WO2014016847A1 - A process for the preparation of cinacalcet hydrochloride and its intermediate - Google Patents
A process for the preparation of cinacalcet hydrochloride and its intermediate Download PDFInfo
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- WO2014016847A1 WO2014016847A1 PCT/IN2012/000550 IN2012000550W WO2014016847A1 WO 2014016847 A1 WO2014016847 A1 WO 2014016847A1 IN 2012000550 W IN2012000550 W IN 2012000550W WO 2014016847 A1 WO2014016847 A1 WO 2014016847A1
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- Prior art keywords
- process according
- reaction
- phenyl
- trifluoromethyl
- carried out
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229960000478 cinacalcet hydrochloride Drugs 0.000 title claims abstract description 14
- 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 title claims abstract description 14
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims abstract description 48
- 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 claims abstract description 23
- APCCHYPQHODSBD-UHFFFAOYSA-N 3-[3-(trifluoromethyl)phenyl]propanal Chemical compound FC(F)(F)C1=CC=CC(CCC=O)=C1 APCCHYPQHODSBD-UHFFFAOYSA-N 0.000 claims abstract description 21
- PWBJWDKDPAPGED-UHFFFAOYSA-N n'-chlorobutanediamide Chemical compound NC(=O)CCC(=O)NCl PWBJWDKDPAPGED-UHFFFAOYSA-N 0.000 claims abstract description 12
- HHQJWDKIRXRTLS-UHFFFAOYSA-N n'-bromobutanediamide Chemical compound NC(=O)CCC(=O)NBr HHQJWDKIRXRTLS-UHFFFAOYSA-N 0.000 claims abstract description 8
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 5
- 150000003385 sodium Chemical class 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- -1 alkali metal alkoxide Chemical class 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 238000000354 decomposition reaction Methods 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- HIZVCIIORGCREW-UHFFFAOYSA-N 1,4-dioxene Chemical compound C1COC=CO1 HIZVCIIORGCREW-UHFFFAOYSA-N 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- 238000006268 reductive amination reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229960003315 cinacalcet Drugs 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 229940086542 triethylamine Drugs 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 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 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000005537 sulfoxonium group Chemical group 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 108010007425 oligomycin sensitivity conferring protein Proteins 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 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 2
- 238000005406 washing Methods 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000002092 calcimimetic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- 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
Definitions
- This invention relates to the field of organic chemistry and more particularly to synthetic process for the preparation ofcinacalcet hydrochloride and its intermediate3-[3-(trifluoromethyl)phenyl]propionaldehyde(I).
- Cinacalcet hydrochloride an optically active calcimimetic drug, has been approved by the U.S. Food and Drug Administration as Sensiper for the treatment of secondary hyperparathyroidism.
- Sensiper for the treatment of secondary hyperparathyroidism.
- Process for the preparation of cinacalcet was reported in Drug of the future, 2002, 27(9), 831-836.
- cinacalcet can be prepared by reacting (R)-(l-naphthyl)ethylamine with 3- ⁇ 3-(trifluoromethyl)phenyl ⁇ propionaldehyde in the presence of titanium tetraisopropoxide to give cinacalcet imine, which was then reduced with sodium cyanoborohydride in ethanol.
- the synthetic procedure was illustrated in scheme I below:
- Route C involves the oxidation of 3-[3- (trifluoromethyl)phenyl]propan-l-ol(IV) with dimethylsulfoxide and activated by phosphrouspentaoxide to afford compound I has been reported in EP Patent No 2327684 (201 1).A11 these methods commonly require expensive reagents, low temperatures and tedious procedures, thus we report here an improved reproducible process and is amenable to scale-up.
- This invention provides a simple and industrially viable process for the synthesis ofcinacalcet hydrochloride and its intermediate 3-[3- (trifluoromethyl)phenyl]propionaldehyde (I) which may be more conveniently prepared and enables the synthesis of Cinacalcet hydrochloride to be carried out in a cost effect manner and avoiding unfavorable reaction.
