WO2023175526A1 - Process for preparation of azabicyclo [3.1.0] hexane intermediates - Google Patents
Process for preparation of azabicyclo [3.1.0] hexane intermediates Download PDFInfo
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- WO2023175526A1 WO2023175526A1 PCT/IB2023/052509 IB2023052509W WO2023175526A1 WO 2023175526 A1 WO2023175526 A1 WO 2023175526A1 IB 2023052509 W IB2023052509 W IB 2023052509W WO 2023175526 A1 WO2023175526 A1 WO 2023175526A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- salt
- caronic
- amide
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 151
- 230000008569 process Effects 0.000 title claims abstract description 147
- 238000002360 preparation method Methods 0.000 title claims abstract description 91
- QRDSDKAGXMWBID-UHFFFAOYSA-N 5-azabicyclo[3.1.0]hexane Chemical compound C1CCN2CC21 QRDSDKAGXMWBID-UHFFFAOYSA-N 0.000 title abstract description 14
- 239000000543 intermediate Substances 0.000 title description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 220
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 claims abstract description 13
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 claims abstract description 13
- 229960000517 boceprevir Drugs 0.000 claims abstract description 12
- 229940125674 nirmatrelvir Drugs 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims description 156
- 150000003839 salts Chemical class 0.000 claims description 139
- 150000001408 amides Chemical class 0.000 claims description 108
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 67
- 239000007800 oxidant agent Substances 0.000 claims description 51
- 239000000203 mixture Substances 0.000 claims description 49
- 239000002904 solvent Substances 0.000 claims description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 42
- 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 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 31
- MSPJNHHBNOLHOC-UHFFFAOYSA-N 3,3-dimethylcyclopropane-1,2-dicarboxylic acid Chemical compound CC1(C)C(C(O)=O)C1C(O)=O MSPJNHHBNOLHOC-UHFFFAOYSA-N 0.000 claims description 30
- 150000001412 amines Chemical class 0.000 claims description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 239000012286 potassium permanganate Substances 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 24
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 23
- 239000012535 impurity Substances 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 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 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 239000008096 xylene Substances 0.000 claims description 14
- 239000004202 carbamide Substances 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 229940086542 triethylamine Drugs 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000005580 one pot reaction Methods 0.000 claims description 8
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 6
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 6
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 5
- 150000008282 halocarbons Chemical class 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 5
- 150000003462 sulfoxides Chemical class 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- OEBXWWBYZJNKRK-UHFFFAOYSA-N 1-methyl-2,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidine Chemical compound C1CCN=C2N(C)CCCN21 OEBXWWBYZJNKRK-UHFFFAOYSA-N 0.000 claims description 4
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-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
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002346 iodo group Chemical group I* 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000003960 organic solvent Substances 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000012425 OXONE® Substances 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 2
- JYLNVJYYQQXNEK-UHFFFAOYSA-N 3-amino-2-(4-chlorophenyl)-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(CN)C1=CC=C(Cl)C=C1 JYLNVJYYQQXNEK-UHFFFAOYSA-N 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- DIBHLCJAJIKHGB-UHFFFAOYSA-N dec-5-ene Chemical compound [CH2]CCCC=CCCCC DIBHLCJAJIKHGB-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- AQBLLJNPHDIAPN-LNTINUHCSA-K iron(3+);(z)-4-oxopent-2-en-2-olate Chemical compound [Fe+3].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O AQBLLJNPHDIAPN-LNTINUHCSA-K 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 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
- 229940094025 potassium bicarbonate Drugs 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229940093956 potassium carbonate Drugs 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
- 229940093932 potassium hydroxide Drugs 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- IKMJGHPYOYVETB-UHFFFAOYSA-N 1,4-dioxane;ethyl acetate Chemical compound CCOC(C)=O.C1COCCO1 IKMJGHPYOYVETB-UHFFFAOYSA-N 0.000 claims 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 13
- 125000003118 aryl group Chemical group 0.000 abstract description 8
- 230000000840 anti-viral effect Effects 0.000 abstract description 6
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 78
- 238000003756 stirring Methods 0.000 description 69
- 239000007787 solid Substances 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- 239000000463 material Substances 0.000 description 16
- 239000007858 starting material Substances 0.000 description 15
- QKAHKEDLPBJLFD-UHFFFAOYSA-N 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione Chemical compound O=C1OC(=O)C2C1C2(C)C QKAHKEDLPBJLFD-UHFFFAOYSA-N 0.000 description 12
- 238000007254 oxidation reaction Methods 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 229910052736 halogen Chemical group 0.000 description 8
- 150000002367 halogens Chemical group 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 6
- 125000005907 alkyl ester group Chemical group 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010908 decantation Methods 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- -1 methoxy, ethoxy Chemical group 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 229940078552 o-xylene Drugs 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 4
- 229940001584 sodium metabisulfite Drugs 0.000 description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000001117 sulphuric acid Substances 0.000 description 4
- 235000011149 sulphuric acid Nutrition 0.000 description 4
- XLOPRKKSAJMMEW-SFYZADRCSA-N Chrysanthemic acid Natural products CC(C)=C[C@@H]1[C@@H](C(O)=O)C1(C)C XLOPRKKSAJMMEW-SFYZADRCSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000010931 ester hydrolysis Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000000638 solvent extraction Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 238000010640 amide synthesis reaction Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- XLOPRKKSAJMMEW-UHFFFAOYSA-N chrysanthemic acid Chemical compound CC(C)=CC1C(C(O)=O)C1(C)C XLOPRKKSAJMMEW-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 208000010710 hepatitis C virus infection Diseases 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- DILISPNYIVRDBP-UHFFFAOYSA-N 2-[3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]-2-naphthalen-2-ylimidazol-4-yl]acetonitrile Chemical compound OC(CNC1=NC=CC(=N1)N1C(=NC=C1CC#N)C1=CC2=CC=CC=C2C=C1)C DILISPNYIVRDBP-UHFFFAOYSA-N 0.000 description 1
- DWKNOLCXIFYNFV-HSZRJFAPSA-N 2-[[(2r)-1-[1-[(4-chloro-3-methylphenyl)methyl]piperidin-4-yl]-5-oxopyrrolidine-2-carbonyl]amino]-n,n,6-trimethylpyridine-4-carboxamide Chemical compound CN(C)C(=O)C1=CC(C)=NC(NC(=O)[C@@H]2N(C(=O)CC2)C2CCN(CC=3C=C(C)C(Cl)=CC=3)CC2)=C1 DWKNOLCXIFYNFV-HSZRJFAPSA-N 0.000 description 1
- UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- FZLSDZZNPXXBBB-KDURUIRLSA-N 5-chloro-N-[3-cyclopropyl-5-[[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl]phenyl]-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine Chemical compound C[C@H]1CN(Cc2cc(Nc3ncc(Cl)c(n3)-c3c[nH]c4cc(C)ccc34)cc(c2)C2CC2)C[C@@H](C)N1 FZLSDZZNPXXBBB-KDURUIRLSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000025721 COVID-19 Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 229910002567 K2S2O8 Inorganic materials 0.000 description 1
- 229910004882 Na2S2O8 Inorganic materials 0.000 description 1
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000013461 intermediate chemical Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006561 solvent free reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- the present invention relates to a process for preparation of azabicyclo [3.1.0] hexane intermediate of Formula-I, a useful intermediates in the preparation of certain antiviral compounds for example boceprevir and nirmatrelvir.
