CN107698643B - A kind of preparation method of dehydroepiandros-sterone - Google Patents
A kind of preparation method of dehydroepiandros-sterone Download PDFInfo
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- CN107698643B CN107698643B CN201711080913.9A CN201711080913A CN107698643B CN 107698643 B CN107698643 B CN 107698643B CN 201711080913 A CN201711080913 A CN 201711080913A CN 107698643 B CN107698643 B CN 107698643B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
Abstract
The present invention relates to the preparation technical fields of steroid hormone drug; more particularly to a kind of preparation method of dehydroepiandros-sterone; including using 4-AD as starting material; dehydroepiandros-sterone successively is prepared through acetylization reaction, ketal reduction reaction " one kettle way " and hydrolysis, in which: catalyst is combined into using the group of the combination of aluminum trichloride (anhydrous) and sulfosalicylic acid or aluminum trichloride (anhydrous) and camphorsulfonic acid in acetylization reaction.Compared with prior art, the resulting dehydroepiandros-sterone Isomers In Products of the present invention only account for 1~3%, and mass yield is greater than 88%, and purification yield is greater than 78%, and product purity is greater than 99%, and prospects for commercial application is wide.
Description
Technical field
The present invention relates to a kind of preparation technical fields of steroid hormone drug, and in particular to a kind of preparation of dehydroepiandros-sterone
Method.
Background technique
Dehydroepiandros-sterone is the important source material for manufacturing steroid hormone class drug.Existing chemical synthesis process is broadly divided into two
Class, the synthetic method of a kind of dehydroepiandros-sterone reported such as 102603839 A of Chinese patent CN, is using Chinese yam saponin as raw material
Diene alcohol acetate is obtained, then is obtained through oximate, rearrangement, sour water solution and basic hydrolysis through acetic acid open loop, chromic anhydride oxidation, elimination reaction
Dehydroepiandros-sterone.This route starting material Chinese yam saponin is resource-constrained, and step is long, cumbersome, yield is low, environmental pollution is tight
Weight, as the development of steroidal industry has been eliminated at present.
It is another kind of, then it is to develop in recent years using 4-AD as the process route of raw material.Such as Chinese patent
The preparation method of the dehydroepiandros-sterone of CN102603841A report, is raw material through over-churning, ketal, reduction reaction and water using 4-AD
Solution reaction synthesis dehydroepiandros-sterone, every step mass yield respectively may be about 107%, 105%, 89%, 79%；The route cost compared with
It is low, but solvent loss is larger, and obtained impurity in products is more, and dehydroepiandros-sterone isomers reaches 7.5%, crude product quality yield
80%；The subtractive process yield for removing 7.5% isomers about loses 15%, points out this in 105017361 A of Chinese patent CN
Route gross mass yield 60% or so.And the preparation method of dehydroepiandros-sterone disclosed in 105017361 A of Chinese patent CN,
Diene alcohol intermediate is extremely unstable, and catalytic hydrogenation uses a large amount of palladium carbons, at high cost, is unfavorable for industrialized production.
Summary of the invention
The purpose of the present invention is the defects of for existing dehydroepiandros-sterone chemical preparation process, provide a high income,
It is easy to operate, isomers is few, it is low in cost, can be achieved dehydroepiandros-sterone industrialized production chemical synthesis process.
The technical solution that this case provides is as follows: using 4-AD for starting material, successively through acetylization reaction, ketal reduction reaction
" one kettle way " and hydrolysis prepare dehydroepiandros-sterone, synthetic route are as follows:
Specifically, technical scheme is as follows:
This case provides firstly the preparation method of dehydroepiandros-sterone aceted intermediate III a kind of, the acetylization reaction
It include: that 4-AD compound ii is added in aceticanhydride, argon gas protects lower 20~30 DEG C of stirrings of controlling temperature, catalyst is added, detection is anti-
After the completion of answering, ice water product is added and is precipitated, filtering is washed to neutrality, dries to obtain compound III；
Catalyst used in above-mentioned acetylization reaction can be aluminum trichloride (anhydrous) and sulfosalicylic acid combination or anhydrous
One of combination in alchlor and camphorsulfonic acid.It is single to use sulfosalicylic acid, product purity 89~90%；List uses anhydrous
The reaction of alchlor reaction substrate about 46% is incomplete.
