CN107619424A - A kind of preparation method of 17 hydroxyl nitrile steroid derivative - Google Patents
A kind of preparation method of 17 hydroxyl nitrile steroid derivative Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of steroidal compounds, more particularly, to the preparation method of the hydroxyl nitrile steroid derivative of kind 17.The present invention is with 3,17 2 ketosteroid compounds (I) are raw material, by 3,17 2 ketosteroid compounds (I) react with acetone cyanohydrin in the solution of weak organic bases obtains 17 β hydroxyl nitriles steroid derivatives (II), and intermediate (II) reacts with acetone cyanohydrin in strong base solution obtains 17 α hydroxyl nitriles steroid derivatives (III).The invention new technology raw material is easy to get, simple to operate, can effectively control side reaction, improves reaction yield and quality；High-risk reaction it is not related in technological design, it is easy to accomplish industrialization；Reacted in the absence of high pollution, alleviate environmental protection treatment pressure.
Description
Technical field
The present invention relates to a kind of preparation method of steroidal compounds, more particularly to a kind of 17- hydroxyl nitriles steroid derivative
Preparation method.
Background technology
C17 dihydroxyacetone (DHA) side chains are the essential characteristics of steroid hormone medicine.With 1,4- androstane diene -3,17- diketone
(ADD), 4- androstanes-alkene -3,17- diketone (4AD), 9 Alpha-hydroxies-androstane-alkene -3,17- diketone (9-OH-AD) or corresponding derivative
The key that thing prepares corticosteroid drug is that C17 positions ketone carbonyl is converted into two carbon side chains.It is anti-using the cyaniding addition of ketone carbonyl
Should, generation alpha-hydroxy nitrile (also known as cyanalcohol), is to increase one of method of carbon atom in carbochain.Prepare the Alpha-hydroxy of steroidal 17 at present
The common method of nitrile steroid derivative has two kinds, method one：Prepare 17- α hydroxyl nitrile steroidals in acid condition using Cymag
Derivative, this method advantage are that cost is relatively low, but this kind of method exist one it is larger the defects of, have hydrogen cyanide production in this method
It is raw, very big risk be present from the angle of safety in production；Method two：It is molten in the mixing of methanol or methanol/water using acetone cyanohydrin
In agent, prepared under the conditions of alkaline (such as potassium carbonate, sodium carbonate, triethylamine), because reaction system alkalescence is strong, the reaction time
It is long, 4,5- cyano group addition accessory substances can be produced in reaction, influence product quality and yield.
Such as：Chinese patent CN87106868 and document steroids, 1990, v55, p109 report by 9 Alpha-hydroxies-
AD is the two methods that starting material prepares 9,17-17 beta-cyanos of alpha-dihydroxy-androstane-4-alkene-3 -one, and yield is relatively low.
Method one：Under room temperature condition, using methanol and acetic acid as solvent, 9- Alpha-hydroxy hero -4- alkene -3,17- diketone (250mg)
With potassium cyanide (250mg) stirring reaction 17 hours.It is post-treated to obtain the pure α of 17- beta-cyanos -9,17 alpha-dihydroxy hero -4- alkene -
3- ketone (170mg), mass yield only 68%.
Method two：9- Alpha-hydroxy hero -4- alkene -3,17- diketone (250mg), acetone cyanohydrin (375 μ l) and 50% sodium hydroxide
Aqueous solution three's mixture is heated to clarifying, and stands overnight at room temperature, it is post-treated obtain pure 17- beta-cyano -9- α, 17- α -
Dihydroxy hero -4- alkene -3- ketone (99mg), mass yield only 39.6%.
Acetone cyanohydrin is also a kind of violent in toxicity, when using method two, in order to improve yield, can typically increase acetone cyanohydrin
Dosage, the molar ratio of acetone cyanohydrin and starting material is generally higher than 5:1.
