CN106632578B - Chloro- -6 β of 3 beta-hydroxy of 5 α -, 19 beta epoxide phytosterols - Google Patents
Chloro- -6 β of 3 beta-hydroxy of 5 α -, 19 beta epoxide phytosterols Download PDFInfo
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Abstract
The present invention relates to one kind chloro- -6 β of 3 beta-hydroxy of 5 α -, 19 beta epoxide phytosterols and preparation method thereof.Chloro- -6 β of 3 beta-hydroxy of 5 α -; the preparation method of 19 beta epoxide phytosterols; the following steps are included: chloro- -6 β of 3 beta-hydroxy of 5 α -, the structure formula (IV) of 19 beta epoxide phytosterols is made by acylation reaction, addition reaction, epoxidation reaction in sterol.The present invention protects 3- hydroxyls using phytosterol cheap and easy to get as starting material, by acetylation, 5,6 additions then 6,19 epoxidations and obtain chloro- -6 β of 3 beta-hydroxy of 5 α -, 19 beta epoxide phytosterols.Starting material of the present invention is easy to get, high income and stabilization.
Description
(1) technical field
The invention belongs to chemical fields, and in particular to chloro- -6 β of 3 beta-hydroxy of one kind 5 α -, 19 beta epoxide phytosterols and its
Preparation method.
(2) background technique
The present invention is to prepare 19- hydroxyl -4-AD intermediate, and 19- hydroxyl -4-AD is a kind of very heavy
The Steroid medicine intermediates wanted can be used for producing 19- hydroxy steroid, 19- demethyl steroidal (19-norsteroid) class drug,
Such as 19- norandrostenedione (such as 19- demethyl -4-AD and 19- demethyl -5(10)-androstenedione), estrone,
Important the 19- demethyl steroidal intermediate and drug such as estradiol, estriol, norethindrone and derivative, mifepristone.
Currently, industrially production 19- hydroxyl -4-AD method be with diene (acetic acid gestation diene alcohol ketone) or
Dehydroepiandros-sterone is raw material, is prepared through chemical reaction.Such as with pregnant steroid -5,16- dien-3-ols acetate (diene alcohol ketone vinegar
Acid esters) for raw material, the Beckmann rearrangement through ketoxime, addition reaction aoxidizes and obtains chloro- -6 β of 3 beta-hydroxy of 5 α -, 19 beta epoxide plants
Sterol, this route steps is more, at high cost, and yield is low.
Patent CN102443038A, CN 104725460A is disclosed using dehydroepiandros-sterone as Material synthesis 19- hydroxyl -4-
The method of androstenedione, this method reaction time is long, high production cost.
Therefore, male although realizing 19- hydroxyl using diene (acetic acid gestation diene alcohol ketone) or dehydroepiandros-sterone as raw material
The industrialized production of alkene diketone, but there are a main problem, i.e. starting material price is higher: acetic acid gestation diene alcohol ketone 1300
Member/kilogram, 2100 yuan/kilogram of dehydroepiandros-sterone, and phytosterol only 130 yuan/kilogram.This project is using phytosterol as just
Beginning raw material, first synthesizes chloro- -6 β of 3 beta-hydroxy of 5 α -, and 19 beta epoxide phytosterol intermediates obtain most using a step biofermentation
Finished product 19- hydroxyl -4-AD.This method is relative to initial feed acetic acid gestation diene alcohol ketone or Dehydroepiandrosterone Acetate
Method, reaction step is few, and product yield is high, and totle drilling cost is low.
(3) summary of the invention
Based on deficiency existing for current technology, the present invention provides one kind chloro- -6 β of 3 beta-hydroxy of 5 α -, 19 beta epoxide plants
Sterol and preparation method thereof, reaction step is few, and product yield is high, and totle drilling cost is low.
The present invention is achieved through the following technical solutions:
Chloro- -6 β of 3 beta-hydroxy of one kind 5 α -, 19 beta epoxide phytosterols are characterized in that its structural formula are as follows:
, since phytosterol is mainly stigmasterol, cupreol and campesterol etc.
It forms, R is sterol alkane branch in reaction equation.