- the invention provides a process for the synthesis of cinacalcet hydrochloride (III), by the reductive amination of 3-[3- (trifluoromethyl)phenyl]propionaldehyde(I) and (R)-(l-napthyl)ethylamine (II) using activated sodium borohydride by an acid.
- the invention provides a process for the synthesis of 3-[3- (trifluoromethyl)phenyl]propionaldehyde(I), a key intermediate used in the synthesis
- Cinacalcet The said process comprises of decomposition of compound of formula VII in the presence of base.
- the invention provides a process for preparing a compound of formula VII, said method comprises of reacting 3-[3- (trifluoromethyl)phenyl]propan-l-ol (IV) with dimethylsulfide and N- chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; orthioanisole and N-chlorosuccinamide; or thioanisole and N-bromosuccinamide in a suitable organic solvent or mixture thereof.
- 3-[3- (trifluoromethyl)phenyl]propan-l-ol (IV) with dimethylsulfide and N- chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; orthioanisole and N-chlorosuccinamide; or thioanisole and N-bromosuccinamide in a suitable organic solvent or mixture thereof.
- the present invention provides a method for producing 3-[3- (trifluoromethyl)phenyl]propionaldehyde(I), a key intermediate used in the synthesis Cinacalcet.
- One embodiment of this invention is directed to a method of producing 3-[3- (trifluoromethyl)phenyl]propionaldehyde (I).
- the said method comprises of decomposition of compound of formula VII in the presence of base.
- the base used in the reaction with the compound of formula (VII) is an alkali metal alkoxide, or an alkali metal hydroxide or alkylamines.
- the alkoxide is preferably a CI -C6 alkoxide, more preferably a C1-C4 alkoxide, and most preferably a methoxide or ethoxide.
- the alkali metal is preferably lithium, sodium or potassium.
- the reaction temperature is suitably in the range from about -25°C to about 10 C°.
- this invention provides a process of synthesis of compound d of formula VII (sulfoxonium complex) said method comprises of reacting3-[3-(trifluoromethyl)phenyl]propan-l-ol (IV) with dimethylsulfide and N-chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; or thioanisole and N-chlorosuccinamide; or thioanisole and N-bromosuccinamide in a suitable organic solvent.
- the solvent used in the reaction of compound of formula VII is benzene, toluene, xylene, dioxane, tetrahydrofuan, chlorinated solvents or a mixture thereof.
- the reaction temperature is suitably in the range from about -25°C to about 10°C.
- This invention provides a process for the oxidation of 3-[3- (trifluoromethyl)phenyl]propan-l-ol (IV) to 3-[3-
- step c Adding organic solvent and dilute HC1 to the reaction mass obtained in step c, e) Isolating cinacalcet hydrochloride.
- reaction mixture was stirred for 3hr at -10°C to -15°C. Completion of reaction was monitored by Gas Chromatography(GC) or Thin layer chromatography (TLC). After completion of reaction, dilute Sodium hydroxide solution (40 g in 1200mL of water) was added slowly at temperature less than -5°C. After the addition, the mixture was warmed to 20°Candstirred for 1 hr at 20°C. The aqueous and organic layers were separated and the product from organic layer was extracted with sodium bisulphate solution(140 g in l lOOmL of water). The product layer was washed with dichloromethane (200mL).
- GC Gas Chromatography
- TLC Thin layer chromatography
- Example -3 Preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde (I) To a solution of 3-[3-(trifluoromethyl)phenyl]propan-l-ol (IV) (lOOg, 0.49 mol) in dichloromethane (2 L) at -10°C to -15°C, dimethyl sulfide (30 g, 0.4828 mol) and triethyl amine (62g, 0.6127mol) were added in a single lot under argon and stirred for 15-30 min. N-Chlorosuccinamide (180 g, 1.3480mol) was added lot wise over lhr while maintaining the internal temperature at -10°Cto -15°C.
