CN106046095B - Synthetic method of 6-ethylchenodeoxycholic acid - Google Patents
Synthetic method of 6-ethylchenodeoxycholic acid Download PDFInfo
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- CN106046095B CN106046095B CN201610394654.6A CN201610394654A CN106046095B CN 106046095 B CN106046095 B CN 106046095B CN 201610394654 A CN201610394654 A CN 201610394654A CN 106046095 B CN106046095 B CN 106046095B
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 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 title abstract description 7
- 229960001601 obeticholic acid Drugs 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000007800 oxidant agent Substances 0.000 claims abstract description 12
- 230000001590 oxidative effect Effects 0.000 claims abstract description 12
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960001091 chenodeoxycholic acid Drugs 0.000 claims abstract description 10
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic 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)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 claims abstract description 10
- 238000005886 esterification reaction Methods 0.000 claims abstract description 10
- 238000007337 electrophilic addition reaction Methods 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
- 230000007062 hydrolysis Effects 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 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 claims description 16
- 239000004380 Cholic acid Substances 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 16
- 229960002471 cholic acid Drugs 0.000 claims description 16
- 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 claims description 16
- 235000019416 cholic acid Nutrition 0.000 claims description 16
- 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 claims description 16
- 235000015170 shellfish Nutrition 0.000 claims description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
- 238000006722 reduction reaction Methods 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 238000007254 oxidation reaction Methods 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000032050 esterification Effects 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 239000001119 stannous chloride Substances 0.000 claims description 3
- 235000011150 stannous chloride Nutrition 0.000 claims description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims 1
- 229910000423 chromium oxide Inorganic materials 0.000 claims 1
- 238000003682 fluorination reaction Methods 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 9
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000002841 Lewis acid Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 150000007517 lewis acids Chemical class 0.000 description 6
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000035126 Facies Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102100038637 Cytochrome P450 7A1 Human genes 0.000 description 2
- 208000004930 Fatty Liver Diseases 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 206010019708 Hepatic steatosis Diseases 0.000 description 2
- 101000957672 Homo sapiens Cytochrome P450 7A1 Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 208000010706 fatty liver disease Diseases 0.000 description 2
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 description 1
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary 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
- 206010061998 Hepatic lesion Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 description 1
- GCSVCUMDOQKEMT-UHFFFAOYSA-N butan-1-amine;hydrofluoride Chemical compound [H+].[F-].CCCCN GCSVCUMDOQKEMT-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- -1 ethanol Chemical compound 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 1
- 229940043259 farnesol Drugs 0.000 description 1
- 229930002886 farnesol Natural products 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 239000011388 polymer cement concrete Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride 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)
- Steroid Compounds (AREA)
Abstract
The invention discloses a synthetic method of 6-ethylchenodeoxycholic acid. The synthetic method comprises steps as follows: chenodeoxycholic acid and an oxidizing agent are subjected to an oxidizing reaction and an esterification reaction, and a compound with a structure represented as a formula III is prepared; hydroxyl and carbonyl on rings of the compound with the structure represented as the formula III are protected with tert-butyldimethylsilyl chloride, and a compound with a structure represented as a formula IV is obtained; the compound with the structure represented as the formula IV and paraldehydeare are subjected to an electrophilic addition reaction and then are subjected to deprotection, and a compound with a structure represented as a formula V is obtained; the compound with the structure represented as the formula V is subjected to catalytic hydrogenation and is subjected to reduction and hydrolysis finally, and the compound 6-ethylchenodeoxycholic acid with a structure represented as a formula VI is obtained. The method is simple and convenient to operate, adopts mild conditions, has higher yield and is suitable for being popularized to industrial production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field and in particular to a kind of Austria shellfish cholic acid (6- ethyl chenodeoxycholic acid) synthesis work
Skill.
Background technology
Liver cirrhosis is clinical common chronic progressive external hepatopathy, is that for a long time or repeated action is formed one or more cause of disease
Diffusivity hepatic lesion.Non-alcohol fatty liver is the new challenge in contemporary medical science field, non-alcoholic fatty liver at no distant date
Disease will be continuously increased to the harm of human health.Shellfish cholic acid difficult to understand belongs to farnesoid X receptor agonist, is subject to by activating farnesol X
Body, the gene expression of suppression cytochrome 7A1 (CYP7A1) indirectly.Because CYP7A1 is the biosynthetic rate-limiting enzyme of cholic acid, because
This shellfish cholic acid difficult to understand can promote cholic acid to synthesize, for treating primary biliary cirrhosiss and non-alcohol fatty liver.
