WO2008010022A2 - A process for preparation of racemic nebivolol - Google Patents
A process for preparation of racemic nebivolol Download PDFInfo
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- WO2008010022A2 WO2008010022A2 PCT/IB2006/004280 IB2006004280W WO2008010022A2 WO 2008010022 A2 WO2008010022 A2 WO 2008010022A2 IB 2006004280 W IB2006004280 W IB 2006004280W WO 2008010022 A2 WO2008010022 A2 WO 2008010022A2
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- WIPO (PCT)
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- compound
- configuration
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- diastereomers
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- 238000000034 method Methods 0.000 title claims abstract description 234
- 230000008569 process Effects 0.000 title claims abstract description 169
- 229960000619 nebivolol Drugs 0.000 title description 90
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 title description 78
- 238000002360 preparation method Methods 0.000 title description 70
- 150000001875 compounds Chemical class 0.000 claims abstract description 561
- 150000003839 salts Chemical class 0.000 claims abstract description 73
- 239000000203 mixture Substances 0.000 claims description 215
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 103
- 239000002904 solvent Substances 0.000 claims description 86
- 238000006243 chemical reaction Methods 0.000 claims description 83
- 230000015572 biosynthetic process Effects 0.000 claims description 76
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 69
- 239000002585 base Substances 0.000 claims description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 65
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 60
- 238000001640 fractional crystallisation Methods 0.000 claims description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 57
- -1 chloro, bromo, iodo Chemical group 0.000 claims description 56
- 125000006239 protecting group Chemical group 0.000 claims description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- 238000002425 crystallisation Methods 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 40
- 230000009467 reduction Effects 0.000 claims description 39
- 239000003054 catalyst Substances 0.000 claims description 33
- 238000004064 recycling Methods 0.000 claims description 33
- 239000003153 chemical reaction reagent Substances 0.000 claims description 30
- 239000002002 slurry Substances 0.000 claims description 29
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 27
- 230000008025 crystallization Effects 0.000 claims description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 239000003960 organic solvent Substances 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 238000006114 decarboxylation reaction Methods 0.000 claims description 20
- 238000001212 derivatisation Methods 0.000 claims description 20
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 20
- 125000006242 amine protecting group Chemical group 0.000 claims description 19
- 125000004122 cyclic group Chemical group 0.000 claims description 19
- 238000010511 deprotection reaction Methods 0.000 claims description 19
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 19
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 18
- 230000007062 hydrolysis Effects 0.000 claims description 18
- 238000006460 hydrolysis reaction Methods 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 16
- 239000006227 byproduct Substances 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 15
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 15
- 238000001953 recrystallisation Methods 0.000 claims description 15
- 230000026030 halogenation Effects 0.000 claims description 14
- 238000005658 halogenation reaction Methods 0.000 claims description 14
- 238000006884 silylation reaction Methods 0.000 claims description 14
- 150000008282 halocarbons Chemical class 0.000 claims description 13
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- 239000002841 Lewis acid Substances 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 12
- 150000007517 lewis acids Chemical class 0.000 claims description 12
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical group C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 11
- 150000001298 alcohols Chemical class 0.000 claims description 11
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 150000007524 organic acids Chemical class 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 150000002170 ethers Chemical class 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical group [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 9
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 8
- 230000009466 transformation Effects 0.000 claims description 8
- 239000011592 zinc chloride Substances 0.000 claims description 8
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 7
- 230000031709 bromination Effects 0.000 claims description 7
- 238000005893 bromination reaction Methods 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 7
- 150000003512 tertiary amines Chemical class 0.000 claims description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 150000001409 amidines Chemical class 0.000 claims description 6
- 239000003849 aromatic solvent Substances 0.000 claims description 6
- 230000002140 halogenating effect Effects 0.000 claims description 6
- 239000011701 zinc Substances 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000004703 alkoxides Chemical class 0.000 claims description 5
- 230000029936 alkylation Effects 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 238000010931 ester hydrolysis Methods 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000003880 polar aprotic solvent Substances 0.000 claims description 5
- 239000010936 titanium Substances 0.000 claims description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 238000007126 N-alkylation reaction Methods 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- MASDFXZJIDNRTR-UHFFFAOYSA-N 1,3-bis(trimethylsilyl)urea Chemical compound C[Si](C)(C)NC(=O)N[Si](C)(C)C MASDFXZJIDNRTR-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 150000001805 chlorine compounds Chemical class 0.000 claims description 3
- 230000005595 deprotonation Effects 0.000 claims description 3
- 238000010537 deprotonation reaction Methods 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 125000005207 tetraalkylammonium group Chemical group 0.000 claims description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 2
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 229910001513 alkali metal bromide Inorganic materials 0.000 claims description 2
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 claims description 2
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 claims description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 2
- 230000001131 transforming effect Effects 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims 1
- 229910052719 titanium Inorganic materials 0.000 claims 1
- 239000000243 solution Substances 0.000 description 77
- 239000000047 product Substances 0.000 description 52
- 239000000725 suspension Substances 0.000 description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 239000000543 intermediate Substances 0.000 description 41
- 238000003786 synthesis reaction Methods 0.000 description 40
- 238000006722 reduction reaction Methods 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000006345 epimerization reaction Methods 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 30
- 239000007787 solid Substances 0.000 description 23
- 238000000926 separation method Methods 0.000 description 22
- 150000002924 oxiranes Chemical class 0.000 description 21
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- 230000037361 pathway Effects 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 17
- 239000012043 crude product Substances 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 239000012452 mother liquor Substances 0.000 description 14
- 229960004592 isopropanol Drugs 0.000 description 13
- JOIVVMUMDLHKRF-UHFFFAOYSA-N 2-chloro-1-(6-fluoro-3,4-dihydro-2h-chromen-2-yl)ethanone Chemical compound O1C(C(=O)CCl)CCC2=CC(F)=CC=C21 JOIVVMUMDLHKRF-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 11
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 0 *NCC(C(CCc1c2)Oc1ccc2F)O Chemical compound *NCC(C(CCc1c2)Oc1ccc2F)O 0.000 description 10
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 150000001299 aldehydes Chemical class 0.000 description 10
- 229940093499 ethyl acetate Drugs 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 229940068174 nebivolol hydrochloride Drugs 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- VNNYULIAEDNUCA-UHFFFAOYSA-N [2-[[benzyl-[[6-fluoro-2-(hydroxymethyl)-3,4-dihydrochromen-2-yl]methyl]amino]methyl]-6-fluoro-3,4-dihydrochromen-2-yl]methanol Chemical compound C1CC2=CC(F)=CC=C2OC1(CO)CN(CC1(CO)OC2=CC=C(F)C=C2CC1)CC1=CC=CC=C1 VNNYULIAEDNUCA-UHFFFAOYSA-N 0.000 description 9
- 238000003776 cleavage reaction Methods 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 230000007017 scission Effects 0.000 description 9
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- ZNJANLXCXMVFFI-UHFFFAOYSA-N 6-fluoro-3,4-dihydro-2h-chromene-2-carboxylic acid Chemical compound FC1=CC=C2OC(C(=O)O)CCC2=C1 ZNJANLXCXMVFFI-UHFFFAOYSA-N 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 238000002955 isolation Methods 0.000 description 7
- JWEXHQAEWHKGCW-VCVZPGOSSA-N (S,R,R,R)-nebivolol hydrochloride Chemical compound [Cl-].C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)C[NH2+]C[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 JWEXHQAEWHKGCW-VCVZPGOSSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000002009 diols Chemical class 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 238000010899 nucleation Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- ODAHUOSPKOMSBG-UHFFFAOYSA-N 1-(6-fluoro-3,4-dihydro-2h-chromen-2-yl)ethanone Chemical compound FC1=CC=C2OC(C(=O)C)CCC2=C1 ODAHUOSPKOMSBG-UHFFFAOYSA-N 0.000 description 5
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
- 238000005580 one pot reaction Methods 0.000 description 5
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- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 238000011917 diastereoselective reduction Methods 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002081 enamines Chemical group 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- LOOOEJSEKGSZMU-UHFFFAOYSA-N ethyl 3-(6-fluoro-3,4-dihydro-2h-chromen-2-yl)-3-oxopropanoate Chemical compound FC1=CC=C2OC(C(=O)CC(=O)OCC)CCC2=C1 LOOOEJSEKGSZMU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 125000005283 haloketone group Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004269 oxiran-2-yl group Chemical group [H]C1([H])OC1([H])* 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000000075 primary alcohol group Chemical group 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- ZRRXKKCBXKWYKK-UHFFFAOYSA-N tert-butyl 3-(6-fluoro-3,4-dihydro-2h-chromen-2-yl)-3-oxopropanoate Chemical compound FC1=CC=C2OC(C(=O)CC(=O)OC(C)(C)C)CCC2=C1 ZRRXKKCBXKWYKK-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates to a novel process for preparation of racemic Nebivolol, its enantiomeric compounds and to novel compounds made by the process. 2. DESCRIPTION OF RELATED ART
- Nebivolol (see Figure IA, showing d-Nebivolol, chemical name: [2R*[R*[R*(S*)]]]- ⁇ > ⁇ s -[iminobis(methylene)]bis[6-fluoro-3 5 4-dihydro-2H-l-benzopyran-2-methanol] or alternatively [2R*[R*[R*(S*)]]l- ⁇ , ⁇ v -[iminobis(methyIene)]bis[6-fluoro-chroman-2-methanol] and Figure IB showing a racemic Nebivolol, which is a mixture of 1- and d- Nebivolol) is known as an adrenergic beta-antagonist, an antihypertensive agent, a platelet aggregation inhibitor and a vasodilating agent.
- Nebivolol is administered as tablets (e.g. , a dosage of 5.45 mg Nebivolol hydrochloride is equivalent to 5 mg Nebivolol) which contain Nebivolol as a racemic mixture of enantiomers SRRR-Nebivolol (dextro cf-Nebivolol) and RSSS-Nebivolol ⁇ levo /-Nebivolol).
- Nebivolol contains four asymmetric centers, and therefore 16 stereoisomers are theoretically possible. However, because of the particular constitution of the structures and configurations of the stereoisomers (e.g., axial symmetry), only 10 stereoisomers (6 diastereomers: 4 dl forms and 2 meso forms) can be formed (Table 1).
- Nebivolol Hydrochloride could be obtained only in a very low yield of 6.6%.
- a PCT patent application publication WO 2004/041805 (Egis Gyogyszergyar RT.) describes a new process for the preparation of racemic [2S[2R*[R[R*]]]] and [2R[2S*[S[S*]]]]- (+) ⁇ , ⁇ s -[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-l-benzopyran-2-methanol] and its pure [2S[2R*[R[R*]]]]]-, and [2R[2S*[S[S*]]]]] enantiomers.
