WO2010128388A2 - An improved process for the preparation of intermediate compounds useful for the preparation of cinacalcet - Google Patents
An improved process for the preparation of intermediate compounds useful for the preparation of cinacalcet Download PDFInfo
- Publication number
- WO2010128388A2 WO2010128388A2 PCT/IB2010/001057 IB2010001057W WO2010128388A2 WO 2010128388 A2 WO2010128388 A2 WO 2010128388A2 IB 2010001057 W IB2010001057 W IB 2010001057W WO 2010128388 A2 WO2010128388 A2 WO 2010128388A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- trifluoromethyl
- phenyl
- cinacalcet
- solvent
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 150000001875 compounds Chemical class 0.000 title abstract description 15
- VDHAWDNDOKGFTD-MRXNPFEDSA-N cinacalcet Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-MRXNPFEDSA-N 0.000 title description 39
- 229960003315 cinacalcet Drugs 0.000 title description 31
- QANQWUQOEJZMLL-PKLMIRHRSA-N cinacalcet hydrochloride Chemical compound Cl.N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 QANQWUQOEJZMLL-PKLMIRHRSA-N 0.000 claims abstract description 29
- JMKMLIWUWJNVIG-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]prop-2-enal Chemical compound FC(F)(F)C1=CC=CC(C=CC=O)=C1 JMKMLIWUWJNVIG-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229960000478 cinacalcet hydrochloride Drugs 0.000 claims abstract description 17
- YDNLMIBCGPTFIK-DUXPYHPUSA-N (e)-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol Chemical compound OC\C=C\C1=CC=CC(C(F)(F)F)=C1 YDNLMIBCGPTFIK-DUXPYHPUSA-N 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 89
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- 239000002904 solvent Substances 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 42
- -1 nitroxyl compound Chemical class 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 20
- YDNLMIBCGPTFIK-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol Chemical compound OCC=CC1=CC=CC(C(F)(F)F)=C1 YDNLMIBCGPTFIK-UHFFFAOYSA-N 0.000 claims description 14
- 150000008064 anhydrides Chemical class 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 8
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 8
- 150000002170 ethers Chemical class 0.000 claims description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 6
- DGQOCLATAPFASR-UHFFFAOYSA-N tetrahydroxy-1,4-benzoquinone Chemical compound OC1=C(O)C(=O)C(O)=C(O)C1=O DGQOCLATAPFASR-UHFFFAOYSA-N 0.000 claims description 6
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 4
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229910019093 NaOCl Inorganic materials 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- WOAHJDHKFWSLKE-UHFFFAOYSA-N 1,2-benzoquinone Chemical compound O=C1C=CC=CC1=O WOAHJDHKFWSLKE-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000003849 aromatic solvent Substances 0.000 claims description 2
- 229940117975 chromium trioxide Drugs 0.000 claims description 2
- BOAMTGHGHLIYHH-UHFFFAOYSA-N cyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C=C1.O=C1C=CC(=O)C=C1 BOAMTGHGHLIYHH-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims 1
- 230000002092 calcimimetic effect Effects 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 239000002243 precursor Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 14
- RTCUCQWIICFPOD-SECBINFHSA-N (1r)-1-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C([C@H](N)C)=CC=CC2=C1 RTCUCQWIICFPOD-SECBINFHSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 10
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 10
- 229940093499 ethyl acetate Drugs 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- APCCHYPQHODSBD-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]propanal Chemical compound FC(F)(F)C1=CC=CC(CCC=O)=C1 APCCHYPQHODSBD-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 102000003982 Parathyroid hormone Human genes 0.000 description 7
- 108090000445 Parathyroid hormone Proteins 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000000199 parathyroid hormone Substances 0.000 description 7
- 229960001319 parathyroid hormone Drugs 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- KSBWHDDGWSYETA-SNAWJCMRSA-N (E)-3-(trifluoromethyl)cinnamic acid Chemical compound OC(=O)\C=C\C1=CC=CC(C(F)(F)F)=C1 KSBWHDDGWSYETA-SNAWJCMRSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- QWXKQVIMGVVIBX-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]propan-1-ol Chemical compound OCCCC1=CC=CC(C(F)(F)F)=C1 QWXKQVIMGVVIBX-UHFFFAOYSA-N 0.000 description 5
- 238000006859 Swern oxidation reaction Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 229940086542 triethylamine Drugs 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 4
- NNMBNYHMJRJUBC-UHFFFAOYSA-N 1-bromo-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(Br)=C1 NNMBNYHMJRJUBC-UHFFFAOYSA-N 0.000 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 description 3
- 102000013830 Calcium-Sensing Receptors Human genes 0.000 description 3
- 108010050543 Calcium-Sensing Receptors Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- YLTJJMIWCCJIHI-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]propanoic acid Chemical compound OC(=O)CCC1=CC=CC(C(F)(F)F)=C1 YLTJJMIWCCJIHI-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 235000019645 odor Nutrition 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical class Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- QQLIGMASAVJVON-UHFFFAOYSA-N 1-naphthalen-1-ylethanone Chemical compound C1=CC=C2C(C(=O)C)=CC=CC2=C1 QQLIGMASAVJVON-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VRGCYEIGVVTZCC-UHFFFAOYSA-N 3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione Chemical compound ClC1=C(Cl)C(=O)C(=O)C(Cl)=C1Cl VRGCYEIGVVTZCC-UHFFFAOYSA-N 0.000 description 1
- AQKTWIMZLCJHDR-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]prop-2-enenitrile Chemical compound FC(F)(F)C1=CC=CC(C=CC#N)=C1 AQKTWIMZLCJHDR-UHFFFAOYSA-N 0.000 description 1
- JMTLMFBJIQWJPW-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]propan-1-amine Chemical compound NCCCC1=CC=CC(C(F)(F)F)=C1 JMTLMFBJIQWJPW-UHFFFAOYSA-N 0.000 description 1
- JLTJGTZUUSSVMZ-UHFFFAOYSA-N 3-phenyl-2-(trifluoromethyl)prop-2-enoic acid Chemical compound OC(=O)C(C(F)(F)F)=CC1=CC=CC=C1 JLTJGTZUUSSVMZ-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 201000002980 Hyperparathyroidism Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- VEUSMNWREGZMPW-RBFZIWAESA-N N-[(1R)-1-naphthalen-1-ylethyl]-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine Chemical compound FC(C=1C=C(C=CC1)C(C=C)N[C@H](C)C1=CC=CC2=CC=CC=C12)(F)F VEUSMNWREGZMPW-RBFZIWAESA-N 0.000 description 1
- 229910020889 NaBH3 Inorganic materials 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910019020 PtO2 Inorganic materials 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- UFZSKZOGLLTGEA-OAQYLSRUSA-N [(1r)-1-naphthalen-1-yl-5-[3-(trifluoromethyl)phenyl]pentyl] carbamate Chemical compound C([C@@H](OC(=O)N)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 UFZSKZOGLLTGEA-OAQYLSRUSA-N 0.000 description 1
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical group ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- QGJOPFRUJISHPQ-UHFFFAOYSA-N carbon disulfide Substances S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- CWUNPFVHATZKFE-MRXNPFEDSA-N cinacalcet carbamate Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)C(=O)OCCCC1=CC=CC(C(F)(F)F)=C1 CWUNPFVHATZKFE-MRXNPFEDSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229940052303 ethers for general anesthesia Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- DYEQMULKZQBEKD-MRXNPFEDSA-N n-[(1r)-1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine Chemical compound N([C@H](C)C=1C=2CCCCC=2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 DYEQMULKZQBEKD-MRXNPFEDSA-N 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000003913 parathyroid carcinoma Diseases 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 208000017954 parathyroid gland carcinoma Diseases 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940116949 sensipar Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to an improved process for the preparation of 3-[3- (trifluoromethyl)phenyl]-2-propenal of Formula (Ilia).
- the present invention also relates to an improved process for the preparation of 3-[3- (trifluoromethyl)phenyl]-2-propen- 1 -ol (IVb).
- the compounds of Formulae INa and IVb are key precursors in the preparation of Calcimimetic agent, Cinacalcet hydrochloride of Formula I.
- N- [( 1 R)- 1 -( 1 -Naphthyl)ethyl]-3 -[3 -(trifluoromethyl)phenyl]propan- 1 -amine hydrochloride is generically known as Cinacalcet.
- Cinacalcet is a second generation calcimimetic agent, which decreases the secretion of parathyroid hormone (PTH) by activating calcium receptors.
