WO2024171021A1 - A process for the preparation of belumosudil and its - Google Patents
A process for the preparation of belumosudil and its Download PDFInfo
- Publication number
- WO2024171021A1 WO2024171021A1 PCT/IB2024/051282 IB2024051282W WO2024171021A1 WO 2024171021 A1 WO2024171021 A1 WO 2024171021A1 IB 2024051282 W IB2024051282 W IB 2024051282W WO 2024171021 A1 WO2024171021 A1 WO 2024171021A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- belumosudil
- solvent
- compound
- preparation
- Prior art date
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- GKHIVNAUVKXIIY-UHFFFAOYSA-N 2-[3-[4-(1h-indazol-5-ylamino)quinazolin-2-yl]phenoxy]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)COC1=CC=CC(C=2N=C3C=CC=CC3=C(NC=3C=C4C=NNC4=CC=3)N=2)=C1 GKHIVNAUVKXIIY-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 229940074162 belumosudil Drugs 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 37
- 230000008569 process Effects 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
- 239000002904 solvent Substances 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 claims description 14
- 239000012535 impurity Substances 0.000 claims description 14
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- XBTOSRUBOXQWBO-UHFFFAOYSA-N 1h-indazol-5-amine Chemical compound NC1=CC=C2NN=CC2=C1 XBTOSRUBOXQWBO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 239000004215 Carbon black (E152) Substances 0.000 claims description 9
- 229930195733 hydrocarbon Natural products 0.000 claims description 9
- 150000002430 hydrocarbons Chemical class 0.000 claims description 9
- 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 claims description 9
- 239000003880 polar aprotic solvent Substances 0.000 claims description 8
- 238000009833 condensation Methods 0.000 claims description 7
- 230000005494 condensation Effects 0.000 claims description 7
- 150000008282 halocarbons Chemical class 0.000 claims description 7
- 230000002140 halogenating effect Effects 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000002346 iodo group Chemical group I* 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 4
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 2
- 229940113088 dimethylacetamide Drugs 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 36
- 239000000543 intermediate Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000008213 purified water Substances 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
- 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 description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 7
- 229910052791 calcium Inorganic materials 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 7
- 229910052700 potassium Inorganic materials 0.000 description 7
- 239000011591 potassium Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052788 barium Inorganic materials 0.000 description 6
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- KPMZEAOZKAQJFK-UHFFFAOYSA-N 2-(3-formylphenoxy)-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)COC1=CC=CC(C=O)=C1 KPMZEAOZKAQJFK-UHFFFAOYSA-N 0.000 description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- ILQJXEIRBCHLOM-UHFFFAOYSA-N CC(C)NC(=O)COC1=CC=CC(=C1)C2=NC3=CC=CC=C3C(=N2)NC4=CC5=C(C=C4)NN=C5.CS(=O)(=O)O Chemical compound CC(C)NC(=O)COC1=CC=CC(=C1)C2=NC3=CC=CC=C3C(=N2)NC4=CC5=C(C=C4)NN=C5.CS(=O)(=O)O ILQJXEIRBCHLOM-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- PDUSWJORWQPNRP-UHFFFAOYSA-N n-propan-2-ylacetamide Chemical compound CC(C)NC(C)=O PDUSWJORWQPNRP-UHFFFAOYSA-N 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- GYPNJSBBOATUPK-UHFFFAOYSA-N 2-chloro-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)CCl GYPNJSBBOATUPK-UHFFFAOYSA-N 0.000 description 2
- YIWUKEYIRIRTPP-UHFFFAOYSA-N 2-ethylhexan-1-ol Chemical compound CCCCC(CC)CO YIWUKEYIRIRTPP-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 229910052792 caesium Inorganic materials 0.000 description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 239000000383 hazardous chemical Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- AOGQPLXWSUTHQB-UHFFFAOYSA-N hexyl acetate Chemical compound CCCCCCOC(C)=O AOGQPLXWSUTHQB-UHFFFAOYSA-N 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 230000026045 iodination Effects 0.000 description 2
- 238000006192 iodination reaction Methods 0.000 description 2
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- HJOVHMDZYOCNQW-UHFFFAOYSA-N isophorone Chemical compound CC1=CC(=O)CC(C)(C)C1 HJOVHMDZYOCNQW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229910052712 strontium Inorganic materials 0.000 description 2
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- 239000000126 substance Substances 0.000 description 2
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- DVMZCYSFPFUKKE-UHFFFAOYSA-K scandium chloride Chemical compound Cl[Sc](Cl)Cl DVMZCYSFPFUKKE-UHFFFAOYSA-K 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000009121 systemic therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229910001935 vanadium oxide Inorganic materials 0.000 description 1
- 229940041260 vanadyl sulfate Drugs 0.000 description 1
- 229910000352 vanadyl sulfate Inorganic materials 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a process for the preparation of Belumosudil or pharmaceutically acceptable salts thereof. Further, the present invention provides a novel intermediate of Belumosudil and process for the preparation thereof.
- Belumosudil mesylate is a substituted quinazoline with 5 -aminoindazole and a phenoxyacetamide component and is chemically known as 2- ⁇ 3-[4-(lH- indazol-5-ylamino)-2-quinazolinyl]phenoxy ⁇ -JV-(propan-2-yl)acetamide methane sulfonate (1: 1).
- the chemical structure is as follows:
- Belumosudil (REZUROCK®) is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2) and indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.
- ROCK2 Rho-associated coiled-coil kinase 2
- CN 106916145 discloses a process for the preparation of Belumosudil, which involves additional tedious steps like ester formation and de-esterification in the preparation of compound of Formula-IV and also involves condensation and cyclization in two steps to obtain Belumosudil as shown in below scheme I:
- WO 2023187697 discloses a process for the preparation of Belumosudil, which is similar to the process of CN 106916145.