Chloro- -6 β of 3 beta-hydroxy of 5 α -, the preparation method of 19 beta epoxide phytosterols, comprising the following steps:
Chloro- -6 β of 3 beta-hydroxy of 5 α -, 19 beta epoxide plants are made by acylation reaction, addition reaction, epoxidation reaction in sterol
The structure formula (IV) of sterol, reaction equation are as follows:
。
Specifically includes the following steps:
Under solvent action, sterol and acid anhydrides carry out acylation reaction, compound ii are obtained, by compound ii under organic solvent
It is acted on chlorinating agent, obtains compound III, finally, by compound III in radical initiator, illumination acts on lower and chloro agent
Effect, obtains 5 α of compound--6 β of chloro- 3 beta-hydroxy, 19 beta epoxide phytosterols IV.
Wherein,
In acylation reaction, sterol be use cheap phytosterol, sterol: acid anhydrides mass ratio be 1:1~10, sterol and
The mass ratio 1:5.5-7 of solvent, reaction temperature are 80~95 DEG C.
During acylation reaction, solvent is toluene, and acid anhydrides is acetic anhydride.
The mass ratio of compound ii and solvent is 1:15~18 in addition reaction, the quality of compound ii and chlorinating agent
Than for 10:6-15, chlorinating agent used is yield and the higher sym-closene of selectivity, and solvent is acetone.
In epoxidation reaction, the mass volume ratio of compound III and solvent is 1W:8V~10V, reaction temperature is 80 DEG C~
90℃.Solid chemical compound III, radical initiator, chloro agent mass ratio are 10:2.05-3.25:8-15.Radical initiator is excellent
Select iodine, benzoyl peroxide, mass ratio 1.75-2.6:0.3-0.65.Solvent for use is dichloroethanes.
Chloro- -6 β of 3 beta-hydroxy of 5 α -, the preparation method of 19 beta epoxide phytosterols, detailed step are as follows:
Firstly, phytosterol and acetic anhydride carry out acylation reaction in the case where toluene is as solvent, compound ii is obtained:
Secondly, compound ii is acted under organic solvent with sym-closene, compound III is obtained, solvent for use is
Acetone.
。
Finally, illumination effect is lower and chloro agent N- chlorosuccinimide is made by compound III in radical initiator iodine
With obtaining 5 α of compound--6 β of chloro- 3 beta-hydroxy, 19 beta epoxide phytosterols IV, used organic solvent is dichloroethanes.
Compound I acylation reaction process are as follows: sterol stirring and dissolving is added in toluene solvant, acetic anhydride is then added, rises
After temperature to 80 DEG C~95 DEG C back flow reaction 4-10h, the tracking reaction of TLC contact plate is subsequently cooled to 55 DEG C~65 DEG C, adds water to complete
0.2-0.8h is stirred, static layering removes water phase (in triplicate), and organic phase vacuum distillation recycling toluene, distillation does not go out to toluene
Until, ethanol solution mashing stirring 0.5-2h is added, cools down, filters, ethanol rinse, drying obtains compound ii；
Compound ii addition reaction process are as follows: compound ii is dissolved into organic solvent-acetone, and a small amount of water is added, is stirred
0.5-2h is mixed, is cooled to -5 DEG C~10 DEG C, the mixed liquor of sym-closene and acetone, compound ii are added dropwise at this temperature
Mass ratio with solvent acetone is 1:15~18, and 2~2.5h is dripped off, and drips off temperature control reaction 50min~1h, TLC tracking and has reacted
Entirely, 7-13% sodium sulfite is added and terminates reaction, vacuum distillation recycling acetone until distillation to acetone does not go out, is added water and stirred and beaten
Compound III is dried to obtain in slurry, 0.5-2h, 40 DEG C~45 DEG C filterings, water elution；
Compound III epoxidization reaction process are as follows: compound III is dissolved into dichloroethanes, compound III and solvent
Mass volume ratio is 1W:8V~10V, and natrium carbonicum calcinatum, iodine, benzoyl peroxide, N- chloro fourth is uniformly added in stirring and dissolving afterwards
Imidodicarbonic diamide slowly rises to 80 DEG C~90 DEG C, reacts 2-4h and is down to room temperature after observing response phenomenon and TLC track fully reacting
0.2-0.8h static layering is added water and stirred, organic layer is washed with 7-13% sodium thiosulfate, and static branch vibration layer is washed with water and washs,
Static layering, organic phase are evaporated under reduced pressure and recycle dichloroethanes, and distillation dries to obtain compounds Ⅳ until not going out.Wherein, solid
Compound (III), natrium carbonicum calcinatum, iodine, benzoyl peroxide, N- chlorosuccinimide mass ratio are 10:5-7:1.75-
2.6:0.3-0.65:8-15.