- the secretion of PTH is normally regulated by the calcium-sensing receptor.
- Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours.
- Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of PTH are an indicator of secondary hyperparathyroidism associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death.
- Cinacalcet is marketed under the name Sensipar ® in the US and, in Europe, it is marketed under the name Mimpara ® and Parareg ® . It has been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma.
- Cinacalcet and its pharmaceutically acceptable salts as calcium receptor-active molecules in US 6,01 1 ,068, US 6,313,146 and disclosed specifically in US 6,21 1 ,244. However, there is no explicit example for the preparation of Cinacalcet.
- Cinacalcet may be prepared by reacting 3-[3-(trifluoromethyl)phenyl]propylamine (V) with 1 -acetylnaphthalene (VI) in the presence of titanium (IV) isopropoxide, to produce an imine (VII) , which is further reacted with ethanolic or methanolic sodium cyanoborohydride to produce racemic Cinacalcet (Ia), and resolution of the racemic Cinacalcet by chiral liquid chromatography to produce Cinacalcet (Ib).
- US '244 also generically discloses a variant process for the preparation of Cinacalcet by reacting 3-trifluoromethylcinnamonitrile (VIII) with diisobutylaluminum hydride to produce intermediate aluminum-imine complex (IX), which is further reacted with (R)-l-(l-naphthyl)ethylamine (X) to produce an imine (Vila), followed by reduction using ethanolic sodium cyanoborohydride to produce 3-(3-(trifluoromethyl)phenyl- N-((R)-l -(naphthalen-l-yl)ethyl)prop-2-en-l -amine (unsaturated Cinacalcet) (II) and reducing unsaturated Cinacalcet to produce Cinacalcet (Ib).
- Cinacalcet may be prepared by reacting (R)-I -(I - naphthyl)ethylamine (X) with 3-[3-(trifluoromethyl)phenyl]propionaldehyde (III) in the presence of titanium (IV) isopropoxide to produce intermediate compound imine (VII), which is further reduced using ethanolic sodium cyanoborohydride.
- Scheme-Ill US 7,250,533 discloses a process for the preparation of Cinacalcet, wherein 3-[3- (trifluoromethyl)phenyl]propanol (IV) is converted to a compound with a good leaving group (IVa), which is further condensed with (R)-l -(l -naphthyl)ethylamine (X) to produce Cinacalcet (Ib).
- the reagents described in the patent, which have good leaving groups are thionyl halide, aliphatic sulfonyl halide and aromatic sulfonyl halide.
- WO 2008/068625 A2 discloses condensation of 3-[3- (trifluoromethyl)phenyl]propionaldehyde (III) with (R)-l-(l -naphthyl)ethylamine (X) in the absence of titanium isopropoxide to produce Cinacalcet (Ib).
- Tetrahedron Letters (2004), 45, 8355 discloses a process for the preparation of precursor compound of the Cinacalcet, namely 3-[3- (trifluoromethyl)phenyl]propionaldehyde (III) by reducing 3-
- EP 0 194 764 B l discloses a process for the preparation of 3-[3-(trifluoromethyl)- phenyljpropionaldehyde (III) by reacting 3-trifiuoromethylbromobenzene (XII) with propargyl alcohol in presence of bis(triphenylphosphine)palladium chloride and cuprous iodide in triethylamine, followed by catalytic hydrogenation to produce the corresponding alcohol (IV), which is further oxidised by a Swern oxidation.
- the major disadvantage with the above processes is the formation of an undesired desfluoro compound (IHb) due to the use of strong reducing agent lithium aluminum hydride (LiAlH 4 ).
- the separation of undesired desfluoro compound (HIb) from 3-[3-(trifluoromethyl)phenyl]propionaldehyde (HI), and 3-[3- (trifluoromethyl)phenyl]propanol (IV) is difficult.
- WO 2008/035212 A2 discloses a process for the preparation of 3-[3- (trifluoromethyl)phenyl]propionaldehyde (III), by reacting 3-[3-
- the present invention is specifically directed towards the process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia), which avoids very low temperature oxidation conditions (-70 to -8O 0 C) as well as the unpleasant odors associated with the prior-art procedures (Swern oxidation).
- the present invention also specifically directed towards the process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb) by reducing mixed anhydride of Formula (XVIII) in the absence of strong reducing agents.
- the main objective of the present invention is to provide a simple and cost effective process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal of Formula (Ilia) with good yields on a commercial scale.
- Another objective of the present invention is to produce Cinacalcet hydrochloride with good yields and quality on a commercial scale.
- the present invention provides an improved process for the preparation of 3-[3- (trifluoromethyl)phenyl]-2-propenal (Ilia),
- the present invention also provides a process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb),
- R represents Cj -3 alkyl, benzyl and substituted benzyl.
- the present invention provides an improved process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb).
- the process comprises, reacting 3-(trifluoromethyl)cinnamic acid (XI) with alkyl chloroformate in the presence of a suitable base and in a suitable solvent to produce a mixed anhydride (XVIII).
- the suitable base used in the reaction includes but are not limited to triethyl amine, isopropyl ethylamine, 4-(dimethylamino)pyridine, potassium carbonate.
- the solvent used in the reaction is ethyl acetate, tetrahydrofuran, methylene chloride, toluene and the like. The most preferred solvent is toluene.
- the reaction may be performed at a temperature ranging from -35 0 C to about 35 0 C based on the solvent or mixture of solvents used for the reaction.
- Alkyl chloroformate is added slowly in a drop-wise manner. Most preferably, this addition is while maintaining the reaction mixture at a temperature of about -20 0 C to about 5 0 C.
- the reaction mixture containing mixed anhydride (XVIII) is (optionally, the salts can be removed by washing with water at low temperature) filtered to remove residual salts and reagents. The filter cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce mixed anhydride (XVIII).
- the suitable reducing agent is selected from sodium borohydride, lithium aluminium hydride, zinc borohydride, calcium borohydride. Most preferred reducing agent is sodium borohydride.
- the solvent used in the reaction includes, but not limited to water, dioxane, toluene, THF or mixtures thereof. Most preferred solvent is THF.
- the reaction may be performed at a temperature ranging from -10 0 C to about 35 0 C based on the solvent or mixture of solvents used for the reaction.
- Cinacalcet prepared by using 3-[3- (trifluoromethyl)phenyl]-2-propen-l -ol (IVb) prepared by above reaction conditions results in desfluoro Cinacalcet impurity (Ic) to less than 0.03% by HPLC analysis.
- the present invention also provides a process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (INa).
- the process comprising, oxidizing 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb) with oxidizing agent in the presence of a solvent to produce 3-[3- (trifluoromethyl)phenyl]-2-propenal (Ilia).
- the suitable oxidizing agent used in the reaction is selected from 2,3-dichloro-5,6-dicyano-l ,4-benzoquinone (DDQ), 3,4,5,6-tetrachloro-l,2-benzoquinone (o-chloranil), 2,3,5,6-tetrachloro-l,4- benzoquinone (p-chloranil), 1 ,4-benzoquinone (p-benzoquinone), manganese dioxide (MnO 2 ), potassium permanganate (KMnU 4 ), potassium dichromate (K 2 Cr 2 O 7 ), chromium trioxide (CrO 3 ) and sodium hypochlorite (NaOCl).
- DDQ 2,3-dichloro-5,6-dicyano-l ,4-benzoquinone
- o-chloranil 3,4,5,6-tetrachloro-l,2-benzoquinone
- p-chloranil 2,3,5,
- Suitable solvent used for oxidation is inert organic solvent selected from acetonitrile, cyclic or acyclic alkanes such as hexane, heptane, methylcyclohexane, aromatic solvents such as toluene, halogenated solvents such as dichloromethane (MDC). dichloroethane, chloroform, esters such as ethyl acetate, butyl acetate, isopropyl acetate or ethers such as diethyl ether, tetrahydroturan or tert-butyl methyl ether and/or mixtures thereof,
- the solvent is MDC, toluene or acetonitrile.
- Oxidation reaction is conducted at a temperature in the range of about -5 0 C to about 25°C and for a time in the range of about 10 min to about 2 hr. More preferably, at a temperature below 15°C, and for a time of about 20 min to about 60 min.
- 3-[3- (trifluoromethyl)phenyl]-2-propenal (Ilia) produced in the above reaction is isolated from the reaction mass by diluting the reaction mass with a solvent selected from dichloromethane, toluene and water followed by layer separation and solvent removal.
