WO2009138993A1 - A process for preparation of montelukast sodium salt - Google Patents
A process for preparation of montelukast sodium salt Download PDFInfo
- Publication number
- WO2009138993A1 WO2009138993A1 PCT/IN2008/000299 IN2008000299W WO2009138993A1 WO 2009138993 A1 WO2009138993 A1 WO 2009138993A1 IN 2008000299 W IN2008000299 W IN 2008000299W WO 2009138993 A1 WO2009138993 A1 WO 2009138993A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- phenyl
- chloro
- propanol
- Prior art date
Links
- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 229960001951 montelukast sodium Drugs 0.000 claims abstract description 19
- ZSHIDKYITZZTLA-FCPABOFRSA-N (1s)-1-[3-[(e)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propan-1-ol Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](O)C1=CC=CC(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)=C1 ZSHIDKYITZZTLA-FCPABOFRSA-N 0.000 claims abstract description 13
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 claims abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims description 4
- OTXHZHQQWQTQMW-UHFFFAOYSA-N (diaminomethylideneamino)azanium;hydrogen carbonate Chemical compound OC([O-])=O.N[NH2+]C(N)=N OTXHZHQQWQTQMW-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 229960004592 isopropanol Drugs 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 description 11
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 11
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 10
- 229960005127 montelukast Drugs 0.000 description 10
- -1 2-(2- (3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol compound Chemical class 0.000 description 8
- WYTRYIUQUDTGSX-UHFFFAOYSA-N 1-phenylpropan-2-ol Chemical compound CC(O)CC1=CC=CC=C1 WYTRYIUQUDTGSX-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- JZMJYZZCDXNLCF-UHFFFAOYSA-M [Na+].[O-]C(=O)CC1CC1 Chemical compound [Na+].[O-]C(=O)CC1CC1 JZMJYZZCDXNLCF-UHFFFAOYSA-M 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- CRBILHZMYDIQRQ-UHFFFAOYSA-N methyl 2-cyclopropylacetate Chemical compound COC(=O)CC1CC1 CRBILHZMYDIQRQ-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 229940072049 amyl acetate Drugs 0.000 description 2
- PGMYKACGEOXYJE-UHFFFAOYSA-N anhydrous amyl acetate Natural products CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 2
- 229940043232 butyl acetate Drugs 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VFAXPOVKNPTBTM-UHFFFAOYSA-N 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid Chemical compound OC(=O)CC1(CS)CC1 VFAXPOVKNPTBTM-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)(c1c(CC[C@](c2cccc(C=Cc(cc3)nc4c3ccc(Cl)c4)c2)SCC2(C*)CC2)cccc1)O Chemical compound CC(C)(c1c(CC[C@](c2cccc(C=Cc(cc3)nc4c3ccc(Cl)c4)c2)SCC2(C*)CC2)cccc1)O 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- MBJMLEKKUBQGEQ-CDRRMRQFSA-N [(1s)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-[2-(oxan-2-yloxy)propan-2-yl]phenyl]propyl] methanesulfonate Chemical compound C=1C=CC=C(CC[C@H](OS(C)(=O)=O)C=2C=C(C=CC=3N=C4C=C(Cl)C=CC4=CC=3)C=CC=2)C=1C(C)(C)OC1CCCCO1 MBJMLEKKUBQGEQ-CDRRMRQFSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical compound [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- LCJPKCFQNCYKNM-UHFFFAOYSA-L disodium 2-cyclopropylacetic acid dihydroxide Chemical compound [OH-].[Na+].[Na+].C1(CC1)CC(=O)O.[OH-] LCJPKCFQNCYKNM-UHFFFAOYSA-L 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- LWCGYSJHYCTYEQ-UHFFFAOYSA-N methyl 2-[1-(acetylsulfanylmethyl)cyclopropyl]acetate Chemical compound COC(=O)CC1(CSC(C)=O)CC1 LWCGYSJHYCTYEQ-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- ZNVGYHOBTCWGTO-UHFFFAOYSA-N solutin Natural products Cc1cc(O)cc2OC(C)(O)C(=O)c12 ZNVGYHOBTCWGTO-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
Definitions
- the present invention relates to a process for the preparation of montelukast sodium salt.
- the process includes (a) reacting 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate to get a compound of Formula III; (b) condensing the compound of Formula III with a compound of Formula IV to get a compound of Formula V; (c) and converting the compound of Formula V to montelukast sodium of Formula I.
