CN106749472B - A kind of -6 α of 3 Alpha-hydroxy--5 β of ethyl -7- ketone-cholane -24- acid preparation method - Google Patents
A kind of -6 α of 3 Alpha-hydroxy--5 β of ethyl -7- ketone-cholane -24- acid preparation method Download PDFInfo
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- cholane
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- 239000002253 acid Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 41
- 239000001257 hydrogen Substances 0.000 claims abstract description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000013019 agitation Methods 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000005265 energy consumption Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 8
- 239000004380 Cholic acid Substances 0.000 description 8
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 8
- 229960002471 cholic acid Drugs 0.000 description 8
- 235000019416 cholic acid Nutrition 0.000 description 8
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 8
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 235000015170 shellfish Nutrition 0.000 description 6
- 239000000284 extract Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 238000010907 mechanical stirring Methods 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- 102100038637 Cytochrome P450 7A1 Human genes 0.000 description 2
- 101000957672 Homo sapiens Cytochrome P450 7A1 Proteins 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- QSHQKIURKJITMZ-OBUPQJQESA-N 5β-cholane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCC)[C@@]2(C)CC1 QSHQKIURKJITMZ-OBUPQJQESA-N 0.000 description 1
- 102100038495 Bile acid receptor Human genes 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- -1 aliphatic alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 description 1
- 229960001601 obeticholic acid Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to technical field of medicine synthesis, are related to the preparation method of one kind 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone-cholane-24- acid.The preparation method is using 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24- acid, alcohol, alkali, water, palladium/carbon catalyst and hydrogen as reaction system, by being 1.4~1.8MPa in Hydrogen Vapor Pressure, reaction temperature is reacted under conditions of being 30~35 DEG C, obtains 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone-cholane-24- acid.By controlling Hydrogen Vapor Pressure, make to react at low temperature and be carried out towards the direction for generating 6 α type isomers, intermediate after hydrogenating double bond need not be using the pyrolytic conversion under alkaline condition, reduce the generation of side reaction, reduce the probability for generating unknown impuritie, the yield and purity for improving target product, reduce energy consumption.
Description
Technical field
The invention belongs to technical field of medicine synthesis, are related to a kind of for synthesizing the preparation of the key intermediate of shellfish cholic acid difficult to understand
Method, more particularly to the preparation method of one kind 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone-cholane-24- acid.
Background technique
(Obeticholic Acid, OCA, chemical name is-7-5 β of Alpha-hydroxy of 3-6 α of Alpha-hydroxy-ethyl-gallbladder to shellfish cholic acid difficult to understand
Alkane -24- acid) research and develop by Intercept drugmaker of the U.S. be successfully that the first original for being used to treat cholestatic liver disease is ground
Medicine.Shellfish cholic acid difficult to understand belongs to farnesoid X receptor agonist, by activating farnesoid X receptor, inhibits cytochromes 7A1 indirectly
(CYP7A1) gene expression.Since CYP7A1 is the rate-limiting enzyme of cholic acid biosynthesis, shellfish cholic acid difficult to understand can inhibit cholic acid
Synthesis, for treating primary biliary cirrhosis and non-alcohol fatty liver.
As the key intermediate for synthesizing shellfish cholic acid difficult to understand, 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone-cholane-24- acid one
It is directly the research and development focus of related pharmacy corporation.Existing patent document (such as CN 101203526A, CN 104781272A, CN
105646633A, CN 105541951A, WO 2015/183794A1, WO 2016/045480A1 etc.) disclosed in preparation method
Pass through the catalytic hydrogenation and 6 of 6 double bonds by 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24- acid of E formula and/or Z formula
Position epimer under alkaline condition pyrolytic conversion method be made.
It follows that (E/Z)-3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24- acid generates after catalytic hydrogenation
Epimer (β of 6 α/6), which generally requires the pyrolytic conversion under alkaline condition, can just obtain 6 single α type isomers, but this kind of
The energy consumption of method is higher, takes a long time, and unknown impuritie is easily adulterated in product, brings difficulty for subsequent purification process, causes
The problems such as shellfish cholic acid yield difficult to understand is low, purity difference.
