compound with structural formula V is as follows:The preparation method of female steroid -4,9- diene -3,17- diketone provided in an embodiment of the present invention has many advantages, such as that operating procedure is simple in synthesis process, raw material is cheap, consumption of organic solvent is small, easy post-processing and is easy to amplify production.
Description
Technical field
The present invention relates to a kind of preparation methods of Mifepristone intermediate, and in particular to a kind of female steroid -4,9- diene -3,
The preparation method of 17- diketone.
Background technique
Mifepristone is a kind of novel endometrium progesterone antagonist, there is termination of early pregnancy, anti-implantation, inhibit ovulation and
The effect for promoting uterus maturation is the drug of a kind of good oral contraception, Robust speaker feature and treatment endometriosis.And
Female steroid -4,9- diene -3,17- diketone is the important intermediate for synthesizing Mifepristone.
The method of preparation mifepristone intermediate female steroid -4,9- diene -3,17- diketone mainly includes following several at present:
First method, using Dioxcin as raw material, obtain acetic acid diene gestation progesterone through 200 DEG C of pressurizations cracking, oxidation, hydrolysis, then
It is anti-through Beckmann rearrangement, addition reaction, substitution reaction, elimination reaction, hydrolysis, oxidation reaction, hydrolysis, oxidation
It answers, final product 4,9- estradiene -3,17- diketone is made in decarboxylic reaction, ten multistep reactions such as addition reaction and elimination reaction.
This method is basic raw material there are four the saponin of steroidal female ring itself to contain, and at high cost, environmental pollution is big, and is carrying out oximate, shellfish
The dosage of solvent and water is larger in the reaction that Ke Man is reset, more sensitive to temperature, is difficult to control, yield is not high, furthermore reacts
The phosphorus oxychloride needed belongs to controlled severe poisonous chemicals.Second method, with 2,3,7,7 α-tetrahydro -1H- indenes -1,5 (6H)
Diketone (CN 108003210A) be raw material, through carbonyl reduction reaction, hydroxyl protection reaction, substitution reaction, double bond reduction reaction,
Hydrolysis of ketal reaction, ring closure reaction, substitution reaction, hydrolysis of ketal reaction, ring closure reaction, hydroxyl deprotection reaction and hydroxyl oxidation
Ten multisteps are reacted, reaction route is longer and cumbersome.
But the method for preparation mifepristone intermediate female steroid -4,9- diene -3,17- diketone all presence at present synthesized
The problems such as complex for operation step in journey, consumption of organic solvent is big, causes serious pollution to the environment.
Summary of the invention
To solve the above problems, preparing the new of female steroid -4,9- diene -3,17- diketone the embodiment of the invention provides a kind of
Method.
The preparation method of female steroid -4,9- diene -3,17- diketone provided in an embodiment of the present invention the following steps are included:
, as reaction raw materials, successively to carry out mixed acid anhydride preparation, grignard to the reaction raw materials with compounds of formula I
The compound with structural formula V is made in reaction, ring-closure reaction, hydrolysis and ring-closure reaction；
The synthetic route of the compound with structural formula V is as follows:
Preferably, the reaction process of the mixed acid anhydride preparation includes:
The first organic solvent will be used to dissolve in the reaction raw materials, and obtain the first solution, first solution will be cooled down
To the first preset temperature and keep the temperature the first preset duration；
Acid binding agent and pivaloyl chloride into first solution, reaction, which generates, has compounds of formula II, and reaction terminates
It is obtained afterwards comprising second solution with compounds of formula II.
Preferably, the ratio of the parts by weight between the reaction raw materials, the acid binding agent and the pivaloyl chloride is 1:
(0.72~1.62 :): (1~1.1).
Preferably, first organic solvent includes at least one in tetrahydrofuran, anhydrous ether and methyltetrahydrofuran
Kind；
The acid binding agent includes at least one of pyridine, triethylamine and benzophenone.
Preferably, first preset temperature is -30 DEG C~-40 DEG C；
First preset duration is 2~4h.
Preferably, the reaction process of the grignard reaction includes:
Under nitrogen protection, the second default temperature will be cooled to comprising second solution with compounds of formula II
Degree, is added dropwise Grignard Reagent, carries out insulation reaction after the completion of dropwise operation, when reaction of the insulation reaction a length of second is default
It is long, resulting reaction system is carried out after the insulation reaction to terminate reaction and post-processing, is obtained comprising having structural formula
The third solution of the compound of III.
Preferably, second preset temperature is -20 DEG C~-60 DEG C；
Second preset duration is 3~5h.
Preferably, the reaction process for terminating reaction includes:
Be added reaction terminating liquid into the reaction system, the reaction terminating liquid include aqueous ammonium chloride solution, hydrochloric acid and
At least one of aqueous acetic acid.
Preferably, the reaction process of the ring-closure reaction includes:
The compound with formula II I is dissolved using the second organic solvent, alkalinity is added into resulting solution
The composition or the alkali solid of solid and water, carry out ring-closure reaction, to the ring-closure reaction after obtain with structure
The compound of formula IV.
Preferably, in the ring-closure reaction, second organic solvent includes tetrahydrofuran, methanol, isopropanol and toluene
At least one of；
The alkali solid includes at least one of potassium hydroxide, potassium tert-butoxide, sodium carbonate and sodium hydroxide.
Preferably, in the ring-closure reaction step, the reaction temperature of the ring-closure reaction is second organic solvent
Reflux temperature；
The reaction time of the ring-closure reaction is 10~12h.
Preferably, the reaction process of the ring-closure reaction further include:
Stratification, isolated organic phase and water are carried out to the reaction solution comprising the compound with structural formula IV
Phase；
The organic phase and the water phase are post-processed.
The step of post-processing includes:
(1) washing lotion is added in the organic phase, washes away the impurity in the organic phase, the washing lotion includes that sodium chloride is molten
One of liquid, sodium bicarbonate solution and sodium carbonate liquor are a variety of；
(2) extractant is added in above-mentioned steps (1) resulting described water phase, remaining in the water phase is had for extracting
Machine phase, the extractant include one of toluene, tetrahydrofuran and methanol or a variety of；
(3) concentration is carried out to the resulting extraction phase of above-mentioned steps (2), to remove the extractant in the extraction phase；
The organic phase is concentrated, to remove the organic solvent in organic phase.Concentration terminates, and merges the dense of extraction phase and organic phase
Contracting liquid, and one of hexamethylene, acetone, n-hexane and methanol is added or multi-solvents；
(4) ice-water bath is carried out to the resulting extraction phase that the solvent has been added of above-mentioned steps (3) and organic phase concentrate
Cooling, solid is precipitated, mixing time is 2~6h；
(5) mixture after the resulting ice-water bath cooling of above-mentioned steps (4) is filtered, and resulting solid is carried out
It is dry, the compound solid with structural formula IV is obtained, the drying temperature of the drying is 50 DEG C~70 DEG C and drying
Time is 2~4h.
Preferably, the weight in the ring-closure reaction, between the compound and the alkali solid with structural formula IV
The ratio of number is 1:(0.47~0.77).