At present, shellfish cholic acid difficult to understand is still in clinical trial, fail large scale investment production application it is known that method in use
The highly basic such as LDA prepare intermediate, this kind of method expensive starting materials and the strict anhydrous and oxygen-free low temperature environment of needs;Make in subsequent step
With this nucleopilic reagent of acetaldehyde, low boiling point, easily it is polymerized, complex operation, is unfavorable for industrialized production.
Content of the invention
The invention aims to solution severe reaction conditions, yield is not high, the problems such as synthetic route is immature, provides
A kind of synthetic method of Austria shellfish cholic acid, this method is easy and simple to handle, mild condition, and yield is higher, is suitable for extending to industrial metaplasia
Produce.
The purpose of the present invention can be reached by following measures:
A kind of synthetic method of Austria shellfish cholic acid, it comprises the steps:
(1) chenodeoxycholic acid and oxidant carry out oxidation reaction and obtain compound (II), then carry out esterification formula
III compound 3 α-carboxyl -7 ketone -5 β cholestane -24- acid methyl ester;
(2) with tert-butyl chloro-silicane, protection is carried out to the hydroxyl on formula III compound ring and carbonyl and obtain formula IV
Compound;
(3) formula IV compound and paraldehydum carry out electrophilic addition reaction, then obtain after deprotection Formula V compound 3 α-
Hydroxyl -6- ethylidene -7- ketone -5 β-cholanic acid -24- methyl ester;
(4) Formula V compound carries out catalytic hydrogenation, finally carries out reduction and hydrolysis obtain Formula IV compound Austria shellfish gallbladder
Acid;
Hereinafter each step of the present invention is elaborated.
Step (1), chenodeoxycholic acid and oxidant carry out oxidation reaction and obtain compound (II), then carry out esterification system
Standby formula III compound 3 α-carboxyl -7 ketone -5 β cholestane -24- acid methyl ester;
In the oxidation reaction, how optionally to aoxidize the hydroxyl on 7 allows the hydroxyl of 3 not react being simultaneously
Relatively more crucial problem in compound (II) synthesis, therefore in oxidation reaction from specific oxidant, be chosen in particular from NBS,
One or more of PCC, chromic acid, experiment finds permissible when being oxidant using NBS (N-bromosuccinimide)
Reach optimal oxidation effectiveness.
The temperature of this oxidation reaction is 20~30 DEG C, and the solvent of oxidation reaction is acetone water mixed solvent.
Esterification compound of formula H and methanol carry out esterification, add sulphuric acid, reaction temperature 55~65 in reaction
℃.Make the alcohol in esterification using methanol in experimental verification, this reaction, compare compared with other alcohol, such as ethanol, more readily soluble
Solution, in addition methanol boiling point is also lower, is easier to remove during post processing.
In the reaction, chenodeoxycholic acid and the mol ratio of oxidant are 1:1~2, preferably 1:1.5.
Step (2), carries out protection with tert-butyl chloro-silicane to the hydroxyl on formula III compound ring and carbonyl and obtains
Formula IV compound;
In the reaction that hydroxyl and carbonyl are protected, using tert-butyl chloro-silicane, it reacts bar to the present invention
Part is gentle, and yield is high, sloughs simplicity.But tert-butyl chloro-silicane is met water and can be generated hydrogen chloride, therefore will ensure to react
The drying of container when carrying out, in addition this blocking group excessively easily slough, if therefore reaction condition control not good; could be serious
Impact yield.
Using lithium diisopropylamine (LDA) typically can be used during tert-butyl chloro-silicane as pulling out hydrogen, form carbon
The alkali of anion, but during using LDA, must assure that anhydrous and oxygen-free environment, and must carry out at -78 DEG C to ensure the peace reacted
Entirely carry out, operating difficultiess, high cost.The method using being added without LDA for the present invention, is controlled so that in room by suitable condition
React under the conditions of temperature and also obtained the higher compound of yield (IV).
