CN109705182A - A kind of preparation method of Nilestriol - Google Patents
A kind of preparation method of Nilestriol Download PDFInfo
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Abstract
本发明提供一种尼尔雌醇的制备方法，以乙炔化物作为起始原料，先与有机酮类进行缩酮反应，再分离出17β‑乙炔化物异构体，再精制得到纯度较高的17a‑乙炔化物，再与溴代环戊烷发生醚化反应得到尼尔雌醇粗品，精制后得到尼尔雌醇精品。与现有技术相比，本发明的制备方法能够制备得到高纯度的尼尔雌醇精品，且从源头上精制了原料，简化了尼尔雌醇的制备工艺，产率高，显著提高了反应经济性，降低了生产成本。
The invention provides a preparation method of nilestriol, which takes acetylide as a starting material, first performs ketal reaction with organic ketones, then separates 17β-acetylene isomer, and then purifies to obtain 17a with higher purity -Acetylene, etherification reaction with bromocyclopentane to obtain nilestriol crude product, and refined nilestriol fine product. Compared with the prior art, the preparation method of the present invention can prepare high-purity nilestriol fine products, and the raw materials are refined from the source, the preparation process of nilestriol is simplified, the yield is high, and the reaction is significantly improved. Economical, reducing production costs.
Description
Technical field
The invention belongs to chemical pharmaceutical technology fields, specifically, being the preparation method about a kind of Nilestriol.
Background technique
Nilestriol, entitled -17 α of 3- (the cyclopentyloxy) -19- demethyl-pregnant steroid -1,3 of chemistry, 5 (10)-triolefin -20-
- 16 α of alkynes, 17- glycol are estriol derivative, are the metabolins of estradiol and oestrone, belong to long-acting slow-release estrogen drugs.
Nilestriol is mainly used for symptom caused by treating menopausal women estrogen deficiency, the comprehensive phase syndrome of climacteric, senile
Vaginitis and atrophic urethritis, prevent postclimacteric cardiovascular disease, pre- anti-osteoporosis etc..
In the prior art, the route of Nilestriol is usually prepared using estrone as raw material, reaction route is long, and reaction process
It is middle to generate a large amount of 17 β-acetylide configurations, it need to be reacted with contracting acetone and the means such as column chromatography are separated, lock out operation complexity,
Low yield, purity is low, causes to react very uneconomical, increased costs.
Therefore, it is necessary to the preparation method of new Nilestriol be researched and developed, to overcome above-mentioned technological deficiency in the prior art.
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of Nilestriol, existing in the prior art above-mentioned scarce to overcome
It falls into.
To achieve the above object, the invention adopts the following technical scheme:
The preparation method of Nilestriol, using acetylide as raw material, including following preparation step:
The first step, ketal reaction
Ketal reaction occurs for acetylide and organic ketone, is filtered, washed, is dried, and the mixing containing ketal (III) is obtained
Object；
Second step, primary purification
The mixture containing ketal (III) of the first step is beaten with appropriate 1,2- dichloroethanes, by flowing back and decolourizing, cool down,
Filtering is washed with the mixed solvent of 1,2- dichloroethanes and ethyl acetate, is dry, obtains 17 α-acetylide (I) crude product；
Third step, secondary refining
17 α-acetylide (I) crude product of second step flows back and is decolourized in dehydrated alcohol, filtered, filtrate is concentrated to dryness,
Then it is carried secretly with appropriate ethyl acetate to dry；Add appropriate 1,2- dichloroethanes, stir evenly, stand overnight, through filtering, 1,
The washing of 2- dichloroethanes, obtains solid；Without drying, aforesaid operations are repeated 1~2 time, and last is done all over obtained solid
It is dry, obtain 17 α-acetylide (I) fine work；
4th step, etherification reaction
17 α-acetylide (I) fine work, Anhydrous potassium carbonate and the dehydrated alcohol of the third step of formula ratio are added in reactor,
1~2h of back flow reaction；Ethyl alcohol-bromocyclopentane mixed solvent of formula ratio is added, and maintains the reflux for 4~6 hours, reaction knot
Shu Houjing is filtered, washed, filtrate is concentrated to dryness, and is obtained solid, and carried secretly to doing 2~3 times with dehydrated alcohol, is obtained female containing Neil
The product of alcohol (IV)；
Product containing Nilestriol is added appropriate petroleum ether, filtering, is washed with the mixed solvent of petroleum ether and ethyl alcohol, obtains
