IT201900001923A1 - BAZEDOXIFENE SALTS USEFUL FOR THE PREPARATION OF BAZEDOXIFENE ACETATE - Google Patents
BAZEDOXIFENE SALTS USEFUL FOR THE PREPARATION OF BAZEDOXIFENE ACETATE Download PDFInfo
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- IT201900001923A1 IT201900001923A1 IT102019000001923A IT201900001923A IT201900001923A1 IT 201900001923 A1 IT201900001923 A1 IT 201900001923A1 IT 102019000001923 A IT102019000001923 A IT 102019000001923A IT 201900001923 A IT201900001923 A IT 201900001923A IT 201900001923 A1 IT201900001923 A1 IT 201900001923A1
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- IT
- Italy
- Prior art keywords
- bazedoxifene
- acid
- benzyloxy
- give
- acetate
- Prior art date
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- UCJGJABZCDBEDK-UHFFFAOYSA-N bazedoxifene Chemical class C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 UCJGJABZCDBEDK-UHFFFAOYSA-N 0.000 title claims description 62
- OMZAMQFQZMUNTP-UHFFFAOYSA-N acetic acid;1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methylindol-5-ol Chemical compound CC(O)=O.C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 OMZAMQFQZMUNTP-UHFFFAOYSA-N 0.000 title claims description 25
- 229960003713 bazedoxifene acetate Drugs 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 12
- 229960000817 bazedoxifene Drugs 0.000 claims description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 18
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 16
- 229960001860 salicylate Drugs 0.000 claims description 14
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- 235000010233 benzoic acid Nutrition 0.000 claims description 10
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 9
- 229960004889 salicylic acid Drugs 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000005711 Benzoic acid Substances 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims description 5
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000006386 neutralization reaction Methods 0.000 claims description 5
- NXAHBBRIVLXMQA-UHFFFAOYSA-N 1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-3-methyl-5-phenylmethoxy-2-(4-phenylmethoxyphenyl)indole Chemical compound C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(OCC=3C=CC=CC=3)C=C2C(C)=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 NXAHBBRIVLXMQA-UHFFFAOYSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- -1 azepan-1-yl Chemical group 0.000 claims description 4
- KRIJKJMYOVWRSJ-UHFFFAOYSA-N 3-methyl-5-phenylmethoxy-2-(4-phenylmethoxyphenyl)-1h-indole Chemical compound C1=C2C(C)=C(C=3C=CC(OCC=4C=CC=CC=4)=CC=3)NC2=CC=C1OCC1=CC=CC=C1 KRIJKJMYOVWRSJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 3
- 229960004050 aminobenzoic acid Drugs 0.000 claims description 3
- 229960004365 benzoic acid Drugs 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- FGCIQSBZGOVNLI-UHFFFAOYSA-N 1-[2-[4-(chloromethyl)phenoxy]ethyl]azepane Chemical compound C1=CC(CCl)=CC=C1OCCN1CCCCCC1 FGCIQSBZGOVNLI-UHFFFAOYSA-N 0.000 claims description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-M 4-aminobenzoate Chemical compound NC1=CC=C(C([O-])=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-M 0.000 claims description 2
- 229940068372 acetyl salicylate Drugs 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- KTUQUZJOVNIKNZ-UHFFFAOYSA-N butan-1-ol;hydrate Chemical compound O.CCCCO KTUQUZJOVNIKNZ-UHFFFAOYSA-N 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229940050390 benzoate Drugs 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001559 benzoic acids Chemical class 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PZDSVLOTAUAGAG-UHFFFAOYSA-N 3-methyl-2-(4-phenylmethoxyphenyl)-1h-indole Chemical compound N1C2=CC=CC=C2C(C)=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 PZDSVLOTAUAGAG-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 230000008416 bone turnover Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 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 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“SALI DI BAZEDOXIFENE UTILI PER LA PREPARAZIONE DI BAZEDOXIFENE ACETATO” "BAZEDOXIFENE SALTS USEFUL FOR THE PREPARATION OF BAZEDOXIFENE ACETATE"
L’invenzione riguarda nuovi sali di Bazedoxifene con acidi benzoici e il loro utilizzo per l’ottenimento di Bazedoxifene acetato (I) in elevata resa e purezza. The invention concerns new salts of Bazedoxifene with benzoic acids and their use to obtain Bazedoxifene acetate (I) in high yield and purity.