Preferably, the reaction process of the hydrolysis and ring-closure reaction includes:
Step a, the compound with structural formula IV, hydrochloric acid and third organic solvent are mixed, carries out the first heat preservation
Reaction, is added the first terminate liquid into resulting first reaction solution after first insulation reaction terminates, obtains hydrolysate
Intermediate；
Step b, the hydrolysate intermediate, alkaline reagent and the 4th organic solvent are mixed, it is anti-carries out the second heat preservation
It answers, the second terminate liquid is added into resulting second reaction solution after second insulation reaction terminates, obtains with structural formula V
Compound.
Preferably, in the step a of the hydrolysis and ring-closure reaction, the third organic solvent includes acetone, first
At least one of benzene, methanol, tetrahydrofuran and isobutanol；
The reaction temperature of first insulation reaction is the reflux temperature of the third organic solvent；
The reaction time of first insulation reaction is 3~4h；
First terminate liquid includes at least one of sodium carbonate liquor, sodium acetate solution and potassium hydroxide solution.
Preferably, it is described hydrolysis and ring-closure reaction in the step a further include:
After the first terminate liquid is added into resulting first reaction solution, after being carried out to the first mixed liquor after termination
Reason；
The step of post-processing includes:
(1) organic solvent in first mixed liquor is concentrated, sequentially added after concentration toluene, sodium chloride and water into
Row extraction, stratification；
(2) toluene is added in above-mentioned steps (1) resulting water phase to continue to extract, stratification；
(3) above-mentioned steps (2) resulting organic phase is washed using 5% sodium chloride solution, obtained in the hydrolysate
Mesosome.
Preferably, in the step b of the hydrolysis and ring-closure reaction, the alkaline reagent is alkali solid and water
Composition or the alkali solid, the alkali solid include in potassium hydroxide, potassium tert-butoxide, sodium carbonate and sodium hydroxide extremely
Few one kind；
The 4th kind of solvent includes at least one of toluene, methanol, acetone, the tert-butyl alcohol and isopropanol；
The reaction temperature of second insulation reaction is the reflux temperature of the 4th organic solvent；
The reaction time of second insulation reaction is 2~3h；
Second terminate liquid includes at least one of aqueous hydrochloric acid solution, aqueous acetic acid and aqueous ammonium chloride solution.
Preferably, the step b of the hydrolysis and ring-closure reaction further include:
After the second terminate liquid is added into resulting second reaction solution, after being carried out to the second mixed liquor after termination
Reason；
The step of post-processing includes:
(1) second mixed liquor is washed using detergent, the detergent includes sodium chloride solution, sodium bicarbonate solution
At least one of with sodium carbonate liquor；
(2) water phase extractant, the water phase extraction are added in the second mixed liquor after above-mentioned steps (1) resulting washing
Agent includes at least one of toluene, tetrahydrofuran and methanol；
(3) organic solvent in above-mentioned steps (2) resulting extraction phase and second mixed liquor is concentrated, after concentration
Concentration mixed liquor is obtained, is added solvent into the concentration mixed liquor, the solvent includes hexamethylene, petroleum ether, isopropanol, just
One of hexane and methanol are a variety of；
(4) the concentration mixed liquor that the solvent is added resulting to above-mentioned steps (3) carries out ice-water bath cooling, solid to be precipitated
Body, mixing time are 2~6h；
(5) above-mentioned steps (4) resulting mixture is filtered and drains processing, place is dried to resulting solid
Reason, obtains the compound solid with structural formula V, and the drying temperature of the drying process is 30 DEG C~50 DEG C and drying
Time is 2~4h.
Preferably, in the hydrolysis and ring-closure reaction, the compound with structural formula IV, between the alkaline reagent
Parts by weight ratio be 1:(0.20~0.30).
The embodiment of the invention provides a kind of preparation method of female steroid -4,9- diene -3,17- diketone, this method, which has, is closed
At operating procedure in the process is simple, raw material is cheap, consumption of organic solvent is small, easy post-processing and is easy to the advantages that amplifying production.
Detailed description of the invention
Fig. 1 is the preparation method flow chart of the female steroid -4,9- diene -3,17- diketone of the embodiment of the present invention.
Specific embodiment
Below in conjunction with specific embodiment, the invention will be further described, but protection model not thereby limiting the invention
It encloses.Raw material employed in following embodiment and instrument are commercially available.
The embodiment of the invention provides a kind of preparation methods of female steroid -4,9- diene -3,17- diketone.Fig. 1 is of the invention real
The preparation method flow chart for applying female steroid -4,9- diene -3,17- diketone of example, with reference to Fig. 1, female steroid -4,9- diene -3,17-
The preparation method of diketone includes:
Step 101, as reaction raw materials, successively to carry out mixed acid anhydride to the reaction raw materials with compounds of formula I
Preparation.
The reaction process of the mixed acid anhydride preparation may comprise steps of:
The first organic solvent will be used to dissolve in the reaction raw materials, and obtain the first solution, first solution will be cooled down
To the first preset temperature and keep the temperature the first preset duration；
Acid binding agent and pivaloyl chloride into first solution, reaction, which generates, has compounds of formula II, and reaction terminates
It is obtained afterwards comprising second solution with compounds of formula II.
Preferably, the ratio of the parts by weight between the reaction raw materials, the acid binding agent and the pivaloyl chloride is 1:
(0.72~1.62 :): (1~1.1).
First organic solvent may include at least one of tetrahydrofuran, anhydrous ether and methyltetrahydrofuran；
The acid binding agent may include at least one of pyridine, triethylamine and benzophenone.
Preferably, first preset temperature is -30 DEG C~-40 DEG C；First preset duration is 2~4h.
Step 102 carries out grignard reaction to step 101 resulting product.
The reaction process of the grignard reaction may comprise steps of:
Under nitrogen protection, the second default temperature will be cooled to comprising second solution with compounds of formula II
Degree, is added dropwise Grignard Reagent, carries out insulation reaction after the completion of dropwise operation, when reaction of the insulation reaction a length of second is default
It is long, resulting reaction system is carried out after the insulation reaction to terminate reaction and post-processing, is obtained comprising having structural formula
The third solution of the compound of III.
Preferably, second preset temperature is -20 DEG C~-60 DEG C；Second preset duration is 3~5h.
Preferably, the reaction process for terminating reaction may comprise steps of: be added into the reaction system anti-
Terminate liquid is answered, the reaction terminating liquid includes at least one of aqueous ammonium chloride solution, hydrochloric acid and aqueous acetic acid.
Step 103 carries out ring-closure reaction to step 102 resulting product.
The reaction process of the ring-closure reaction may comprise steps of:
The compound with formula II I is dissolved using the second organic solvent, alkalinity is added into resulting solution
The composition or the alkali solid of solid and water, carry out ring-closure reaction, to the ring-closure reaction after obtain with structure
The compound of formula IV.