- Oxidation reaction is optionally carried out in the presence of nitroxyl compound, which is selected from 2,2,6,6-tetramethyl-l -piperidinyloxy free radical (TEMPO), when the oxidizing agent sodium hypochlorite (NaOCl) is used . It was found to be advantageous to add the oxidizing agent in portions to the reaction mixture.
- acid is added to maintain the pH of the reaction mixture to a pH of about 8-9.5.
- the acid is selected from aqueous hydrochloric acid, aqueous sulfuric acid, p-toluene sulfonic acid, trifluoroacetic acid, and acetic acid. More preferably, aqueous HCl is added.
- the major advantage with the process (oxidation) of the present invention is that it avoids very low temperature oxidation conditions (-70 to -80 0 C) as well as the unpleasant odors associated with the prior-art procedures (Swern oxidation).
- the present invention also relates to the use of above compounds 3-[3-(trifluorornethyl)phenyl]-2-propen-l -ol (IVb) and 3-[3- (trifiuoromethyl)phenyl]-2-propenal (Ilia) to produce Cinacalcet hydrochloride.
- 3-(3-(TrifluoromethyI)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l -amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (Ha) can be prepared by reductive amination of 3-[3-(trifluoromethyl)phenyl]-2-propenal (NIa) with (R)-I -(I -naphthyl)ethylamine (X), in the presence of a reducing agent selected from sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride (NaBH 3 CN) in a solvent selected from ethyl acetate, tetrahydrofuran, isopropyl acetate, acetonitrile to produce 3-(trifluoromethyl)phenyl-N-((R)-l -(naphthalen- 1- yl)e
- the reaction mixture containing the 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen- l -yl)ethyl)prop-2-en-l -amine (unsaturated Cinacalcet) (II) is cooled and optionally residual salts and reagents are filtered from the reaction mixture. The filter cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce crude 3-(trifluoromethyl)phenyl-N-((R)-l -(naphthalen- l-yl)ethyl)prop-2-en- 1 -amine (unsaturated Cinacalcet) (II).
- 3-(3-(trifluoromethyl)phenyl-N-((R)- 1 -(naphthalen- 1 -yl)ethyl)prop-2-en- 1 -amine can also be recovered from the reaction mixture by extraction from the reaction mixture using a solvent selected from the group consisting of C 4 . 8 ethers, chlorinated solvents, C 3-6 esters, C5.8 cyclic, aromatic and aliphatic hydrocarbons and mixtures thereof. More preferably, the solvent is ethyl acetate, dichloromethane (DCM), toluene or mixtures thereof.
- DCM dichloromethane
- 3-(3-(trifluoromethyl)phenyl-N-((R)-l -(naphthalen- l-yl)ethyl)prop-2- en-1 -amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (Ha) can also be prepared by converting 3-[3-(trifluoromethyl)phenyl]-2-propen-l -ol (IVb) into a good leaving group by reacting with a reagent containing the leaving group, which is selected from thionyl halide, aliphatic sulfonyl halide and aromatic sulfonyl halide.
- the thionyl halide is either thionyl bromide or thionyl chloride, while the preferred aliphatic sulfonyl halide is methanesulfonyl chloride and the preferred aromatic sulfonyl halide is benzenesulfonyl chloride, 4- nitrobenzenesulfonyl chloride or p-toluenesulfonyl chloride.
- the suitable inert organic solvents for the above reaction include but are not limited to halogenated solvents, such as dichloromethane, ethylene dichloride, and chloroform; ether, toluene and the like.
- the reaction may be performed at a temperature ranging from 0 0 C to about 35 0 C based on the solvent or mixture of solvents used for the reaction.
- the reagent containing the leaving group is added to the solution of 3-[3-(trifluoromethyl)phenyl]-2-propen-l -oI (IVb) in organic solvent. More preferably, the reagent is added slowly in a drop-wise manner. Most preferably, this addition is while maintaining the reaction mixture at a temperature of about O 0 C to about 10°C.
- the reaction is carried out in presence or absence of a base.
- the leaving group is sulfonyl chloride
- the reaction is carried out in presence of a base.
- the organic base is an amine, more preferably, triethylamine, diisopropylethylamine, and pyridine.
- the sufficient period of time necessary for obtaining compound (IVc) will depend on the para meters of the reaction.
- maintaining the reaction mixture for about 4 to about 24 hours. More preferably, the reaction mixture is maintained for about 8 hour to about 15 hours.
- X represents a leaving group selected from Cl, Br, C 1 . 3 alkyl sulfonate or C 6 - I o aryl sulfonate.
- the compound (IVc) obtained by the above process can be isolated by precipitation of compound from the reaction mixture or by removing the solvent from the reaction mixture.
- the compound (IVc) is condensed with (R)- 1 -( 1 -naphthyl)ethylamine (X) in the presence of suitable base in a solvent to produce 3-(3-(trifluoromethyl)phenyl-N- ((R)- l-(naphthalen-l-yl)ethyl)prop-2-en-l -amine (unsaturated Cinacalcet) (II).
- the suitable base used in the reaction is selected from an inorganic base such as alkali carbonate, more preferably, K 2 CO 3 , Na 2 CO 3 , CS 2 CO 3 , NaHCO 3 or KHCO 3 .
- the most preferred base is K 2 CO 3 .
- the solvent is an organic solvent selected from acetonitrile, toluene, methyl isobutyl ketone (MIBK), and acetone, more preferably acetonitrile.
- the reaction may be performed at a temperature ranging from about 25°C to about reflux temperature of the solvent or mixture of solvents used for the reaction.
- the reaction time is about 5 to about 24 hours, more preferably about 10 to about 20 hours. After completion of the reaction, filtering off the salts obtained in the reaction and evaporating to obtain a residue.
- 3-(3-(trifluoromethyl)phenyl-N-((R)-l -(naphthalen- 1 -yl)ethyl)prop-2- en-1 -amine can also be recovered from the reaction mixture by extraction from the reaction mixture using a solvent selected from the group consisting of C 4 . 8 ethers, chlorinated solvents, C 3-6 esters, C 5 . 8 cyclic, aromatic and aliphatic hydrocarbons and mixtures thereof. More preferably, the solvent is ethyl acetate, dichloromethane (DCM), toluene or mixtures thereof.
- DCM dichloromethane
- the process further comprises, reducing 3-(3-(trifluoromethyl)phenyl-N-((R)-l - (naphthalen-l -yl)ethyl)prop-2-en-l -amine hydrochloride (Ha), preferably, by catalytic hydrogenation (i.e., with hydrogen in the presence of catalyst) to produce Cinacalcet hydrochloride (I).
- unsaturated Cinacalcet hydrochloride Ha
- catalytic hydrogenation i.e., with hydrogen in the presence of catalyst
- the hydrochloride salt of 3-(3-(trifluoromethyl)phenyl-N-((R)- 1 -(naphthalen- 1 -yl)ethyl)prop-2-en-l- amine may be dissolved in a lower alcohol selected from Ci -C 4 aliphatic, straight chain or branched alcohol, and exposed to H 2 pressure in the presence of a catalyst such as Pd/C or PtO 2 or Raney nickel.
- a catalyst such as Pd/C or PtO 2 or Raney nickel.
- hydrogen is present at a pressure of about 1 atmosphere to about 1000 psi and at a temperature about 0 0 C to 35°C.
- Cinacalcet hydrochloride typically, the hydrogenation is carried out over a period of about 1 to about 6 hours to produce Cinacalcet hydrochloride.
- the reaction mixture containing Cinacalcet hydrochloride is cooled and filtered.
- the filtered cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce Cinacalcet hydrochloride, which is isolated by the addition of organic solvent selected from acetonitrile, ether, heptane, methyl isobutyl ketone (MIBK).
- MIBK methyl isobutyl ketone
- the present invention also relates to use of Cinacalcet hydrochloride produced by above processes in the preparation of pharmaceutical compositions.
- Stage- 1 Method a: Preparation of 3-(3-(trifluoromethyl)phenyll-2-propen-l-ol (IVb)
- Ethyl chloroformate (78.05 g, 719 mmol) was slowly added to a mixture of 3- (trifluoromethyl)cinnamic acid (100 g, 463 mmol) and triethylamine (56.1 g, 555 mmol) in toluene (800 ml) at -5°C to -1O 0 C and stirring was continued at O 0 C for 3 hrs.