Sfondo dell’invenzione Background of the invention
Il Bazedoxifene acetato (1-[4-(2-azepan-1-il-etossi)benzil]-2-(4-idrossifenil)-3-metil-5-idrossiindolo acetato) di formula (I) è un modulatore selettivo dei recettori per gli estrogeni (SERM), registrato in Europa nel trattamento dell’osteoporosi post-menopausale in donne con aumentato rischio di fratture. Bazedoxifene acetate (1- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-hydroxyphenyl) -3-methyl-5-hydroxyindole acetate) of formula (I) is a selective modulator of estrogen receptors (SERMs), registered in Europe in the treatment of postmenopausal osteoporosis in women at increased risk of fractures.
Il composto agisce come agonista e/o antagonista recettoriale a seconda del tipo di cellula e tessuto. I suoi effetti sono simil-estrogenici a livello dell’osso (riduzione dei marcatori biochimici del turnover osseo e del riassorbimento) e del fegato (riduzione di colesterolo LDL e lipoproteine), mentre sono anti-estrogenici su endometrio e mammella. Sono in corso studi per il suo potenziale utilizzo nel trattamento del cancro della mammella e del pancreas. The compound acts as a receptor agonist and / or antagonist depending on the type of cell and tissue. Its effects are estrogenic-like at the bone level (reduction of biochemical markers of bone turnover and resorption) and the liver (reduction of LDL cholesterol and lipoproteins), while they are anti-estrogenic on the endometrium and breast. Studies are underway for its potential use in the treatment of breast and pancreatic cancer.
La preparazione del Bazedoxifene e dei suoi sali è descritta in numerosi documenti brevettuali, ad esempio in US 5998402, US 6479535, US 6005102, EP 0802183, EP 1025077, WO 2011022596 e in Journal of Medicinal Chemistry, Vol 44, 1564-1567, 2001. The preparation of Bazedoxifene and its salts is described in numerous patent documents, for example in US 5998402, US 6479535, US 6005102, EP 0802183, EP 1025077, WO 2011022596 and in Journal of Medicinal Chemistry, Vol 44, 1564-1567, 2001 .
L’intermedio chiave per la maggior parte delle sintesi descritte è il composto 3-metil-5-benzilossi-2-(4-benzilossifenil)-1H-indolo 1 che viene convertito a Bazedoxifene acetato (I) attraverso la via sintetica riportata nello Schema 1, che prevede l’alchilazione di 1 con 1-[2-[4-(clorometil)fenossi]etil]azepano di formula 2 in presenza di una base a dare l’intermedio 1-{4-[2-(azepan-1-il)etossi]benzil}-5-(benzilossi)-2-[4-(benzilossi)fenil]-3-metil-1H-indolo 3. L’idrogenazione catalitica di 3 fornisce Bazedoxifene base libera 4, che viene infine salificato con acido acetico a dare Bazedoxifene acetato (I). The key intermediate for most of the syntheses described is the compound 3-methyl-5-benzyloxy-2- (4-benzyloxyphenyl) -1H-indole 1 which is converted to Bazedoxifene acetate (I) by the synthetic route shown in the Scheme 1, which provides for the alkylation of 1 with 1- [2- [4- [4- (chloromethyl) phenoxy] ethyl] azepane of formula 2 in the presence of a base to give the intermediate 1- {4- [2- (azepan- 1-yl) ethoxy] benzyl} -5- (benzyloxy) -2- [4- (benzyloxy) phenyl] -3-methyl-1H-indole 3. The catalytic hydrogenation of 3 gives Bazedoxifene free base 4, which is finally salified with acetic acid to give Bazedoxifene acetate (I).
Schema 1 Scheme 1
US 2005/0227964 descrive il sale di Bazedoxifene con acido ascorbico per l’impiego come principio attivo. US 2005/0227964 describes the Bazedoxifene salt with ascorbic acid for use as an active ingredient.