Preferably, in the ring-closure reaction, second organic solvent includes tetrahydrofuran, methanol, isopropanol and toluene
At least one of；
The alkali solid includes at least one of potassium hydroxide, potassium tert-butoxide, sodium carbonate and sodium hydroxide.
Preferably, in the ring-closure reaction step, the reaction temperature of the ring-closure reaction is second organic solvent
Reflux temperature；The reaction time of the ring-closure reaction is 10~12h.
Preferably, the reaction process of the ring-closure reaction can with the following steps are included:
Stratification, isolated organic phase and water are carried out to the reaction solution comprising the compound with structural formula IV
Phase；
The organic phase and the water phase are post-processed；
The step of post-processing may include:
(1) washing lotion is added in the organic phase, washes away the impurity in the organic phase, the washing lotion includes that sodium chloride is molten
One of liquid, sodium bicarbonate solution and sodium carbonate liquor are a variety of；
(2) extractant is added in above-mentioned steps (1) resulting described water phase, remaining in the water phase is had for extracting
Machine phase, the extractant include one of toluene, tetrahydrofuran and methanol or a variety of；
(3) concentration is carried out to the resulting extraction phase of above-mentioned steps (2), to remove the extractant in the extraction phase；
The organic phase is concentrated, to remove the organic solvent in organic phase.Concentration terminates, and merges the dense of extraction phase and organic phase
Contracting liquid, and one of hexamethylene, acetone, n-hexane and methanol is added or multi-solvents；
(4) ice-water bath is carried out to the resulting extraction phase that the solvent has been added of above-mentioned steps (3) and organic phase concentrate
Cooling, solid is precipitated, mixing time is 2~6h；
(5) mixture after the resulting ice-water bath cooling of above-mentioned steps (4) is filtered, and resulting solid is carried out
It is dry, the compound solid with structural formula IV is obtained, the drying temperature of the drying is 50 DEG C~70 DEG C and drying
Time is 2~4h.
Preferably, the weight in the ring-closure reaction, between the compound and the alkali solid with structural formula IV
The ratio of number is 1:(0.47~0.77).
Step 104 is hydrolyzed step 103 resulting product and ring-closure reaction, and the chemical combination with structural formula V is made
Object.
In the embodiment of the present invention, the synthetic route of the compound with structural formula V is as follows:
Preferably, the reaction process of the hydrolysis and ring-closure reaction may comprise steps of:
Step a, the compound with structural formula IV, hydrochloric acid and third organic solvent are mixed, carries out the first heat preservation
Reaction, is added the first terminate liquid into resulting first reaction solution after first insulation reaction terminates, obtains hydrolysate
Intermediate；
Step b, the hydrolysate intermediate, alkaline reagent and the 4th organic solvent are mixed, it is anti-carries out the second heat preservation
It answers, the second terminate liquid is added into resulting second reaction solution after second insulation reaction terminates, obtains with structural formula V
Compound.
Preferably, in the step a of the hydrolysis and ring-closure reaction, the third organic solvent includes acetone, first
At least one of benzene, methanol, tetrahydrofuran and isobutanol；
The reaction temperature of first insulation reaction is the reflux temperature of the third organic solvent；
The reaction time of first insulation reaction is 3~4h；
First terminate liquid includes at least one of sodium carbonate liquor, sodium acetate solution and potassium hydroxide solution.
Preferably, it is described hydrolysis and ring-closure reaction in the step a can with the following steps are included:
After the first terminate liquid is added into resulting first reaction solution, after being carried out to the first mixed liquor after termination
Reason；
The step of post-processing, may comprise steps of:
(1) organic solvent in first mixed liquor is concentrated, sequentially added after concentration toluene, sodium chloride and water into
Row extraction, stratification；
(2) toluene is added in above-mentioned steps (1) resulting water phase to continue to extract, stratification；
(3) above-mentioned steps (2) resulting organic phase is washed using 5% sodium chloride solution, obtained in the hydrolysate
Mesosome.
Preferably, in the step b of the hydrolysis and ring-closure reaction, the alkaline reagent is alkali solid and water
Composition or the alkali solid, the alkali solid include in potassium hydroxide, potassium tert-butoxide, sodium carbonate and sodium hydroxide extremely
Few one kind；
The 4th kind of solvent includes at least one of toluene, methanol, acetone, the tert-butyl alcohol and isopropanol；
The reaction temperature of second insulation reaction is the reflux temperature of the 4th organic solvent；
The reaction time of second insulation reaction is 2~3h；
Second terminate liquid includes at least one of aqueous hydrochloric acid solution, aqueous acetic acid and aqueous ammonium chloride solution.
Preferably, it is described hydrolysis and ring-closure reaction the step b can with the following steps are included:
After the second terminate liquid is added into resulting second reaction solution, after being carried out to the second mixed liquor after termination
Reason；
The step of post-processing may include:
(1) second mixed liquor is washed using detergent, the detergent includes sodium chloride solution, sodium bicarbonate solution
At least one of with sodium carbonate liquor；
(2) water phase extractant, the water phase extraction are added in the second mixed liquor after above-mentioned steps (1) resulting washing
Agent includes at least one of toluene, tetrahydrofuran and methanol；
(3) organic solvent in above-mentioned steps (2) resulting extraction phase and second mixed liquor is concentrated, after concentration
Concentration mixed liquor is obtained, is added solvent into the concentration mixed liquor, the solvent includes hexamethylene, petroleum ether, isopropanol, just
One of hexane and methanol are a variety of；
(4) the concentration mixed liquor that the solvent is added resulting to above-mentioned steps (3) carries out ice-water bath cooling, solid to be precipitated
Body, mixing time are 2~6h；
(5) above-mentioned steps (4) resulting mixture is filtered and drains processing, place is dried to resulting solid
Reason, obtains the compound solid with structural formula V, and the drying temperature of the drying process is 30 DEG C~50 DEG C and drying
Time is 2~4h.
Preferably, in the hydrolysis and ring-closure reaction, the compound with structural formula IV, between the alkaline reagent
Parts by weight ratio be 1:(0.20~0.30).
The preparation method of female steroid -4,9- diene -3,17- diketone provided in an embodiment of the present invention, which has in synthesis process, to be operated
Step is simple, raw material is cheap, consumption of organic solvent is small, easy post-processing and is easy to the advantages that amplifying production.
It is carried out below by preparation method of the following embodiment to female steroid -4,9- diene -3,17- diketone provided by the present application
It is described in detail.
Embodiment 1
The preparation of mixed acid anhydride
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the fitting temperature meter and perseverance of clean dried
Press dropping funel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, 400mL tetrahydro furan is sequentially added
It mutters the compound that there is structural formula I with 50g, stirring and dissolving is simultaneously cooled to -30 DEG C, 50g pivaloyl chloride is added dropwise, after 0.5h is dripped off,
Instill 45g triethylamine, after 1h is dripped off, insulation reaction 2h.After liquid phase testing result Indicator Reaction is complete, obtain comprising having general formula
Second solution of the compound of II, the volume of the second solution are about 450mL.