- Formula I wherein “R1” is selected from hydrogen, alkyl, aryl or aralkyl BACKGROUND OF THE INVENTION
- Azabicyclo [3.1.0] hexane intermediates are valuable intermediate in the preparation of certain antiviral compounds for example boceprevir an important drug for the treatment of human hepatitis C virus infections (HCV) and nirmatrelvir, recently approved drug for the treatment of COVID-19.
- Boceprevir and Nirmatrelvir chemically known as (1R,5S)-N-[3-Amino-1- (cyclobutylmethyl)-2,3dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl] amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3azabicyclo[3.1.0]hexan-2(S)- carboxamide and (1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl)-3- ((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide and are having the following chemical structures:
- WO2004/113295, CN101020680A, CN101863866B, WO2007/075790, WO2010/08828, WO2012/049688 and WO2014/061034 disclosed preparation of azabicyclo [3.1.0] hexane intermediate of Formula I.
- the process disclosed in art is as follows: The processes disclosed in the art involves preparation of benzyl caronic amide of Formula V or Formula VI staring from alkyl ester of either chrysanthemic acid or cypermethric acid by oxidation in presence of potassium permanganate or ozone in acetone or a mixture of acetone: water and followed by ester hydrolysis to obtain caronic acid of Formula III.
- the obtained caronic acid of Formula III was cyclized to caronic anhydride in presence of acetic anhydride and then the caronic anhydride was converted to benzyl caronic amide of Formula V followed by de-benzylation to obtain the caronic amide of Formula VI followed by formation of azabicyclo [3.1.0] hexane intermediate of Formula I in multiple ways by involving different chemical conversions as described above.
- the present invention provides an improved process for preparation of intermediates of azabicyclo [3.1.0] hexane of Formula I specifically compound of Formula III, Formula V and Formula VI.
- the present invention provides a process for preparation of a compound of Formula III or a salt thereof, comprising: reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain compound of Formula III.
- the present invention provides a process for preparation of compound of Formula III or a salt thereof, comprising: reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity.
- the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula III or a salt thereof with benzyl amine to obtain a compound of Formula IV or a salt thereof, and b) cyclizing the compound of Formula IV or a salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V.
- the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, wherein R is alkyl or halogen, b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V.
- the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, wherein R is alkyl or halogen, b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity.
- the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, wherein R is alkyl or halogen, b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V; wherein the steps a) to c) are carried out in one-pot reaction.
- the present invention provides a process for preparation of compound of Formula III or a salt thereof, comprising: reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain compound of Formula III.
- the present invention provides a process for preparation of compound of Formula III or a salt thereof, comprising: reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain compound of Formula III; wherein both the compound of Formula IIa or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity.
- the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, Formula III Formula IIa b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and Formula III Formula IV c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V.
- the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V; wherein the steps a) to c) are carried out in one-pot reaction.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: reacting a compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: reacting a compound of Formula III or a salt thereof with a suitable source of amine in presence of a suitable catalyst to obtain caronic amide of Formula VI.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: reacting a compound of Formula III or a salt thereof with a suitable source of amine in presence of a suitable catalyst and a suitable solvent to obtain caronic amide of Formula VI.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: reacting a compound of Formula III or a salt thereof with a suitable source of amine in presence of a suitable solvent to obtain caronic amide of Formula VI.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, and b) reacting the compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, and b) reacting the compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: a) reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, and b) reacting the compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: a) reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, and b) reacting the compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI; wherein both the compound of Formula IIa or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity.
- the present invention provides a process for purification of caronic amide of Formula VI or a salt thereof, comprising: a) suspending or dissolving caronic amide of Formula VI or a salt thereof in a suitable solvent at a suitable temperature, and b) isolating the pure caronic amide of Formula VI or a salt thereof.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: a) reacting a compound of Formula III or a salt thereof with a suitable source of amine optionally in presence of a suitable solvent and/or a suitable catalyst to obtain a caronic amide of Formula VI, b) suspending or dissolving the caronic amide of Formula VI or a salt thereof obtained in step a) in a suitable solvent at a suitable temperature, and c) isolating caronic amide of Formula VI or a salt thereof.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: a) reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, b) reacting the compound of Formula III or a salt thereof with a suitable source of amine optionally in presence of a suitable solvent and/or a suitable catalyst to obtain a caronic amide of Formula VI, c) suspending or dissolving the caronic amide of Formula VI or a salt thereof obtained in step b) in a suitable solvent at a suitable temperature, and d) isolating caronic amide of Formula VI or a salt thereof.
- the present invention provides an improved process for preparation of compound of Formula I, comprising: a) preparing a compound of Formula III or Formula V or Formula VI according to the processes described as above embodiments, and b) converting the compound of Formula III or Formula V or Formula VI in to compound of Formula I; wherein the “R1” is selected from hydrogen, alkyl, aryl or aralkyl.
- the present invention provides an improved process for preparation of boceprevir, comprising: a) preparing a compound of Formula III or Formula V or Formula VI according to the processes described as above embodiments, b) converting the compound of Formula III or Formula V or Formula VI into compound of Formula I, and c) converting the compound of Formula I in to boceprevir.
- the present invention provides an improved process for preparation of nirmatrelvir, comprising: a) preparing a compound of Formula III or Formula V or Formula VI according to the processes described as above embodiments, b) converting the compound of Formula III or Formula V or Formula VI into compound of Formula I, and c) converting the compound of Formula I in to nirmatrelvir.
- the present invention provides a composition comprising boceprevir or nirmatrelvir, prepared by the process of compound of Formula III, Formula V, Formula VI and/or Formula I of the present invention and at least one pharmaceutically acceptable excipient.
- a composition comprising boceprevir or nirmatrelvir, prepared by the process of compound of Formula III, Formula V, Formula VI and/or Formula I of the present invention and at least one pharmaceutically acceptable excipient.
- the present invention encompasses an improved process for the preparation of intermediates of azabicyclo [3.1.0] hexane of Formula I with high product yield and quality wherein “R1” is selected from hydrogen, alkyl, aryl or aralkyl Wherein the improvements include oxidation at acid compound of Formula II or its salt thereof; wherein “R” is alkyl or halogen, in which alkyl esterification and subsequent ester hydrolysis steps as disclosed in the art are not necessary. Further during the process for preparation of benzyl caronic amide of Formula V the formation of intermediate caronic anhydride as disclosed in the art is not necessary instead the compound of Formula III is directly converted to benzyl caronic amide of Formula V with the help of Benzyl amine.
- the present invention also involve preparation of caronic amide of Formula VI by direct cyclization of caronic acid of Formula III without involving formation of caronic anhydride, protected caronic amide and subsequent deprotection steps.
- the present invention provides a process for preparation of compound of Formula III or a salt thereof, comprising: reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain compound of Formula III.
- the present invention provides a process for preparation of compound of Formula III or a salt thereof, comprising: reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity.
- alkyl used herein is selected from but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl and the like.
- the alkyl may be further substituted with a suitable substituent, which may be selected from the group comprising halogen, aryl and the like.
- the term “halogen” used herein is selected from bromo, chloro or Iodo.