In the reaction of this step, formula III compound and tert-butyl chloro-silicane and imidazoles are in the effect of acid binding agent
Under reacted, reaction temperature be 20~30 DEG C, reaction dissolvent be oxolane.Described acid binding agent can using pyridine, triethylamine,
Triethanolamine, N, accelerine, N,N-dimethylformamide etc.;But it was found that, suitable acid binding agent and its use
Amount is also to improve the key factor of reaction yield;The present invention through experimental verification when using triethylamine as acid binding agent and
The mole of acid binding agent is 1.6~2.5 with the amount ratio with compound III:When 1, or more preferably adopt 2:When 1, Ke Yida
To optimal reaction effect.
In the reaction, formula III compound and the mol ratio of tert-butyl chloro-silicane are 1:1.5~3.5, preferably 1:
2~3, most preferably 1:2.2.
Step (3), formula IV compound and paraldehydum carry out electrophilic addition reaction, then obtain Formula V chemical combination after deprotection
Thing 3 Alpha-hydroxy -6- ethylidene -7- ketone -5 β-cholanic acid -24- methyl ester,
Formula IV compound carries out electrophilic addition reaction, after reaction with paraldehydum and boron trifluoride diethyl etherate at -35~0 DEG C
Add tetrabutyl ammonium fluoride to carry out deprotection reaction at 0~30 DEG C, obtain Formula V compound.
In electrophilic addition reaction, it is used paraldehydum to add reaction as aldehyde precursors, paraldehydum is stable, and it is strong
Under acid condition, depolymerization is acetaldehyde, and in this reaction, boron trifluoride diethyl etherate is strong Lewis acid, can make to generate acetaldehyde in reaction, from
And avoid acetaldehyde and preserve difficult, the not high problem of purity.The synthesis of compound (V) is key one step preparing shellfish cholic acid difficult to understand,
The carbon of the positively charged on 6 carbanion attack acetaldehyde, allows the oxygen on acetaldehyde remove the group of attack positively charged in reaction, thus de-
Remove a molecular water, generate double bond, so needing Lewis acid to participate in reaction provide positive charged group.Therefore select suitable Lewis acid
Particularly significant to the yield improving compound (V).
Lewis acid used in this reaction is selected from aluminum chloride, iron chloride or boron trifluoride diethyl etherate, but experiment finds,
When Lewis acid is done using boron trifluoride diethyl etherate, higher yield can be obtained.Based on the characteristic of boron trifluoride diethyl etherate, concrete
It is ensured that carrying out in anhydrous condition during use.
The solvent of this electrophilic addition reaction can be selected for dichloromethane.
In this step, formula IV compound and the mol ratio of paraldehydum, boron trifluoride diethyl etherate and tetrabutyl ammonium fluoride are
1:4~6:3~5:0.5~2.
Step (4), Formula V compound carries out catalytic hydrogenation, finally carries out reduction and hydrolysis obtain Formula IV compound Austria
Shellfish cholic acid,
Formula V compound carries out hydrogenation reaction under palladium carbon catalysis, and reaction temperature is 20~30 DEG C, and reaction dissolvent can be selected for ice
Acetic acid;Carry out reduction reaction in 20~30 DEG C in the presence of reducing agent after hydrogenation reaction, be eventually adding sodium hydroxide in 90~
Be hydrolyzed at 110 DEG C reaction, obtains shellfish cholic acid difficult to understand.
Formula V compound, after the step completing catalytic hydrogenation, needs 7 carbonyls optionally to be reduced, therefore
Select suitable go back original reagent very crucial, reducing agent can be real using sodium borohydride, potassium borohydride, stannous chloride or lithium aluminium hydride reduction
Issue after examination and approval existing, higher reduction effect can be reached when reducing agent is using sodium borohydride.Formula V compound and the mol ratio of reducing agent
For 1:5~8, experiment finds that when mol ratio be 1:Optimal yield can be reached when 6.
, with chenodeoxycholic acid as raw material, oxidized, esterification, electrophilic addition, catalytic hydrogenation, reductive hydrolysis 5 step are anti-for the present invention
6- ethyl chenodeoxycholic acid (shellfish cholic acid difficult to understand) should be obtained, total recovery reaches 40%.Its structure warp1HNMR, MS analysis and testing technology is true
Recognize.The method has following characteristics:
(1) dangerous substances such as LDA are not used, reaction condition is gentle, improves the low temperature environment in document, and in addition to hydrogenation
All can carry out at ambient pressure, easy and simple to handle, equipment requirements are low, suitable laboratory is prepared and industrialized production;
(2) use paraldehydum as aldehyde precursors, solve the problem that acetaldehyde purity is not high, is difficult to preserve;
(3) often step product isolate and purify easier, single step yield is all higher with gross production rate;
(4) reaction needed raw material all can be by industrialized production, cheap easy acquisition.
