CN107698643A - A kind of preparation method of dehydroepiandros-sterone - Google Patents
A kind of preparation method of dehydroepiandros-sterone Download PDFInfo
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- CN107698643A CN107698643A CN201711080913.9A CN201711080913A CN107698643A CN 107698643 A CN107698643 A CN 107698643A CN 201711080913 A CN201711080913 A CN 201711080913A CN 107698643 A CN107698643 A CN 107698643A
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- dehydroepiandros
- sterone
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- 0 CC(CC1)(C(CC2)C3C1[C@@](C)(*CC(O*)=C1)C1=CC3)C2=O Chemical compound CC(CC1)(C(CC2)C3C1[C@@](C)(*CC(O*)=C1)C1=CC3)C2=O 0.000 description 2
- HFOFVDJHNUVKGD-BTKGWRIZSA-N C[C@@](CC1)(C2OC2CC2)C2C2C1[C@@](C)(CC[C@@H](C1)O)C1=CC2 Chemical compound C[C@@](CC1)(C2OC2CC2)C2C2C1[C@@](C)(CC[C@@H](C1)O)C1=CC2 HFOFVDJHNUVKGD-BTKGWRIZSA-N 0.000 description 1
- AEMFNILZOJDQLW-WFZCBACDSA-N C[C@](CC1)(C(CC2)C(CC3)C1[C@@](C)(CC1)C3=CC1=O)C2=O Chemical compound C[C@](CC1)(C(CC2)C(CC3)C1[C@@](C)(CC1)C3=CC1=O)C2=O AEMFNILZOJDQLW-WFZCBACDSA-N 0.000 description 1
- FMGSKLZLMKYGDP-INNQQZFDSA-N C[C@](CC1)(C(CC2)C3C1[C@@](C)(CC[C@@H](C1)O)C1=CC3)C2=O Chemical compound C[C@](CC1)(C(CC2)C3C1[C@@](C)(CC[C@@H](C1)O)C1=CC3)C2=O FMGSKLZLMKYGDP-INNQQZFDSA-N 0.000 description 1
Classifications
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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 preparing technical field of steroid hormone medicine, and in particular to a kind of preparation method of dehydroepiandros-sterone, including using 4 AD as starting material, dehydroepiandros-sterone is prepared through acetylization reaction, ketal reduction reaction " one kettle way " and hydrolysis successively, wherein：Catalyst is combined as using aluminum trichloride (anhydrous) and the combination of sulfosalicylic acid or aluminum trichloride (anhydrous) and camphorsulfonic acid in acetylization reaction.Compared with prior art, the dehydroepiandros-sterone Isomers In Products of present invention gained only account for 1~3%, and mass yield is more than 88%, refine yield and are more than 78%, product purity is more than 99%, and prospects for commercial application is wide.
Description
Technical field
The present invention relates to a kind of preparing technical field of steroid hormone medicine, and in particular to a kind of preparation of dehydroepiandros-sterone
Method.
Background technology
Dehydroepiandros-sterone is the important source material for manufacturing steroid hormone class medicine.Existing chemical synthesis process is broadly divided into two
Class, the synthetic method of a kind of dehydroepiandros-sterone reported such as the A of Chinese patent CN 102603839, 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 initiation material Chinese yam saponin is resource-constrained, and step is long, cumbersome, yield is low, environmental pollution is tight
Weight, has been eliminated at present with the development of steroidal industry.
It is another kind of, then it is the process route using 4-AD as raw material developed in recent years.Such as Chinese patent
The preparation method of the dehydroepiandros-sterone of CN102603841A reports, is raw material through over-churning, ketal, reduction reaction and water using 4-AD
Solution reaction synthesis dehydroepiandros-sterone, often walks mass yield and 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%, and this is pointed out in the A of Chinese patent CN 105017361
Route gross mass yield 60% or so.And the preparation method of dehydroepiandros-sterone disclosed in the A of Chinese patent CN 105017361, its
Diene alcohol intermediate is extremely unstable, and catalytic hydrogenation uses a large amount of palladium carbons, and cost is high, is unfavorable for industrialized production.
The content of the invention
The purpose of the present invention is for the defects of existing dehydroepiandros-sterone chemical preparation process, there is provided a high income,
It is easy to operate, isomers is few, cost is cheap, the chemical synthesis process of dehydroepiandros-sterone industrialized production can be achieved.