In addition, when using Acetone cyanohydrin method, different starting materials, different reaction conditions, such as：Solvent species and structure
Into the species of, alkaline reagent, the configuration of final product can all be had an impact.Such as Fudan University Zhang Beina's in 2006 is rich
Scholar's paper《The utilization of natural sterols resource --- the synthesis 2 of 1,2 methoxyestradiols, from ADD synthesizing efficient cortin structures
Convert the exploration and research of key method》In mention, when 4AD reacts with acetone cyanohydrin in the basic conditions, can generate 4- androstanes-
Alkene -3- ketone -17- β hydroxyl nitriles and 4- androstanes-alkene -3- ketone -17- α two kinds of isomers of hydroxyl nitrile, the solvent ratios of methanol/water can shadow
Ring the configuration of final product.Document steroids, 1990, v55, p109 are reported under identical reaction conditions, different bottoms
Thing and acetone cyanohydrin react to have obtained configuration different cyanides, 9- Alpha-hydroxies hero -4- alkene -3,17- diketone and acetone cyanohydrin/hydrogen
Sodium oxide molybdena/water reacts to obtain 17- beta-cyano -9- α, 17- alpha-dihydroxy hero -4- alkene -3- ketone, but under the same reaction conditions,
4AD has obtained the opposite beta-hydroxy hero -4- alkene -3- ketone of 17 alpha-cyano -17 of configuration.But Chinese patent CN104497089 is reported
9 Alpha-hydroxy hero -4- alkene -3,17- diketone and acetone cyanohydrin/potassium carbonate/methanol/water react to have obtained 17- alpha-cyano -9- α, and 17
Beta-dihydroxy hero -4- alkene -3- ketone.Document steroids, 2013v78, p1339 report 4AD with acetone cyanohydrin in different condition
Under obtained the opposite cyanide of configuration, when 4AD and acetone cyanohydrin/sodium carbonate/methanol/water react to have obtained 17 beta-cyanos -17
Alpha-hydroxy hero -4- alkene -3- ketone, the beta-hydroxy of 17 alpha-cyano -17 has but been obtained when 4AD, acetone cyanohydrin react in the presence of triethylamine
Hero -4- alkene -3- ketone.Document steroids, 2006v71, p, 908 report 4AD and ADD respectively in acetone cyanohydrin/methanol/carbonic acid
Being reacted under the conditions of potassium, obtained the different product of configuration, the former has obtained the Alpha-hydroxy hero -4- alkene -3- ketone of 17 beta-cyano -17, after
Person has obtained the beta-hydroxy hero -1,4- diene -3- ketone of 17 alpha-cyano -17.It can be seen that the ketosteroid compounds of 3,17- bis- and acetone cyanohydrin
When reaction prepares 17 cyanides of steroidal, course of reaction is complex, it should be noted that influence factor it is a lot.
The content of the invention
A kind of preparation method of 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that by the ketosteroid compounds of 3,17- bis-
(I) react in the solution of weak organic bases with acetone cyanohydrin and obtains 17- β hydroxyl nitriles steroid derivatives (II), intermediate (II) and
Acetone cyanohydrin reacts in strong base solution obtains 17- α hydroxyl nitriles steroid derivatives (III),
For having structure：
=or-or
For double bond or singly-bound；
R is H or CH3, one or more of the weak organic bases in carboxylate, pyridine or pyridine homologue are described
Hydroxide of the highly basic selected from alkali metal or alkaline-earth metal, bicarbonate, carbonate, one kind in sulphite or organic amine
Or it is several, described organic amine does not include pyridine and pyridine homologue.
The preparation method of a kind of 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that described weak organic bases choosing
One or more from potassium acetate, sodium acetate, sodium formate, sodium citrate, ammonium acetate, pyridine or pyridine homologue, it is described
Highly basic is selected from potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, sodium sulfite, triethylamine, ethylenediamine, hexahydropyridine, hydrogen-oxygen
Change the one or more in sodium, potassium hydroxide or DBU.
The preparation method of a kind of 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that the weak organic bases are selected from
Potassium acetate, sodium acetate or pyridine, described highly basic are selected from potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate or sodium sulfite.
The preparation method of a kind of 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that described weak organic bases are
Potassium acetate, described highly basic are potassium carbonate.
A kind of preparation method of the 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that in step 1, according to weight
For amount than calculating, the rate of charge of compound (I) and acetone cyanohydrin is 1:0.6-1.0, compound (I) and the rate of charge of weak organic bases are
1:0.05-0.2；In step 2, calculated according to weight ratio meter, the rate of charge of compound (II) and acetone cyanohydrin is 1:0.1-0.5,
The rate of charge of compound (II) and highly basic is 1:0.02-0.2.