Catalyst aluminum trichloride (anhydrous) dosage used in above-mentioned acetylization reaction be starting material 4-AD weight 2%~
4%, the sulfosalicylic acid or camphorsulfonic acid are the 4%~6% of starting material 4-AD weight.
It is solvent that aceticanhydride is reactant in above-mentioned acetylization reaction again, preferably, in the present invention system only 3~
5V.The reaction system of this step (CN102603841A) aceticanhydride/p-methyl benzenesulfonic acid system compared with prior art, the dosage of aceticanhydride by
15~45V is down to 3~5V, greatly reduces COD in waste water, reduces environmentally friendly cost.
Preferably, key reaction parameter includes: under inert gas shielding, instead in the above-mentioned acetylization reaction of the present invention
Answering temperature is 20~30 DEG C.
Reaction system prepare compound III according to the invention, starting material 4-AD fully reacting, aceted intermediate
It closes object III HPLC purity and is promoted to 99% or more by 96~97%.
1 acetylization reaction prior art PTS/ aceticanhydride acetylation system of table and aluminum trichloride (anhydrous) of the present invention and sulfosalisylic
Acid/aceticanhydride or aluminum trichloride (anhydrous) and camphorsulfonic acid/the comparison is as follows for aceticanhydride system:
Secondly, including the following steps: the present invention also provides a kind of preparation method of dehydroepiandros-sterone
(1) acetylization reaction prepare compound III
Compound ii (4-AD) is added in aceticanhydride, argon gas protects lower 20~30 DEG C of stirrings of controlling temperature, and the first catalysis is added
Agent, is added ice water after the reaction was completed, and product is precipitated, filters, is washed to neutrality, dry to obtain compound III；Wherein, it described first urges
Agent one of combination in aluminum trichloride (anhydrous) and sulfosalicylic acid combination or aluminum trichloride (anhydrous) and camphorsulfonic acid；Its
In, the aluminum trichloride (anhydrous) dosage is the 2~4% of compound ii weight, the dosage of the sulfosalicylic acid or camphorsulfonic acid
It is the 4~6% of compound ii weight.
Aceticanhydride is that reactant is solvent again in this acetylization reaction, preferably, in the present invention system only 3~
5V。
Compound ii in the acetylization reaction: aceticanhydride: aluminum trichloride (anhydrous): the weight of sulfosalicylic acid or camphorsulfonic acid
Volume ratio is 1W:3~5V:0.02~0.04W:0.04~0.06W.
(2) prepare compound V is reacted in ketal, reduction " one kettle way "
Compound III is added in methylene chloride, under argon gas protection, ethylene glycol, triethyl orthoformate and second is added
Catalyst boron trifluoride ether；TLC is detected after the reaction was completed, and 0.05V triethylamine quenching reaction is added, obtains the dichloro of compounds Ⅳ
Dichloromethane is stand-by.
The ethanol solution of sodium borohydride is added dropwise in the ethanol solution of anhydrous calcium chloride under protection of argon gas,
0.5h is stirred in temperature control -30~-15 DEG C, obtains the dehydrated alcohol suspension of calcium borohydride；
The dichloromethane solution of compounds Ⅳ is added dropwise to temperature control -30~-15 in the dehydrated alcohol suspension of calcium borohydride
DEG C stirring 15h after, be added dropwise 50% acetic acid quenching reaction, be concentrated elutriation, dry to obtain compound V；
Compound III in the ketal, reduction reaction: ethylene glycol: triethyl orthoformate: boron trifluoride ether: methylene chloride
Proportion be 1W:0.6~1V:0.6~1V:0.02~0.05W:5V~7V；
Anhydrous calcium chloride used in the ketal, reduction reaction or anhydrous magnesium chloride: sodium borohydride: dehydrated alcohol is matched
Than being 0.6~0.8W:0.2~0.4W:25~35V.