- the racemates a6 or a7 can be transformed by reacting with benzylamine to the corresponding benzylated aminoalkohols a8 and a9.
- a benzyl protected Nebivolol AB mixture alO may be prepared by reacting of the racemate a8 (RS/SR) with the epoxide racemate a6 (RR/SS) or by reacting of racemate a9 (RR/SS) with the epoxide racemate a7 (RS/SR).
- the protecting group may be removed in the final step by catalytic hydrogenation to give a Nebivolol AB mixture all.
- Scheme Ib shows further methods for the synthesis of the analogous 2-chromanyl- aldehydes (al4) and 2-oxiranyl-chromanes (al6) as key intermediates for the synthesis of Nebivolol derivatives having different substituents at the aromatic moiety.
- the aldehyde al4 can be obtained by low temperature reduction of the imidazolide of al2 or by the same reduction of the ester al3.
- the aldehyde al4 is then converted into the 2- oxiranyl-chromans al6 by reaction with sodium hydride and trimethyl sulfoxonium iodide in dimethyl sulfoxide in an analogous reaction as described above.
- 2-oxiranyI-chromans al6 Another possibility for the synthesis of 2-oxiranyI-chromans al6 is the oxidation of 2-vinylchroman al5 with 3- chlorobenzenecarboperoxide (the source of 2-vinylchroman al5 is not described in these patents but according to EP 0334429 (see also below), compound al4 can be converted into compound al5 by a Wittig reaction).
- Scheme 1 c demonstrates that diastereomeric mixtures consisting of desired and undesired diastereomers (i.e., RSSS/SRRR and RSRR/SRSS) can be produced by the method shown in Scheme Ia.
- aldehyde a5 is very unstable as stated in a PCT publication WO 2004/041805;
- a6/a7 from a5 may be hazardous because it is known that the use of sodium hydride in solvents like DMSO, dimethylformamide (DMF), dimethylacetam ⁇ de (DMA) and DMI can cause an exotherm and therefore, cause a runaway reaction (see UK Chemical Reaction Hazards Forum: "Sodium Hydride/DMF process stopped”);
- the (S)-6- fluoro-chroman-2-yl-carboxylic acid b4 was first converted to the aldehyde b5 according to the procedure, already mentioned in scheme Ib.
- the epoxide b6 could be then obtained by reacting of b5 with sodium hydride and trimethyl sulfoxonium iodide in dimethyl sulfoxide.
- the (R)-6-fluoro-chroman-2-yl-carboxylic acid b8 was first esterified to b9.
- Epoxide blO was synthesized in a one-pot procedure by reduction of b9 to the corresponding aldehyde followed by reaction with sodium hydride and trimethyl sulfoxonium iodide in dimethyl sulfoxide.
- the epoxide ring of blO was opened by substitution with benzylamine to give the second key fragment bll , which was then reacted with the epoxide b6 to obtain benzyl-protected Z-Nebivolol bl2.
- Final deprotection by catalytical hydrogenation of bl2 gave /-Nebivolol.
- WO 2004/041805 describes the enantioselective synthesis of d- and /-Nebivolol (see Schemes 3a-c).
- the compound c4 was then reacted separately with protected glycerinealdehydes c6 (obtained from vitamin C) to give ell and cl2 or with c8 (obtained from D-mannitol) to give cl3 and el4 after the cycling.
- the enantiomeric J-Nebivolol was prepared in the analogous fashion, wherein the starting compounds were the S,R-isomer cl3 and R,R-isomer cl4 of isopropylidene protected (T, ,2 s - dihydroxy-ethyl)-6-fluoro-chroman-4-one (pathways 3 and 4, Scheme 3c).
- Racemic Nebivolol was obtained by preparing a 1 : 1 mixture of the intermediates c23 and c33 before performing the last hydrogenation step (yield 52%).
- the strategy is based on the syntheses of the chiral chroman fragments dl2 (R, R- configuration) and d21 (S, S-configuration) as key intermediates in convergent pathways which are finally coupled to give, after deprotection, J-Nebivolol.
- the essential step for the syntheses of these chiral chromans is the Zr-catalyzed kinetic resolution of the racemic intermediates d7 and dl6.
- the starting material for the preparation of chromane fragment dl2 was the salicylic aldehyde d3, which was synthesized either by formylation of compound dl or by reaction of the lithiated compound d2 at -6O 0 C with DMF.
- the allylic cycloheptene epoxide which could be obtained by epoxidation of cycloheptadiene was then reacted with aldehyde d4 to give the racemic compound d7 by a regioselective and stereoselective nucleophilic opening of epoxide d8.
- Wacker oxidation of the terminal double bond and subsequent catalytic hydrogenation delivered intermediate dl9, which was further converted by a photochemical Norrish type II cleavage and ozonolysis into the aldehyde d21.
- Z)-Nebivolol was then obtained by reductive amination of compounds dl2 and d21 followed by removal of the silyl ether protection groups.
- step of preparing compound dl2 from dll requires low temperature (-78 0 C) and special equipment for the ozonolysis;
- the basis for the enantioselective strategy is the asymmetric one-pot Sharpless epoxidation of allyl alcohol e7 using (-)-DET and (+)-DET to provide both enantiomeric diols e8 and el2 after a cyclization step.
- the starting compound was 4-fluoro-phenol el, which was first converted into the allylether e2. Claisen rearrangement at 21O 0 C followed by protection of the phenol group (e3) with TBDMS-Cl gave the intermediate e4.
- the primary alcohol e5 was obtained by hydroboration and subsequent oxidative treatment using H 2 O 2 .
- This product was converted into the ⁇ , ⁇ -unsaturated ester e6 by one pot oxidation with Dess-Martin periodane and Wittig olefination. Afterwards, the compound e6 was reduced with DIBAL-H to the allyl alcohol el.
- the route was divided into two pathways each starting with the asymmetric Sharpless epoxidation and cyclization in one pot.
- the diol e8 could be obtained in 65% yield by using (-)-DET.
- Selective tosylation of the primary alcohol e8 and substitution of e9 with azide followed by catalytical reduction of elO gave the aminoalcohol ell.
- the diol el2 was synthesized in an almost similar manner as diol e8 but with the exception that (+)-DET was used for the Sharpies epoxidation to give the corresponding enantiomeric compound.
- Step of making compound e3 from e2 requires high temperature for the Claisen rearrangement, which is not practicable a in scale-up procedure;
- the present invention provides new compounds and intermediates as well as processes that can be used directly for the selective synthesis of Nebivolol or racemic ([2S*[R*[R[R*]]]]]- and ([2R*[S*[S[S*]]]]]-( ⁇ )- alpha,alpha' -[imino-bis(methylene)]bis[6-fluoro-chroman-2- methanol] of the formula (I) and its pure ([2S[2R*[R[R*]]]]]- and ([2R*[S*[S[S*]]]]]- enantiomeric compounds and pharmaceutically acceptable salts thereof.
- LG is a member selected from the group consisting of chloro, bromo, iodo, alkylsulfonyloxy and arylsufonyloxy;
- RSSS/SRRR diastereomeric mixture having a ratio of a RSSS/SRRR diastereomeric configuration to a SRSR or RRSS diastereomeric configuration, wherein said ratio is at least
- RSSS/SRRR (I) PG Bn separated from major RSSS/SRRR (Xa)
- the starting compound is the 6-fluoro-chroman-2-carboxylic acid II, which is converted by appropriate transformations (steps 1, 2, and 3) into compound V bearing a suitable leaving group (LG).
- Coupling of compound Villa with compound V gives a diastereomeric mixture of compounds IXa and Xb, whereupon compound IXa is selectively isolated and almost selectively reduced to a mixture of compounds Xa (major) and Xb (minor). This mixture is then deprotected, and after salt formation using HCl, racemic Nebivolol hydrochloride I is selectively crystallized. The overall yield is 8%; however, additional amounts of compound V used for step 7 were not taken into account.
- the protecting group is a benzyl group.
- the leaving group is a chloro or bromo group.
- step (b) the compound of formula (V) is provided in the amount of about 1.0 to about 1.5 equivalents.
- the organic solvent is a polar aprotic solvent selected from the group consisting of DMF, DMA and NMP.
- the base is at least one of tertiary amines, alkali metal carbonate or alkali metal hydrogen carbonate.
- the base is sodium hydrogen carbonate.
- about 1.5 to about 2.5 equivalents of the base are used.
- catalyst in step (c) is at least one of alkali metal bromides, alkali metal iodides, tetraalkyl ammonium bromides or tetraalkylammonium iodides.
- the catalyst is sodium bromide.
- about 0.1 to about 0.25 equivalents of the catalyst are used and most preferably, 0.15 equivalents of the catalysts are used.
- step (c) said N-alkylation is carried out at a temperature between about room temperature and about 80 0 C.
- step (d) the fractional crystallization is carried out in a solvent.
- the solvent is acetonitrile.
- a free amine is used for the fractional crystallization.
- about 0.4/n to about 0.6/n equivalents of the silylating reagent are used and n is an amount of transferred silyl groups per the silylating reagent.
- the silylating reagent is at least one of trimethylsilyl chloride, HMDS or BSU.
- a silylation reagent is used for derivatization prior to the fractional crystallization from the solvent.
- the derivatization is carried out in the presence of about 1.0 to about 2.0 equivalents of a base.
- the base is imidazole.
- step (dl) said separating the diastereomers of the compound of formula (IX) or the compound of formula (IX') is carried out in acetonitrile, methyl tert-butyl ether (MTBE), cyclohexane or mixtures thereof.
- step (d2) is carried out for the RSR/SRS configuration of the compound of formula (IX) or (IX").
- the RSS/SRR configuration in the mixture is obtained in at about nine fold excess of the RSR/SRS.
- step (d2) the mixture is cooled using the temperature gradient from about 7O 0 C to about 2O 0 C. In a preferred embodiment, the temperature gradient is from 70 0 C to 40 0 C.
- step (d2) said epimerizing is carried out in the presence of at least 0.1 equivalents of the base. In certain embodiments, said epimerizing is carried out in the presence of at least 0.25 equivalents of the base.
- the base in step (d2) is a member selected from the group consisting of an alkoxide, an amidine, a guanidine and a phosphazene.
- the base is an amidine.
- the base is diazabicycloundecene.
- water if present cannot exceed 1.0%. In certain embodiments, in step (d2) water if present cannot exceed 0.1%.
- step (e) said reducing is carried out for the RSS/SRR configuration the compound of formula (IX) or the compound of formula in a solvent with alkali borohydride, tetrabutylammonium borohydride, alkali-SELECTRIDE or zinc borohydride, optionally in a presence of a Lewis acid.
- the Lewis acid is at least one of Ti(OAlkyl) 4 , ZnCl 2 alkali halide or alkaline earth halide.
- the solvent is at least one of an ether, an alcohol or a halogenated hydrocarbon.
