IT201900005906A1 - PROCEDURE FOR THE PREPARATION OF CONJUGATES OF A CHOLANIC ACID - Google Patents
PROCEDURE FOR THE PREPARATION OF CONJUGATES OF A CHOLANIC ACID Download PDFInfo
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- IT201900005906A1 IT201900005906A1 IT102019000005906A IT201900005906A IT201900005906A1 IT 201900005906 A1 IT201900005906 A1 IT 201900005906A1 IT 102019000005906 A IT102019000005906 A IT 102019000005906A IT 201900005906 A IT201900005906 A IT 201900005906A IT 201900005906 A1 IT201900005906 A1 IT 201900005906A1
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- Prior art keywords
- acid
- formula
- process according
- alcohol
- butanol
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 27
- RPKLZQLYODPWTM-KBMWBBLPSA-N cholanoic acid Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)CC2 RPKLZQLYODPWTM-KBMWBBLPSA-N 0.000 title description 2
- 238000002360 preparation method Methods 0.000 title description 2
- BHTRKEVKTKCXOH-UHFFFAOYSA-N Taurochenodesoxycholsaeure Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)CC2 BHTRKEVKTKCXOH-UHFFFAOYSA-N 0.000 claims description 49
- BHTRKEVKTKCXOH-LBSADWJPSA-N tauroursodeoxycholic 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)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-LBSADWJPSA-N 0.000 claims description 48
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 31
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 22
- 239000003960 organic solvent Substances 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 15
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic 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-UZVSRGJWSA-N 0.000 claims description 13
- 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 description 12
- 229960003080 taurine Drugs 0.000 claims description 12
- 229960001661 ursodiol Drugs 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 11
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- -1 heteroaromatic tertiary amine Chemical class 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 238000010533 azeotropic distillation Methods 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 claims description 4
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003613 bile acid Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 230000001587 cholestatic effect Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic 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)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009655 industrial fermentation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- BHTRKEVKTKCXOH-AYSJQVDDSA-N taurochenodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)C1C2C2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-AYSJQVDDSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
- C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
-
- 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)
- Peptides Or Proteins (AREA)
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“PROCEDIMENTO DI PREPARAZIONE DI CONIUGATI DI UN ACIDO COLANICO” "PROCEDURE FOR PREPARATION OF CONJUGATES OF A CHOLANIC ACID"
CAMPO DELL’INVENZIONE FIELD OF THE INVENTION
La presente invenzione è diretta ad un procedimento per la purificazione dell’acido tauroursodesossicolico, il coniugato con taurina dell’acido ursodesossicolico, che trova uso nel trattamento delle sindromi colestatiche. The present invention is directed to a process for the purification of tauroursodeoxycholic acid, the conjugate of ursodeoxycholic acid with taurine, which is used in the treatment of cholestatic syndromes.
STATO DELLA TECNICA STATE OF THE TECHNIQUE
L’acido tauroursodesossicolico, noto anche come TUDCA e avente la seguente formula (I): Tauroursodeoxycholic acid, also known as TUDCA and having the following formula (I):
è un acido biliare presente nel nostro organismo e trova uso come agente in patologie colestatiche, ad esempio cirrosi biliare primitiva, colangite sclerosante primitiva, colestasi associata alla fibrosi cistica o intraepatica familiare, e calcolosi colesterinica. is a bile acid present in our body and is used as an agent in cholestatic diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis associated with familial cystic or intrahepatic fibrosis, and cholesterol stones.
Su scala industriale l’acido tauroursodesossicolico di formula (I) viene ottenuto in diversi modi. Mentre in origine veniva ottenuto dalla bile di orso, oggi viene ottenuto tramite fermentazione industriale, come ad esempio descritto da Xu et al. in Microb. Cell. Fact (2019) 18:34, utilizzando cellule di E. coli modificate, oppure per via sintetica, ad esempio partendo dall’acido ursodesossicoli co di formula (II) On an industrial scale, the formula (I) tauroursodeoxycholic acid is obtained in different ways. While originally obtained from bear bile, today it is obtained through industrial fermentation, as described by Xu et al. in Microb. Cell. Fact (2019) 18:34, using modified E. coli cells, or synthetically, for example starting from ursodeoxic acid of formula (II)
come descritto ad esempio in EP 0 629 634 oppure in IT 1197330. as described for example in EP 0 629 634 or in IT 1197330.