- the compound of Formula II specifically represents as following compound of Formula IIa:
- the compound of Formula II, preferably Formula IIa which is used herein as a starting material is known in the art and can be prepared by any known methods. For example, may be prepared as per the process disclosed in US4237058.
- the suitable oxidizing agent used in aforementioned process is selected from the group consisting of but not limited to bromine, hydrogen peroxide (H 2 O 2 ), Potassium persulfate (K 2 S 2 O 8 ), sodium persulfate (Na 2 S 2 O 8 ), ammonium persulfate ((NH 4 ) 2 S 2 O 8 ), potassium monopersulfate (KHSO 5 ), sodium monopersulfate (NaHSO5), potassium permanganate (KMnO 4 ), sodium permanganate (NaMnO 4 ) and the like and mixture thereof; preferably bromine, sodium persulfate, potassium permanganate and mixture thereof; more preferably potassium permanganate.
- the aforementioned oxidation step may be carried out in presence of a suitable solvent and / or a base.
- the suitable solvent selected from the group consisting of ethers, esters, ketones, halogenated hydrocarbons, aprotic organic solvents, water and mixture thereof.
- Ethers include but are not limited to tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; esters include but are not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like; ketones include but are not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aprotic organic solvent, include but are not limited to N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2- imidazolidinone, acetonitrile and the like; water and mixture thereof; preferably acetone, methylene chloride, water and mixture thereof; more
- the suitable base may be selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium-butoxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, triethyl amine, diisopropyl ethyl amine and the like and mixtures thereof; preferably sodium hydroxide or potassium hydroxide and more preferably sodium hydroxide.
- the present invention provides a process for preparation of compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity; preferably added in about 4 to about 5 parts of the total quantity.
- the present invention provides a process for preparation of compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 equal parts of the total quantity; preferably added in about 4 to about 5 equal parts of the total quantity.
- the present invention provides a process for preparation of compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity in a sequential manner one after another; preferably added in about 4 to about 5 parts of the total quantity in a sequential manner one after another.
- the present invention provides a process for preparation of compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 equal parts of the total quantity in a sequential manner one after another; preferably added in about 4 to about 5 equal parts of the total quantity in a sequential manner one after another.
- the present invention provides a process for preparation of compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity in a sequential manner one after another at a temperature of about 0°C to about 60°C; preferably added in about 4 to about 5 parts of the total quantity in a sequential manner one after another at a temperature of about 20°C to about 30°C.
- the present invention provides a process for preparation of compound of Formula III; wherein the compound of Formula II or a salt thereof is added in about 3 to about 10 parts of the total quantity in about 30 min to about 4 hrs; preferably added in about 4 parts of the total quantity in about 1 hr to about 2 hrs.
- the present invention provides a process for preparation of compound of Formula III; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity in about 5 min to 30 mins; preferably added in about 5 parts of the total quantity in about 10 min to about 15 mins.
- the present invention provides a process for preparation of compound of Formula III; wherein the total quantity of oxidizing agent is about 1.5 to about 5 equivalents to starting compound of formula IIa. In another embodiment, the present invention provides a process for preparation of compound of Formula III; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity and each part contains about 0.15 to 1.65 equivalents to starting compound of formula IIa; preferably added in about 5 parts of the total quantity and each part contains about 0.2 to 1.5 equivalents to starting compound of formula IIa.
- the aforementioned oxidation step may be carried out in presence of a suitable acid, wherein the acid is selected from the group consisting of acetic acid, propanoic acid, p-toluenesulfonic acid and benzoic acid and the like and mixture thereof.
- a suitable acid selected from the group consisting of acetic acid, propanoic acid, p-toluenesulfonic acid and benzoic acid and the like and mixture thereof.
- the reaction of a Formula IIa or a salt thereof with a suitable oxidizing agent is carried out at a temperature of about 25°C to reflux temperature; preferably at about 25°C to about 65°C; more preferably at about 35°C to about 40°C.
- the resultant compound of Formula III may be advantageously processed to next step or optionally the obtained compound of Formula III can be isolated from the reaction mass by conventional techniques such as precipitation by cooling the reaction mass, isolated by solvent extraction or precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably if isolation involves compound of Formula III can be isolated by adjusting the pH of the reaction to about less than 2.0 with a suitable acid such as hydrochloric acid, sulfuric acid and the like; preferably with sulfuric acid at a temperature of about 5°C to about 15°C and extracting the compound of Formula III with a suitable water immiscible organic solvent such as ethyl acetate, methylene chloride and the like; preferably with ethyl acetate and concentrating the product containing organic layer .
- a suitable acid such as hydrochloric acid, sulfuric acid and the like
- sulfuric acid at a temperature of about 5°C to about 15°C
- a suitable water immiscible organic solvent such as
- the present invention provides a compound of Formula III prepared by the process described as above having a purity of at least about 95%, as measured by HPLC, preferably at least about 97% as measured by HPLC.
- the present invention provides an improved process for the preparation of benzyl caronic amide of Formula V, comprising preparing the caronic acid of Formula III as process just described as above, and converting the caronic acid of Formula III in to benzyl caronic amide of Formula V.
- the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and b) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain a compound of Formula V.
- the compound of Formula III which is used herein as a starting material, can be prepared by the process as in accordance with above embodiments or any methods known in art.
- the step a) reaction may be carried out with a suitable solvent, wherein the suitable solvent is selected from the group consisting of but not limited to amides, sulfoxides, aromatic hydrocarbons and the like and mixtures thereof.
- the amides include, but are not limited to dimethylacetamide, dimethylformamide, N- methylpyrrolidone and the like and mixtures thereof; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like and mixtures thereof; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture thereof; preferably dimethyl sulfoxide, toluene, xylene and the like and mixture thereof; more preferably xylene.
- the step a) reaction may be carried without use of any solvent as mentioned above as the reactant benzyl amine is used as both reactant and solvent.
- the benzyl amine used in the current invention can be substituted or unsubstituted benzyl amine, wherein the substituents include but are not limited to halo such as bromo, chloro or fluoro, iodo; C1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl and the like; O-alkyl such as methoxy, ethoxy and the like; aryl such as phenyl and the like; or O-aryl such as benzyloxy and the like.
- halo such as bromo, chloro or fluoro, iodo
- C1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl and the like
- O-alkyl such as methoxy, ethoxy and the like
- aryl such
- the C1- 4 alkyl, aryl and O-aryl may be further substituted with a suitable substituent, which may be selected from the group comprising halogen, aryl and the like.
- a suitable substituent which may be selected from the group comprising halogen, aryl and the like.
- the reaction of Formula III or salt thereof with benzyl amine is carried out at a temperature of about 50°C to reflux temperature; preferably at about 100°C to about 150°C; more preferably at about 135°C to about 145°C.
- the resultant compound of Formula IV may be isolated as a solid or as such reaction mass may be converted to a compound of Formula V without isolating the compound of Formula IV as solid by directly adding a suitable cyclizing agent to the step a) solution.
- the suitable cyclizing agent used in the step b) is selected from the group consisting of but not limited to acetic anhydride, sulfuric acid, para toluene sulfonic acid and the like and mixture thereof; preferably acetic anhydride.
- the cyclization reaction of step b) is carried out at a temperature of about 50°C to reflux temperature; preferably at about 100°C to about 150°C; more preferably at about 135°C to about 145°C.