- said reducing is carried out at temperatures between about -20 0 C and about room temperature.
- step (f) said deprotectihg is carried out by catalytic hydrogenation.
- step (g) said purifying the compound of formula (I) is done by a slurry of its hydrochloride salt in a solvent.
- the slurry is carried out in methanol as the solvent.
- said providing the compound of formula (VITI) includes: (i) reducing the racemic compound of formula (V) in a solvent and optionally in a presence of a Lewis acid, wherein LG is bromine or chlorine to give a diastereomeric mixture of compounds of formula (VI)
- PG is a benzyl group.
- At least one of the diastereomers of the compound of formula V ⁇ i having a RR/SS or RS/SR configuration is isolated.
- a recycling process of undesired diastereomers produced during the process is provided, which reduces the costs and makes the process of making Nebivolol more efficient. Specifically, during the selective preparations of compounds Villa and Xa, the undesired diastereomers are formed as minor products. Thus, recycling of the waste presents an economical and ecological advantage over prior methods of making Nebivolol.
- the alkylation of compound Villa with compound V forms a diastereomeric mixture (a 1/lmixture of IXa and IXb), wherein the recycling step enables the transformation of the undesired form IXb either by selective cleavage into compound Villa or by a suitable epimerization step into a mixture of compounds IXa and IXb followed by selective isolation of desired diastereomer IXa.
- recycling the RR/SS configuration of the compound of formula (VIII) is conducted, wherein said recycling comprises: providing the RR/SS configuration of the compound of formula (VDI) with a protective group; and inversion of the alcohol configuration to provide the SR/RS configuration of formula Vi ⁇ .
- the reducing agent is selected from alkali borohydride, tetraalkylammonium borohydride, zinc borohydride, alkali triacetoxyborohydride, SUPERHYDRIDE, RED-AL, alkali-SELECTRIDE or coordinated borohydrides.
- the reduction is carried out under Meerwein Pondorf Verley conditions.
- said reducing is carried out by catalytic hydrogenation.
- the Lewis acid is a member selected from the group consisting of alkali or alkaline earth chlorides, zinc chloride, titanium(IV) alkoxide, and aluminium trialkoxide.
- step i) said reducing is carried out under conditions which give an RR/SS isomer of the compound of formula (VI) in excess.
- said reducing is carried out at a temperature between about-78°C and about room temperature.
- said reducing is carried out at the temperature between -20°C and room temperature.
- the solvent is a member selected from the group consisting of alcohols, ethers, halogenated hydrocarbons and aromatic solvents.
- step ii) said forming the mixture of diastereomers of the compound of formula (VII) is carried out in a solvent and in a presence of a base.
- the solvent is an alcohol and the base an alkali alkoholate.
- 1.0 to 2.0 equivalents of the base are used.
- step ii) said forming of the mixture of diastereomers of the compound of formula (VII) is carried out at temperatures between O 0 C and 40 0 C.
- step iv) the fractional crystallization is carried out in toluene, acetonitrile, a Cj-C 3 -alcohol, an ether or mixtures thereof.
- the Cj-C 3 -alcohol is 2- propanol and the ether is at least one of diisopropylether or MTBE.
- said providing the racemic compound of formula (V) comprises:
- R COOB " (IVb) wherein R is hydrogen or COOR S and wherein R" is C]-C 6 alkyl or aryl-Ci alkyl; and (4) halogenating the compound of formula (IV) and optionally conducting hydrolysis and decarboxylation to give the compound of formula (V).
- step (1) the carboxylic acid is transformed into a corresponding acid chloride.
- the base is a tertiary amine. In certain embodiments, 1 to 3 equivalents of Meldrums acids are used. In certain embodiments, in step (2), the reaction temperature is between about -10 0 C and about +30 0 C. In certain embodiments, in step (3) the compound of formula (JH) is hydrolyzed in a mixture of an organic acid and water to give a compound of formula (IV) wherein R is H. In a preferred embodiment, the organic acid is acetic acid and the hydrolysis is carried out at a reflux temperature.
- step (3) the compound of formula (JV) having R as COOR' and R v as Ci-C 6 alkyl or aryl-C
- the alkoholysis is carried out with ethanol and tert-b ⁇ tanol.
- the alkoholysis is carried out at temperatures between about 70 0 C and about 80 0 C.
- the solvent is at least one of alcohol or toluene.
- the compound of formula (IV) wherein R is H is transformed to a corresponding silylenol ether having the terminal double bond by silylation.
- the silylation is done by a kinetically controlled deprotonation using lithium diisopropyl amide (LDA) followed by silylation at about - 78 0 C to about -40 0 C.
- LDA lithium diisopropyl amide
- the silylation is done at -78°C to -70 0 C.
- the silylating reagent is TMSCl.
- the halogenation is carried out by using a brominating reagent.
- the bromination reagent is N-bromosuccinimide .
- step (4) the compound of formula (IV) wherein R is COOR' is first halogenated and then transformed into the compound of formula (V) by ester hydrolysis followed by decarboxylation.
- the halogenation is done in a presence of a catalyst.
- about 1.0 to about 1.5 equivalents of N-bromosuccinimide, N- chlorosuccinimide or SO 2 Cl 2 are used as halogenation reagents.
- about 0.2 equivalents to 0.4 equivalents of Mg(ClO 4 ) 2 are used as a catalyst.
- step (4) said halogenating is carried out at temperatures between O 0 C and about room temperature.
- step (4) after said halogenating the hydrolysis of the ester followed by decarboxylation is carried out in an aqueous organic acid solution.
- the organic acid is at least one of trifluoro acetic acid, formic acid and acetic acid.
- the hydrolysis and decarboxylation are carried out at temperatures between about 75°C and about 90°C.
- the process further includes recycling an RSR/SRS or RRR/SSS configuration of the compound of formula (IX) or (IX'), wherein said recycling comprises: epimerizing the RSR/SRS or RRR/SSS configuration of the compound of formula (IX) or (IX') to give a mixture of the RSS/SRR configuration containing the RSR/SRS configuration of diastereomers of formula (IX) or formula (IX') or RRS/SSR configuration containing, the RRR/SSS configuration of diastereomers of formula (IX) or formula (IX') and separating the mixture by fractional crystallization after salt formation or after derivatization to obtain substantially pure diastereomers of formula (IX) or formula (IX') having the RSS/SRR or RRS/SSR configuration.
- the process further includes recycling an RSR/SRS or RRR/SSS configuration of the compound of formula (IX) or (IX') wherein said recycling comprises: cleaving the RSR/SRS or RRR/SSS configuration of the compound of formula (IX) or (IX') to give a mixture comprising an RS/SR or RR/SS configuration of diastereomers of formula (VIH); and separating the RS/SR or RR/SS configuration of diastereomers of formula (VIII). Further provided is a compound of formula (III)
- R COOR- (IVb) wherein R is hydrogen or COOR' and R N is C r C 6 alkyl or aryl-Q alkyl. Further provided is a compound of formula (V)
- LG is bromine or chlorine
- LG is bromine or chlorine
- PG is protecting group selected from hydrogen, allyl and aryl-Qalkyl.
- enantiomerically pure Nebivolol (1-NebivoIol or d- Nebivolol) may also be obtained, e.g., after resolution of compound II (see Schemes 6b and 6c).
- Each of the enantiomers (S-II and R-II) may be transformed by the same methods as described for the corresponding racemic compound II (compare Scheme 6a) to give the first key intermediates S-V and R-V.
- L-Nebivolol -Hydrochloride (Scheme 6b) may be then prepared by the synthesis of R-VIIIa starting from R-V, followed by coupling with S-V (step 11), selective reduction (step 12), deprotection and salt formation (step 13).
- D-Nebivolol-Hydrochloride may be prepared in the same manner with the exception that, in contrast to the synthesis of 1- Nebivolol, the enantiomeric intermediate S-VIIIa will be prepared from S-V and then coupled with R-V (Scheme 6c, step 11). Selective reduction (step 12) followed by deprotection and salt formation will give d-Nebivolol-Hydrochloride.
- the process of preparing a compound of formula (I) as a racemic mixture or an enantomerically pure form and pharmaceutically acceptable salts thereof includes:
- PG is hydrogen or an amine protecting group, wherein the amine protecting group is at least one of an allyl group or an aryl-Ci alkyl group and wherein the compound of formula (VIII) is enantiomeric compound having an RS or SR configuration;
- the process further comprises cleaving the RRR/SSS configuration of the compound of formula (IX) or the compound of formula (IX') to give the compound of formula (VIH) as the diastereomer having RR/SS configuration.
- the process further comprises epimerizing the RRR/SSS configuration of the compound of formula (IX) or the compound of formula (IX') to give said mixtures of diastereomers having the RRR/SSS and RRS/SSR configuration of the compound of formula (IX) or the compound of formula (IX').
- the process further comprises cleaving the RRR/SSS configuration of the compound of formula (IX) or the compound of formula (IX') to give the compound of formula (VIII) as the diastereomer having RR/SS configuration.
- the process includes
- Novel compounds discovered by the inventors include the following:
- Figure IA depicts a structural formula of d-Nebivolol
- Figure IB depicts a structural formula of racemic Nebivolol. ⁇
- Figure 2 is an atom-numbering schematic representation of the molecule of compound VBQa (50% probability ellipsoids; H-atoms given arbitrary displacement parameters for clarity).
- Figure 3 is a 13 C-NMR graph of compound IXa in a cyclic semi-keta] form.
- Figure 4 is a 13 C-NMR graph of compound Kb in a cyclic semi-ketal form.
- Figure 5 is an atom-numbering schematic representation of the molecule of compound IXb in a cyclic semi-ketal form.
- Figure 6 is a scheme demonstrating a process of making racemic Nebivolol and its pharmaceutically acceptable salts.
- Figure 7 is a scheme demonstrating the simultaneous epimerization-crystallization procedure of the invention.
- Figure 8 is a scheme demonstrating the preferred example of the simultaneous epimerization-crystallization procedure of the invention, wherein the protective group is a benzyl group.
- Figure 9 is a scheme demonstrating a process of making racemic Nebivolol and its pharmaceutically acceptable salts wherein step 7b depicts the simultaneous epimerization- crystallization step of the invention.
- the present invention provides new compounds and methods for the synthesis of a racemic Nebivolol and its pharmaceutically acceptable salts as well as an enantiomerically pure Nebivolol and its pharmaceutically acceptable salts.
- This invention was driven by a desire to create a more efficient process having fewer reaction steps by avoiding steps of separating enantiomers prior to making a racemic mixture.
- One example of separating enantiomers is described in WO 2004/041805 (Scheme 3b). Since all enantiomers were separated during early stages of the process, up to 30 steps in four convergent pathways were necessary to produce racemic Nebivolol.