Calcium borohydride used in the ketal, reduction " one kettle way " reaction step is by sodium borohydride and anhydrous calcium chloride
The in-situ preparation in -30~-15 DEG C of dehydrated alcohol.In addition, calcium borohydride also can be used magnesium borohydride to substitute.
Compared with the tradition sodium borohydride and potassium borohydride that use, the change reacted using calcium borohydride or magnesium borohydride
Object V is closed, isomer proportion is down to 5% by 12%.
(3) hydrolysis prepare compound I
In acetone by compounds Ⅳ dissolution, diluted acid is added.React 1h, end of reaction.Elutriation is concentrated, dries to remove hydrogen meter
Androsterone.
Note: W described in text indicates weight, and V indicates volume.When W unit is g, the Unit/mL of V；When W unit is kg, V
Unit L.
Compared with prior art, the beneficial effects of the present invention are: synthesizing dehydroepiandros-sterone using synthetic schemes of the invention,
It reacts easy to control, has saved process, solvent loss is low, low in cost.Gained dehydroepiandros-sterone Isomers In Products only 1~3%,
Mass yield is greater than 88%, and purification yield is greater than 78%, and product purity is greater than 99%, and prospects for commercial application is wide.
Specific embodiment
Presently in connection with embodiment, the present invention is described in further detail, and application of the invention is not limited to following
Embodiment, the accommodation in any form done to the present invention fall within protection scope of the present invention.
The embodiment of the present invention:
Embodiment 1
(1) acetylization reaction:
Under argon gas protection, compound ii 1Kg, aceticanhydride 3L, aluminum trichloride (anhydrous) 30g, sulfosalisylic are added in a kettle
Sour 50g, 20~30 DEG C of reaction 5h of temperature control.TLC is detected after the reaction was completed, and ice water 12L is added, and stirs 2h, product is precipitated sufficiently；
Neutrality is washed to after filtering, vacuum drying for 24 hours, obtains off-white color compound III 1.14Kg, weight yield 114%, HPLC purity
99.3%, starting material left 0.4%.
(2) ketal, reduction reaction:
Under argon gas protection, compound III 1.14Kg, methylene chloride 5.7L, ethylene glycol 0.7L, primitive nail are added in a kettle
Triethylenetetraminehexaacetic acid ester 0.7L and catalyst boron trifluoride ether 23mL, reacts 5h by 20~30 DEG C of temperature control, and TLC detection reaction is completed
Afterwards, 46mL triethylamine quenching reaction is added, obtains the dichloromethane solution of compounds Ⅳ, for use.
Under argon gas protection, anhydrous calcium chloride 0.7Kg, dehydrated alcohol 22L, stirring to dissolved clarification, cooling are added in a kettle
To -20 DEG C, for use；Under argon gas protection, sodium borohydride 0.25Kg is added in dehydrated alcohol 7.5L, and 0~5 DEG C of temperature control is stirred to molten
Clearly；This sodium borohydride solution is added dropwise in the dehydrated alcohol calcium chloride solution prepared, controls Nei Wen -20~-15 DEG C, drop finishes
Stirring 0.5h obtains the dehydrated alcohol suspension of calcium borohydride.
The dichloromethane solution of compounds Ⅳ is added dropwise in calcium borohydride system, controls Nei Wen -20~-15 DEG C.Drop finishes
15h is stirred, TLC detection reaction terminates.50% aqueous acetic acid quenching reaction is added dropwise, controls Nei Wen -20~-15 DEG C.50 DEG C dense
Be reduced to it is solvent-free steam, 11.4L ice water elutriation, 5.7L water washing filter cake after filtering.40 DEG C are dried under vacuum to constant weight, obtain white solid
V 1.12Kg of body compound, weight yield 98.2%, HPLC purity 86.59%, isomers 4.78%.
