CN109627275A - A kind of bis- dehydrogenation -17a- hydroxyl progesterone product preparation methods of 1,6- - Google Patents
A kind of bis- dehydrogenation -17a- hydroxyl progesterone product preparation methods of 1,6- Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
Abstract
The present invention provides the bis- dehydrogenation -17a- hydroxyl progesterone product preparation methods of 1,6- of one kind, including uses Isosorbide-5-Nitrae-androsadiendione i.e. IDD for raw material, so that IDD molecule is reacted under base catalysis in the first organic solvent with acetone cyanohydrin first, obtains hydroxyl cyanogen object；Then by hydroxyl cyanogen object in the presence of methyl-magnesium-halide, the second organic solvent and acid, the bis- dehydrogenation -17a- hydroxyl progesterones of 1,6- are prepared；It is heated to reflux decoloration in toluene, acetone or C4 or less low-carbon alcohols with active carbon again and is recrystallized, product is obtained.Many advantages, such as present invention is using IDD as raw material, and the opposite conventional production methods for making raw material with Chinese yam saponin are extensive with raw material sources, process economics environmental protection, production cost declines to a great extent.It no longer needs in the present invention using more expensive and toxic DDQ and tetrachloroquinone dehydrogenating agent；Recycled can be recycled in solvent used in technique, not only economical, but also environmental protection, is very beneficial to industrialized production.
Description
Technical field
The invention belongs to the fabricating technologies of steroid hormone pharmaceutical intermediate, and in particular to arrive the bis- dehydrogenations-of 1,6- of one kind
17a- hydroxyl progesterone product preparation method.
Background technique
Cyproterone acetate acetate, abbreviation CPA are commonly called as cyproterone, the entitled chloro- 1.2a- methine -17a of 6- of chemistry
Pregnant steroid-the Isosorbide-5-Nitrae of hydroxyl-- diene -3,20- diketone -17- acetate, is a kind of progestational hormone medicine, is clinically mainly used for women and keeps away
Pregnant, women acne, the treatment etc. of the classes disease such as hirsutism, baldness caused by male androgen hypersecretion is also used for male
The treatment of the diseases such as benign prostatauxe, early prostate cancer, market are huge.The production method of CPA is with from Chinese yam plant
Middle extraction Chinese yam saponin is obtained through the reaction of 8 steps such as protection, oxidation, cracking, elimination, epoxidation, Ovshinsky oxidation, upper bromine, debrominate
Key intermediate 17a- hydroxyl progesterone is raw material, through 6,1 dehydrogenation, 1,2 ciprofloxacin eye drops, 17 acylations, 5,6 epoxies
The seven steps reaction such as change, 6 open loops of chlorination cyclopropyl, cyclopropyl closed loops is made, and the Some routes of synthetic route are shown in attached drawing 1.Wherein 6
Bis- dehydrogenation -17a- the hydroxyl progesterones of 1,6- obtained by position, 1 double dehydrogenation are the key intermediate for producing CPA, prior synthesizing method
It is using 17a- hydroxyl progesterone as raw material, is first dehydrogenating agent in 17a- hydroxyl progesterone using tetrachloroquinone in ethyl acetate solvent
6 dehydrogenations of molecule continue 1 dehydrogenation in molecule, pass through two then again in dioxane solvent using DDQ as dehydrogenating agent
Dehydrogenation reaction is walked, the bis- dehydrogenation -17a- hydroxyl progesterones of 1,6- are made.Bis- dehydrogenation -17a- hydroxyl progesterone the production technologies of 1, the 6-,
It is de- come 1 and 6 to 17a- hydroxyl progesterone molecule respectively using more expensive and toxic DDQ and tetrachloroquinone dehydrogenating agent
Hydrogen, products obtained therefrom is of poor quality after every step reaction treatment, is both needed to be handled with a large amount of bucks, and it is more to generate waste water, not easy to handle, easily dirty
Contaminate environment；Production technology is complicated for operation, and two steps synthesis total recovery is less than 45%, high production cost, it is often more important that, with wild
Chinese yam plant resources are increasingly depleted, and artificial growth Chinese yam plant, also because of the increasingly rising of the planting costs such as artificial, chemical fertilizer, lead
It causes the production cost of saponin, diene to be doubled and redoubled, the production cost of the bis- dehydrogenation -17a- hydroxyl progesterones of 1,6- is caused further to mention
Height, causing CPA production cost, also when the river rises the boat goes up.The CPA market price is caused to sharp rise, already to global CPA bulk pharmaceutical chemicals market
Produce significant impact.