I procedimenti descritti in EP 0 629 634 oppure in IT 1197330 prevedono la reazione di un sale dell’acido ursodesossicolico di formula (II) con un alocarbonilestere, ad esempio con un derivato di formula (III) The processes described in EP 0 629 634 or in IT 1197330 provide for the reaction of a salt of ursodeoxycholic acid of formula (II) with a halocarbonyl ester, for example with a derivative of formula (III)
Cl-COOR Cl-COOR
(III), (III),
dove Cl è cloro e R è scelto tra un gruppo consistente in un C1-C6 alchile, fenile oppure benzile, a formare un’anidride mista di formula (IV): where Cl is chlorine and R is chosen from a group consisting of a C1-C6 alkyl, phenyl or benzyl, to form a mixed anhydride of formula (IV):
La reazione dell’anidride mista di formula (IV) con taurina di formula (V): The reaction of the mixed anhydride of formula (IV) with taurine of formula (V):
porta all’acido tauroursodesossicolico di formula (I). leads to the formula (I) tauroursodeoxycholic acid.
L’acido tauroursodesossicolico di formula (I) così ottenuto deve quindi essere separato sia dai sali formatisi durante la reazione, dalla taurina di formula (V) non reagita, che dagli acidi biliari, ad esempio dell’acido ursodesossicolico di formula (II) non reagito, come da ulteriori acidi biliari eventualmente presenti nella miscela di reazione di partenza. The tauroursodeoxycholic acid of formula (I) thus obtained must therefore be separated both from the salts formed during the reaction, from the unreacted taurine of the formula (V), and from the bile acids, for example of the ursodeoxycholic acid of the formula (II) not reacted, as from further bile acids possibly present in the starting reaction mixture.
I brevetti EP 0 400 695 e EP 0629 634 descrivono dei procedimenti per ottenere l’acido tauroursodesossicolico di formula (I) e la sua purificazione tramite cromatografia, ad esempio utilizzando delle resine ioniche. Patents EP 0 400 695 and EP 0629 634 describe processes for obtaining tauroursodeoxycholic acid of formula (I) and its purification by chromatography, for example using ionic resins.
Il procedimento in IT 1197330 prevede una purificazione dell’acido tauroursodesossicolico di formula (I) tramite l’aggiunta di un acido, portando il pH a circa 2, e la concentrazione della soluzione. Il residuo ottenendo viene sciolto in etanolo, la taurina non reagita viene eliminata tramite filtrazione e l’acido tauroursodesossicolico di formula (I) viene precipitato dalla soluzione per aggiunta di acetone, etil acetato oppure una loro miscela. The procedure in IT 1197330 provides for a purification of tauroursodeoxycholic acid of formula (I) by adding an acid, bringing the pH to about 2, and the concentration of the solution. The resulting residue is dissolved in ethanol, the unreacted taurine is eliminated by filtration and the tauroursodeoxycholic acid of formula (I) is precipitated from the solution by adding acetone, ethyl acetate or a mixture thereof.
EP 2 137 206 prevede la separazione dei sali e di taurina non reagita da sali alcalini oppure alcalino terrosi dell’acido tauroursodesossicolico di formula (I) tramite aggiunta da 0,8 a 1,4 equivalenti di un acido e lasciando riposare la soluzione per un periodo da 10 a 180 minuti. La taurina precipitata viene separata, poi la successiva aggiunta di un solvente organico porta a precipitazione dell’acido tauroursodesossicolico di formula (I). EP 2 137 206 provides for the separation of the salts and unreacted taurine from the alkaline or alkaline earth salts of the tauroursodeoxycholic acid of formula (I) by adding from 0.8 to 1.4 equivalents of an acid and letting the solution stand for a period from 10 to 180 minutes. The precipitated taurine is separated, then the subsequent addition of an organic solvent leads to the precipitation of the formula (I) tauroursodeoxycholic acid.
