CN112898369A - Process for the preparation of obeticholic acid - Google Patents
Process for the preparation of obeticholic acid Download PDFInfo
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- CN112898369A CN112898369A CN201911225181.7A CN201911225181A CN112898369A CN 112898369 A CN112898369 A CN 112898369A CN 201911225181 A CN201911225181 A CN 201911225181A CN 112898369 A CN112898369 A CN 112898369A
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 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 22
- 229960001601 obeticholic acid Drugs 0.000 title abstract description 21
- 238000002360 preparation method Methods 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 78
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 238000006722 reduction reaction Methods 0.000 claims description 13
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 11
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical group CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 9
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 230000009466 transformation Effects 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- 238000007171 acid catalysis Methods 0.000 claims description 5
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical group [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 5
- 150000008282 halocarbons Chemical class 0.000 claims description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 238000005580 one pot reaction Methods 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims description 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 4
- 238000006114 decarboxylation reaction Methods 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- KVBCYCWRDBDGBG-UHFFFAOYSA-N azane;dihydrofluoride Chemical class [NH4+].F.[F-] KVBCYCWRDBDGBG-UHFFFAOYSA-N 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 239000000852 hydrogen donor Substances 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000012467 final product Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- 239000008213 purified water Substances 0.000 description 16
- 229910001868 water Inorganic materials 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- 230000035484 reaction time Effects 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- -1 p-methylbenzyl Chemical group 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 5
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 5
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 5
- 238000002386 leaching Methods 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N Butanol Natural products CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 229910001867 inorganic solvent Inorganic materials 0.000 description 4
- 239000003049 inorganic solvent Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 4
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000005815 base catalysis Methods 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 150000003138 primary alcohols Chemical class 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BXWLVQXAFBWKSR-UHFFFAOYSA-N 2-methoxy-5-methylsulfonylbenzoic acid Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(O)=O BXWLVQXAFBWKSR-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 238000011217 control strategy Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 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
- 239000000945 filler Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940055679 ocaliva Drugs 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- VTORJPDWMOIOIQ-UHFFFAOYSA-N tert-butyl(diphenyl)silane Chemical compound C=1C=CC=CC=1[SiH](C(C)(C)C)C1=CC=CC=C1 VTORJPDWMOIOIQ-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical class [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a process for the preparation of obeticholic acid; specifically, the compound shown in the formula (1) is prepared by adopting a brand-new intermediate and route, the method is simple to operate, the purity of the prepared final product is high, the impurity types and the total amount of impurities are obviously reduced, and the registration quality requirements of medicines and the clinical medication safety can be met.
Description
The technical field is as follows:
the invention relates to the field of drug synthesis, in particular to a method for preparing obeticholic acid, and particularly relates to a method for synthesizing obeticholic acid (6-ethyl chenodeoxycholic acid).
Background art:
obeticholic Acid (product name Ocaliva) is a new generation of Primary Biliary Cirrhosis (PBC) treatment drug developed by Intercept pharmaceutical, Inc., which was approved by FDA in the United states and marketed earlier than 27.5.2016 and approved by the European Union at 12.12.2016, and is a globalized drug for treating Primary Biliary Cirrhosis (PBC), which was the first drug approved for PBC treatment in the last 20 years.
Recently, Intercept Pharmaceuticals announced that Obeticholic acid (OCA) has been filed by the U.S. food and drug administration as a New Drug Application (NDA) for the treatment of fibrosis caused by non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) is the only investigational therapy currently used for the treatment of NASH patients that meets the primary endpoint of the phase 3 clinical study, and is the only FDA-specified breakthrough therapy currently used for the treatment of NASH fibrosis.
The structural formula of obeticholic acid is shown as a formula (1):
most of the existing synthetic routes use 3 alpha-hydroxy-6-ethylidene-7-ketone-5 beta-cholic acid represented by a formula (II) as a raw material to synthesize obeticholic acid. The compound represented by the formula (II) can be commercially produced at present, is provided by a plurality of suppliers, has relatively sufficient research on related substances, and fully meets various conditions as a starting material for synthesizing obeticholic acid.
WO02/072598 and WO 2013/192097 disclose methods for obtaining obeticholic acid by palladium on carbon catalytic reduction of a compound represented by formula (ii), followed by conformational transformation, and finally reduction with sodium borohydride as follows:
reaction conditions and reagents:
(a)H2SO4,MeOH,50～55℃,3h,90％；
(b) LDA, TMSCl, THF, and silica gel column chromatography at-60-65 deg.C for 5 h;
(c)BF3.MeCN,CH3CHO, DCM, 60 ℃ below zero to 65 ℃ below zero for 2.5h, and then heating to 5 ℃ below zero to 10 ℃ below zero for 2 h;
(d)NaOH,H2o, EtOH, 20-25 ℃ for 1H, using EtOH and H2Recrystallizing twice with O, the yield is 52%;
(e)10wt％Pd/C,H2,NaOH,H2o, 20-25 ℃ for 10H, then heating to 95-100 ℃ for 2H, and using EtOH and H2Recrystallizing twice with O, the yield is 79%;
(f)NaBH4and recrystallizing NaOH, H2O for 6 hours at 70-75 ℃ by using n-butyl alcohol ethyl ester twice.