Filter cake dissolved again with q. s. methylene chloride, dichloromethane layer is washed to neutrality, and isolates dichloromethane layer, then to dichloro
Methane layer carries out dehydration and decolorization, is filtered, washed, and filtrate is concentrated to dryness, and obtains solid, and petroleum ether is added again, filters, use stone
The washing of the mixed solvent of oily ether and ethyl alcohol, obtains Nilestriol (IV) crude product；
The quality of the Anhydrous potassium carbonate of addition is 2.5~3 times of the 17 α-acetylide fine work quality being added；
The mass volume ratio of the bromocyclopentane of the 17 α-acetylide fine work and addition that are added is 1:(1.0~2.5) g/
ml；
5th step, product purification
Nilestriol (IV) crude product of 4th step passes through appropriate ethyl acetate backflow and decolourizes, is filtered, washed, filtrate concentration
To doing, ethyl alcohol is carried secretly 2~3 times, is concentrated to dryness, is added appropriate petroleum ether, filtering, is washed with the mixed solvent of petroleum ether and ethyl alcohol
Filter cake is washed, checked for impurities content, if unqualified, repetitive operation dries until checked for impurities qualification, obtains Nilestriol
(IV) fine work.
In 5th step, according to Cp2015 Chinese Pharmacopoeia standard, unknown impuritie content should be less than 0.1%.5th step
In, if impurity content is unqualified, repetitive operation, until checked for impurities is qualified.In general, repetitive operation 0~2 time.
According to the present invention, in the first step, the mass volume ratio of the acetylide and the organic ketone is 1:(0.5
~2) g/ml, the time of the ketal reaction are 3~4 hours.
According to the present invention, in the first step, the organic ketone in the ketal reaction is acetone or methyl iso-butyl ketone (MIBK)；Institute
Stating ketal reaction uses perchloric acid for catalyst.
Those skilled in the art are known, and the ketal reaction can also use other catalyst in the prior art, such as:
Fluoboric acid, the lewis acids such as p-methyl benzenesulfonic acid, the concentrated sulfuric acid.
According to the present invention, it in the first step, after the ketal reaction, is adjusted using the aqueous solution of organic base or inorganic base
Then the pH of reaction system is filtered, washed, is dried, obtain the mixture containing ketal to neutrality.
It should be understood readily by those skilled in this art, the prior art can be respectively adopted in the aqueous solution of the organic base or inorganic base
In the aqueous solution of common organic base or inorganic base.Preferably, the organic base is selected from one of triethylamine or pyridine or two
Kind；The aqueous solution of the inorganic base is selected from sodium bicarbonate aqueous solution, aqueous sodium carbonate, calcium carbonate aqueous solution, sodium hydroxide water
One or more of solution, potassium bicarbonate aqueous solution and wet chemical.
According to the present invention, the reflow step of the second step, the mixture and 1 containing ketal (III), 2- dichloroethanes
Mass volume ratio be 1:(3~7) g/ml.
It should be understood readily by those skilled in this art, the reflux temperature is different according to the boiling point of solvent and changes.Described
In two steps, the reflux temperature is preferably 83.5 ± 3 DEG C.
According to the present invention, in the second step, the in the mixed solvent of 1, the 2- dichloroethanes and ethyl acetate, described 1,
The volume ratio of 2- dichloroethanes and ethyl acetate is (4~8): 1.
Preferably, the volume ratio of the in the mixed solvent, 1, the 2- dichloroethanes and ethyl acetate is 4:1.
According to the present invention, in the third step, the mass volume ratio of the 17 α-acetylide crude product and dehydrated alcohol is
1:(20~50) g/ml；The mass volume ratio of the 17 α-acetylide crude product and ethyl acetate is 1:(1~3) g/ml；It is described
The mass volume ratio of 17 α-acetylide crude product and 1,2- dichloroethanes is 1:(0.5~1.5) g/ml.
Preferably, the aforesaid operations of the third step repeat 1 time.
According to the present invention, in the 4th step, the mass volume ratio of the 17 α-acetylide fine work and dehydrated alcohol is
1:(20~50) g/ml.
In 4th step, the terminal of the back flow reaction are as follows: detect raw material peak≤10% of 17 α-acetylide.
