A method of using androstenedione as Material synthesis lithocholic acid
(1) technical field
It is the present invention relates to organic chemical synthesis technical field, in particular to a kind of using androstenedione as the side of Material synthesis lithocholic acid
Method.
(2) background technique
Lithocholic acid also known as 3a- hydroxyl -5 β-cholanic acid, belong to one of cholic acid, are a kind of secondary bile acid, the following institute of structural formula
Show, be present in the cholelith of people, the bile of ox rabbit and ox, pig, association reaction occurs in liver, with taurolithocholic acid or sweet ammonia
Lithocholic acid form comes across in bile, and changes of contents has important references value in hepatic disease diagnosis.Existing research table
Bright, lithocholic acid and its derivative have a variety of physiological activity, and the property of can choose kills the cancer cell of a few types, and to normal thin
Born of the same parents do not have toxic action, show that lithocholic acid has broad application prospects as chemotherapy class drug.
Lithocholic acid is a kind of important medicine raw material, its main source is to extract animal bile, but bile source has at present
Limit, content is lower and extraction difficulty is larger;The relevant report obtained by chemical synthesis is seldom, develops one based on this present invention
The new lithocholic acid synthetic route of item.
At present it is known that the synthetic method of lithocholic acid have it is following several:
By deoxycholic aicd by the reaction of seven steps synthesize lithocholic acid (Journal of Biological Chemistry, 1946,
162,555-563), total recovery 23% since raw material deoxycholic aicd is equally difficult to obtain, and is needed using expensive catalyst two
Platinum oxide, it is at high cost, be not suitable for industrialized production.
CN201710404532 describes a kind of method by cholic acid for Material synthesis lithocholic acid, but final step huang-Minlon reaction
200 DEG C of high temperature and 98% hydrazine hydrate are needed, operation is difficult to realize in workshop and has certain risk.
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(3) summary of the invention
In order to compensate for the shortcomings of the prior art, the present invention provides a kind of using androstenedione as the method for Material synthesis lithocholic acid.
The present invention is achieved through the following technical solutions:
A method of using androstenedione as Material synthesis lithocholic acid, it is characterised in that:
Using androstenedione as raw material, comprising the following steps:
(1) 3 enol ether protection reaction: to protecting to 3 ketone carbonyls for androstenedione, the compound A of high-purity, i.e. 3- are obtained
Methoxyl group -3,5- diene androstane -17- ketone;
(2) wittig reacts: compound A being carried out Wittig with phosphorus ylide reagent and is reacted, the target product of high-purity is obtained
Compound B, i.e. 3- methoxyl group -17 (Z)-pregnant steroid -3 (4), 5 (6), 17 (20)-triolefin;
(3) 3 enol ether deprotection reactions: compound B dissolution, acidification slough protection, obtain high-purity target product compound
C, i.e., 17 (Z)-pregnant steroid -4,17 (20)--3 ketone of diene;
(4) 17 side chain addition reactions: it by compound C in methylene chloride and methyl acrylate atmosphere, is urged with ethyl aluminum dichloride
Change, in 17 upper introducing side chains, obtains target product compound D;
(5) 3 carbonyl reduction reactions: target product compound D passes through tri-tert lithium aluminium hydride reduction for 3 carbonyl selective reductions
For Alpha-hydroxy, the target product compound E of higher degree is obtained;
(6) saponification: target product compound E is dissolved in solvent, saponified under basic conditions reacts to obtain higher degree
Target product compound F;
(7) catalytic hydrogenation reaction: under the catalysis of catalyst by target product compound F, hydrogen addition restores double bond, is compared
Preferably there is stereoselectivity target product lithocholic acid.
In step (1), it is added androstenedione in reaction vessel, trimethyl orthoacetate is added dropwise after tetrahydrofuran in p-methyl benzenesulfonic acid;
Controlling reaction temperature is 25 ~ 30 DEG C, and the reaction time is 2 ~ 4h, and reaction system requires anhydrous and oxygen-free condition;To use after the reaction was completed
Triethylamine adjusts pH 8 ~ 10, is directly concentrated, is washed using methanol;40 DEG C of product are dried under vacuum to moisture less than 0.1%, i.e., high-purity
The compound A of degree.
Further, androstenedione is raw material, and p-methyl benzenesulfonic acid is catalyst, and tetrahydrofuran is solvent;Wherein androstenedione:
Anhydrous p-methyl benzenesulfonic acid: the molar ratio of trimethyl orthoacetate is 1:0.02:2.4;M (androstenedione): V(tetrahydrofuran): V(first
Alcohol)=1:4:0.7.