- This invention also provides a method of preparation of racemic Nebivolol, in which the formation of undesired diastereomers (e.g., SRSS/RSRR) in the final steps is reduced to a minimum by facilitating the purification and increasing the efficiency.
- undesired diastereomers e.g., SRSS/RSRR
- inventors have discovered that effective preparation of Nebivolol can advantageously utilize differences in solubility of other diastereomeric Nebivolol compounds as their HCl salts.
- the racemic Nebivolol meso form (as HCl salt) having the configuration RSRS has an increased solubility as compared to the solubility of Nebivolol hydrochloride, whereas the second meso form having the configuration RRSS has a comparable solubility to that of Nebivolol hydrochloride.
- RRSS-meso form equals 1.0%
- RSRS-meso form is above 15%.
- a selective preparation of racemic Nebivolol which may contain only a selected diastereomer (e.g., RSRS-meso form) as a possible impurity, which can be easily removed by a simple recrystallization due to the higher solubility. Therefore, a difficult and low yielding purification of the final product is avoided by this synthetic strategy because the formation of poorly soluble Nebivolol diastereomers (SRRS/RSSR, RRSS, SRSS/RSRR and RRRR/SSSS) is prevented.
- a selected diastereomer e.g., RSRS-meso form
- Another aspect of the present invention is to provide a diastereoselective synthesis of the intermediate Villa containing the preferred syn-configuration.
- This compound is a useful intermediate in the above described synthetic strategy for the selective preparation of racemic Nebivolol, since it can only form as a contaminant the diastereomer having the RSRS configuration which can be easily removed in the final steps (Scheme 6a, steps 8. and 9).
- Yet another aspect of the present invention is to provide an efficient method for selective reduction of compound IXa wherein the formation of the undesired RSRS isomer is reduced to a minimum.
- the starting material for the present process is compound II, a racemic acid, which can be prepared by different routes according to the methods disclosed in U.S. Patent No.5,171 ,865 (see also counterpart EP 0331078) and U.S. Patent No. 4,985,574 (see also counterpart EP 0264586).
- Step 1 involves preparation of (+)-5-[6-fluorochroman-2-carbonyl]-2, 2-dimethyl[l, 3]dioxane-4, 6-dione (compound III) from compound II as shown in Scheme 7.
- the racemic acid II is transformed in an activated acid derivative which is then reacted with Meldrum”s acid in an organic solvent and in the presence of a base to give the corresponding acylated Meldrumate III as a novel compound and a useful intermediate in the synthesis of Nebivolol.
- the acylation of Meldru ⁇ f s acid can be carried out in the manner similar to a conventional procedure, e.g., as disclosed in J. Org. Chem. 43(10), 1978, 2087.
- the carboxylic group can be activated in a conventional manner, e.g., as a carboxylic acide halide by using PHaI 5 , PHaI 3 , SOHaI 2 , (COHaI) 2 , as a carboxylic acid anhydride, as an activated ester, etc.
- Activation as an acid halide is preferred, and the chloride is the most preferred acid halide, which is prepared with 1 to 5 equivalents SOCl 2 , preferably with 1-3 equivalents, in the presence of catalytical amounts of DMF.
- This reaction can be carried out without the use of any solvent or in a solvent such as, for example, benzene, alkyl or halogen substituted benzene, halogenated hydrocarbons, etc.
- a solvent such as, for example, benzene, alkyl or halogen substituted benzene, halogenated hydrocarbons, etc.
- Alkyl or halogen substituted benzene are preferred solvents and toluene is the most preferred solvent.
- the reaction temperature can have a range from room temperature to the boiling point of the solvent. In a preferred embodiment, the reaction temperature ranges from 6O 0 C to 90 0 C in toluene as the solvent.
- the acyl chloride can be obtained in almost quantitative yield by evaporation of the solvent together with the excess of chlorination reagent.
- the acylation of Meldrum v s acid can be done in the same solvent as used for the activation of the carboxylic acid.
- Halogenated hydrocarbons are the preferred solvents and methylene chloride is most preferred.
- the Meldrum" s acid is used in molar proportions of 1 to 3 moles per mole of compound II, preferably in 1 to 1.5 moles per mole of compound II.
- the reaction is carried out in the presence of an organic or inorganic base, preferably in the presence of an organic base such as, for example, tertiary amine and most preferably in the presence of pyridine. In certain embodiments, 1 to 5 equivalents, preferably 1.5 to 3 equivalents of pyridine are used as the base.
- the reaction temperature may range between about -10 0 C (but not below the melting point of the pure solvent, e.g., benzene) and about + 30 0 C, preferably between 0 0 C and room temperature.
- the reaction carried out in this temperature range (0 0 C-RT) will be typically completed within 2 hours.
- the mixture is hydrolyzed and extracted with water or a diluted aqueous solution of an inorganic acid, preferably a 5% tolO% aqueous hydrochloride solution.
- the organic solvent is evaporated and the residue may be used directly for the next step or purified by a recrystallization or by slurry in an organic solvent.
- the residue is purified by slurry in an ether and most preferably in methyl tertiary- butyl ether (MTBE) or in diisopropyl ether.
- MTBE methyl tertiary- butyl ether
- Nebivolol If the preparation of enantiomerically pure Nebivolol is desired, it can be achieved by resolution of compound II using e.g. (+)-dehydroabietylamine as described in U.S. Patent No. 6,545,040.
- Step 2 involves preparation of compound IV, Scheme 6a, wherein R is H, yielding (+) ⁇ 1- (6-fluoro-chroman-2-yl)-ethanone (compound IVa, Scheme 8, Route A), or COOR' , wherein R' is alkyl or substituted alkyl, yielding ( ⁇ )-3-(6-fluorochroman-2-yl)-3-oxo-propionic acid alkyl ester (compound IVb, Scheme 9, Route B).
- Reaction of compound III with alcohols gives the corresponding beta-keto ester IVb as a novel compound and useful intermediate for the synthesis of Nebivolol, wherein R' is alkyl or substituted alkyl.
- This alcoholysis can be carried out with primary, secondary or tertiary alcohols, preferably with primary and tertiary alcohols and most preferably with ethanol or tert- butanol.
- a solvent the alcohol itself or an inert aromatic solvent can be used.
- Ethanol is the preferred solvent for the synthesis of the corresponding ethyl ester and toluene is the preferred solvent for the synthesis of the terr-butyl ester.
- the reaction temperature may have a range from reflux temperature for low boiling alcohols up to reflux temperature for toluene or the reflux temperature of the corresponding toluene/alcohol azeotrope.
- Preferred temperatures for the preparation of beta-keto ethyl ester as well as for the beta-keto tert-butyl ester are in a range from about 70 to about 80 0 C.
- the reaction mixture may be worked up in a usual manner, e.g., by an extractive method, and the crude product may be used directly for the next step or purified by column chromatography.
- Step 3 involves preparation of compound V from compound IV, e.g., (+)-2 ⁇ bromo-l-(6- fluoro-chroman-2-yl)-ethanone (compound Va) and (+)-2-chloro-l-(6-fluo ⁇ >chroman-2-yl)- ethanone (compound Vb) (Schemes 10 and l la-c).
- the compound IV prepared according to step 2 can be used for the synthesis of compound V having a suitable leaving group (LG).
- suitable leaving groups include substituted and non substituted alkyl and aryl sulfonic acid derivatives and halogen atoms.
- leaving groups are halogen atoms and the most preferred leaving groups are bromine (compound Va) and chlorine (compound Vb).
- the silyl enol ether can be obtained by kinetically controlled deprotonation using a strong base followed by silylation.
- a solvent include ethers or mixtures of ethers with such solvents, in which solutions of the strong bases are commonly available.
- the preferred preparation of the silyl enol ether uses lithium diisopropylamide (LDA) as the base, trimethylsilyl chloride (TMSCl) as a silylating reagent and tetrahydrofuran (THP) as the ether.
- LDA lithium diisopropylamide
- TMSCl trimethylsilyl chloride
- THF tetrahydrofuran
- Route B is an alternative preparation of the halogenated compounds Va and Vb, which gives a better selectivity than that of route A (see Scheme 1 Ia).
- the reaction in route B, can be carried out at higher, more convenient temperatures by successive halogenation of the beta-keto ester IVb, followed by hydrolysis and decarboxylation.
- the halogenation can be done with a suitable halogenation reagent with or without a catalyst.
- Typical halogenation reagents for the preparation of the corresponding bromides or chlorides include, for example, NBS, NCS, and SO 2 Cl 2 .
- a non-limiting example of a catalyst includes Mg(ClC ⁇ ) 2 .
- Suitable solvents for this reaction include acetonitrile, esters or halogenated hydrocarbons; acetonitrile, ethyl acetate and methylene chloride are preferred.
- 1.0 to 1.5 equivalents of the halogenation reagent and 0.3 equivalents of the catalyst can be used.
- the reaction proceeds between O 0 C and room temperature to a complete conversion within 3-4 hours. Higher temperatures for the halogenation should be avoided because of possible side reactions, and lower temperature may prolong the reaction time.
- the following ester hydrolysis and decarboxylation to form compound V can be done in an aqueous ornon-aqueous acid solution at higher temperatures. Mineral acids or organic acids maybe used.
- Compound IVb as the ethyl or terf-butyl ester maybe used as the starting material, with the fer/-butyl ester being preferred.
- the hydrolysis and decarboxylation of the corresponding halogenated beta keto ethyl ester may be preferably carried out with an aqueous trifiuoro acetic acid solution.
- the hydrolysis and decarboxylation of the corresponding halogenated beta keto tert-butyl ester is carried out preferably in a mixture of formic acid and acetic acid and preferably in the presence of water.
- the reaction temperature for the ester hydrolysis and decarboxylation is in a range from about 60 0 C to about 100 0 C, preferably 75-90 0 C.
- the purification of compound V may be done by as aforementioned for compound Va. Since compound Vb shows greater storage stability than compound Va, compound Vb is preferred.
- compound Vc may be prepared by similar transformation starting directly with the haloketones Va or Vb (see Scheme 1 Ic)
- LG R--SO 3 (Vc)
- R'" alkyl, aryl
- Step 4 involves preparation of compound VI as shown in Scheme 12 below.
- Non- limiting examples of compound VI include ( ⁇ )-2-chloro- 1 -[6-fluoro-(2R*)-chroman-2-yl]-( IR*)- ethan- 1 -ol (intermediate Via), ( ⁇ )-2-chloro- 1 -[6 ⁇ fluoro-(2R*)-chroman-2-yl]-( 1 S *)-ethan- 1 -ol (intermediate VIb), ( ⁇ )-2-brorno-H6-fluoro-(2R*)-chroman--2--yl]-( 1 R*)-ethan- 1 -ol (intermediate VIc), and (+)-2-bromo-l-[6-fluoro-(2R*)-chroman-2-yl]-(lS ;l! )-ethan-l-ol (intermediate VId).