The preparation method of a kind of 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that described step one and step
Rapid two reaction temperature is 35-50 DEG C.
The preparation method of a kind of 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that described step one and step
Rapid two reaction temperature is 42-47 DEG C.
The preparation method of a kind of 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that described step one is molten
One or more of the agent in water, lower alcohol, the one kind of the solvent of described step two in water, lower alcohol, chlorohydrocarbon
It is or several.
The preparation method of a kind of 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that described step one and step
One or more of rapid two solvent in water, methanol.
The preparation method of described a kind of 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that described 3,17- diketone
Steroidal compounds (I) are selected from the Alpha-hydroxy -3,17- diketone of 1,4- androstane dienes -11, the beta-hydroxy -3,17- of 1,4- androstane dienes -11
Diketone, 4- androstanes-alkene -3,17- diketone, 9 Alpha-hydroxies-androstane-4-alkene-3,17- diketone, 16 Alpha-Methyl -1,4,9- androstanes triolefins -
3,17- diketone, 4- androstanes-alkene -3,11,17- triketones, 1,4- androstane diene -3,11,17- triketones, 16 Alpha-Methyl -4,9- androstanes
Diene -3,17- diketone, 4,9- androstane diene -3,17- diketone.
The technical advantages of the present invention are that：
1. the yield of 17- α hydroxyl nitrile steroid derivatives can be improved, the generation of accessory substance is reduced.
2. reaction system is stable, experimental repeatability is strong, has general applicability for a variety of substrates.
3. step 1 can reduce the dosage of organic solvent only with water as solvent, whole course of reaction, simultaneously
Reduce the dosage of noxious material acetone cyanohydrin, reduce cost, it is also more green.
Embodiment
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.Person skilled is it will be understood that the equivalent substitution made of technical characteristic to the present invention, or is correspondingly improved,
Still fall within protection scope of the present invention.
Inventive embodiments 1 prepare 16 Alpha-Methyl -4,9- by starting material of 16 Alpha-Methyl -4,9- androstane diene -3,17- diketone
Androstane diene -3- ketone -17- α hydroxyl nitriles
Step 1：150ml water and 20g potassium acetates are added in reactor, stirring and dissolving, 16 α-first is added into reactor
Base -4,9- androstane diene -3,17- diketone 100g, 20ml methanol and 100ml acetone cyanohydrins, 45~50 DEG C are heated to, insulation
React, control raw material disappears substantially in TLC；Reacting liquid temperature is reduced to 0~10 DEG C, is filtered, filter cake is washed with water, and filter cake infrared lamp is done
It is dry to obtain the Alpha-Methyl -4,9- androstane diene -3- ketone -17- β hydroxyl nitriles of 105g 16, mass yield 105%.
Step 2：
Method 1：It is complete molten by being stirred in 55ml water and 2.6g saleratus addition reactor, then add 16 α of 55g-first
Base -4,9- androstane diene -3- ketone -17- β hydroxyl nitriles, 100ml methanol and 11ml acetone cyanohydrins, 40~45 DEG C are heated to, protected
Temperature is reacted, and control 16 Alpha-Methyl -4,9- androstane diene -3- ketone -17- β hydroxyl nitriles in TLC disappears substantially；Reacting liquid temperature is reduced to 0
~10 DEG C, reaction solution is diluted in a large amount of water, adjusts pH=5 with concentrated hydrochloric acid, filter, filter cake is washed with water, and filter cake infrared lamp is done
It is dry to obtain Alpha-Methyl -4, the 9- androstane diene -3- ketone -17- α hydroxyl nitriles of 55.6g 16, mass yield 101%, detected through HPLC, crude product
In 16 Alpha-Methyl -4,9- androstane diene -3- ketone -17- α hydroxyl nitriles content be 91%, the content of 4,5- cyano group addition accessory substances
For 4%.