Beneficial effects of the present invention: the present invention is protected using phytosterol cheap and easy to get as starting material by acetylation
3- hydroxyls, 5,6 additions then 6,19 epoxidations and chloro- -6 β of 3 beta-hydroxy of 5 α -, 19 beta epoxide plant steroids
Alcohol.Starting material of the present invention is easy to get, high income and stabilization.
(4) specific embodiment
Embodiment 1
Acylation reaction:
150ml toluene is added in tri- mouthfuls of reaction flasks of 500ml, is added with stirring 20 g solid sterols, 20ml is then added
Acetic anhydride is warming up to 80 DEG C~95 DEG C back flow reaction 7h, after sampling TLC point plate analysis to fully reacting, is cooled to 55 with cold water
DEG C, 20ml water is added and stirs 0.5h, static layering removes water phase, and organic phase is secondary with 20ml washing respectively, and organic phase decompression is steamed
Recycling toluene is evaporated, is steamed until toluene does not go out, 75ml dehydrated alcohol mashing stirring 1h is added, is then cooled to 10 DEG C of filterings, uses
The elution of 10ml dehydrated alcohol, dries to obtain solid chemical compound (II) 21.5g, yield 98%.
Addition reaction:
300ml acetone is added in three mouthfuls of reaction flasks of 1000ml, is added with stirring 20g solid chemical compound (II), and adds
Enter 30ml water stirring 1h, be cooled to 0 DEG C, slowly drip the mixed liquor in 16g sym-closene and 80ml acetone, 2h is dripped off, so
Temperature control reacts 50min afterwards, terminates reaction with 10% sodium sulfite 50ml after TLC contact plate fully reacting, then heats to 30 DEG C and subtract
Pressure is distilled to recover acetone.It steams until acetone does not go out, 400ml water is added and heats up 40 DEG C of stirring to pulp 1h filtering, and with 100ml water
Elution, flood do to obtain solid chemical compound (III) 21.5g, yield 96%.
Epoxidation reaction:
100ml dichloroethanes is added in three mouthfuls of reaction flasks of 500ml, is added with stirring 10g solid chemical compound (III), stirs
Natrium carbonicum calcinatum 6g, iodine 2.25g are backed into after mixing 0.5h, then benzoyl peroxide 0.37g, N- chlorosuccinimide 10g delays
Slowly 80 DEG C~90 DEG C are warming up to, 3h is reacted, room temperature is down to after TLC contact plate fully reacting, water 40g is added to wash, stir static point of 0.5h
Layer, organic layer wash 1~1.5h, static layering with 10% sodium thiosulfate 40ml, and organic phase uses organic phase weight 10% again
Water washing, static layering, organic layer are evaporated under reduced pressure and recycle dichloroethanes.Distillation dries to obtain solid chemical compound until not going out
(IV) 8.2g, yield 82%.
Embodiment 2
Acylation reaction:
187.5 ml toluene are added in tri- mouthfuls of reaction flasks of 500ml, are added with stirring solid sterol 25g, then quickly drip
Enter acetic anhydride 25ml, be to slowly warm up to 95 DEG C of back flow reaction 7h, after sampling TLC point plate analysis to fully reacting, is cooled down with cold water
To 55 DEG C, 25ml water is added and stirs 0.5h, static layering removes water phase, and organic phase is washed two times respectively with 25ml water, organic to subtract each other
Pressure is distilled to recover solvent toluene, steams until toluene does not go out, obtains after drying to solid chemical compound 26.8g(II), yield is
97.5%。
Addition reaction:
150ml acetone and 10g solid chemical compound (II) are added in three mouthfuls of reaction flasks of 500ml, is stirring evenly and then adding into
15ml water continues to stir 1h, is cooled to -5 DEG C with brine ice, the mixing of 13g sym-closene and 50ml acetone is slowly added dropwise
Liquid keeps temperature 2.5h to drip off, and then temperature control reacts 55min again, after TLC contact plate fully reacting, with 10% sodium sulfite 25ml
Make reaction terminating, then 20ml water is added into reaction flask, at 40 DEG C after stirring to pulp 1h, filters, and eluted with 50ml water, drying
Obtain solid chemical compound (III) 10.5g, yield 95%.