- reaction mixture was stirred for 3hr at -10°C to -15°C. Completion of reaction was monitored by Gas Chromatography(GC) or Thin layer chromatography (TLC). After completion of reaction, dilute Sodium hydroxide solution (40 g in 1200mL of water) was added slowly at temperature less than -5°C. After the addition, the mixture was warmed to 20°Cand stirred for 1 hr at 20°C. The aqueous and organic layers were separated and the product from organic layer was extracted with sodium bisulphate solution(140 g in HOOmL of water). The product layer was washed with dichloromethane (200mL).
- GC Gas Chromatography
- TLC Thin layer chromatography
Abstract
This invention relates to a process for the preparation of cinacalcet hydrochloride and its key intermediate 3-[3-(trifluoromethyl) phenyl]propionaldehyde, said process comprising reductive amination of 3-[3-(trifluoromethyl)phenyl]propionaldehyde and (R)-(1-napthylethylamine) in presence of activated sodium borohydride by an acid; the invention also provides a process for preparing 3- [3-(trifluoromethyl)phenyl]propionaldehyde by reacting 3-[3- (trifluoromethyl)phenyl]propan-1-ol (IV) with dimethylsulfide and N-chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; or thioanisole and N-chlorosuccinamide; or thioanisole and N-bromosuccinamide in a suitable organic solvent.
Description
A PROCESS FOR THE PREPARATION OF CINACALCET HYDROCHLORIDE AND ITS INTERMEDIATE FIELD OF THE INVENTION
This invention relates to the field of organic chemistry and more particularly to synthetic process for the preparation ofcinacalcet hydrochloride and its intermediate3-[3-(trifluoromethyl)phenyl]propionaldehyde(I).
BACKGROUND OF THE INVENTION
Cinacalcet hydrochloride (HI), an optically active calcimimetic drug, has been approved by the U.S. Food and Drug Administration as Sensiper for the treatment of secondary hyperparathyroidism. A condition characterized by the oversecretion of parathyroid hormone in patients with chronic kidney disease on dialysis. Process for the preparation of cinacalcet was reported in Drug of the future, 2002, 27(9), 831-836. According to the journal, cinacalcet can be prepared by reacting (R)-(l-naphthyl)ethylamine with 3-{3-(trifluoromethyl)phenyl}propionaldehyde in the presence of titanium tetraisopropoxide to give cinacalcet imine, which was then reduced with sodium cyanoborohydride in ethanol. The synthetic procedure was illustrated in scheme I below:
i).Ti(0-i-Pr)4 »)· NaCNBH3 Methanol ;Con HCI
Scheme-1
There are three approaches for the preparation of 3-[3- (trifluoromethyl)phenyl]propionaldehyde (I), the key intermediate for the synthesis of Cinacalcet hydrochloride (III). In route A, the preparation of Ibyswern oxidation of 3-[3-(trifluoromethyl)phenyl]propan-l-ol(IV) has been reported in Tetrahedron Letters,(45),8355-8358,(2004)/0ot«ote 12. In route B the preparation of I by reacting 3-[3-(trifluoromethyl)phenyl]propan-l-ol(IV) with 2,2,6,6-tetramethylpiperidine-l-oxyl(TEMPO) and sodium hypochlorite in the presence of potassium bromide in methylene chloride has been reported in patent PCT publication WO 2008/035212. Route C, involves the oxidation of 3-[3- (trifluoromethyl)phenyl]propan-l-ol(IV) with dimethylsulfoxide and activated by phosphrouspentaoxide to afford compound I has been reported in EP Patent No 2327684 (201 1).A11 these methods commonly require expensive reagents, low temperatures and tedious procedures, thus we report here an improved reproducible process and is amenable to scale-up.