The mass volume ratio of the methylene chloride of the 17 α-acetylide fine work and addition that are added is 1:(10~20) g/ml；
According to the present invention, in the 4th step, in the washing step of the dichloromethane layer, with ethyl acetate to filter cake into
Row washing.
According to the present invention, in the 4th step, the in the mixed solvent of the petroleum ether and dehydrated alcohol, the petroleum ether with
The volume ratio of dehydrated alcohol is 2:1.
According to the present invention, in the 4th step, to dichloromethane layer carry out dehydration and decolorization the step of in, using desiccant into
Row dehydration, is decolourized using decolorising agent；
The desiccant is selected from anhydrous sodium sulfate, one of anhydrous magnesium sulfate, anhydrous calcium chloride and molecular sieve.
The decolorising agent is selected from one of active carbon, carclazyte or absorption resin.
Preferably, in the 4th step, to dichloromethane layer carry out dehydration and decolorization the step of in, be added proper amount of acetone, nothing
Aqueous sodium persulfate, active carbon, stirring.The mass volume ratio of the 17 α-acetylide fine work and acetone is 1:(3~5) g/ml.
Preferably, the mass volume ratio of the 17 α-acetylide fine work and acetone is 1:4g/ml.
According to the present invention, in the 5th step, the mass volume ratio of the 17 α-acetylide fine work and ethyl acetate is
1:(4~6) g/ml；
In 5th step, into the system that step (1) is concentrated to dryness be added petroleum ether the step of in, the 17 α-acetylene
The mass volume ratio of compound fine work and petroleum ether is 1:(0.4~0.6) g/ml.
Compared with prior art, the present invention has following advantageous effects:
The preparation method of Nilestriol of the invention first carries out raw material using acetylide mixture as starting material
Processing obtains 17a- acetylide fine work to isolate 17 β-acetylide, then with 17a- acetylide fine work and bromo ring penta
Alkane carries out etherification reaction, obtains Nilestriol, and the purity for the Nilestriol fine work being prepared is higher than 98%.With in the prior art
It is compared using the route that estrone prepares Nilestriol as raw material, the Neil of high-purity can be prepared in preparation method of the invention
Female alcohol fine work, and raw material has been refined from source, the preparation process of Nilestriol is simplified, yield is high, significantly improves reaction
Economy reduces production cost.
Detailed description of the invention
Fig. 1 is the synthetic route schematic diagram of Nilestriol of the invention.The first step is given in figure to the 4th step, the 4th step
Nilestriol crude product is prepared.5th step is the refining and edulcoration process of Nilestriol crude product.
Specific embodiment
Below in conjunction with specific embodiment, the invention will be further described.It should be understood that following embodiment is merely to illustrate this
Invention is not for limiting the scope of the invention.
In the following example, raw material used is commercially available.
Acetylide includes 17a- acetylide (full name 3,16a, 17 β-trihydroxy -17a- acetenyl -1,3,5 (10) -
Triolefin -19- demethyl-female steroid) and 17 β-acetylide (full name 3,16a, -17 β of 17a- trihydroxy-acetenyl -- 1,3,5
(10)-triolefin -19- demethyl-female steroid), (II) both configurations.Only 17a- acetylide is etherified with bromocyclopentane
Reaction can just obtain Nilestriol of the invention.
In the following example, those skilled in the art refer to can't see solvent outflow cold it is understood that be concentrated to dryness
Condenser.
Embodiment 1 prepares Nilestriol
It prepares the sodium bicarbonate aqueous solution that mass concentration is 3%: weighing sodium bicarbonate 2.7g and be put into beaker, addition is drunk
Water 87.3ml, dissolved clarification are configured to the sodium bicarbonate aqueous solution that mass concentration is 3%.
The first step, ketal reaction
178ml acetone, 120g acetylide are put into 500ml reaction flask, is opened under stirring, and 0.98ml high chlorine is put into
Acid stirs 15 minutes, stands 3 hours.Stirring is opened, the sodium bicarbonate aqueous solution that the mass concentration of above-mentioned preparation is 3% is dripped
It is added in reaction system and (pays attention to control rate of addition, lead to slug to prevent the generation of a large amount of bubbles)；After being added dropwise, continue to stir
5 minutes, stand 1 hour；Filtering, filter cake are eluted 3 times with drinking water, until cleaning solution is neutrality, if the pH > 7 of cleaning solution,
Then continue to be washed with water, until cleaning solution be neutrality, filter cake vacuum drying to constant weight, 50~70 DEG C of drying temperature, vacuum degree≤-
0.08MPa obtains the mixture containing ketal.