- montelukast sodium is sodium [R- (E)]-l-[[[l-[3-[2-(7-chloro-2- quinolinyl) ethenyl] phenyl]-3-[2-(l -hydroxy- 1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetate having the structural Formula I and is known from U.S. Patent No. 5,565,473.
- Montelukast sodium is a leukotriene antagonist and is thus useful as an antiasthmatic, anti-allergic, anti-inflammatory and cytoprotective agent.
- Montelukast sodium is currently indicated for the treatment of asthma and allergic rhinitis.
- 5,565,473 discloses a process for preparing montelukast sodium by reacting 2-(2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3- (methanesulfonyloxy) propyl) phenyl)-2-propoxy) tetra hydro pyran with methyl 1- (acetylthiomethyl) cyclopropane acetate in presence of hydrazine, cesium carbonate in acetonitrile as solvent to get methyl ester of montelukast in pyran protected form, which is further reacted with pyridinium p-toluene sulfonate, sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to afford montelukast sodium of Formula (I).
- U.S. Patent No. 5,614,632 discloses a process for preparing montelukast sodium by reacting dilithium dianion of l-(mercaptomethyl) cyclopropaneacetic acid with 2-(2- (3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol compound to afford montelukast. It is further converted to its corresponding sodium salt via dicyclohexyl amine salt.
- U.S. Patent application US 20050256156 discloses a process for preparing pharmaceutically acceptable salt of montelukast by (a) activating the 2-(2-(3 (S)-(3- (2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-(( ⁇ -hydroxy) propyl) phenyl)-2- propanol with a benzylsulfonyl or mesyl group; (b) reacting the product of step a with l-(mercaptomethyl) cyclopropaneacetic acid alkyl ester in a solvent and in the presence of a cosolvent and a base; and (c) hydrolyzing the product of step b to obtain a pharmaceutically acceptable salt of montelukast.
- U.S. Patent application US 20050234241 discloses a process for preparing montelukast by the mesylation of 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2-propanol using methane sulfonyl chloride and condensation of the resulting mesylate with a compound of formula (VI)
- U.S. Patent application US 20050245569 discloses a process for preparing montelukast sodium by using intermediate compound of Formula VIII.
- U.S. Patent application US 20050107612 discloses a process for the preparation of montelukast or a salt thereof by reacting 2-[l-[l R-3- [2-(7-chloroquinoline-2-yl) vinyl [phenyl]-3-[2-methoxy carbonyl phenyl] propyl sulfonyl methyl] cyclopropyl] acetic acid or a salt thereof with methyl magnesium chloride or methyl magnesium bromide in an organic solvent.
- U.S. Patent application US 20060194839 discloses a process for preparing montelukast sodium by using [R- (E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-(2-benzyloxy-methyl) propyl) thiomethyl-cyclopropaneacetic acid intermediate.
- PCT application WO 2006008751 discloses a process for the preparation of montelukast free acid by reacting methyl 2-[(3S)-[3-[(2E)-(7-chloro quinolin-2-yl) ethenyl] phenyl] -3 -halopropyl] benzoate with l-(mercapto methyl) cyclopropane acetic acid in the presence of alkali hydrides or alkoxides to get 2-[l-[l(R)-[3-[2-(7- chloroquinoline-2-yl) ethenyl] phenyl] -3 -[2-(methoxycarbonyl) phenyl] propyl sulfonyl methyl] cyclopropane acetic acid, which on reaction with grignard reagent yield montelukast free acid.
- the first aspect of the present invention is to provide a process for the preparation of montelukast sodium salt of Formula I
- Formula III (b) condensing the compound of Formula III with a compound of Formula IV, wherein R is hydrogen or alkyl or substituted alkyl of Ci to C 4 carbon atoms in straight or branched chain form,
- the second aspect of the present invention is to provide a compound of Formula III
- the third aspect of the present invention is to provide a compound of Formula III
- the 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II may be prepared by any of the methods known in the art including those described in U.S. Patent Nos. 5,565,473; 5,614,632 and WO 95/18107.
- the 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II may be reacted with diphenyl chloro phosphate to get a compound of Formula III,
- reaction of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3- hydroxypropyl) - phenyl-2-propanol of Formula II with diphenyl chloro phosphate may be carried out in an organic solvent in the presence of base.
- organic solvent examples include chlorinated hydrocarbons solvent or N, N- dimethylformamide or mixture(s) thereof.