- the aforesaid prior art processes have difficulties with one or the other drawbacks such as multiple reaction steps, use of hazardous chemicals, column chromatography and/or low purity of intermediates and leads the process commercially not viable. Therefore, there is a need to develop an alternative process for the preparation of Belumosudil and its intermediates, which is simple, reduces number of steps, involves inexpensive raw materials and non-hazardous chemicals.
- the inventors of present invention have found an alternative process for the preparation of Belumosudil as well as intermediates thereof, which involves use of a novel intermediate, single step for condensation and cyclization of Formula-IV and reduces number of steps than the prior art.
- the objective of the present invention is to provide a process for the preparation of Belumosudil or pharmaceutically acceptable salts thereof from an intermediate of Formula-V :
- the present invention provides a process for the preparation of Belumosudil of Formula-I or pharmaceutically acceptable salts thereof,
- the present invention provides an intermediate of
- the present invention provides a process for the preparation of intermediate of Formula-V, which comprises condensation of 3- hydroxybenzaldehyde of Formula-VII with 2-halo-N-isopropylacetamide of Formula- VIII to obtain compound of the Formula-V :
- Formula-VII Formula-VIII Formula-V wherein X is selected from fluoro, chloro, bromo and iodo.
- the pharmaceutically acceptable salts or salts of the present invention comprises inorganic acid or organic acid.
- the inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid;
- the organic acid is selected from acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicyclic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methane sulfonic acid, ethane sulfonic acid, and oxalic acid.
- the intermediates and starting materials of the present invention are used as free base or salt thereof.
- the suitable solvent comprises halogenated hydrocarbon, ketone, nitrile, hydrocarbon, alcohol, ether, ester, polar aprotic solvents, and water or the any combination thereof.
- the halogenated hydrocarbon solvent is selected from 1- bromopropane, dichloromethane, ethylene dichloride, chloroform, tetrachloroethylene, carbon tetrachloride, chlorobenzene, 1,2-dichlorobenzene and 1,2-difluorobenzene.
- the ketone solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, mesityl oxide, isophorone, methyl isopropyl ketone, acetophenone, cyclopentanone, methyl sec-butyl ketone and pentanone.
- the nitrile solvent is selected from acetonitrile and benzonitrile.
- the hydrocarbon solvent is selected from hexane, heptane, cyclohexane, octane, pentane, isopentane, nonane, benzene, toluene, xylene and ethylbenzene.
- the alcohol solvent is selected from methanol, ethanol, tert-butanol, isopropanol, benzyl alcohol, 1,4-butanediol, tert-butyl alcohol, 2-ethylhexanol, isobutanol, 2-m ethyl - 1-butanol, 2-pentanol, 1,3 -propanediol and propylene glycol.
- the ether solvent is selected from methyl t-butyl ether, diethylether, tetrahydrofuran, 1,4-dioxane, dibenzyl ether, tert-amyl ethyl ether, cyclopentyl methyl ether, diisopropyl ether, dimethoxy ethane, ethyl tert-butyl ether, 2-methyltetrahydrofuran, polyethylene glycol and tetrahydropyran.
- the ester solvent is selected from ethyl acetate, isopropyl acetate, benzyl benzoate, tert-butyl acetate, butyl acetate, diethyl carbonate, ethyl acetoacetate, ethyl butyrate, ethylene carbonate, hexyl acetate, isoamyl acetate, isobutyl acetate, methyl acetate, methyl propionate and propyl acetate.
- the polar aprotic solvents is selected from dimethylacetamide, formamide, acetamide, N-methylpyrrolidine (NMP), dimethyl formamide, n- methylformamide, l,3-dimethyl-2-imidazolidinone, n-formylmorpholine, 2- pyrrolidone, tetramethylurea, n-vinylpyrrolidone and n-vinylacetamide and dimethyl sulfoxide.
- the present invention provides a process for the preparation of Belumosudil, a compound of Formula-I or pharmaceutically acceptable salts which comprises the steps of:
- step a) The addition of 2-aminobenzamide in step a) is performed in lot-wise addition or direct charging to enhance the reaction completion while controlling contamination of impurities.
- step a) i.e. condensation and cyclization is carried out in the presence or absence of a reagent and solvent to obtain compound of Formula- IV.
- the suitable reagent comprises sodium metabisulfite, sodium bisulfite, zinc chloride, copper chloride, iron chloride, lanthanum chloride, gadolinium chloride, yttrium chloride, scandium chloride, sodium dithionite, gallium trifluoromethanesulfonate, vanadyl acetylacetonate, vanadium oxide and vanadyl sulfate or combination thereof.
- the suitable reagent comprises sodium metabisulfite and sodium bisulfite.
- the suitable solvent comprises polar aprotic solvents such as formamide, acetamide, dimethyl formamide, dimethylacetamide, NMP, dimethyl sulfoxide and the like; hydrocarbon solvent; halogenated hydrocarbon solvent; nitrile or combination thereof.
- This step is carried out at a temperature of about 0 °C to about 200 °C or to reflux based on the solvent used.
- the reaction is carried out at about 100 to 130 °C for a period of about 1 hour to about 20 hours or until the completion of the reaction.
- the resultant compound of Formula IV is further purified by using purification techniques such as recrystallization, anti-solvent technique, and/or crash cooling.
- the solvent used for the purification comprises halogenated hydrocarbon solvent, alcohol, hydrocarbon, ester, ether, water, or combination thereof.
- the suitable halogenating reagent in step b) comprises chlorinating agent, brominating agents, fluorination reagents, or iodination reagents.
- the chlorinating agent is selected from thionyl chloride, phosphrous oxychloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, calcium hypochlorite or combination thereof.
- the brominating agent is selected from phosphorus oxybromide, phosphorus tribromide, bromine chloride, and aluminum tribromide or combination thereof;
- the fluorination reagent is selected from phosphorus trifluoride, phosphorus pentafluoride or combination thereof;
- the iodination reagent is selected from phosphorus triiodide and phosphorus pentaiodide or combination thereof.
