CN108070014A - A kind of preparation method of compound and its application in shellfish cholic acid difficult to understand is prepared - Google Patents
A kind of preparation method of compound and its application in shellfish cholic acid difficult to understand is prepared Download PDFInfo
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- CN108070014A CN108070014A CN201610978192.2A CN201610978192A CN108070014A CN 108070014 A CN108070014 A CN 108070014A CN 201610978192 A CN201610978192 A CN 201610978192A CN 108070014 A CN108070014 A CN 108070014A
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- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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Abstract
The invention discloses a kind of preparation methods of the shellfish cholic acid intermediate difficult to understand such as 1 compound of formula, comprise the following steps：Under the action of lewis acid, 2 compound of formula obtains 1 compound of formula with acetaldehyde through Mukaiyama hydroxyl alcohol condensation reactions, the present invention also announces application of the compound in synthesis shellfish cholic acid difficult to understand such as formula 1, this method have many advantages, such as safe, product be convenient for separating-purifying, it is easy to operate, at low cost, beneficial to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation method of pharmaceutical intermediate and its close
Application in Cheng Aobei cholic acid.
Background technology
Shellfish cholic acid difficult to understand is the anti-primary biliary cirrhosis drug of Intercept pharmaceuticals research and development, at present document report
The synthetic method of Dao Aobei cholic acid has following several：
Patent WO2013192097, CN201380043964, CN201510847868 disclose report with by 3 Alpha-hydroxies-
- 5 β of 7- ketone groups-cholanic acid occurs esterification and 3-5 β of Alpha-hydroxy-7- ketone groups-cholanic acid methyl esters is made for raw material and 2 methanol, so
Afterwards with alkali, the reaction of protective agent trim,ethylchlorosilane, which generates, protects product, then through aldol condensation, then hydrolyze, the reduction of two steps, system
Target compound is obtained, reaction scheme is as follows：
The route wherein LDA is lithium diisopropylamine, and TMSCl is trim,ethylchlorosilane, BF3·OEt2It is borontrifluoride
Borate ether, Pd/C Shi Palladium carbon, it is identical that related skeleton symbol herein represents meaning, no longer another explanation.
For this route when being reacted by formula B and protective agent, LDA usage amounts are larger, and single step reaction protects generation two simultaneously
Silicon ether protecting group, system impurity is more after reaction, is unfavorable for subsequent reactions, and when 2 prepare compound 1 of reactant uses hazardous agents
Boron trifluoride ether or boron trifluoride acetonitrile react poor controllability, dangerous high, and long-time ultralow temperature is needed to react, no
Suitable for industrialized production.
The patents such as WO2006122977 disclose following route：
First be prepared into compound C by compound B for raw material in this route, it is post-treated after prepare compound D again, reaction behaviour
Make cumbersome, and need to heat, be unfavorable for reducing cost, this route still uses boron trifluoride ether to be catalyzed as aldol condensation
Agent, with poor controllability, the shortcomings such as safety coefficient is low.
WO200272598, CN201510384385 disclose a kind of method for preparing shellfish cholic acid difficult to understand, and route is as follows：
Wherein n-BuLi is n-BuLi, and P-TsOH is to toluic acid.
Although this route reaction step is shorter, when compound B prepare compound C1, will use bromoethane or iodoethane,
Expensive raw material price and source is not easy to obtain, LDA usage amounts are larger, increase danger, it is necessary to using ultralow temperature equipment, normal-butyl
Lithium danger is larger, and route purification is more difficult, while the isomer impurities generated are difficult to away, are unfavorable for industrial production.
Though above-mentioned technical proposal synthesis shellfish cholic acid difficult to understand respectively has its own advantage, exist and use high-risk reagent boron trifluoride second
Ether, using expensive raw material, severe reaction conditions, environmental pollution is serious, and yield is low, and cost is higher, is unfavorable for industrialized production
Deficiency.
The content of the invention
The purpose of the present invention is reagent is endangered used in the process of overcoming above-mentioned prior art preparation shellfish cholic acid difficult to understand and its intermediate
Dangerous degree is big, the shortcomings of isolating and purifying difficulty, be not easy to industrialize, provides that a kind of safer, reaction condition of reaction is mild, operation
The synthetic method of easy, environment amenable shellfish cholic acid intermediate difficult to understand.