Summary of the invention
For above situation, the present invention is intended to provide a kind of prepare 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone-with high selectivity
The new method of cholane -24- acid.By controlling the pressure of hydrogen, make reaction different towards 6 α types of generation are conducive under cryogenic
The direction of structure body carries out, and the intermediate after hydrogenating double bond need not be efficiently reduced using the pyrolytic conversion under alkaline condition
The generation of side reaction reduces the probability for generating unknown impuritie, improves the yield and purity of target product, reduce energy
Consumption.
Specifically, the present invention adopts the following technical scheme:
On the one hand, the present invention provides the preparation method of one kind 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone-cholane-24- acid,
It includes the following steps:
Under agitation, be added into reaction vessel 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24- acid, alcohol,
Alkali, water and palladium/carbon catalyst are passed through nitrogen after closed reaction vessel and are replaced, then be passed through hydrogen and replaced and control hydrogen
Atmospheric pressure reacts between 1.4~1.8MPa in 30~35 DEG C, until 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24-
Reaction is terminated when sour fully reacting, reaction solution is filtered, and filtrate is adjusted with acid to pH=2, and organic solvent is added and is extracted, will
Organic phase is concentrated to dryness in 30~35 DEG C, obtains 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone-cholane-24- acid.
In the above preparation method, the stirring is completed using mechanical stirring device or magnetic stirring apparatus.
In the above preparation method, the alcohol is lower aliphatic alcohols, any one in methanol, ethyl alcohol, isopropanol,
It is preferred that methanol.
In the above preparation method, the alkali is either inorganic base, is also possible to organic base；The inorganic base is selected from hydrogen
Sodium oxide molybdena, potassium hydroxide, barium hydroxide, any one in calcium hydroxide, preferably sodium hydroxide；The organic base is selected from second two
Amine, diethylamine, triethylamine, any one in pyridine, preferably triethylamine.
In the above preparation method, between -5 β of the alkali and the 3 Alpha-hydroxy -6- ethylidene -7- ketone-cholane -24- acid
Molar ratio be 1~4:1, preferably 2.5:1.
In the above preparation method, the palladium/carbon catalyst is aqueous palladium/carbon catalyst, and water content is 50%~75%
Wt, preferably 66.7%wt, the palladium load capacity in stem-based catalyst are 5%~15%wt, preferably 10%wt.
In the above preparation method, the palladium/carbon catalyst (with dry basis) and the 3 Alpha-hydroxy -6- ethylidene -
Weight ratio between -5 β of 7- ketone-cholane -24- acid is 0.02~0.2:1, preferably 0.05:1.
In the above preparation method, the acid is inorganic acid, any one in hydrochloric acid, phosphoric acid, sulfuric acid, preferably phosphorus
Acid.
In the above preparation method, the organic solvent is any one in methylene chloride, chloroform, ethyl acetate
Kind, preferably methylene chloride.
The present invention creatively has found: can influence two kinds of isomeries in product by the Hydrogen Vapor Pressure in control reaction system
The ratio of body, and not being between Hydrogen Vapor Pressure and target product (6 α type isomers) purity is simple linear relationship.Initially,
With the increase of Hydrogen Vapor Pressure, the content of 6 α type isomers is consequently increased, but when Hydrogen Vapor Pressure is more than 1.8MPa, 6 β types are different
The content of structure body starts to increase again.Therefore, the size of Hydrogen Vapor Pressure is can to obtain the determinant of individual isomer.
The present invention is made to react under cryogenic by the pressure of control hydrogen towards being conducive to generate 6 α type isomers
Direction carries out, and the intermediate after hydrogenating double bond need not effectively reduce secondary anti-using the pyrolytic conversion under alkaline condition
The generation answered reduces the probability for generating unknown impuritie, improves the yield and purity of target product, reduce energy consumption.
Detailed description of the invention
Fig. 1 is the HPLC map of the catalytic hydrogenation product prepared under the Hydrogen Vapor Pressure of 0.5~1.0MPa.
Fig. 2 is the HPLC map of the catalytic hydrogenation product prepared under the Hydrogen Vapor Pressure of 1.0~1.4MPa.