- the resultant compound of Formula V can be isolated by conventional techniques such as precipitation by cooling the reaction mass, isolated by solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably isolated by concentrating the reaction mass under vacuum at below 80°C and followed by adding a suitable solvent such as isopropanol and then filtering the product.
- the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, wherein R is alkyl or halogen, b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V; wherein the steps a) to c) are carried out in one-pot reaction.
- the aforementioned step a) to step c) are carried out in one-pot reaction by following the process as described in above embodiments of the present invention.
- compound of Formula V obtained by the processes described as above, having purity of at least about 99% as measured by HPLC, preferably at least about 99.5% as measured by HPLC.
- Compound of Formula III and Formula V are key cost contributor in the preparation of certain antiviral compounds for example boceprevir and nirmatrelvir.
- Preparation of caronic acid of Formula III according to the prior art involves oxidation of either chrysanthemic acid ester or cypermethric acid ester in presence of potassium permanganate or ozone in acetone or a mixture of acetone and water and followed by ester hydrolysis.
- the oxidation process disclosed under the prior literatures suffers from forming a heterogeneous reaction mass throughout the reaction and this may be due to the use of alkyl ester intermediates in acetone or a mixture of acetone and water. Due to the heterogeneous reaction system the oxidizing agent used in the process may not be available for complete oxidation as a result additional quantities of oxidizing agent required to complete the reaction, therefore inconsistent output with low pure and lower yields. Further the oxidation at ester compound of Formula II as disclosed under the prior literature involves addition of oxidizing agent to the total quantity of starting material of Formula II in either acetone or a mixture of acetone and water.
- oxidizing agent like potassium permanganate is having tendency with rapid reactivity with the starting material which leads to instant release of excess oxygen and high chances of sudden shoot up of reaction pressure and temperature thereby high chances of explosion.
- the disclosed processes involves preparation of benzyl caronic amide of Formula V in two steps, which involves first cyclization of caronic acid of Formula III to form caronic anhydride followed by amide formation.
- the two step process disclosed under the prior literatures not only lengthy but also requires additional step of isolation and drying process of caronic anhydride, which leads to operational inconvenience and burden on equipment occupancy.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, and b) reacting the compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: reacting a caronic acid of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI.
- the compound of Formula III which is used herein as a starting material is known in the art and can be prepared by any known methods. For example, can be prepared as per the process disclosed in the above embodiments or can be prepared by following the process disclosed in WO2004/113295.
- Reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine may be carried out either in neat reaction or in a suitable solvent, wherein the suitable solvent is selected from the group consisting of but not limited to amides, sulfoxides, aromatic hydrocarbons and the like, water and mixtures thereof.
- the amides include, but are not limited to dimethylacetamide, dimethylformamide, N- methylpyrrolidone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene, diphenyl ether and the like and mixture thereof; preferably dimethyl sulfoxide, toluene, xylene, water and mixtures thereof; more preferably xylene, water and mixtures thereof.
- the source of amine is selected from the group consisting of but not limited to urea, ammonia, formamide and the like and mixtures thereof.
- reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine may be carried out in presence of a suitable catalyst, wherein the suitable catalyst is selected from the group consisting of but not limited to 1,8-Diazabicyclo[5.4.0]undec- 7-ene (DBU), triethylamine, trimethylamine, dimethylamine, diethylamine, dibenzoyl peroxide, toluene-4-sulfonic acid, hydrogen peroxide, pyridine, dimethylaminopyridine, acetic acid, tetrabutyl ammonium bromide, azobisisobutyronitrile, copper(I)/DBU catalyst, copper(II) acetate, copper(I) bromide, iron(III) acetylacetonate, ruthenium based catalysts, molecular sieves, tetra methyl guanidine, 7-methyl-1,5,7- triazabicyclo[4.4.0]dec-5-ene
- reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine is carried out in presence of a suitable catalyst.
- reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine is carried out in presence of a suitable catalyst and a suitable solvent.
- reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine is carried out in presence of a suitable solvent.
- the reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine is carried out at a temperature of about 50°C to about 200°C; preferably at about 100°C to about 150°C; more preferably at about 135°C to about 145°C.
- the compound of Formula VI may be isolated from the reaction mass by conventional techniques such as solvent extraction, solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably isolated by cooling the reaction mass and filtering the solids.
- preparation of caronic amide of Formula VI or a salt thereof by reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine is always possibility to formation of mono amide and/or diamide impurities along with unreacted starting material and these impurities mostly separated through the mother liquors.
- the mono amide and diamide impurities specifically represents as following compounds:
- the present inventors have surprisingly found that the mother liquors which contain unwanted impurities such as unreacted caronic acid and/or mono amide and/or diamide impurities are utilized as solvent source for the additional batches of the process of the above embodiments.
- the reuse of mother liquors as solvent source is advantageously increases the overall product yield as the unwanted impurities accumulated in the mother liquors are converted into compound of Formula VI in each batch of the process.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising reacting a caronic acid of Formula III or a salt thereof with a suitable source of amine and mother liquors containing unwanted impurities selected from unreacted caronic acid and/or mono amide and/or diamide impurities obtained from the above embodiments.
- the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising reacting a caronic acid of Formula III or a salt thereof with a suitable source of amine and mother liquors containing unwanted impurities selected from unreacted caronic acid and/or mono amide and/or diamide impurities obtained from the above embodiments; wherein the source of amine, reaction temperature and other process conditions are same as the process as described just as above.
- the present invention provides a compound of Formula VI or a salt thereof prepared by the process described as above having a purity of at least about 97%, as measured by HPLC, preferably at least about 99% as measured by HPLC; and having less than 0.5%, preferably less than 0.2% each of unreacted starting material caronic acid and/or mono amide and/or diamide impurities as measured by HPLC.
- the caronic amide of Formula VI or a salt thereof prepared by the process of the present invention or prepared by any other processes is further purified to remove impurities such as mono amide and/or diamide impurities along with unreacted starting material by solvent purification.
- the present invention provides a process for purification of caronic amide of Formula VI or a salt thereof, comprising: a) suspending or dissolving caronic amide of Formula VI or a salt thereof in a suitable solvent at a suitable temperature, and b) isolating the pure caronic amide of Formula VI or a salt thereof.
- the step a) process may be involve suspending or dissolving a compound of Formula VI having unreacted caronic acid and/or mono amide and/or diamide impurities more than 0.5% by HPLC in a suitable solvent at a temperature of about ambient temperature to reflux temperature; preferably at about 50°C to about 60°C.
- the suitable solvent used to suspend or dissolve compound of Formula VI having about more than 0.5% unreacted caronic acid and/or mono amide and/or diamide impurities by HPLC is selected from the group consisting of but is not limited to esters, ethers, ketones, nitriles, halogenated hydrocarbons, aliphatic or alicyclic hydrocarbons, aromatic hydrocarbons and the like, water and mixtures thereof.
- esters include, but are not limited to ethyl acetate, methyl acetate and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aliphatic or alicyclic hydrocarbons include, but are not limited to hexane, heptane, pentane, cyclohexane, cycloheptane, cyclopentane and the like; aromatic hydrocarbons include, but are not limited
- the pure compound of Formula VI having unreacted caronic acid and/or mono amide and/or diamide impurities less than 0.5% by HPLC may be isolated from the reaction mass by conventional techniques such as solvent extraction, solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably isolated by cooling the reaction mass and filtering the solids.