In step (2), compound A is dissolved in tetrahydrofuran, is carried out Wittig with phosphorus ylide reagent and is reacted, consersion unit
Predrying is needed, the stringent anhydrous and oxygen-free of system, at 50 DEG C or so, reaction time 6h, reaction solution is orange red for reaction temperature control
To blood red suspension, to stop reacting with cold water after the reaction was completed;After petroleum ether extraction, oily is concentrated at 35 DEG C
Target compound is precipitated using methanol in substance.
Further, compound A: Ethyltriphenylphosphonium brimide: the molar ratio of potassium tert-butoxide is 1:3.5 ~ 4:5.2, m (chemical combination
Object A): V (tetrahydrofuran)=1:8;The phosphorus ylide reagent is Ethyltriphenylphosphonium brimide.
In step (3), compound B is dissolved in tetrahydrofuran, instill dilute hydrochloric acid, react at room temperature 10 ~ 30min, 40 DEG C of product
Vacuum drying, moisture is less than 0.15%, m (compound B): V (THF): V (30% HCl)=1:5:1.2.
In step (4), compound C is first reacted into 3h at 0 DEG C or less with methyl acrylate, adds ethyl aluminum dichloride continuation
28 ~ 35 DEG C of temperature are gone to after reaction 4h, the reaction time is three days, and reaction requires anhydrous and oxygen-free, cold water treatment;Compound C: the third
E pioic acid methyl ester: molar ratio 1:2.4:12, m (compound C): the V(DCM of ethyl aluminum dichloride)=1:15.
In step (5), reaction temperature control is at -10 DEG C ~ 0 DEG C, and the reaction time is 3 ~ 8h, and diluted acid adjusts PH after the reaction was completed
To 5 ~ 6;It is extracted using ethyl acetate, being concentrated under reduced pressure after extraction is oily target product E;D: three tert-butoxy hydrogen of compound
Change molar ratio 1:2.3, m (compound D): V (THF)=1:15 of aluminium lithium.
In step (6), for the reaction temperature of saponification at 70 ~ 80 DEG C, 5 ~ 6h of reaction time, 30% dilute hydrochloric acid adjusts PH
Molar ratio=1:6 ~ 7 of 2.0 or so, compound E:KOH, m (compound E): V (MeOH): V (H2O)=1:15:25.
In step (7), 4 ~ 8h of reaction time, room temperature reaction, compound F: molar ratio 1:0.06 ~ 0.1 of catalyst;M (changes
Close object F): V (MeOH)=1:30;The catalyst is Pd/C (10%).
Specific synthetic route is as follows:
1, the preparation of 3- methoxyl group -3,5- diene androstane -17- ketone compound (A)
2,3- methoxyl group -17 (Z)-pregnant steroid -3 (4), 5 (6), the preparation of 17 (20)-triene compound (B)
3,17 (Z)--3 ketone compound of pregnant steroid -4,17 (20)-diene (C) preparation
4, the preparation of compound (D)
5, the preparation of compound (E)
6, the preparation of compound (F)
7, the preparation of lithocholic acid
The beneficial effects of the present invention are: the present invention uses androstenedione cheap and easy to get for raw material, innovative has synthesized stone gallbladder
Acid, process route is simple, and every step reaction yield is high, at low cost, solves the problems, such as that lithocholic acid is difficult to large-scale production, is suitble to work
Industry metaplasia produces.
(4) specific embodiment
Embodiment 1:
The preparation of compound (A) 3- methoxyl group -3,5- diene androstane -17- ketone:
The addition 20g 4-AD into reaction kettle, the addition anhydrous THF of 80ml, 14ml methanol and 0.24g's is anhydrous to first
20.1g trimethyl orthoacetate is added in benzene sulfonic acid under nitrogen protection, is warming up to 30 DEG C, insulation reaction 4h, TLC tracking is reacted, instead
After answering, triethylamine is added and adjusts reaction system PH 8 ~ 10.It is concentrated under reduced pressure, a small amount of methanol washing filters, filtrate is crossed column, obtained
To yellowish color substance, 40 DEG C of vacuum drying obtain 19.7g product, molar yield 94%.