WO 2009/012734 descrive sali di Bazedoxifene con acidi policarbossilici quali acido fumarico, succinico, ossalico, citrico e tartarico, o con acido formico. I sali con acidi policarbossilici, in particolare il sale fumarato, sono utili per la purificazione di Bazedoxifene, come rivendicato in US 8034807 e EP 21855108. WO 2009/012734 describes salts of Bazedoxifene with polycarboxylic acids such as fumaric, succinic, oxalic, citric and tartaric acids, or with formic acid. The salts with polycarboxylic acids, in particular the fumarate salt, are useful for the purification of Bazedoxifene, as claimed in US 8034807 and EP 21855108.
WO 2011/022596 descrive sali di Bazedoxifene con acidi forti quali acido cloridrico, acido metansolfonico, acido fosforico e acido solforico, utili per la purificazione di Bazedoxifene e per la successiva preparazione di Bazedoxifene acetato (I) dopo liberazione della base libera. WO 2011/022596 describes salts of Bazedoxifene with strong acids such as hydrochloric acid, methanesulfonic acid, phosphoric acid and sulfuric acid, useful for the purification of Bazedoxifene and for the subsequent preparation of Bazedoxifene acetate (I) after release of the free base.
WO 2012/007451 descrive il sale di Bazedoxifene con acido lattico, mentre WO 2012/007453 descrive il sale di Bazedoxifene con acido nicotinico e acido propionico, utili come principi attivi di composizioni. WO 2012/007451 describes the Bazedoxifene salt with lactic acid, while WO 2012/007453 describes the Bazedoxifene salt with nicotinic acid and propionic acid, useful as active ingredients of compositions.
Descrizione dell’invenzione Description of the invention
L’invenzione riguarda nuovi sali di Bazedoxifene con acidi benzoici e il loro utilizzo per l’ottenimento di Bazedoxifene acetato (I) in elevata resa e purezza. The invention concerns new salts of Bazedoxifene with benzoic acids and their use to obtain Bazedoxifene acetate (I) in high yield and purity.
Oggetto dell’invenzione è anche un procedimento per la preparazione di Bazedoxifene acetato (I) a partire da 1-{4-[2-(azepan-1-il)etossi]benzil}-5-(benzilossi)-2-[4-(benzilossi)fenil]-3-metil-1H-indolo 3 comprendente i seguenti passaggi: The subject of the invention is also a process for the preparation of Bazedoxifene acetate (I) starting from 1- {4- [2- (azepan-1-yl) ethoxy] benzyl} -5- (benzyloxy) -2- [4 - (benzyloxy) phenyl] -3-methyl-1H-indole 3 comprising the following steps:
a) deprotezione dei gruppi benzilici di 1-{4-[2-(azepan-1-il)etossi]benzil}-5-(benzilossi)-2-[4-(benzilossi)fenil]-3-metil-1H-indolo 3 a dare Bazedoxifene base libera 4 come intermedio non isolato; a) deprotection of 1- {4- [2- (azepan-1-yl) ethoxy] benzyl} -5- (benzyloxy) -2- [4- (benzyloxy) phenyl] -3-methyl-1H- benzyl groups indole 3 to give Bazedoxifene free base 4 as a non-isolated intermediate;
b) salificazione di 4 con un acido scelto tra acido salicilico, acido benzoico, acido p-amminobenzoico e acido acetilsalicilico a dare Bazedoxifene salificato con detti acidi 5; b) salification of 4 with an acid selected from salicylic acid, benzoic acid, p-aminobenzoic acid and acetylsalicylic acid to give Bazedoxifene salified with said acids 5;
c) isolamento di 5 e sua conversione in Bazedoxifene acetato (I). Il procedimento dell’invenzione è riassunto nello Schema 2. c) isolation of 5 and its conversion into Bazedoxifene acetate (I). The process of the invention is summarized in Scheme 2.