- reducing agents can be used for the preparation of the halomethyl alcohols
- reduction agents e.g., borohydride or aluminiumhydride reduction reagents as well as the reagents that are useful for Meerwein Pondorf Verley reductions.
- reduction agents include LiBH 4 , NaBH 4 , KBH 4 N(nBu) 4 BH 4 , Zn(BH 4 ) 2 , NaH(Oac) 3 , Superhydride ® , Red-Al, Li-Selectride, BH 3 XSMe 2 or the like.
- suitable catalysts are catalysts that do not give side reactions with halogenated compounds (e.g., the catalyst as disclosed and cited in WO 03/064357).
- the reduction may be carried out in the absence or in the presence of a Lewis acid, such as, for example, MgCl 2 , CaCl 2 , BaCl 2 , ZnCl 2 Al(Oalkyl) 3) Ti(Oalkyl) 4 BF 3 XOEt 2 and the like.
- Suitable solvents include ethers, alcohols, halogenated hydrocarbons, halogenated or alkylated aromatic solvents and the like, with the exception, that halogenated solvents are unsuited for catalytic reductions.
- Preferred halomethyl ketones of compound V bear chlorine or bromine as the substituent "LG".
- the ratio of diastereomeric configurations RR/SS to RS/SR is from about 0.3 to about 2, preferably 1.1 to 2, and most preferably 1.2 to 2.
- the reaction can be worked up in a manner known in the art, by concentrating the reaction mixture and dissolving the residue in a water immiscible solvent, preferably toluene or MTBE, followed by successive washing with an aqueous acid solution, preferably 2N HCl solution followed by washing with water and/or an alkaline solution, preferably NaHCO 3 solution.
- a water immiscible solvent preferably toluene or MTBE
- an aqueous acid solution preferably 2N HCl solution followed by washing with water and/or an alkaline solution, preferably NaHCO 3 solution.
- the diastereomeric product mixture may be purified by column chromatography or used directly for the next step. It was observed that in contrast to the reduction of compound Vb, the reduction of compound Va proceeds with partial cyclization to the corresponding epoxides (compounds Vila and VIIb, see below).
- Step 5 involves preparation of compound VII from compound VI as shown in Scheme 13.
- Non-limiting examples of compound VII include +)-6-fluoro-[(2R*)-oxiran-2-yl]-(2S*)- chromane (compound Vila) and (+)-6-fluoro-[(2R*)-oxiran-2 ⁇ yl]-(2R*)-chromane (compound VIIb).
- VI is conveniently carried out in solvents such as, for example, ethers or alcohols with a base such as, for example, alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal alkoxides, alkali or alkaline earth metal carbonates, tertiary amines or alkali hydrides.
- a base such as, for example, alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal alkoxides, alkali or alkaline earth metal carbonates, tertiary amines or alkali hydrides.
- the use of alkali alkoxides in alcohols as the solvent is preferred, and most preferred is the use of sodium methoxide in methanol as the solvent.
- the temperature for this reaction may range between about 0 0 C and about 40 0 C, preferably between 15 0 C and 25°C.
- About 1.0 to about 2.0 equivalents of the base may be used and 1.1 equivalents are preferred.
- the excess base is typically neutralized by addition of an acid, preferably acetic acid.
- the mixture is then concentrated, and the residue is dissolved in a suitable solvent, e.g., an ether or a halogenated hydrocarbon. Washing this solution off with a half saturated aqueous sodium chloride solution and concentration of the organic layer gives epoxides of compound VII.
- a suitable solvent e.g., an ether or a halogenated hydrocarbon. Washing this solution off with a half saturated aqueous sodium chloride solution and concentration of the organic layer gives epoxides of compound VII.
- a suitable solvent e.g., an ether or a halogenated hydrocarbon. Washing this solution off with a half saturated aqueous sodium chloride solution and concentration of the organic layer gives epoxides of compound VII.
- the reaction is carried out using a mixture of diastereomeric halomethyl alcohols of formula VI, then the corresponding diastereomeric epoxid
- Step 6 involves preparation of compound VIII from compound VII as shown in Scheme 14 and separation of the diastereomers.
- Non-limiting examples of compound VIII include ( ⁇ )-2- Benzylamino-l-[6-fluoro-(2R*)-chroman-2-yl]-(lS*)-ethan-l-ol (compound Villa) and (+)-2- Benzylamino-l-[6-fluoro-(2R*)-chroman-2-yl]-(lR*)-ethan-l-ol (compound VIIIb).
- Suitable protective groups include hydrogen or a suitable amine protecting group.
- Preferred are protecting groups which permit the subsequent alkylation step (step 7) and can be easily removed in the final step by a simple deprotection method. Therefore, preferred PG is an allyl group, a substituted or unsubstituted arylmethyl group. IfPG is a benzyl group, then the preparation of compounds VIII may be carried out in the same manner as described in EP 0145067 but without any prior separation of the diastereomeric mixture of compounds Vila and VIIb.
- a chromatographic separation of the oily compounds Vila and VIIb is not necessary in this method, and that the diastereomeric mixture can be separated by fractional crystallization after conversion to Villa and VDIb. Therefore, in a preferred embodiment of the procedure, a mixture of Vila and VIIb is reacted with benzylamine to give the corresponding diastereomeric mixture of the compounds Villa and VIIIb, which is further separated by fractional crystallization. Since compounds Villa and VIIIb have basic properties, the fractional crystallization may be carried out not only with the free amine but also with an appropriate salt. Compound Villa as well as compound VIIIb are useful intermediates for the preparation of Nebivolol and therefore this method can be used for the selective preparation of both isomers in a commercial scale process.
- an equimolar or an enriched diastereomeric mixture of compounds Vila (syn) and VIIb (anti) at ratio syn/anti of more or equal 1 , produced according to steps 4 and 5, is treated with an excess benzylamine (> 3 equivalents) in a C]-C 3 - alcohol as the solvent at temperatures ranging from about room temperature to about 50 0 C.
- the reaction is carried out at 40 0 C with 3 equivalents of benzylamine in 2-propanol.
- the reaction mixture is cooled to initiate the crystallization. It was found that the preferred reaction solvent is suitable for the fractional crystallization.
- Additional crops may be obtained by further crystallization of the concentrated mother liquors from the same alcohol or mixture of this alcohol with ethers, preferably diisopropyl ether. Further enrichment of the diastereomeric ratio with regard to compound Villa can be obtained by recrystallization or by slurry in Cj -C 3 - alcohols, ethers, toluene, acetonitrile or mixtures thereof.
- the compound Villa could be obtained according to the aforementioned procedure containing 5% or less of compound VIIIb.
- the relative configuration of the preferred compound VIIIa was confirmed by single X-ray measurement as shown in Table 3 below.
- Step 7 involves preparation of compound IX from compounds VIII and V and separation of diastereomers of compound IX.
- compound IX include ( ⁇ )-2- ⁇ Benzyl-[2-(6-fluoro-(2R*)-chroman-2-yl)-(2S*)-hydroxy-ethyl]-amino ⁇ - 1 -(6-fluoro-(2S*)- chroman-2-yl)-ethanone (compound IXa) (Scheme 15) and (+)-2- ⁇ Benzyl-[2-(6-fluoro-(2R*)- chroman-2-yI)-(2S*)-hydroxy-ethyl]-amino ⁇ -l-(6-fluoro-(2R*)-chroman-2-yl)-ethanone (compound IXb) (see Scheme 17).
- suitable leaving groups (LG) of compound V include halogen, alkylsulfonyloxy groups, substituted or unsubstituted arylsulfonyloxy groups or the like.
- Preferred leaving groups are halogen and the most preferred leaving groups are bromine (compound Va) and chlorine (compound Vb).
- Protecting groups (PG) are described in Step 6; a benzyl group is the most preferred protecting group.
- the alkylation reactions are conveniently carried out in a suitable inert organic solvent or mixture of such solvents and in the presence of a base and a suitable amount of a catalyst.
- exemplary solvents include substituted or halogenated hydrocarbons such as methylene chloride, dichloroethane etc.; ether, e.g., THF, dioxane, dimethoxyethane and polar aprotic solvents, e.g., DMF, DMA, N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO) and the like.
- Preferred solvents are polar aprotic solvents. 1.0-1.5 equivalents of compound V may be used, and 1.1 equivalents are preferred.
- Exemplary bases include tertiary amines, e.g., triethylamine, pyridine, alkali metal carbonate, alkali metal hydrogen carbonate or sodium hydride. Preferred bases are alkali metal hydrogen carbonates and most preferred is sodium hydrogen carbonate. 1.5-2.5 equivalents of the base may be used, and 2.0 equivalents are preferred.
- Exemplary catalysts for acceleration of the reaction include alkali metal halides or tetraalkylammonium halides. If the leaving group is chloride, then the corresponding bromides or iodides are preferred and most preferably, sodium bromide or sodium iodide. At least 0.1 equivalents of the catalyst may be used and 0.15 equivalents are preferred.
- the reaction may be carried out at temperatures between about room temperature and about 8O 0 C. Lower temperatures may prolong the reaction time and higher temperatures may cause side reactions.
- the mixture can be worked up by an extractive method as known in the art. Evaporation of the solvent after the extraction and crystallization of the diastereomeric mixture by using a suitable anti-solvent delivers the diastereomeric compounds IXa and IXb, which may be separated by column chromatography or by fractional crystallization from a suitable solvent. Since the compounds IXa and IXb have basic properties, the fractional crystallization may be carried out with the free amine mixture or with appropriate salts.
- the separation of a mixture of compounds IXa and IXb could be effected by fractional crystallization of the free amines from acetonitrile as solvent.
- Suitable derivatization of compounds IXa and IXb may also be useful for separation of the diastereomeric mixture.
- the inventors have discovered that the diastereomer IXb can be selectively silylated in the presence of the diastereomer IXa. Because of the higher solubility of the silylated compound IXb compared with the non-silylated compounds, the efficiency of the fractional crystallization can be significantly increased.
- the silylation may be carried out in organic solvents or mixture of solvents such as ethers, esters, halogenated hydrocarbons, aromatic solvents (e.g., toluene, chlorobenzene, etc.), polar aprotic solvents (e.g,, DMF, DMSO) with a silylating reagent, if necessary in the presence of a base.
- organic solvents include acetonitrile, THF and MTBE and mixtures thereof. If bases are necessary, then amines, e.g., triethylamine, pyridine, imidazole, etc., alkali metal carbonate or alkali metal hydrogen carbonate may be used.
- Amines are the preferred organic solvents and the most preferred is imidazole. 1.0-2.0 equivalents of the base may be used, and 1.5 equivalents are preferred.