Through detecting, in mixture of the gained containing ketal, the purity of 17 α-acetylide is 60%.
Second step, primary purification
164.4ml1, the mixture containing ketal of 2- dichloroethanes, the 30g first step, stirring are put into 250ml reaction flask
Under the conditions of, 83.5 ± 3 DEG C are heated to, heat preservation reflux 30 minutes, reaction system is cooled with circulating water room temperature, keeps the temperature 1 hour, quiet
It sets 15 hours or more；Then it filters, drain, the dichloroethanes that filter cake is 4:1 with 12ml volume ratio: the mixed solvent of ethyl acetate
Elution, then vacuum drying, to constant weight, drying temperature is 50~70 DEG C, and vacuum degree≤- 0.08MPa obtains 17 α of about 18g-acetylene
Compound crude product.
Through detecting, the purity 85% of 17 α-acetylide in 17 α of gained-acetylide crude product.
Third step, secondary refining
(1), under the interior investment 660ml dehydrated alcohol of 1000ml reaction flask, stirring condition, 18g second step is successively put into
17a acetylide crude product, 6g active carbon, 78 DEG C or so reflux are decolourized 1 hour；It filters while hot, the hot dehydrated alcohol of gained filter cake
Washing, and cleaning solution is incorporated to filtrate；Gained filtrate decompression is concentrated to dryness, and primary with 30ml ethyl acetate band, continues to be concentrated
To after dry, 12ml dichloroethanes is put into, crystal in bottle is smashed, stirs evenly, stand overnight；It filters, drain, then with 12ml dichloro
Hexane filter cake continues to drain.
(2), step (1) is repeated, obtained filter cake vacuum drying to constant weight, 50~70 DEG C of drying temperature, vacuum degree≤-
0.08MPa obtains 17 α of about 11g-acetylide fine work.
Through detecting, the purity of 17 α-acetylide is 98% in 17 α of gained-acetylide fine work.
4th step, etherification reaction
9.8ml dehydrated alcohol and 9.8ml bromocyclopentane are uniformly mixed, being configured to volume ratio is 1:1 dehydrated alcohol-bromine
For pentamethylene mixed solvent.
(1), 12.6g Anhydrous potassium carbonate, 176ml dehydrated alcohol are put into reaction flask, stir lower investment 17 α of 5g-ethinylation
Object fine work is heated to 78 DEG C or so, is kept for system return stirring 1 hour；Then system is kept to be in micro- reflux state, it will be above-mentioned
19.6ml dehydrated alcohol-bromocyclopentane mixed solvent of preparation is added drop-wise in reaction flask, and control time for adding is 1 hour left side
It is right；After being added dropwise, continue back flow reaction 5 hours.HPLC analysis is done in sampling, if raw material peak > 10% of 17 α-acetylide,
Continue to keep the temperature back flow reaction, every 1 hour sample detection, until raw material peak≤10% of 17 α-acetylide, stops reaction.
(2), reaction system after reaction, is cooled to room temperature, is stood；5g aluminium oxide is spread in funnel, is filtered, and filter cake is every
It is secondary to be washed with the hot dehydrated alcohol of 20ml, it washs 2 times altogether, cleaning solution is incorporated to filtrate, and gained filtrate is through being concentrated to dryness, then again
10ml dehydrated alcohol is added, continues to be concentrated to dryness, blends crystal, repeats that 10ml dehydrated alcohol is added, continues to be concentrated under reduced pressure
To after dry, it is cooled to room temperature, obtains etherification product.