Therefore, this field needs a kind of preparation method of new bis- dehydrogenation -17a- hydroxyl progesterones of 1,6-.
Summary of the invention
Therefore, the bis- dehydrogenation -17a- hydroxyl progesterone product preparation methods of 1,6- of one kind, the method includes using Isosorbide-5-Nitrae-hero
Diene diketone, that is, IDD be raw material, make first 17 ketone in IDD molecule in the first organic solvent with acetone cyanohydrin in base catalysis
Under react, in 17 introducing beta-hydroxies and alpha-cyano, obtain hydroxyl cyanogen object；Then by hydroxyl cyanogen object in methyl-magnesium-halide, second
In the presence of organic solvent and acid, the bis- dehydrogenation -17a- hydroxyl progesterones of 1,6- are prepared；Again by the bis- dehydrogenations-of obtained 1,6-
17a- hydroxyl progesterone is heated to reflux decoloration in toluene, acetone or C4 or less low-carbon alcohols with active carbon and recrystallizes, and obtains 1,6-
Double dehydrogenation -17a- hydroxyl progesterone products.
In a kind of specific embodiment, first organic solvent is acetone cyanohydrin, methylene chloride, DME, acetic acid second
One or more of ester, THF and C4 or less low-carbon alcohols, preferably described first organic solvent are methanol.
In a kind of specific embodiment, the alkali is organic base or inorganic base, preferably pyridine, triethylamine, carbonic acid
One of sodium and sodium hydroxide are a variety of, more preferable sodium carbonate.
In a kind of specific embodiment, second organic solvent is in methylene chloride, toluene, ether and THF
One or more, preferably described second organic solvent are THF.
In a kind of specific embodiment, it is described acid be organic acid or inorganic acid, preferably acetic acid, p-methyl benzenesulfonic acid,
One of hydrochloric acid and sulfuric acid are a variety of, more preferable hydrochloric acid.
In a kind of specific embodiment, it is 10~100 DEG C that IDD, which reacts reaction temperature in the step of generating hydroxyl cyanogen object,
Reaction temperature is 30~100 DEG C in the step of reaction of hydroxyl cyanogen object generates 1,6- bis- dehydrogenation -17a- hydroxyl progesterones, and reaction process
In include first adding methyl-magnesium-halide into the second organic solvent and hydroxyl cyanogen object grignard addition reaction occurs, then add acid for grignard
The hydrolysis of grignard object that addition reaction obtains, be then recovered under reduced pressure organic solvent and plus water obtain after elutriation that 1, the 6- is bis- to be taken off
Hydrogen -17a- hydroxyl progesterone.
In a kind of specific embodiment, the method also includes first phytosterol being used to prepare after microbial fermentation
Obtain the IDD.
In a kind of specific embodiment, the method also includes first the deodorization in soybean oil production process being used to distillate
The isolated phytosterol of object.
The object of the present invention is to provide a kind of preparation methods of new bis- dehydrogenation -17a- hydroxyl progesterones of 1,6-, using IDD
For raw material, through 17 hydroxyl cyanidings, the two-step reactions such as 17 cyano grignard additions and sour water solution synthesize the bis- dehydrogenation -17a- hydroxyls of 1,6-
Base progesterone, synthetic route are shown in Fig. 2.Obviously, which has raw material sources are wide, technological operation is easy, production economy is environmentally friendly etc. to be permitted
More advantages overcome expensive synthesis material in above-mentioned traditional processing technology, complex operation, environmental protection treatment hardly possible, high production cost
Etc. many deficiencies.