- the compound of Formula VI obtained by the processes described as above having purity of at least about 99% as measured by HPLC, preferably at least about 99.5% as measured by HPLC and less than 0.5%, preferably less than 0.2% as measured by HPLC of each of unreacted starting material caronic acid and/or mono amide and/or diamide impurities.
- Compound of Formula VI is the key cost contributor in the preparation of certain antiviral compounds for example boceprevir and nirmatrelvir.
- the disclosed processes involve preparation of caronic amide of Formula VI in three steps, which involves first cyclization of caronic acid of Formula III to form caronic anhydride, amide formation to obtain protected caronic amide and followed by de-protection.
- These three step process disclosed under the prior literatures not only lengthy but also requires additional step of isolation and drying process of caronic anhydride and protected caronic amide, which leads to operational inconvenience and burden on equipment occupancy.
- the present invention encompasses an improved process for the preparation of compound of Formula VI with high yields and high purity by direct reaction of caronic acid of Formula III with a source of amine, without involving formation of caronic anhydride, protected caronic amide and subsequent deprotection steps using hazardous deprotecting agents.
- catalyst as used in this application means a substance that increases reaction rate by altering the reaction mechanism.
- Nitro reaction as used in this application means a step forward in the direction of solvent free reactions and an alternative approach that eliminates the use of a solid support as well as solvent from the reaction.
- one-pot means a process uses a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one solvent/reactor. This is much desired by chemists because avoiding a lengthy separation process and purification of the intermediate chemical compounds can save time and resources, improves the efficiency of a chemical reaction, and offers better chemical yield.
- the present invention encompasses an improved process for the preparation of intermediates of azabicyclo [3.1.0] hexane of Formula I with high product yield and quality by the following scheme:
- the present invention provides an improved process for the preparation of compound of Formula I, comprising preparing the compound of Formula V and/or compound of Formula VI as process described above, and converting the compound of Formula V and/or compound of Formula VI in to compound of Formula I by any process known in the art for example WO2004/113295, CN101020680A, CN101863866B, WO2007/075790, WO2010/08828, WO2012/049688 and WO2014/061034.
- the present invention provides use of compound of Formula V and/or compound of Formula VI prepared as process described above, as an intermediate in the preparation of certain antiviral compounds for example boceprevir or nirmatrelvir.
- EXAMPLES The following non-limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.
- EXAMPLE-1 Preparation of compound of Formula III (addition of both Formula IIa and oxidizing agent - in part wise one after another sequentially) Compound of Formula IIa (100 g), water (500 mL) were added in to a round bottom flask at 20-30°C.
- reaction mass was added second part of potassium permanganate (37.8 g) at 20-30°C and followed by addition of second part of solution of Formula IIa (150 mL) for a period of 1.5 to 2 hrs at same temperature and repeat the addition of potassium permanganate and Formula IIa in another three lots at same temperature.
- Reaction mass was heated to 35-40°C and stir for 2-4 hrs at same temperature.
- After completion of the reaction by TLC cool the reaction mass to 10°C and was added sodium metabisulfite solution at below 30°C and stir for 60 min at same temperature.
- Reaction mass pH was adjusted to less than 2.0 with sulphuric acid (187 g) and stir for 60 min.
- EXAMPLE-2 Preparation of compound of Formula V Compound of Formula III (100 g), o-xylene (400 mL) were added in to a round bottom flask with dean stark condenser at 20-30°C. Reaction mass heated to 135-140°C and was added benzyl amine solution (68 g was dissolved in 100 mL o-xylene) in 3-4 hrs at same temperature. Reaction mass was stir for 2-3 hrs at 140-145°C (water was collected by azeotropically).
- Reaction mass was allowed to cool to 30-35°C and was added acetic anhydride (13 g) at same temperature. Reaction mass was heated to 140-145°C and stir for 2-3 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80°C and concentrated under vacuum and co-distilled with isopropyl alcohol (100 mL) at below 80°C. To the obtained residue was added isopropyl alcohol (150 mL) at 25-30°C and stir for 2-3 hrs at same temperature. Reaction mass was cool to 0-5°C, filtered the solids and washed the wet cake with chilled isopropyl alcohol (100 mL) and dry the wet material at 60-65°C to obtain title compound. Wt.: 120 g.
- EXAMPLE-3 One pot process of compound of Formula V Compound of Formula IIa (100 g), water (500 mL) were added in to a round bottom flask at 20-30°C. To the reaction mass was added aqueous sodium hydroxide (26 mL) at 20- 30°C and stir for 10 min at same temperature. Then the solution was divided in to 4 equivalent parts and kept a side (4 ⁇ 150 mL). In another round bottom flask was added water (500 mL) and first part of potassium permanganate (37.8 g) at 20-30°C and stir for 10 min.
- Reaction mass pH was adjusted to below 2.0 with sulphuric acid (187 g) at below 30°C and stir for 60 min at same temperature.
- ethyl acetate 600 mL
- filtered and washed the wet cake with water 100 mL
- the product containing organic layer was separated and concentrated under vacuum at below 55°C.
- o-xylene 400 mL
- Reaction mass was heated to 135-140°C and was added benzyl amine solution (68 g in 100 mL o-xylene) in 3-4 hrs at same temperature.
- Reaction mass was stirred for 2-3 hrs at 140-145°C (19-20 mL of water was collected by azeotropically). Reaction mass was allowed to cool to 30-35°C and was added acetic anhydride (13 g) at same temperature. Reaction mass was heated to 140-145°C and stir for 2-3 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80°C and concentrated under vacuum and co-distilled with isopropyl alcohol (100 mL) at below 80°C. To the obtained residue was added isopropyl alcohol (150 mL) at 25-30°C and stir for 2-3 hrs at same temperature.
- reaction mass was added potassium permanganate (20 ⁇ 3.14 g) and compound of Formula II ethyl ester (20 ⁇ 1.41 g) in part wise one after another sequentially at 50-55°C (observed heterogeneous reaction mass). After 2 hr of stirring, reaction was not completed by TLC. To the reaction mass was added additional potassium permanganate (2 ⁇ 9.4 g) and stirred for 1 hr. The heterogeneous reaction mass was allowed to cool to 10°C and was added sodium metabisulfite solution at below 30°C and stir for 60 min at same temperature. To the reaction mass was added sulphuric acid (94.5 g) at below 30°C and stir for 60 min at same temperature.
- reaction mass was added toluene (55 mL) and stir for 10 min at 30°C. Then the product containing organic layer was separated and concentrated under vacuum at below 65°C. The obtained residue was cool to 10°C and was added sodium hydroxide solution (22.5 g dissolved in 75 mL water) at same temperature. Reaction mass was heated to 50°C and stir for 2 hr at same temperature. After completion of the reaction, reaction mass was cool to 10°C and pH was adjusted to 1.0-2.0 with HCl (43 mL) and stir for 10 min at same temperature. Then the product was extracted with ethyl acetate (2 ⁇ 85 mL) and concentrated to obtain the title compound. Wt.: 8.1 g.