- the suitable reagent comprises chlorinating agent.
- step b) is carried out in presence of a suitable base and solvent to obtain compound of Formula-II.
- the suitable base in step b) comprises diisopropylethylamine, triethylamine, diisopropylamine, diethylamine, piperidine, pyridine N-methyl morpholine (NMM), N,N-dimethylbenzylamine, picoline, lutidine, N,N- dimethylaniline, tert.butyl amine, 4-dimethylaminopyridine (DMAP), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and l,4-diazabicyclo[2.2.2]octane (DABCO) or mixture of thereof.
- the suitable base comprises diisopropylethylamine, triethylamine, diisopropylamine and diethylamine.
- the suitable solvent in step b) comprises hydrocarbon, halogenated hydrocarbon, polar aprotic solvent and N-methylformamide or combination thereof.
- This process step is carried out at a temperature of about 0 to about 150 °C or at a higher temperature based on the solvent used.
- the reaction is conducted for a period of about 1 hour to about 15 hours or until the completion of the reaction.
- the resultant compound of Formula-II is used for the next step without isolation.
- step c) involves reaction of compound of Formula-II with 5-amino-lH-indazole of the Formula-Ill in presence of solvent and suitable base to obtain Belumosudil or salt thereof.
- the suitable base in step c) comprises carbonate of lithium, sodium, potassium, barium, calcium, magnesium; bicarbonate of sodium, potassium, barium, calcium and magnesium; hydroxides of alkali metals like sodium, potassium, lithium, barium, calcium, cesium, strontium and magnesium, alkoxide of metal like sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or mixture of thereof.
- the suitable solvent in step c) comprises alcohol, hydrocarbon solvent, polar aprotic solvents, ether solvent, nitrile solvent, ketone solvent or combination thereof.
- This process is conducted at a temperature of about 0 to about 150 °C or at a higher temperature based on the solvent used, for a period of about 1 hour to about 15 hours or until the completion of the reaction.
- the obtained Belumosudil is optionally punned by recrystallization or slurry in a solvent like water, alcohol, or combination thereof. Further, the salt of Belumosudil is obtained by treating it with an acid in the presence of suitable solvent.
- the suitable solvent comprises alcohol, hydrocarbon solvent, polar aprotic solvent, ether solvent, nitrile solvent, ketone solvent, or combination thereof.
- the present invention provides a process for the preparation of intermediate of Formula-V, which comprises condensation of 3- hydroxybenzaldehyde of Formula-VII with 2-halo-N-isopropylacetamide of Formula- VIII to obtain compound of the Formula-V :
- Formula-VII Formula-VIII Formula-V wherein X is selected from fluoro, chloro, bromo and iodo
- the suitable base comprises an inorganic base, which is selected from carbonate of lithium, sodium, potassium, barium, calcium, magnesium; bicarbonate of sodium, potassium, barium, calcium and magnesium; hydroxides of alkali metals like sodium, potassium, lithium, barium, calcium, cesium, strontium and magnesium; oxides of metal like potassium, sodium, calcium, lithium, zinc, iron, cobalt, chrome, copper, manganese and nickel; alkoxide of metal like sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide or mixture of thereof.
- the suitable solvent in the above reaction comprises polar aprotic solvent, nitrile solvent, hydrocarbon, ketone solvent, alcohol, halogenated hydrocarbon solvent or combination thereof.
- the present invention provides Belumosudil intermediate of Formula- V or salts thereof:
- the compound of the Formula-V is used in the preparation of Belumosudil or pharmaceutically acceptable salts thereof.
- present invention provides Belumosudil or pharmaceutically acceptable salts thereof, which is substantially free of impurities represented by the following compounds of Formula II to V and IX to XII:
- the impurities set forth above are identified by standard analytical techniques known to a person of skill in the art such as High-Performance Liquid Chromatography (HPLC) and Mass Spectrometry (MS).
- HPLC High-Performance Liquid Chromatography
- MS Mass Spectrometry
- the term "substantially free of impurities” refers to the Belumosudil or pharmaceutically acceptable salts thereof obtained by the process of the present invention having less than from about 0.15% w/w to about 0.05% w/w (as determined by HPLC) of the above specified impurities.
- Isopropylamine (209.4g) was dissolved in methylene chloride (600 ml) at 20-30 °C and cooled the reaction mass to -15 to 0°C. Thereafter, a solution of chloroacetyl chloride (200g) in methylene chloride (200ml) was added slowly to reaction mass at -15 to 0°C. The reaction mass was stirred at -15 to 0°C for Ih and filtered and then washed with methylene chloride (600ml). The aqueous sodium chloride solution (400 ml; 10%w/w) was added to the reaction mass and separated the layers. The organic layer was concentrated at a temperature below 50°C under atmospheric pressure.
- the concentrated mass obtained in example 1 was added to N,N- dimethylformamide (600ml) at temperature below 50°C and then concentrated under reduced pressure.
- the reaction mass was cooled to 20-30°C.
- 3- hydroxybenzaldehyde (VII) 205.44g
- potassium carbonate 244.75g
- the reaction mass was stirred at 60-70°C for 12 h and cooled to 45-50°C.
- the purified water ( ⁇ 3000ml) was added slowly at maintaining temperature of about 45-50°C, cooled to 20-30°C and stirred for 30 ⁇ 5 min. Thereafter, the product slurry was cooled to 2-8°C and stirred for 30 ⁇ 5.
- Example 6 Preparation of 2-(3-(4-chloroquinazolin-2-yl)phenoxy)-N- isopropylacetamide (II): 2-(3-quinazolin-4(3H)-one)phenoxy)-N -isopropylacetamide (IV) (200g) was dissolved in toluene (3000ml) and cooled the reaction mass to 5-15°C. Diisopropylethylamine (115g) and subsequently phosphorus oxychloride (127.3g) were added slowly to reaction mass at 5-15°C. The reaction mass was stirred for 30 ⁇ 5 at 5-15°C and raised the temperature of the reaction to 75-85°C.