Tuttavia rimane la necessità di trovare un nuovo e sicuro metodo alternativo per la purificazione dell’acido tauroursodesossicolico di formula (I), che insieme all’elevata resa sia particolarmente idoneo per la sua produzione a livello industriale. In particolare, rimane necessario un procedimento che permetta non soltanto di separare l’acido tauroursodesossicolico di formula (I) da sali presenti nella miscela di reazione, ed in particolare dalla taurina di formula (V) non reagita, ma anche da altri acidi colanici, ad esempio il prodotto di partenza, l’acido ursodesossicolico di formula (II), non reagito oppure altri acidi colanici presenti nel prodotto di partenza come impurezze. However, there remains the need to find a new and safe alternative method for the purification of tauroursodeoxycholic acid of formula (I), which together with the high yield is particularly suitable for its industrial production. In particular, a process remains necessary which allows not only to separate the tauroursodeoxycholic acid of formula (I) from salts present in the reaction mixture, and in particular from the unreacted taurine of formula (V), but also from other cholanic acids, for example the starting product, the unreacted ursodeoxycholic acid of formula (II) or other cholanic acids present in the starting product as impurities.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
Oggetto dell’invenzione è un procedimento per la purificazione dell’acido tauroursodesossicolico avente la seguente formula (I): The subject of the invention is a process for the purification of tauroursodeoxycholic acid having the following formula (I):
oppure un suo sale, or one of its salt,
comprendente: comprising:
- l’estrazione dell’acido tauroursodesossicolico di formula (I) da una soluzione acquosa con un C4-C7 alcol; - the extraction of tauroursodeoxycholic acid of formula (I) from an aqueous solution with a C4-C7 alcohol;
- l’aggiunta di un ulteriore solvente organico diverso da un C4-C7 alcol; - the addition of an additional organic solvent other than a C4-C7 alcohol;
oppure, in alternativa a detta aggiunta, il raffreddamento ad una temperatura al di sotto di 5°C, preferibilmente a circa 0°C oppure inferiore; or, as an alternative to said addition, cooling to a temperature below 5 ° C, preferably at about 0 ° C or lower;
- l’aggiunta di un acido protico (HX) ad ottenere la precipitazione di acido tauroursodesossicolico di formula (I), e - the addition of a protic acid (HX) to obtain the precipitation of tauroursodeoxycholic acid of formula (I), and
- l’isolamento dell’acido tauroursodesossicolico di formula (I). - the isolation of the formula (I) tauroursodeoxycholic acid.
Questo procedimento permette di separare l’acido tauroursodesossicolico di formula (I) sia dai sali e dalla taurina di formula (V) presenti nella miscela di reazione, che da altri acidi colanici presenti, ad esempio l’acido ursodesossicolico di formula (II), e di ottenere in condizioni sicure un prodotto avente sorprendentemente un elevato grado di purezza, così da soddisfare i requisiti regolatori richiesti per gli API. This process makes it possible to separate the tauroursodeoxycholic acid of formula (I) both from the salts and taurine of formula (V) present in the reaction mixture, and from other cholanic acids present, for example ursodeoxycholic acid of formula (II), and to obtain in safe conditions a product having a surprisingly high degree of purity, so as to satisfy the regulatory requirements required for APIs.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Oggetto dell’invenzione è un procedimento per la purificazione dell’acido tauroursodesossicolico avente la seguente formula (I): The subject of the invention is a process for the purification of tauroursodeoxycholic acid having the following formula (I):
oppure un suo sale, or one of its salt,
comprendente: comprising:
- l’estrazione dell’acido tauroursodesossicolico di formula (I) da una soluzione acquosa con un C4-C7 alcol; - the extraction of tauroursodeoxycholic acid of formula (I) from an aqueous solution with a C4-C7 alcohol;
- l’aggiunta di un ulteriore solvente organico diverso da un C4-C7 alcol; - the addition of an additional organic solvent other than a C4-C7 alcohol;
oppure, in alternativa a detta aggiunta, il raffreddamento ad una temperatura al di sotto di 5°C, preferibilmente a circa 0°C oppure inferiore; or, as an alternative to said addition, cooling to a temperature below 5 ° C, preferably at about 0 ° C or lower;
- l’aggiunta di un acido protico (HX) ad ottenere la precipitazione di acido tauroursodesossicolico di formula (I), e - the addition of a protic acid (HX) to obtain the precipitation of tauroursodeoxycholic acid of formula (I), and
- l’isolamento dell’acido tauroursodesossicolico di formula (I). - the isolation of the formula (I) tauroursodeoxycholic acid.
Un sale dell’acido tauroursodesossicolico di formula (I) è preferibilmente un sale farmaceuticamente accettabile. Esempi di sali farmaceuticamente accettabili comprendono sali derivati da una base appropriata, quali sali di un metallo alcalino (come sodio oppure potassio), di un metallo alcalino terroso (come calcio oppure magnesio), di ammonio e NR’4<+>, dove R’ è un C1-C4 alchile. A salt of tauroursodeoxycholic acid of formula (I) is preferably a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include salts derived from an appropriate base, such as salts of an alkali metal (such as sodium or potassium), of an alkaline earth metal (such as calcium or magnesium), of ammonium and NR'4 <+>, where R is a C1-C4 alkyl.
La concentrazione dell’acido tauroursodesossicolico di formula (I) nella soluzione acquosa di partenza può essere compresa tra 0,1 e 70% p/p, tipicamente tra 2 e 50%, ad esempio circa 5%, 10%, 20%, 30%, oppure 40%. The concentration of the tauroursodeoxycholic acid of formula (I) in the starting aqueous solution can be between 0.1 and 70% w / w, typically between 2 and 50%, for example about 5%, 10%, 20%, 30 %, or 40%.