Schema 2 Scheme 2
In una realizzazione dell’invenzione, la deprotezione dei gruppi benzilici di 3 avviene impiegando idrogeno, o una sorgente di idrogeno quale ad esempio ammonio formiato, ammonio acetato, cicloesadiene, in presenza di un catalizzatore quale ad esempio nichel Raney, ossido di platino, platino o palladio supportati su carbone. La reazione viene condotta in un solvente inerte scelto tra: alcoli, quali ad esempio metanolo, etanolo, isopropanolo, butanolo e sec-butanolo; eteri, quali ad esempio tetraidrofurano e diossano; esteri, ad esempio acetato di etile, acetato di isopropile e acetato di terzbutile; idrocarburi aromatici, quali ad esempio toluene e xilene; e loro miscele. Si opera ad una temperatura compresa tra 10°C e 75°C, con tempi di reazione compresi tra 3 e 24 ore a seconda del tipo di catalizzatore impiegato, della sua quantità e della scala della reazione. In an embodiment of the invention, the deprotection of the benzyl groups of 3 takes place using hydrogen, or a source of hydrogen such as ammonium formate, ammonium acetate, cyclohexadiene, in the presence of a catalyst such as nickel Raney, platinum oxide, platinum or palladium supported on carbon. The reaction is carried out in an inert solvent selected from: alcohols, such as for example methanol, ethanol, isopropanol, butanol and sec-butanol; ethers, such as for example tetrahydrofuran and dioxane; esters, for example ethyl acetate, isopropyl acetate and tertzbutyl acetate; aromatic hydrocarbons, such as for example toluene and xylene; and their mixtures. The process is carried out at a temperature between 10 ° C and 75 ° C, with reaction times between 3 and 24 hours depending on the type of catalyst used, its quantity and the scale of the reaction.
Tipicamente si impiega idrogeno gassoso operando alla pressione di 2-4 atm in presenza di palladio supportato su carbone, in una miscela di toluene e sec-butanolo ad una temperatura compresa tra 40-80°C e, su una scala multichilogrammo, la reazione è tipicamente completa in 5 – 16 ore. Typically, hydrogen gas is used operating at a pressure of 2-4 atm in the presence of palladium supported on carbon, in a mixture of toluene and sec-butanol at a temperature between 40-80 ° C and, on a multi-kilogram scale, the reaction is typically complete in 5 to 16 hours.
Al termine della reazione il catalizzatore viene filtrato e alla soluzione di 4 così ottenuta viene aggiunta acqua e una quantità stechiometrica o un lieve eccesso molare, rispetto al prodotto di partenza 3, di un acido benzoico scelto tra acido salicilico, acido benzoico, acido p-amminobenzoico e acido acetilsalicilico. La massa di reazione viene tipicamente riscaldata ad una temperatura compresa tra 30-50°C ottenendosi la precipitazione di Bazedoxifene salificato con detti acidi 5 che viene isolato per raffreddamento a 0-5 °C seguito da filtrazione. Preferibilmente la salificazione di 4 è condotta in una miscela di acqua, toluene e sec-butanolo. In una realizzazione preferita Bazedoxifene base libera 4 è salificato con acido salicilico o con acido benzoico a dare, rispettivamente, Bazedoxifene salicilato 5a o Bazedoxifene benzoato 5b. L’impiego di acido salicilico per dare Bazedoxifene salicilato 5a è particolarmente preferito. At the end of the reaction, the catalyst is filtered and water and a stoichiometric quantity or a slight molar excess, with respect to the starting product 3, of a benzoic acid selected from salicylic acid, benzoic acid, p- acid are added to the 4 solution thus obtained. aminobenzoic and acetylsalicylic acid. The reaction mass is typically heated to a temperature between 30-50 ° C obtaining the precipitation of salified Bazedoxifene with said acids 5 which is isolated by cooling to 0-5 ° C followed by filtration. Preferably, the salification of 4 is carried out in a mixture of water, toluene and sec-butanol. In a preferred embodiment, Bazedoxifene free base 4 is salified with salicylic acid or with benzoic acid to give Bazedoxifene salicylate 5a or Bazedoxifene benzoate 5b, respectively. The use of salicylic acid to give Bazedoxifene salicylate 5a is particularly preferred.
I sali di Bazedoxifene con acidi benzoici vengono tipicamente ottenuti con rese superiori all’ 80%. Essi presentano una elevata purezza, tipicamente superiore al 99%, e possono essere impiegati per la preparazione di Bazedoxifene acetato (I) senza ulteriore purificazione. In particolare, Bazedoxifene salicilato 5a presenta una purezza HPLC superiore al 99,5%. Bazedoxifene salts with benzoic acids are typically obtained with yields greater than 80%. They have a high purity, typically greater than 99%, and can be used for the preparation of Bazedoxifene acetate (I) without further purification. In particular, Bazedoxifene salicylate 5a has an HPLC purity greater than 99.5%.