- the reaction mass was stirred at 75-85°C and cooled to 25-30°C.
- Methylene chloride (2000ml) and purified water (1000ml) were added and then allowed the layers to settle and separated the layers.
- Toluene (335ml) -methylene chloride (65ml) solvent mixture (400ml) was added to aqueous layer. The layers were allowed to settle and separated.
- the 5%w/w aqueous sodium bicarbonate solution (900m) was added to obtained organic layer, and then the layers were separated.
- the obtained organic layer ( ⁇ 5200ml) was filtered and washed with methylene chloride (50ml) (Purity by HPLC: 97.28%).
- the organic layer obtained in example 6 was concentrated at below 50°C under reduced pressure and cooled to 20-25°C.
- Sodium bicarbonate (54.77g) and followed by ethanol (600ml) were added to the reaction mass at 20-25 °C.
- 5 -aminoindazole (III) solution in ethanol ( ⁇ 1400ml; by dissolving 77.35g of 5 -aminoindazole in 1300ml of ethanol) at 20-25°C was added to reaction mass and raised the temperature to 70-80°C and then stirred at 70-80°C for 3hours.
- the reaction mass was cooled to 20-30°C and stirred for 30 ⁇ 5 min.
- the reaction mass was filtered and washed with ethanol (400ml).
- the obtained wet product was added to purified water (2000ml) and stirred for 30 ⁇ 5 min.
- the obtained product was filtered and washed with purified water (2x300ml) and then with ethanol (2x300ml).
- the obtained wet filtered mass ( ⁇ 370g) was dried under reduced pressure for 2h ⁇ 15 min without applying heating. Thereafter, the solid was dried at 50-60°C for 6h under reduced pressure to obtain Belumosudil (Yield: 200g, 74.55%, Purity by HPLC: 99.91%).
- Example 8 Purification of Belumosudil base: Ethanol (1600ml) was added to the belumosudil base ( ⁇ 370g), heated the reaction mass to 70-80°C, stirred for lh ⁇ 10 min and then cooled to 10-15°C. The reaction mass was filtered and washed with pre-cooled ethanol (400ml). The purified water (2000ml) was added to the wet Belumosudil and stirred for 30 ⁇ 5 at 20-30 °C min. The resultant reaction mass was filtered and washed with purified water (2x300ml). The filtered mass was washed with ethanol (2x300ml) at 20- 30°C and dried under reduced pressure for 2h ⁇ 15 min without applying heating. Thereafter, the solid was dried at 50-60°C for 6h under reduced pressure to obtain Belumosudil base (Yield: 190g, 70.82%, Purity by HPLC: 99.91%)
- Belumosudil base 100 g was suspended in ethanol (3000 ml) and heated the reaction mixture to 70-75°C.
- the obtained mass was filtered at 20-30°C and washed with ethanol (2x200 ml).
- the wet filtered mass was dried under reduced pressure for 2h ⁇ 15min without applying heating. Thereafter, the solid was dried at 50-60°C under reduced pressure to obtain Belumosudil mesylate (Yield: 110g, 90.80%, Purity by HPLC: 99.97%).
- Impurity Formula IV 0.02%
- Impurity Formula II 0.01%
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Abstract
The present invention relates to a process for the preparation of Belumosudil or pharmaceutically acceptable salts thereof. Further, the present invention relates to Belumosudil novel intermediate of Formula-V and its process for the preparation.
Description
A PROCESS FOR THE PREPARATION OF BELUMOSUDIL AND ITS INTERMEDIATES
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Belumosudil or pharmaceutically acceptable salts thereof. Further, the present invention provides a novel intermediate of Belumosudil and process for the preparation thereof.
BACKGROUND OF THE INVENTION
Belumosudil mesylate is a substituted quinazoline with 5 -aminoindazole and a phenoxyacetamide component and is chemically known as 2-{3-[4-(lH- indazol-5-ylamino)-2-quinazolinyl]phenoxy}-JV-(propan-2-yl)acetamide methane sulfonate (1: 1). The chemical structure is as follows:
Belumosudil (REZUROCK®) is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2) and indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.
US 8,357,693 describes Belumosudil or salt thereof and a general process for the preparation of Belumosudil, which involves multi-step process of about 10 steps.
CN 106916145 discloses a process for the preparation of Belumosudil, which involves additional tedious steps like ester formation and de-esterification
in the preparation of compound of Formula-IV and also involves condensation and cyclization in two steps to obtain Belumosudil as shown in below scheme I:
Scheme I
WO 2023187697 discloses a process for the preparation of Belumosudil, which is similar to the process of CN 106916145. The aforesaid prior art processes have difficulties with one or the other drawbacks such as multiple reaction steps, use of hazardous chemicals, column chromatography and/or low purity of intermediates and leads the process commercially not viable. Therefore, there is a need to develop an alternative process for the preparation of Belumosudil and its intermediates, which is simple, reduces number of steps, involves inexpensive raw materials and non-hazardous chemicals.
The inventors of present invention have found an alternative process for the preparation of Belumosudil as well as intermediates thereof, which involves use of a novel intermediate, single step for condensation and cyclization of Formula-IV and reduces number of steps than the prior art.
OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a process for the preparation of Belumosudil or pharmaceutically acceptable salts thereof from an intermediate of Formula-V :
In another objective of the present invention is to provide a novel intermediate of Formula-V and process for the preparation thereof.
SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for the preparation of Belumosudil of Formula-I or pharmaceutically acceptable salts thereof,
Formula-I which comprises the steps of:
(a) reacting a compound of the Formula-V with 2-aminobenzamide of Formula- VI to obtain compound of Formula-IV;
(b) halogenating the compound of Formula-IV with a halogenating agent to obtain compound of Formula-II; and
wherein X is selected from fluoro, chloro, bromo and iodo.
(c) condensing the compound of Formula-II with 5-amino-lH-indazole to obtain Belumosudil or pharmaceutically acceptable salts thereof.
In another aspect, the present invention provides an intermediate of
Formula-V
In another aspect, the present invention provides a process for the preparation of intermediate of Formula-V, which comprises condensation of 3- hydroxybenzaldehyde of Formula-VII with 2-halo-N-isopropylacetamide of Formula- VIII to obtain compound of the Formula-V :
Formula-VII Formula-VIII Formula-V
wherein X is selected from fluoro, chloro, bromo and iodo.
DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutically acceptable salts or salts of the present invention comprises inorganic acid or organic acid. The inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; The organic acid is selected from acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicyclic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methane sulfonic acid, ethane sulfonic acid, and oxalic acid.
The intermediates and starting materials of the present invention are used as free base or salt thereof.
The suitable solvent comprises halogenated hydrocarbon, ketone, nitrile, hydrocarbon, alcohol, ether, ester, polar aprotic solvents, and water or the any combination thereof. The halogenated hydrocarbon solvent is selected from 1- bromopropane, dichloromethane, ethylene dichloride, chloroform, tetrachloroethylene, carbon tetrachloride, chlorobenzene, 1,2-dichlorobenzene and 1,2-difluorobenzene. The ketone solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, mesityl oxide, isophorone, methyl isopropyl ketone, acetophenone, cyclopentanone, methyl sec-butyl ketone and pentanone. The nitrile solvent is selected from acetonitrile and benzonitrile. The hydrocarbon solvent is selected from hexane, heptane, cyclohexane, octane, pentane, isopentane, nonane, benzene, toluene, xylene and ethylbenzene. The alcohol solvent is selected from methanol, ethanol, tert-butanol, isopropanol, benzyl alcohol, 1,4-butanediol, tert-butyl alcohol, 2-ethylhexanol, isobutanol, 2-m ethyl - 1-butanol, 2-pentanol, 1,3 -propanediol and propylene glycol. The ether solvent is selected from methyl t-butyl ether, diethylether, tetrahydrofuran, 1,4-dioxane,
dibenzyl ether, tert-amyl ethyl ether, cyclopentyl methyl ether, diisopropyl ether, dimethoxy ethane, ethyl tert-butyl ether, 2-methyltetrahydrofuran, polyethylene glycol and tetrahydropyran. The ester solvent is selected from ethyl acetate, isopropyl acetate, benzyl benzoate, tert-butyl acetate, butyl acetate, diethyl carbonate, ethyl acetoacetate, ethyl butyrate, ethylene carbonate, hexyl acetate, isoamyl acetate, isobutyl acetate, methyl acetate, methyl propionate and propyl acetate. The polar aprotic solvents is selected from dimethylacetamide, formamide, acetamide, N-methylpyrrolidine (NMP), dimethyl formamide, n- methylformamide, l,3-dimethyl-2-imidazolidinone, n-formylmorpholine, 2- pyrrolidone, tetramethylurea, n-vinylpyrrolidone and n-vinylacetamide and dimethyl sulfoxide.
In an aspect, the present invention provides a process for the preparation of Belumosudil, a compound of Formula-I or pharmaceutically acceptable salts
which comprises the steps of:
(a) reacting a compound of the Formula-V with 2-aminobenzamide of Formula- VI to obtain compound of Formula-IV;
(b) halogenating the compound of Formula-IV with a halogenating agent to obtain compound of Formula-II; and
wherein X is selected from fluoro, chloro, bromo and iodo
(c) condensing the compound of Formula-II with 5-amino-lH-indazole to obtain Belumosudil or pharmaceutically acceptable salts thereof.
The addition of 2-aminobenzamide in step a) is performed in lot-wise addition or direct charging to enhance the reaction completion while controlling contamination of impurities.
The process of step a) i.e. condensation and cyclization is carried out in the presence or absence of a reagent and solvent to obtain compound of Formula- IV.
The suitable reagent comprises sodium metabisulfite, sodium bisulfite, zinc chloride, copper chloride, iron chloride, lanthanum chloride, gadolinium chloride, yttrium chloride, scandium chloride, sodium dithionite, gallium trifluoromethanesulfonate, vanadyl acetylacetonate, vanadium oxide and vanadyl sulfate or combination thereof. In an embodiment, the suitable reagent comprises sodium metabisulfite and sodium bisulfite.
The suitable solvent comprises polar aprotic solvents such as formamide, acetamide, dimethyl formamide, dimethylacetamide, NMP, dimethyl sulfoxide and the like; hydrocarbon solvent; halogenated hydrocarbon solvent; nitrile or combination thereof. This step is carried out at a temperature of about 0 °C to about 200 °C or to reflux based on the solvent used. In an embodiment, the
reaction is carried out at about 100 to 130 °C for a period of about 1 hour to about 20 hours or until the completion of the reaction.
The resultant compound of Formula IV is further purified by using purification techniques such as recrystallization, anti-solvent technique, and/or crash cooling. The solvent used for the purification comprises halogenated hydrocarbon solvent, alcohol, hydrocarbon, ester, ether, water, or combination thereof.
The suitable halogenating reagent in step b) comprises chlorinating agent, brominating agents, fluorination reagents, or iodination reagents. The chlorinating agent is selected from thionyl chloride, phosphrous oxychloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, calcium hypochlorite or combination thereof. The brominating agent is selected from phosphorus oxybromide, phosphorus tribromide, bromine chloride, and aluminum tribromide or combination thereof; The fluorination reagent is selected from phosphorus trifluoride, phosphorus pentafluoride or combination thereof; The iodination reagent is selected from phosphorus triiodide and phosphorus pentaiodide or combination thereof. In an embodiment, the suitable reagent comprises chlorinating agent.