L’estrazione da una soluzione acquosa con un C4-C7 alcol permette di concentrare l’acido tauroursodesossicolico di formula (I) nel C4-C7 alcol, mentre al contrario, i sali presenti nella miscela di reazione ed in particolare la taurina di formula (V) rimangono nella fase acquosa. The extraction from an aqueous solution with a C4-C7 alcohol allows to concentrate the tauroursodeoxycholic acid of formula (I) in the C4-C7 alcohol, while on the contrary, the salts present in the reaction mixture and in particular the taurine of formula ( V) remain in the aqueous phase.
Un C4-C7 alcol in accordo alla presente invenzione può essere lineare, ramificato oppure ciclico. Un C4-C7 alcol può essere scelto per esempio tra 1butanolo, sec-butanolo, ter-butanolo, 1-pentanolo, 2-pentanolo, 3-pentanolo, 1-cicloesanolo, e 1-eptanolo, preferibilmente tra 1-butanolo, 2-butanolo, terbutanolo e 1-cicloesanolo, ed è più preferibilmente 1-butanolo. A C4-C7 alcohol according to the present invention can be linear, branched or cyclic. A C4-C7 alcohol can be selected for example from 1-butanol, sec-butanol, tert-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-cyclohexanol, and 1-heptanol, preferably between 1-butanol, 2- butanol, terbutanol and 1-cyclohexanol, and is more preferably 1-butanol.
Un solvente organico diverso da un C4-C7 alcol può essere un solvente polare aprotico, ad esempio dimetilformammide, dimetilsolfossido o acetonitrile; un solvente etereo, ad esempio metilterbutiletere, tetraidrofurano oppure diossano; un chetone, ad esempio metiletilchetone, metilisobutilchetone oppure acetone; un solvente estereo, ad esempio un acetato di un C1-C5 alcol lineare o ramificato, preferibilmente etile acetato; un solvente clorurato, ad esempio diclorometano, cloroformio o clorobenzene; oppure una miscela di due o più, tipicamente due o tre, di suddetti solventi. An organic solvent other than a C4-C7 alcohol can be an aprotic polar solvent, for example dimethylformamide, dimethyl sulfoxide or acetonitrile; an ethereal solvent, for example methylterbutyl ether, tetrahydrofuran or dioxane; a ketone, for example methyl ethyl ketone, methyl isobutyl ketone or acetone; an ester solvent, for example an acetate of a linear or branched C1-C5 alcohol, preferably ethyl acetate; a chlorinated solvent, for example dichloromethane, chloroform or chlorobenzene; or a mixture of two or more, typically two or three, of the above solvents.
Un solvente organico diverso da un C4-C7 alcol preferito è acetone. L’aggiunta del solvente organico diverso da un C4-C7 alcol può essere effettuata prima oppure dopo l’aggiunta dell’acido protico (HX). L’aggiunta dell’acido (HX) può essere addirittura in miscela con il solvente diverso da un C4-C7 alcol. An organic solvent other than a preferred C4-C7 alcohol is acetone. The addition of the organic solvent other than a C4-C7 alcohol can be carried out before or after the addition of protic acid (HX). The addition of the acid (HX) can even be mixed with the solvent other than a C4-C7 alcohol.
In un aspetto preferito il solvente organico diverso da un C4-C7 alcol viene aggiunto all’estratto prima di aggiungere l’acido protico (HX). In a preferred aspect, the organic solvent other than a C4-C7 alcohol is added to the extract before adding the protic acid (HX).
In un ulteriore aspetto preferito la soluzione viene concentrata prima di aggiungere l’acido protico (HX). In a further preferred aspect, the solution is concentrated before adding the protic acid (HX).
La concentrazione può essere effettuata mediante distillazione, ad esempio mediante distillazione azeotropica. Nel caso il C4-C7 alcol sia 1-butanolo, la temperatura a cui viene effettuata la distillazione azeotropica è tra circa 70°C e la temperatura di reflusso, preferibilmente tra circa 80° e circa 115°C, ad esempio circa 90°C, 100°C oppure 110°C. La distillazione può essere eseguita a pressione ambiente oppure a pressione ridotta. Concentration can be carried out by distillation, for example by azeotropic distillation. In case the C4-C7 alcohol is 1-butanol, the temperature at which the azeotropic distillation is carried out is between about 70 ° C and the reflux temperature, preferably between about 80 ° and about 115 ° C, for example about 90 ° C , 100 ° C or 110 ° C. Distillation can be carried out at ambient pressure or at reduced pressure.