La conversione di Bazedoxifene salificato 5 in Bazedoxifene acetato (I) avviene mediante la neutralizzazione di Bazedoxifene salificato 5 con una base a dare Bazedoxifene base libera 4, seguita dalla salificazione di 4 con acido acetico a dare Bazedoxifene acetato (I). The conversion of salified Bazedoxifene 5 to Bazedoxifene acetate (I) occurs by neutralization of salified Bazedoxifene 5 with a base to give Bazedoxifene free base 4, followed by salification of 4 with acetic acid to give Bazedoxifene acetate (I).
Il passaggio di neutralizzazione viene tipicamente condotto a una temperatura compresa tra 20-25°C impiegando una base scelta tra ammoniaca e NaOH. La neutralizzazione viene tipicamente condotta in un sistema bifasico costituito da acqua e un solvente organico scelto tra toluene, secbutanolo, etile acetato e loro miscele. Preferibilmente la base è una soluzione acquosa di ammoniaca e si opera in un sistema bifasico costituito da acqua, sec-butanolo e toluene. Al termine della neutralizzazione la fase organica viene distillata sotto vuoto a dare Bazedoxifene base libera 4 che viene convertito in Bazedoxifene acetato (I) con metodi noti. The neutralization step is typically carried out at a temperature of between 20-25 ° C using a base chosen from ammonia and NaOH. Neutralization is typically carried out in a two-phase system consisting of water and an organic solvent selected from toluene, secbutanol, ethyl acetate and their mixtures. Preferably the base is an aqueous solution of ammonia and one operates in a two-phase system consisting of water, sec-butanol and toluene. At the end of the neutralization the organic phase is distilled under vacuum to give Bazedoxifene free base 4 which is converted into Bazedoxifene acetate (I) by known methods.
In una realizzazione dell’invenzione, il procedimento dell’invenzione comprende la preparazione di 1-{4-[2-(azepan-1-il)etossi]benzil}-5-(benzilossi)-2-[4-(benzilossi)fenil]-3-metil-1H-indolo 3 per reazione di 3-metil-5-benzilossi-2-[4-(benzilossi)fenil]-1H-indolo 1 con 1-(2-[4-(clorometil)fenossi]etil]esaidro-1H-azepina 2, o un suo sale, preferibilmente il sale cloridrato, in presenza di una base, secondo metodi noti. In an embodiment of the invention, the process of the invention comprises the preparation of 1- {4- [2- (azepan-1-yl) ethoxy] benzyl} -5- (benzyloxy) -2- [4- (benzyloxy) phenyl] -3-methyl-1H-indole 3 by reaction of 3-methyl-5-benzyloxy-2- [4- (benzyloxy) phenyl] -1H-indole 1 with 1- (2- [4- (chloromethyl) phenoxy ] ethyl] hexahydro-1H-azepine 2, or a salt thereof, preferably the hydrochloride salt, in the presence of a base, according to known methods.
I sali di Bazedoxifene 5a-d sono nuovi. Un ulteriore aspetto dell’invenzione è pertanto un composto scelto tra Bazedoxifene salicilato 5a, Bazedoxifene benzoato 5b, Bazedoxifene p-amminobenzoato 5c e Bazedoxifene acetilsalicilato 5d, preferibilmente Bazedoxifene salicilato 5a. The salts of Bazedoxifene 5a-d are new. A further aspect of the invention is therefore a compound selected from Bazedoxifene salicylate 5a, Bazedoxifene benzoate 5b, Bazedoxifene p-aminobenzoate 5c and Bazedoxifene acetylsalicylate 5d, preferably Bazedoxifene salicylate 5a.
Bazedoxifene acetato (I) ottenuto mediante il procedimento dell’invenzione è sostanzialmente privo delle tipiche impurezze che accompagnano i procedimenti di sintesi di questo principio attivo. Bazedoxifene acetate (I) obtained by the process of the invention is substantially devoid of the typical impurities that accompany the processes of synthesis of this active ingredient.
In particolare, l’impiego dei sali 5a-d nella sintesi di Bazedoxifene acetato (I) presenta vantaggi in termini sia di resa sia di purezza rispetto ai sali di Bazedoxifene descritti in WO 2009012734 e in WO 2011022596. In particular, the use of 5a-d salts in the synthesis of Bazedoxifene acetate (I) has advantages in terms of both yield and purity compared to the Bazedoxifene salts described in WO 2009012734 and in WO 2011022596.