(3) hydrolysis:
Under argon gas protection, compounds Ⅳ 1.12Kg, acetone 15L, water 1.5L, p-methyl benzenesulfonic acid 78g are added in a kettle,
45~50 DEG C of reaction 1h of temperature control.TLC is detected after the reaction was completed, adds 160mL triethylamine quenching reaction.10L acetone is concentrated out, is added
11L water continues to be concentrated into solvent-free ooze.It is cooled to 0 DEG C, stirs 1h.Filtering, 2L water washing filter cake.50 DEG C of drying, obtain white
Chemical compounds I 907g, weight yield 80.9%, isomers 1.85%, HPLC purity 88.9%.
Embodiment 2
(1) acetylization reaction:
Under argon gas protection, compound ii 1Kg, aceticanhydride 5L, aluminum trichloride (anhydrous) 20g, camphorsulfonic acid are added in a kettle
40g, 20~30 DEG C of reaction 5h of temperature control.TLC is detected after the reaction was completed, and ice water 12L is added, and stirs 2h, product is precipitated sufficiently；It crosses
Water after filter is washed till neutrality, and 40 DEG C of vacuum drying for 24 hours, obtain off-white color compound III 1.12Kg, weight yield 112%, HPLC purity
99.1%, starting material left 0.6%.
(2) ketal reduction reaction:
Under argon gas protection, compound III 1.12Kg, methylene chloride 6.7L, ethylene glycol 0.9L, primitive nail are added in a kettle
Triethylenetetraminehexaacetic acid ester 0.9L and catalyst boron trifluoride ether 34mL, reacts 5h by 20~30 DEG C of temperature control, and TLC detection reaction is completed
Afterwards, 68mL triethylamine quenching reaction is added, the dichloromethane solution for obtaining compounds Ⅳ is stand-by.
Under argon gas protection, anhydrous calcium chloride 0.88Kg, dehydrated alcohol 26L, stirring to dissolved clarification, cooling are added in a kettle
To -25 DEG C, for use；Under argon gas protection, sodium borohydride 0.42Kg is added in dehydrated alcohol 12L, 0~5 DEG C of temperature control stirring to dissolved clarification；
This sodium borohydride solution is added dropwise in the dehydrated alcohol calcium chloride solution prepared, controls Nei Wen -25~-20 DEG C, drop, which finishes, to be stirred
Mix the dehydrated alcohol suspension that 0.5h obtains calcium borohydride.
The dichloromethane solution of compounds Ⅳ is added dropwise in calcium borohydride system, controls Nei Wen -25~-20 DEG C.Drop finishes
19h is stirred, TLC detection reaction terminates.50% aqueous acetic acid quenching reaction is added dropwise, controls Nei Wen -25~-20 DEG C.50 DEG C dense
Be reduced to it is solvent-free steam, 11.2L ice water elutriation, 5.6L water washing filter cake after filtering.40 DEG C are dried under vacuum to constant weight, obtain white solid
V 1.09Kg of body compound, weight yield 97.3%, HPLC purity purity 84.03%, isomers 4.92%.
(3) hydrolysis:
Under argon gas protection, compounds Ⅳ 1.09Kg, acetone 14L, water 1.4L, p-methyl benzenesulfonic acid 76g, control are added in reaction kettle
45~50 DEG C of reaction 1h of temperature.TLC is detected after the reaction was completed, adds 150mL triethylamine quenching reaction.9L acetone is concentrated out, 10L is added
Water continues to be concentrated into solvent-free ooze.It is cooled to 0 DEG C, stirs 1h.Filtering, 2L water washing filter cake.50 DEG C of drying, obtain whitening
Close I 880g of object, weight yield 80.7%, HPLC purity 88.9%, isomers 2.31%.