Specific embodiment
With reference to embodiments the present invention is described further, but protection scope of the present invention be not limited to following each
Embodiment.
Reagent and instrument
Chenodeoxycholic acid (98%, Hubei Yuancheng Saichuang Technology Co., Ltd.);Tert-butyl chloro-silicane, imidazoles, four
Butyl ammonium fluoride, paraldehydum (GC, Shanghai Aladdin biochemical technology limited company);N-bromosuccinimide, tetrahydrochysene
Furan, triethylamine (AR, Chengdu Ke Long chemical reagent factory);Boron trifluoride diethyl etherate (CP, Chengdu Ke Long chemical reagent factory);Boron
Sodium hydride, sulphuric acid, hydrochloric acid, 10% (mass fraction) palladium carbon, remaining reagent is AR.
X-5 micro melting point apparatus (temperature control type) (Nanjing Jia Meilun scientific instrument company limited), not calibrated.Bruker
Avance III (500MHz) nuclear magnetic resonance chemical analyser (German Burker company);Finnigan TSQ Quantum ultra AM
Mass spectrograph (Finnigan company of the U.S.).
Embodiment 1, the synthesis of 13 Alpha-hydroxy -7- ketone -5 β-cholanic acid -24- methyl ester (III)
Take 2g (5.1mmol) chenodeoxycholic acid (I), 1.3g (7.3mmol) N-bromosuccinimide is justified in 100mL single port
In the flask of bottom, add 48mL acetone-water (3:1, volume ratio), stirring reaction 4h under room temperature, finish through TLC detection reaction.To burning
Add 10mL 20% (mass fraction) sodium sulfite in bottle, be evaporated acetone, then use 5mL hydrochloric acid solution (5%) to be acidified, treat
Solid filters after separating out, and filtering residue is washed to neutrality, is dried, with re-dry after dehydrated alcohol recrystallization, obtains white solid 1.84g.
Take gained white solid in 150mL single necked round bottom flask, add 60mL methanol, be heated to 60 DEG C, Deca 1mL
98% concentrated sulphuric acid, return stirring reacts 12h, finishes through TLC detection reaction, adds 2g sodium bicarbonate, after bubble-free generates, mistake
Filter excess bicarbonate, filtrate revolving is removed most of methanol, remaining liq is extracted with ethyl acetate, and is evaporated acetic acid second
Ester, obtains white solid 1.66g and is compound (III), yield 91%.1H NMR(CDCl3,500MHz)δ:0.65 (3H, s,
18-CH3), 0.80 (3H, s, 19-CH3), 0.95 (3H, s, 21-CH3), 3.57 (1H, m, 3-CH) 3.65 (3H, s ,-CO2CH3).
In the oxidation reaction of this example, be respectively adopted NBS, PCC, chromic acid, DMSO/ oxalyl chloride, potassium permanganate be oxygen
Agent, the consumption of oxidant is 1.5 times of the amount of compound (I) material, and other conditions are identical with this example, investigates different oxidations
The impact to product for the agent, the results are shown in Table 1.
Table 1
Embodiment 2,3 α, the synthesis of 7- bis- (tert-butyl group dimethylsilyloxy) -6- alkene -5 β-cholanic acid -24- methyl ester (IV)
Take 5g (12.4mmol) compound (III) in 150mL single necked round bottom flask, add the oxolane that 25mL is dried
And dissolve, take 4.1g (27.3mmol) tert-butyl chloro-silicane and 2g (29.8mmol) imidazoles to be added slowly to be stirred continuously
Solution in, take 10mL triethylamine to be slowly added into this solution after 0.5h, under room temperature after all adding stir 4h, through TLC detection
Reaction finishes.Add 25mL saturated solution of sodium bicarbonate in solution, be back to after room temperature after solution temperature, be extracted with ethyl acetate
Organic faciess, after saturated brine washing, anhydrous sodium sulfate drying, revolving obtains brown oil solid 6.63g and is compound (IV),
Yield 84%.1H NMR(CDCl3,500MHz)δ:0~0.2 (12H, m, 3,7-OSi (t-Bu) Me2), 0.66 (3H, s, 18-
CH3), 0.70 (3H, s, 19-CH3), 0.92 (3H, s, 21-CH3), 3.50 (1H, m, 3-CH) 3.68 (3H, s ,-CO2CH3),4.70
(1H, dd, 6-CH).