- the reaction mass was filtered to remove triethylamine HCl salts and washed with toluene (200 ml). The filtrate was concentrated to produce mixed anhydride (133 g).
- Aqueous sodium borohydride solution (26.38 g, 694 mmol in water 82 ml) was added slowly to a mixture of mixed anhydride in dioxane (400 ml) at 0-5 0 C and stirred for 2 hrs. Acetone (40 ml) was added and concentrated the reaction mass. Toluene (400 ml) and water (200 ml) were added to the residue and the aqueous layer was extracted with toluene (200 ml). Combined toluene layer was washed with water and concentrated under reduced pressure to get 3-[3-(trifluoromethyl)phenyl]- 2-propen-l -ol (84.2 g, 90%).
- Aqueous sodium borohydride solution (6.6 g, 174 mmol in water 21 ml) was added slowly to a mixture of mixed anhydride in tetrahydrofuran (100 ml) at 0-5 0 C and stirred for 2 hrs. Acetone (10 ml) was added and concentrated the reaction mass. Toluene (100 ml) and water (50 ml) were added to the residue, and the aqueous layer was extracted with toluene (50 ml). Combined toluene layer was washed with water, concentrated under reduced pressure to produce 3-[3-(trifluoromethyl)phenyl]-2- propen-l -ol (17.3 g, 74%).
- Titanium isoproxide (2.13 g, 7.5 mmol) was added to the mixture of 3-[3- (Trifluoromethyl)phenyl]-2-propenal (15 g, 75 mmol) and (R)-I -(I- naphthyl)ethylamine (1 1.54 g, 68 mmol) at 10-15° and stirred for 6 hrs.
- Ethyl acetate (360 ml) was added and filtered to remove the salts.
- the resulting clear solution was hydrogenated at 1 Kg/cm 2 in the presence of 5% pd on carbon (1.2 g) at 0-5 0 C. The reaction mass was filtered to remove the catalyst.
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Abstract
The present invention provides an improved process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (IIIa), (formula IIIa) and 3-[3-(trifluoromethyl)phenyl]-2-propen-1-ol (IVb), (formula IVb) The compounds of Formula IIIa and IVb are key precursors in the preparation of Calcimimetic agent, Cinacalcet hydrochloride of Formula I.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF INTERMEDIATE COMPOUNDS USEFUL FOR THE PREPARATION OF
CINACALCET
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 3-[3- (trifluoromethyl)phenyl]-2-propenal of Formula (Ilia).
Formula HIa
The present invention also relates to an improved process for the preparation of 3-[3- (trifluoromethyl)phenyl]-2-propen- 1 -ol (IVb).
Formula IVb
The compounds of Formulae INa and IVb are key precursors in the preparation of Calcimimetic agent, Cinacalcet hydrochloride of Formula I.
HC| Formula I
BACKGROUND OF THE INVENTION
N- [( 1 R)- 1 -( 1 -Naphthyl)ethyl]-3 -[3 -(trifluoromethyl)phenyl]propan- 1 -amine hydrochloride is generically known as Cinacalcet.
Cinacalcet is a second generation calcimimetic agent, which decreases the secretion of parathyroid hormone (PTH) by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents
increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of PTH are an indicator of secondary hyperparathyroidism associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death.
Cinacalcet is marketed under the name Sensipar® in the US and, in Europe, it is marketed under the name Mimpara® and Parareg®. It has been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma.
NPS Pharmaceuticals disclosed generically Cinacalcet and its pharmaceutically acceptable salts as calcium receptor-active molecules in US 6,01 1 ,068, US 6,313,146 and disclosed specifically in US 6,21 1 ,244. However, there is no explicit example for the preparation of Cinacalcet.
According to the generic process disclosed in US '244 Cinacalcet may be prepared by reacting 3-[3-(trifluoromethyl)phenyl]propylamine (V) with 1 -acetylnaphthalene (VI) in the presence of titanium (IV) isopropoxide, to produce an imine (VII) , which is further reacted with ethanolic or methanolic sodium cyanoborohydride to produce racemic Cinacalcet (Ia), and resolution of the racemic Cinacalcet by chiral liquid chromatography to produce Cinacalcet (Ib).
The process is as shown in Scheme -I below:
Scheme-I
US '244 also generically discloses a variant process for the preparation of Cinacalcet by reacting 3-trifluoromethylcinnamonitrile (VIII) with diisobutylaluminum hydride to produce intermediate aluminum-imine complex (IX), which is further reacted with (R)-l-(l-naphthyl)ethylamine (X) to produce an imine (Vila), followed by reduction using ethanolic sodium cyanoborohydride to produce 3-(3-(trifluoromethyl)phenyl- N-((R)-l -(naphthalen-l-yl)ethyl)prop-2-en-l -amine (unsaturated Cinacalcet) (II) and reducing unsaturated Cinacalcet to produce Cinacalcet (Ib).
The process is as shown in Scheme -II below:
Scheme-II
Similarly, using the process disclosed in US '244, as well as Drugs of the Future 2002, 2" (9), 831-836, Cinacalcet may be prepared by reacting (R)-I -(I - naphthyl)ethylamine (X) with 3-[3-(trifluoromethyl)phenyl]propionaldehyde (III) in the presence of titanium (IV) isopropoxide to produce intermediate compound imine (VII), which is further reduced using ethanolic sodium cyanoborohydride.
The process is as shown in Scheme -III below:
Cinacalcet
Ob)
Scheme-Ill
US 7,250,533 discloses a process for the preparation of Cinacalcet, wherein 3-[3- (trifluoromethyl)phenyl]propanol (IV) is converted to a compound with a good leaving group (IVa), which is further condensed with (R)-l -(l -naphthyl)ethylamine (X) to produce Cinacalcet (Ib). The reagents described in the patent, which have good leaving groups are thionyl halide, aliphatic sulfonyl halide and aromatic sulfonyl halide.
The process is as shown in Scheme -IV below:
US 7,393,967 discloses a process for the preparation of Cinacalcet, which comprises, condensing 3-bromotrifluorotoluene (XII) with allyl amine (XIII) to produce 3- (trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l -yl)ethyl)prop-2-en-l -amine (unsaturated Cinacalcet) (II), which is further reduced in presence of Pd/C to produce Cinacalcet (Ib).
The process is as shown in Scheme -V below:
Scheme-V
US 2007/0259964 Al discloses a process for the preparation of Cinacalcet (Ib), wherein 3-(trifluoromethyl)cinnamic acid (XI) is reduced to obtain 3-[3- (trifluoromethyl)phenyl]propanoic acid (XIa) followed by converting to corresponding reactive derivative (XIV), which is further condensed with (R)-I-(I- naphthyl)ethylamine (X) in the presence of a base to produce N-[( I S)-I-(I- naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide (XV) and followed by reduction to produce Cinacalcet (Ib).
The process is as shown in Scheme -VT below:
(XIV)
Scheme- Vl
The major disadvantage with the above process is the formation of (~ 2%) desfluoro Cinacalcet (Ic), due to the use of strong reducing agent such as BH3. The separation of undesired desfluoro Cinacalcet (Ic) from Cinacalcet (Ib) is difficult and require repeated crystallization, resulting in a significant loss of yield.
Formula Ic
WO 2008/068625 A2 discloses condensation of 3-[3- (trifluoromethyl)phenyl]propionaldehyde (III) with (R)-l-(l -naphthyl)ethylamine (X) in the absence of titanium isopropoxide to produce Cinacalcet (Ib).
The process is as shown in Scheme -VH below:
Scheme- VII
US 7,294,735 discloses a process for the purification Cinacalcet hydrochloride by treating Cinacalcet base having 3 to 6% of 3-(3-(trifluoromethyl)phenyl)propyl-(R)- l-(naphthalen-l-yl)ethyl carbamate (Cinacalcet carbamate) (XVI) in a solvent selected from acetone, C2-8 ethers and water with hydrochloric acid.
Formula XVI
Tetrahedron Letters (2004), 45, 8355, discloses a process for the preparation of precursor compound of the Cinacalcet, namely 3-[3- (trifluoromethyl)phenyl]propionaldehyde (III) by reducing 3-
(trifluoromethyl)cinnamic acid (XI) to the corresponding alcohol (IV) followed by Swern oxidation.