This method oxidizes about 10% of the functional groups to carbonyl groups (Impurity III) via high temperature 3 alpha-OH in the presence of palladium on carbon, while intermediate dimeric impurities (Impurity IV) are readily formed under Acid catalysis during the intermediate work-up (see Weidong Feng et al (Process Research and Impurity Control Strategy for Objective Acid, a Farnesoid X Receptor Agonist)). This not only affects the yield of the reaction, but also greatly reduces the product quality. Meanwhile, the route needs to carry out configuration conversion in a sodium hydroxide aqueous solution at high temperature, so that the energy consumption is high, and the quality of the raw material medicines is not favorably controlled.
The invention content is as follows:
based on the concept of 'quality source design', the invention provides a novel preparation method of obeticholic acid.
Specifically, the invention provides a preparation method of a compound shown as a formula I, which comprises the following steps:
(1) removing the hydroxyl protecting group R from the compound represented by the formula (7)2And converted to a compound of formula (I):
wherein R is2Is a silane protecting group; preferably, R2TMS, TES, TBDMS, TIPS or TBDPS.
Further, the invention also provides a preparation method of the compound shown in the formula (7), wherein the compound shown in the formula (7) is prepared from the compound shown in the formula (6) through a reduction reaction:
wherein R is2Is a silane protecting group; preferably, R2TMS, TES, TBDMS, TIPS or TBDPS.
Further, the invention also provides a preparation method of the compound shown in the formula (6), wherein the compound shown in the formula (6) is prepared by converting the configuration of the compound shown in the formula (5):
wherein R is2Is a silane protecting group; preferably, R2TMS, TES, TBDMS, TIPS or TBDP.
Further, the present invention provides a method for producing a compound represented by formula (5), wherein the compound represented by formula (5) is obtained by converting a compound represented by formula (3):
wherein R is2Is a silane protecting group, R1Is H, C1-C20Alkyl, benzyl substituted by one or more substituents, allyl, wherein the substituent is C1～C6Straight or branched alkyl, C1～C6Alkoxy, or halogen; such as p-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl, 2-methyl-3-chlorophenylmethyl;
preferably, R2TMS, TES, TBDMS, TIPS or TBDP;
provided that when R is1When the compound is H, the compound shown in the formula (5) is directly obtained from the compound shown in the formula (3) through reduction reaction to obtain the compound shown in the formula (5);
when R is1When not H, i.e. when R1Is C1-C20Alkyl, benzyl substituted by one or more substituents, allyl, wherein the substituents areThe substituent is C1～C6Straight or branched alkyl, C1～C6Alkoxy, or halogen, the compound of formula (3) is converted to the compound of formula (5) by reduction and decarboxylation protecting group, preferably the compound of formula (3) is reacted with decarboxylation protecting group by reduction in a one-step reaction. Further, the present invention provides a process for producing a compound represented by the formula (3), wherein the compound represented by the formula (3) is obtained by converting a compound represented by the formula (2) by reacting with a halogenosilane:
wherein R is2Is a silane protecting group, R1Is H, C1-C20Alkyl, benzyl substituted by one or more substituents, allyl, wherein the substituent is C1～C6Straight or branched alkyl, C1～C6Alkoxy, or halogen. Preferably, R2TMS, TES, TBDMS, TIPS or TBDP.
Further, the present invention provides a process for producing a compound represented by the formula (2), wherein the compound represented by the formula (2) is obtained by condensing a compound represented by the formula (1) with an alcohol to form an ester:
wherein R is1Is C1-C20Alkyl, benzyl substituted by one or more substituents, allyl, wherein the substituent is C1～C6Straight or branched alkyl, C1～C6Alkoxy, or halogen; further preferably, R1Is C1-C6Alkyl, benzyl, by C1-C6Alkyl and/or halogen substituted benzyl.