The present invention provides a kind of preparation method of shellfish cholic acid intermediate difficult to understand as shown in 1 compound of formula, and it includes following steps
Suddenly：Under Louis acid catalysis, acetaldehyde and compound 2 through Mukaiyama hydroxyls alcohol condensation 1 compound of production to get.
[formula (1)]
Its step carries out as the following formula：
Wherein R1For methyl or ethyl or tertiary butyl or benzyl, R2For trimethyl silicon substrate or triethyl group silicon substrate.
Heretofore described lewis acid is solid metal chlorides, and heretofore described solid Lewis acid is anhydrous chlorine
Change aluminium, anhydrous ferric trichloride, anhydrous zinc chloride, special preferred anhydrous Aluminum chloride；Compound 2 is with lewis acidic equivalent proportion
1.0: 5.0~15.0；Compound 2 and the equivalent proportion of acetaldehyde are 1.0: 1.5~2.0；Setting-up point is -10 DEG C~-40 DEG C,
It is preferred that -25 DEG C~-30 DEG C.
2 compound of Chinese style of the present invention carries out in a solvent with acetaldehyde through the condensation reaction of Mukaiyama hydroxyl alcohol, as long as solvent is not
Reaction is hindered, is had to raw material outside certain solubility, there is no particular limitation, Ke Yishi：Aliphatic hydrocarbon solvents, fragrance
One or more in varsol or ether solvent, wherein the Aliphatic hydrocarbon solvents can be n-hexane or normal heptane or
Hexamethylene etc., aromatic hydrocarbon solvent can be benzene or toluene, and ether solvent can be glycol dimethyl ether, tetrahydrofuran, Isosorbide-5-Nitrae two
Six ring of oxygen, special preferred tetrahydrofuran.
1 compound of formula of the present invention, for the application in shellfish cholic acid difficult to understand is prepared.
In the preparation method of Austria's shellfish cholic acid intermediate of the present invention, after reaction, the simply side of post processing can be passed through
Method such as crystallizes or column chromatography obtains the higher product of purity.After preferred extraction of the invention, the anti-of next step is directly carried out
It should.
Further, 1 compound of formula prepares shellfish cholic acid difficult to understand by following route：
In the preparation method of the preparation shellfish cholic acid difficult to understand of 1 compound of formula of the present invention, wherein 1 compound of formula to compound
D is carried out in accordance with the following steps：Compound 1 is mixed with solvent, adds in the aqueous solution of alkali, when reaction 6~12 is small at a certain temperature,
Subtract and organic solvent is evaporated off, it is 2~3 to adjust reaction system pH, and solid is precipitated, and filters drying.
Further, 1 compound of formula is prepared in the preparation method of shellfish cholic acid difficult to understand, and wherein compound 1 arrives compound D
Alkali is the one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, preferably hydroxide in step
Sodium, molar ratio are compound 1：Sodium hydroxide is 1.0: 5.0~15.0, is preferably 1.0: 10.0；Reaction temperature is 25 DEG C
~70 DEG C, preferably 40 DEG C~50 DEG C.
1 compound of formula of the present invention is prepared in the preparation method of shellfish cholic acid difficult to understand, wherein step compound D to compound
E is carried out in accordance with the following steps：Compound D is dissolved with organic solvent, is reduced by catalysis, when room temperature reaction 12~18 is small
Object E is closed, is filtered, concentration is recrystallized to give compound E.
Further, 1 compound of formula is prepared in the preparation method of shellfish cholic acid difficult to understand, wherein compound D to compound E
Reduction reaction used in reducing catalyst Wei Palladium carbon, Raney Ni, You Xuan Palladium carbon, solvent for methanol, tetrahydrofuran, ethyl alcohol or third
Ketone, preferably methanol.
1 compound of formula of the present invention is prepared in the preparation method of shellfish cholic acid difficult to understand, and wherein compound E is pressed to shellfish cholic acid difficult to understand
It is carried out according to following steps：Compound E obtains shellfish cholic acid difficult to understand through reduction, and when reaction 3~5 is small at 100 DEG C~115 DEG C, concentration is molten
Solution extracts after adding in water, is dried to obtain shellfish cholic acid difficult to understand.