In this example reaction, it is respectively adopted pyridine, triethylamine, DMA, triethanolamine, N, N- dimethyl methyl
Amide is acid binding agent, and the consumption of acid binding agent is 2 times of the amount of compound (III) material, and other conditions are identical with this example reaction,
Investigate the different impacts to product for the acid binding agent, the results are shown in Table 2.
Table 2
In this example reaction, the mole dosage ratio of adjustment triethylamine and formula III compound, other conditions are reacted with this example
Identical, it is shown in Table 3 to the impact producing.
Table 3
In this example reaction, the mole dosage ratio of adjustment tert-butyl chloro-silicane and formula III compound, other
Part is identical with this example reaction, and it is shown in Table 4 to the impact producing.
Table 4
Embodiment 3, the synthesis of 3 Alpha-hydroxy -6- ethylidene -7- ketone -5 β-cholanic acid -24- methyl ester (V)
Take 12.7g (23.2mmol) compound (IV) and dichloromethane (20mL) in 150mL single necked round bottom flask, cooling
To -30 DEG C, add 1.7mL (0.121mol) paraldehydum to be stirred continuously, in stirring, be slowly added dropwise 2.2mL (0.09mol) trifluoro
Change borate ether, after stirring lower reaction 1h, 0 DEG C can be warming up to.Then add dichloromethane 20mL in solution, be stirred overnight, warp
TLC detection reaction finishes, and adds 6.5g (25mmol) tetrabutyl ammonium fluoride in solution, adds 50mL after stirring 1h in solution
Stand after saturated solution of sodium bicarbonate, extract organic faciess with dichloromethane, saturated brine washs, anhydrous sodium sulfate drying, decompression
Distillation, with rapid column chromatography (petroleum ether:Ethyl acetate=7:3, v/v) separately obtaining white solid 6.7g is compound
(V), yield 67%.1H NMR(CDCl3,500MHz)δ:0.64 (3H, s, 18-CH3), 0.91 (3H, s, 19-CH3), 0.99
(3H, s, 21-CH3), 1.71 (3H, d, 2 '-CH3), 2.77 (1H, dd, 8-CH), 3.65 (3H, s ,-CO2CH3) 6.21 (1H, dd,
1’-CH).
In this example, it is respectively adopted aluminum chloride, iron chloride, zinc chloride and boron trifluoride diethyl etherate as Lewis acid, its consumption
It is 4 times of formula IV compound mole, other conditions keep constant, test its impact to compound V yield, the results are shown in Table
5.
Table 5
Embodiment 4, the synthesis of 6- ethyl chenodeoxycholic acid (VI)
Take 3.0g (6.97mmol) compound (V) in 500mL autoclave, throw after adding the dissolving of 150mL glacial acetic acid
Enter 0.5g palladium carbon, after extracting the air in container out, be passed through hydrogen exchange 2 times, more logical hydrogen is to 2atm, stirring is lower to react 12h.Instead
Palladium carbon should be filtered to remove after stopping, solution is concentrated, mixed liquor is dissolved in water and the mixture of ethyl acetate, uses unsaturated carbonate
Hydrogen sodium solution washs, and aqueous phase is extracted with ethyl acetate, saturated brine washing after two organic faciess mixing, and anhydrous sodium sulfate drying subtracts
Pressure distillation.
Product is dissolved in 50mL methanol, adds 1.5g sodium borohydride, under room temperature, stir 2h, add acetic acid stopped reaction,
After ethyl acetate extraction product, washing, it is dried, vacuum distillation concentrates, rapid column chromatography (petroleum ether:Ethyl acetate=1:1, v/
V) separate and obtain viscous brown shape solid 2.53g.
Products therefrom is dissolved in 20mL methanol, adds 0.5g sodium hydroxide and 5mL water, be stirred at reflux reaction 5h, will be molten
After liquid concentrates, it is slowly added into 5% hydrochloric acid acidifying, filter after solid separates out, filter cake is washed with water to neutrality, after being dried, use second
Acetoacetic ester recrystallization, obtains white solid 2.45g, yield 83%.M.p.108~110 DEG C;1H NMR(CDCl3,500MHz)δ:
0.56 (3H, s, 18-CH3), 0.72 (3H, t, 6-CH2CH3), 2.20 (2H, m, 23-CH2), 3.11 (1H, m, 7-CH) 3.44
(1H, m, 3-CH).MS,m/z:420.6.