Hence, there is still a need for an improved process for preparing cinacalcet hydrochloride and its intermediate 3-[3-
(trifluoromethyl)phenyl]propionaldehyde(I) that can take care of prior art disadvantages. This invention provides a simple and industrially viable process for the synthesis ofcinacalcet hydrochloride and its intermediate 3-[3- (trifluoromethyl)phenyl]propionaldehyde (I) which may be more conveniently prepared and enables the synthesis of Cinacalcet hydrochloride to be carried out in a cost effect manner and avoiding unfavorable reaction.
SUMMARY OF THE INVENTION
In one aspect the invention provides a process for the synthesis of cinacalcet hydrochloride (III), by the reductive amination of 3-[3- (trifluoromethyl)phenyl]propionaldehyde(I) and (R)-(l-napthyl)ethylamine (II) using activated sodium borohydride by an acid.
In another aspect the invention provides a process for the synthesis of 3-[3- (trifluoromethyl)phenyl]propionaldehyde(I), a key intermediate used in the synthesis
Cinacalcet. The said process comprises of decomposition of compound of formula VII in the presence of base.
In another aspect the invention provides a process for preparing a compound of formula VII, said method comprises of reacting 3-[3- (trifluoromethyl)phenyl]propan-l-ol (IV) with dimethylsulfide and N- chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; orthioanisole and N-chlorosuccinamide; or thioanisole and N-bromosuccinamide in a suitable organic solvent or mixture thereof. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method for producing 3-[3- (trifluoromethyl)phenyl]propionaldehyde(I), a key intermediate used in the synthesis Cinacalcet.
One embodiment of this invention is directed to a method of producing 3-[3- (trifluoromethyl)phenyl]propionaldehyde (I). The said method comprises of decomposition of compound of formula VII in the presence of base. The base used in the reaction with the compound of formula (VII) is an alkali metal alkoxide, or an alkali metal hydroxide or alkylamines. The alkoxide is preferably a CI -C6 alkoxide, more preferably a C1-C4 alkoxide, and most preferably a methoxide or ethoxide. The alkali metal is preferably lithium, sodium or potassium. The reaction temperature is suitably in the range from about -25°C to about 10 C°. In another embodiment this invention provides a process of synthesis of compound d of formula VII (sulfoxonium complex) said method comprises of
reacting3-[3-(trifluoromethyl)phenyl]propan-l-ol (IV) with dimethylsulfide and N-chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; or thioanisole and N-chlorosuccinamide; or thioanisole and N-bromosuccinamide in a suitable organic solvent. The solvent used in the reaction of compound of formula VII is benzene, toluene, xylene, dioxane, tetrahydrofuan, chlorinated solvents or a mixture thereof. The reaction temperature is suitably in the range from about -25°C to about 10°C.
This invention provides a process for the oxidation of 3-[3- (trifluoromethyl)phenyl]propan-l-ol (IV) to 3-[3-
(trifluoromethyl)phenyl]propionaldehyde (I), which is operationally simple, highly selective, and efficient. This process would effectively allow an overall transformation such as: RR'CHOH + C12 — -->RR'CO + 2HC1, which is mediated by a sulfide. The operability of this scheme has now been demonstrated. For example, treatment of dimethyl sulfide in carbon tetrachloride at 0°C with 1 equiv of chlorine or N-Chlorosuccinamide in carbon tetrachloride at 0°C results in rapid formation of the partially insoluble complex V or VI which when cooled to - 20°C and treated with 3-[3-(trifluoromethyl)phenyl]propan-l-ol (IV) for 2 hr at - 20°C with stirring is converted to the sulfoxonium complex VII . Addition of 2 equiv of triethylamine removal of the cooling bath, and isolation after 5 min afford pure 3-[3-(trifluoromethyl)phenyl]propionaldehyde (I) in ca.85% yield.