- TMSCl silylating reagent
- HMDS hydroxysulfate
- BSU hydroxysulfate
- TMSCl hydroxysulfate
- n the possible amount of transferred silyl groups per silylating reagent. Fewer equivalents may give an insufficient separation and more equivalents may result in the loss of a yield.
- the reaction is typically carried out in a temperature range between about O 0 C and about room temperature. Lower temperature may prolong the reaction time and higher temperatures may cause an insufficient selectivity.
- the isolation of compound IXa from a mixture consisting of IXa and IXb by fractional crystallization or by selective derivatization of IXb followed by crystallization of IXa is preferred.
- substantially pure diastereomers as used herein means at least 50% pure, preferably 80 %pure and more preferably 95%pure. NMR measurements of the separated diastereomers have indicated that both isomers cyclize to a semi-ketal form.
- Step 8 involves preparation of compound X as shown in Scheme 18.
- Non-limiting examples of compound X include ( ⁇ )-[2R*[R*[R*(S*)]]l- ⁇ 5 ⁇ "-
- PG may be hydrogen or an appropriate amine protecting group as defined above. Preferred are the same protecting groups as already described for Steps 6a-c and 7.
- borohydride or aluminiumhydride reduction reagents which may be selected from, e.g., LiBH 4 , NaBH 4 , KBH 4 NCnBu) 4 BH 4 , Zn(BH 4 ) 2 , NaH(Oac) 3 , Superhydride ® (sodium triethylborohydride), Red-Al ® (sodium bis(2- methoxyethoxy)aluminum hydride), Li-Selectride ® (tri-sec-butylborohydride, Li, K), BH 3 XSMe 2 or the like, or such reagents which are useful for Meerwein Pondorf Verley reductions.
- Meerwein Pondorf Verley reductions are reversible (Oppenauer Oxidation). Since compound Xa contains two secondary alcohol groups which may be in an oxididation/reduction equilibrium with the reduction reagent, a mixture of three diastereomers (benzylated Nebivolol (RSSS/SRRR) and the two meso forms thereof (RSRS and RRSS)) may be formed. To avoid such side reactions, the hydroxyl group of compound IXa may be protected before the Meerwein Ponndorf Verley reduction is carried out. Another possibility is the continuous distillation of the ketone (e.g. acetone if isopropanol is used as hydride donor).
- ketone e.g. acetone if isopropanol is used as hydride donor
- Catalytic hydrogenation of compound IXa may be a further option but if PG is a reduction labile protective group (e.g. benzyl) then deprotection must be taken into account.
- the reductions may be carried out in absence or in presence of a Lewis acid selected from
- Suitable solvents are ether, alcohols, halogenated hydrocarbons, or the like, with the exception that halogenated solvents are unsuited for catalytic reductions.
- the reduction is conveniently carried out at -20°C to room temperature. Even though lower temperatures may increase the selectivity, the reaction time will be extended, and higher temperature may cause a lost of selectivity.
- Table 5 shows typical results for the selective reduction of compound IXa.
- the ratio of diastereomeric configurations RSSS/SRRR to RSRS is from about 1 to about 20, preferably 2 to 20, and most preferably 4 to 20.
- the work up procedure can be done in a normal manner.
- the diastereomeric product mixture may be separated by column chromatography or by fractional crystallization. Since the compounds Xa and Xb have basic properties, salt formation prior to the fractional crystallization is a further option.
- the diastereomeric product mixture may be also used as crude product without further purification for the next step.
- Step 9 involves preparation of ( ⁇ )-[2R*[R*[R*(S*)]]l- ⁇ , ⁇ s -[iminobis(methylene)]bis[6- fluoro-chroman-2-methanol] hydrochloride (compound I) and separation from the byproduct (+)- [2R*[S*[R*(S*)]]l- ⁇ , ⁇ ⁇ -[iminobis-(methylene)]bis[6-fluoro-chroman-2-methanol] hydrochloride as shown in Scheme 19.
- the final steps for the preparation of racemic Nebivolol hydrochloride include deprotection, salt formation and purification by fractional crystallization to remove the byproducts, mainly the undesired diastereomer having the RSRS configuration.
- PG may have the same meaning as already described above, and if PG is other than hydrogen, the deprotection may be carried out by known procedures. Since benzyl groups are most preferred, the deprotection can be carried out by catalytic hydrogenation. If compound Xa contains compound Xb as a byproduct, then the purification may be done by fractional crystallization. Since compounds Xa and Xb have basic properties after deprotection, the fractional crystallization may be done after an appropriate salt formation. It was found that a mixture consisting of Nebivolol and its RSRS diastereomer can be readily separated by fractional crystallization after formation of the HCl salt or any other pharmaceutically acceptable salt.
- Compound I may be converted to its pharmaceutically acceptable non-toxic acid addition salt formed by treatment with appropriate acids, such as, for example, inorganic acids, such as hydrohalic acid, e.g. hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2- hydroxy-l,2,3-propane-tricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfamic
- the salt formation using HCl is preferred for the fractional crystallization to provide readily pharmaceutically acceptable HCl salt of Nebivolol.
- the fractional crystallization maybe generally done in suitable solvents in which Nebivolol is less soluble than its RSRS diastereomer. Alcohols as solvents for the fractional crystallization are preferred and methanol is the most preferred solvent.
- STEPS FOR RECYCLING OF DIASTEREOMERS This invention also incudes steps for the diastereomer recycling formed during the process.
- the recycling step can be conducted using e.g. a Mitsunobu reaction for inversion of the secondary alcohol group for recycling of the undesired diastereomer V ⁇ II(b) formed in Step 6.
- a suitable protection (PG" ) of the nitrogen may be required.
- suitable protective groups PG" include formation of corresponding carbamates by using e.g., alkyl chloroformates or formation of corresponding amides by using carboxylic acid chlorides or anhydrides.
- the protective group can be introduced after separation of the diastereomeric mixture by fractional crystallization followed by isolation of the undesired diastereomer from the mother liquors.
- Step 7 Recycling option for compounds formed in Step 7 In Step 7, a mixture of two diastereomers is formed (compounds IXa and IXb) which is separated by fractional crystallization.
- There are two options for a recycling of the undesired diastereomerIXb Scheme 2 J , Tables 6, 7, 8). The first one is an epimerization of the undesired diastereomer IXb to give again a mixture consisting of IXa and IXb which can be separated by the above described method.
- Table 6 Epimerization studies in various solvents containing 10% 1,8- Diazabicyclo[5.4.0]undec-7 ⁇ ene (DBU), starting from IXa/IXb ratio of about 23/77.
- DBU 1,8- Diazabicyclo[5.4.0]undec-7 ⁇ ene
- Table 7 Epimerization studies in DMF containing 5% 1 ,8-Diazabicyclo[5.4.0]undec-7- ene (DBU) at 30 0 C, starting from IXa/IXb ratio of about 23/77. The mixtures were analyzed by HPLC
- Table 8 Epimerization studies in toluene containing 5% l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) at 30 0 C, starting from DCa/IXb ratio of about 23/77. The mixtures were analyzed by
- the second recycling option includes the cleavage of the undesired dia ⁇ tereomer IXb to give a mixture of compound Villa and some byproducts.
- the cleavage may be done by a tautoterism of the aminoketone into the enamine form followed by hydrolysis using methods known in the art.
- the compound Villa could then be isolated and reintroduced into the process again as shown in Scheme 21.
- Nebivolol meso forms obtained according to the above described processes may be directly converted to Nebivolol after a suitable protection (e.g. cyclic carbamate, cyclic silyl group etc.), followed by inversion of the secondary alcohol group (e.g. by Mitsunobu reaction) and deprotection as shown in Scheme 23.
- a suitable protection e.g. cyclic carbamate, cyclic silyl group etc.
- inversion of the secondary alcohol group e.g. by Mitsunobu reaction
- Reactions for protecting, deprotecting and inversion can be performed by methods known in art.
- this invention provides new methods and conditions to increase the diastereomeric ratio of IXa and IXb in step 7 ( Figure 6) from about 1:1 up to 9:1 before the isolation of IXa is carried out (see Figures 7-9).
- the increase of the diastereomeric ratio can be obtained using a simultaneous epimerization-ciystallization procedure comprising an epimerization of a mixture consisting of compounds IXa and IXb in a ratio of about 1:1, in the presence of a suitable base and in an organic solvent wherein the solubility of compound IXa is slightly worse than the solubility of compound IXb.
- Figure 7 shows the simultaneous epimerization-crystallization procedure which is a dynamic process for enriching the diastereomeric ratio and obtaining the desired diastereomer (compounds IX are illustrated in the acyclic forms).
- a protective group may be any appropriate amine protecting group.
- PG is preferably selected from an allyl group or a substituted or unsubstituted arylmethyl group; the most preferred PG is a benzyl group (Bn).
- Suitable bases for the epimerization can be selected from alkoxides, amidines, guanidines or phosphazenes, preferred bases are amidines such as, for example, diazabicycloundecene (DBU), diazabicyclononene (DBN) and the most preferred base is DBU.
- the base may be used in at least 0.05 equivalents and 0.25 equivalents are preferred.
- the epimerization is preferably carried out in a temperature range between 2O 0 C and 7O 0 C and most preferably between 40 0 C and 70 0 C. Lower temperatures can also be u sed but they prolong the reaction time and higher temperatures may cause a higher degradation rate.
- the epimerization can be carried out under isothermal conditions but slow cooling of a mixture within the described temperature range is preferred.
- the organic solvent can be selected from solvents in which a suspension can be formed within the described temperature range to carry out the simultaneous crystallization-epimerization procedure of the invention. Suitable solvents are generally selected from aprotic solvents e.g., aromatic solvents, ethers, esters, amides or nitriles or from protic solvents, such as, for example, alcohols.
- Acidic solvents which inactivate the base by salt formation, are preferably excluded.
- reaction is conveniently carried out by slow cooling of a suspension containing equimolar amounts of compounds IXa and IXb in the presence of a base.
- Compound IXa wherein the amount of the undesired diastereomer is ⁇ 1 % can be isolated in yields up to 74% and in only one step without the need of several recrystallizations, selective derivatizations or additional recycling steps as described above.
- the simultaneous epimerization-crystallization procedure comprises simultaneous (a) an epimerization of a mixture consisting of compounds IXa and IXb in the presence of a suitable base and in an organic solvent and (b) favoured crystallization of IXa from the mixture. It is necessary that during the epimerization, the compound IXa is removed from the equilibrium by simultaneous crystallization. The epimerization studies were done in solution and not in suspension.
- the simultaneous epimerization-crystallization procedure for synthesis of compound IXa is superior to the above described crystallization and recycling methods because the preparation of IXa according to the selective derivatization process yielded IXa only in a yield of 41% as compared to the yield of 74% according to the simultaneous epimerization-crystallization process.
- Figure 8 shows the epimerization of a mixture of compounds IXa and IXb, wherein PG is a benzyl group (Bn).