Method 2：By 100ml water, 3g sodium sulfites, the Alpha-Methyl -4,9- androstane diene -3- ketone -17- β hydroxyl nitriles of 50g 16,
5ml acetone cyanohydrins, add agitating and heating in reactor and be warming up to 42~47 DEG C, insulation reaction, control 16 Alpha-Methyl -4,9- in TLC
Androstane diene -3- ketone -17- β hydroxyl nitriles disappear substantially；Reacting liquid temperature is reduced to 0~10 DEG C, reaction solution is diluted in a large amount of water
In, adjust pH=5 with concentrated hydrochloric acid, filter, filter cake is washed with water, filter cake infrared lamp it is dry the Alpha-Methyl -4,9- androstanes two of 51g 16
Alkene -3- ketone -17- α hydroxyl nitriles, mass yield 102%, are detected through HPLC, and 16 Alpha-Methyl -4,9- androstane diene -3- ketone in crude product -
The content of 17- α hydroxyl nitriles is 91%, and the content of 4,5- cyano group addition accessory substances is 5%.
Inventive embodiments 2 prepare 4,9- androstane diene -3- ketone -17- α by starting material of 4,9- androstane diene -3,17- diketone
Hydroxyl nitrile
Step 1：75ml water and 2.5g sodium acetates are added in reactor, stirring and dissolving, it is male that 4,9- is added into reactor
Steroid diene -3,17- diketone 50g, 30ml acetone cyanohydrins, are heated to 42~47 DEG C, insulation reaction, and it is basic that raw material is controlled in TLC
Disappear；Reacting liquid temperature is reduced to 0~10 DEG C, is filtered, filter cake is washed with water, filter cake infrared lamp it is dry 52g 4,9- androstanes two
Alkene -3- ketone -17- β hydroxyl nitriles, mass yield 104%.
Step 2：It is complete molten by being stirred in 52ml water and 1.05g potassium carbonate addition reactor, then add 52g 4,9- androstanes
Diene -3- ketone -17- β hydroxyl nitriles, 105ml ethanol and 5.25ml acetone cyanohydrins, are heated to 43~46 DEG C, insulation reaction,
4,9- androstane diene -3- ketone -17- β hydroxyl nitriles are controlled in TLC to disappear substantially；Reacting liquid temperature is reduced to 0~10 DEG C, by reaction solution
It is diluted in a large amount of water, adjusts pH=5 with concentrated hydrochloric acid, filter, filter cake is washed with water, and filter cake infrared lamp is dry that 50.5g 4,9- are male
Steroid diene -3- ketone -17- α hydroxyl nitrile crude products, mass yield 101%, are detected through HPLC, and 4,9- androstane dienes -3- ketone in crude product -
The content of 17- α hydroxyl nitriles is 92%, and the content of 4,5- cyano group addition accessory substances is 3%.
Inventive embodiments 3 using the beta-hydroxy -3,17- diketone of 1,4- androstane dienes -11 as starting material prepare 1,4- androstane dienes -
11 beta-hydroxy -3- ketone -17- α hydroxyl nitriles
Step 1：By 60ml water, 4ml pyridines, beta-hydroxy -3,17- diketone 40g, 8ml ethanol of 1,4- androstane dienes -11 and
32ml acetone cyanohydrins are added in reactor and stirred, and are heated to 40~45 DEG C, insulation reaction, and control raw material disappears substantially in TLC；
Reacting liquid temperature is reduced to 0~10 DEG C, is filtered, filter cake is washed with water, filter cake infrared lamp it is dry 41.5g 1,4- androstane dienes -11
Beta-hydroxy -3- ketone -17- β hydroxyl nitriles, mass yield 104%.
Step 2：It is complete molten by being stirred in 41.5ml water and 4.15g sodium carbonate addition reactor, then add 41.5g 1,4-
Beta-hydroxy -3- ketone -17- β the hydroxyl nitriles of androstane diene -11,83ml dichloromethane and 20.7ml acetone cyanohydrins, it is heated to 41~
46 DEG C, insulation reaction, the beta-hydroxy -3- ketone -17- β hydroxyl nitriles of 1,4- androstane dienes -11 are controlled in TLC and are disappeared substantially；Reduce reaction solution
Reaction solution is diluted in a large amount of water by temperature to 0~10 DEG C, is adjusted pH=5 with concentrated hydrochloric acid, is filtered, filter cake is washed with water, and filter cake is red
Outer lamp it is dry 40g1, the beta-hydroxy -3- ketone -17- α hydroxyl nitriles of 4- androstane dienes -11, mass yield 100%, detected through HPLC,
The content of Isosorbide-5-Nitrae-beta-hydroxy -3- ketone -17- α hydroxyl nitriles of androstane diene -11 is 90% in crude product, 4,5- cyano group addition accessory substances
Content is 5%.