(3), 2ml petroleum ether is added in the etherification product in step (2), blends crystal, filtered, after draining, with 4ml volume
It sufficiently washed once, drain than the petroleum ether for 2:1-dehydrated alcohol mixed solvent.The petroleum ether-for being again 2:1 with 2ml volume ratio
Dehydrated alcohol mixed solvent sufficiently washed once, and drain, and obtain solid I.Then above-mentioned solid I is dissolved with 70ml methylene chloride,
Methylene chloride phase is obtained, purifies water washing methylene chloride phase with 140ml every time, is washed 3 times altogether, until water phase is detected as in pH
Property.Methylene chloride phase is isolated, and 20ml acetone, 3g anhydrous sodium sulfate, 0.7g active carbon are added in methylene chloride phase, stirring
0.5 hour, filtering, gained filter cake was washed with 10ml ethyl acetate, and cleaning solution is incorporated to filtrate, and gained filtrate decompression is concentrated to dryness,
Then system is cooled to room temperature, 2ml petroleum ether is added, after smashing crystal, stood.Filtering after draining, first uses 4ml volume ratio
It sufficiently washed once, drain, then the petroleum ether-for being 2:1 with 2mlL volume ratio for petroleum ether-dehydrated alcohol mixed solvent of 2:1
Dehydrated alcohol mixed solvent sufficiently washed once, and drain, and obtain Nilestriol crude product, not dry to direct plunge into next step.
5th step, product purification
(1), it is living that 28ml ethyl acetate, whole Nilestriol crude products of the 4th step preparation, 0.7g are successively put into reaction flask
Property charcoal, reflux decoloration 0.5 hour, filter while hot, wash filter cake with 14ml ethyl acetate, cleaning solution is incorporated to filtrate, gained filtrate
It is concentrated under reduced pressure, and twice with the entrainment of 7ml dehydrated alcohol, is finally concentrated to dryness.
(2), 2.8ml petroleum ether is added into the system that step (1) is concentrated to dryness, stirs evenly, stands 1~2 hour, then mistake
It filters, drain, then the petroleum ether for being 2:1 with 8.4ml volume ratio-dehydrated alcohol mixed solvent is washed, drained, gained filter cake vacuum is dried
It does to constant weight, 30~50 DEG C of drying temperature, vacuum degree≤- 0.095MPa obtains about 2g Nilestriol finished product.
Through detecting, resulting Nilestriol finished product purity is 98.6%.
Embodiment 2 prepares Nilestriol
The first step, ketal reaction
Basic step is same as Example 1, and difference is, replaces 178ml acetone using 60ml methylisobutylketone, stands anti-
It answers 3 hours, the mass volume ratio of raw material acetylide and methylisobutylketone is 0.5g/ml.
Through detecting, the purity of 17 α-acetylide is 56% in mixture of the gained containing ketal.
Second step, primary purification
Basic step is same as Example 1, and difference is, using 90ml dichloroethanes, dichloroethanes and ethyl acetate
The volume ratio of in the mixed solvent, 1,2 dichloroethanes and ethyl acetate is 6:1.
Through detecting, the purity of 17 α-acetylide is 80% in 17 α of gained-acetylide crude product.
Third step, secondary refining
Basic step is same as Example 1, and difference is:
1), in step (1), the volume of dehydrated alcohol used in reflow step is 360ml；Band does ethyl acetate used
Volume is 18ml；The volume of 1,2- dichloroethanes used in impurity elimination is 9ml.
2), step (1) operation repeats 1 time.
Through detecting, the purity of 17 α-acetylide is 97% in 17 α of gained-acetylide fine work.
4th step, etherification reaction
Basic step is same as Example 1, and difference is:
1), the volume of dehydrated alcohol used in reflow step is 100ml；The quality of Anhydrous potassium carbonate used is 12.5g,
Back flow reaction 1h.
2), the volume of bromocyclopentane is that 5ml continues back after dehydrated alcohol-bromocyclopentane mixed solvent is added dropwise
Stream reaction 4h.
3) volume for the methylene chloride being added is 50ml.
Obtain Nilestriol crude product.
Step 5: product purification
Basic step is same as Example 1, and difference is:
In the purification step that flows back, the volume of the ethyl acetate of addition is 20ml；Add into the system that step (1) is concentrated to dryness
In the step of entering petroleum ether, the volume of the petroleum ether of addition is 2ml.
Dehydrated alcohol is carried secretly 2 times.
Through detecting, the purity of gained Nilestriol finished product is 98.5%.
Embodiment 3 prepares Nilestriol
The first step, ketal reaction
Basic step is same as Example 1, and difference is, replaces 178ml acetone using 240ml acetone, it is small to stand reaction 4
When, the mass volume ratio of raw material acetylide and acetone is 2g/ml.