Ad esempio, US 8034807 e EP 2185510, derivanti da WO 2009012734, rivendicano Bazedoxifene fumarato (sale con stechiometrica 2:1) come intermedio per ottenere Bazedoxifene acetato (I) puro. Sebbene gli esempi di questi documenti riportino una resa maggiore del 90% e l’ottenimento di una purezza superiore al 99% per Bazedoxifene fumarato, la ripetizione da parte degli inventori della presente invenzione della procedura in essi descritta a partire dall’intermedio 3 porta all’ottenimento di Bazedoxifene fumarato con una resa inferiore al 60% ed una purezza HPLC minore del 98%. Sorprendentemente, il procedimento della presente invenzione permette di ottenere Bazedoxifene salicilato 5a con una resa maggiore dell’80% ed una purezza superiore al 99,5%, dal quale si ottiene Bazedoxifene acetato (I) con una resa maggiore del 90% ed una purezza superiore al 99,9%. For example, US 8034807 and EP 2185510, deriving from WO 2009012734, claim Bazedoxifene fumarate (salt with stoichiometric 2: 1) as an intermediate to obtain pure Bazedoxifene acetate (I). Although the examples in these documents report a yield greater than 90% and a purity greater than 99% obtained for Bazedoxifene fumarate, the repetition by the inventors of the present invention of the procedure described therein starting from intermediate 3 leads to Obtaining Bazedoxifene fumarate with a yield lower than 60% and an HPLC purity lower than 98%. Surprisingly, the process of the present invention allows to obtain Bazedoxifene salicylate 5a with a yield greater than 80% and a purity greater than 99.5%, from which Bazedoxifene acetate (I) is obtained with a yield greater than 90% and a purity more than 99.9%.
I sali di Bazedoxifene 5a-d sono vantaggiosi anche rispetto ai sali di Bazedoxifene con vari acidi forti, rivendicati in WO 2011022596 come utili nella purificazione di Bazedoxifene base 4. In prove di salificazione di Bazedoxifene base 4 con acido cloridrico o acido solforico gli inventori della presente invenzione hanno trovato che il prodotto tende a decomporsi e a colorarsi, generando varie impurezze non note. The salts of Bazedoxifene 5a-d are also advantageous over the salts of Bazedoxifene with various strong acids, claimed in WO 2011022596 as useful in the purification of Bazedoxifene base 4. In salification tests of Bazedoxifene base 4 with hydrochloric acid or sulfuric acid the inventors of the present invention have found that the product tends to decompose and color, generating various unknown impurities.
L’invenzione è ora illustrata dai seguenti esempi. The invention is now illustrated by the following examples.
Esempio 1: Preparazione del Bazedoxifene salicilato 5a Example 1: Preparation of Bazedoxifene salicylate 5a
In un reattore inox o smaltato, capace di idrogenare, si caricano 29,4 Kg (0,04517 moli) di 1-{4-[2-(azepan-1-il)etossi]benzil}-5-(benzilossi)-2-[4-(benzilossi)fenil]-3-metil-1H-indolo 3, 73,5 kg di toluolo, 73,5 kg di alcool butilico secondario e 0,75 Kg di Pd/C al 5%. 29.4 Kg (0.04517 moles) of 1- {4- [2- (azepan-1-yl) ethoxy] benzyl} -5- (benzyloxy) - are loaded into a stainless steel or enamelled reactor, capable of hydrogenating. 2- [4- (benzyloxy) phenyl] -3-methyl-1H-indole 3, 73.5 kg of toluene, 73.5 kg of secondary butyl alcohol and 0.75 kg of 5% Pd / C.