- the IXa and IXb compounds are illustrated in the open-chain (acyclic) form.
- equilibrium of the acyclic forms IXa and IXb with the corresponding cyclic forms IXa v and IXb" is present.
- the acyclic form is required, which has an acidic proton at the chiral centre in alpha position to the carbonyl group.
- a slurry of a mixture consisting of an almost equimolar ratio of compounds IXa and IXb in acetonitrile is heated to an internal temperature of 70 0 C. After cooling to 60°C, DBU (0.25 eq.) is added, and the epimerization is carried out by cooling the mixture to 4O 0 C using the temperature gradient described in Table 9.
- the reaction is stopped by adding acetic acid (0.25 eq.) and the mixture is cooled to 25°C.
- the crude product is isolated by filtration and further purified by forming a slurry in acetonitrile. The filtration is done after finishing of simultaneous epimerization-crystallization process to isolate IXa.
- the following slurry in acetonitrile is only an additional purification step for removing remaining impurities and small amounts of the undesired diastereomer.
- Table 10 shows the success of the epimerization monitored by regular in-process controls (IPC) (determined by HPLC).
- Figure 9 demonstrates a process of making racemic Nebivolol and its pharmaceutically acceptable salts wherein step 7b depicts the simultaneous epimerization-crystallization step of the invention.
- Parameters for the simultaneous epimerization-crystallization step of the invention were selected based on realization that the solubility of compound Ka is less than the solubility of compound IXb.
- IXa can be crystallized in favour and therewith removed from the equilibrium while in solution the equilibrium of both diastereomers can be regenerated by epimerization of the undesired diastereomer IXb in presence of a base.
- Equilibrium was investigated at different temperatures with a certain base in a certain solvent and cooling rates. The cooling is necessary to complete the crystallization and to optimize the yield. Since the cooling reduces the solubility of both diastereomers, conditions for further crystallization in favour of the desired diastereomer were obtained.
- Thionylchloride (109.21 g, 918 mmol) was added under nitrogen atmosphere at20-25°C to a suspension of 6-fluorochroman-2-carboxyIic acid (90.00 g, 459 mmol) and DMF ( 1.68 g, 23 mmol) in toluene (635 ml). Afterwards, the suspension was heated to an internal temperature of
- Example 1 was reproduced using 16 g of 6-fluorochroman-2-carboxylic acid, and the residue obtained after work up and evaporation of methylene chloride was used directly for Step 2, route A.
- a mixture of thus obtained crude product (compound III) with water (40 ml) and acetic acid (40 ml) was heated for 70 min to reflux and then cooled to room temperature.
- the reaction mixture was extracted with methylene chloride (40 ml), and the organic layer was twice washed with 1 N aqueous NaOH solution (each 20 ml). After drying over MgSO 4 , the organic layer was filtrated and evaporated.
- Step 2 Preparation of (+)-3-(6-fluorochroman-2-yl)-3-oxo-propionic acid ethyl ester (compound IVb as ethylester).
- Example 1 was reproduced using 16 g of ⁇ -fluorochroman ⁇ -carboxylic acid and the residue obtained after work up and evaporation of methylene chloride was used directly for Step 2, route B.
- a suspension of this crude product (compound III) in ethanol (150 ml) was heated to reflux for 75 min, whereupon a clear solution was obtained.
- the residue was portioned between methylene chloride (80 ml) and water (80 ml).
- the phases were separated, and the organic layer extracted with 1 N aqueous NaOH solution (40 ml).
- the methylene chloride solution was dried over MgSO 4 , filtrated and evaporated.
- Step 2 Preparation of (+)-3-(6-fluorochroman-2-yl)-3-oxo-propionic acid tert- butyl ester (compound IVb as ester).
- Terf-butanol (83.90 g) was added at room temperature to a suspension of compound III (94.00 g) (obtained by the process as described in Example 1) in toluene (280 ml). The suspension was heated to the internal temperature of 70-80 0 C, whereupon a clear solution was obtained under simultaneous evolution of a gas. The reaction was completed within 80 min. The mixture was cooled to room temperature and extracted successively with saturated NaHCO 3 solution (235 ml) and saturated NaCl solution.
- Step 3 Preparation of (+)-2-brorao-l-(6-fluoro-chroman-2-yl)-ethanone (compound Va).
- TMSCl (3.2 ml) was added to a solution of 2 M LDA (9.0 ml) in 20 ml THF at -IS 0 C within 10 min.
- a white solid precipitated and the suspension were portioned between cyclohexane (100 ml) and cold 10% NaHCO 3 solution (60 ml). The aqueous layer was diluted with water (20 ml) and separated.
- Step 3 Preparation of ( ⁇ )-2-bromo-l-(6-fluoro-chroman-2-yl)-ethanone (compound Va).
- N-Bromo succinimide (NBS) (5.04 g) was added at 5-10°C in portions to a solution of compound lYb-tert-b ⁇ ty) ester ( 10.0 g) (obtained by the process as described in Example 4) and Mg(C10 4 ) 2 (2.32 g) in ethyl acetate (100 ml). The reaction was subsequently monitored by HPLC. After the addition, the mixture was stirred at 5-10 0 C for 45min. Since 16% of the adduct remained, additional NBS (1.0 g) was added. The mixture was stirred for 20 min at 5-10 0 C, then allowed to warm to room temperature and stirred for 20 min at this temperature.
- NBS N-Bromo succinimide
- the filter cake was washed with ethyl acetate (100 ml), and the combined filtrates were extracted successively with saturated NaCl solution (150 ml) and water (150 m ⁇ ) and afterwards concentrated in vacuo (60 mbar) to give a brown oil ( 116.82 g).
- the brown oil was taken up in a mixture of acetic acid (420 ml), formic acid (390 ml) and water (80 ml). The solution was heated to an internal temperature of 80-90 0 C, whereupon an evolution of a gas was observed.
- Steps 1-3 Preparation of (+)-2-chloro-l-(6-fluoro-chroman-2-yl)-ethanone (compound Vb) from ⁇ -fluorochroman ⁇ -carboxylic acid (II)
- a mixture of 6-fluorochroman-2-carboxylic acid (114.4 g, assay 99%, 577 mmol), thionylchloride (83.15 g, 692 mmol) and DMF (2.18 g, 30 mmol) in toluene (471 g) was slowly heated under nitrogen atmosphere to an internal temperature of 70-80 0 C (at an internal temperature of 57 Q C an evolution of a gas started).
- Example 9 Step 4: Preparation of (+)-2-chloro-l-(6-fluoro-(2R*)-chroman-2-yl)-(lR*)-ethan-l-ol (compound Via) and ( ⁇ )-2-chloro-l-(6-fluoro-(2S t -)-chroman-2-yl)-(lR :
- LG Cl: major RR/SS ("syn", Via) minor RS/SR ("anti”, VIb)
- Compound Vb (33.74 g) was added at 0-5 0 C to a solution of ZnCl 2 (40.3 g) in methanol
- the reaction was monitored by HPLC and after stirring for 3.5 h at 20-25°C, additional methanolic NaOMe solution (30%, 1.4 g) was added. After the reaction was completed (within 3.5 h), the mixture was neutralized by addition of acetic acid and then concentrated in vacuo. The residue was portioned between methylene chloride (300 ml) and a semi saturated NaCl solution (200 ml).
- Example 11 Step 6: Preparation of ( ⁇ )-2-Benzylamino- l-[6-fluoro-(2R*)-chroman-2-yl]-(lS*)-ethan- l-ol (compound Villa) and ( ⁇ )-2-Benzylamino-l-[6-fluoro-(2R*)-chroman-2-yI]-(lR !l! )-ethan-l- ol (compound VIIIb) and separation of the diastereomers Villa and VIIIb
- a mixture of compounds Vila and VIIb (ratio: 57/43) was slowly added (within 1.5 h) at an internal temperature of 40 0 C to a solution of benzylamine (5.4 g) in 2-propanol (30 ml) . After completion of the reaction monitored by HPLC, the solution was cooled to room temperature and seeding material was added. Next, the diastereomers Villa and VIIIb were separated by fractional crystallization. The suspension was stirred at room temperature for 1 h and filtrated to give a colorless solid after drying in vacuo (1.01 g). The mother liquor was concentrated until 25 g residue was obtained. Afterwards, the concentrated mixture was heated to 60 0 C and cooled within 3 h to 0-5 0 C.
- Diastereomer VIIIb could be e.g., obtained from the mother liquor after concentration to dryness followed by an extractive work up and crystallization.
- Example 12 Steps 4-6: Preparation of (+)-2-BenzyIamino-l-[6-fl ⁇ oro-(2R*)-chiOman-2-yl]-(lS*)- ethan-1-ol (compound Villa) and (+)-2-Benzylamino-l-[6-fluoro-(2R*)-chroman-2-y]]-(]R :!: )- ethan- 1 -ol (compound VIIIb) from (+)-2-chloro- 1 -(6-fluoro-chroman-2-yl)-ethanone (compound Vb) and separation of the dia ⁇ tereomers Villa and VIIIb
- the crude product was dissolved in acetonitrile (294 ml) by heating to reflux. The solution was slowly cooled to 0-5 0 C (6-7h), filtrated and the filter cake washed with acetonitrile (38 ml).
- Step 7 Preparation of (+)-2- ⁇ BenzyH2 ⁇ 6-fluoro-(2R*)-chroman--2-yIH2S*)-hydroxy-- ethyl]-amino ⁇ -l-(6-fluoro-(2S*)-chroman-2-yl)'ethanone (compound IXa), ( ⁇ )-4-Benzyl-2-[6- fluoro-(2R*)-chroman-2-yl]-(6S*)-[6-fluoro-(2S*)-chroman-2-yl]-mo ⁇ holin-2'-ol (compound IXa ), ( ⁇ >2- ⁇ Benzyl-[2-(6-fluoro-(2R*)-chroman-2-yl)-(2S*)-hydroxy-ethyl]-amino ⁇ - 1 -(6- fluoro-(2R*)-chroman ⁇ 2-yl)-ethanone (compound IXb),
- the diastereomeric mixture of compounds IXa/IXa * and IXb/IXb N was dissolved in acetonitrile at an internal temperature of 70 0 C.
- the light yellow solution was seeded, cooled to room temperature (within 2-3 h) and stirred at this temperature for 1.5-2 h.