Through detecting, the purity of 17 α-acetylide is 67% in mixture of the gained containing ketal.
Step 2:
Basic step is same as Example 1, and difference is, using 210ml dichloroethanes, dichloroethanes and ethyl acetate
The volume ratio of in the mixed solvent, 1,2 dichloroethanes and ethyl acetate is 8:1.
Through detecting, the purity of 17 α-acetylide is 90% in 17 α of gained-acetylide crude product.
Third step, secondary refining
Basic step is same as Example 1, and difference is, the volume of dehydrated alcohol used in reflow step is 900ml；Band
The volume for doing ethyl acetate used is 54ml；The volume of 1,2- dichloroethanes used in impurity elimination is 27ml.
Step (1) operation is repeated 2 times.
Through detecting, 17 α of gained-acetylide fine work after testing, wherein the purity of 17 α-acetylide be 99%
4th step, etherification reaction
Basic step is same as Example 1, and difference is:
1), the volume of dehydrated alcohol used in reflow step is 250ml；The quality of Anhydrous potassium carbonate used is 15g, is returned
Stream reaction 2h.
2), the volume of bromocyclopentane is 12.5ml, after dehydrated alcohol-bromocyclopentane mixed solvent is added dropwise, after
Continuous back flow reaction 6h.
3) volume for the methylene chloride being added is 100ml.
Obtain Nilestriol crude product.
5th step, product purification
Basic step is same as Example 1, and difference is:
In the purification step that flows back, the volume of the ethyl acetate of addition is 30ml；Add into the system that step (1) is concentrated to dryness
In the step of entering petroleum ether, the volume of the petroleum ether of addition is 3ml.
Dehydrated alcohol is carried secretly 3 times.
Through detecting, the purity of gained Nilestriol finished product is 99%.
Embodiment 4 prepares Nilestriol
Basic step is same as Example 1, and difference is, in the 5th step, using atlapulgite as decolorising agent, anhydrous sulphur
Sour magnesium is as desiccant.
Through detecting, the purity of gained Nilestriol finished product is 98.5%.
Embodiment 5 prepares Nilestriol
Basic step is same as Example 1, and difference is, in the 5th step, using macroporous absorbent resin as decolorising agent, nothing
Water calcium chloride is as desiccant.
Through detecting, the purity of gained Nilestriol finished product is 98.5%.
Embodiment 6 prepares Nilestriol
Basic step is same as Example 1, and difference is, in third step, is added without acetone in methylene chloride phase.
Through detecting, the purity of gained Nilestriol finished product is 98.4%.
In above embodiments, in the mixture containing ketal of first step preparation, the purity of 17 α-acetylide is 56~
67%.In the 17 α-acetylide crude product of second step preparation, the purity of 17 α-acetylide is 80~90%, third step preparation
In 17 α-acetylide fine work, the purity of 17 α-acetylide is 97~99%.The purity of Nilestriol of 5th step preparation is
98.4~99%.
Specific embodiments of the present invention are described in detail above, but it is only used as example, the present invention is not intended to limit
In particular embodiments described above.To those skilled in the art, it any equivalent modifications to the practical progress and replaces
In generation, is also all among scope of the invention.Therefore, without departing from the spirit and scope of the invention made by equal transformation and repair
Change, all should be contained within the scope of the invention.