The technical scheme is that the preparation method of 1,6- bis- dehydrogenation -17a- hydroxyl progesterones: with Isosorbide-5-Nitrae-hero diene two
Ketone (abbreviation IDD) is starting material, urges 17 in IDD molecule ketone with acetone cyanohydrin in alkali in the first organic solvent
Change lower generation addition reaction and obtains hydroxyl cyanogen object in 17 introducing b hydroxyls and a cyano；Then by 17 a in hydroxyl cyanogen object molecule
Cyano occurs grignard addition reaction with methyl-magnesium-halide Grignard Reagent in a second organic solvent, introduces 21 methyl and 20
Enamine, 17 hydroxyls change into a by b, which does not need to be separated, and are directly lauched 20 enamines in molecule in acid catalysis
Solution, translates into 20 ketone, so that target product 1 is obtained, the bis- dehydrogenation -17a- hydroxyl progesterones of 6-.
First IDD is dissolved in the first organic solvent, reacts to obtain hydroxyl cyanogen object with acetone cyanohydrin under base catalysis；Again by hydroxyl
Cyanogen object is dissolved in the second organic solvent, and the solution of methyl-magnesium-halide Grignard Reagent is added dropwise, brings it about grignard addition reaction, instead
After having answered, the aqueous hydrolysis of acid is directly added dropwise, it is post-treated that the bis- dehydrogenation -17a- hydroxyl progesterones of 1,6- are just made.
Further, the concrete operations synthesized are as follows:
A: the preparation of hydroxyl cyanogen object
Starting material IDD is dissolved in the first organic solvent, is stirred, acetone cyanohydrin is added to 10~100 DEG C in temperature control,
2% aqueous alkali is slowly added dropwise, drips off within about 2-2.5 hours, then keeps the temperature and is reacted 2~3 hours in 10~100 DEG C, TLC confirmation is anti-
Terminal is answered, after having reacted, divides water, is washed, recycling organic solvent, tap water elutriation, then with alcohol water is concentrated under reduced pressure in organic layer
Solution crystallization, obtains hydroxyl cyanogen object, 98.0% or more HPLC content, weight yield 95~100%.
The preparation of the bis- dehydrogenation -17a- hydroxyl progesterones of B:1,6-
Magnesium powder, organic solvent are added into reactor, stirred, temperature control is slowly passed through methyl halogenated alkane to 20~80 DEG C,
It is spare to obtain Grignard Reagent until magnesium powder completely disappears for reaction 4-6 hours；
Hydroxyl cyanogen object is dissolved in the second organic solvent, is stirred, above-mentioned get ready is slowly added dropwise to 30~100 DEG C in temperature control
Grignard Reagent, about 1-1.5 hour drip off, then keep the temperature and react 2~3 hours in 30~100 DEG C, and TLC confirms reaction end, have reacted
Afterwards, then slowly acid is added dropwise, in 30~100 DEG C heat preservation hydrolysis 2-3 hours, TLC confirmation reaction end is organic after having hydrolyzed
Recycling organic solvent is concentrated under reduced pressure in layer, and system residue cools to 10~30 DEG C, and tap water elutriation, filtering, filtrate is added
Environmental protection treatment pond is sent to handle after pretreatment；Filter cake washing, drying obtain the bis- dehydrogenation -17a- hydroxyl progesterone crude products of 1,6-, HPLC
97.0% or more content, weight yield 100~105%.Bis- dehydrogenation -17a- hydroxyl progesterone the crude products of above-mentioned 1,6- have been dissolved in
In solvent, active carbon is added, reflux decoloration 1-1.5 hours is filtered while hot, washes charcoal with suitable solvent, filter cake send producer to return
It receives, filtrate and washing lotion merge, and solvent is concentrated under reduced pressure to there is crystal precipitation, is subsequently cooled to -5~0 degree of crystallization 3-4 hours, filters,
Washing, drying, obtains the bis- dehydrogenation -17a- hydroxyl progesterone products of 1,6-, and 228~232 DEG C of fusing point, HPLC content 99.0-99.5%,
Disposing mother liquor is applied, this step weight total recovery 90-95%, synthesizes total recovery 86-90%.