- EXAMPLE-5 Preparation of compound of Formula III (from ethyl ester of compound of Formula II) Water (300 mL) and acetone (75 mL) was added in to a round bottom flask and heated to at 25-30°C. To the reaction mass was added potassium permanganate (128.5 g) at 25- 30°C and stir for 10 min at same temperature. To the reaction mass was added slowly compound of Formula II ethyl ester (56.5 g) in 7-8 hr at 25-30°C (observed heterogeneous reaction mass). Reaction mass was heated to 35-40°C. After 4 hr of stirring, reaction was not completed by TLC.
- reaction mass was heated to 50°C and stir for 2 hr at same temperature. After completion of the reaction, reaction mass was cool to 10°C and pH was adjusted to 1.0-2.0 with HCl (85 mL) and stir for 10 min at same temperature. Then the product was extracted with ethyl acetate (2 ⁇ 300 mL) and concentrated to obtain the title compound. Wt.: 20.5 g. Purity by HPLC: 93.5%.
- EXAMPLE-6 Preparation of compound of Formula VI Compound of Formula III (100 g), Urea (43.7 g) and water (200 mL) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 135-145°C and stir for 2-3 hrs at same temperature.
- Reaction mass was cool to 70-75°C and was added 1,8- diazabicyclo[5.4.0]undec-7-ene (10 g) at same temperature. Reaction mass was heated to 135-145°C and stir for 3-4 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added water (200 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 86 g.
- EXAMPLE-7a Compound of Formula III (100 g), Urea (43.7 g) and mother liquors (200 mL) obtained from Ex-2 were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 135-145°C and stir for 24 hrs at same temperature. After completion of the reaction, reaction mass was allowed to cool to 80-85°C and was added water (200 mL) and stir for 30 min at same temperature. Then, reaction mass was further allowed to cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 84 g.
- reaction mass was allowed to cool to 80-85°C and was added water (200 mL) and stir for 30 min at same temperature. Then, reaction mass was further allowed to cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 87 g. Purity by HPLC: 99.5%; Formula III by HPLC: 0.26%; mono amide by HPLC: 0.55% and di amide by HPLC: 0.12%.
- reaction mass was further cool to 25-35°C and stir for 2 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (5 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 83 g. Purity by HPLC: 99.9%; Formula III by HPLC: 0.1%; mono amide by HPLC: 0.02% and di amide by HPLC: 0.03%.
- EXAMPLE-9 Preparation of compound of Formula VI Compound of Formula III (50 g) and ammonia solution (150 mL) were added in to a round bottom flask at 25-35°C.
- reaction mass was heated to 160-165°C and collected the water during the heating and stir for 8-9 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added a mixture of cyclohexane and water (100 mL) and stir for 15 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled a mixture of cyclohexane and water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 83 g.
- reaction mass was cool to 80-85°C and was added water (150 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 2 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (25 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 39.5 g. Purity by HPLC: 99.8%; Formula III by HPLC: Not detected; mono amide by HPLC: 0.04% and di amide by HPLC: 0.2%.
- EXAMPLE-12 Preparation of compound of Formula VI Compound of Formula II (10 g), Urea (4.36 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 eq) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 130-140°C and stir for 4-8 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added water (20 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature.
- reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 86 g. Purity by HPLC: 99.8%; Formula III by HPLC: Not detected; mono amide by HPLC: 0.1% and di amide by HPLC: 0.05%.
- EXAMPLE-15 Purification of compound of Formula VI Compound of Formula VI (20 g; HPLC Purity: 97.5%; Formula III by HPLC: 0.9%; mono amide by HPLC: 0.5% and di amide by HPLC: 0.4%) and water (40 mL) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 50-60°C and stir for 2 hrs at same temperature. Reaction mass was cool to 25-30°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with water (10 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 39.5 g.
Abstract
The present invention generally relates to a process for preparation of azabicyclo [3.1.0] hexane intermediate of Formula (I), an intermediate for preparation of certain antiviral compounds for example boceprevir and nirmatrelvir. Wherein "R1" is selected from hydrogen, alkyl, aryl or aralkyl.
Description
“PROCESS FOR PREPARATION OF AZABICYCLO [3.1.0] HEXANE INTERMEDIATES” PRIORITY: This application claims the benefit under Indian Provisional Application No.(S) 202241014235 filed on 16th March, 2022 entitled “Process for preparation of azabicyclo [3.1.0] hexane intermediates” and 202241020524 filed on 05th April, 2022 entitled “Process for preparation of azabicyclo [3.1.0] hexane intermediates” the contents of each of which are incorporated by reference herein. FIELD OF THE INVENTION The present invention relates to a process for preparation of azabicyclo [3.1.0] hexane intermediate of Formula-I, a useful intermediates in the preparation of certain antiviral compounds for example boceprevir and nirmatrelvir.
Formula I wherein “R1” is selected from hydrogen, alkyl, aryl or aralkyl BACKGROUND OF THE INVENTION Azabicyclo [3.1.0] hexane intermediates are valuable intermediate in the preparation of certain antiviral compounds for example boceprevir an important drug for the treatment of human hepatitis C virus infections (HCV) and nirmatrelvir, recently approved drug for the treatment of COVID-19. Boceprevir and Nirmatrelvir, chemically known as (1R,5S)-N-[3-Amino-1- (cyclobutylmethyl)-2,3dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl] amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3azabicyclo[3.1.0]hexan-2(S)- carboxamide and (1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl)-3- ((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide and are having the following chemical structures:
Various known literatures for example: WO2004/113295, CN101020680A, CN101863866B, WO2007/075790, WO2010/08828, WO2012/049688 and WO2014/061034 disclosed preparation of azabicyclo [3.1.0] hexane intermediate of Formula I. The process disclosed in art is as follows:
The processes disclosed in the art involves preparation of benzyl caronic amide of Formula V or Formula VI staring from alkyl ester of either chrysanthemic acid or
cypermethric acid by oxidation in presence of potassium permanganate or ozone in acetone or a mixture of acetone: water and followed by ester hydrolysis to obtain caronic acid of Formula III. The obtained caronic acid of Formula III was cyclized to caronic anhydride in presence of acetic anhydride and then the caronic anhydride was converted to benzyl caronic amide of Formula V followed by de-benzylation to obtain the caronic amide of Formula VI followed by formation of azabicyclo [3.1.0] hexane intermediate of Formula I in multiple ways by involving different chemical conversions as described above. The processes described under the known literatures involves lengthy process to prepare compound of Formula III, Formula V and Formula VI, for example use of alkyl ester of either chrysanthemic acid or cypermethric acid in the preparation of Formula III and use of caronic anhydride in the preparation of protected caronic amide of Formula V and finally de-protection to obtain caronic amide of Formula VI, involves one or more additional steps of esterification and then hydrolysis and also formation of anhydride, which steps makes the process lengthy thereby the intermediates produced with these processes are relatively expensive. Hence, it’s important to develop a simple and cost effective process for preparation of compound of Formula III, Formula V and Formula VI for making azabicyclo [3.1.0] hexane intermediate of Formula I with high yield and cost effective. SUMMARY OF THE INVENTION Accordingly, the present invention provides an improved process for preparation of intermediates of azabicyclo [3.1.0] hexane of Formula I specifically compound of Formula III, Formula V and Formula VI. In accordance with one embodiment, the present invention provides a process for preparation of a compound of Formula III or a salt thereof, comprising: reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain compound of Formula III.