- chlorinated hydrocarbons solvent examples include dichloromethane, dichloroethane, chloroform, carbon terra chloride or mixture(s) thereof.
- bases include organic base such as trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, morpholine, DBU (1, 8-diazabicyclo- [5. 4. 0]-undec-7-ene), DBN (1, 5-diazabicyclo- [4.3.0] non-5- ene), 4-dimethylaminopyridine, or mixture(s) thereof.
- organic base such as trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, morpholine, DBU (1, 8-diazabicyclo- [5. 4. 0]-undec-7-ene), DBN (1, 5-diazabicyclo- [4.3.0] non-5- ene), 4-dimethylaminopyridine, or mixture(s) thereof.
- the base may be used in an amount of 1.0-6.0 molar equivalents of compound of Formula II.
- the reaction of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3- hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate may be carried out at a temperature in the range of -70°C to -10°C for 0.5 hour to 3 hours
- the 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol of Formula III may be extracted with halogenated hydrocarbons solvent such as dichloromethane, dichloroethane, carbon tetra chloride, or mixture(s) thereof.
- halogenated hydrocarbons solvent such as dichloromethane, dichloroethane, carbon tetra chloride, or mixture(s) thereof.
- the 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol of Formula III may be isolated from the organic layer after washing the organic layer with aqueous hydrochloride solution / aqueous sodium bicarbonate solution / sodium chloride solution and concentrating under reduced pressure and stirring with a mixture of alkyl acetate solvents and hydrocarbon solvents or ether solvents at a temperature in the range of 0°C to 30°C.
- alkyl acetate solvents include methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, amyl acetate, or mixture(s) thereof.
- hydrocarbon solvents examples include n-hexane, hexanes, heptanes, toluene, xylene, or mixture(s) thereof.
- ether solvents include diethyl ether, diisopropyl ether, methyl tert-butyl ether, or mixture(s) thereof.
- the isolation of compound of Formula III may be accomplished by cooling, filtration or a combination thereof.
- the compound of Formula III may be dried under reduced pressure at a temperature in the range of 10°C to 30 0 C.
- the compound of Formula III obtained from step a may be further reacted with a compound of Formula IV in organic solvent in the presence of base at a temperature in the range of 0 0 C to 30 0 C for 3 hours to 24 hours, to get a compound of Formula V;
- the compound of Formula IV may be prepared by methods known in the art.
- organic solvent examples include dimethylsulfoxide, N, N-dimethylformamide or tetrahydrofuran.
- Examples of base include inorganic base or organic base.
- inorganic base examples include alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, or mixture(s) thereof.
- alkali metal carbonate examples include lithium carbonate, sodium carbonate or potassium carbonate or cesium carbonate.
- alkali metal bicarbonate examples include sodium bicarbonate or potassium bicarbonate.
- alkali metal hydroxide examples include sodium hydroxide or potassium hydroxide.
- organic base examples include trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, morpholine, DBU (1, 8- diazabicyclo- [5. 4. 0]-undec-7-ene), DBN (1, 5-diazabicyclo- [4.3.0] non-5-ene), 4- dimethylaminopyridine or 1-aminoguanidine bicarbonate.
- the compound of Formula V may be extracted with alkyl acetate solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate or amyl acetate.
- alkyl acetate solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate or amyl acetate.
- the compound of Formula V may be isolated from the organic layer after washing the organic layer with sodium chloride solution and concentrating under reduced pressure
- the compound of Formula V may be reacted with alkali metal hydroxide in organic solvent to get montelukast sodium of Formula I.
- reaction of compound of Formula V with alkali metal hydroxide may be carried out at a temperature in the range of 0 0 C to 3O 0 C for 1 hour to 55 hours.
- Example of alkali metal hydroxide includes sodium hydroxide.
- organic solvent examples include methanol, ethanol, n-propanol, iso propanol, butanol, diethyl ether, tetrahydrofuran or mixture(s) thereof.
- the isolation of montelukast sodium of Formula I may be accomplished by crystallization with hydrocarbon solvents.
- hydrocarbon solvents examples include hexanes, heptanes, toluene, xylene, acetonitrile or mixture(s) thereof.
- the isolation of montelukast sodium of Formula I may be accomplished by cooling, filtration or a combination thereof.
- the montelukast sodium of Formula I may be dried under reduced pressure at a temperature in the range of 25°C to 30 0 C.
- R is hydrogen or alkyl or substituted alkyl of Ci to C 4 carbon atoms in straight or branched chain form.