- Step 7 Preparation of ( ⁇ )-2- ⁇ Benzyl-t2-(6-fluoro-(2R*)-chroman-2-yl)-(2S*)-hydroxy- ethyl]-amino)-l-(6-fluoro-(2S*)-chroman-2-yl)-ethanone (compound IXa), (+)-4-BenzyI-2-[6- fluoro-(2R*)-chroman-2-yl]-(6S*)-[6-fluoro-(2S % )-chroman-2-yl]-morpholin-2-ol (compound IXa v ), ( ⁇ )-2- ⁇ Benzyl-[2-(6-fluoro-(2R*)-chroman-2-yl)'(2S*)'-hydroxy-ethyl]-amino ⁇ -l-(6- fluoro-(2R*)-chroma ⁇ -2-yl)-etha ⁇ one (compound I
- Step 8 Preparation of (+)-[2R*[R*[R*(S*)]]l- ⁇ , ⁇ N -[[(phenylmethyl)imino]bis- (methylene)]bis[6-fluoro-chroman-2-methanol] (compound Xa) and ( ⁇ H2R*[S*[R*(S*)]]]]- ⁇ I ⁇ '-[[(phenylmethyl)imino]bis(methylene)]bis[6-fluoro-chroman-2-methanol] (compound Xb)
- KBH 4 (3.15 g, 56.73 mmol) was added to a solution of compound IXa/IXa" (28.0 g, prepared according to example 14) and Ti(OiPr) 4 (32.9 g, 113.5 mmol) in DME (280 ml) at an internal temperature of 0 0 C. After stirring at this temperature for 21 h (monitored by HPLC), the mixture was allowed to warm to room temperature and hydrochloric acid (280 ml, 10% aqueous solution) was added slowly. The suspension was stirred for 2.5 h.
- the suspension was filtered and the wet product washed first with a mixture of DME (25 ml) and hydrochloric acid (25 ml, 2N aqueous solution), then with hydrochloric acid (50 ml, 2N aqueous solution) and twice with water (each 50 ml).
- the wet product was suspended in ethanol (120 ml) and heated to 5O 0 C. Afterwards, an aqueous solution of NaOH (8.3 g, 30%) was added to give initially a clear solution and the mixture was heated to 60 0 C. After the crystallization started, water was added (33ml) and the suspension was cooled to room temperature.
- Example 17 Step 9: Preparation of ( ⁇ )-[2R*[R*[R*(S*)]]l- ⁇ > ⁇ x -[iminobis(methylene)]bis[6-fluoro- chroman-2-methanol] hydrochloride (compound I) and separation from the byproduct (+)- [2R*[S*[R :) --(S*)]]l- ⁇ , ⁇ s -[iminobis-(methylene)]bis[6'fluoro-chroman-2-methano]] hydrochloride
- RSSS/SBRR I
- RSRS byproduct
- Example 19 Preparation of (+)-2- ⁇ Benzyl-[2-(6-fluoro-(2R*)-chroman-2-yl)-(2S :i: )-hydroxy-ethyl]-amino ⁇ -l- (6-fluoro-(2S*)-chroman-2-yl)-ethanone (compound IXa) ⁇ ( ⁇ )-4-Benzyl-2-[6-fluoro-(2R*)- chroman-2-yl]-(6S*)-[6-fluoro-(2S*)-chroman-2-yl]-morpholin-2-ol (compound IXa v )
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US12/159,255 US20090048457A1 (en) | 2005-12-28 | 2006-12-28 | Process for preparation of racemic nebivolol |
AU2006346311A AU2006346311B2 (en) | 2005-12-28 | 2006-12-28 | A process for preparation of racemic Nebivolol |
CA2635479A CA2635479C (en) | 2005-12-28 | 2006-12-28 | A process for preparation of racemic nebivolol |
NZ570104A NZ570104A (en) | 2005-12-28 | 2006-12-28 | A process for preparation of racemic nebivolol |
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US11/319,287 US7560575B2 (en) | 2005-12-28 | 2005-12-28 | Process for preparation of racemic Nebivolol |
US11/319,287 | 2005-12-28 | ||
EP06000149A EP1803715A1 (en) | 2005-12-28 | 2006-01-04 | A process for preparation of racemic nebivolol |
EP06000149.2 | 2006-01-04 | ||
US79015006P | 2006-04-07 | 2006-04-07 | |
US60/790,150 | 2006-04-07 | ||
EP06010861.0 | 2006-05-26 | ||
EP06010861A EP1803716B1 (en) | 2005-12-28 | 2006-05-26 | A process for preparation of racemic nebivolol |
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WO2011009628A1 (en) | 2009-07-23 | 2011-01-27 | Zach System Spa | Process for preparing nebivolol |
WO2011098474A1 (en) | 2010-02-11 | 2011-08-18 | Menarini International Operations Luxembourg S.A. | Process for the preparation of nebivolol |
CN102186835A (en) * | 2008-10-31 | 2011-09-14 | Zach系统股份公司 | Process for preparing nebivolol |
WO2012095707A1 (en) | 2010-11-30 | 2012-07-19 | Menarini International Operations Luxembourg S.A. | Process for the preparation of nebivolol |
CN102816141A (en) * | 2012-09-10 | 2012-12-12 | 济南爱思医药科技有限公司 | Method for preparing nebivolol racemate hydrochloride |
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DE102014107132A1 (en) | 2014-05-20 | 2015-11-26 | Corden Pharma International Gmbh | Process for the preparation of epoxides which can be used in the preparation of nebivolol and its derivatives |
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ITMI20080547A1 (en) * | 2008-03-31 | 2009-10-01 | Zach System Spa | NEBIVOLOL PREPARATION PROCESS |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0145067A2 (en) * | 1983-12-05 | 1985-06-19 | Janssen Pharmaceutica N.V. | Derivatives of 2,2'-iminobisethanol |
EP0334429A1 (en) * | 1988-03-23 | 1989-09-27 | Janssen Pharmaceutica N.V. | Agents for lowering the blood pressure |
WO1999032476A1 (en) * | 1997-12-19 | 1999-07-01 | Bayer Corporation | Carboxyl substituted chroman derivatives useful as beta 3 adrenoreceptor agonists |
WO2004041805A1 (en) * | 2002-11-06 | 2004-05-21 | EGIS Gyógyszergyár Rt. | NEW PROCESS FOR THE PREPARATION OF RACEMIC ([2S[2R*[R[R*]]]] and ([2R[2S*[S[S*]]]]-(±)- α,α' -[imino-bis(methylene)]bis[6-fluorochroman-2-methanol] AND ITS PURE [2S[2R*[R[R*]& |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4654362A (en) * | 1983-12-05 | 1987-03-31 | Janssen Pharmaceutica, N.V. | Derivatives of 2,2'-iminobisethanol |
EP0264586B1 (en) * | 1986-08-28 | 1991-04-03 | Sanwa Kagaku Kenkyusho Co., Ltd. | Hydantoin derivatives for treating complications of diabetes |
US6545040B1 (en) * | 1988-03-23 | 2003-04-08 | Janssen Pharmaceutica N.V. | Method of lowering the blood pressure |
TW355683B (en) * | 1994-02-17 | 1999-04-11 | Janssen Pharmaceutica Nv | Composition containing micronized nebivolol |
SE509833C2 (en) * | 1997-05-16 | 1999-03-15 | Tetra Laval Holdings & Finance | Device for application of straw |
-
2006
- 2006-05-26 EP EP06010861A patent/EP1803716B1/en not_active Not-in-force
- 2006-12-28 AU AU2006346311A patent/AU2006346311B2/en not_active Ceased
- 2006-12-28 CA CA2635479A patent/CA2635479C/en not_active Expired - Fee Related
- 2006-12-28 US US12/159,255 patent/US20090048457A1/en not_active Abandoned
- 2006-12-28 WO PCT/IB2006/004280 patent/WO2008010022A2/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0145067A2 (en) * | 1983-12-05 | 1985-06-19 | Janssen Pharmaceutica N.V. | Derivatives of 2,2'-iminobisethanol |
EP0334429A1 (en) * | 1988-03-23 | 1989-09-27 | Janssen Pharmaceutica N.V. | Agents for lowering the blood pressure |
WO1999032476A1 (en) * | 1997-12-19 | 1999-07-01 | Bayer Corporation | Carboxyl substituted chroman derivatives useful as beta 3 adrenoreceptor agonists |
WO2004041805A1 (en) * | 2002-11-06 | 2004-05-21 | EGIS Gyógyszergyár Rt. | NEW PROCESS FOR THE PREPARATION OF RACEMIC ([2S[2R*[R[R*]]]] and ([2R[2S*[S[S*]]]]-(±)- α,α' -[imino-bis(methylene)]bis[6-fluorochroman-2-methanol] AND ITS PURE [2S[2R*[R[R*]& |
Non-Patent Citations (2)
Title |
---|
CHANDRASEKHAR S ET AL: "Enantioselective Total Synthesis of the Antihypertensive Agent (S,R,R,R)-Nebivolol" TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 56, no. 34, 18 August 2000 (2000-08-18), pages 6339-6344, XP004214993 ISSN: 0040-4020 cited in the application * |
DATABASE REGISTRY [Online] 24 November 2003 (2003-11-24), XP002368863 Database accession no. RN 620176-90-1 * |
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WO2011009628A1 (en) | 2009-07-23 | 2011-01-27 | Zach System Spa | Process for preparing nebivolol |
WO2011098474A1 (en) | 2010-02-11 | 2011-08-18 | Menarini International Operations Luxembourg S.A. | Process for the preparation of nebivolol |
JP2014503509A (en) * | 2010-11-30 | 2014-02-13 | メナリーニ インターナショナル オペレーションズ ルクセンブルク エス.エー. | Method for the preparation of nebivolol |
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CN103709132A (en) * | 2014-01-17 | 2014-04-09 | 江苏八巨药业有限公司 | Method for preparing nebivolol midbody |
CN103709132B (en) * | 2014-01-17 | 2015-08-19 | 江苏八巨药业有限公司 | A kind of preparation method of Nebivolol Intermediates |
EP2907810A1 (en) | 2014-02-14 | 2015-08-19 | Corden Pharma International GmbH | A new method for producing nebivolol hydrochloride of high purity |
EP2907809A1 (en) | 2014-02-14 | 2015-08-19 | Corden Pharma International GmbH | Base-free process for the preparation of ketone intermediates usable for manufacture of nebivolol |
DE102014107132A1 (en) | 2014-05-20 | 2015-11-26 | Corden Pharma International Gmbh | Process for the preparation of epoxides which can be used in the preparation of nebivolol and its derivatives |
WO2017024980A1 (en) * | 2015-08-07 | 2017-02-16 | 上海现代制药海门有限公司 | Crystallization separation method for nebivolol hydrochloride intermediate mixture |
Also Published As
Publication number | Publication date |
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AU2006346311B2 (en) | 2011-02-24 |
WO2008010022A3 (en) | 2008-06-19 |
EP1803716A1 (en) | 2007-07-04 |
CA2635479A1 (en) | 2008-01-24 |
AU2006346311A1 (en) | 2008-01-24 |
EP1803716B1 (en) | 2012-07-25 |
US20090048457A1 (en) | 2009-02-19 |
CA2635479C (en) | 2012-07-17 |
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