Further, 1 compound of formula is prepared in the preparation method of shellfish cholic acid difficult to understand, compound E to compound Austria shellfish
Reducing agent described in cholic acid is selected from sodium borohydride, potassium borohydride, lithium aluminium hydride reduction, preferably aluminium isopropoxide, sodium borohydride, reaction dissolvent
It is water or methanol.
The synthesis shellfish cholic acid difficult to understand and its new process of intermediate that the present invention provides, have the beneficial effect that：Mistake operated by the present invention
Journey is avoided without using high cost, excessive risk reagent boron trifluoride ether using hazardous agents n-BuLi, need not be used super
Cryo Equipment, reduces the usage amount of LDA, and security increases, and reduces cost, have reaction condition it is mild, it is easy to operate, to ring
Border is friendly, production cost is low, is suitable for the advantages that industrialized production.
Specific embodiment
The present invention is more specifically illustrated by following embodiments, however, the embodiment is not intended to limit the present invention
Scope.
The synthesis of 1 compound 1 of embodiment
Under nitrogen protection into reaction bulb, addition compound 2 (20g, 0.036mol), tetrahydrofuran 100ml, be cooled to-
20~-30 DEG C, aluminum trichloride (anhydrous) (24.0g, 0.18mol) is then added in, stirs 30min, acetaldehyde solution (w=is added dropwise
29.5%, 10.8g, 0.0729mol) reaction 2~3 it is small when after room temperature reaction 2 it is small when, add in sodium bicarbonate solution reaction is quenched,
Stir 1 it is small when, water mutually with dichloromethane 100ml extract, merge, washing, organic phase anhydrous sodium sulfate drying, subtract and steam to obtain rufous
Oil body 15g, yield 95.5%,.Structural identification data is：1H NMR (600MHz, CDCl3) 1.06 (d, 3H), 1.16 (s, 6H),
1.24-1.49 (m, 4H), 1.27-1.52 (m, 2H), 1.35~1.60 (m, 7H), 1.47-1.72 (m, 6H), 1.71s, 3H),
2.09-2.34 (m, 4H), 2.10-2.28 (m, 3H), 3.67 (s, 3H) 6.17 (q, J=7.2Hz, 1H).
The synthesis of 2 compound 1 of embodiment
Under nitrogen protection into reaction bulb, addition compound 2 (20g, 0.036mol), tetrahydrofuran 100ml, be cooled to-
25~-30 DEG C, anhydrous ferric trichloride (29.2g, 0.18mol) is then added in, stirs 30min, acetaldehyde solution (w=is added dropwise
29.5%, 10.8g, 0.0729mol) reaction 2~3 it is small when, when rear room temperature reaction 2 is small, adds in sodium bicarbonate solution and reaction be quenched,
Stir 1 it is small when, layering, water mutually with dichloromethane 100ml extract, merge, washing, anhydrous sodium sulfate drying, subtract and steam to obtain rufous
Oil body 14.6g, yield 93.0%.Structural identification data is：MS(M+1)+=431.6.
The synthesis of 3 compound 1 of embodiment
Under nitrogen protection into reaction bulb, addition compound 2 (20g, 0.036mol), tetrahydrofuran 100ml, be cooled to-
25~-35 DEG C, then add in anhydrous zinc chloride (24.5g, 0.18mol), stir 30min, be added dropwise acetaldehyde solution (w=29.5%,
10.8g, 0.0729mol) reaction 2~3 it is small when after room temperature reaction 2 it is small when, add in sodium bicarbonate solution and be quenched reaction, it is small to stir 1
When, layering, water is mutually extracted with dichloromethane 100ml, is merged, washing, and anhydrous sodium sulfate drying subtracts and steams to obtain rufous oil body
15.1g, yield 96.2%.Structural identification data is：MS(M+1)+=431.6.