Embodiment 2
Compound (B) 3- methoxyl group -17 (Z)-pregnant steroid -3 (4), 5 (6), the preparation of 17 (20)-triolefin:
With 1 products therefrom compound (A) of embodiment for raw material;18g Ethyltriphenylphosphonium brimide is added into reaction kettle, nothing is added
Potassium tert-butoxide 8g is added portionwise in water THF 144ml, under nitrogen protection, low temperature, and temperature is no more than 0 DEG C, and solution is orange red at this time
Compound (A) 3- methoxyl group -3,5- diene androstane -17- ketone 4.2g is added to blood red suspension, low-temp reaction 1h in color, continues
50 DEG C of reaction 6h are gone to after low-temp reaction 0.5h, cold water is quenched, and is concentrated into oily mater for 35 DEG C after petroleum ether extraction, methanol is precipitated
Target compound.High-purity compound B 3- methoxyl group -17 (Z)-pregnant steroid -3 (4), 5 (6), 17 (20)-triolefin are obtained by filtration
40.5kg, molar yield 92.7%.
Embodiment 3
The preparation of compound (C) 17 (Z)--3 ketone of pregnant steroid -4,17 (20)-diene:
With 2 products therefrom compound (B) of embodiment for raw material;By compound B 3- methoxyl group -17 (Z)-pregnant steroid -3 (4), 5 (6),
17 (20)-triolefin 4.05g are dissolved with 20ml THF, the deprotection of 4.8ml30% dilute hydrochloric acid are added dropwise, after the reaction was completed, with acetic acid second
Ester dilution, 10% sodium bicarbonate wash 2 times, and saturated common salt water washing, anhydrous sodium sulfate is dry, are concentrated under reduced pressure, obtain yellow oily
Substance is added cold methanol and is precipitated, and filtering obtains high-purity compound C 17 (Z)--3 ketone 3.76g of pregnant steroid -4,17 (20)-diene,
Filtrate PE:EA=5:1 crosses column.Compound C is dried in vacuo in 40 DEG C, molar yield 97%.
Embodiment 4
The preparation of compound (D):
With 3 products therefrom compound (C) of embodiment for raw material;Compound (C) 5.6g and 3.9ml methyl acrylate is in 50ml dichloro
It is mixed in methane, low temperature nitrogen protection is lower to react 3h, and ethyl aluminum dichloride 29ml is added dropwise, and temperature is no more than 0 DEG C, turns after continuing anti-4h
To 28-35 DEG C of temperature, the reaction time is three days, and reaction requires anhydrous and oxygen-free, and cold water is quenched, 30mlDCM extraction, and sodium bicarbonate is full
With washing 2 times, saturated common salt water washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure as oily mater.Cross column purification.Obtain target
Combination product (D) 6.7g, molar yield 93.3%.
Embodiment 5
The preparation of compound (E):
With 4 products therefrom compound (D) of embodiment for raw material;5.0g compound (D) is added into reaction kettle, anhydrous THF is added
50ml, reaction temperature are controlled at -10 DEG C ~ 0 DEG C, and three tertiary butyoxy aluminium lithium 7.6g, 3 ~ 8h of reaction time are added portionwise, and are reacted
Diluted acid adjusts PH to 5 ~ 6 after the completion.Ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure as oil
Shape target product (E) 4.6g.Molar yield 91%.
Embodiment 6
The preparation of compound (F):
With 5 products therefrom compound (E) of embodiment for raw material;It is (insoluble to be added less that 3.0g compound (E) is dissolved in 40ml methanol
Measure THF) it is added dissolved in the water of 4.7g potassium hydroxide, temperature is maintained at 70 ~ 80 DEG C, and 5 ~ 6h of reaction time, TLC detection are reacted
After the completion, 30% dilute hydrochloric acid adjusts PH2.0 or so, and ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate is dry, decompression
Concentration is yellow substance 2.6g, molar yield 90%.
Embodiment 7
The preparation of compound lithocholic acid:
With 6 products therefrom compound (F) of embodiment for raw material;2g compound (F) is added to reaction kettle, the dissolution of 60ml methanol is complete
(insoluble that a small amount of THF can be added), is carefully added into the Pd/C catalyst of 0.2g 10%, reacts 4 ~ 8h, TLC monitoring experiment at room temperature
After the completion, filtering eliminates catalyst, and organic phase is concentrated under reduced pressure, and obtains yellow oily substance, and the target of THF/MeOH recrystallization produces
Object lithocholic acid 1.6g, molar yield 83%.
The present invention is described by way of example above, but the present invention is not limited to above-mentioned specific embodiment, all to be based on
Any changes or modifications that the present invention is done are fallen within the scope of the claimed invention.