Fig. 3 is the HPLC map of the catalytic hydrogenation product prepared under the Hydrogen Vapor Pressure of 1.4~1.8MPa.
Fig. 4 is the HPLC map of the catalytic hydrogenation product prepared under the Hydrogen Vapor Pressure of 1.8~2.5MPa.
Fig. 5 is the HPLC map of the catalytic hydrogenation product prepared under the Hydrogen Vapor Pressure of > 2.5MPa.
Specific embodiment
The technical solution in the present invention is made below in conjunction with specific embodiments further elucidated above.Unless otherwise saying
Bright, reagent used in the following example, material, instrument etc. can be obtained by routine business means.
Embodiment 1: -6 α of 3 Alpha-hydroxy (β)-ethyl -7- ketone -5 is prepared under conditions of Hydrogen Vapor Pressure is 0.5~1.0MPa
β-cholane -24- acid.
Be added into tri- mouthfuls of reaction flasks of 100ml 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24- acid (5.03g,
12.07mmol) and methanol (25ml).Sodium hydroxide (1.26g, 31.5mmol) is added in water (25ml) and is made into lye, then
Lye is added in reaction flask, magnetic agitation dissolves solid all.Pd/C (0.76g, load capacity is added into reaction flask again
10%wt, water content 66.7%wt), closed rear nitrogen is replaced 3 times, then is passed through hydrogen, controls Hydrogen Vapor Pressure with hydrogen pressure reducing valve
Between 0.5~1.0MPa, reacted in 30~35 DEG C.It is monitored using TLC (solvent is ethyl acetate: petroleum ether=1:1v/v)
Reaction process, until terminating reaction when raw material point disappears.Reaction solution is filtered, the appropriate water washing of filter cake, merging filtrate, is added
The pH value of filtrate is adjusted to 2 or so by phosphoric acid, and methylene chloride extracts (50ml × 3 time), merges organic layer, dense in 35 DEG C of decompressions
It is reduced to dry, it is sour (4.04g) to obtain -6 α (β) of 3 Alpha-hydroxy of solid product--5 β of ethyl -7- ketone-cholane -24-, yield 79.96%.
HPLC testing result shows that the content of 6 α type isomers in product is 8.77%, and the content of 6 β type isomers is 91.03%, such as
Shown in Fig. 1.
Embodiment 2: -6 α of 3 Alpha-hydroxy (β)-ethyl -7- ketone -5 is prepared under conditions of Hydrogen Vapor Pressure is 1.0~1.4MPa
β-cholane -24- acid.
Be added into tri- mouthfuls of reaction flasks of 100ml 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24- acid (5.01g,
12.03mmol) and methanol (25ml).Sodium hydroxide (1.20g, 30.0mmol) is added in water (25ml) and is made into lye, then
Lye is added in reaction flask, mechanical stirring dissolves solid all.Pd/C (0.75g, load capacity is added into reaction flask again
10%wt, water content 66.7%wt), closed rear nitrogen is replaced 3 times, then is passed through hydrogen, controls Hydrogen Vapor Pressure with hydrogen pressure reducing valve
Between 1.0~1.4MPa, reacted in 30~35 DEG C.It is monitored using TLC (solvent is ethyl acetate: petroleum ether=1:1v/v)
Reaction process, until terminating reaction when raw material point disappears.Reaction solution is filtered, the appropriate water washing of filter cake, merging filtrate, is added
The pH value of filtrate is adjusted to 2 or so by phosphoric acid, and methylene chloride extracts (50ml × 3 time), merges organic phase, is concentrated under reduced pressure in 35 DEG C
To doing, -6 α (β) of 3 Alpha-hydroxy of solid product--5 β of ethyl -7- ketone-cholane -24- acid (4.05g), yield 80.42% are obtained.
HPLC testing result shows that the content of 6 α type isomers in product is 45.65%, and the content of 6 β type isomers is 52.86%, such as
Shown in Fig. 2.