The actual conditions of the bis- dehydrogenation -17a- hydroxyl progesterones of above-mentioned synthesis 1,6- are further described below again:
Above-mentioned synthesis A: the first organic solvent described in the preparation of hydroxyl cyanogen object, can be acetone cyanohydrin, methylene chloride, DME,
One or more of ethyl acetate, THF, C4 or less low-carbon alcohols etc.；Used in the aqueous alkali of synthesis catalyst 2% used
Alkali can be organic base such as pyridine, triethylamine etc., also optional inorganic base such as sodium carbonate, sodium hydroxide etc.；Synthesis reaction temperature 10
~100 DEG C；Depending on different reaction systems；Weight proportion between reactant is: IDD: acetone cyanohydrin: 2% buck=1g:
0.5~1.0g:1.5.0~3.0g；Proportion between reactant and solvent is: IDD: organic solvent=1g:2~12ml.
Second has described in Grignard Reagent synthesis in the preparation of the above-mentioned bis- dehydrogenation -17a- hydroxyl progesterones of synthesis B:1,6-
Solvent can be one or more of methylene chloride, toluene, ether, THF etc.；Methyl halogenated alkane can used in synthesis
To be chloromethanes, bromomethane or iodomethane；20~50 DEG C of above-mentioned Grignard reagent synthesis reaction temperature；Weight proportion between reactant
It is: magnesium: alkyl halide=1g:2.5~4.0g；Proportion between reactant and solvent is: magnesium: organic solvent=1g:2~12ml.
The organic solvent of the grignard reaction in the preparation of the bis- dehydrogenation -17a- hydroxyl progesterones of above-mentioned synthesis B:1,6-,
It can be one or more of toluene, benzene, chloroform, tetrahydrofuran, dioxane etc.；Hydrolysis acid used can be organic acid
Such as acetic acid, p-methyl benzenesulfonic acid, also optional inorganic acid such as hydrochloric acid, sulfuric acid etc.；The reaction temperature of grignard reaction and hydrolysis is
30~100 DEG C；Weight proportion between reactant is: IDD: grignard reagent solution=1g:5~15ml；Between reactant and solvent
Proportion is: IDD: reaction organic solvent=1g:2~10ml.
It is organic molten used in the product purification in the preparation of the above-mentioned bis- dehydrogenation -17a- hydroxyl progesterones of synthesis B:1,6-
Agent can be one or more of toluene, acetone, C4 or less low-carbon alcohols such as methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol etc.；Purification
40~100 DEG C of temperature of control；The weight proportion of each storeroom is: crude product: active carbon=1g:0.03~0.10g；Crude product and solvent
Between proportion be crude product: organic solvent=1g:3-10ml.
Particularly, most preferred process of the present invention is described as follows:
Above-mentioned synthesis A: the preferred acetone cyanohydrin of organic solvent described in the preparation of hydroxyl cyanogen object, dosage is few, and recycling is convenient；Synthesis
Alkali, preferably sodium carbonate used in the aqueous alkali of catalyst 2% used, effect is good, and economic and environment-friendly；Synthesis reaction temperature
It is economical and conveniently it is preferred that 25~30 DEG C；Weight proportion between reactant is: IDD: acetone cyanohydrin: 2% buck=1g:0.5g:
2.0g；Proportion between reactant and solvent is: IDD: organic solvent=1g:2ml.