The process is as shown in Scheme -VIII below:
Scheme- VIII
EP 0 194 764 B l discloses a process for the preparation of 3-[3-(trifluoromethyl)- phenyljpropionaldehyde (III) by reacting 3-trifiuoromethylbromobenzene (XII) with propargyl alcohol in presence of bis(triphenylphosphine)palladium chloride and cuprous iodide in triethylamine, followed by catalytic hydrogenation to produce the corresponding alcohol (IV), which is further oxidised by a Swern oxidation.
The process is as shown in Scheme -IX below:
Scheme-IX
The above processes involve the use of reagents, such as oxalyl chloride and dimethyl sulfoxide in the Swern oxidation, which are unstable and does not result in high yield, making the process difficult on industrial scale.
Further, the major disadvantage with the above processes is the formation of an undesired desfluoro compound (IHb) due to the use of strong reducing agent lithium aluminum hydride (LiAlH4). The separation of undesired desfluoro compound (HIb) from 3-[3-(trifluoromethyl)phenyl]propionaldehyde (HI), and 3-[3- (trifluoromethyl)phenyl]propanol (IV) is difficult.
Formula IUb
WO 2008/035212 A2 discloses a process for the preparation of 3-[3- (trifluoromethyl)phenyl]propionaldehyde (III), by reacting 3-[3-
(trifluoromethyl)phenyl]propanol (IV) with sodium hypochlorite / 2,2,6,6,- tetramethy-1-piperidinyloxy free radical (TEMPO).
The process is as shown in Scheme -X below:
(IV) (HI)
Scheme-X
Hence, there is a need to develop a process, which provides 3-[3- (trifluoromethyl)phenyl]-2-propenal (Ilia) and 3-[3-(trifluoromethyl)phenyl]-2- propen-l-ol (IVb) with good yields on a commercial scale.
The present invention is specifically directed towards the process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia), which avoids very low
temperature oxidation conditions (-70 to -8O0C) as well as the unpleasant odors associated with the prior-art procedures (Swern oxidation).
The present invention also specifically directed towards the process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb) by reducing mixed anhydride of Formula (XVIII) in the absence of strong reducing agents.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a simple and cost effective process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal of Formula (Ilia) with good yields on a commercial scale.
Another objective of the present invention is to produce Cinacalcet hydrochloride with good yields and quality on a commercial scale.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of 3-[3- (trifluoromethyl)phenyl]-2-propenal (Ilia),
Formula HIa
which comprises: oxidizing 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb)
Formula IVb
with suitable oxidizing agent, optionally in the presence of a catalyst in a solvent to produce 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia).
According to another embodiment, the present invention also provides a process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb),
Formula IVb
which comprises: reducing mixed anhydride of Formula (XVIII) with a suitable reducing agent in a solvent,
Formula XVTII
wherein R represents Cj-3 alkyl, benzyl and substituted benzyl.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the invention, the present invention provides an improved process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb).
The process comprises, reacting 3-(trifluoromethyl)cinnamic acid (XI) with alkyl chloroformate in the presence of a suitable base and in a suitable solvent to produce a mixed anhydride (XVIII). The suitable base used in the reaction includes but are not limited to triethyl amine, isopropyl ethylamine, 4-(dimethylamino)pyridine, potassium carbonate. The solvent used in the reaction is ethyl acetate, tetrahydrofuran, methylene chloride, toluene and the like. The most preferred solvent is toluene. The reaction may be performed at a temperature ranging from -350C to about 350C based on the solvent or mixture of solvents used for the reaction. Alkyl chloroformate is added slowly in a drop-wise manner. Most preferably, this addition
is while maintaining the reaction mixture at a temperature of about -200C to about 50C. The reaction mixture containing mixed anhydride (XVIII) is (optionally, the salts can be removed by washing with water at low temperature) filtered to remove residual salts and reagents. The filter cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce mixed anhydride (XVIII).
Reducing the mixed anhydride (XVIII) with a suitable reducing agent in a solvent to produce 3-[3-(trifluoromethyl)phenyl]-2-propen-l -ol (IVb). The suitable reducing agent is selected from sodium borohydride, lithium aluminium hydride, zinc borohydride, calcium borohydride. Most preferred reducing agent is sodium borohydride. The solvent used in the reaction includes, but not limited to water, dioxane, toluene, THF or mixtures thereof. Most preferred solvent is THF. The reaction may be performed at a temperature ranging from -100C to about 350C based on the solvent or mixture of solvents used for the reaction. After the completion of reaction, as ascertained by the known methods such as HPLC, acetone is added to the reaction mass and extracted with a solvent selected from toluene, ethyl acetate, dichloromethane, hexane and the solvent is removed to produce 3-[3- (trifiuoromethyl)phenyl]-2-propen- 1 -ol (IVb).
It has been observed that Cinacalcet prepared by using 3-[3- (trifluoromethyl)phenyl]-2-propen-l -ol (IVb) prepared by above reaction conditions results in desfluoro Cinacalcet impurity (Ic) to less than 0.03% by HPLC analysis.
According to another embodiment, the present invention also provides a process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (INa).
The process comprising, oxidizing 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb) with oxidizing agent in the presence of a solvent to produce 3-[3- (trifluoromethyl)phenyl]-2-propenal (Ilia). The suitable oxidizing agent used in the reaction is selected from 2,3-dichloro-5,6-dicyano-l ,4-benzoquinone (DDQ), 3,4,5,6-tetrachloro-l,2-benzoquinone (o-chloranil), 2,3,5,6-tetrachloro-l,4- benzoquinone (p-chloranil), 1 ,4-benzoquinone (p-benzoquinone), manganese
dioxide (MnO2), potassium permanganate (KMnU4), potassium dichromate (K2Cr2O7), chromium trioxide (CrO3) and sodium hypochlorite (NaOCl).
Suitable solvent used for oxidation is inert organic solvent selected from acetonitrile, cyclic or acyclic alkanes such as hexane, heptane, methylcyclohexane, aromatic solvents such as toluene, halogenated solvents such as dichloromethane (MDC). dichloroethane, chloroform, esters such as ethyl acetate, butyl acetate, isopropyl acetate or ethers such as diethyl ether, tetrahydroturan or tert-butyl methyl ether and/or mixtures thereof, Preferably, the solvent is MDC, toluene or acetonitrile.
Oxidation reaction is conducted at a temperature in the range of about -50C to about 25°C and for a time in the range of about 10 min to about 2 hr. More preferably, at a temperature below 15°C, and for a time of about 20 min to about 60 min. 3-[3- (trifluoromethyl)phenyl]-2-propenal (Ilia) produced in the above reaction is isolated from the reaction mass by diluting the reaction mass with a solvent selected from dichloromethane, toluene and water followed by layer separation and solvent removal.
Oxidation reaction is optionally carried out in the presence of nitroxyl compound, which is selected from 2,2,6,6-tetramethyl-l -piperidinyloxy free radical (TEMPO), when the oxidizing agent sodium hypochlorite (NaOCl) is used . It was found to be advantageous to add the oxidizing agent in portions to the reaction mixture. After addition of oxidizing agent, acid is added to maintain the pH of the reaction mixture to a pH of about 8-9.5. The acid is selected from aqueous hydrochloric acid, aqueous sulfuric acid, p-toluene sulfonic acid, trifluoroacetic acid, and acetic acid. More preferably, aqueous HCl is added.
The major advantage with the process (oxidation) of the present invention is that it avoids very low temperature oxidation conditions (-70 to -800C) as well as the unpleasant odors associated with the prior-art procedures (Swern oxidation).
In another embodiment, the present invention also relates to the use of above compounds 3-[3-(trifluorornethyl)phenyl]-2-propen-l -ol (IVb) and 3-[3- (trifiuoromethyl)phenyl]-2-propenal (Ilia) to produce Cinacalcet hydrochloride.
3-(3-(TrifluoromethyI)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l -amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (Ha) can be prepared by reductive amination of 3-[3-(trifluoromethyl)phenyl]-2-propenal (NIa) with (R)-I -(I -naphthyl)ethylamine (X), in the presence of a reducing agent selected from sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride (NaBH3CN) in a solvent selected from ethyl acetate, tetrahydrofuran, isopropyl acetate, acetonitrile to produce 3-(trifluoromethyl)phenyl-N-((R)-l -(naphthalen- 1- yl)ethyl)prop-2-en-l -amine (unsaturated Cinacalcet) (II). The reaction may be performed at a temperature ranging from about 0°C to about 500C based on the solvents used for the reaction. The above reaction is optionally conducted in presence of an acid selected from acetic acid.