Sulfoxonium Complex- VII
R= Methyl or Phenyl
Scheme-2
The oxidation of 3-[3-(trifluoromethyl)phenyl]propan-l-ol (IV) can be effected even more cleanly and efficiently (85 % yield) using the reported complex V or VI from dimethyl sulfide and chlorine or N-chlorosuccinimide under carefully controlled conditions.
According to another aspect of the present invention there is provided an improved process for the preparation of cinacalcet hydrochloride in high yield, which comprises
a) Adding 3-[3-(trifluoromethyl)phenyl]propionaldehyde to (R)-(l- napthyl)ethylamine at room temperature.,
b) Reacting activated sodium borohydride by an acid with the reaction mass obtained in step a.,
c) Quinching the step b reaction mass in aqeous base.,
d) Adding organic solvent and dilute HC1 to the reaction mass obtained in step c, e) Isolating cinacalcet hydrochloride.
Hereinafter the invention is explained more specifically referring to the working examples, it being understood that the examples incur no restricting effect on the invention.
Example 1
Preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde (I) To a solution of 3-[3-(trifluoromethyl)phenyl]propan-l-ol (IV) (lOOg, 0.49 mol) in toluene (2 L) at -10°C to -15°C, dimethyl sulfide (30 g, 0.4828 mol) and triethyl amine (62g, 0.6127mol) were added in a single lot under argon and stirred for 15- 30 min. N-Chlorosuccinamide (180 g, 1.3480mol) was added lot wise over lhr while maintaining the internal temperature at -10°Cto -15°C. The reaction mixture was stirred for 3hr at -10°C to -15°C. Completion of reaction was monitored by Gas Chromatography(GC) or Thin layer chromatography (TLC). After completion of reaction, dilute Sodium hydroxide solution (40 g in 1200mL of water) was added slowly at temperature less than -5°C. After the addition, the mixture was warmed to 20°Candstirred for 1 hr at 20°C. The aqueous and organic layers were separated and the product from organic layer was extracted with sodium bisulphate solution(140 g in l lOOmL of water). The product layer was washed
with dichloromethane (200mL). Sodium carbonate solution (25% inwater) was added to product aqueous layer to adjust pH to 9.5 to 9.8. The product was extracted with dichloromethane and concentrated under vaccum to give 3-[3- (trifluoromethyl)phenyl]propionaldehydeasayellowoil(84 g, 85% yield).
Example -2
Preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde (I) To a stirred solution of 3-[3-(trifluoromethyl)phenyl]propan-l-ol (IV) (lOg, 0.049mol) in dichloromethane, thioanisole (11.3 g, 0.09 mol) and triethylamine (18.5 g, 0.09 mol) were added at 0°C in a single lot under argon. The solution was cooled to -10°C to -15°C. N-Chlorosuccinamide (12.2 g, 0.091mol) was added lot wise over lhr to the reaction mixture while maintaining the internal temperature at -10°C to -15°C. The reaction mixture was stirred for 3hr at -10°C to -15°C. Completion of reaction was monitored by Gas Chromatography(GC) or thin layer chromatography (TLC). After completion of reaction, dilute sodium hydroxide solution (4 g in 120 mL of water) was slowly added below -5°C. After the addition, the reaction mixture was warmed to 20°C and stirred for lhr. The aqueous and organic layers were separated. The product from organic layer was extracted with sodium bisulphitesolution(14 g in 110 mL of water). The aqueous product layer was washed with dichloromethane.The aqueous layer was collected and pH was adjusted to 9.5 to 9.8 with sodium carbonate solution (25% in water). The product was extracted with dichloromethane. Organic layer was concentrated under vaccum to give 3-[3-(trifluoromethyl)phenyl]propionaldehyde as a yellow oil(6.9 g, 70% yield).