In un ulteriore aspetto preferito, la soluzione viene concentrata, quindi viene aggiunto il solvente organico diverso da un C4-C7 alcol ed infine viene aggiunto l’acido protico (HX). In a further preferred aspect, the solution is concentrated, then the organic solvent other than a C4-C7 alcohol is added and finally the protic acid (HX) is added.
Il rapporto tra il C4-C7 alcol ed il solvente organico diverso come definito sopra nella miscela può tipicamente variare tra circa 10:1 (volume di C4-C7 alcol:volume solvente organico) e 1:10000 (v:v), preferibilmente tra circa 5:1 (v:v) e circa 1:1000 (v:v), più preferibilmente tra circa 2:1 (v:v) e circa 1:100 (v:v), ad esempio 1.1 (v:v), 1:2 (v:v), 1:5 (v:v), 1:10 (v:v) oppure 1:50 (v:v). Nel caso sia effettuata una concentrazione della soluzione di estrazione, il rapporto si riferisce al rapporto nella miscela dopo la concentrazione della soluzione di estrazione. The ratio between the C4-C7 alcohol and the different organic solvent as defined above in the mixture can typically vary between about 10: 1 (volume of C4-C7 alcohol: volume of organic solvent) and 1: 10000 (v: v), preferably between about 5: 1 (v: v) and about 1: 1000 (v: v), more preferably between about 2: 1 (v: v) and about 1: 100 (v: v), e.g. 1.1 (v: v ), 1: 2 (v: v), 1: 5 (v: v), 1:10 (v: v) or 1:50 (v: v). In case a concentration of the extraction solution is carried out, the ratio refers to the ratio in the mixture after the concentration of the extraction solution.
Il raffreddamento della soluzione di estrazione comprendente l’acido tauroursodesossicolico di formula (I), può essere effettuato ad una temperatura al di sotto di 5°C, preferibilmente a circa 0°C oppure inferiore, ad esempio a -5°C, -10°C oppure -20°C. Il raffreddamento può essere eseguito lentamente, ad esempio ad una velocità compresa tra circa 0,1 e 0,4°C al minuto. The cooling of the extraction solution comprising the tauroursodeoxycholic acid of formula (I), can be carried out at a temperature below 5 ° C, preferably at about 0 ° C or lower, for example at -5 ° C, -10 ° C or -20 ° C. Cooling can be performed slowly, for example at a rate of between about 0.1 and 0.4 ° C per minute.
L’aggiunta di un acido protico (HX) porta alla precipitazione di acido tauroursodesossicolico di formula (I), ma non degli altri acidi colanici, in particolare dell’acido ursodesossicolico di formula (II), oppure in una misura molto inferiore. The addition of a protic acid (HX) leads to the precipitation of tauroursodeoxycholic acid of formula (I), but not of the other cholanic acids, in particular of ursodeoxycholic acid of formula (II), or to a much lesser extent.
L’acido protico (HX) può essere un acido minerale oppure organico. Un acido minerale può essere ad esempio scelto nel gruppo comprendente l’acido solforico, l’acido fosforico ed un acido alogenidrico, che preferibilmente è acido cloridrico. Protic acid (HX) can be a mineral or organic acid. A mineral acid can for example be chosen from the group comprising sulfuric acid, phosphoric acid and a halogenhydric acid, which is preferably hydrochloric acid.
Un acido organico può essere ad esempio scelto nel gruppo comprendente un acido solfonico, tipicamente acido canforsolfonico, acido paratoluensolfonico, acido metansolfonico o acido trifluorometansolfonico; un acido aril-carbossilico, tipicamente acido benzoico; ed un acido C1-C4 alchil-carbossilico, dove il gruppo C1-C4 alchilico può essere lineare o ramificato, eventualmente sostituito da uno o più atomi di alogeno, preferibilmente da uno a tre atomi di cloro o fluoro, tipicamente acido acetico o acido trifluoroacetico. An organic acid can for example be selected from the group comprising a sulphonic acid, typically camphorsulfonic acid, paratoluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid; an aryl carboxylic acid, typically benzoic acid; and a C1-C4 alkyl-carboxylic acid, where the C1-C4 alkyl group can be linear or branched, possibly replaced by one or more halogen atoms, preferably from one to three chlorine or fluorine atoms, typically acetic acid or trifluoroacetic acid .