The reaction mixture containing the 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen- l -yl)ethyl)prop-2-en-l -amine (unsaturated Cinacalcet) (II) is cooled and optionally residual salts and reagents are filtered from the reaction mixture. The filter cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce crude 3-(trifluoromethyl)phenyl-N-((R)-l -(naphthalen- l-yl)ethyl)prop-2-en- 1 -amine (unsaturated Cinacalcet) (II).
3-(3-(trifluoromethyl)phenyl-N-((R)- 1 -(naphthalen- 1 -yl)ethyl)prop-2-en- 1 -amine (unsaturated Cinacalcet) (II) can also be recovered from the reaction mixture by extraction from the reaction mixture using a solvent selected from the group consisting of C4.8 ethers, chlorinated solvents, C3-6 esters, C5.8 cyclic, aromatic and aliphatic hydrocarbons and mixtures thereof. More preferably, the solvent is ethyl acetate, dichloromethane (DCM), toluene or mixtures thereof.
3 -(3 -(Trifluoromethyl)pheny 1-N-((R)- 1 -(naphthalen- 1 -yl)ethyl)prop-2-en- 1 -amine (unsaturated Cinacalcet) (II) produced by the above methods is treated with
hydrochloric acid in a solvent selected from acetonitrile, THF, ethers, ethyl acetate, methyl isobutyl ketone (MIBK), ketone, toluene to produce hydrochloride salt of 3- (3-(trifluoromethyl)phenyl-N-((R)- 1 -(naphthalen- 1 -yl)ethyl)prop-2-en- 1 -amine (unsaturated Cinacalcet hydrochloride) (Ha), which is isolated by evaporating the solvent or precipitation of compound from the reaction mixture, by cooling the reaction mixture, followed by addition of an organic solvent.
Alternatively, 3-(3-(trifluoromethyl)phenyl-N-((R)-l -(naphthalen- l-yl)ethyl)prop-2- en-1 -amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (Ha) can also be prepared by converting 3-[3-(trifluoromethyl)phenyl]-2-propen-l -ol (IVb) into a good leaving group by reacting with a reagent containing the leaving group, which is selected from thionyl halide, aliphatic sulfonyl halide and aromatic sulfonyl halide. More preferably, the thionyl halide is either thionyl bromide or thionyl chloride, while the preferred aliphatic sulfonyl halide is methanesulfonyl chloride and the preferred aromatic sulfonyl halide is benzenesulfonyl chloride, 4- nitrobenzenesulfonyl chloride or p-toluenesulfonyl chloride.
The suitable inert organic solvents for the above reaction include but are not limited to halogenated solvents, such as dichloromethane, ethylene dichloride, and chloroform; ether, toluene and the like. The reaction may be performed at a temperature ranging from 00C to about 350C based on the solvent or mixture of solvents used for the reaction. The reagent containing the leaving group is added to the solution of 3-[3-(trifluoromethyl)phenyl]-2-propen-l -oI (IVb) in organic solvent. More preferably, the reagent is added slowly in a drop-wise manner. Most preferably, this addition is while maintaining the reaction mixture at a temperature of about O0C to about 10°C.
The reaction is carried out in presence or absence of a base. When the leaving group is sulfonyl chloride, the reaction is carried out in presence of a base. Preferably, the organic base is an amine, more preferably, triethylamine, diisopropylethylamine, and pyridine. The sufficient period of time necessary for obtaining compound (IVc) will depend on the para meters of the reaction. Preferably, maintaining the reaction
mixture for about 4 to about 24 hours. More preferably, the reaction mixture is maintained for about 8 hour to about 15 hours.
Formula IVc
wherein X represents a leaving group selected from Cl, Br, C1.3 alkyl sulfonate or C6-Io aryl sulfonate.
The compound (IVc) obtained by the above process can be isolated by precipitation of compound from the reaction mixture or by removing the solvent from the reaction mixture.
The compound (IVc) is condensed with (R)- 1 -( 1 -naphthyl)ethylamine (X) in the presence of suitable base in a solvent to produce 3-(3-(trifluoromethyl)phenyl-N- ((R)- l-(naphthalen-l-yl)ethyl)prop-2-en-l -amine (unsaturated Cinacalcet) (II). The suitable base used in the reaction is selected from an inorganic base such as alkali carbonate, more preferably, K2CO3, Na2CO3, CS2CO3, NaHCO3 or KHCO3. The most preferred base is K2CO3. The solvent is an organic solvent selected from acetonitrile, toluene, methyl isobutyl ketone (MIBK), and acetone, more preferably acetonitrile. The reaction may be performed at a temperature ranging from about 25°C to about reflux temperature of the solvent or mixture of solvents used for the reaction. The reaction time is about 5 to about 24 hours, more preferably about 10 to about 20 hours. After completion of the reaction, filtering off the salts obtained in the reaction and evaporating to obtain a residue. The residue containing 3 -(3- (trifluoromethyl)phenyl-N-((R)- 1 -(naphthalen- 1 -yl)ethyl)prop-2-en- 1 -amine (unsaturated Cinacalcet) (II) in a solvent selected from toluene, methyl isobutyl ketone (MIBK) is washed with acidic solution, followed by washing with sodium chloride solution and isolating 3-(3-(trifluoromethyl)phenyl-N-((R)-l -(naphthalen- 1- yl)ethyl)prop-2-en-l -amine (unsaturated Cinacalcet) (II) by removing the solvent.
Alternatively, 3-(3-(trifluoromethyl)phenyl-N-((R)-l -(naphthalen- 1 -yl)ethyl)prop-2- en-1 -amine (unsaturated Cinacalcet) (II) can also be recovered from the reaction
mixture by extraction from the reaction mixture using a solvent selected from the group consisting of C4.8 ethers, chlorinated solvents, C3-6 esters, C5.8 cyclic, aromatic and aliphatic hydrocarbons and mixtures thereof. More preferably, the solvent is ethyl acetate, dichloromethane (DCM), toluene or mixtures thereof.
3-(3-(Trifluoromethyl)phenyl-N-((R)- 1 -(naphthalen- 1 -yl)ethyl)prop-2-en- 1 -amine
(unsaturated Cinacalcet) (II) produced by any of the above methods is treated with hydrochloric acid in a solvent selected from acetonitrile, THF, ethers, ethylacetate, methyl isobutyl ketone (MIBK), ketone, toluene to produce hydrochloride salt of 3- (3-(trifluoromethyl)phenyl-N-((R)- 1 -(naphthalen- 1 -yl)ethyl)prop-2-en- 1 -amine
(unsaturated Cinacalcet hydrochloride) (Ha), which is isolated by evaporating the solvent or precipitation of compound from the reaction mixture, by cooling the reaction mixture, followed by addition of an organic solvent.
The process further comprises, reducing 3-(3-(trifluoromethyl)phenyl-N-((R)-l - (naphthalen-l -yl)ethyl)prop-2-en-l -amine hydrochloride (unsaturated Cinacalcet hydrochloride) (Ha), preferably, by catalytic hydrogenation (i.e., with hydrogen in the presence of catalyst) to produce Cinacalcet hydrochloride (I). The hydrochloride salt of 3-(3-(trifluoromethyl)phenyl-N-((R)- 1 -(naphthalen- 1 -yl)ethyl)prop-2-en-l- amine (unsaturated Cinacalcet hydrochloride) (Ha) may be dissolved in a lower alcohol selected from Ci -C4 aliphatic, straight chain or branched alcohol, and exposed to H2 pressure in the presence of a catalyst such as Pd/C or PtO2 or Raney nickel. Preferably, hydrogen is present at a pressure of about 1 atmosphere to about 1000 psi and at a temperature about 00C to 35°C. Typically, the hydrogenation is carried out over a period of about 1 to about 6 hours to produce Cinacalcet hydrochloride. The reaction mixture containing Cinacalcet hydrochloride is cooled and filtered. The filtered cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce Cinacalcet hydrochloride, which is isolated by the addition of organic solvent selected from acetonitrile, ether, heptane, methyl isobutyl ketone (MIBK).
The present invention also relates to use of Cinacalcet hydrochloride produced by above processes in the preparation of pharmaceutical compositions.