In the above method, preferably, the compound represented by the formula (7) is reacted with an acid or tetrabutylammonium fluoride to obtain a compound represented by the formula (1);
reacting the compound shown in the formula (6) with sodium borohydride or potassium borohydride to convert the compound shown in the formula (7);
subjecting the compound shown in the formula (5) to configuration transformation under alkaline conditions to prepare a compound shown in a formula (6);
when R is1When the hydrogen is not H, the compound shown in the formula (3) is subjected to hydrogenation reduction in an organic solvent, is firstly converted into the compound shown in the formula (4), and then is hydrolyzed in the presence of alkali to obtain the compound shown in the formula (5);
condensing a compound represented by formula (1) with an alcohol to form an ester under acid catalysis to produce a compound represented by formula (2), or reacting a compound represented by formula (1) with a halogenated hydrocarbon to form an ester in the presence of a base to produce a compound represented by formula (2).
More specifically, the invention provides a preparation method of obeticholic acid (a compound shown in a formula (1)), and a specific reaction route is shown as follows:
wherein R is1＝H、C1-C20Alkyl, benzyl substituted with one or more substituents), allyl, wherein the substituent is C1～C6
Straight or branched alkyl, C1～C6Alkoxyalkyl, halo; r2Is a silane protecting group including, but not limited to, TMS, TES, TBDMS, TIPS, or TBDPS, and the like.
In a more preferred embodiment of the above process,
step 1: condensing a compound of formula (1) with an alcohol to form an ester under acid catalysis to produce a compound of formula (2), or reacting a compound of formula (1) with a halogenated hydrocarbon to form an ester in the presence of a base to produce a compound of formula (2);
wherein a compound represented by formula (1) is reacted with an alcohol under acid catalysis to produce a compound represented by formula (2):
among them, the acid used is not limited as long as it can be used in the ester forming reaction with the carboxyl group using an alcohol, and the acid may be, for example, sulfuric acid, HCl, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, formic acid, propionic acid, or the like, preferably an inorganic acid, most preferably sulfuric acid.
The alcohol used may be a primary alcohol such as methanol, ethanol, propanol, butanol, benzyl alcohol, or phenethyl alcohol, a secondary alcohol such as isopropanol, isobutanol, isoamyl alcohol, or cyclohexanol, etc., a tertiary alcohol such as t-butanol, etc. Preferably a primary alcohol, most preferably methanol or ethanol; the reaction temperature is 0 ℃ to 100 ℃ and the reaction time is 1h to 24 h.
In another embodiment, a compound of formula (2) is produced by reacting a compound of formula (1) with a halogenated hydrocarbon under base catalysis:
specifically, the base to be used is not limited as long as it can be used in the reaction of a carboxyl group with an ester, and an inorganic base is preferable, and potassium carbonate is most preferable; the reaction temperature is 35 ℃ to 100 ℃, and the reaction time is 5h to 24 h; wherein the content of the first and second substances,
in which X is a leaving functional group, e.g. X is Cl, Br, I, or CF3SO4-，R3、R4Are independent of each other H, C1-C19Alkyl, phenyl, C1-C19Alkyl-substituted phenyl, or vinyl, and the like.
As the halogenated hydrocarbon, a benzyl halide or a substituted benzyl halide is preferred, and benzyl bromide and benzyl chloride are most preferred.
Step 2: reacting a compound of formula (2) with a halosilane in the presence of a base to produce a compound of formula (3):
among them, the base to be used is not limited as long as it can be used in the reaction of a hydroxyl group with a halosilane to form a silyl ether. For example, an organic base such as sodium bicarbonate, sodium hydride, potassium carbonate, triethylamine, pyridine, diisopropylethylamine, or imidazole, etc., may be mentioned, with imidazole being most preferred.
The halosilane is preferably trimethylhalosilane, triethylhalosilane, t-butyldimethylsilhalosilane, triisopropylhalosilane, t-butyldiphenylhalosilane, or the like, and most preferably t-butyldimethylsilhalosilane.
Preferably, the reaction temperature is from 0 ℃ to 80 ℃, and preferably from 10 ℃ to 35 ℃; the reaction time is 5min to 10h, and preferably 2h to 4 h.
In another more preferred embodiment, when R1And H, reacting the compound of formula (1) with a halosilane to produce a compound of formula (3) under base catalysis:
wherein, the base used is not limited as long as it can be used in the reaction of hydroxyl group with halosilane to form silyl ether; organic bases such as triethylamine, pyridine, diisopropylethylamine, or imidazole, etc. are preferred, with imidazole being most preferred.
The halosilane is preferably trimethylhalosilane, triethylhalosilane, t-butyldimethylsilhalosilane, triisopropylhalosilane, t-butyldiphenylhalosilane, or the like, and most preferably t-butyldimethylsilhalosilane.
Preferably, the reaction temperature is from 0 ℃ to 80 ℃, and preferably from 10 ℃ to 35 ℃; the reaction time is 4h to 24 h. And preferably from 4h to 10 h.