It is organic molten described in Grignard Reagent synthesis in the preparation of the above-mentioned bis- dehydrogenation -17a- hydroxyl progesterones of synthesis B:1,6-
Agent, preferably THF, convenient post-treatment；The methyl halogenated preferred chloromethanes of alkane, economical used in synthesis；Above-mentioned Grignard Reagent
Preferably 30~35 DEG C of synthesis reaction temperature；Weight proportion between reactant is preferred: magnesium: chloromethanes=1g:2.8g；Reactant with it is molten
Proportion between agent is preferred: magnesium: organic solvent=1g:8ml.
The organic solvent of the grignard reaction in the preparation of the bis- dehydrogenation -17a- hydroxyl progesterones of above-mentioned synthesis B:1,6-,
It is preferred that tetrahydrofuran, effect is good, convenient post-treatment；The hydrolysis preferred hydrochloric acid of acid used, economy are convenient；Grignard reaction and hydrolysis are anti-
Preferably 50~55 DEG C of the reaction temperature answered；Weight proportion between reactant is preferred: IDD: grignard reagent solution=1g:8ml；Instead
It answers the proportion between object and solvent preferred: IDD: reacting organic solvent=1g:8ml.
It is organic molten used in the product purification in the preparation of the above-mentioned bis- dehydrogenation -17a- hydroxyl progesterones of synthesis B:1,6-
Agent, preferably ethanol, refining effect is good, safety and environmental protection, facilitates recycling；Preferably 80 DEG C of extraction temperature；The weight proportion of each storeroom
It is: crude product: active carbon=1g:0.05g；Proportion between crude product and solvent is crude product: organic solvent=1g:5ml.
The beneficial effect comprise that
1, the present invention prepares the bis- dehydrogenation -17a- hydroxyl progesterones of 1,6- by raw material of IDD, opposite to make raw material with Chinese yam saponin
Conventional production methods, have raw material sources extensive, process economics environmental protection, many advantages, such as production cost declines to a great extent.This hair
For bright method compared with conventional production methods, raw material is cheap and easily-available, and simple process environmental protection, product yield is high, high-quality, with former at present
Material price calculates, and raw materials for production cost reduces 50-55%.
2, it no longer needs in the present invention using more expensive and toxic DDQ and tetrachloroquinone dehydrogenating agent；It is used in technique
Solvent, recycled can be recycled, it is not only economical, but also environmental protection, be very beneficial to industrialized production.
Detailed description of the invention
Fig. 1 is traditional bis- dehydrogenation -17a- hydroxyl progesterone synthetic route charts of production 1,6-.
Fig. 2 is that the bis- dehydrogenation -17a- hydroxyl progesterone synthetic route charts of 1,6- are produced in the present invention.
Specific embodiment
In order to which main points and spirit of the invention are described in more detail, name several embodiments and be explained.
In the following example, the method includes first included using the deodorization distillate in soybean oil production process
The step of Crystallization Separation, obtains phytosterol, specifically for example with prior art CN200680047150.1,
Method described in CN200710014171.X or CN101074258B is prepared from the deodorization distillate in soybean oil production process
Obtain phytosterol.Then using the method microbial fermentation in the prior art as described in CN1250709C phytosterol is turned
Turn to Isosorbide-5-Nitrae-androsadiendione i.e. IDD.It and then further include following steps.
Embodiment 1
A: the preparation of hydroxyl cyanogen object
In a 1000ml there-necked flask, starting material IDD100g, acetone cyanohydrin 250ml, temperature control to 40~45 is added
DEG C, stirring is completely dissolved IDD, and then 2% sodium carbonate aqueous alkali, about 2-2.5 is slowly added dropwise at 20~25 DEG C in temperature control
Hour drips off, then keeps the temperature and react 2~3 hours in 25~30 DEG C, and TLC confirms reaction end, and after having reacted, recycling is concentrated under reduced pressure
The solvent acetone cyanalcohol of 90-95% is applied, and residue is cooled to 20~25 DEG C, adds 500ml tap water elutriation, is filtered, filter
The processing of Ye Song waste water processing station, filter cake are crystallized with the alcohol water blend of 500ml 40%, obtain hydroxyl cyanogen object 98.6g, HPLC content
98.2%, weight yield 98.6%.