Epoxidation reaction:
140ml dichloroethanes and 15g solid chemical compound (III) are added in three mouthfuls of reaction flasks of 500ml, after stirring 30min
Natrium carbonicum calcinatum 9g is added, iodine 2.88g, benzoyl peroxide 0.88g, N- chlorosuccinimide 19g then heat to 84 DEG C
After back flow reaction 3g, TLC contact plate fully reacting, 30 DEG C plus water 60g washings are down to, wash 30min static layering, organic layer is again
1h is washed with 10% sodium thiosulfate 60ml, static layering, then organic phase is washed one time with 60ml again, after layering, organic phase
It is evaporated under reduced pressure and is recycled dichloroethanes, steams until not going out, solid chemical compound (IV) 12.1g, yield 81.5% is obtained after drying.
Embodiment 3
Acylation reaction:
126ml toluene is added in tri- mouthfuls of reaction flasks of 500ml, is added with stirring 20 g solid sterols, is then added
92.5ml acetic anhydride is warming up to 80 DEG C of back flow reaction 10h, after sampling TLC point plate analysis to fully reacting, is cooled to cold water
60 DEG C, 20ml water is added and stirs 0.8h, static layering removes water phase, and organic phase is washed three times with 25ml respectively, organic phase decompression
It is distilled to recover toluene, is steamed until toluene does not go out, 75ml dehydrated alcohol mashing stirring 0.5h is added, is then cooled to 15 DEG C of mistakes
Filter is eluted with 15ml dehydrated alcohol, dries to obtain solid chemical compound (II), yield 97%.
Addition reaction:
379ml acetone is added in three mouthfuls of reaction flasks of 1000ml, is added with stirring 20g solid chemical compound (II), and adds
Enter 37ml water stirring 2h, be cooled to -5 DEG C, slowly drip the mixed liquor in 12g sym-closene and 80ml acetone, 3h is dripped off, so
Temperature control reacts 60min afterwards, terminates reaction with 7% sodium sulfite 71ml after TLC contact plate fully reacting, then heats to 35 DEG C and subtract
Pressure is distilled to recover acetone.It steams until acetone does not go out, 400ml water is added and heats up 43 DEG C of stirring to pulp 1h filtering, and with 100ml water
Elution, flood do to obtain solid chemical compound (III), yield 96%.
Epoxidation reaction:
90ml dichloroethanes is added in three mouthfuls of reaction flasks of 500ml, is added with stirring 10g solid chemical compound (III), stirs
Natrium carbonicum calcinatum 5g, iodine 2.6g, benzoyl peroxide 0.3g, N- chlorosuccinimide 8g are backed into after mixing 0.5h, then slowly
80 DEG C are warming up to, 4h is reacted, room temperature is down to after TLC contact plate fully reacting, water 45g is added to wash, stirs 0.8h static layering, it is organic
Layer washs 1~1.5h, static layering with 7% sodium thiosulfate 58ml, and organic phase uses the water washing of organic phase weight 15% again,
Static layering, organic layer are evaporated under reduced pressure and recycle dichloroethanes.Distillation dries to obtain solid chemical compound (IV) until not going out, and receives
Rate 84%.
Embodiment 4
Acylation reaction:
187.5 ml toluene are added in tri- mouthfuls of reaction flasks of 500ml, are added with stirring solid sterol 25g, then quickly drip
Enter acetic anhydride 231ml, be to slowly warm up to 90 DEG C of back flow reaction 4h, after sampling TLC point plate analysis to fully reacting, is cooled down with cold water
To 65 DEG C, 25ml water is added and stirs 0.2h, static layering removes water phase, and organic phase is washed two times respectively with 30ml water, organic to subtract each other
Pressure is distilled to recover solvent toluene, steams until toluene does not go out, obtains after drying to solid chemical compound, yield 98.1%.