And step 3: carrying out hydrogenation reduction reaction on the compound shown in the formula (3) in an organic solvent under the catalysis of palladium carbon to generate a compound shown in the formula (4);
among them, the solvent used is preferably a methanol/tetrahydrofuran mixed solvent; the reaction temperature is preferably from 25 ℃ to 80 ℃, most preferably from 45 ℃ to 60 ℃; the hydrogen donor used is preferably ammonium formate, hydrogen, cyclohexene, cyclohexadiene, formic acid or the like.
And 4, step 4: hydrolyzing the compound represented by formula (4) in the presence of a base to produce a compound represented by formula (5);
among them, the base to be used is not limited as long as it can be used in the carboxylic ester hydrolysis reaction. Preferably an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or potassium carbonate, most preferably sodium hydroxide;
the solvent used includes organic solvents, inorganic solvents and mixed solvents of organic and inorganic solvents, preferably methanol, tetrahydrofuran, methanol/water, or tetrahydrofuran/water, most preferably methanol/water.
Preferably, the reaction temperature is from 0 ℃ to 100 ℃, more preferably from 20 ℃ to 45 ℃; the reaction time is from 30min to 16h, preferably from 4h to 12 h.
In another preferred embodiment, the compound of formula (5) is prepared by reacting the compound of formula (3) with a decarboxylating protecting group in one pot under palladium-carbon catalysis.
In this case, the compound represented by the formula (3) is preferably R1Is benzyl, benzyl substituted by one or more substituents, wherein the substituent is C1～C6Straight or branched alkyl, C1～C6Alkoxy, or halogen.
The solvent used is an organic solvent, preferably methanol, tetrahydrofuran, ethanol or a mixed solvent of 2 (or 3) thereof, and the reaction temperature is preferably 25 ℃ to 80 ℃, and most preferably 45 ℃ to 60 ℃; the hydrogen donor used is preferably ammonium formate; the reaction time is from 1h to 24h, preferably from 4h to 8 h.
And 5: subjecting the compound of formula (5) to high temperature configurational transformation under basic conditions to produce a compound of formula (6):
herein, the base to be used is not limited as long as it can be used in the configuration reversal reaction at this step. Preferably an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or potassium carbonate, most preferably sodium hydroxide.
The solvent used includes organic solvents, inorganic solvents and mixed solvents of organic and inorganic solvents, preferably methanol, tetrahydrofuran, methanol/water, or tetrahydrofuran/water, most preferably methanol/water.
The reaction temperature is 20 ℃ to 110 ℃, preferably 60 ℃ to 90 ℃.
The reaction time is from 0.5h to 12h, preferably from 2h to 5 h.
Step 6: reacting a compound represented by formula (6) with sodium borohydride or potassium borohydride to produce a compound represented by formula (7):
preferably, the solvent used for the reaction is preferably; methanol, methanol/alkaline water, methanol/water, or water, at a reaction temperature of 60 ℃ to 110 ℃, preferably 75 ℃ to 110 ℃, for a reaction time of 1h to 10h, preferably 3h to 5 h.
In another more specific embodiment, the compound of formula (7) is prepared from the compound of formula (5) by one-pot configuration transformation and carbonyl reduction; among them, the solvent used is preferably: methanol, methanol/alkaline water, methanol/water, or water, at a reaction temperature of 60 ℃ to 110 ℃, preferably 75 ℃ to 110 ℃, for a reaction time of 1h to 10h, preferably 3h to 5 h.
And 7: reacting a compound represented by formula (7) with an acid or tetrabutylammonium fluoride, followed by recrystallization, to give a compound represented by formula (i):
preferably, the acid used is not limited as long as it can be used in the reaction using the desiliconized group protecting group, and the acid may be, for example, sulfuric acid, HCl, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, formic acid, propionic acid, or the like, preferably an inorganic acid, most preferably hydrochloric acid.
The reaction temperature is 0 ℃ to 60 ℃, preferably 10 ℃ to 35 ℃.
Further preferably, after the reaction is finished, purifying the obtained compound represented by the formula (1) by a recrystallization method, wherein a recrystallization solvent is n-butyl acetate, or a mixed solution of butyl acetate and n-heptane, or a mixed solution of ethyl acetate and n-heptane; more preferably, the volume ratio of butyl acetate to n-heptane in the mixed solution of butyl acetate and n-heptane is 1: 3-5, and the volume ratio of ethyl acetate to n-heptane in the mixed solution of ethyl acetate and n-heptane is 1: 3-5.
The terms:
TMS means: trimethylsilane;
TES means: triethylsilane;
TBDMS, i.e. TBS, means: tert-butyldimethylsilane;
TIPS means: triisopropylsilane;
TBDPS means: tert-butyl diphenylsilane.