The synthesis of 4 compound 1 (R1 is ethyl) of embodiment
Under nitrogen protection into reaction bulb, addition compound 2 (20g, 0.036mol), tetrahydrofuran 100ml, be cooled to-
25~-35 DEG C, aluminum trichloride (anhydrous) (24.0g, 0.18mol) is then added in, stirs 30min, acetaldehyde solution (w=is added dropwise
29.5%, 10.8g, 0.0729mol) temperature control reaction 2~3 it is small when after room temperature reaction 2 it is small when, add in sodium bicarbonate solution be quenched instead
Should, when stirring 1 is small, layering, water is mutually extracted with dichloromethane 100ml, is merged, washing, and anhydrous sodium sulfate drying subtracts and steams reddish brown
Color oil body 14g, yield 94.3%.Structural identification data is：1H NMR (600MHz, CDCl3) 1.06 (d, 3H), 1.16 (s,
6H), 1.24-1.49 (m, 7H), 1.27-1.52 (m, 2H), 1.35~1.60 (m, 7H), 1.47-1.72 (m, 6H), 1.71s,
3H), 2.09-2.34 (m, 4H), 2.10-2.28 (m, 3H), 4.12 (m, 2H) 6.17 (q, J=7.2Hz, 1H), MS (M+1)+=
445.6。
The synthesis of 5 compound 1 (R1 is ethyl) of embodiment
Under nitrogen protection into reaction bulb, addition compound 2 (20g, 0.036mol), tetrahydrofuran 100ml, be cooled to-
25~-30 DEG C, anhydrous ferric trichloride (29.2g, 0.18mol) is then added in, stirs 30min, acetaldehyde solution (w=is added dropwise
29.5%, 10.8g, 0.0729mol) temperature control reaction 2~3 it is small when after room temperature reaction 2 it is small when, add in sodium bicarbonate solution be quenched instead
Should, when stirring 1 is small, layering, water is mutually extracted with dichloromethane 100ml, is merged, washing, and anhydrous sodium sulfate drying subtracts and steams reddish brown
Color oil body 15g, yield 92.6%.MS(M+1)+=445.6.
The synthesis of 6 compound 1 (R1 is ethyl) of embodiment
Under nitrogen protection into reaction bulb, addition compound 2 (20g, 0.036mol), tetrahydrofuran 100ml, be cooled to-
25~-30 DEG C, then add in anhydrous zinc chloride (24.5g, 0.18mol), stir 30min, be added dropwise acetaldehyde solution (w=29.5%,
10.8g, 0.0729mol) temperature control reaction 2~3 it is small when after room temperature reaction 2 it is small when, add in sodium bicarbonate solution reaction is quenched, stirring
1 it is small when, layering, water mutually with dichloromethane 100ml extract, merge, washing, anhydrous sodium sulfate drying, subtract and steam to obtain rufous oil body
15g, yield 94.2%.MS(M+1)+=445.6.
The synthesis of 7 compound D of embodiment
Into reaction bulb, compound 1 (R1 is methyl) (20g, 0.046mol) and methanol 100ml are added in, adds in 100ml hydrogen
Sodium hydroxide solution (18.6g, 0.46mol), when room temperature reaction 12 is small, vacuum distillation removes methanol, cooling, with the hydrochloric acid of 3mol/L
It is 2~3 to adjust reaction system pH, and a large amount of khaki solids are precipitated, and is filtered, and filter cake washing, dry, ethyl alcohol refines, and obtains white solid
11g, yield 56.8%.186.3~188.2 DEG C of (documents of mp：185~188 DEG C).1H NMR (600MHz, CDOD) δ：3.45~
3.47 (m, 1H), 2.84~2.86 (m, 1H), 2.52 (t, 1H, J--11.4Hz), 1.28 (S, 3H), 0.98 (d, J=6.6Hz,
3H), 0.83 (t, J=7.2Hz, 3H), 0.73 (s, 3H).
The synthesis of 8 compound E of embodiment
Into reaction bulb, compound D (10g, 0.024mol) and methanol, Palladium carbon 0.5g is added in, hydrogen under 1.3 atmospheric pressure
Be stirred at room temperature down 12 it is small when, filter, filtrate decompression distillation, obtain white solid 9g, yield 98.4%.