Example -3 Preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde (I)
To a solution of 3-[3-(trifluoromethyl)phenyl]propan-l-ol (IV) (lOOg, 0.49 mol) in dichloromethane (2 L) at -10°C to -15°C, dimethyl sulfide (30 g, 0.4828 mol) and triethyl amine (62g, 0.6127mol) were added in a single lot under argon and stirred for 15-30 min. N-Chlorosuccinamide (180 g, 1.3480mol) was added lot wise over lhr while maintaining the internal temperature at -10°Cto -15°C. The reaction mixture was stirred for 3hr at -10°C to -15°C. Completion of reaction was monitored by Gas Chromatography(GC) or Thin layer chromatography (TLC). After completion of reaction, dilute Sodium hydroxide solution (40 g in 1200mL of water) was added slowly at temperature less than -5°C. After the addition, the mixture was warmed to 20°Cand stirred for 1 hr at 20°C. The aqueous and organic layers were separated and the product from organic layer was extracted with sodium bisulphate solution(140 g in HOOmL of water). The product layer was washed with dichloromethane (200mL). Sodium carbonate solution (25% inwater) was added to product aqueous layer to adjust pH to 9.5 to 9.8. The product was extracted with dichloromethane and concentrated under vaccum to give 3-[3-(trifluoromethyl)phenyl]propionaldehyde as a yellow oil(80 g, 81% yield).
Example -4
Preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde (I)
To a solution of chlorine (3.2 g, 0.045mol) incarbon tetrachloride at -10°C, a solution of thioanisole (5.6 g, 0.045 mol) of in dichloromethanewas added under argon. A white precipitate appeared immediately after addition of the sulfide. The mixture was cooled to -20°C, and a solution of 3-[3- (trifluoromethyl)phenyl]propan-l-ol (IV) (5g, 0.025mol) in dichloromethane was added dropwise. Stirring was continued for 90min at -20°C, and then a solution of triethylamine (4.9g, 0.05 mol)indichloromethane was added dropwise. The cooling bath was removed, and after 5min ether was added. The product from organic layer was extracted with sodium bisulphate solution(7 g in 60mL of
water). The product layer was washed with dichloromethane. To the aqueous layer pH was adjusted to 9.5 to 9.8 with sodium carbonate solution (20% in water) and then extracted with dichloromethane. The organic layer was concentrated under vaccum to give 3-[3-(trifluoromethyl)phenyl]propionaldehyde as a yellow oil(2.75 gr, 55% yield).
Example -5
Preparation of Cinacalcet Hydrochloride (III)
3-[3-(trifluoromethyl)phenyl]propionaldehyde(5.9 g, 0.029 mol) was added to (R)-(l-naphthyle)ethylamine (5 g, 0.029 mol) for 30 min at room temperature and stirred for lhour. Mixture of boric acid (1.81g, 0.029 mol) and sodium borohydride (1.08g, 0.029 mol) was slowly added lot wise for 1 hour at room temperature. Stirred for 12 hours at room temperature, Completion of reaction was monitored by TLC. After the completion of reaction slowly added aqeoussodiumbicorbonate (6 g in 100 ml water) for 30min. Extract the reaction mass with ethylacetate (70 ml). Wash the ethylacetate layer with water (20 ml). Distill of ethyl acetate under vaccum and charged hexane (100 ml) and water (20 ml). Slowly added con.HCl for 30 min to get pH 1 to 3.Stirr for 3 hours at room temperature and filter followed by washing with mixure of hexane and water. Crude product is dissolved in acetonitrile (30 ml) and heat to 50-60°C. The clear solution was cooled to 0-5°C and stir for 2 hours. Filter the reaction mass followed by washing with chilled acetonitrile (10 ml).The wet product was dried under vaccum at 50°C to yield Cinacalcet Hydrochloride as a white solid, (9.2 g, 80%).
Claims
1. A process for preparing a compound of formula (I):
I
comprising of decomposition of compound of formula VII in the presence of a base.