Inventive embodiments 4 prepare 4- androstanes-alkene -3- ketone -17- α hydroxyl nitriles by starting material of 4- androstanes-alkene -3,17- diketone
Step 1：300ml water and 31.5g sodium formates are added in reactor, stirring and dissolving, it is male that 4- is added into reactor
Steroid-alkene -3,17- diketone 200g, 40ml methanol and 140ml acetone cyanohydrins, are heated to 35~40 DEG C, insulation reaction, in TLC
Control raw material disappears substantially；Reacting liquid temperature is reduced to 0~10 DEG C, is filtered, filter cake is washed with water, filter cake infrared lamp it is dry 208g
4- androstanes-alkene -3- ketone -17- β hydroxyl nitriles, mass yield 104%.
Step 2：By 10.4ml triethylamines, 208g 4- androstanes-alkene -3- ketone -17- β hydroxyl nitriles, 206ml chloroforms and
39.6ml acetone cyanohydrins are added in reactor and stirred, and are heated to 40~45 DEG C, insulation reaction, and 4- androstane-alkene-is controlled in TLC
3- ketone -17- β hydroxyl nitriles disappear substantially；Reacting liquid temperature is reduced to 0~10 DEG C, reaction solution is diluted in a large amount of water, with dense salt
Acid for adjusting pH=5, filter, filter cake is washed with water, filter cake infrared lamp it is dry 209g 4- androstanes-alkene -3- ketone -17- α hydroxyl nitriles, matter
Yield 104.5% is measured, is detected through HPLC, the content of 4- androstanes-alkene -3- ketone -17- α hydroxyl nitriles is 91% in crude product, 4,5- cyano group
The content of addition accessory substance is 4%.
Inventive embodiments 5 prepare 16 Alpha-Methyl -1 by starting material of 16 Alpha-Methyl -1,4,9- androstanes triolefin -3,17- diketone,
4,9- androstane triolefin -3- ketone -17- α hydroxyl nitriles
Step 1：150ml water and 12g sodium citrates are added in reactor, stirring and dissolving, added into reactor 16 α-
Methyl isophthalic acid, 4,9- androstanes triolefin -3,17- diketone 100g, 20ml isopropanols and 90ml acetone cyanohydrins, are heated to 41~45
DEG C, insulation reaction, control raw material disappears substantially in TLC；Reacting liquid temperature is reduced to 0~10 DEG C, is filtered, filter cake is washed with water, filter cake
Infrared lamp it is dry the Alpha-Methyl -1,4,9- androstane triolefin -3- ketone -17- β hydroxyl nitriles of 103g 16, mass yield 103%.
Step 2：103ml water and 2.06g sodium hydroxides are added in reactor stir it is complete molten, then add the α of 103g 16-
Methyl isophthalic acid, 4,9- androstane triolefin -3- ketone -17- β hydroxyl nitriles, 206ml methanol and 20.6ml acetone cyanohydrins, it is heated to 43~
48 DEG C, insulation reaction, 16 Alpha-Methyl -1,4,9- androstane triolefin -3- ketone -17- β hydroxyl nitriles are controlled in TLC and are disappeared substantially；Reduce reaction
Reaction solution is diluted in a large amount of water by liquid temperature degree to 0~10 DEG C, is adjusted pH=5 with concentrated hydrochloric acid, is filtered, filter cake is washed with water, filter cake
Infrared lamp it is dry the Alpha-Methyl -1,4,9- androstane triolefin -3- ketone -17- α hydroxyl nitriles of 105g 16, mass yield 105%, through HPLC
Detect, 16 Alpha-Methyls-Isosorbide-5-Nitrae in crude product, the content of 9- androstane triolefin -3- ketone -17- α hydroxyl nitriles is 92%, 4,5- cyano group addition pairs
The content of product is 4%.
Inventive embodiments 6 prepare 4- androstane-alkene -3,11- diketone-by starting material of 4- androstanes-alkene -3,11,17- triketones
17- α hydroxyl nitriles
Step 1：120ml water and 14.4g ammonium acetates are added in reactor, stirring and dissolving, it is male that 4- is added into reactor
Steroid-alkene -3,11,17- triketone 80g, 10ml methanol, 10ml isopropanols and 48ml acetone cyanohydrins, 44~49 DEG C are heated to, protected
Temperature is reacted, and control raw material disappears substantially in TLC；Reacting liquid temperature is reduced to 0~10 DEG C, is filtered, filter cake is washed with water, filter cake infrared lamp
Dry 84g 4- androstanes-alkene -3,11- diketone -17- β hydroxyl nitriles, mass yield 105%.