Si idrogena a 40-80°C 2- 4 atm di pressione di idrogeno per alcun ore. Alla fine della reazione il catalizzatore viene filtrato e si aggiungono alla soluzione 7,1 kg (0,0514 moli) di acido salicilico e 117,6 Kg di acqua distillata. La massa di reazione è scaldata a 30-50°C fino a ottenere cristallizzazione. Si raffredda a 0-5°C e si centrifuga lavando con 29,4 Kg di toluolo e poi con 29,4 Kg di acqua distillata. Dopo essiccamento si ottengono circa 21,0 Kg di Bazedoxifene salicilato 5a avente una purezza HPLC del 99,74%. It is hydrogenated at 40-80 ° C 2- 4 atm of hydrogen pressure for a few hours. At the end of the reaction the catalyst is filtered and 7.1 kg (0.0514 moles) of salicylic acid and 117.6 kg of distilled water are added to the solution. The reaction mass is heated to 30-50 ° C until crystallization is obtained. It is cooled to 0-5 ° C and centrifuged by washing with 29.4 kg of toluene and then with 29.4 kg of distilled water. After drying, about 21.0 kg of Bazedoxifene salicylate 5a are obtained, having an HPLC purity of 99.74%.
Resa: 80,9%. Yield: 80.9%.
Esempio 2 - Preparazione del Bazedoxifene benzoato 5b Example 2 - Preparation of Bazedoxifene benzoate 5b
La procedura dell’esempio 1 viene ripetuta impiegando 6,3 Kg (0,0514 moli) di acido benzoico in luogo dell’acido salicilico. The procedure of example 1 is repeated using 6.3 kg (0.0514 moles) of benzoic acid in place of salicylic acid.
Si ottengono 21,8 Kg di Bazedoxifene benzoato 5b avente purezza HPLC >99,5%. 21.8 Kg of Bazedoxifene benzoate 5b are obtained with HPLC purity> 99.5%.
Resa: 82,5%. Yield: 82.5%.
Esempio 3: Preparazione del Bazedoxifene acetato (I) Example 3: Preparation of Bazedoxifene acetate (I)
In un reattore inox o smaltato si caricano 21,0 Kg (0,0345 moli) di Bazedoxifene salicilato 5a, 42,0 Kg di alcool butilico secondario, 42,0 Kg di toluolo, 84 Kg di acqua distillata e 2,52 Kg (0,0445 moli) di ammoniaca 30%. Si agita a 20-25°C. Una volta ottenuta soluzione completa, la fase acquosa inferiore viene separata ed eliminata. La fase organica viene distillata sottovuoto fino a dare un residuo denso ma agitabile. Al residuo vengono aggiunti 231 Kg di acetone. Si scalda a 35-55°C fino ad ottenere soluzione completa, quindi si colano 2,31 Kg (0,0385 moli) di acido acetico glaciale. La massa precipitata viene mantenuta a 35-55°C per circa 30’, quindi si raffredda a 0-5°C e si centrifuga lavando con 21,0 Kg di acetone. Dopo essiccamento si ottengono circa 17,0 Kg di Bazedoxifene acetato avente purezza HPLC > 99,9%. 21.0 Kg (0.0345 moles) of Bazedoxifene salicylate 5a, 42.0 Kg of secondary butyl alcohol, 42.0 Kg of toluene, 84 Kg of distilled water and 2.52 Kg ( 0.0445 mol) of ammonia 30%. It is stirred at 20-25 ° C. Once complete solution is obtained, the lower aqueous phase is separated and eliminated. The organic phase is distilled under vacuum to give a dense but agitable residue. 231 Kg of acetone are added to the residue. The mixture is heated to 35-55 ° C until complete solution is obtained, then 2.31 Kg (0.0385 moles) of glacial acetic acid are poured. The precipitated mass is kept at 35-55 ° C for about 30 ', then it is cooled to 0-5 ° C and centrifuged by washing with 21.0 kg of acetone. After drying, about 17.0 kg of Bazedoxifene acetate are obtained having an HPLC purity> 99.9%.
Resa: 92,9 % Yield: 92.9%
Esempio 4: Preparazione del Bazedoxifene acetato (I) Example 4: Preparation of Bazedoxifene acetate (I)
La procedura dell’esempio 3 viene ripetuta impiegando 20,4 Kg (0,0345 moli) di Bazedoxifene benzoato 5b in luogo di Bazedoxifene salicilato 5a. The procedure of Example 3 is repeated using 20.4 Kg (0.0345 moles) of Bazedoxifene benzoate 5b in place of Bazedoxifene salicylate 5a.
Si ottengono circa 16,7 Kg di Bazedoxifene acetato (I) avente purezza HPLC > 99,5%. About 16.7 Kg of Bazedoxifene acetate (I) are obtained having HPLC purity> 99.5%.
Resa: 91%. Yield: 91%.
Claims (11)
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