The preparation of the bis- dehydrogenation -17a- hydroxyl progesterones of B:1,6-
In a 1000ml there-necked flask, 35g magnesium powder, 800ml tetrahydrofuran, stirring is added, heat preservation is passed through in 30-35 DEG C
98g chloromethanes after having led to, continues to be stirred to react 4~6 hours, until magnesium powder disappears substantially, it is spare to obtain Grignard Reagent；
In another 1000ml there-necked flask, hydroxyl cyanogen object prepared by the above-mentioned A of 100g, 500mlTHF, stirring heating is added
To 50~55 DEG C, the above-mentioned about 800ml grignard reagent solution got ready is slowly added dropwise, drips off within about 1-1.5 hours, is further continued for heat preservation and stirs
Mix reaction 2~3 hours, TLC detects reaction end, and after having reacted, about 500ml 6N hydrochloric acid is slowly added dropwise to PH2-3, after dripping off
In 50~55 DEG C continuation hydrolysis 2-3 hours, TLC detection hydrolysis completely, after having reacted, about 90-95% is concentrated under reduced pressure out
The THF processing of THF, recycling are applied.600ml tap water is added in above-mentioned residual night again, and system is cooled to 5~10 DEG C, stirs
It mixes crystallization 2~3 hours, filters, filtrate send waste water processing station to handle, filter cake originally water washing to neutrality, 70 DEG C or less drying,
Obtain grignard object: 1,6- bis- dehydrogenation -17a- hydroxyl progesterone crude product 103.6g, HPLC contents 98.2%, weight yield 103.6%.
It takes the bis- dehydrogenation -17a- hydroxyl progesterone crude product 100g of above-mentioned 1,6- to be added into a 1000ml there-necked flask, adds 500ml wine
Essence is stirred at 30-35 DEG C and is made it completely dissolved, and 5g active carbon is then added, and is heated reflux 1.5-2 hours, is then dropped
Temperature filters, filter cake about 100ml alcohol foam washing, filter cake send producer to recycle, and filtrate is normal after merging with washing lotion while hot to 55-60 degree
Pressure is concentrated into recycling about 88-90% alcohol, then system is cooled to -5~0 DEG C, and stirring and crystallizing 3~4 hours, filtering, filtrate was returned
It receives solvent to apply with mother liquor material, filter cake is washed with a small amount of 50% ethanol water, and 70 DEG C or less drying obtain the bis- dehydrogenations-of 1,6-
17a- hydroxyl progesterone product 92.5g, 228.5~230.0 DEG C of fusing point, HPLC content 99.6%, weight yield 92.5%.
Embodiment 2
A: the preparation of hydroxyl cyanogen object
In a 1000ml there-necked flask, starting material IDD100g, acetone cyanohydrin 50ml, methanol 500ml, temperature control is added
To 40~45 DEG C, stirring is completely dissolved IDD, and then temperature control is at 20~25 DEG C, and slowly the sodium hydroxide alkali of dropwise addition 2% is water-soluble
Liquid, about 2-2.5 hour drip off, then keep the temperature and react 2~3 hours in 25~30 DEG C, and TLC confirms reaction end, after having reacted, decompression
The methanol of concentration and recovery 90-95% and the mixing solvent of acetone cyanohydrin are applied, and residue is cooled to 20~25 DEG C, adds
500ml tap water elutriation, filtering, filtrate send waste water processing station to handle, and filter cake is crystallized with the alcohol water blend of 500ml 40%, obtain
Hydroxyl cyanogen object 97.8g, HPLC content 98.5%, weight yield 97.8%.