The technical scheme that this case provides is as follows：4-AD is used as starting material, successively through acetylization reaction, ketal reduction reaction
" one kettle way " and hydrolysis prepare dehydroepiandros-sterone, and synthetic route is：
Specifically, technical scheme is as follows：
This case provide firstly a kind of dehydroepiandros-sterone aceted intermediate III preparation method, the acetylization reaction
Including：4-AD compound iis are added in aceticanhydride, lower 20~30 DEG C of stirrings of controlling temperature of argon gas protection, add catalyst, detection is anti-
After the completion of answering, add frozen water product and separate out, filtering, be washed to neutrality, dry to obtain compound III；
The catalyst used in above-mentioned acetylization reaction can be aluminum trichloride (anhydrous) and sulfosalicylic acid combination, or anhydrous
One kind in being combined 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.
The catalyst aluminum trichloride (anhydrous) dosage used in above-mentioned acetylization reaction for starting material 4-AD weight 2%~
4%, the sulfosalicylic acid or camphorsulfonic acid are the 4%~6% of starting material 4-AD weight.
Aceticanhydride is that reactant is solvent again in above-mentioned acetylization reaction, preferably, only 3 in system of the present invention~
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 in the above-mentioned acetylization reaction of the present invention：Under inert gas shielding, instead
It is 20~30 DEG C to answer temperature.
Complete, the aceted intermediate according to reaction system prepare compound III, starting material the 4-AD reaction of the present invention
Compound III HPLC purity is promoted to more than 99% by 96~97%.
The acetylization reaction prior art PTS/ aceticanhydride acetylation systems of table 1 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, present invention also offers a kind of preparation method of dehydroepiandros-sterone, comprise the following steps：
(1) acetylization reaction prepare compound III
Compound ii (4-AD) is added in aceticanhydride, lower 20~30 DEG C of stirrings of controlling temperature of argon gas protection, adds the first catalysis
Agent, adds frozen water after the completion of reaction, product separates out, filters, is washed to neutrality, dry to obtain compound III；Wherein, described first urge
The one kind of agent in 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, only 3 in system of the present invention~
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) ketal, reduction " one kettle way " reaction prepare compound V
Compound III is added in dichloromethane, under argon gas protection, adds ethylene glycol, triethyl orthoformate, and second
Catalyst BFEE；After the completion of TLC detection reactions, add 0.05V triethylamines and reaction is quenched, obtain 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 argon gas protection,
0.5h is stirred in temperature control -30~-15 DEG C, obtains the absolute ethyl alcohol suspension of calcium borohydride；
The dichloromethane solution of compounds Ⅳ is added dropwise to temperature control -30~-15 in the absolute ethyl alcohol suspension of calcium borohydride
After DEG C stirring 15h, 50% acetic acid is added dropwise and is quenched reaction, concentration elutriation, dries to obtain compound V；
Compound III in the ketal, reduction reaction:Ethylene glycol:Triethyl orthoformate:BFEE:Dichloromethane
Proportioning be 1W:0.6~1V:0.6~1V:0.02~0.05W:5V~7V；
The anhydrous calcium chloride or anhydrous magnesium chloride used in the ketal, reduction reaction:Sodium borohydride:Absolute ethyl alcohol is matched somebody with somebody
Than being 0.6~0.8W:0.2~0.4W:25~35V.
The calcium borohydride used in the ketal, reduction " one kettle way " reactions steps is by sodium borohydride and anhydrous calcium chloride
Generated in -30~-15 DEG C of absolute ethyl alcohol situs.In addition, calcium borohydride also can use magnesium borohydride to substitute.
Compared with the tradition sodium borohydride and potassium borohydride that use, the change reacting to obtain using calcium borohydride or magnesium borohydride
Compound V, its isomer proportion are down to 5% by 12%.
(3) hydrolysis prepare compound I
By compounds Ⅳ dissolving in acetone, diluted acid is added.1h is reacted, reaction finishes.Elutriation is concentrated, hydrogen meter must be removed by drying
Androsterone.
Note：W described in text represents weight, and V represents volume.When W units are g, V Unit/mL；When W units are kg, V
Unit L.
Compared with prior art, the beneficial effects of the invention are as follows:Dehydroepiandros-sterone is synthesized using the synthetic schemes of the present invention,
React easy to control, saved process, solvent loss is low, and cost is cheap.Gained dehydroepiandros-sterone Isomers In Products only 1~3%,
Mass yield is more than 88%, refines yield and is more than 78%, product purity is more than 99%, and prospects for commercial application is wide.