- 1-Aminoguanidine bicarbonate (14.4 gm) and 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)- ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol (14 gm) were added to solution of l-(mercaptomethyl) cyclopropane acetic acid (14.4 gm) in tetrahydrofuran (100 ml) at 25°C and resulting reaction mixture was stirred for 2 hours at 40°C to 45 °C. The reaction mixture was treated with sodium chloride solution (5%, 100 ml) and extracted by ethyl acetate (100 ml).
- Example 6 Preparation of [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt Sodium hydroxide (1.2 gm) was added to a solutin of [R- (E)]-l-[[[l-[3-[2-(7-chloro- 2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid (7 gm) in methanol ( 42 ml) at 25°C.
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Abstract
The present invention relates to a process for the preparation of montelukast sodium salt. The process includes (a) reacting 2-(2-(3-(S)-(3-(7-chloro-2- quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula (II) with diphenyl chloro phosphate to get a compound of Formula III; (b) condensing the compound of Formula III with a compound of Formula IV to get compound of Formula V; (c) and converting the compound of Formula V to montelukast sodium of Formula (I).
Description
A PROCESS FOR PREPARATION OF MONTELUKAST SODIUM SALT
Field of The Invention
The present invention relates to a process for the preparation of montelukast sodium salt. The process includes (a) reacting 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate to get a compound of Formula III; (b) condensing the compound of Formula III with a compound of Formula IV to get a compound of Formula V; (c) and converting the compound of Formula V to montelukast sodium of Formula I.
Background of The Invention
Chemically, montelukast sodium is sodium [R- (E)]-l-[[[l-[3-[2-(7-chloro-2- quinolinyl) ethenyl] phenyl]-3-[2-(l -hydroxy- 1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetate having the structural Formula I and is known from U.S. Patent No. 5,565,473.
Formula I
Montelukast sodium is a leukotriene antagonist and is thus useful as an antiasthmatic, anti-allergic, anti-inflammatory and cytoprotective agent. Montelukast sodium is currently indicated for the treatment of asthma and allergic rhinitis.
U.S. Patent No. 5,565,473 discloses a process for preparing montelukast sodium by reacting 2-(2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3- (methanesulfonyloxy) propyl) phenyl)-2-propoxy) tetra hydro pyran with methyl 1- (acetylthiomethyl) cyclopropane acetate in presence of hydrazine, cesium carbonate in acetonitrile as solvent to get methyl ester of montelukast in pyran protected form, which is further reacted with pyridinium p-toluene sulfonate, sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to afford montelukast sodium of Formula (I).
U.S. Patent No. 5,614,632 discloses a process for preparing montelukast sodium by reacting dilithium dianion of l-(mercaptomethyl) cyclopropaneacetic acid with 2-(2- (3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol compound to afford montelukast. It is further converted to its corresponding sodium salt via dicyclohexyl amine salt.
U.S. Patent application US 20050256156 discloses a process for preparing pharmaceutically acceptable salt of montelukast by (a) activating the 2-(2-(3 (S)-(3- (2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-((α-hydroxy) propyl) phenyl)-2- propanol with a benzylsulfonyl or mesyl group; (b) reacting the product of step a with l-(mercaptomethyl) cyclopropaneacetic acid alkyl ester in a solvent and in the presence of a cosolvent and a base; and (c) hydrolyzing the product of step b to obtain a pharmaceutically acceptable salt of montelukast.
U.S. Patent application US 20050234241 discloses a process for preparing montelukast by the mesylation of 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2-propanol using methane sulfonyl chloride and condensation of the resulting mesylate with a compound of formula (VI)
Formula VI Formula VII
where X=CN or CONH2 or mixture of compound of formula (VI) wherein X=CN and compound of formula (VI) wherein X=CONH2 to give a compound of formula (VII) where X=CN or CONH2. This compound is hydrolyzed to afford Montelukast, and it is isolated in the form of an amine salt, which is then converted into sodium salt of Montelukast in a conventional method.
U.S. Patent application US 20050245569 discloses a process for preparing montelukast sodium by using intermediate compound of Formula VIII.
Formula VIII
U.S. Patent application US 20050107612 discloses a process for the preparation of montelukast or a salt thereof by reacting 2-[l-[l R-3- [2-(7-chloroquinoline-2-yl) vinyl [phenyl]-3-[2-methoxy carbonyl phenyl] propyl sulfonyl methyl] cyclopropyl]
acetic acid or a salt thereof with methyl magnesium chloride or methyl magnesium bromide in an organic solvent.