Grignard reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, second that 450mL is added is molten
Liquid, temperature are down to -40 DEG C, and Grignard Reagent (chlorine [3- (2,5,5- trimethyls -1,3- bis- that 300mL concentration is 1.1mol/L are added dropwise
Oxane -2- base) propyl]-magnesium), 2~3h is dripped off, insulation reaction 3h, and after liquid phase testing result Indicator Reaction is complete, 200g is added
The aqueous acetic acid that mass fraction is 1%, carries out termination reaction.Reaction solution is transferred in separatory funnel, is layered；Water phase is used
The extraction of 100mL tetrahydrofuran, then be layered；Merge organic phase, obtain the third solution comprising the compound with formula II I,
The volume of third solution is about 850mL.
Ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, in mechanical stirring state the four-hole boiling flask in, sequentially add 850mL third solution and
50g potassium hydroxide, stirring and dissolving are simultaneously warming up to reflux, insulation reaction 10h, and liquid phase testing result Indicator Reaction is complete.
Resulting reaction solution is transferred in separatory funnel, stratification.200mL mass fraction, which is added, to organic layer is
10% NaCl solution washes away organic phase impurity.100mL tetrahydrofuran is added into water phase, extraction merges organic phase afterwards.Subtract
Pressure concentration tetrahydrofuran organic layer to it is dense not go out until.Adding hexamethylene, ice-water bath cooling stirs 5h, obtains a large amount of white solids,
After filtering is drained, 60 DEG C of dry 3h obtain the compound with structural formula IV, the weight of the compound with structural formula IV
For 65.1g.
Hydrolysis and ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Into the four-hole boiling flask in mechanical stirring state, compound, 500mL that 100g has structural formula IV are sequentially added
Acetone, the HCL aqueous solution that 25mL concentration is 2mol/L, stirring and dissolving are simultaneously warming up to reflux, insulation reaction 3h, liquid phase testing result
Indicator Reaction is complete.
150mL water and 2g sodium carbonate tune PH is added to neutrality.Acetone to the greatest extent is concentrated under reduced pressure, 800mL toluene, 10g chlorination is added
Sodium and 200mL water simultaneously stir, stratification.Water phase is extracted with 100mL toluene, combining methylbenzene layer, is 5% with 100g mass fraction
Sodium chloride solution washing merge after toluene layer, then be layered, give up water phase, obtain the organic phase solution containing hydrolyzing intermediate.
Add 100g isopropanol and 25g potassium tert-butoxide solid into the toluene solution containing hydrolyzing intermediate, stirring and dissolving is simultaneously
It is warming up to reflux, insulation reaction 2h, liquid phase testing result Indicator Reaction is complete.Add aqueous acetic acid to terminate reaction, adjusts PH into
Property.Stratification, organic phase washs with the sodium chloride solution that 300g mass fraction is 30%, and reduced pressure toluene organic layer is to dense
Until not going out.Adding hexamethylene, 3h is stirred in ice-water bath cooling, a large amount of faint yellow solids are obtained, after filtering is drained, 40 DEG C of dry 3h,
The compound with structural formula V is obtained, the quality of the compound with structural formula V is 67.1g.
The embodiment of the invention provides a kind of preparation method of female steroid -4,9- diene -3,17- diketone, this method, which has, is closed
At operating procedure in the process is simple, raw material is cheap, consumption of organic solvent is small, easy post-processing and is easy to the advantages that amplifying production.
Embodiment 2
The preparation of mixed acid anhydride
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the fitting temperature meter and perseverance of clean dried
Press dropping funel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, 400mL tetrahydro furan is sequentially added
The compound muttered with 50g with structural formula I, stirring and dissolving is simultaneously cooled to -35 DEG C, while tri- second of 50g pivaloyl chloride and 45g is added dropwise
Amine, after 1h is dripped off, insulation reaction 2h.After liquid phase testing result Indicator Reaction is complete, obtain comprising having compounds of formula II
The second solution, the volume of the second solution is about 450mL.
Grignard reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, second that 450mL is added is molten
Liquid, temperature are down to -45 DEG C, and Grignard Reagent (chlorine [3- (2,5,5- trimethyls -1,3- bis- that 300mL concentration is 1.1mol/L are added dropwise
Oxane -2- base) propyl]-magnesium), 2~3h is dripped off, insulation reaction 3h, and after liquid phase testing result Indicator Reaction is complete, 200g is added
The aqueous ammonium chloride solution that mass fraction is 1%, carries out termination reaction.Reaction solution is transferred in separatory funnel, is layered；Water phase is used
The extraction of 100mL tetrahydrofuran, then be layered；Merge organic phase, obtains comprising the compound third solution with formula II I, the
The volume of three solution about 850mL, be concentrated under reduced pressure tetrahydrofuran organic layer to it is dense not go out until.
Ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state, the of the III containing compound is sequentially added
Three solution, 500mL toluene and 30g potassium hydroxide, stirring and dissolving are simultaneously warming up to reflux, and insulation reaction 12h, liquid phase testing result refers to
Show fully reacting.
Resulting reaction solution is transferred in separatory funnel, stratification.200mL mass fraction, which is added, to organic layer is
10% NaCl solution washes away organic phase impurity.50mL toluene is added into water phase, extraction merges organic phase afterwards.It is concentrated under reduced pressure
Toluene organic layer to it is dense not go out until.Add hexamethylene and acetone, ice-water bath cooling stirs 3h, obtains a large amount of white solids, filters
After draining, 60 DEG C of dry 3h obtain the compound with structural formula IV, and the weight of the compound with structural formula IV is
63.5g。
Hydrolysis and ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Into the four-hole boiling flask in mechanical stirring state, compound, 500mL that 100g has structural formula IV are sequentially added
Acetone, the HCL aqueous solution that 25mL concentration is 2mol/L, stirring and dissolving are simultaneously warming up to reflux, insulation reaction 3h, liquid phase testing result
Indicator Reaction is complete.
150mL water and 2g sodium carbonate tune PH is added to neutrality.Acetone to the greatest extent is concentrated under reduced pressure, 800mL toluene, 10g chlorination is added
Sodium and 200mL water simultaneously stir, stratification.Water phase is extracted with 100mL toluene, combining methylbenzene layer, is 5% with 100g mass fraction
Sodium chloride solution washing merge after toluene layer, then be layered, give up water phase, obtain the organic phase solution containing hydrolyzing intermediate.
Add the 140g tert-butyl alcohol and 20g potassium tert-butoxide solid into the toluene solution containing hydrolyzing intermediate, stirring and dissolving is simultaneously
It is warming up to reflux, insulation reaction 2h, liquid phase testing result Indicator Reaction is complete.Add aqueous hydrochloric acid solution to terminate reaction, adjusts PH into
Property.Stratification, organic phase are washed with the sodium chloride solution that 300g mass fraction is 30%, and water phase is extracted with 100mL toluene, are closed
And toluene organic phase.Be concentrated under reduced pressure toluene organic layer to it is dense not go out until.Add petroleum ether and isopropanol, ice-water bath cooling, stirring
3h obtains a large amount of faint yellow solids, and after filtering is drained, 40 DEG C of dry 3h obtain the compound with structural formula V, have structure
The quality of the compound of Formula V is 65.3g.