Wherein, C1-C20The alkyl refers to a straight chain or branched chain alkyl containing 1-20 carbon atoms, and a cycloalkyl; c1～C6The alkyl refers to a straight chain or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n-butyl, cyclohexyl, n-hexyl and the like.
The invention provides a brand-new preparation method of obeticholic acid (a compound shown in a formula (1)), which avoids the generation of impurities III and IV, remarkably improves the quality of obeticholic acid, and is simple to operate and remarkably improves the yield.
Description of the drawings:
FIG. 1 shows: LC-MS diagrams of the compound of formula (1) obtained according to the procedures of example 9 and example 10; wherein, fig. 1A shows a mass spectrometry liquid phase diagram: FIG. 1B shows an ion spectrum; FIG. 1C shows the MS spectrum, m/z 419[420-H ]]-,m/z 465[420+HCOO-],m/z 839[2m-H]-。
FIG. 2 shows: hydrogen spectra of the compounds of formula (1) obtained according to the methods of example 9 and example 10.
FIG. 3 shows: liquid phase chromatography (HPLC) of the compound of formula (1) obtained according to the methods of example 9 and example 10.
FIG. 4 shows: liquid phase chromatography (HPLC) of the compound of formula (1) obtained according to the methods of example 9 and example 11.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The technical solutions of the present invention are further described below with reference to specific examples, and it should be understood that the following contents are only for illustrating the contents of the present invention and should not be used to limit the scope of the present invention.
The HPLC detection method of the compound of formula (1) used in the present invention is a self-control method, wherein Area% 0.2 is the actual impurity content in the product; the detection conditions of HPLC are as follows:
according to high performance liquid chromatography (Chinese pharmacopoeia 2015 edition of the four-part general rules 0512), octadecylsilane chemically bonded silica is used as filler (Waters CORTECS C18)+4.6 mm. times.150 mm, 2.7 μm or equivalent performance column), using 0.1% trifluoroacetic acid in water (1.0 ml trifluoroacetic acid, 1000ml water) as mobile phase A and acetonitrile-methanol (900: 100) as mobile phase B, gradient washing was carried out according to the following procedureRemoving; the flow rate was 1.0ml per minute; the column temperature was 40 ℃; detecting with an electric spray detector.
Process for preparing the compounds of formula (1) according to the invention1H-NMR detection is carried out by using a BRUKER instrument, and a solvent is DMSO.
Example 1 preparation of compound 2-a:
methanol (500ml) and the compound of formula (1) (50.0g) were added to a reaction flask at room temperature, concentrated sulfuric acid (0.5g) was added dropwise with stirring, and the mixture was heated under reflux for 10 hours. After the reaction solution was cooled to 20 ℃, saturated sodium bicarbonate was added to neutralize the sulfuric acid. The reaction solution is concentrated to dryness, and then 500ml of ethyl acetate and 250ml of saturated sodium bicarbonate aqueous solution are added, stirred evenly and kept stand for layering. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give wax-like substance 2-a (50g, yield 96.7%). Purity 99.29% (E configuration 96.75%, Z configuration 2.54%). Ms: m/z 431.15(M + H).
Example 2 preparation of compound 2-b:
acetonitrile (200ml), a compound (22.0g) of formula (1), anhydrous K2CO3(14.6g) and benzyl bromide (9.9g) are sequentially added into a reaction bottle, stirred, heated and refluxed for 8-15 h. Disappearance of starting material was detected by TLC (ethyl acetate/n-heptane ═ 1/1). And cooling the reaction liquid to room temperature, filtering, and leaching the filter cake with acetonitrile. Mixing filtrates, and concentrating under reduced pressure at temperature not higher than 50 deg.C to dry. Dissolving the concentrated material in ethyl acetate (250ml), adding purified water (100ml), stirring, and standing for layering. Drying the organic layer with anhydrous sodium sulfate, filtering, leaching the filter cake, controlling the temperature to be less than or equal to 45 ℃, and concentrating under reduced pressure to obtain brown oily matter 2-b which is overweight. Purity: 98.45%, Ms: m/z 507.40(M + H).