Addition reaction:
130ml acetone and 10g solid chemical compound (II) are added in three mouthfuls of reaction flasks of 500ml, is stirring evenly and then adding into
20ml water continues to stir 0.5h, is cooled to 10 DEG C with brine ice, and the mixed of 15g sym-closene and 61ml acetone is slowly added dropwise
Liquid is closed, temperature 2.5h is kept to drip off, then temperature control reacts 50min again, after TLC contact plate fully reacting, with 13% sodium sulfite
19ml makes reaction terminating, then 25ml water is added into reaction flask, at 45 DEG C after stirring to pulp 2h, filters, and eluted with 60ml water,
Dry to obtain solid chemical compound, yield 96.3%.
Epoxidation reaction:
120ml dichloroethanes and 15g solid chemical compound (III) are added in three mouthfuls of reaction flasks of 500ml, after stirring 25min
Natrium carbonicum calcinatum 10.5g is added, then iodine 2.62g, benzoyl peroxide 0.98g, N- chlorosuccinimide 22.5g heat up
To 90 DEG C of back flow reaction 2h, TLC contact plate fully reactings, 25 DEG C plus water 65g washings are down to, wash 0.2h static layering, it is organic
Layer washs 0.8h with 13% sodium thiosulfate 47ml again, and static layering, then organic phase is washed one time with 55ml again, after layering,
Organic phase is evaporated under reduced pressure and recycles dichloroethanes, steams until not going out, obtains solid chemical compound (IV) after drying, yield 83.2%.
Embodiment 5
Acylation reaction:
201ml toluene is added in tri- mouthfuls of reaction flasks of 500ml, is added with stirring solid sterol 25g, then quickly instills
Acetic anhydride 46ml is to slowly warm up to 95 DEG C of back flow reaction 5h, after sampling TLC point plate analysis to fully reacting, is cooled to cold water
55 DEG C, 20ml water is added and stirs 0.4h, static layering removes water phase, and organic phase is washed two times respectively with 35ml water, organic phase decompression
It is distilled to recover solvent toluene, steams until toluene does not go out, obtains after drying to solid chemical compound, yield 98.3%.
Addition reaction:
160ml acetone and 10g solid chemical compound (II) are added in three mouthfuls of reaction flasks of 500ml, is stirring evenly and then adding into
20ml water continues to stir 1.5h, is cooled to 5 DEG C with brine ice, the mixing of 10g sym-closene and 57ml acetone is slowly added dropwise
Liquid keeps temperature 2h to drip off, and then temperature control reacts 55min again, after TLC contact plate fully reacting, is made with 10% sodium sulfite 27ml
Reaction terminating, then 27ml water is added into reaction flask, it at 42 DEG C after stirring to pulp 1h, filters, and eluted with 60ml water, dries
Solid chemical compound, yield 96.2%.
Epoxidation reaction:
135ml dichloroethanes and 15g solid chemical compound (III) are added in three mouthfuls of reaction flasks of 500ml, after stirring 20min
Natrium carbonicum calcinatum 9g, iodine 3g, benzoyl peroxide 0.75g, N- chlorosuccinimide 15g is added, then heats to 85 DEG C and returns
Stream reaction 2h after TLC contact plate fully reacting, is down to 28 DEG C plus water 70g washings, washs 0.5h static layering, organic layer is used again
10% sodium thiosulfate 55ml washs 0.6h, and static layering, then organic phase is washed one time with 55ml again, after layering, organic phase
It is evaporated under reduced pressure and is recycled dichloroethanes, steams until not going out, obtains solid chemical compound (IV) after drying, yield 83.8%.