L’acido protico (HX) può essere utilizzato in quantità circa stechiometrica, oppure in eccesso, oppure in difetto rispetto alle moli dell’acido tauroursodesossicolico di formula (I), tipicamente da circa 0,5 a circa 4,0 moli di acido protico (HX) per mole di acido tauroursodesossicolico di formula (I), preferibilmente da circa 0,5 a circa 2,0 moli, più preferibilmente circa equimolare, ad esempio 0,6 moli, 0,7 moli, 0,8 moli, 0, 9 moli, 1,0 moli, 1,1 moli, 1,2 moli, 1,2 moli, 1,3 moli, 1,4 moli, 1,5 moli 1,6 moli, 1,7 moli, 1,8 moli, 1,9 moli, 2,0 moli, 2,5 moli, 3,0 moli, 3,5 moli oppure 4,0 moli di acido protico (HX) per mole di acido tauroursodesossicolico di formula (I). The protic acid (HX) can be used in approximately stoichiometric quantities, or in excess or in defect with respect to the moles of the tauroursodeoxycholic acid of formula (I), typically from about 0.5 to about 4.0 moles of protic acid (HX) per mole of tauroursodeoxycholic acid of formula (I), preferably from about 0.5 to about 2.0 moles, more preferably about equimolar, for example 0.6 moles, 0.7 moles, 0.8 moles, 0 , 9 moles, 1.0 moles, 1.1 moles, 1.2 moles, 1.2 moles, 1.3 moles, 1.4 moles, 1.5 moles 1.6 moles, 1.7 moles, 1, 8 moles, 1.9 moles, 2.0 moles, 2.5 moles, 3.0 moles, 3.5 moles or 4.0 moles of protic acid (HX) per mol of tauroursodeoxycholic acid of formula (I).
L’aggiunta dell’acido protico (HX) può essere effettuata a temperatura ambiente, oppure ad una temperatura inferiore oppure uguale a circa 20°C, preferibilmente compresa tra circa 0°C e circa 20°C, più preferibilmente compresa tra circa 5°C e circa 10°C, oppure può essere effettuata ad una temperatura superiore oppure uguale a circa 30°C, preferibilmente compresa tra circa 30°C e la temperatura di reflusso della miscela comprendente l’acido tauroursodesossicolico di formula (I), ad esempio a circa 40°C, a circa 50°C, a circa 60°C oppure a circa 70°C. The addition of the protic acid (HX) can be carried out at room temperature, or at a temperature lower than or equal to about 20 ° C, preferably between about 0 ° C and about 20 ° C, more preferably between about 5 ° C and about 10 ° C, or it can be carried out at a temperature higher than or equal to about 30 ° C, preferably between about 30 ° C and the reflux temperature of the mixture comprising the tauroursodeoxycholic acid of formula (I), for example about 40 ° C, about 50 ° C, about 60 ° C or about 70 ° C.
Un’aggiunta dell’acido protico (HX) a temperatura ambiente oppure superiore alla soluzione di estrazione dell’acido tauroursodesossicolico di formula (I) senza preventiva aggiunta del solvente organico diverso da un C4-C7 alcol non porta alla precipitazione del prodotto oppure a rese basse tali da rendere il procedimento non praticabile a livello industriale, quindi tale aggiunta senza preventiva aggiunta del solvente organico diverso da un C4-C7 alcol è tipicamente effettuata ad una temperatura inferiore a quella ambiente come riportato sopra. An addition of protic acid (HX) at room temperature or higher to the extraction solution of tauroursodeoxycholic acid of formula (I) without prior addition of the organic solvent other than a C4-C7 alcohol does not lead to precipitation of the product or to yields low such as to make the process impracticable at an industrial level, therefore this addition without prior addition of the organic solvent other than a C4-C7 alcohol is typically carried out at a temperature lower than the ambient one as reported above.
L’acido tauroursodesossicolico di formula (I) così ottenuto può essere ulteriormente purificato, ad esempio tramite cristallizzazione da acqua come descritto in IT 1197330 oppure EP 2 137 206, oppure tramite cromatografia come descritto in EP 0 629 634 oppure EP 0 400 695. The tauroursodeoxycholic acid of formula (I) thus obtained can be further purified, for example by crystallization from water as described in IT 1197330 or EP 2 137 206, or by chromatography as described in EP 0 629 634 or EP 0 400 695.
La dimensione dei cristalli dell’acido tauroursodesossicolico di formula (I) ottenuti in accordo al presente procedimento è caratterizzata da un valore di D90 compreso tra 5 e 250 µm, tipicamente sotto i 100 µm (Malvern Laser Diffraction Mastersizer 3000 con cella di misura Hydro 3000S). Se desiderato tale valore può essere ridotto mediante micronizzazione o fine molitura. The crystal size of the tauroursodeoxycholic acid of formula (I) obtained in accordance with the present procedure is characterized by a value of D90 between 5 and 250 µm, typically below 100 µm (Malvern Laser Diffraction Mastersizer 3000 with Hydro 3000S measuring cell ). If desired, this value can be reduced by micronization or fine milling.