Embodiment 3
(1) acetylization reaction:
Under argon gas protection, compound ii 1Kg, aceticanhydride 4L, aluminum trichloride (anhydrous) 40g, sulfosalisylic are added in a kettle
Sour 60g, 20~30 DEG C of reaction 5h of controlling temperature.TLC is detected after the reaction was completed, and ice water 12L is added, and is stirred 2h, is analysed product sufficiently
Out；Neutrality is washed to after filtering, 40 DEG C of vacuum drying for 24 hours, obtain off-white color compound III 1.12Kg, mass yield 112%, HPLC
Purity 99.2%, starting material left 0.5%.
(2) ketal reduction reaction:
Under argon gas protection, compound III 1.12Kg, methylene chloride 7.8L, ethylene glycol 1.0L, primitive nail are added in a kettle
Triethylenetetraminehexaacetic acid ester 1.0L and catalyst boron trifluoride ether 50mL, reacts 5h by 20~30 DEG C of temperature control, and TLC detection reaction is completed
Afterwards, 100mL triethylamine quenching reaction is added, the dichloromethane solution for obtaining compounds Ⅳ is stand-by.
Under argon gas protection, anhydrous magnesium chloride 0.67Kg, dehydrated alcohol 21L, stirring to dissolved clarification, cooling are added in a kettle
To -30 DEG C, for use；Under argon gas protection, sodium borohydride 0.42Kg is added in dehydrated alcohol 12L, 0~5 DEG C of temperature control stirring to dissolved clarification.
This solution is added dropwise in the dehydrated alcohol magnesium chloride solution prepared, controls Nei Wen -30~-25 DEG C, complete 0.5h is dripped and obtains boron hydrogen
Change the dehydrated alcohol suspension of magnesium.
The dichloromethane solution of compounds Ⅳ is added dropwise in magnesium borohydride system, controls Nei Wen -30~-25 DEG C.Drop finishes
19h is stirred, TLC detection reaction terminates.50% aqueous acetic acid quenching reaction is added dropwise, controls Nei Wen -30~-25 DEG C.50 DEG C dense
Be reduced to it is solvent-free steam, 11.2L ice water elutriation, 5.6L water washing filter cake after filtering.40 DEG C are dried under vacuum to constant weight, obtain white solid
V 1.07Kg of body compound, mass yield 95.5%, HPLC purity 86.45%, content of isomer 5.26%.
(3) hydrolysis:
Under argon gas protection, compounds Ⅳ 1.07Kg, acetone 14L, water 1.4L, p-methyl benzenesulfonic acid 74g are added in a kettle,
45~50 DEG C of reaction 1h of temperature control.TLC is detected after the reaction was completed, adds 148mL triethylamine quenching reaction.9L acetone is concentrated out, is added
10L water continues to be concentrated into solvent-free ooze.It is cooled to 0 DEG C, stirs 1h.Filtering, 2L water washing filter cake.50 DEG C of drying, obtain white
Chemical compounds I 860g, mass yield 80.4%, HPLC purity 86.89%, isomers 2.88%.
Claims (8)
1. a kind of preparation method of dehydroepiandros-sterone intermediate, the dehydroepiandros-sterone intermediate is compound III, feature
It is, the preparation method includes: that compound II and aceticanhydride react to obtain compound III under the action of catalyst, wherein described
Catalyst be selected from the combination of aluminum trichloride (anhydrous) and sulfosalicylic acid or the combination of aluminum trichloride (anhydrous) and camphorsulfonic acid, by changing
The poidometer of object II is closed, aluminum trichloride (anhydrous) dosage is 2~4%, and the dosage of sulfosalicylic acid or camphorsulfonic acid is 4~6%,
2. the preparation method of dehydroepiandros-sterone intermediate compound III according to claim 1, which is characterized in that described
Compound II and aceticanhydride w/v be 1W: 3~5V；Wherein the W indicates weight, and V indicates volume, when W unit is g
When, the unit of V is mL, and when W unit is kg, the unit of V is L.