The process of step b) is carried out in presence of a suitable base and solvent to obtain compound of Formula-II.
The suitable base in step b) comprises diisopropylethylamine, triethylamine, diisopropylamine, diethylamine, piperidine, pyridine N-methyl morpholine (NMM), N,N-dimethylbenzylamine, picoline, lutidine, N,N- dimethylaniline, tert.butyl amine, 4-dimethylaminopyridine (DMAP), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and l,4-diazabicyclo[2.2.2]octane (DABCO) or mixture of thereof. In an
embodiment, the suitable base comprises diisopropylethylamine, triethylamine, diisopropylamine and diethylamine.
The suitable solvent in step b) comprises hydrocarbon, halogenated hydrocarbon, polar aprotic solvent and N-methylformamide or combination thereof. This process step is carried out at a temperature of about 0 to about 150 °C or at a higher temperature based on the solvent used. The reaction is conducted for a period of about 1 hour to about 15 hours or until the completion of the reaction. The resultant compound of Formula-II is used for the next step without isolation.
The process of step c) involves reaction of compound of Formula-II with 5-amino-lH-indazole of the Formula-Ill in presence of solvent and suitable base to obtain Belumosudil or salt thereof.
The suitable base in step c) comprises carbonate of lithium, sodium, potassium, barium, calcium, magnesium; bicarbonate of sodium, potassium, barium, calcium and magnesium; hydroxides of alkali metals like sodium, potassium, lithium, barium, calcium, cesium, strontium and magnesium, alkoxide of metal like sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or mixture of thereof.
The suitable solvent in step c) comprises alcohol, hydrocarbon solvent, polar aprotic solvents, ether solvent, nitrile solvent, ketone solvent or combination thereof.
This process is conducted at a temperature of about 0 to about 150 °C or at a higher temperature based on the solvent used, for a period of about 1 hour to about 15 hours or until the completion of the reaction.
The obtained Belumosudil is optionally punned by recrystallization or slurry in a solvent like water, alcohol, or combination thereof. Further, the salt of Belumosudil is obtained by treating it with an acid in the presence of suitable solvent. The suitable solvent comprises alcohol, hydrocarbon solvent, polar aprotic solvent, ether solvent, nitrile solvent, ketone solvent, or combination thereof.
In another aspect, the present invention provides a process for the preparation of intermediate of Formula-V, which comprises condensation of 3- hydroxybenzaldehyde of Formula-VII with 2-halo-N-isopropylacetamide of Formula- VIII to obtain compound of the Formula-V :
Formula-VII Formula-VIII Formula-V wherein X is selected from fluoro, chloro, bromo and iodo
The reaction of 3 -hydroxybenzaldehyde of Formula-VII with 2-halo-N- isopropylacetamide of Formula-VIII is conducted in presence or absence of a suitable base and solvent to obtain compound of Formula-V.
The suitable base comprises an inorganic base, which is selected from carbonate of lithium, sodium, potassium, barium, calcium, magnesium; bicarbonate of sodium, potassium, barium, calcium and magnesium; hydroxides of alkali metals like sodium, potassium, lithium, barium, calcium, cesium, strontium and magnesium; oxides of metal like potassium, sodium, calcium, lithium, zinc, iron, cobalt, chrome, copper, manganese and nickel; alkoxide of metal like sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide or mixture of thereof.
The suitable solvent in the above reaction comprises polar aprotic solvent, nitrile solvent, hydrocarbon, ketone solvent, alcohol, halogenated hydrocarbon solvent or combination thereof. In another aspect, the present invention provides Belumosudil intermediate of Formula- V or salts thereof:
Formula-V
The compound of the Formula-V is used in the preparation of Belumosudil or pharmaceutically acceptable salts thereof.
In one embodiment, present invention provides Belumosudil or pharmaceutically acceptable salts thereof, which is substantially free of impurities represented by the following compounds of Formula II to V and IX to XII:
The impurities set forth above are identified by standard analytical techniques known to a person of skill in the art such as High-Performance Liquid Chromatography (HPLC) and Mass Spectrometry (MS).
As used herein, the term "substantially free of impurities", refers to the Belumosudil or pharmaceutically acceptable salts thereof obtained by the process of the present invention having less than from about 0.15% w/w to about 0.05% w/w (as determined by HPLC) of the above specified impurities.
The starting materials used in this aspect, 3 -hydroxy benzaldehyde (VII), 2-halo-N-isopropylacetamide (VIII), 2-aminobenzamide (VI) and 5 -amino indazole (III) are obtained according to any method known in the art, for example, Journal of Organic Syntheses, 29, 63, 1949, Journal of Organic Chemistry (1948), 13, 347-52, Journal of the American Chemical Society, 1943, 65, 10, 1804-1806 and Canadian Journal of Chemistry (1979), 57(15), 1958-66.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
EXAMPLES
Example 1: Preparation of 2-Chloro-N-isopropylacetamide (VIII):
Isopropylamine (209.4g) was dissolved in methylene chloride (600 ml) at 20-30 °C and cooled the reaction mass to -15 to 0°C. Thereafter, a solution of chloroacetyl chloride (200g) in methylene chloride (200ml) was added slowly to reaction mass at -15 to 0°C. The reaction mass was stirred at -15 to 0°C for Ih and
filtered and then washed with methylene chloride (600ml). The aqueous sodium chloride solution (400 ml; 10%w/w) was added to the reaction mass and separated the layers. The organic layer was concentrated at a temperature below 50°C under atmospheric pressure.