Step 2：It is complete molten by being stirred in 250ml water and 16.8g sodium acid carbonates addition reactor, it is male then to add 84g 4-
Steroid-alkene -3,11- diketone -17- β hydroxyl nitriles, 168ml ethanol and 32ml acetone cyanohydrins, 41~46 DEG C are heated to, insulation is anti-
Should, 4- androstanes-alkene -3,11- diketone -17- β hydroxyl nitriles are controlled in TLC and are disappeared substantially；Reacting liquid temperature is reduced to 0~10 DEG C, will be anti-
Answer liquid to be diluted in a large amount of water, adjust pH=5 with concentrated hydrochloric acid, filter, filter cake is washed with water, and filter cake infrared lamp is dry that 81g 4- are male
Steroid-alkene -3,11- diketone -17- α hydroxyl nitriles, mass yield 101%, is detected, 4- androstanes-alkene -3,11- bis- in crude product through HPLC
The content of ketone -17- α hydroxyl nitriles is 91%, and the content of 4,5- cyano group addition accessory substances is 5%.
Inventive embodiments 7 using the Alpha-hydroxy -3,17- diketone of 1,4- androstane dienes -11 as starting material prepare 1,4- androstane dienes -
11 Alpha-hydroxy -3- ketone -17- α hydroxyl nitriles
Step 1：By 5.5ml 2- picolines, 1,4- androstane dienes -11 Alpha-hydroxy -3,17- diketone 55g, 6ml ethanol,
6ml isopropanols and 44ml acetone cyanohydrins are added in reactor and stirred, and are heated to 41~46 DEG C, insulation reaction, are controlled in TLC former
Material is basic to disappear；Reacting liquid temperature is reduced to 0~10 DEG C, is filtered, filter cake is washed with water, and filter cake infrared lamp is dry that 58g 1,4- are male
Alpha-hydroxy -3- ketone -17- β the hydroxyl nitriles of steroid diene -11, mass yield 105%.
Step 2：It is complete molten by being stirred in 100ml water and 1.16g lithium hydroxides addition reactor, then add 58g 1,4-
Alpha-hydroxy -3- ketone -17- beta-hydroxy the nitriles of androstane diene -11,116ml dichloromethane and 29ml acetone cyanohydrins, it is heated to 42~
48 DEG C, insulation reaction, Alpha-hydroxy -3- ketone -17- beta-hydroxy itrile groups this disappearance of 1,4- androstane dienes -11 is controlled in TLC；Reduce reaction
Reaction solution is diluted in a large amount of water by liquid temperature degree to 0~10 DEG C, is adjusted pH=5 with concentrated hydrochloric acid, is filtered, filter cake is washed with water, filter cake
Infrared lamp it is dry the Alpha-hydroxy -3- ketone -17- α hydroxyl nitriles of 58.5g 1,4- androstane dienes -11, mass yield 106%, through HPLC
Detect, the content of Isosorbide-5-Nitrae-Alpha-hydroxy -3- ketone -17- α hydroxyl nitriles of androstane diene -11 is 92% in crude product, 4,5- cyano group addition by-products
The content of thing is 4%.
For inventive embodiments 8 with 9 Alpha-hydroxies-androstane-4-alkene-3,17- diketone is that starting material prepares 9 Alpha-hydroxies-androstane -4-
Alkene -3- ketone -17- α hydroxyl nitriles
Step 1：By 27.6ml 3- picolines, 9 Alpha-hydroxies-androstane-4-alkene-3,17- diketone 175g, 30ml isopropanols
Add in reactor and stir with 122.5ml acetone cyanohydrins, be heated to 38~43 DEG C, insulation reaction, it is basic to control raw material in TLC
Disappear；Reacting liquid temperature is reduced to 0~10 DEG C, is filtered, filter cake is washed with water, filter cake infrared lamp it is dry the Alpha-hydroxies of 180g 9-hero
Gona-4-en-3-one -17- β hydroxyl nitriles, mass yield 103%.