The embodiment of the invention provides a kind of preparation method of female steroid -4,9- diene -3,17- diketone, this method, which has, is closed
At operating procedure in the process is simple, raw material is cheap, consumption of organic solvent is small, easy post-processing and is easy to the advantages that amplifying production.
Embodiment 3
The preparation of mixed acid anhydride
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the fitting temperature meter and perseverance of clean dried
Press dropping funel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, 400mL tetrahydro furan is sequentially added
The compound muttered with 50g with structural formula I, stirring and dissolving is simultaneously cooled to -30 DEG C, while tri- second of 50g pivaloyl chloride and 45g is added dropwise
Amine, after 1h is dripped off, insulation reaction 2h.After liquid phase testing result Indicator Reaction is complete, obtain comprising having compounds of formula II
The second solution, the volume of the second solution is about 450mL.
Grignard reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, second that 450mL is added is molten
Liquid, temperature are down to -40 DEG C, and Grignard Reagent (chlorine [3- (2,5,5- trimethyls -1,3- bis- that 300mL concentration is 1.1mol/L are added dropwise
Oxane -2- base) propyl]-magnesium), 2~3h is dripped off, insulation reaction 4h, and after liquid phase testing result Indicator Reaction is complete, 200g is added
The aqueous ammonium chloride solution that mass fraction is 1%, carries out termination reaction.Reaction solution is transferred in separatory funnel, is layered；Water phase is used
The extraction of 100mL tetrahydrofuran, then be layered；Merge organic phase, obtain the third solution comprising the compound with formula II I,
The volume of third solution is about 850mL, be concentrated under reduced pressure tetrahydrofuran organic layer to it is dense not go out until.
Ring-closure reaction
Clean irritated 1000mL four-hole boiling flask is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state, the of the III containing compound is sequentially added
Three solution, 500mL toluene and 30g potassium hydroxide, stirring and dissolving are simultaneously warming up to reflux, and insulation reaction 12h, liquid phase testing result refers to
Show fully reacting.
Resulting reaction solution is transferred in separatory funnel, stratification.200mL mass fraction, which is added, to organic layer is
10% NaCl solution washes away organic phase impurity.50mL toluene is added into water phase, extraction merges organic phase afterwards.It is concentrated under reduced pressure
Toluene organic layer to it is dense not go out until.Add hexamethylene and acetone, ice-water bath cooling stirs 3h, obtains a large amount of white solids, filters
After draining, 60 DEG C of dry 3h obtain the compound with structural formula IV, and the weight of the compound with structural formula IV is
64.3g。
Hydrolysis and ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Into the four-hole boiling flask in mechanical stirring state, compound, 500mL that 100g has structural formula IV are sequentially added
Acetone, the HCL aqueous solution that 25mL concentration is 2mol/L, stirring and dissolving are simultaneously warming up to reflux, insulation reaction 3h, liquid phase testing result
Indicator Reaction is complete.
150mL water and 2g sodium carbonate tune PH is added to neutrality.Acetone to the greatest extent is concentrated under reduced pressure, toluene 800mL, 10g chlorination is added
Sodium and the stirring of 200mL water, stratification.Water phase is extracted with 100mL toluene, combining methylbenzene layer, is 5% with 100g mass fraction
Sodium chloride solution washing, then be layered, give up water phase, obtains the organic phase solution containing hydrolyzing intermediate.
Add the 200g tert-butyl alcohol and 30g potassium tert-butoxide solid into the toluene solution containing hydrolyzing intermediate, stirring and dissolving is simultaneously
It is warming up to reflux, insulation reaction 2h, liquid phase testing result Indicator Reaction is complete.Add aqueous hydrochloric acid solution to terminate reaction, adjusts PH into
Property.Stratification, organic phase are washed with the sodium chloride solution that 300g mass fraction is 30%, and water phase is extracted with 100mL toluene, are closed
And toluene organic phase.Be concentrated under reduced pressure toluene organic layer to it is dense not go out until.Adding n-hexane and methanol, 3h is stirred in ice-water bath cooling,
A large amount of faint yellow solids are obtained, after filtering is drained, 40 DEG C of dry 3h obtain the compound with structural formula V, have structural formula V
Compound quality be 66.7g.
The embodiment of the invention provides a kind of preparation method of female steroid -4,9- diene -3,17- diketone, this method, which has, is closed
At operating procedure in the process is simple, raw material is cheap, consumption of organic solvent is small, easy post-processing and is easy to the advantages that amplifying production.
Embodiment 4
The preparation of mixed acid anhydride
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the fitting temperature meter and perseverance of clean dried
Press dropping funel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, 400mL tetrahydro furan is sequentially added
It mutters the compound that there is structural formula I with 50g, stirring and dissolving is simultaneously cooled to -40 DEG C, 55g pivaloyl chloride is added dropwise, after 0.5h is dripped off,
Instill 36g pyridine, after 1h is dripped off, insulation reaction 4h.After liquid phase testing result Indicator Reaction is complete, obtain comprising having general formula II
Compound the second solution, the volume of the second solution about 450mL.
Grignard reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, second that 450mL is added is molten
Liquid, temperature are down to -25 DEG C, and Grignard Reagent (chlorine [3- (2,5,5- trimethyls -1,3- bis- that 300mL concentration is 1.1mol/L are added dropwise
Oxane -2- base) propyl]-magnesium), 2~3h is dripped off, insulation reaction 3h, and after liquid phase testing result Indicator Reaction is complete, 200g is added
The aqueous acetic acid that mass fraction is 1%, carries out termination reaction.Reaction solution is transferred in separatory funnel, is layered；Water phase is used
The extraction of 100mL tetrahydrofuran, then be layered；Merge organic phase, obtain the third solution comprising the compound with formula II I,
The volume of third solution is about 850mL.
Ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, in mechanical stirring state the four-hole boiling flask in, sequentially add 850mL third solution and
40g potassium hydroxide, stirring and dissolving are simultaneously warming up to reflux, insulation reaction 11h, and liquid phase testing result Indicator Reaction is complete.
Resulting reaction solution is transferred in separatory funnel, stratification.200mL mass fraction, which is added, to organic layer is
10% sodium bicarbonate solution washes away organic phase impurity.50mL toluene is added into water phase, extraction merges organic phase afterwards.Decompression
Be concentrated tetrahydrofuran organic layer to it is dense not go out until.Add hexamethylene, ice-water bath cooling stirs 4h, obtains a large amount of white solids, mistake
After filter is drained, 60 DEG C of dry 3h obtain the compound with structural formula IV, and the weight of the compound with structural formula IV is
64.5g。
Hydrolysis and ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Into the four-hole boiling flask in mechanical stirring state, compound, 500mL that 100g has structural formula IV are sequentially added
Acetone, the HCL aqueous solution that 25mL substance withdrawl syndrome is 2mol/L, stirring and dissolving are simultaneously warming up to reflux, insulation reaction 3h, liquid phase
Testing result Indicator Reaction is complete.