Example 3 preparation of compound 3-b:
under the protection of N2, acetonitrile (300ml), a compound 2-b (26.80g) and tert-butyldimethylsilyl chloride (9.55g) are sequentially added into a reaction bottle, and imidazole (9.00g) is added at the temperature of 10-20 ℃. Stirring and reacting for 3-4 h at 20-25 ℃. Disappearance of starting material was detected by TLC (ethyl acetate/n-heptane ═ 1/3). Cooling the reaction liquid to room temperature, controlling the temperature to be less than or equal to 45 ℃, and concentrating under reduced pressure until the reaction liquid is dry. Dissolving the concentrated material in ethyl acetate (300ml), adding purified water, stirring, refining and layering. The organic layer was washed with purified water. Drying the organic layer with anhydrous sodium sulfate, filtering, leaching the filter cake with ethyl acetate, controlling the temperature to be less than or equal to 45 ℃, and concentrating under reduced pressure to obtain a light yellow oily substance 3-b with overweight (the theoretical amount is 32.8 g). The purity is more than or equal to 98.0 percent. Ms: m/z 621.45(M + H).
Example 4 preparation of compound 3-c:
N2under protection, DMF (300ml), compound (1) (22.0g) and tert-butyldimethylsilyl chloride (9.55g) are sequentially added into a reaction bottle, and imidazole (9.00g) is added at the temperature of 10-20 ℃. Stirring and reacting for 3-4 h at 20-25 ℃. Disappearance of starting material was detected by TLC (ethyl acetate/n-heptane ═ 1/3). Cooling the reaction liquid to room temperature, controlling the temperature to be less than or equal to 60 ℃, and concentrating under reduced pressure until the reaction liquid is dry. Dissolving the concentrated material in ethyl acetate (300ml), adding purified water, stirring, refining and layering. The organic layer was washed with purified water. Drying the organic layer with anhydrous sodium sulfate, filtering, leaching the filter cake with ethyl acetate, controlling the temperature to be less than or equal to 45 ℃, decompressing and concentrating to obtain a light yellow oily substance, and recrystallizing with n-heptane to obtain a white solid 3-c (6.52g, yield: 23.3%). The purity is more than or equal to 98.0 percent. Ms: m/z531.30(M + H).
Example 5 preparation of compound 5-a:
N2tetrahydrofuran (100g), compound 3-a (54.5g), methanol (200g), ammonium formate (18.92g), and 10% palladium on carbon (10.9g) were added in this order to a reaction flask with protection. Stirring and dissolving uniformly. And controlling the external temperature to be 50-55 ℃, and stirring and reacting for 4-8 h. Filtering the reaction solution, controlling the temperature of the filtrate to be less than or equal to 50 ℃, and concentrating the filtrate under reduced pressure until the filtrate is nearly dry. Ethyl acetate (300ml) and purified water (100ml) were added thereto, and the mixture was stirred well and allowed to stand for separation. The organic phase is washed with purified water. Dried over anhydrous sodium sulfate. Filtering, concentrating and drying to obtain oily matter 4-a. Tetrahydrofuran (200ml) was added, and 200ml of a 2N aqueous solution of sodium hydroxide was added to the solution, followed by reaction with stirring for 4 to 6 hours. The reaction mixture was concentrated, adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate 2 times. The combined organic phase was washed once with purified water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, slurried with 300ml of n-heptane, filtered and dried to give 5-a as a white solid (42.63g, yield: 80%). Purity is more than or equal to 93.0% (mixed spinning), Ms: m/z 533.45(M + H).
Example 6 preparation of compound 5-a:
N2tetrahydrofuran (100ml), compound 3-b (32.80g), methanol (150ml), ammonium formate (9.99g), and 10% palladium on carbon (6.56g) were added in this order to a reaction flask with the aid of a blanket. Stirring and dissolving uniformly. And controlling the external temperature to be 50-55 ℃, and stirring and reacting for 4-8 h. Filtering the reaction solution, controlling the temperature of the filtrate to be less than or equal to 50 ℃, and concentrating the filtrate under reduced pressure until the filtrate is nearly dry. Ethyl acetate (300ml) and purified water (100ml) were added thereto, the mixture was stirred uniformly, and 1N diluted hydrochloric acid was added dropwise thereto to adjust ph to 4-5. The aqueous layer was extracted and washed with ethyl acetate. The organic layers were combined and washed 2 times with purified water. The organic layer was dried over anhydrous sodium sulfate. Filtering, and concentrating to obtain white solid or oil. 250ml of n-heptane was added and slurried to give 5-a (24.0g, yield: 85.29%) as a white solid. Purity is more than or equal to 93.0% (mixed spinning), Ms: m/z 533.45(M + H).