The synthesis of the shellfish cholic acid difficult to understand of embodiment 9
Into reaction bulb, add in compound E (9g, 0.020mmol) and be added in there-necked flask, add in the hydroxide of 1mol/L
Sodium water solution 90ml is heated to reflux after stirring and dissolving, adds in sodium borohydride, and when reaction 4 is small, the reaction was complete for thin-layer chromatography detection,
100ml water and 100ml methanol are added in, is concentrated under reduced pressure, obtains yellow liquid, adds in ethyl acetate 200ml extractions, water mutually uses acetic acid second
Ester 100ml is extracted, and is merged, and anhydrous sodium sulfate drying is evaporated under reduced pressure to 7 grams of white solid, adds in absolute ethyl alcohol 70ml, heat back
Stream dissolving when -5 DEG C of cooling crystallizations 12 are small, filters, dry, obtains white powder 5.8g, yield 66.3%.Mp 109.6~111.2
DEG C (document：108~110 DEG C).1H NMR (600MHz, CDCl3) δ：3.71 (S, 1H), 3.40~3.43 (m, 1H), 0.94
(d, J=6.6Hz, 3H), 0.90~0.93 (m, 6H), 0.67 (s, 3H).
Claims (8)
1. a kind of preparation method of 1 compound of formula, it is characterised in that comprise the following steps：Under lewis acid catalyst effect,
2 compound of formula obtains compound 1 with acetaldehyde through Mukaiyama hydroxyl alcohol condensation reactions,
Wherein R1For methyl or ethyl or tertiary butyl or benzyl, R2For trimethyl silicon substrate or triethyl group silicon substrate.
2. the preparation method of 1 compound of formula according to claim 1, it is characterised in that：The lewis acid is anhydrous trichlorine
Change aluminium, anhydrous ferric trichloride, anhydrous zinc chloride.
3. the preparation method of 1 compound of formula according to claim 2, it is characterised in that：Compound 2 and lewis acidic equivalent
Than for 1.0: 5.0~15.0.
4. the preparation method of 1 compound of formula according to claim 1, it is characterised in that：Compound 2 and the equivalent proportion of acetaldehyde are
1.0: 1.5~2.0.
5. the preparation method of 1 compound of formula according to claim 1, it is characterised in that：Setting-up point for -10 DEG C~-
40℃。
6. the preparation method of 1 compound of formula according to claim 1, it is characterised in that：Reaction dissolvent is aliphatic category hydro carbons
Solvent, aromatic hydrocarbon solvent, ether solvent.
7. 1 compound of formula is prepared into method according to claim 6, it is characterised in that：Aliphatic category solvent for just oneself
Alkane, normal heptane, hexamethylene, aromatic hydrocarbon solvent is toluene, benzene, and ether solvent is methyl tertiary butyl ether(MTBE), glycol dimethyl ether, four
Hydrogen furans, Isosorbide-5-Nitrae dioxane.
8. 1 compound of formula according to claim 1, the application in shellfish cholic acid difficult to understand is prepared.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072746A (en) * | 2019-12-26 | 2020-04-28 | 中山百灵生物技术有限公司 | Preparation method of 6- α -ethyl-7-ketocholic acid |
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| CN101203526A (en) * | 2005-05-19 | 2008-06-18 | 伊莱吉尔瑞公司 | Process for preparing 3alpha(beta)-7alpha(beta)-dihydroxy-6alpha(beta)-alkyl-5beta-cholanic acid |
| CN107936078A (en) * | 2016-10-13 | 2018-04-20 | 上海科胜药物研发有限公司 | A kind of new method for preparing shellfish cholic acid difficult to understand |
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2016
- 2016-11-08 CN CN201610978192.2A patent/CN108070014A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101203526A (en) * | 2005-05-19 | 2008-06-18 | 伊莱吉尔瑞公司 | Process for preparing 3alpha(beta)-7alpha(beta)-dihydroxy-6alpha(beta)-alkyl-5beta-cholanic acid |
| CN107936078A (en) * | 2016-10-13 | 2018-04-20 | 上海科胜药物研发有限公司 | A kind of new method for preparing shellfish cholic acid difficult to understand |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072746A (en) * | 2019-12-26 | 2020-04-28 | 中山百灵生物技术有限公司 | Preparation method of 6- α -ethyl-7-ketocholic acid |
| CN111072746B (en) * | 2019-12-26 | 2021-04-06 | 中山百灵生物技术股份有限公司 | Preparation method of 6-alpha-ethyl-7-ketocholic acid |
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Application publication date: 20180525 |