The preparation of the bis- dehydrogenation -17a- hydroxyl progesterones of B:1,6-
In a 1000ml there-necked flask, 35g magnesium powder, 800ml tetrahydrofuran, stirring is added, heat preservation is passed through in 30-35 DEG C
148g bromomethane after having led to, continues to be stirred to react 4~6 hours, until magnesium powder disappears substantially, it is spare to obtain Grignard Reagent；
In another 1000ml there-necked flask, hydroxyl cyanogen object prepared by the above-mentioned A of 100g, 500ml toluene, stirring heating is added
To 50~55 DEG C, the above-mentioned about 800ml grignard reagent solution got ready is slowly added dropwise, drips off within about 1-1.5 hours, is further continued for heat preservation and stirs
Mix reaction 2~3 hours, TLC detects reaction end, and after having reacted, about 500ml 6N sulfuric acid is slowly added dropwise to PH2-3, after dripping off
In 50~55 DEG C continuation hydrolysis 2-3 hours, TLC detection hydrolysis completely, after having reacted, about 90-95%THF is concentrated under reduced pressure out
With the mixing solvent of toluene (THF and toluene of recycling mix solvent and handle rear enclosure use).600ml is added in above-mentioned residual night again certainly
Water, and system is cooled to 5~10 DEG C, stirring and crystallizing 2~3 hours, filtering, filtrate sent waste water processing station to handle, and filter cake is used
Originally water washing to neutrality, 70 DEG C or less drying obtains grignard object: 1,6- bis- dehydrogenation -17a- hydroxyl progesterone crude product 102.4g,
HPLC content 97.8%, weight yield 102.4%.Take the bis- dehydrogenation -17a- hydroxyl progesterone crude product 100g of above-mentioned 1,6- by above-mentioned
The refining methd of the bis- dehydrogenation -17a- hydroxyl progesterone crude products of 1,6- described in one B of embodiment is recrystallized, and it is bis- de- to obtain 1,6-
Hydrogen -17a- hydroxyl progesterone product 91.2g, 229~231 DEG C of fusing point, HPLC content 99.5%, weight yield 91.2%.
Embodiment 3
A: the preparation of hydroxyl cyanogen object
In a 1000ml there-necked flask, starting material IDD100g is added, acetone cyanohydrin 50ml, DME500ml, temperature control is extremely
40~45 DEG C, stirring is completely dissolved IDD, and then 2% triethylamine aqueous alkali is slowly added dropwise at 20~25 DEG C in temperature control,
It drips off within about 2-2.5 hours, then keeps the temperature and reacted 2~3 hours in 25~30 DEG C, TLC confirms reaction end, after having reacted, depressurizes dense
The mixing solvent for retracting the DME and acetone cyanohydrin that receive 90-95% is applied, and residue is cooled to 20~25 DEG C, adds 500ml certainly
Water elutriation, filtering, filtrate send waste water processing station to handle, and filter cake is crystallized with the alcohol water blend of 500ml 40%, obtain hydroxyl cyanogen object
96.2g, HPLC content 98.2%, weight yield 96.2%.
The preparation of the bis- dehydrogenation -17a- hydroxyl progesterones of B:1,6-
In a 1000ml there-necked flask, 35g magnesium powder, 800ml ether is added, stirring is kept the temperature in 35-40 DEG C of dropwise addition 186g
Iodomethane after dripping off, continues to be stirred to react 4~6 hours, until magnesium powder disappears substantially, it is spare to obtain Grignard Reagent；
In another 1000ml there-necked flask, hydroxyl cyanogen object prepared by the above-mentioned A of 100g, 500mlTHF, stirring heating is added
To 50~55 DEG C, the above-mentioned about 800ml grignard reagent solution got ready is slowly added dropwise, drips off within about 1-1.5 hours, is further continued for heat preservation and stirs
Mix reaction 2~3 hours, TLC detects reaction end, and after having reacted, about 500ml 6N sulfuric acid is slowly added dropwise to PH2-3, after dripping off
In 50~55 DEG C continuation hydrolysis 2-3 hours, TLC detection hydrolysis completely, after having reacted, about 90-95%THF is concentrated under reduced pressure out
With the mixing solvent of ether (THF and ether of recycling mix solvent and handle rear enclosure use).600ml is added in above-mentioned residual night again certainly
Water, and system is cooled to 5~10 DEG C, stirring and crystallizing 2~3 hours, filtering, filtrate sent waste water processing station to handle, and filter cake is used
Originally water washing to neutrality, 70 DEG C or less drying obtains grignard object: 1,6- bis- dehydrogenation -17a- hydroxyl progesterone crude product 103.2g,
HPLC content 97.6%, weight yield 103.2%.Take the bis- dehydrogenation -17a- hydroxyl progesterone crude product 100g of above-mentioned 1,6- by above-mentioned
The refining methd of the bis- dehydrogenation -17a- hydroxyl progesterone crude products of 1,6- described in one B of embodiment is recrystallized, and it is bis- de- to obtain 1,6-
Hydrogen -17a- hydroxyl progesterone product 92.7g, 229~230 DEG C of fusing point, HPLC content 99.6%, weight yield 92.7%.