Example 7 preparation of compound 7-a:
adding purified water (240ml), sodium hydroxide (5.40g) and a compound 5-a (24.0g) into a reaction bottle, uniformly stirring after adding, adding methanol (360ml), controlling the temperature to be 75-80 ℃, stirring for reacting for 5 hours, cooling the reaction liquid, controlling the temperature to be 0-5 ℃, and dropwise adding 1N diluted hydrochloric acid to adjust the ph to be 4-5. The aqueous layer was extracted and washed with ethyl acetate. The organic layers were combined and washed 2 times with purified water. The organic layer was dried over anhydrous sodium sulfate. Filtering, and concentrating to obtain white solid or oil. 250ml of n-heptane was added and slurried to give 6-a as a white solid (19.56g, yield: 81.50%). Purity is more than or equal to 93.0%, Ms: m/z 533.45(M + H).
Purified water (180ml), sodium hydroxide (4.05g) and compound 6-a (18.0g) were added to a reaction flask, and after the addition, methanol (250ml) was added thereto with stirring. Controlling the temperature to be 75-80 ℃, and stirring to dissolve. 3.83g of sodium borohydride was added to the reaction vessel in 3 portions (1.28 g for the first portion, 1.28g for the second portion, and 1.27g for the third portion, with an interval of 15min or more for each portion). The reaction was then refluxed for 3 h. Cooling the reaction solution, controlling the temperature to be less than or equal to 50 ℃, decompressing and concentrating, and removing the methanol. And controlling the temperature of the rest material liquid to be 0-5 ℃, and adjusting the pH value to be 3-4 by using 1N diluted hydrochloric acid. The aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined and washed with purified water for 3 times. The organic layer was dried over anhydrous sodium sulfate, filtered, and rinsed with ethyl acetate. Concentrating under reduced pressure to obtain colorless oily substance or solid 7-a, and overweight. Purity is more than or equal to 85.0%, Ms: m/z 533.40 (M-H).
Example 8 preparation of compound 7-a:
purified water (240ml), sodium hydroxide (5.40g) and compound 5-a (24.0g) were added to a reaction flask, and after the addition, methanol (288g) was added thereto with stirring. Controlling the temperature to be 75-80 ℃, and stirring to dissolve. 5.11g of sodium borohydride was added to the reaction vessel in 3 portions (1.70 g for the first portion, 1.70g for the second portion, and 1.71g for the third portion, with an interval of 15min or more for each portion). The reaction was then refluxed for 3 h. Cooling the reaction solution, controlling the temperature to be less than or equal to 50 ℃, decompressing and concentrating, and removing the methanol. And controlling the temperature of the rest material liquid to be 0-5 ℃, and adjusting the pH value to be 3-4 by using 1N diluted hydrochloric acid. The aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined and washed with purified water for 3 times. The organic layer was dried over anhydrous sodium sulfate, filtered, and rinsed with ethyl acetate. Concentrating under reduced pressure to obtain colorless oily substance or solid 7-a, and overweight. Purity is more than or equal to 85.0%, Ms: m/z 533.40 (M-H).
Example 9 preparation of compound (1):
tetrahydrofuran (100ml) and the compound 7-a (24.09g) were added to a reaction flask in this order, and the mixture was stirred uniformly after the addition. The temperature is controlled at 20-25 ℃, and about 212.0g of 1N diluted hydrochloric acid is added. After the addition, the reaction was stirred at room temperature for 15 hours. TLC (ethyl acetate/n-heptane 1/1, phosphomolybdic acid color) detected 7-a reaction to essentially disappeared or very faint. The reaction solution was concentrated to remove tetrahydrofuran, extracted with ethyl acetate, and the organic layer was washed with 30% aqueous sodium chloride solution. Adding 24.1kg of anhydrous sodium sulfate into the organic layer, drying, filtering, leaching with ethyl acetate, controlling the temperature to be less than or equal to 50 ℃, concentrating under reduced pressure until the organic layer is nearly dry, adding 150ml of n-heptane, pulping, controlling the temperature to be 20-25 ℃, and stirring for 1 h. Filtering, and drying to obtain white powder.
Example 10: purification of Compound (1)
The white powder obtained in example 9 was recrystallized 2 times from 6v/w n-butyl acetate to give obeticholic acid of formula (I) in yield: 66 percent. HPLC purity is more than or equal to 99.0%. Ms: m/z 419.35(M-H), mass spectrum as shown in figure 1, hydrogen spectrum as shown in figure 2, and liquid phase spectrum as shown in figure 3.
Example 11: purification of Compound (1)
The white powder obtained in example 9 was recrystallized 2 times from butyl acetate/n-heptane 1/3 or ethyl acetate/n-heptane 1/3 to give obeticholic acid of formula (I) in yield: 85%, purity not less than 99.0%, mass spectrum as shown in figure 1, hydrogen spectrum as shown in figure 2, and liquid phase spectrum as shown in figure 4.