Step 2：By 9 Alpha-hydroxies of 8.9mlDBU, 180g-androstane-4-alkene-3 -one-17- β hydroxyl nitriles, 178ml ethanol and
34ml acetone cyanohydrins are added in reactor and stirred, and are heated to 40~45 DEG C, insulation reaction, controlled in TLC 9 Alpha-hydroxies-androstane-
4- alkene -3- ketone -17- β hydroxyl nitriles disappear substantially；Reacting liquid temperature is reduced to 0~10 DEG C, reaction solution is diluted in a large amount of water,
Adjust pH=5 with concentrated hydrochloric acid, filter, filter cake is washed with water, filter cake infrared lamp it is dry 9 Alpha-hydroxies of 181g-androstane-4-alkene-3-
Ketone-17- α hydroxyl nitriles, mass yield 103%, are detected through HPLC, 9 Alpha-hydroxies-androstane-4-alkene-3 -one-17- α hydroxyls in crude product
The content of nitrile is 91%, and the content of 4,5- cyano group addition accessory substances is 5%.
Inventive embodiments 9 prepare 1,4- androstane dienes -3,11- by starting material of 1,4- androstane diene -3,11,17- triketones
Diketone -17- α hydroxyl nitriles
Step 1：15ml 2,6- lutidines is added in reactor, added into reactor 1,4- androstane dienes-
3,11,17- triketone 100g, 20ml isopropanols and 85ml acetone cyanohydrins, are heated to 42~47 DEG C, insulation reaction, are controlled in TLC
Raw material disappears substantially；Reacting liquid temperature is reduced to 0~10 DEG C, is filtered, filter cake is washed with water, filter cake infrared lamp it is dry 102g 1,
4- androstane diene -3,11- diketone -17- β hydroxyl nitriles, mass yield 102%.
Step 2：It is complete molten by being stirred in 250ml water and 2.04g barium hydroxides addition reactor, then add 102g 1,4-
Androstane diene -3,11- diketone -17- β hydroxyl nitriles, 204ml methanol and 25.5ml acetone cyanohydrins, 44~49 DEG C are heated to, protected
Temperature is reacted, and control 1,4- androstane diene -3,11- diketone -17- β hydroxyl nitriles disappear substantially in TLC；Reacting liquid temperature is reduced to 0~10
DEG C, reaction solution is diluted in a large amount of water, adjusts pH=5 with concentrated hydrochloric acid, filter, filter cake is washed with water, and filter cake infrared lamp is dry
101g Isosorbide-5-Nitraes-androstane diene -3,11- diketone -17- α hydroxyl nitriles, mass yield 101%, are detected, Isosorbide-5-Nitrae-hero in crude product through HPLC
The content of steroid diene -3,11- diketone -17- α hydroxyl nitriles is 91%, and the content of 4,5- cyano group addition accessory substances is 4%.
Comparative examples 1 use acetone cyanohydrin/potassium carbonate/methanol/water method, with Isosorbide-5-Nitrae-Alpha-hydroxy -3 of androstane diene -11,
17- diketone is that starting material prepares the Alpha-hydroxy -3- ketone -17- α hydroxyl nitriles of 1,4- androstane dienes -11
Referring in particular to Fudan University Zhang Beina in 2006 thesis for the doctorate《The utilization of natural sterols resource --- 1,2 methoxies
The synthesis 2 of base estradiol, exploration and research from ADD synthesizing efficient cortin thaumatropy key methods》, P74 pages 4.8
Point, the experimental procedure of the prepare compound 14 of compound 8.Alpha-hydroxy -3- ketone -17- α hydroxyl nitrile the crude products of 1,4- androstane dienes -11
Mass yield is 100%, is detected through HPLC, and the content of Isosorbide-5-Nitrae-Alpha-hydroxy -3- ketone -17- α hydroxyls of androstane diene -11 is in crude product
80%, the content of 4,5- cyano group addition accessory substances is 15%, and the content of 4,5- cyano group addition accessory substances is 2% after recrystallization.