U.S. Patent application US 20060194839 discloses a process for preparing montelukast sodium by using [R- (E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-(2-benzyloxy-methyl) propyl) thiomethyl-cyclopropaneacetic acid intermediate.
PCT application WO 2006008751 discloses a process for the preparation of montelukast free acid by reacting methyl 2-[(3S)-[3-[(2E)-(7-chloro quinolin-2-yl) ethenyl] phenyl] -3 -halopropyl] benzoate with l-(mercapto methyl) cyclopropane acetic acid in the presence of alkali hydrides or alkoxides to get 2-[l-[l(R)-[3-[2-(7- chloroquinoline-2-yl) ethenyl] phenyl] -3 -[2-(methoxycarbonyl) phenyl] propyl sulfonyl methyl] cyclopropane acetic acid, which on reaction with grignard reagent yield montelukast free acid.
The above prior art procedures involve more number of steps, which include a series of protections and deprotections of diol intermediate, usage of hazardous and costly raw materials such as n-butyl lithium, hydrazine, pyridinium p-toluenesulfonate, grignard reagent. The processes of the prior art references involve tedious workup to isolate the required product and thus results in excess time cycle, which in turn rendering the process more costly and less eco friendly thus the process is not amenable for commercial scale up.
Summary of The Invention
In light of the above drawbacks in the prior art processes, there is a need for the development of a simple, convenient and efficient process for the preparation of montelukast sodium salt, which is convenient to operate on an industrial scale.
The first aspect of the present invention is to provide a process for the preparation of montelukast sodium salt of Formula I
Formula I
comprising the steps of:
(a) reacting 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3- hydroxypropyl)- phenyl-2-propanol of Formula II
Formula II
with diphenyl chloro phosphate to get a compound of Formula III;
Formula III
(b) condensing the compound of Formula III with a compound of Formula IV, wherein R is hydrogen or alkyl or substituted alkyl of Ci to C4 carbon atoms in straight or branched chain form,
to get a compound of Formula V;
Formula V
(c) and converting the compound of formula V to montelukast sodium of Formula I.
The second aspect of the present invention is to provide a compound of Formula III
Formula III
The third aspect of the present invention is to provide a compound of Formula III
Formula III used for the preparation of montelukast sodium salt of Formula I
Formula I
Detailed Description of the Invention
The 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II may be prepared by any of the methods known in the art including those described in U.S. Patent Nos. 5,565,473; 5,614,632 and WO 95/18107.
The 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II may be reacted with diphenyl chloro phosphate to get a compound of Formula III,
The reaction of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3- hydroxypropyl) - phenyl-2-propanol of Formula II with diphenyl chloro phosphate may be carried out in an organic solvent in the presence of base.
Examples of organic solvent include chlorinated hydrocarbons solvent or N, N- dimethylformamide or mixture(s) thereof.
Examples of chlorinated hydrocarbons solvent include dichloromethane, dichloroethane, chloroform, carbon terra chloride or mixture(s) thereof.
Examples of bases include organic base such as trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, morpholine, DBU (1, 8-diazabicyclo- [5. 4. 0]-undec-7-ene), DBN (1, 5-diazabicyclo- [4.3.0] non-5- ene), 4-dimethylaminopyridine, or mixture(s) thereof.
The base may be used in an amount of 1.0-6.0 molar equivalents of compound of Formula II.
The reaction of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3- hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate may be carried out at a temperature in the range of -70°C to -10°C for 0.5 hour to 3 hours
The 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol of Formula III may be extracted with halogenated hydrocarbons solvent such as dichloromethane, dichloroethane, carbon tetra chloride, or mixture(s) thereof.
The 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol of Formula III may be isolated from the organic layer after washing the organic layer with aqueous hydrochloride solution / aqueous sodium bicarbonate solution / sodium chloride solution and concentrating under reduced pressure and stirring with a mixture of alkyl acetate solvents and hydrocarbon solvents or ether solvents at a temperature in the range of 0°C to 30°C.
Examples of alkyl acetate solvents include methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, amyl acetate, or mixture(s) thereof.
Examples of hydrocarbon solvents include n-hexane, hexanes, heptanes, toluene, xylene, or mixture(s) thereof.
Examples of ether solvents include diethyl ether, diisopropyl ether, methyl tert-butyl ether, or mixture(s) thereof.