Embodiment
Presently in connection with embodiment, the present invention is further detailed explanation, and application of the invention is not limited to following
Embodiment, any formal accommodation 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.After the completion of TLC detection reactions, frozen water 12L is added, 2h is stirred, product is fully separated out；
Neutrality is washed to after filtering, 24h is dried in vacuo, 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, dichloromethane 5.7L, ethylene glycol 0.7L, primitive nail are added in a kettle
Triethylenetetraminehexaacetic acid ester 0.7L, and catalyst BFEE 23mL, 20~30 DEG C of temperature control react 5h, and TLC detection reactions are completed
Afterwards, 46mL triethylamines are added and reaction is quenched, obtain the dichloromethane solution of compounds Ⅳ, it is stand-by.
Under argon gas protection, anhydrous calcium chloride 0.7Kg, absolute ethyl alcohol 22L are added in a kettle, are stirred to dissolved clarification, cooling
It is stand-by to -20 DEG C；Under argon gas protection, sodium borohydride 0.25Kg is added in absolute ethyl 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 absolute ethyl alcohol calcium chloride solution prepared, controls Nei Wen -20~-15 DEG C, drop finishes
Stirring 0.5h obtains the absolute ethyl 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 reactions terminate.50% aqueous acetic acid is added dropwise reaction is quenched, control Nei Wen -20~-15 DEG C.50 DEG C dense
Be reduced to it is solvent-free steam, 11.4L frozen water elutriations, 5.7L water washings filter cake after filtering.40 DEG C are dried under vacuum to constant weight, obtain white solid
The 1.12Kg of body compound V, 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.After the completion of TLC detection reactions, add 160mL triethylamines that reaction is quenched.10L acetone is concentrated out, is added
11L water, continue to be concentrated into solvent-free ooze.0 DEG C is cooled to, stirs 1h.Filtering, 2L water washing filter cakes.50 DEG C of drying, are obtained 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.After the completion of TLC detection reactions, frozen water 12L is added, 2h is stirred, product is fully separated out；Cross
Water after filter is washed till neutrality, 40 DEG C of vacuum drying 24h, obtains 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, dichloromethane 6.7L, ethylene glycol 0.9L, primitive nail are added in a kettle
Triethylenetetraminehexaacetic acid ester 0.9L, and catalyst BFEE 34mL, 20~30 DEG C of temperature control react 5h, and TLC detection reactions are completed
Afterwards, 68mL triethylamines are added and reaction is quenched, the dichloromethane solution for obtaining compounds Ⅳ is stand-by.
Under argon gas protection, anhydrous calcium chloride 0.88Kg, absolute ethyl alcohol 26L are added in a kettle, are stirred to dissolved clarification, cooling
It is stand-by to -25 DEG C；Under argon gas protection, sodium borohydride 0.42Kg is added in absolute ethyl alcohol 12L, 0~5 DEG C of stirring of temperature control to dissolved clarification；
This sodium borohydride solution is added dropwise in the absolute ethyl alcohol calcium chloride solution prepared, controls Nei Wen -25~-20 DEG C, drop, which finishes, to be stirred
Mix the absolute ethyl 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 reactions terminate.50% aqueous acetic acid is added dropwise reaction is quenched, control Nei Wen -25~-20 DEG C.50 DEG C dense
Be reduced to it is solvent-free steam, 11.2L frozen water elutriations, 5.6L water washings filter cake after filtering.40 DEG C are dried under vacuum to constant weight, obtain white solid
The 1.09Kg of body compound V, 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 reactor
45~50 DEG C of reaction 1h of temperature.After the completion of TLC detection reactions, add 150mL triethylamines that reaction is quenched.9L acetone is concentrated out, adds 10L
Water, continue to be concentrated into solvent-free ooze.0 DEG C is cooled to, stirs 1h.Filtering, 2L water washing filter cakes.50 DEG C of drying, obtain whitening
The 880g of compound I, 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.After the completion of TLC detection reactions, frozen water 12L is added, 2h is stirred, product is fully analysed
Go out；Neutrality is washed to after filtering, 40 DEG C of vacuum drying 24h, obtains 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, dichloromethane 7.8L, ethylene glycol 1.0L, primitive nail are added in a kettle
Triethylenetetraminehexaacetic acid ester 1.0L, and catalyst BFEE 50mL, 20~30 DEG C of temperature control react 5h, and TLC detection reactions are completed
Afterwards, 100mL triethylamines are added and reaction is quenched, the dichloromethane solution for obtaining compounds Ⅳ is stand-by.
Under argon gas protection, anhydrous magnesium chloride 0.67Kg, absolute ethyl alcohol 21L are added in a kettle, are stirred to dissolved clarification, cooling
It is stand-by to -30 DEG C；Under argon gas protection, sodium borohydride 0.42Kg is added in absolute ethyl alcohol 12L, 0~5 DEG C of stirring of temperature control to dissolved clarification.