Claims (10)
1. a kind of preparation method of 17- α hydroxyl nitriles steroid derivative (III), it is characterized in that by the ketosteroid compounds of 3,17- bis-
(I) react in the solution of weak organic bases with acetone cyanohydrin and obtains 17- β hydroxyl nitriles steroid derivatives (II), intermediate (II) and
Acetone cyanohydrin reacts in strong base solution obtains 17- α hydroxyl nitriles steroid derivatives (III),
For having structure：
For double bond or singly-bound；
R is H or CH3, and one or more of the weak organic bases in carboxylate, pyridine or pyridine homologue, described is strong
Hydroxide of the alkali selected from alkali metal or alkaline-earth metal, bicarbonate, carbonate, sulphite or one kind or several in organic amine
Kind, described organic amine does not include pyridine and pyridine homologue.
A kind of 2. preparation method of 17- α hydroxyl nitriles steroid derivative (III) as claimed in claim 1, it is characterized in that described is weak
The one kind or several of organic base in potassium acetate, sodium acetate, sodium formate, sodium citrate, ammonium acetate, pyridine or pyridine homologue
Kind, described highly basic is selected from potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, sodium sulfite, triethylamine, ethylenediamine, hexahydro
One or more in pyridine, sodium hydroxide, potassium hydroxide or DBU.
3. a kind of preparation method of 17- α hydroxyl nitriles steroid derivative (III) as claimed in claim 2, weak have it is characterized in that described
Machine alkali is selected from potassium acetate, sodium acetate or pyridine, and described highly basic is selected from potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate or Asia
Sodium sulphate.
A kind of 4. preparation method of 17- α hydroxyl nitriles steroid derivative (III) as claimed in claim 3, it is characterized in that described is weak
Organic base is potassium acetate, and described highly basic is potassium carbonate.
5. a kind of preparation method of 17- α hydroxyl nitriles steroid derivative (III) as described in claim 1-4 is any, it is characterized in that
In step 1, calculated according to weight ratio meter, the rate of charge of compound (I) and acetone cyanohydrin is 1:0.6-1.0, compound (I) with it is weak
The rate of charge of organic base is 1:0.05-0.2；In step 2, calculated according to weight ratio meter, compound (II) and the throwing of acetone cyanohydrin
Material is than being 1:The rate of charge of 0.1-0.5, compound (II) and highly basic is 1:0.02-0.2.
A kind of 6. preparation method of 17- α hydroxyl nitriles steroid derivative (III) as claimed in claim 5, it is characterized in that described step
Rapid one and step 2 reaction temperature be 35-50 DEG C.
A kind of 7. preparation method of 17- α hydroxyl nitriles steroid derivative (III) as claimed in claim 6, it is characterized in that described step
Rapid one and step 2 reaction temperature be 42-47 DEG C.
8. a kind of preparation method of 17- α hydroxyl nitriles steroid derivative (III), its feature as described in claim 1-4,6,7 are any
It is one or more of the solvent of described step one in water, lower alcohol, the solvent of described step two is selected from water, rudimentary
One or more in alcohol, chlorohydrocarbon.
A kind of 9. preparation method of 17- α hydroxyl nitriles steroid derivative (III) as claimed in claim 8, it is characterized in that the step
One and one or more of the solvent in water, methanol of step 2.
10. a kind of preparation method of 17- α hydroxyl nitriles steroid derivative (III) as described in claim 1-4,6,7,9 are any,
It is characterized in that the described ketosteroid compounds of 3,17- bis- (I) be selected from the Isosorbide-5-Nitrae-Alpha-hydroxy -3,17- of androstane diene -11 diketone, Isosorbide-5-Nitrae -
Beta-hydroxy-the 3,17- of androstane diene -11 diketone, 4- androstanes-alkene -3,17- diketone, 9 Alpha-hydroxies-androstane-4-alkene-3,17- diketone,
16 Alpha-Methyls-Isosorbide-5-Nitrae, 9- androstane triolefins -3,17- diketone, 4- androstanes-alkene -3,11,17- triketones, Isosorbide-5-Nitrae-androstane diene -3,11,
17- triketones, 16 Alpha-Methyl -4,9- androstane diene -3,17- diketone, 4,9- androstane diene -3,17- diketone.
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| CN112898365A (en) * | 2021-03-08 | 2021-06-04 | 营口德瑞化工有限公司 | Synthesis method of 17 beta-cyano-17 alpha-hydroxyandrost-4-en-3-one |
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