The isolation of compound of Formula III may be accomplished by cooling, filtration or a combination thereof.
The compound of Formula III may be dried under reduced pressure at a temperature in the range of 10°C to 300C.
The compound of Formula III obtained from step a may be further reacted with a compound of Formula IV in organic solvent in the presence of base at a temperature in the range of 00C to 300C for 3 hours to 24 hours, to get a compound of Formula V;
The compound of Formula IV may be prepared by methods known in the art.
Examples of organic solvent include dimethylsulfoxide, N, N-dimethylformamide or tetrahydrofuran.
Examples of base include inorganic base or organic base.
Examples of inorganic base include alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, or mixture(s) thereof.
Examples of alkali metal carbonate include lithium carbonate, sodium carbonate or potassium carbonate or cesium carbonate.
Examples of alkali metal bicarbonate include sodium bicarbonate or potassium bicarbonate.
Examples of alkali metal hydroxide include sodium hydroxide or potassium hydroxide.
Examples of organic base include trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, morpholine, DBU (1, 8-
diazabicyclo- [5. 4. 0]-undec-7-ene), DBN (1, 5-diazabicyclo- [4.3.0] non-5-ene), 4- dimethylaminopyridine or 1-aminoguanidine bicarbonate.
The compound of Formula V may be extracted with alkyl acetate solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate or amyl acetate.
The compound of Formula V may be isolated from the organic layer after washing the organic layer with sodium chloride solution and concentrating under reduced pressure
The compound of Formula V may be reacted with alkali metal hydroxide in organic solvent to get montelukast sodium of Formula I.
The reaction of compound of Formula V with alkali metal hydroxide may be carried out at a temperature in the range of 00C to 3O0C for 1 hour to 55 hours.
Example of alkali metal hydroxide includes sodium hydroxide.
Examples of organic solvent include methanol, ethanol, n-propanol, iso propanol, butanol, diethyl ether, tetrahydrofuran or mixture(s) thereof.
The isolation of montelukast sodium of Formula I may be accomplished by crystallization with hydrocarbon solvents.
Examples of hydrocarbon solvents include hexanes, heptanes, toluene, xylene, acetonitrile or mixture(s) thereof.
The isolation of montelukast sodium of Formula I may be accomplished by cooling, filtration or a combination thereof.
The montelukast sodium of Formula I may be dried under reduced pressure at a temperature in the range of 25°C to 300C.
The schematic diagram for the process of preparing montelukast sodium of Formula I is provided below:
Diphenyl chloro phosphate
Formula II Formula III
Formula IV
Formula V
Formula I
Wherein R is hydrogen or alkyl or substituted alkyl of Ci to C4 carbon atoms in straight or branched chain form.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES:
Example 1: Preparation of methyl ester of l-(mercaptomethyl) cyclopropane acetic acid
Thionyl chloride (7.4 ml) was added to solution of l-(mercaptomethyl) cyclopropane acetic acid (10.0 gm) in methanol (100 ml) at 0-5°C. The reaction mixture thus obtained was stirred at 60-650C for 2 hours and concentrated under reduced pressure^ to get methyl ester of 1 -(mercaptomethyl) cyclopropane acetic acid. Yield: 9.0 gm
Example 2: Preparation of 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol
4-Dimethylaminopyridine (29.3 gm) was added to solution of 2-(2-(3 (S)-(3-(7- chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl) phenyl-2-propanol (50 gm) in dichloromethane (200 ml) and N, N-dimethylformamide (50 ml) at 250C. The resulting reaction mixture was stirred for 30 minutes, cooled to -400C and diphenyl chloro phosphate (37 gm) was added and reaction mixture was further stirred for 2 hours at -250C to -200C. The resulting reaction mixture was treated with water (500 ml) and extracted with dichloromethane (500 ml). The organic layer was washed by aqueous hydrochloride solution (0.5 N, 200 ml), and water (500 ml). The organic layer was dried and concentrated under reduced pressure to get oily residue. The oily residue was dissolved in ethyl acetate (250 ml), diluted with diisopropyl ether (2000
ml) and then stirred for 12 hours at 25-30°C. The resulting solids were filtered and dried at 30°C under reduced pressure to get yellow colored compound. Yield: 51.5 gm
Example 3: Preparation of 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol
4-Dimethylaminopyridine (5.3 gm) was added to solution of 2-(2-(3 (S)-(3-(7-chloro- 2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl) phenyl-2-propanol (5 gm) in dichloromethane (50 ml) at 25°C. The resulting reaction mixture was stirred for 30 minutes, cooled to -70°C and diphenyl chloro phosphate (7.5 ml) was added and reaction mixture was further stirred for 2 hours at -65°C to -70°C. The resulting reaction mixture was treated with water (25 ml) and extracted with dichloromethane (20 ml). The organic layer was washed by aqueous hydrochloride solution (0.5 M, 20 ml), sodium bicarbonate solution (5 %, 20 ml) and sodium chloride solution (saturated). The organic layer was dried and concentrated under reduced pressure to get oily residue. The oily residue was dissolved in ethyl acetate (25 ml), diluted with hexane (200 ml) and then stirred for 12 hours at 25-30°C. The resulting solids were filtered and dried at 30°C under reduced pressure to get yellow colored compound. Yield: 7.3 gm
Example 4: Preparation of [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid.