Example 2: Preparation of 2-(3-formylphenoxy)-N-isopropylacetamide (V):
The concentrated mass obtained in example 1 was added to N,N- dimethylformamide (600ml) at temperature below 50°C and then concentrated under reduced pressure. The reaction mass was cooled to 20-30°C. Thereafter, 3- hydroxybenzaldehyde (VII) (205.44g) and subsequently potassium carbonate (244.75g) were added to the concentrated mass and raised the temperature to 65- 70°C. The reaction mass was stirred at 60-70°C for 12 h and cooled to 45-50°C. The purified water (~3000ml) was added slowly at maintaining temperature of about 45-50°C, cooled to 20-30°C and stirred for 30±5 min. Thereafter, the product slurry was cooled to 2-8°C and stirred for 30±5. The obtained product was filtered at 2-8°C and washed with pre-cooled purified water (600ml) followed by with methyl tertiary-butyl ether (200ml) at 5- 15 °C. The wet filtered mass (~426g) was dried under the reduced pressure for 2h±15 min without applying heating, thereafter, continued drying at 40-50°C to obtain 2-(3-formylphenoxy)- N-isopropylacetamide (V) (Yield: 300g, 76.5%, Purity by HPLC: 99.85%, 1H NMR (300 MHz, CDC13)5 (ppm): 9.99 (s, 1H), 7.50-7.43 (m, 3H), 7.23- 7.19(m,lH), 6.25 (br, NH, 1H), 4.51(s, 2H), 4.21-4.19(m, lH),1.21(d, J=6.6Hz, 6H).
Example 3: Purification of 2-(3-formylphenoxy)-N-isopropylacetamide (V):
The obtained wet filtered mass (~426g) in example 2 was suspended in methyl tertiary butyl ether (1800ml), heated to 50-55 °C and stirred for 30±5 min. Thereafter, the mass was cooled to 2-8°C and stirred for 30±5 min. The obtained product was filtered at 2-8 °C and washed with pre-cooled methyl tertiary butyl ether (400ml). The wet filtered mass (~420g) was dried under the reduced pressure for 2h±15 min without applying heating, thereafter, continued drying at
40-50°C to obtain 2-(3-formylphenoxy)-N-isopropylacetamide (V) (Yield: 255g, 65%, Purity by HPLC: 99.95%).
Example 4: Preparation of 2-(3-quinazolin-4(3H)-one)phenoxy)-N- isopropylacetamide (IV):
2-(3-formylphenoxy)-N-isopropylacetamide (V) (230g) was added to 2- aminobenzamide (VI) (148.60g), and subsequently sodium metabisulfite (148.2 g) and N,N’ -dimethylacetamide (1380ml) were added at 20-30°C. Thereafter, raised the temperature of reaction mass to 115-125°C. The reaction mass was stirred till the completion of the compound of Formula V, cooled the reaction mass to 20- 30°C. The purified water (2760ml) was slowly added to the reaction mass at a temperature below 40°C and stirred at 20-30°C for 30±5 min. The obtained solid was filtered and washed with purified water (2x345ml) and methylene chloride (2x230ml). The resultant filtered mas was dried under reduced pressure for 2h±15min without applying heating and then dried at 50-60°C to obtain 2-(3- quinazolin-4(3H)-one)phenoxy)-N-isopropylacetamide (IV) (Yield: 306g, 92.1%, Purity by HPLC: 99.91%).
Example 5: Purification of 2-(3-quinazolin-4(3H)-one)phenoxy)-N- isopropylacetamide (IV):
2-(3-quinazolin-4(3H)-one)phenoxy)-N -isopropylacetamide (IV) (~425g) obtained in example 4 was suspended in methylene chloride (1380ml) at 20-30°C and heat the reaction mass to reflux at 35-40°C. The reaction mass was stirred for 30±5 min at 20-30°C. The obtained mass was filtered and washed with methylene chloride (2x230ml) at 20-30°C. The wet filtered mass was dried under reduced pressure for 2h±15min without heating and then dried at 50-60°C under reduced pressure to obtain 2-(3-quinazolin-4(3H)-one)phenoxy)-N-isopropylacetamide (IV) (Yield: 285g, 81.5%, Purity by HPLC: 99.95%).
Example 6: Preparation of 2-(3-(4-chloroquinazolin-2-yl)phenoxy)-N- isopropylacetamide (II):
2-(3-quinazolin-4(3H)-one)phenoxy)-N -isopropylacetamide (IV) (200g) was dissolved in toluene (3000ml) and cooled the reaction mass to 5-15°C. Diisopropylethylamine (115g) and subsequently phosphorus oxychloride (127.3g) were added slowly to reaction mass at 5-15°C. The reaction mass was stirred for 30±5 at 5-15°C and raised the temperature of the reaction to 75-85°C. The reaction mass was stirred at 75-85°C and cooled to 25-30°C. Methylene chloride (2000ml) and purified water (1000ml) were added and then allowed the layers to settle and separated the layers. Toluene (335ml) -methylene chloride (65ml) solvent mixture (400ml) was added to aqueous layer. The layers were allowed to settle and separated. The 5%w/w aqueous sodium bicarbonate solution (900m) was added to obtained organic layer, and then the layers were separated. The obtained organic layer (~5200ml) was filtered and washed with methylene chloride (50ml) (Purity by HPLC: 97.28%).
Example 7: Preparation of Belumosudil (I):
The organic layer obtained in example 6 was concentrated at below 50°C under reduced pressure and cooled to 20-25°C. Sodium bicarbonate (54.77g) and followed by ethanol (600ml) were added to the reaction mass at 20-25 °C. Thereafter, 5 -aminoindazole (III) solution in ethanol (~1400ml; by dissolving 77.35g of 5 -aminoindazole in 1300ml of ethanol) at 20-25°C was added to reaction mass and raised the temperature to 70-80°C and then stirred at 70-80°C for 3hours. The reaction mass was cooled to 20-30°C and stirred for 30±5 min. The reaction mass was filtered and washed with ethanol (400ml). The obtained wet product was added to purified water (2000ml) and stirred for 30±5 min. The obtained product was filtered and washed with purified water (2x300ml) and then with ethanol (2x300ml). The obtained wet filtered mass (~370g) was dried under reduced pressure for 2h±15 min without applying heating. Thereafter, the solid was dried at 50-60°C for 6h under reduced pressure to obtain Belumosudil (Yield: 200g, 74.55%, Purity by HPLC: 99.91%).