Embodiment 3: -6 α of 3 Alpha-hydroxy (β)-ethyl -7- ketone -5 is prepared under conditions of Hydrogen Vapor Pressure is 1.4~1.8MPa
β-cholane -24- acid.
Be added into tri- mouthfuls of reaction flasks of 100ml 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24- acid (5.02g,
12.05mmol) and methanol (25ml).Sodium hydroxide (1.21g, 30.00mmol) is added in water (25ml) and is made into lye, then
Lye is added in reaction flask, magnetic agitation dissolves solid all.Pd/C (0.76g, load capacity is added into reaction flask again
10%wt, water content 66.7%wt), closed rear nitrogen is replaced 3 times, then is passed through hydrogen, controls Hydrogen Vapor Pressure with hydrogen pressure reducing valve
Between 1.4~1.8MPa, reacted in 30~35 DEG C.It is monitored using TLC (solvent is ethyl acetate: petroleum ether=1:1) anti-
Process is answered, until terminating reaction when raw material point disappears.Reaction solution is filtered, the appropriate water washing of filter cake, merging filtrate, phosphorus is added
The pH value of filtrate is adjusted to 2 or so by acid, and methylene chloride extracts (50ml × 3 time), is merged organic phase, is concentrated under reduced pressure into 35 DEG C
It is dry, obtain -6 α (β) of 3 Alpha-hydroxy of solid product--5 β of ethyl -7- ketone-cholane -24- acid 4.03g, yield 79.89%.HPLC inspection
Survey the result shows that, the content of 6 α type isomers is 98.02% in product, and the contents of 6 β type isomers is 1.14%, such as Fig. 3 institute
Show.
Embodiment 4: -6 α of 3 Alpha-hydroxy (β)-ethyl -7- ketone -5 is prepared under conditions of Hydrogen Vapor Pressure is 1.8~2.5MPa
β-cholane -24- acid.
Be added into tri- mouthfuls of reaction flasks of 100ml 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24- acid (5.01g,
12.03mmol) and methanol (25ml).Sodium hydroxide (1.24g, 31.00mmol) is added in water (25ml) and is made into lye, then
Lye is added in reaction flask, magnetic agitation dissolves solid all.Pd/C (0.77g, load capacity is added into reaction flask again
10%wt, water content 66.7%wt), closed rear nitrogen is replaced 3 times, then is passed through hydrogen, controls Hydrogen Vapor Pressure with hydrogen pressure reducing valve
Between 1.8~2.5MPa, reacted in 30~35 DEG C.It is monitored using TLC (solvent is ethyl acetate: petroleum ether=1:1) anti-
Process is answered, until terminating reaction when raw material point disappears.Reaction solution is filtered, the appropriate water washing of filter cake, merging filtrate, phosphorus is added
The pH value of filtrate is adjusted to 2 or so by acid, and methylene chloride extracts (50ml × 3 time), is merged organic phase, is concentrated under reduced pressure into 35 DEG C
It is dry, obtain -6 α (β) of 3 Alpha-hydroxy of solid product--5 β of ethyl -7- ketone-cholane -24- acid (4.05g), yield 80.42%.HPLC
Testing result shows that the content of 6 α type isomers in product is 51.48%, and the content of 6 β type isomers is 44.50%, such as Fig. 4
It is shown.
Embodiment 5: -6 α of 3 Alpha-hydroxy (β)--5 β of ethyl -7- ketone-gallbladder is prepared under conditions of Hydrogen Vapor Pressure is greater than 2.5MPa
Alkane -24- acid.