1-Aminoguanidine bicarbonate (14.4 gm) and 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)- ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol (14 gm) were added to solution of l-(mercaptomethyl) cyclopropane acetic acid (14.4 gm) in tetrahydrofuran (100 ml) at 25°C and resulting reaction mixture was stirred for 2 hours at 40°C to
45 °C. The reaction mixture was treated with sodium chloride solution (5%, 100 ml) and extracted by ethyl acetate (100 ml). The organic layer was separated and concentrated under reduced pressure to get [R- (E)]-l-[[[l-[3-[2-(7-chloro-2- quinolinyl) ethenyl] phenyl] -3 -[2-(I -hydroxy- 1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid. Yield: 10.8 gm
Example 5: Preparation of [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid methyl ester.
Sodium hydroxide solution (47 %, 1.56 gm) was added to solution of methyl ester of l-(mercaptomethyl) cyclopropane acetic acid (2.97 gm) in N, N-dimethylformamide.. (25 ml) at 25°C under inert atmosphere. The reaction mixture thus obtained was stirred for 30 minutes at 25°C and solution of 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)- ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol (25%, 22 ml) in tetrahydrofuran was added and resulting reaction mixture was stirred for 12 hours at 20°C. The reaction mixture was treated with sodium chloride solution (5%, 100 ml) and extracted by ethyl acetate (100 ml). The organic layer was washed two times with, water (50 ml each), dried over sodium sulphate and concentrated under reduced pressure to get [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3 -[2-(I- hydroxy- 1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid methyl ester. Yield: 3.0 gm
Example 6: Preparation of [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt
Sodium hydroxide (1.2 gm) was added to a solutin of [R- (E)]-l-[[[l-[3-[2-(7-chloro- 2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid (7 gm) in methanol ( 42 ml) at 25°C. The resulting reaction mixture was stirred 5 hours at 20°C to 25°C and then concentrated under reduced pressure to get slurry. The slurry was treated with acetonitrile (40 ml) to get [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3 -[2-(I -hydroxy- 1- methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt. Yield: 6.2 gm
Example 7: Preparation of [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt
Sodium hydroxide solution (10 %, 2.5 gm) was added to solution of [R- (E)]-l-[[[l- [3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid methyl ester (2.9 gm) in methanol (7.6 ml) at 25-30°C. The resulting turbid solution was diluted with tetrahydrofuran (0.5 ml) and stirred for 50 hours at 25-30°C. The resulting reaction mixture was concentrated under reduced pressure to get oily residue. The residue .was diluted with ethyl acetate (20 ml) and water (10 ml) and organic layer separated. The organic layer was washed by sodium chloride solution (5%, 5 ml) and diluted with heptane (20 ml). The resulting heavy liquid was separated, stripped with ethanol and evaporated to get R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2- (1 -hydroxy- 1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt. Yield: 1.3 gm
Claims
1. A process for the preparation of montelukast sodium salt of Formula I
Formula I comprising the steps of:
(a) reacting 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3- hydroxypropyl)- phenyl-2-propanol of Formula II
Formula II
with diphenyl chloro phosphate to get a compound of Formula III;
Formula III (b) condensing the compound of Formula III with a compound of Formula IV, wherein R is hydrogen, alkyl or substituted alkyl of Ci to C4 carbon atoms in straight or branched chain form,
to get a compound of Formula V;
Formula V
(c) and converting the compound of formula V to montelukast sodium of Formula I.