La purezza dell’acido tauroursodesossicolico di formula (I) ottenuto in accordo ai procedimenti qui descritti è inaspettamente superiore a 98% valutata mediante analisi HPLC a 195 nm, ad esempio a 98,5%, 99,0%, 99,5% oppure superiore al 99,9%. The purity of the tauroursodeoxycholic acid of formula (I) obtained according to the procedures described herein is unexpectedly higher than 98% evaluated by HPLC analysis at 195 nm, for example at 98.5%, 99.0%, 99.5% or more than 99.9%.
L’acido tauroursodesossicolico di formula (I) utilizzato come materiale di partenza nella soluzione può essere una sua forma commerciale oppure un grezzo di reazione, ad esempio ottenuto tramite il seguente procedimento comprendente: The tauroursodeoxycholic acid of formula (I) used as starting material in the solution can be its commercial form or a raw reaction, for example obtained through the following procedure comprising:
a) la salificazione dell’acido ursodesossicolico di formula (II): a) the salification of ursodeoxycholic acid of formula (II):
con un’ammina terziaria alifatica oppure eteroaromatica; with an aliphatic or heteroaromatic tertiary amine;
b) il trattamento del sale dell’acido ursodesossicolico di formula (II) con un b) the treatment of the ursodeoxycholic acid salt of formula (II) with a
derivato di formula (III): derivative of formula (III):
dove R è scelto tra un gruppo consistente in un C1-C6 alchile, fenile oppure where R is selected from a group consisting of a C1-C6 alkyl, phenyl or
benzile; e benzyl; And
c) la reazione dell’anidride mista di formula (IV) ottenuta nel passaggio b): c) the reaction of the mixed anhydride of formula (IV) obtained in step b):
dove R è come sopra definito, where R is as defined above,
con taurina di formula (V) o un suo sale: with taurine of formula (V) or one of its salt:
opzionalmente in presenza di una base. optionally in the presence of a base.
Esempi di ammine terziarie alifatiche oppure eteroaromatiche sono trietilammina, tri-n-butilammina, metil-piperidina, etil-piperidina oppure piridina. Examples of aliphatic or heteroaromatic tertiary amines are triethylamine, tri-n-butylamine, methyl-piperidine, ethyl-piperidine or pyridine.
Un sale di taurina di formula (V) è preferibilmente un sale farmaceuticamente accettabile. Esempi di sali farmaceuticamente accettabili comprendono sali derivati da una base appropriata, quali sali di un metallo alcalino (come sodio oppure potassio), di un metallo alcalino terroso (come calcio oppure magnesio), di ammonio e NR’4<+>, dove R’ è un C1-C4 alchile. A taurine salt of formula (V) is preferably a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include salts derived from an appropriate base, such as salts of an alkali metal (such as sodium or potassium), of an alkaline earth metal (such as calcium or magnesium), of ammonium and NR'4 <+>, where R is a C1-C4 alkyl.
La base opzionale può essere, ad esempio, una base inorganica, tipicamente un idrossido di un metallo alcalino come ad esempio sodio idrossido o potassio idrossido, o alcalino terroso, come ad esempio calcio idrossido o bario idrossido, più preferibilmente un idrossido di sodio, potassio o bario; o un C1-C6 alcolato, ad esempio sodio o potassio etossido, o tert-butossido; oppure una base organica, quale un’ammina terziaria, ad esempio trietilammina o diisopropiletilammina. The optional base can be, for example, an inorganic base, typically an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or alkaline earth, such as calcium hydroxide or barium hydroxide, more preferably a sodium hydroxide, potassium or barium; or a C1-C6 alcoholate, for example sodium or potassium ethoxide, or tert-butoxide; or an organic base, such as a tertiary amine, for example triethylamine or diisopropylethylamine.
I seguenti esempi illustrano ulteriormente l’invenzione. The following examples further illustrate the invention.