Be added into tri- mouthfuls of reaction flasks of 100ml 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24- acid (5.02g,
12.05mmol) and methanol (25ml).Sodium hydroxide (1.25g, 31.25mmol) is added in water (25ml) and is made into lye, then
Lye is added in reaction flask, mechanical stirring dissolves solid all.Pd/C (0.76g, load capacity is added into reaction flask again
10%wt, water content 66.7%wt), closed rear nitrogen is replaced 3 times, then is passed through hydrogen, controls Hydrogen Vapor Pressure with hydrogen pressure reducing valve
In 2.5MPa or more, reacted in 30~35 DEG C.Using TLC (solvent is ethyl acetate: petroleum ether=1:1) monitoring react into
Journey, until terminating reaction when raw material point disappears.Reaction solution is filtered, the appropriate water washing of filter cake, merging filtrate, phosphoric acid is added will
The pH value of filtrate is adjusted to 2 or so, and methylene chloride extracts (50ml × 3 time), merges organic phase, is concentrated to dryness in 35 DEG C,
It is sour (4.07g) to obtain -6 α (β) of 3 Alpha-hydroxy of solid product--5 β of ethyl -7- ketone-cholane -24-, yield 80.69%.HPLC detection
The result shows that the content of 6 α type isomers is 2.92% in product, the content of 6 β type isomers is 96.81%, as shown in Figure 5.
Claims (8)
1. the preparation method of one kind 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone-cholane-24- acid, it is characterised in that:
The Hydrogen Vapor Pressure in reaction system is controlled between 1.4~1.8MPa；
The preparation method includes the following steps: under agitation, and 3 Alpha-hydroxy -6- ethylidene -7- are added into reaction vessel
- 5 β of ketone-cholane -24- acid, alcohol, alkali, water and palladium/carbon catalyst is passed through nitrogen after closed reaction vessel and is replaced, then be passed through
Hydrogen is replaced and controls Hydrogen Vapor Pressure between 1.4~1.8MPa, is reacted in 30~35 DEG C, until 3 Asia Alpha-hydroxy -6- second
Reaction is terminated when -5 β of base -7- ketone-cholane -24- acid fully reacting, reaction solution is filtered, and filtrate is adjusted with acid to pH=2, is added
Organic solvent is extracted, and organic phase is concentrated to dryness in 30~35 DEG C, obtains 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone-
Cholane -24- acid.
2. preparation method according to claim 1, it is characterised in that:
Any one of the alcohol in methanol, ethyl alcohol, isopropanol.
3. preparation method according to claim 1, it is characterised in that:
The alkali is in sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, ethylenediamine, diethylamine, triethylamine, pyridine
Any one.
4. preparation method according to claim 1, it is characterised in that:
Molar ratio between -5 β of the alkali and the 3 Alpha-hydroxy -6- ethylidene -7- ketone-cholane -24- acid is 1~4:1.
5. preparation method according to claim 1, it is characterised in that:
The palladium/carbon catalyst is aqueous palladium/carbon catalyst, and water content is 50%~75%wt, and the palladium in stem-based catalyst is negative
Carrying capacity is 5%~15%wt.
6. preparation method according to claim 1, it is characterised in that:
With the palladium/carbon catalyst of dry basis and the 3 Alpha-hydroxy -6- ethylidene -7- ketone -5 β-cholane -24- acid
Between weight ratio be 0.02~0.2:1.
7. preparation method according to claim 1, it is characterised in that:
Any one of the acid in hydrochloric acid, phosphoric acid, sulfuric acid.
8. preparation method according to claim 1, it is characterised in that:
Any one of the organic solvent in methylene chloride, chloroform, ethyl acetate.
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| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, use and solid form of obeticholic acid |
| CN105669811A (en) * | 2014-11-17 | 2016-06-15 | 正大天晴药业集团股份有限公司 | Novel 7-keto-6β-alkylcholanic acid derivatives in the preparation of obeticholic acid and its use in the field of medicine |
| WO2016173524A1 (en) * | 2015-04-29 | 2016-11-03 | 正大天晴药业集团股份有限公司 | Chenodeoxycholic acid derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, use and solid form of obeticholic acid |
| CN105669811A (en) * | 2014-11-17 | 2016-06-15 | 正大天晴药业集团股份有限公司 | Novel 7-keto-6β-alkylcholanic acid derivatives in the preparation of obeticholic acid and its use in the field of medicine |
| CN104558086A (en) * | 2014-12-25 | 2015-04-29 | 康美（北京）药物研究院有限公司 | Preparation method for 5 beta-3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-cholanic acid |
| WO2016173524A1 (en) * | 2015-04-29 | 2016-11-03 | 正大天晴药业集团股份有限公司 | Chenodeoxycholic acid derivative |
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