This solution is added dropwise in the absolute ethyl alcohol magnesium chloride solution prepared, controls Nei Wen -30~-25 DEG C, dripped complete 0.5h and obtain boron hydrogen
Change the absolute ethyl 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 reactions terminate.50% aqueous acetic acid is added dropwise reaction is quenched, control Nei Wen -30~-25 DEG C.50 DEG C dense
Be reduced to it is solvent-free steam, 11.2L frozen water elutriations, 5.6L water washings filter cake after filtering.40 DEG C are dried under vacuum to constant weight, obtain white solid
The 1.07Kg of body compound V, 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.After the completion of TLC detection reactions, add 148mL triethylamines that reaction is quenched.9L acetone is concentrated out, is added
10L water, continue to be concentrated into solvent-free ooze.0 DEG C is cooled to, stirs 1h.Filtering, 2L water washing filter cakes.50 DEG C of drying, are obtained 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, described dehydroepiandros-sterone intermediate is compound III, its feature
It is, described preparation method includes：Compound ii and aceticanhydride react to obtain compound III under catalyst action, wherein described
Catalyst is selected from aluminum trichloride (anhydrous) and the combination of sulfosalicylic acid or the combination of aluminum trichloride (anhydrous) and camphorsulfonic acid, by chemical combination
The weight meter of thing II, aluminum trichloride (anhydrous) dosage are 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, it is characterised in that described
Compound ii and the w/v of aceticanhydride be 1W：3~5V.
3. a kind of preparation method of dehydroepiandros-sterone, the structure of dehydroepiandros-sterone (chemical compounds I) is as follows：
It is characterized in that:
1) acetylization reaction：Compound ii, aceticanhydride and the first catalyst react under noble gas protection, obtain compound III, described
First catalyst is selected from：The combination of aluminum trichloride (anhydrous) and sulfosalicylic acid or the combination of aluminum trichloride (anhydrous) and camphorsulfonic acid；
2) ketal, reduction reaction：Compound III is dissolved in dichloromethane, under noble gas protection, adds ethylene glycol, primitive nail triethylenetetraminehexaacetic acid
Ester and the second catalyst, obtain the dichloromethane solution of compounds Ⅳ；This solution is added drop-wise to hydroboration under noble gas protection
In calcium or the ethanol solution of magnesium borohydride, -30 DEG C~-15 DEG C of temperature control reacts to obtain compound V, and second catalyst is
BFEE；
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, it is characterised in that change in step 1) acetylization reaction
Compound 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.
5. the preparation method of dehydroepiandros-sterone according to claim 3, it is characterised in that step 1) acetylization reaction temperature
For 20~30 DEG C.
6. the preparation method of dehydroepiandros-sterone according to claim 3, it is characterised in that step 2) ketal, reduction reaction
The middle calcium borohydride used or magnesium borohydride, it is to be existed under argon gas protection by anhydrous calcium chloride or anhydrous magnesium chloride and sodium borohydride
Temperature control -30~-15 DEG C reaction obtains in absolute ethyl alcohol.
7. the preparation method of the dehydroepiandros-sterone according to claim 3 or 6, it is characterised in that step 2) ketal, reduction are anti-
The anhydrous calcium chloride or anhydrous magnesium chloride that should be used:Sodium borohydride:The w/v of absolute ethyl alcohol is 0.6~0.8W:0.2~
0.4W:25~35V.
8. the preparation method of dehydroepiandros-sterone according to claim 3, it is characterised in that step 2) ketal, reduction reaction
During middle prepare compound IV, compound III:Ethylene glycol:Triethyl orthoformate:BFEE:The bulking value of dichloromethane
Than being 1W:0.6~1V:0.6~1V:0.02~0.05V:5~7V.
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Cited By (3)
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| CN113493814A (en) * | 2020-04-01 | 2021-10-12 | 湖南引航生物科技有限公司 | Dehydroepiandrosterone biosynthesis method |
| CN113621672A (en) * | 2021-07-30 | 2021-11-09 | 浙江神洲药业有限公司 | Novel method for preparing dehydroepiandrosterone |
| CN114195844A (en) * | 2021-12-29 | 2022-03-18 | 湖北武当安泰药业有限公司 | Preparation method of dehydroepiandrosterone |
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| CN114195844A (en) * | 2021-12-29 | 2022-03-18 | 湖北武当安泰药业有限公司 | Preparation method of dehydroepiandrosterone |
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