3. a kind of preparation method of dehydroepiandros-sterone, the structure of dehydroepiandros-sterone (compound I) are as follows:
It is characterized by:
1) acetylization reaction: compound II, aceticanhydride and the first catalyst react under noble gas protection, obtain compound III, institute
It states the first catalyst to be selected from: the group of the combination of aluminum trichloride (anhydrous) and sulfosalicylic acid or aluminum trichloride (anhydrous) and camphorsulfonic acid
It closes；
2) ketal, reduction reaction: compound III dissolves in methylene chloride, and under noble gas protection, ethylene glycol, orthoformic acid three is added
Ethyl ester and the second catalyst, obtain the dichloromethane solution of compound IV；This solution is added drop-wise to boron hydrogen under noble gas protection
In the ethanol solution for changing calcium or magnesium borohydride, -30 DEG C~-15 DEG C of temperature control react compound V, second catalyst are
Boron trifluoride ether；
3) hydrolysis: compound V, water and acid react in a solvent, obtain dehydroepiandros-sterone
4. the preparation method of dehydroepiandros-sterone according to claim 3, which is characterized in that change in step 1) acetylization reaction
Closing object II: aceticanhydride: aluminum trichloride (anhydrous): the w/v of sulfosalicylic acid or camphorsulfonic acid is 1W: 3~5V: 0.02~
0.04W: 0.04~0.06W；Wherein the W indicates weight, and V indicates volume, and when W unit is g, the unit of V is mL, when W is mono-
When position is kg, the unit of V is L.
5. the preparation method of dehydroepiandros-sterone according to claim 3, which is characterized in that step 1) acetylization reaction temperature
It is 20~30 DEG C.
6. the preparation method of dehydroepiandros-sterone according to claim 3, which is characterized in that step 2) ketal, reduction reaction
Used in calcium borohydride or magnesium borohydride, be to be existed under protection of argon gas by anhydrous calcium chloride or anhydrous magnesium chloride and sodium borohydride
Temperature control -30~-15 DEG C reaction obtains in dehydrated alcohol.
7. the preparation method of dehydroepiandros-sterone according to claim 6, which is characterized in that step 2) ketal, reduction reaction
The anhydrous calcium chloride or anhydrous magnesium chloride used: sodium borohydride: the w/v of dehydrated alcohol is 0.6~0.8W: 0.2~
0.4W: 25~35V；Wherein the W indicates weight, and V indicates volume, and when W unit is g, the unit of V is mL, when W unit is kg
When, the unit of V is L.
8. the preparation method of dehydroepiandros-sterone according to claim 3, which is characterized in that step 2) ketal, reduction reaction
When middle prepare compound IV, compound III: ethylene glycol: triethyl orthoformate: boron trifluoride ether: the weighing body of methylene chloride
Product ratio is 1W: 0.6~1V: 0.6~1V: 0.02~0.05V: 5~7V；Wherein the W indicates weight, and V indicates volume, when W is mono-
When position is g, the unit of V is mL, and when W unit is kg, the unit of V is L.
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| CN113493814B (en) * | 2020-04-01 | 2023-03-31 | 湖南引航生物科技有限公司 | Dehydroepiandrosterone biosynthesis method |
| CN113621672B (en) * | 2021-07-30 | 2023-07-07 | 浙江神洲药业有限公司 | Novel method for preparing dehydroepiandrosterone |
| CN114195844B (en) * | 2021-12-29 | 2023-03-17 | 湖北武当安泰药业有限公司 | Preparation method of dehydroepiandrosterone |
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| CN105503985A (en) * | 2016-02-23 | 2016-04-20 | 浙江仙琚制药股份有限公司 | Method for preparing epiandrosterone |
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