Claims (3)
1. chloro- -6 β of 3 beta-hydroxy of one kind 5 α -, the preparation method of 19 beta epoxide phytosterols, it is characterised in that: 5 α-chloro- 3
- 6 β of beta-hydroxy, the structural formula of 19 beta epoxide phytosterols are (IV),, wherein R is sterol
Alkane branch；
Chloro- -6 β of 3 beta-hydroxy of 5 α -, the preparation method of 19 beta epoxide phytosterols, comprising the following steps:
Chloro- -6 β of 3 beta-hydroxy of 5 α -, 19 beta epoxide phytosterols are made by acylation reaction, addition reaction, epoxidation reaction in sterol
Structure formula (IV)；
Specifically includes the following steps:
Under solvent action, sterol and acid anhydrides carry out acylation reaction, obtain compound ii, by compound ii under organic solvent with chlorine
It is acted on for reagent, obtains compound III, finally, illumination effect is lower and chloro agent acts on by compound III in radical initiator,
Obtain 5 α of compound--6 β of chloro- 3 beta-hydroxy, 19 beta epoxide phytosterols IV；
Wherein: in acylation reaction, sterol: acid anhydrides mass ratio is 1:1~10, the mass ratio 1:5.5-7 of sterol and solvent, reaction temperature
Degree is 80~95 DEG C；
The mass ratio of compound ii and solvent is 1:15~18 in addition reaction, and the mass ratio of compound ii and chlorinating agent is
10:6-15；
In epoxidation reaction, the mass volume ratio of compound III and solvent is 1W:8V~10V, and reaction temperature is 80 DEG C~90 DEG C；
Solid chemical compound III, radical initiator, chloro agent mass ratio are 10:2.05-3.25:8-15；In epoxidation reaction, free radical
Initiator is iodine, benzoyl peroxide, mass ratio 1.75-2.6:0.3-0.65；
In acylation reaction, sterol is phytosterol, and solvent is toluene, and acid anhydrides is acetic anhydride；
In addition reaction, chlorinating agent used is sym-closene, and solvent is acetone；
In epoxidation reaction, when synthesizing compounds Ⅳ, solvent for use is dichloroethanes；
Compound I acylation reaction process are as follows: sterol stirring and dissolving is added in toluene solvant, acetic anhydride is then added, is warming up to
After 80 DEG C~95 DEG C back flow reaction 4-10h, the tracking reaction of TLC contact plate is subsequently cooled to 55 DEG C~65 DEG C, adds water and stirs to complete
0.2-0.8h, static layering remove water phase, and until distillation to toluene does not go out, ethyl alcohol is added in organic phase vacuum distillation recycling toluene
Solution mashing stirring 0.5-2h, cools down, filtering, ethanol rinse, and drying obtains compound ii；
Compound ii addition reaction process are as follows: compound ii is dissolved into organic solvent-acetone, and a small amount of water is added, is stirred
0.5-2h is cooled to -5 DEG C~10 DEG C, at this temperature be added dropwise sym-closene and acetone mixed liquor, compound ii with
The mass ratio of solvent acetone is 1:15~18, and 2~2.5h is dripped off, and drips off temperature control reaction 50min~1h, TLC and tracks fully reacting,
Sodium sulfite solution is added and terminates reaction, vacuum distillation recycling acetone adds water and stirs mashing until distillation to acetone does not go out,
Compound III is dried to obtain in 0.5-2h, 40 DEG C~45 DEG C filterings, water elution；
Compound III epoxidization reaction process are as follows: compound III is dissolved into dichloroethanes, the quality of compound III and solvent
Volume ratio is 1W:8V~10V, and natrium carbonicum calcinatum, iodine, benzoyl peroxide, N- chloro succinyl is uniformly added in stirring and dissolving afterwards
Imines slowly rises to 80 DEG C~90 DEG C, reacts 2-4h and is down to room temperature after observing response phenomenon and TLC track fully reacting and adds water
0.2-0.8h static layering is stirred, organic layer is washed with hypo solution, and static branch vibration layer is washed with water and washs, static
Layering, organic phase are evaporated under reduced pressure and recycle dichloroethanes, and distillation dries to obtain compounds Ⅳ until not going out.
2. chloro- -6 β of 3 beta-hydroxy of 5 α-according to claim 1, the preparation method of 19 beta epoxide phytosterols, feature exist
In: in compound III epoxidization reaction process: solid chemical compound III, natrium carbonicum calcinatum, iodine, benzoyl peroxide, N- chloro fourth
Imidodicarbonic diamide mass ratio is 10:5-7:1.75-2.6:0.3-0.65:8-15.
3. chloro- -6 β of 3 beta-hydroxy of 5 α-according to claim 2, the preparation method of 19 beta epoxide phytosterols, feature exist
In the mass concentration of: sodium sulfite solution, hypo solution be 7-13%.
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