Esempio 1 - Sintesi della soluzione acquosa dell’acido tauroursodesossicolico di formula (I) Example 1 - Synthesis of the aqueous solution of tauroursodeoxycholic acid of formula (I)
160 g (0,408 moli) di acido ursodesossicolico di formula (II) vengono salificati con circa 45,0 g (0,448 moli) di trietilammina in 1200 ml di metilisobutilchetone. 46 g (0,42 moli) di etil cloroformiato vengono aggiunti alla miscela mantenendo la temperatura non superiore a 25°C. La miscela di reazione così ottenuta viene raffreddata a circa 0°C e si aggiungono 60 g (0,40 moli) del sale sodico di taurina in 80 ml di acqua. Terminata l’aggiunta si lascia riscaldare a temperatura ambiente. Si separa la fase acquosa e si lava la fase organica tre volte con 80 ml di acqua. Le fasi acquose vengono unite e sottoposte alla purificazione come descritto nei seguenti esempi. 160 g (0.408 moles) of ursodeoxycholic acid of formula (II) are salified with about 45.0 g (0.448 moles) of triethylamine in 1200 ml of methyl isobutyl ketone. 46 g (0.42 moles) of ethyl chloroformate are added to the mixture maintaining the temperature not higher than 25 ° C. The reaction mixture thus obtained is cooled to about 0 ° C and 60 g (0.40 moles) of the sodium salt of taurine in 80 ml of water are added. Once the addition is complete, it is allowed to warm to room temperature. The aqueous phase is separated and the organic phase is washed three times with 80 ml of water. The aqueous phases are combined and subjected to purification as described in the following examples.
Esempio 2 - Purificazione dell’acido tauroursodesossicolico di formula (I) Example 2 - Purification of tauroursodeoxycholic acid of formula (I)
320 ml di 1-butanolo vengono aggiunti alla soluzione acquosa dell’acido tauroursodesossicolico di formula (I), ottenuto come descritto in Esempio 1, e la fase acquosa viene scartata. Un’analisi di un campione esiccato dell’estratto con butanolo ha un contenuto di acido tauroursodesossicolico di formula (I) di circa 30% e di acido ursodesossicolico di formula (II) di circa 3-5% (valutato mediante analisi HPLC a 195 nm). Si aggiungono circa 1500 ml di acetone alla soluzione organica e quindi 40 g di HCl a 37%. Il prodotto ottenuto viene isolato tramite filtrazione e dopo essiccazione si ottengono 96 g di tauroursodesossicolico di formula (I) con una resa dell’45% e dove il contenuto dell’acido ursodesossicolico di formula (II) è dello 0,16%. 320 ml of 1-butanol are added to the aqueous solution of tauroursodeoxycholic acid of formula (I), obtained as described in Example 1, and the aqueous phase is discarded. An analysis of a dried sample of the extract with butanol has a content of tauroursodeoxycholic acid of formula (I) of about 30% and of ursodeoxycholic acid of formula (II) of about 3-5% (evaluated by HPLC analysis at 195 nm ). About 1500 ml of acetone are added to the organic solution and then 40 g of HCl at 37%. The product obtained is isolated by filtration and after drying 96 g of tauroursodeoxycholic of formula (I) are obtained with a yield of 45% and where the content of ursodeoxycholic acid of formula (II) is 0.16%.
Esempio 3 - Purificazione dell’acido tauroursodesossicolico di formula (I) Example 3 - Purification of tauroursodeoxycholic acid of formula (I)
320 ml di 1-butanolo vengono aggiunte alla soluzione acquosa dell’acido tauroursodesossicolico di formula (I), così come ottenuto in Esempio 1, e la fase acquosa viene scartata. Si aggiungono ulteriori 480 ml di 1-butanolo e la miscela organica viene sottoposta a distillazione azeotropica fino ad ottenere una soluzione, dove il contenuto dell’acqua è 5% oppure inferiore. Si porta la soluzione ad una temperatura a circa 50°C e si aggiungono 800 ml di acetone e quindi 40 g di HCl 37%. Si mantiene la miscela a circa 50-60°C per circa 6 ore e quindi si raffredda a temperatura ambiente. Il prodotto ottenuto viene isolato tramite filtrazione, lavato con acetone e dopo essiccazione si ottengono 190 g di acido tauroursodesossicolico di formula (I) con una resa del 80%. 320 ml of 1-butanol are added to the aqueous solution of tauroursodeoxycholic acid of formula (I), as obtained in Example 1, and the aqueous phase is discarded. A further 480 ml of 1-butanol are added and the organic mixture is subjected to azeotropic distillation until a solution is obtained, where the water content is 5% or less. The solution is brought to a temperature of about 50 ° C and 800 ml of acetone and then 40 g of 37% HCl are added. The mixture is kept at about 50-60 ° C for about 6 hours and then it is cooled to room temperature. The product obtained is isolated by filtration, washed with acetone and after drying 190 g of tauroursodeoxycholic acid of formula (I) are obtained with a yield of 80%.
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