In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula III or a salt thereof, comprising: reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity.
In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula V, comprising:
a) reacting a compound of Formula III or a salt thereof with benzyl amine to obtain a compound of Formula IV or a salt thereof, and
b) cyclizing the compound of Formula IV or a salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V.
In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, wherein R is alkyl or halogen, b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V. In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, wherein R is alkyl or halogen, b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity. In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, wherein R is alkyl or halogen, b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V; wherein the steps a) to c) are carried out in one-pot reaction. In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula III or a salt thereof, comprising: reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain compound of Formula III.
In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula III or a salt thereof, comprising: reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain compound of Formula III; wherein both the compound of Formula IIa or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity.
In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula V, comprising:
a) reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III,
Formula III Formula IIa b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and
Formula III Formula IV c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V. In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V; wherein the steps a) to c) are carried out in one-pot reaction. In accordance with another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: reacting a compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI.
In accordance with another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: reacting a compound of Formula III or a salt thereof with a suitable source of amine in presence of a suitable catalyst to obtain caronic amide of Formula VI. In accordance with another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: reacting a compound of Formula III or a salt thereof with a suitable source of amine in presence of a suitable catalyst and a suitable solvent to obtain caronic amide of Formula VI. In accordance with another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: reacting a
compound of Formula III or a salt thereof with a suitable source of amine in presence of a suitable solvent to obtain caronic amide of Formula VI. In accordance with another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising:
a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, and
b) reacting the compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI. In accordance with another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, and b) reacting the compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity. In accordance with another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising:
a) reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, and
b) reacting the compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI. In accordance with another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: a) reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, and b) reacting the compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI; wherein both the compound of Formula IIa or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity. In accordance with another embodiment, the present invention provides a process for purification of caronic amide of Formula VI or a salt thereof, comprising: a) suspending or dissolving caronic amide of Formula VI or a salt thereof in a suitable solvent at a suitable temperature, and b) isolating the pure caronic amide of Formula VI or a salt thereof. In accordance with another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: a) reacting a compound of Formula III or a salt thereof with a suitable source of amine optionally in presence of a suitable solvent and/or a suitable catalyst to obtain a caronic amide of Formula VI, b) suspending or dissolving the caronic amide of Formula VI or a salt thereof obtained in step a) in a suitable solvent at a suitable temperature, and c) isolating caronic amide of Formula VI or a salt thereof. In accordance with another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising:
a) reacting a compound of Formula IIa or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, b) reacting the compound of Formula III or a salt thereof with a suitable source of amine optionally in presence of a suitable solvent and/or a suitable catalyst to obtain a caronic amide of Formula VI, c) suspending or dissolving the caronic amide of Formula VI or a salt thereof obtained in step b) in a suitable solvent at a suitable temperature, and d) isolating caronic amide of Formula VI or a salt thereof. In accordance with another embodiment, the present invention provides an improved process for preparation of compound of Formula I, comprising:
a) preparing a compound of Formula III or Formula V or Formula VI according to the processes described as above embodiments, and b) converting the compound of Formula III or Formula V or Formula VI in to compound of Formula I; wherein the “R1” is selected from hydrogen, alkyl, aryl or aralkyl. In accordance with another embodiment, the present invention provides an improved process for preparation of boceprevir, comprising: a) preparing a compound of Formula III or Formula V or Formula VI according to the processes described as above embodiments, b) converting the compound of Formula III or Formula V or Formula VI into compound of Formula I, and c) converting the compound of Formula I in to boceprevir. In accordance with another embodiment, the present invention provides an improved process for preparation of nirmatrelvir, comprising: a) preparing a compound of Formula III or Formula V or Formula VI according to the processes described as above embodiments, b) converting the compound of Formula III or Formula V or Formula VI into compound of Formula I, and
c) converting the compound of Formula I in to nirmatrelvir. In accordance with another embodiment, the present invention provides a composition comprising boceprevir or nirmatrelvir, prepared by the process of compound of Formula III, Formula V, Formula VI and/or Formula I of the present invention and at least one pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION The present invention provides an improved process for preparation of intermediates of azabicyclo [3.1.0] hexane of Formula I specifically compound of Formula III, Formula V and Formula VI. The present invention encompasses an improved process for the preparation of intermediates of azabicyclo [3.1.0] hexane of Formula I with high product yield and quality
wherein “R1” is selected from hydrogen, alkyl, aryl or aralkyl Wherein the improvements include oxidation at acid compound of Formula II or its salt thereof; wherein “R” is alkyl or halogen, in which alkyl esterification and subsequent ester hydrolysis steps as disclosed in the art are not necessary. Further during the process for preparation of benzyl caronic amide of Formula V the formation of intermediate caronic anhydride as disclosed in the art is not necessary instead the compound of Formula III is directly converted to benzyl caronic amide of Formula V with the help of Benzyl amine. Further, the present invention also involve preparation of caronic amide of Formula VI by direct cyclization of caronic acid of Formula III without involving formation of caronic anhydride, protected caronic amide and subsequent deprotection steps. In accordance with one embodiment, the present invention provides a process for preparation of compound of Formula III or a salt thereof, comprising: reacting a
compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain compound of Formula III.
In another embodiment, the present invention provides a process for preparation of compound of Formula III or a salt thereof, comprising: reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity.
Unless otherwise specified the term “alkyl” used herein is selected from but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl and the like. Optionally the alkyl may be further substituted with a suitable substituent, which may be selected from the group comprising halogen, aryl and the like. Unless otherwise specified the term “halogen” used herein is selected from bromo, chloro or Iodo. In another preferred embodiment, the compound of Formula II specifically represents as following compound of Formula IIa:
The compound of Formula II, preferably Formula IIa which is used herein as a starting material is known in the art and can be prepared by any known methods. For example, may be prepared as per the process disclosed in US4237058. The suitable oxidizing agent used in aforementioned process is selected from the group consisting of but not limited to bromine, hydrogen peroxide (H2O2), Potassium persulfate (K2S2O8), sodium persulfate (Na2S2O8), ammonium persulfate ((NH4)2S2O8), potassium monopersulfate (KHSO5), sodium monopersulfate (NaHSO5), potassium permanganate (KMnO4), sodium permanganate (NaMnO4) and the like and mixture thereof; preferably bromine, sodium persulfate, potassium permanganate and mixture thereof; more preferably potassium permanganate. The aforementioned oxidation step may be carried out in presence of a suitable solvent and / or a base. The suitable solvent selected from the group consisting of ethers, esters, ketones, halogenated hydrocarbons, aprotic organic solvents, water and mixture thereof. Ethers include but are not limited to tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; esters include but are not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like; ketones include but are not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aprotic organic solvent, include but are not limited to N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2- imidazolidinone, acetonitrile and the like; water and mixture thereof; preferably acetone, methylene chloride, water and mixture thereof; more preferably water. The suitable base may be selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium-butoxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, triethyl amine, diisopropyl ethyl amine and the like and mixtures thereof; preferably sodium hydroxide or potassium hydroxide and more preferably sodium hydroxide. In a preferred embodiment, the present invention provides a process for preparation of compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity; preferably added in about 4 to about 5 parts of the total quantity.