Reduction reaction is respectively adopted the sodium borohydride of 6 times of Formula V compound moles, potassium borohydride, lithium aluminium hydride reduction and
Stannous chloride is reducing agent, and other conditions are prepared the reaction of Formula IV compound using the same method of this example, divide to Formula IV
The yield of compound is as shown in table 6.
Table 6
Sodium borohydride is adopted to be reducing agent in reduction reaction, the mol ratio of adjustment sodium borohydride and Formula V compound respectively,
Other conditions are prepared the reaction of Formula IV compound using the same method of this example, divide the yield such as table 7 to Formula IV compound
Shown.
Table 7
Claims (12)
1. a kind of synthetic method of Austria shellfish cholic acid is it is characterised in that it comprises the steps:
(1) chenodeoxycholic acid and oxidant carry out oxidation reaction and obtain compound (II), then carry out esterification and prepare formula III
Compound 3 α-carboxyl -7 ketone -5 β cholestane -24- acid methyl ester;
(2) formula III compound and tert-butyl chloro-silicane and imidazoles in the presence of acid binding agent triethylamine to formula III chemical combination
Hydroxyl on thing ring and carbonyl carry out protection and obtain formula IV compound;
(3) formula IV compound and paraldehydum carry out electrophilic addition reaction, then obtain after deprotection Formula V compound 3 Alpha-hydroxy-
6- ethylidene -7- ketone -5 β-cholanic acid -24- methyl ester;
(4) Formula V compound carries out catalytic hydrogenation, finally carries out reduction and hydrolysis obtain Formula IV compound Austria shellfish cholic acid;
2. method according to claim 1 is it is characterised in that in step (1), described oxidant be selected from NBS, PCC, three
One or more of chromium oxide;The temperature of oxidation reaction is 20~30 DEG C.
3. method according to claim 2 is it is characterised in that in step (1), described oxidant is selected from NBS.
4. method according to claim 1 is it is characterised in that in step (1), chenodeoxycholic acid and oxidant mole
Than for 1:1~2.
5. method according to claim 4 is it is characterised in that in step (1), chenodeoxycholic acid and oxidant mole
Than for 1:1.5.
6. method according to claim 1 is it is characterised in that in step (1), esterification compound of formula H and first
Alcohol carries out esterification, adds sulphuric acid in reaction, and reaction temperature is 55~65 DEG C.
7. method according to claim 1 is it is characterised in that in step (2), acid binding agent and compound III mole with
Amount ratio is 1.6~2.5:1;Formula III compound is 1 with the mol ratio of tert-butyl chloro-silicane:1.5~3.5.
8. method according to claim 7 is it is characterised in that in step (2), acid binding agent and compound III mole with
Amount ratio is 2:1;Formula III compound is 1 with the mol ratio of tert-butyl chloro-silicane:2~3.
9. method according to claim 1 is it is characterised in that in step (3), formula IV compound and paraldehydum and three
Fluorination borate ether carries out electrophilic addition reaction at -35~0 DEG C, adds tetrabutyl ammonium fluoride to carry out at 0~30 DEG C after reaction
Deprotection reaction, obtains Formula V compound.
10. method according to claim 1 is it is characterised in that in step (4), Formula V compound enters under palladium carbon catalysis
Row hydrogenation reaction, carries out reduction reaction after hydrogenation reaction in the presence of reducing agent, is eventually adding sodium hydroxide and is hydrolyzed instead
Should, obtain shellfish cholic acid difficult to understand.
11. methods according to claim 10 are it is characterised in that in step (4), hydrogenation reaction temperature is 20~30 DEG C;
Reducing agent is selected from sodium borohydride, potassium borohydride, stannous chloride or lithium aluminium hydride reduction, and reduction reaction temperature is 20~30 DEG C, Formula V chemical combination
Thing is 1 with the mol ratio of reducing agent:5~8;Hydrolysising reacting temperature is 90~110 DEG C.
12. methods according to claim 11 are it is characterised in that in step (4), hydrogenation reaction temperature is 20~30 DEG C;
Reducing agent is selected from sodium borohydride, and Formula V compound is 1 with the mol ratio of reducing agent:6.
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