2. The process according to claim 1, wherein compound of formula VII is formed by reacting 3-[3-(trifluoromethyl)phenyl]propan-l-ol (IV) with dimethylsulfide and N-chlorosuccinamide; or
dimethylsulfide and N-bromosuccinamide; or
dimethylsulfide and chlorine gas; or
- thioanisole and N-chlorosuccinamide; or
thioanisole and N-bromosuccinamide); or
- thioanisole and chlorine gas
3. The process according to claim 2, wherein said reaction is carried out in the presence of a solvent.
4. The process according to claim 3, wherein said solvent is benzene, toluene, xylene, dioxene, THF, chlorinated solvents or a mixture thereof.
5. The process according to claim 2, wherein the reaction is carried out at a temperature in the range from about -25°C to about 10°C.
The process according to claim 1 , wherein the said base is an alkali metal alkoxide, or an alkali metal hydroxide or alkylamines.
The process according to claim 6, wherein said alkali metal is Lithium, Sodium or Potassium.
8. The process according to claim 1, wherein the reaction with the compound of formula VII is carried out at a temperature in the range from about - 25°C to about 20° C
9. A process for the preparation of Cinacalcet hydrochloride (III) in high yield which comprises
b) Reacting activated sodium borohydride by an acid with the reaction mass obtained in step a.,
c) Quinching the step b reaction mass in aqueous dilute base.,
d) Adding organic solvent and dilute HCL to the reaction mass obtained in step c,
e) Isolating cinacalcet hydrochloride.
10. The process according to claim 9, in step a wherein the reaction is carried out at room temperature.
11. The process according to claim 10, wherein the reaction is carried out at about -10 to 50°C.
12. A process according to claim 9 in step b, wherein the suitable acids are boric acid, benzoic acid and para toluene sulfonic acid.
13. The process according to claim 9, wherein the aqueous inorganic base used in step c is carried out aqueous sodium hydroxide, aqueous sodium carbonate, aqueous potassium carbonate and potassium hydroxide.
14. The process according to claim 9, wherein the organic solvent used in step c is carried out tetrahydrofuran, diisopropyl ether, diethyl ether, di-tert- butyl ether, diglyme, dimethoxythane, dimethoxymethane or methoxyethane.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016027211A3 (en) * | 2014-08-18 | 2016-04-28 | Mehta Api Pvt. Ltd. | Process for the preparation of cinacalcet and its pharmaceutically acceptable salts |
| JP2016079134A (en) * | 2014-10-17 | 2016-05-16 | 富士フイルムファインケミカルズ株式会社 | Ketone compound production process |
| CN111103374A (en) * | 2019-08-07 | 2020-05-05 | 南京生命能科技开发有限公司 | Method for determining content of 2,2,6, 6-tetramethylpiperidine oxide in cinacalcet hydrochloride |
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| WO2008035212A2 (en) | 2006-06-08 | 2008-03-27 | Medichem, S.A. | Processes for preparing intermediate compounds useful for the preparation of cinacalcet |
| EP2327684A1 (en) | 2009-11-26 | 2011-06-01 | Dipharma Francis S.r.l. | A process for the preparation of cinacalcet and intermediates thereof |
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| 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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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016027211A3 (en) * | 2014-08-18 | 2016-04-28 | Mehta Api Pvt. Ltd. | Process for the preparation of cinacalcet and its pharmaceutically acceptable salts |
| JP2016079134A (en) * | 2014-10-17 | 2016-05-16 | 富士フイルムファインケミカルズ株式会社 | Ketone compound production process |
| CN111103374A (en) * | 2019-08-07 | 2020-05-05 | 南京生命能科技开发有限公司 | Method for determining content of 2,2,6, 6-tetramethylpiperidine oxide in cinacalcet hydrochloride |
| CN111103374B (en) * | 2019-08-07 | 2023-11-28 | 南京生命能科技开发有限公司 | Method for measuring content of 2, 6-tetramethylpiperidine oxide in cinacalcet hydrochloride |
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