2. The process according to claim 1, wherein reaction of 2-(2-(3-(S)-(3-(7-chloro-2- quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate is carried out in organic solvents such as chlorinated hydrocarbons solvent or N, N-dimethylformamide or mixture(s) thereof in the presence of base such as trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, morpholine, DBU (1,8- diazabicyclo- [5. 4. 0]-undec-7-ene), DBN (1, 5-diazabicyclo- [4.3.0] non-5-ene) and 4-dimethylaminopyridine.
3. The process according to claims 1 or 2, wherein reaction of 2-(2-(3-(S)-(3-(7- chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate is carried out at a temperature in the range of -7O0C to -100C for 0.5 hour to 3 hours.
4. The process according to claim 1 , wherein compound of Formula III obtained from step a is further reacted with a compound of Formula IV in organic solvent such as dimethylsulfoxide, N, N-dimethylformamide and tetrahydrofuran in the presence of base at a temperature in the range oft 0°C to 300C for 3 hours to 24 hours
5. The process according to claim 4, wherein the base is selected from the group comprising of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, morpholine, DBU (1, 8-diazabicyclo- [5. 4. O]- undec-7-ene), DBN (1, 5-diazabicyclo- [4.3.0] non-5-ene), 4-dimethylaminopyridine or 1-aminoguanidine bicarbonate.
6. The process according to claim 1 , wherein a compound of Formula V is converted into montelukast sodium of Formula I by sodium hydroxide in organic solvent such as methanol, ethanol, n-propanol, iso propanol, butanol, diethyl ether, tetrahydrofuran or mixture(s) thereof.
7. The process according to claims 6, wherein reaction of a compound of Formula V with sodium hydroxide is carried out at a temperature in the range of 00C to 300C for 1 hour to 55 hours.
8. The process according to claim 6, wherein isolation of montelukast sodium of Formula I is accomplished by crystallization with hydrocarbon solvents such as hexanes, heptanes, toluene, xylene, acetonitrile, cooling, filtration or a combination thereof.
9. A compound of Formula III
Formula III
10. A compound of claim 9, used for the preparation of montelukast sodium salt of Formula I
Formula I
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012020271A1 (en) | 2010-08-11 | 2012-02-16 | Richter Gedeon Nyrt. | Process for the preparation of montelukast sodium |
| CN102442947A (en) * | 2011-11-01 | 2012-05-09 | 上海璎黎科技有限公司 | Preparation method of Montelukast Sodium intermediate |
| CN111892535A (en) * | 2020-08-27 | 2020-11-06 | 鲁南制药集团股份有限公司 | Synthesis method of montelukast sodium |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050256156A1 (en) * | 2004-04-21 | 2005-11-17 | Evgeny Shapiro | Processes for preparing montelukast sodium |
| WO2006008751A2 (en) * | 2004-07-19 | 2006-01-26 | Matrix Laboratories Ltd | Process for the preparation of montelukast and its salts |
| WO2008072872A1 (en) * | 2006-12-14 | 2008-06-19 | Hanmi Pharm. Co., Ltd. | Method of preparing montelukast and intermediates used therein |
-
2008
- 2008-05-13 WO PCT/IN2008/000299 patent/WO2009138993A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050256156A1 (en) * | 2004-04-21 | 2005-11-17 | Evgeny Shapiro | Processes for preparing montelukast sodium |
| WO2006008751A2 (en) * | 2004-07-19 | 2006-01-26 | Matrix Laboratories Ltd | Process for the preparation of montelukast and its salts |
| WO2008072872A1 (en) * | 2006-12-14 | 2008-06-19 | Hanmi Pharm. Co., Ltd. | Method of preparing montelukast and intermediates used therein |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012020271A1 (en) | 2010-08-11 | 2012-02-16 | Richter Gedeon Nyrt. | Process for the preparation of montelukast sodium |
| CN102442947A (en) * | 2011-11-01 | 2012-05-09 | 上海璎黎科技有限公司 | Preparation method of Montelukast Sodium intermediate |
| CN102442947B (en) * | 2011-11-01 | 2013-10-16 | 上海璎黎科技有限公司 | Preparation method of Montelukast Sodium intermediate |
| CN111892535A (en) * | 2020-08-27 | 2020-11-06 | 鲁南制药集团股份有限公司 | Synthesis method of montelukast sodium |
| CN111892535B (en) * | 2020-08-27 | 2023-04-11 | 鲁南制药集团股份有限公司 | Synthesis method of montelukast sodium |
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