150mL water and 1.55g sodium acetate tune PH is added to neutrality.Acetone to the greatest extent is concentrated under reduced pressure, toluene 800mL, 10g chlorine is added
Change sodium and the stirring of 200mL water, stratification.Water phase is extracted with 100mL toluene, combining methylbenzene layer, is 5% with 100g mass fraction
Sodium chloride solution washing, then be layered, give up water phase, obtain the organic phase solution containing hydrolyzing intermediate.
Add the 160g tert-butyl alcohol and 25g potassium hydroxide solid into the toluene solution containing hydrolyzing intermediate, stirring and dissolving is simultaneously
It is warming up to reflux, insulation reaction 2h, liquid phase testing result Indicator Reaction is complete.Add aqueous hydrochloric acid solution to terminate reaction, adjusts PH into
Property.Stratification, organic phase washs with the sodium chloride solution that 300g mass fraction is 30%, and reduced pressure toluene organic layer is to dense
Until not going out.Adding n-hexane and methanol, 3h is stirred in ice-water bath cooling, a large amount of faint yellow solids are obtained, after filtering is drained, 40 DEG C
Dry 3h, obtains the compound with structural formula V, and the quality of the compound with structural formula V is 66.9g.
The embodiment of the invention provides a kind of preparation method of female steroid -4,9- diene -3,17- diketone, this method, which has, is closed
At operating procedure in the process is simple, raw material is cheap, consumption of organic solvent is small, easy post-processing and is easy to the advantages that amplifying.
Embodiment 5
The preparation of mixed acid anhydride
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the fitting temperature meter and perseverance of clean dried
Press dropping funel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, 400mL tetrahydro furan is sequentially added
The compound muttered with 50g with structural formula I, stirring and dissolving is simultaneously cooled to -35 DEG C, while instilling 55g pivaloyl chloride and 81g hexichol
Ketone, after 1.5h is dripped off, insulation reaction 3h.After liquid phase testing result Indicator Reaction is complete, obtain comprising the change with general formula II
The second solution of object is closed, the volume of the second solution is about 500mL.
Grignard reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, second that 500mL is added is molten
Liquid, temperature are down to -35 DEG C, and Grignard Reagent (chlorine [3- (2,5,5- trimethyls -1,3- bis- that 330mL concentration is 1.1mol/L are added dropwise
Oxane -2- base) propyl]-magnesium), 2~3h is dripped off, insulation reaction 3h, and after liquid phase testing result Indicator Reaction is complete, 220g is added
The aqueous acetic acid that mass fraction is 1%, carries out termination reaction.Reaction solution is transferred in separatory funnel, is layered；Water phase is used
The extraction of 100mL tetrahydrofuran, then be layered；Merge organic phase, it is molten to obtain the third comprising the compound III with formula II I
Liquid, the volume of third solution are about 900mL, be concentrated under reduced pressure tetrahydrofuran organic layer to it is dense not go out until.
Ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state, the of the III containing compound is sequentially added
Three solution, 500mL toluene, 45g potassium hydroxide, stirring and dissolving are simultaneously warming up to reflux, and insulation reaction 11h, liquid phase testing result refers to
Show fully reacting.
Resulting reaction solution is transferred in separatory funnel, stratification.200mL mass fraction, which is added, to organic layer is
10% sodium carbonate liquor washes away organic phase impurity.50mL toluene is added into water phase, extraction merges organic phase afterwards.It depressurizes dense
Contracting tetrahydrofuran organic layer to it is dense not go out until.Add hexamethylene, ice-water bath cooling stirs 4h, obtains a large amount of white solids, filters
After draining, 60 DEG C of dry 3h are obtained with structural formula IV compound, and the weight of the compound with structural formula IV is
62.5g。
Hydrolysis and ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Into the four-hole boiling flask in mechanical stirring state, compound, 500mL that 100g has structural formula IV are sequentially added
Acetone, the HCL aqueous solution that 25mL concentration is 2mol/L, stirring and dissolving are simultaneously warming up to reflux, insulation reaction 3h, liquid phase testing result
Indicator Reaction is complete.
150mL water and 1g potassium hydroxide tune PH is added to neutrality.Acetone to the greatest extent is concentrated under reduced pressure, toluene 800mL, 10g chlorine is added
Change sodium and the stirring of 200mL water, stratification.Water phase is extracted with 100mL toluene, combining methylbenzene layer, is 5% with 100g mass fraction
Sodium chloride solution washing, then be layered, give up water phase, obtain the organic phase solution containing hydrolyzing intermediate.
Add 100g isopropanol and 25g sodium hydrate solid into the toluene solution containing hydrolyzing intermediate, stirring and dissolving is simultaneously
It is warming up to reflux, insulation reaction 2h, liquid phase testing result Indicator Reaction is complete.Add ammonium chloride solution to terminate reaction, adjusts PH into
Property.Stratification, organic phase washs with the sodium chloride solution that 300g mass fraction is 30%, and reduced pressure toluene organic layer is to dense
Until not going out.Adding hexamethylene, 3h is stirred in ice-water bath cooling, a large amount of faint yellow solids are obtained, after filtering is drained, 40 DEG C of dry 3h,
The compound with structural formula V is obtained, the quality of the compound with structural formula V is 64.2g.
The embodiment of the invention provides a kind of preparation method of female steroid -4,9- diene -3,17- diketone, this method, which has, is closed
At operating procedure in the process is simple, raw material is cheap, consumption of organic solvent is small, easy post-processing and is easy to the advantages that amplifying production.
Embodiment 6
The preparation of mixed acid anhydride
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the fitting temperature meter and perseverance of clean dried
Press dropping funel.
Under nitrogen protection, into the four-hole boiling flask in mechanical stirring state of selection, 400mL tetrahydro furan is sequentially added
It mutters the compound that there is structural formula I with 50g, stirring and dissolving is simultaneously cooled to -45 DEG C, 50g pivaloyl chloride is added dropwise, after 0.5h is dripped off,
Instill 45g triethylamine, after 1h is dripped off, insulation reaction 2h.After liquid phase testing result Indicator Reaction is complete, obtain comprising having general formula
The second solution of the compound II of II, the volume of the second solution are about 450mL.
Grignard reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, it is filled into the four-hole boiling flask in mechanical stirring state of selection, adds the second of 450mL molten
Liquid, temperature are down to -45 DEG C, and Grignard Reagent (chlorine [3- (2,5,5- trimethyls -1,3- bis- that 300mL concentration is 1.1mol/L are added dropwise
Oxane -2- base) propyl]-magnesium), 2~3h is dripped off, and insulation reaction 3h, liquid phase testing result Indicator Reaction is complete, and 200g matter is added
The aqueous acetic acid that score is 1% is measured, termination reaction is carried out.Reaction solution is transferred in separatory funnel, is layered；Water phase is used
The extraction of 100mL tetrahydrofuran, then be layered；Merge organic phase, it is molten to obtain the third comprising the compound III with formula II I
Liquid, the volume of third solution are about 850mL.
Ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Under nitrogen protection, in mechanical stirring state four-hole boiling flask in, sequentially add 850mL third solution and
50g sodium hydroxide, stirring and dissolving are simultaneously warming up to reflux, insulation reaction 10h, and liquid phase testing result Indicator Reaction is complete.
Resulting reaction solution is transferred in separatory funnel, stratification.200mL mass fraction, which is added, to organic layer is
10% NaCl solution washes away organic phase impurity.100mL tetrahydrofuran is added into water phase, extraction merges organic phase afterwards.Subtract
Pressure concentration tetrahydrofuran organic layer to it is dense not go out until.Add isopropanol and petroleum ether, 4h is stirred in ice-water bath cooling, is obtained a large amount of
White solid, after filtering is drained, 60 DEG C of dry 3h obtain the compound with structural formula IV, the change with structural formula IV
The weight for closing object is 65.5g.
Hydrolysis and ring-closure reaction
The 1000mL four-hole boiling flask of clean dried is chosen, which is equipped with the thermometer and constant pressure drop of clean dried
Liquid funnel.
Into the four-hole boiling flask in mechanical stirring state, compound, 500mL that 100g has structural formula IV are sequentially added
Acetone, the HCL aqueous solution that 25mL concentration is 2mol/L, stirring and dissolving are simultaneously warming up to reflux, insulation reaction 3h, liquid phase testing result
Indicator Reaction is complete.
150mL water and 1g potassium hydroxide tune PH is added to neutrality.Acetone to the greatest extent is concentrated under reduced pressure, 800mL toluene, 10g chlorine is added
Change sodium and the stirring of 200mL water, stratification.Water phase is extracted with 100mL toluene, combining methylbenzene layer, is 5% with 100g mass fraction
Sodium chloride solution washing, then be layered, give up water phase, obtain the organic phase solution containing hydrolyzing intermediate.
Add the 160g tert-butyl alcohol and 25g potassium tert-butoxide solid into the toluene solution containing hydrolyzing intermediate, stirring and dissolving is simultaneously
It is warming up to reflux, insulation reaction 2h, liquid phase testing result Indicator Reaction is complete.Add aqueous acetic acid to terminate reaction, adjusts PH into
Property.Stratification, organic phase washs with the sodium chloride solution that 300g mass fraction is 30%, and reduced pressure toluene organic layer is to dense
Until not going out.Adding hexamethylene, 3h is stirred in ice-water bath cooling, a large amount of faint yellow solids are obtained, after filtering is drained, 40 DEG C of dry 3h,
The compound with structural formula V is obtained, the quality of the compound with structural formula V is 67.8g.
The embodiment of the invention provides a kind of preparation method of female steroid -4,9- diene -3,17- diketone, this method, which has, is closed
At operating procedure in the process is simple, raw material is cheap, consumption of organic solvent is small, easy post-processing and is easy to the advantages that amplifying generation.
The above is only a preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-mentioned implementation
Example.All technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It is noted that for the art
Those of ordinary skill for, improvements and modifications without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
A kind of application of the preparation method of female steroid -4,9- diene -3,17- diketone provided by the present invention is carried out above
It is discussed in detail, used herein a specific example illustrates the principle and implementation of the invention, above embodiments
Illustrate to be merely used to help understand method and its core concept of the invention；At the same time, for those skilled in the art, according to
According to thought of the invention, there will be changes in the specific implementation manner and application range, in conclusion the content of the present specification
It should not be construed as limiting the invention.
Claims (19)
1. the invention discloses a kind of preparation methods of female steroid -4,9- diene -3,17- diketone, which is characterized in that the method packet
It includes:
It is anti-as reaction raw materials, the reaction raw materials are successively carried out with mixed acid anhydride preparation, grignard with compounds of formula I
It answers, ring-closure reaction, hydrolysis and ring-closure reaction, the compound with structural formula V is made；
The synthetic route of the compound with structural formula V is as follows:
2. preparation method according to claim 1, which is characterized in that the reaction process of mixed acid anhydride preparation includes:
The first organic solvent will be used to dissolve in the reaction raw materials, obtain the first solution, first solution is cooled to the
One preset temperature simultaneously keeps the temperature the first preset duration；
Acid binding agent and pivaloyl chloride into first solution, reaction, which generates, has compounds of formula II, after reaction
To including second solution with compounds of formula II.
3. preparation method according to claim 2, which is characterized in that the reaction raw materials, the acid binding agent and the spy
The ratio of parts by weight between valeric chloride is 1:(0.72~1.62 :): (1~1.1).
4. preparation method according to claim 2, which is characterized in that first organic solvent includes tetrahydrofuran, nothing
At least one of water ether and methyltetrahydrofuran；
The acid binding agent includes at least one of pyridine, triethylamine and benzophenone.
5. preparation method according to claim 2, which is characterized in that first preset temperature is -30 DEG C~-40 DEG C；
First preset duration is 2~4h.
6. preparation method according to claim 2, which is characterized in that the reaction process of the grignard reaction includes:
Under nitrogen protection, it will be cooled to the second preset temperature comprising second solution with compounds of formula II, dripped
Add Grignard Reagent, carry out insulation reaction after the completion of dropwise operation, when reaction of the insulation reaction a length of second preset duration, institute
Resulting reaction system is carried out after stating insulation reaction to terminate reaction and post-processing, is obtained comprising having formula II I's
The third solution of compound.
7. preparation method according to claim 6, which is characterized in that second preset temperature is -20 DEG C~-60 DEG C；
Second preset duration is 3~5h.
8. preparation method according to claim 6, which is characterized in that it is described terminate reaction reaction process include:
Reaction terminating liquid is added into the reaction system, the reaction terminating liquid includes aqueous ammonium chloride solution, hydrochloric acid and acetic acid
At least one of aqueous solution.
9. preparation method according to claim 6, which is characterized in that the reaction process of the ring-closure reaction includes:
The compound with formula II I is dissolved using the second organic solvent, alkali solid is added into resulting solution
With the composition or the alkali solid of water, carry out ring-closure reaction, to the ring-closure reaction after obtain with structural formula IV
Compound.
10. preparation method according to claim 9, which is characterized in that in the ring-closure reaction, second organic solvent
Including at least one of tetrahydrofuran, methanol, isopropanol and toluene；
The alkali solid includes at least one of potassium hydroxide, potassium tert-butoxide, sodium carbonate and sodium hydroxide.
11. preparation method according to claim 9, which is characterized in that in the ring-closure reaction step, the ring-closure reaction
Reaction temperature be second organic solvent reflux temperature；
The reaction time of the ring-closure reaction is 10~12h.
12. preparation method according to claim 9, which is characterized in that the reaction process of the ring-closure reaction further include:
Stratification, isolated organic phase and water phase are carried out to the reaction solution comprising the compound with structural formula IV；
The organic phase and the water phase are post-processed.