Example 8: Purification of Belumosudil base:
Ethanol (1600ml) was added to the belumosudil base (~370g), heated the reaction mass to 70-80°C, stirred for lh±10 min and then cooled to 10-15°C. The reaction mass was filtered and washed with pre-cooled ethanol (400ml). The purified water (2000ml) was added to the wet Belumosudil and stirred for 30±5 at 20-30 °C min. The resultant reaction mass was filtered and washed with purified water (2x300ml). The filtered mass was washed with ethanol (2x300ml) at 20- 30°C and dried under reduced pressure for 2h±15 min without applying heating. Thereafter, the solid was dried at 50-60°C for 6h under reduced pressure to obtain Belumosudil base (Yield: 190g, 70.82%, Purity by HPLC: 99.91%)
Example 9: Preparation of Belumosudil mesylate:
Belumosudil base (100 g) was suspended in ethanol (3000 ml) and heated the reaction mixture to 70-75°C. The methanesulfonic acid (25.50g) solution in ethanol (2000ml) was added slowly to the reaction mass for 5h. Thereafter, stirred the reaction mass for lh±10 min, cooled to 20-30°C and then stirred for lh±15 min. The obtained mass was filtered at 20-30°C and washed with ethanol (2x200 ml). The wet filtered mass was dried under reduced pressure for 2h±15min without applying heating. Thereafter, the solid was dried at 50-60°C under reduced pressure to obtain Belumosudil mesylate (Yield: 110g, 90.80%, Purity by HPLC: 99.97%).
Impurity Formula IV: 0.02%,
Impurity Formula II: 0.01%
Impurity Formula III, Impurity Formula V, Impurity Formula IX, Impurity Formula X, Impurity Formula XI and Impurity Formula XII: Not detected
Claims
1. A process for the preparation of Belumosudil of Formula (I), or a pharmaceutically acceptable salt thereof:
which comprises the steps of:
(a) reacting a compound of the Formula-V with 2-aminobenzamide of Formula- VI to obtain compound of Formula-IV;
(b) reacting the compound of Formula-IV with a halogenating agent to obtain compound of Formula-II; and
wherein X is selected from fluoro, chloro, bromo and iodo.
(c) condensing the compound of Formula-II with 5-amino-lH-indazole to obtain Belumosudil or salt thereof.
2. The process as claimed in claim 1, wherein the step a) is carried out in presence of suitable reagent such as sodium metabisulfite and sodium bisulfite.
3. The process as claimed in claim 1, wherein the halogenating agent is chlorinating agent.
4. The process as claimed in claim 1, wherein the suitable solvent is selected from the group comprising polar aprotic solvents, hydrocarbon solvent, halogenated hydrocarbon, nitrile solvent, alcohol, ether solvent, ketone solvent or the any combination thereof.
5. The process as claimed in claim 1, wherein the steps b) and c) are carried out in presence of base.
7. A process for the preparation of Belumosudil intermediate of Formula- V, which comprises condensation of 3 -hydroxybenzaldehyde of Formula-VII with 2-halo-N-isopropylacetamide of Formula-VIII:
Formula-VII Formula-VIII Formula-V wherein X is selected from fluoro, chloro, bromo and iodo.
8. The process as claimed in claim 7, wherein the condensation is carried out in presence of inorganic base.
9. The process as claimed in claim 7, wherein suitable solvent is selected from the group comprising dimethyl acetamide, dimethylformamide, acetonitrile, benzonitrile, toluene, acetone, N-methyl-2-pyrrolidone, methanol, ethanol, dimethyl sulfoxide, toluene, dichloromethane or mixture of thereof or the any combination thereof.
Formula-V
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6479499B1 (en) * | 2000-06-28 | 2002-11-12 | National Science Council | 2-phenyl-4-quinazolinone compounds, 2-phenyl-4-alkoxy-quinazoline compounds and their pharmaceutical compositions |
US7691883B2 (en) * | 2003-09-17 | 2010-04-06 | Sumitomo Chemical Company, Limited | Cinnamoyl compound and use of the same |
US8889698B2 (en) * | 2007-02-01 | 2014-11-18 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular diseases |
CN106916145A (en) * | 2017-03-06 | 2017-07-04 | 上海应用技术大学 | The synthetic method of SLx 2119 |
IN202241047970A (en) * | 2022-08-23 | 2024-03-01 |
-
2024
- 2024-02-12 WO PCT/IB2024/051282 patent/WO2024171021A1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6479499B1 (en) * | 2000-06-28 | 2002-11-12 | National Science Council | 2-phenyl-4-quinazolinone compounds, 2-phenyl-4-alkoxy-quinazoline compounds and their pharmaceutical compositions |
US7691883B2 (en) * | 2003-09-17 | 2010-04-06 | Sumitomo Chemical Company, Limited | Cinnamoyl compound and use of the same |
US8889698B2 (en) * | 2007-02-01 | 2014-11-18 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular diseases |
CN106916145A (en) * | 2017-03-06 | 2017-07-04 | 上海应用技术大学 | The synthetic method of SLx 2119 |
IN202241047970A (en) * | 2022-08-23 | 2024-03-01 |
Non-Patent Citations (1)
Title |
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DATABASE PUBCHEM COMPOUND 29 February 2008 (2008-02-29), ANONYMOUS: "2-(3-formylphenoxy)-N-propan-2ylacetamide", XP093203952, retrieved from PUBCHEM Database accession no. 24710882 * |
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