The above content is combine specific preferred embodiment to the further description of the invention made, and it cannot be said that originally
The specific implementation of invention is only limited to these instructions.For those of ordinary skill in the art to which the present invention belongs, not
Under the premise of being detached from present inventive concept, several simple deductions and replacement can also be made, all shall be regarded as belonging to guarantor of the invention
Protect range.
Claims (8)
1. one kind 1, the bis- dehydrogenation -17a- hydroxyl progesterone product preparation methods of 6-, the method includes using Isosorbide-5-Nitrae-hero diene two
Ketone, that is, IDD is raw material, occurs that 17 in IDD molecule ketone under base catalysis in the first organic solvent with acetone cyanohydrin
Reaction, in 17 introducing beta-hydroxies and alpha-cyano, obtains hydroxyl cyanogen object；Then by hydroxyl cyanogen object in methyl-magnesium-halide, second organic molten
In the presence of agent and acid, the bis- dehydrogenation -17a- hydroxyl progesterones of 1,6- are prepared；Again by the bis- dehydrogenation -17a- hydroxyls of obtained 1,6-
Progesterone is heated to reflux decoloration in toluene, acetone or C4 or less low-carbon alcohols with active carbon and recrystallizes, and obtains the bis- dehydrogenations-of 1,6-
17a- hydroxyl progesterone product.
2. the method according to claim 1, wherein first organic solvent be acetone cyanohydrin, methylene chloride,
One or more of DME, ethyl acetate, THF and C4 or less low-carbon alcohols, preferably described first organic solvent are methanol.
3. the method according to claim 1, wherein the alkali is organic base or inorganic base, preferably pyridine, three
One of ethamine, sodium carbonate and sodium hydroxide are a variety of, more preferable sodium carbonate.
4. the method according to claim 1, wherein second organic solvent is methylene chloride, toluene, ether
One or more of with THF, preferably described second organic solvent is THF.
5. the method according to claim 1, wherein the acid is organic acid or inorganic acid, preferably acetic acid, right
One of toluenesulfonic acid, hydrochloric acid and sulfuric acid are a variety of, more preferable hydrochloric acid.
6. the method according to claim 1, wherein reaction temperature is in the step of IDD reaction generates hydroxyl cyanogen object
10~100 DEG C, reaction temperature is 30~100 DEG C in the step of reaction of hydroxyl cyanogen object generates 1,6- bis- dehydrogenation -17a- hydroxyl progesterones,
It and include first adding methyl-magnesium-halide into the second organic solvent and hydroxyl cyanogen object grignard addition reaction occurs, then add in reaction process
The grignard object that acid adding obtains grignard addition reaction hydrolyzes, and organic solvent is then recovered under reduced pressure and obtains institute after adding water to carry out elutriation
State the bis- dehydrogenation -17a- hydroxyl progesterones of 1,6-.
7. the method according to claim 1, wherein the method also includes first using phytosterol through microorganism
The IDD is prepared after fermentation.
8. the method according to the description of claim 7 is characterized in that the method also includes first using in soybean oil production process
The isolated phytosterol of deodorization distillate.
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