The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
EXAMPLES: Example 1
Preparation of Cinacalcet HCI from 3-[3-(trifluoromethyl)phenyl)-2-propen-l- ol :
Stage- 1 : Method a: Preparation of 3-(3-(trifluoromethyl)phenyll-2-propen-l-ol (IVb)
Ethyl chloroformate (78.05 g, 719 mmol) was slowly added to a mixture of 3- (trifluoromethyl)cinnamic acid (100 g, 463 mmol) and triethylamine (56.1 g, 555 mmol) in toluene (800 ml) at -5°C to -1O0C and stirring was continued at O0C for 3 hrs. The reaction mass was filtered to remove triethylamine HCl salts and washed with toluene (200 ml). The filtrate was concentrated to produce mixed anhydride (133 g). Aqueous sodium borohydride solution (26.38 g, 694 mmol in water 82 ml) was added slowly to a mixture of mixed anhydride in dioxane (400 ml) at 0-50C and stirred for 2 hrs. Acetone (40 ml) was added and concentrated the reaction mass. Toluene (400 ml) and water (200 ml) were added to the residue and the aqueous layer was extracted with toluene (200 ml). Combined toluene layer was washed with water and concentrated under reduced pressure to get 3-[3-(trifluoromethyl)phenyl]- 2-propen-l -ol (84.2 g, 90%).
Method b: Ethyl chloroformate (19.5 g, 180 mmol) was slowly added to a mixture of 3- (trifluoro-methyl)cinnamic acid (25 g, 1 16 mmol) and triethylamine (14.61 g, 145 mmol) in toluene (200 ml) at -5°C to -1O0C and stirring was continued at 00C for 3 hrs. The reaction mass was filtered to remove triethylamine HCl salts and washed with toluene (50 ml). The filtrate was concentrated to get mixed anhydride (31.5 g,
95%). Aqueous sodium borohydride solution (6.6 g, 174 mmol in water 21 ml) was added slowly to a mixture of mixed anhydride in tetrahydrofuran (100 ml) at 0-50C and stirred for 2 hrs. Acetone (10 ml) was added and concentrated the reaction mass. Toluene (100 ml) and water (50 ml) were added to the residue, and the aqueous layer was extracted with toluene (50 ml). Combined toluene layer was washed with water, concentrated under reduced pressure to produce 3-[3-(trifluoromethyl)phenyl]-2- propen-l -ol (17.3 g, 74%).
Stage-2: Preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (IHa)
Sodium bicarbonate solution (8.3 g, 99 mmol in water 85 ml) was added to a solution of 3-[3-(trifluoromethyl)phenyI]-2-propen-l-ol (20 g, 99 mmol), TEMPO free radical (0.22 g) and acetonitrile (80 ml). ~13% Sodium hypochlorite solution (73.8 g) was added to the above reaction mass over a period of 20 min at 0-5°C with stirring while maintaining the pH of the reaction mass at 8.5-9.5 using dil. HCl. After 1 hr additional stirring, methylene chloride (80 ml) followed by water (70 ml) were added. The organic layer was washed with sodium sulphite solution followed by sodium chloride solution. The organic layer was concentrated to produce 3-[3- (trifluoromethyl)phenyl]-2-propenal (17.4 g, 88%). l»
Stage-3:
Preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l- yl)ethyl)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet HCI) (Ha) 3-[3-(Trifluoromethyl)phenyl]-2-propenal (10 g, 50 mmol) was added to a solution of (R)-l -(l-naphthyl)ethylamine (8.46 g, 49 mmol) in tetrahydrofuran (250 ml). The resulting clear solution was stirred for 15 min, and acetic acid (4 g) and sodium triacetoxyborohydride (prepared separately by treating 2.6 g of sodium borohydride and 12.5 g of acetic acid in 50 ml of tetrahydrofuran) were added at 10-150C. After stirring for 2 hr at room temperature, the reaction mass was concentrated. The resulting residue was dissolved in methylene chloride (150 ml) and washed with IN HCl solution to remove unreacted amine. Separated organic layer was washed with sodium carbonate solution. The organic layer was concentrated to produce unsaturated Cinacalcet base (16.2 g). The residue containing unsaturated Cinacalcet
base was dissolved in acetonitrile (20 ml) and acidified with HCl. The resulting mass was concentrated and product was isolated from acetonitrile to produce unsaturated Cinacalcet HCl as white solid (10.7 g, 55%). 1H NMR (CDCl3) (δ ppm): - 10.82 (br.s, I H), 10.34 (br.s, I H), 7.27-8.30 (m, HH), 6.47 (m, I H), 6.16 (d, I H), 5.25 (m, I H), 3.71 (m, I H), 3.39 (m, I H), 1.97 (d, 3H); MS (m/z): 356.1 [M+l].
Stage-4:
Preparation of Cinacalcet HCl
A mixture of unsaturated Cinacalcet hydrochloride (9g, 23 mmol) and 5% Pd/C (0.9g) in methanol (90 ml) was hydrogenated at 3 Kg/cm2 for 2 hr. The reaction mass was filtered and concentrated under reduced pressure. Acetonitrile (36 ml) was added. The resulting precipitate was stirred at 5°C for 2 hr, filtered and dried to produce Cinacalcet hydrochloride (7.6 g, 84%).
HPLC purity: 99.7% Desfluoro impurity: 0.02%
Example 2:
Preparation of Cinacalcet HCl from 3-[3-(trifluoromethyl)phenyl]-2-propenal :
Stage 1 : Preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (IHa)
Method a:
3-[3-(Trifluoromethyl)phenyl]-2-propen-l-oI (25 g, 124 mmol) was added into a solution of toluene (225 ml) at 25-300C. 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) (30.9 g, 136 mmol) was added to the above solution at 5-1O0C. The slurry was stirred for 7 hrs at 25-300C and filtered at the same temperature. The filtrate was washed with 5% aqueous sodium bicarbonate solution and concentrated under reduced pressure to produce 3-[3-(trifluoromethyl)phenyl]-2-propenal (22.3 g, 90%). HPLC purity: 96.21 %.
Method b:
3-[3-(Trifluoromethyl)phenyl]-2-propen-l -ol (1 1 g, 55 mmol) was added into toluene (1 10 ml) at 25°C. Activated manganese dioxide (71 g, 816 mmol) was added to the solution at 280C. The slurry was stirred for 5 hrs and the inorganic salts were
filtered at 28°C. The filtrate was concentrated under reduced pressure to produce 3- [3-(trifluoromethyl)phenyl]-2-propenal (8.4 g, 77%). HPLC purity: 97.62 %.
Stage-2:
Preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)- prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet hydrochloride) (Ha) Method a:
3-[3-(Trifluoromethyl)phenyl]-2-propenal (20 g, 100 mmol) was added to a solution of (R)-l -(l-naphthyl)ethylamine (15.39 g, 90 mmol) in tetrahydrofuran (500 ml) at 25-300C and the solution was cooled to 10-150C. Acetic acid (7.8 g) and sodium triacetoxyborohydride (prepared separately by treating 5.17 g of sodium borohydride and 24.5 g of acetic acid in 100 ml of tetrahydrofuran) were added to the solution. The reaction mass was concentrated by removing THF after stirring for 2 hr at 5-10° C. The resulting residue was dissolved in toluene (200 ml) and washed with IN HCl solution to remove unreacted amine. The organic layer was concentrated to produce unsaturated Cinacalcet hydrochloride, which was isolated from acetonitrile and dried to produce unsaturated Cinacalcet hydrochloride (26.8 g, 68 %). HPLC purity: 99.63 %.
Method b:
3-[3-(Trifluoromethyl)phenyl]-2-propenal (8 g, 40 mmol) was added to a solution of (R)-l-(l -naphthyl)ethylamine (6.15 g, 36 mmol) in tetrahydrofuran (200 ml) at 25- 3O0C and the solution was cooled to 10-150C. Acetic acid (3.12 g) and sodium triacetoxyborohydride (prepared separately by treating 2.06 g of sodium borohydride and 9.75 g of acetic acid in 40 ml of tetrahydrofuran) were added to the solution. The reaction mass was concentrated by removing THF after stirring for 2 hr at 5-10° C. The resulting residue was dissolved in toluene (80 ml) and washed with IN HCl solution to remove unreacted amine. The organic layer was concentrated to produce unsaturated Cinacalcet hydrochloride, which was isolated from acetonitrile and dried to produce unsaturated Cinacalcet hydrochloride (10.4 g, 66 %). HPLC purity: 99.28 %.