As can be seen from the attached figures 3 and 4, the content of single impurities and total impurities in the purified final product is remarkably reduced, the registration quality requirement can be met, and all impurities are known impurities according to spectrogram. And the intermediate 3 alpha hydroxyl is protected, so that the generation of intermediate impurities III and IV is avoided, and the yield and quality of the product are greatly improved.
Claims (15)
1. A process for preparing a compound of formula I, comprising:
(1) removing the hydroxyl protecting group R from the compound represented by the formula (7)2And converted to a compound of formula (I):
wherein R is2Is a silane protecting group.
2. The method according to claim 1, wherein the compound represented by formula (7) is prepared from the compound represented by formula (6) by a reduction reaction, or is prepared from the compound represented by formula (5) by a one-pot method comprising configuration transformation and carbonyl reduction:
wherein R is2Is a silane protecting group.
3. The method according to claim 2, wherein the compound represented by formula (6) is prepared from the compound represented by formula (5) by configurational transformation:
wherein R is2Is a silane protecting group.
4. The method according to claim 3, wherein the compound represented by formula (5) is obtained by converting a compound represented by formula (3):
wherein R is2Is a silane protecting group, R1Is H, C1-C20Alkyl, benzyl substituted by one or more substituents, allyl, wherein the substituent is C1～C6Straight or branched alkyl, C1～C6Alkoxy, or halogen;
provided that when R is1When the compound is H, the compound shown in the formula (5) is directly obtained from the compound shown in the formula (3) through reduction reaction to obtain the compound shown in the formula (5);
when R is1Is H, C1-C20Alkyl, benzyl substituted by one or more substituents, allyl, wherein the substituent is C1～C6Straight or branched alkyl, C1～C6Alkoxy, or halogen, the compound of formula (3) is converted to the compound of formula (5) by reduction and decarboxylation protecting group reaction.
5. The method according to claim 4, wherein the compound represented by formula (3) is obtained by converting a compound represented by formula (2) by reacting with a halosilane:
wherein R is2Is a silane protecting group, R1Is H, C1-C20Alkyl, benzyl substituted by one or more substituents, allyl, wherein the substituent is C1～C6Straight or branched alkyl, C1～C6Alkoxy, or halogen.
6. The method according to claim 5, wherein the compound represented by formula (2) is obtained by condensing a compound represented by formula (1) with an alcohol to form an ester:
wherein R is1Is C1-C20Alkyl, benzyl substituted by one or more substituents, allyl, wherein the substituent is C1～C6Straight or branched alkyl, C1～C6Alkoxy, or halogen.
7. The method of any one of claims 1 to 6, wherein R is2TMS, TES, TBDMS, TIPS or TBDPS.
8. The method according to claim 1, wherein the compound represented by formula (7) is reacted with an acid or tetrabutylammonium fluoride to obtain the compound represented by formula (1).
9. The process according to claim 8, wherein the compound represented by the formula (1) is purified by recrystallization after the reaction is completed, wherein the recrystallization solvent is n-butyl acetate, a mixed solution of butyl acetate and n-heptane, or a mixed solution of ethyl acetate and n-heptane.
10. The method according to claim 2, wherein the reducing agent used in the reduction reaction is sodium borohydride or potassium borohydride.
11. The method according to claim 3, wherein the compound represented by formula (6) is produced by subjecting the compound represented by formula (5) to configurational transformation under basic conditions.
12. The method of claim 4, wherein R is the ratio of R to R1When not H, the compound of formula (3) is reduced by hydrogenation in an organic solvent to convert it into a compound of formula (4), and then the compound is reacted in the presence of a baseHydrolyzing the compound shown in the formula (4) to obtain a compound shown in a formula (5), wherein a hydrogen donor is ammonium formate, hydrogen, cyclohexene, cyclohexadiene or formic acid;
or, the compound shown in the formula (3) is reduced and reacts with the decarboxylation protecting group in one pot under the catalysis of palladium carbon to prepare the compound shown in the formula (5).
13. The method of claim 5, wherein the halosilane is a trimethylhalosilane, triethylhalosilane, t-butyldimethylhalosilane, triisopropylhalosilane, or t-butyldiphenylhalosilane.
14. The method according to claim 6, wherein the compound of formula (1) is condensed with an alcohol to form an ester under acid catalysis to produce the compound of formula (2), or the compound of formula (1) is reacted with a halogenated hydrocarbon to form an ester in the presence of a base to produce the compound of formula (2).
15. A compound characterized by the following structure:
wherein R is1Is H, C1-C20Alkyl, benzyl substituted by one or more substituents, allyl, wherein the substituent is C1～C6Straight or branched alkyl, C1～C6Alkoxy, or halogen; r2TMS, TES, TBDMS, TIPS or TBDPS; preferably, R1Is H or benzyl, R2Is TBDMS.
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