Claims (10)
1. a kind of preparation method of Nilestriol, which is characterized in that using acetylide as raw material, including following preparation step:
The first step, ketal reaction
Ketal reaction occurs for acetylide and organic ketone, is filtered, washed, is dried, obtains the mixture containing ketal；
Second step, primary purification
The mixture containing ketal and appropriate 1,2- dichloroethanes of the first step are beaten, by reflux purification, cooling, filtering, with 1,
The washing of the mixed solvent of 2- dichloroethanes and ethyl acetate, drying, obtain 17 α-acetylide crude product；
Third step, secondary refining
17 α-acetylide the crude product of second step flows back and is decolourized in dehydrated alcohol, filtered, filtrate is concentrated to dryness, then with suitable
Amount ethyl acetate is carried secretly to dry；Appropriate 1,2- dichloroethanes is added, stirs evenly, stands overnight, through filtering, 1,2-, bis- chloroethene
Alkane washing, obtains solid；Without drying, aforesaid operations are repeated 1~2 time, and last is dry all over obtained solid, obtain 17
α-acetylide fine work；
4th step, etherification reaction
17 α-acetylide fine work, Anhydrous potassium carbonate and the dehydrated alcohol of the third step of formula ratio are added in reactor, reflux is anti-
Answer 1~2h；Ethyl alcohol-bromocyclopentane mixed solvent of formula ratio is added, and maintains the reflux for 4~6 hours, is passed through after reaction
Be filtered, washed, filtrate is concentrated to dryness, obtain solid, and carried secretly to 2~3 times dry with dehydrated alcohol, obtain the production containing Nilestriol
Object；
Product containing Nilestriol is added appropriate petroleum ether, filtering, is washed with the mixed solvent of petroleum ether and ethyl alcohol, obtained filter
Cake is dissolved with q. s. methylene chloride again, and dichloromethane layer is washed to neutrality, and isolates dichloromethane layer, then to methylene chloride
Layer carries out dehydration and decolorization, is filtered, washed, and filtrate is concentrated to dryness, and obtains solid, and petroleum ether is added again, filters, use petroleum ether
It is washed with the mixed solvent of ethyl alcohol, obtains Nilestriol crude product；
The quality of the Anhydrous potassium carbonate of addition is 2.5~3 times of the 17 α-acetylide fine work quality being added；
The mass volume ratio of the bromocyclopentane of the 17 α-acetylide fine work and addition that are added is 1:(1.0~2.5) g/ml；
5th step, product purification
The Nilestriol crude product of 4th step pass through appropriate ethyl acetate backflow and decolourize, be filtered, washed, filtrate is concentrated to dryness, second
Alcohol is carried secretly 2~3 times, is concentrated to dryness, is added appropriate petroleum ether, filtering, washs filter cake with the mixed solvent of petroleum ether and ethyl alcohol,
Checked for impurities content, if unqualified, repetitive operation dries until checked for impurities qualification, obtains Nilestriol fine work.
2. the preparation method of Nilestriol according to claim 1, which is characterized in that in the first step, the acetylene
The mass volume ratio of compound and the organic ketone is 1:(0.5~2) g/ml, the time of the ketal reaction is 3~4 hours.
3. the preparation method of Nilestriol according to claim 1, which is characterized in that in the first step, the ketal
Organic ketone in reaction is acetone or methyl iso-butyl ketone (MIBK)；The ketal reaction uses perchloric acid for catalyst.
4. the preparation method of Nilestriol according to claim 1, which is characterized in that in the first step, the ketal
After reaction, then the pH for adjusting reaction system using the aqueous solution of organic base or inorganic base is filtered, washed, is dried to neutrality,
Obtain the mixture containing ketal.
5. the preparation method of Nilestriol according to claim 1, which is characterized in that the reflow step of the second step,
The mass volume ratio of the mixture containing ketal and 1,2- dichloroethanes is 1:(3~7) g/ml.
6. the preparation method of Nilestriol according to claim 1, which is characterized in that in the second step, described 1,2-
The volume ratio of the in the mixed solvent of dichloroethanes and ethyl acetate, 1, the 2- dichloroethanes and ethyl acetate is (4~8): 1.
7. the preparation method of Nilestriol according to claim 1, which is characterized in that in the third step, 17 α-
The mass volume ratio of acetylide crude product and dehydrated alcohol is 1:(20~50) g/ml；17 α-acetylide the crude product and acetic acid
The mass volume ratio of ethyl ester is 1:(1~3) g/ml；The mass volume ratio of the 17 α-acetylide crude product and 1,2- dichloroethanes
For 1:(0.5~1.5) g/ml.
8. the preparation method of Nilestriol according to claim 1, which is characterized in that in the 4th step, 17 α-
The mass volume ratio of acetylide fine work and dehydrated alcohol is 1:(20~50) g/ml.
9. the preparation method of Nilestriol according to claim 1, which is characterized in that in the 4th step, the dichloro
In the washing step of methane layer, filter cake is washed with ethyl acetate.
10. the preparation method of Nilestriol according to claim 1, which is characterized in that in the 5th step, 17 α-
The mass volume ratio of acetylide fine work and ethyl acetate is 1:(4~6) g/ml；
In 5th step, be added petroleum ether the step of in, the mass volume ratio of the 17 α-acetylide fine work and petroleum ether
For 1:(0.4~0.6) g/ml.
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