The step of post-processing includes:
(1) washing lotion is added in the organic phase, washes away the impurity in the organic phase, the washing lotion include sodium chloride solution,
One of sodium bicarbonate solution and sodium carbonate liquor are a variety of；
(2) extractant is added in above-mentioned steps (1) resulting described water phase, it is remaining organic in the water phase for extracting
Phase, the extractant include one of toluene, tetrahydrofuran and methanol or a variety of；
(3) concentration is carried out to the resulting extraction phase of above-mentioned steps (2), to remove the extractant in the extraction phase；To institute
It states organic phase to be concentrated, to remove the organic solvent in organic phase.Concentration terminates, and merges the concentration of extraction phase and organic phase
Liquid, and one of hexamethylene, acetone, n-hexane and methanol is added or multi-solvents；
(4) ice-water bath cooling is carried out to the resulting extraction phase that the solvent has been added of above-mentioned steps (3) and organic phase concentrate,
Solid is precipitated, mixing time is 2~6h；
(5) mixture after the resulting ice-water bath cooling of above-mentioned steps (4) is filtered, and resulting solid is done
It is dry, the compound solid with structural formula IV is obtained, when the drying temperature of the drying is 50 DEG C~70 DEG C and is dry
Between be 2~4h.
13. preparation method according to claim 9, which is characterized in that described that there is structural formula IV in the ring-closure reaction
Compound and the alkali solid between parts by weight ratio be 1:(0.47~0.77).
14. preparation method according to claim 9, which is characterized in that the reaction process packet of the hydrolysis and ring-closure reaction
It includes:
Step a, the compound with structural formula IV, hydrochloric acid and third organic solvent are mixed, carry out the first insulation reaction,
The first terminate liquid is added into resulting first reaction solution after first insulation reaction terminates, obtains among hydrolysate
Body；
Step b, the hydrolysate intermediate, alkaline reagent and the 4th organic solvent are mixed, carries out the second insulation reaction, to
The second terminate liquid is added into resulting second reaction solution after terminating in second insulation reaction, obtains the change with structural formula V
Close object.
15. preparation method according to claim 14, which is characterized in that in the step of the hydrolysis and ring-closure reaction
In a, the third organic solvent includes at least one of acetone, toluene, methanol, tetrahydrofuran and isobutanol；
The reaction temperature of first insulation reaction is the reflux temperature of the third organic solvent；
The reaction time of first insulation reaction is 3~4h；
First terminate liquid includes at least one of sodium carbonate liquor, sodium acetate solution and potassium hydroxide solution.
16. preparation method according to claim 14, which is characterized in that the step in the hydrolysis and ring-closure reaction
A further include:
After the first terminate liquid is added into resulting first reaction solution, the first mixed liquor after termination is post-processed；
The step of post-processing includes:
(1) organic solvent in first mixed liquor is concentrated, toluene, sodium chloride and water are sequentially added after concentration and is extracted
It takes, stratification；
(2) toluene is added in above-mentioned steps (1) resulting water phase to continue to extract, stratification；
(3) above-mentioned steps (2) resulting organic phase is washed using 5% sodium chloride solution, obtains the hydrolysate intermediate.
17. preparation method according to claim 14, which is characterized in that in the step of the hydrolysis and ring-closure reaction
In b, the alkaline reagent is the composition or the alkali solid of alkali solid and water, and the alkali solid includes hydroxide
At least one of potassium, potassium tert-butoxide, sodium carbonate and sodium hydroxide；
The 4th kind of solvent includes at least one of toluene, methanol, acetone, the tert-butyl alcohol and isopropanol；
The reaction temperature of second insulation reaction is the reflux temperature of the 4th organic solvent；
The reaction time of second insulation reaction is 2~3h；
Second terminate liquid includes at least one of aqueous hydrochloric acid solution, aqueous acetic acid and aqueous ammonium chloride solution.
18. preparation method according to claim 14, which is characterized in that the step b of the hydrolysis and ring-closure reaction
Further include:
After the second terminate liquid is added into resulting second reaction solution, the second mixed liquor after termination is post-processed；
The step of post-processing includes:
(1) second mixed liquor is washed using detergent, the detergent includes sodium chloride solution, sodium bicarbonate solution and carbon
At least one of acid sodium solution；
(2) water phase extractant, the water phase extractant packet are added in the second mixed liquor after above-mentioned steps (1) resulting washing
Include at least one of toluene, tetrahydrofuran and methanol；
(3) organic solvent in above-mentioned steps (2) resulting extraction phase and second mixed liquor is concentrated, is obtained after concentration
Mixed liquor is concentrated, solvent is added into the concentration mixed liquor, the solvent includes hexamethylene, petroleum ether, isopropanol, n-hexane
With one of methanol or a variety of；
(4) the concentration mixed liquor that the solvent is added resulting to above-mentioned steps (3) carries out ice-water bath cooling, solid is precipitated,
Mixing time is 2~6h；
(5) above-mentioned steps (4) resulting mixture is filtered and drains processing, resulting solid is dried, is obtained
To the compound solid with structural formula V, the drying temperature of the drying process is 30 DEG C~50 DEG C and drying time
For 2~4h.
19. preparation method according to claim 14, which is characterized in that described to have in the hydrolysis and ring-closure reaction
The ratio of parts by weight between the compound of structural formula IV, the alkaline reagent is 1:(0.20~0.30).
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113861158A (en) * | 2021-11-22 | 2021-12-31 | 湖南新合新生物医药有限公司 | Method for synthesizing methyl diene diketone key intermediate |
| CN114195845A (en) * | 2021-12-31 | 2022-03-18 | 湖南新合新生物医药有限公司 | Preparation method of 19-nor-4-androstenedione |
| CN115353540A (en) * | 2022-09-21 | 2022-11-18 | 中国科学院上海有机化学研究所 | Synthetic method and application of phenolic steroid compound |
| CN117304244A (en) * | 2023-08-14 | 2023-12-29 | 江西君业生物制药有限公司 | Preparation method of 19-nor-4-androstenedione |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113861158A (en) * | 2021-11-22 | 2021-12-31 | 湖南新合新生物医药有限公司 | Method for synthesizing methyl diene diketone key intermediate |
| CN113861158B (en) * | 2021-11-22 | 2023-02-10 | 湖南新合新生物医药有限公司 | Method for synthesizing methyl diene diketone key intermediate |
| CN114195845A (en) * | 2021-12-31 | 2022-03-18 | 湖南新合新生物医药有限公司 | Preparation method of 19-nor-4-androstenedione |
| CN115353540A (en) * | 2022-09-21 | 2022-11-18 | 中国科学院上海有机化学研究所 | Synthetic method and application of phenolic steroid compound |
| CN115353540B (en) * | 2022-09-21 | 2023-08-11 | 中国科学院上海有机化学研究所 | A kind of synthetic method and application of phenolic steroid compound |
| CN117304244A (en) * | 2023-08-14 | 2023-12-29 | 江西君业生物制药有限公司 | Preparation method of 19-nor-4-androstenedione |
| CN117304244B (en) * | 2023-08-14 | 2024-09-20 | 江西君业生物制药有限公司 | Preparation method of 19-nor-4-androstenedione |
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