Stage-3:
Preparation of Cinacalcet HCI
Method a:
A mixture of unsaturated Cinacalcet hydrochloride (25g, 64 mmol) and 5% Pd/C (2.5g) in methanol (90 ml) were hydrogenated at 3 Kg/cm2 for 2.5 hr at 20-250C. The reaction mass was filtered and concentrated to remove methanol under reduced pressure. Acetonitrile (87.5 ml) was added. The resulting precipitate was stirred at 0- 50C for 3 hr, filtered and dried to produce Cinacalcet hydrochloride (22.3 g, 89%). HPLC purity: 99.9%
Method b:
A mixture of unsaturated Cinacalcet hydrochloride (9g, 23 mmol) and 5% Pd/C (0.9g) in methanol (72 ml) was hydrogenated at 3 Kg/cm2 for 3 hr at 20-250C. The reaction mass was filtered and concentrated to remove methanol under reduced pressure. Acetonitrile (31.5 ml) was added. The resulting precipitate was stirred at 0- 50C for 3 hr, filtered and dried to produce Cinacalcet hydrochloride (7 g, 77 %). HPLC purity: 99.6%
Method c: Titanium isoproxide (2.13 g, 7.5 mmol) was added to the mixture of 3-[3- (Trifluoromethyl)phenyl]-2-propenal (15 g, 75 mmol) and (R)-I -(I- naphthyl)ethylamine (1 1.54 g, 68 mmol) at 10-15° and stirred for 6 hrs. Ethyl acetate (360 ml) was added and filtered to remove the salts. The resulting clear solution was hydrogenated at 1 Kg/cm2 in the presence of 5% pd on carbon (1.2 g) at 0-50C. The reaction mass was filtered to remove the catalyst. The resulting filtrate was washed with IN HCl solution to remove impurities. The resulting organic layer was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, filtered and dried to produce pure Cinacalcet hydrochloride. (13 g, 44%).
Claims
1. A process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (HIa),
Formula IHa 
which comprises: oxidizing 3-[3-(trifluoromethyl)phenyl]-2-propen-l -ol (IVb)
Formula IVb 
with suitable oxidizing agent, optionally in the presence of a catalyst, in a solvent to produce 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia).
2. The process according to claim 1 , wherein suitable oxidizing agent used in the reaction is selected from 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), 3,4,5,6-tetrachloro-l ,2-benzoquinone (ø-chloranil), 2,3,5,6- tetrachloro-l ,4-benzoquinone (p-chloranil), 1 ,4-benzoquinone (p- benzoquinone), manganese dioxide (MnO2), potassium permanganate (ICMnO4), potassium dichromate (K2Cr2O7), chromium trioxide (CrO3) and sodium hypochlorite (NaOCl). f
3. The process according to claim 1 , wherein the catalyst is selected from a nitroxyl compound.
4. The process according to claim 3, wherein the nitroxyl compound is selected from 2,2,6,6-tetramethyl- 1 -piperidinyloxy free radical (TEMPO).
5. The process according to claim 1 , wherein solvent is inert organic solvent , selected from acetonitrile, cyclic or acyclic alkanes such as hexane, heptane, methylcyclohexane; aromatic solvents such as toluene; halogenated solvents such as dichloromethane, dichloroethane, chloroform; esters such as ethyl acetate, butyl acetate, isopropyl acetate or ethers such as diethyl ether, tetrahydrofuran or tert-butyl methyl ether and/or mixtures thereof.
6. The process as claimed in claim 1, wherein 3-[3-(trifluoromethyl)phenyl]-2- propenal (NIa) is converted to Cinacalcet hydrochloride.
7. A process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propen-l -ol (IVb),
Formula IVb 
which comprises: reducing mixed anhydride of Formula (XVIII) with a suitable reducing agent in a solvent,
Formula XVIII 
wherein R represents C 1.3 alkyl, benzyl and substituted benzyl.
8. The process according to claim 7, wherein suitable reducing agent is selected from sodium borohydride, lithium aluminium hydride, zinc borohydride, and calcium borohydride.
9. The process according to claim 7, wherein solvent is selected from water, dioxane, toluene, THF and mixtures there of.
10. The process as claimed in claim 7, wherein 3-[3-(trifluoromethyl)phenyl]-2- propen-1-ol (IVb) is converted to Cinacalcet hydrochloride.
1 1. A pharmaceutical composition of Cinacalcet hydrochloride prepared by the process according to any of the claims 6 & 10,
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| IN1068/CHE/2009 | 2009-05-08 | ||
| IN1068CH2009 | 2009-05-08 | ||
| IN407CH2010 | 2010-02-17 | ||
| IN407/CHE/2010 | 2010-02-17 |
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| PCT/IB2010/001057 WO2010128388A2 (en) | 2009-05-08 | 2010-05-10 | An improved process for the preparation of intermediate compounds useful for the preparation of cinacalcet |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9290439B2 (en) | 2012-09-07 | 2016-03-22 | Produits Chimiques Auxiliaires Et De Synthese | Process for preparing cinacalcet and pharmaceutically acceptable salts thereof |
| WO2016193882A1 (en) * | 2015-05-29 | 2016-12-08 | Lupin Limited | Process for preparation of cinacalcet intermediate and cinacalcet hydrochloride |
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| EP0194764B1 (en) | 1985-02-18 | 1989-07-12 | The Wellcome Foundation Limited | Pesticidal compounds |
| US6011068A (en) | 1991-08-23 | 2000-01-04 | Nps Pharmaceuticals, Inc. | Calcium receptor-active molecules |
| US6211244B1 (en) | 1994-10-21 | 2001-04-03 | Nps Pharmaceuticals, Inc. | Calcium receptor-active compounds |
| US6313146B1 (en) | 1991-08-23 | 2001-11-06 | Nps Pharmaceuticals, Inc. | Calcium receptor-active molecules |
| US7250533B2 (en) | 2005-05-16 | 2007-07-31 | Teva Pharmaceutical Industries Ltd | Process for preparing Cinacalcet hydrochloride |
| US20070259964A1 (en) | 2006-04-27 | 2007-11-08 | Revital Lifshitz-Liron | Process for the preparation of cinacalcet base |
| US7294735B2 (en) | 2005-05-23 | 2007-11-13 | Teva Pharmaceutical Industries Ltd. | Purification of cinacalcet |
| WO2008035212A2 (en) | 2006-06-08 | 2008-03-27 | Medichem, S.A. | Processes for preparing intermediate compounds useful for the preparation of cinacalcet |
| WO2008068625A2 (en) | 2006-06-08 | 2008-06-12 | Medichem, S.A. | Processes for preparing cinacalcet hydrochloride and polymorphic forms thereof |
| US7393967B2 (en) | 2006-04-27 | 2008-07-01 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of cinacalcet base |
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|---|---|---|---|---|
| NZ229761A (en) * | 1988-07-12 | 1991-10-25 | Ici Pharma | Substituted thiazole derivatives for use as inhibitors of enzyme 5-lipoxygenase; pharmaceutical compositions and preparatory processes |
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| EP0194764B1 (en) | 1985-02-18 | 1989-07-12 | The Wellcome Foundation Limited | Pesticidal compounds |
| US6011068A (en) | 1991-08-23 | 2000-01-04 | Nps Pharmaceuticals, Inc. | Calcium receptor-active molecules |
| US6313146B1 (en) | 1991-08-23 | 2001-11-06 | Nps Pharmaceuticals, Inc. | Calcium receptor-active molecules |
| US6211244B1 (en) | 1994-10-21 | 2001-04-03 | Nps Pharmaceuticals, Inc. | Calcium receptor-active compounds |
| US7250533B2 (en) | 2005-05-16 | 2007-07-31 | Teva Pharmaceutical Industries Ltd | Process for preparing Cinacalcet hydrochloride |
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| US7393967B2 (en) | 2006-04-27 | 2008-07-01 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of cinacalcet base |
| WO2008035212A2 (en) | 2006-06-08 | 2008-03-27 | Medichem, S.A. | Processes for preparing intermediate compounds useful for the preparation of cinacalcet |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9290439B2 (en) | 2012-09-07 | 2016-03-22 | Produits Chimiques Auxiliaires Et De Synthese | Process for preparing cinacalcet and pharmaceutically acceptable salts thereof |
| US9598350B2 (en) | 2012-09-07 | 2017-03-21 | Produits Chimiques Auxiliaries Et De Synthese | Process for preparing cinacalcet and pharmaceutically acceptable salts thereof |
| WO2016193882A1 (en) * | 2015-05-29 | 2016-12-08 | Lupin Limited | Process for preparation of cinacalcet intermediate and cinacalcet hydrochloride |
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| WO2010128388A3 (en) | 2011-04-07 |
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