In a preferred embodiment, the present invention provides a process for preparation of compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 equal parts of the total quantity; preferably added in about 4 to about 5 equal parts of the total quantity. In a preferred embodiment, the present invention provides a process for preparation of compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity in a sequential manner one after another; preferably added in about 4 to about 5 parts of the total quantity in a sequential manner one after another. In a preferred embodiment, the present invention provides a process for preparation of compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 equal parts of the total quantity in a sequential manner one after another; preferably added in about 4 to about 5 equal parts of the total quantity in a sequential manner one after another. In a preferred embodiment, the present invention provides a process for preparation of compound of Formula III; wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity in a sequential manner one after another at a temperature of about 0°C to about 60°C; preferably added in about 4 to about 5 parts of the total quantity in a sequential manner one after another at a temperature of about 20°C to about 30°C. In a preferred embodiment, the present invention provides a process for preparation of compound of Formula III; wherein the compound of Formula II or a salt thereof is added in about 3 to about 10 parts of the total quantity in about 30 min to about 4 hrs; preferably added in about 4 parts of the total quantity in about 1 hr to about 2 hrs. In a preferred embodiment, the present invention provides a process for preparation of compound of Formula III; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity in about 5 min to 30 mins; preferably added in about 5 parts of the total quantity in about 10 min to about 15 mins.
In another embodiment, the present invention provides a process for preparation of compound of Formula III; wherein the total quantity of oxidizing agent is about 1.5 to about 5 equivalents to starting compound of formula IIa. In another embodiment, the present invention provides a process for preparation of compound of Formula III; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity and each part contains about 0.15 to 1.65 equivalents to starting compound of formula IIa; preferably added in about 5 parts of the total quantity and each part contains about 0.2 to 1.5 equivalents to starting compound of formula IIa. Optionally, the aforementioned oxidation step may be carried out in presence of a suitable acid, wherein the acid is selected from the group consisting of acetic acid, propanoic acid, p-toluenesulfonic acid and benzoic acid and the like and mixture thereof. The reaction of a Formula IIa or a salt thereof with a suitable oxidizing agent is carried out at a temperature of about 25°C to reflux temperature; preferably at about 25°C to about 65°C; more preferably at about 35°C to about 40°C. After completion of the reaction, the resultant compound of Formula III may be advantageously processed to next step or optionally the obtained compound of Formula III can be isolated from the reaction mass by conventional techniques such as precipitation by cooling the reaction mass, isolated by solvent extraction or precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably if isolation involves compound of Formula III can be isolated by adjusting the pH of the reaction to about less than 2.0 with a suitable acid such as hydrochloric acid, sulfuric acid and the like; preferably with sulfuric acid at a temperature of about 5°C to about 15°C and extracting the compound of Formula III with a suitable water immiscible organic solvent such as ethyl acetate, methylene chloride and the like; preferably with ethyl acetate and concentrating the product containing organic layer . The present invention provides a compound of Formula III prepared by the process described as above having a purity of at least about 95%, as measured by HPLC, preferably at least about 97% as measured by HPLC. In another embodiment, the present invention provides an improved process for the preparation of benzyl caronic amide of Formula V, comprising preparing the caronic acid
of Formula III as process just described as above, and converting the caronic acid of Formula III in to benzyl caronic amide of Formula V. In another embodiment, the present invention provides a process for preparation of compound of Formula V, comprising:
a) reacting a compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and
b) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain a compound of Formula V. The compound of Formula III, which is used herein as a starting material, can be prepared by the process as in accordance with above embodiments or any methods known in art. The step a) reaction may be carried out with a suitable solvent, wherein the suitable solvent is selected from the group consisting of but not limited to amides, sulfoxides, aromatic hydrocarbons and the like and mixtures thereof. The amides include, but are not limited to dimethylacetamide, dimethylformamide, N- methylpyrrolidone and the like and mixtures thereof; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like and mixtures thereof; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture thereof; preferably dimethyl sulfoxide, toluene, xylene and the like and mixture thereof; more preferably xylene. In another embodiment, optionally the step a) reaction may be carried without use of any solvent as mentioned above as the reactant benzyl amine is used as both reactant and solvent.
In another embodiment, the benzyl amine used in the current invention can be substituted or unsubstituted benzyl amine, wherein the substituents include but are not limited to halo such as bromo, chloro or fluoro, iodo; C1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl and the like; O-alkyl such as methoxy, ethoxy and the like; aryl such as phenyl and the like; or O-aryl such as benzyloxy and the like. Optionally the C1- 4 alkyl, aryl and O-aryl may be further substituted with a suitable substituent, which may be selected from the group comprising halogen, aryl and the like. The reaction of Formula III or salt thereof with benzyl amine is carried out at a temperature of about 50°C to reflux temperature; preferably at about 100°C to about 150°C; more preferably at about 135°C to about 145°C. After completion of the step a) reaction, the resultant compound of Formula IV may be isolated as a solid or as such reaction mass may be converted to a compound of Formula V without isolating the compound of Formula IV as solid by directly adding a suitable cyclizing agent to the step a) solution. The suitable cyclizing agent used in the step b) is selected from the group consisting of but not limited to acetic anhydride, sulfuric acid, para toluene sulfonic acid and the like and mixture thereof; preferably acetic anhydride. The cyclization reaction of step b) is carried out at a temperature of about 50°C to reflux temperature; preferably at about 100°C to about 150°C; more preferably at about 135°C to about 145°C. After completion of the step b) reaction, the resultant compound of Formula V can be isolated by conventional techniques such as precipitation by cooling the reaction mass, isolated by solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably isolated by concentrating the reaction mass under vacuum at below 80°C and followed by adding a suitable solvent such as isopropanol and then filtering the product. In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula V, comprising: a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III, wherein R is alkyl or halogen,
b) reacting the compound of Formula III or salt thereof with benzyl amine to obtain a compound of Formula IV or salt thereof, and c) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V; wherein the steps a) to c) are carried out in one-pot reaction. The aforementioned step a) to step c) are carried out in one-pot reaction by following the process as described in above embodiments of the present invention. In another embodiment, compound of Formula V obtained by the processes described as above, having purity of at least about 99% as measured by HPLC, preferably at least about 99.5% as measured by HPLC. Compound of Formula III and Formula V are key cost contributor in the preparation of certain antiviral compounds for example boceprevir and nirmatrelvir. Preparation of caronic acid of Formula III according to the prior art involves oxidation of either chrysanthemic acid ester or cypermethric acid ester in presence of potassium permanganate or ozone in acetone or a mixture of acetone and water and followed by ester hydrolysis. The oxidation process disclosed under the prior literatures suffers from forming a heterogeneous reaction mass throughout the reaction and this may be due to the use of alkyl ester intermediates in acetone or a mixture of acetone and water. Due to the heterogeneous reaction system the oxidizing agent used in the process may not be available for complete oxidation as a result additional quantities of oxidizing agent required to complete the reaction, therefore inconsistent output with low pure and lower yields. Further the oxidation at ester compound of Formula II as disclosed under the prior literature involves addition of oxidizing agent to the total quantity of starting material of Formula II in either acetone or a mixture of acetone and water. Generally oxidizing agent like potassium permanganate is having tendency with rapid reactivity with the starting material which leads to instant release of excess oxygen and high chances of sudden shoot up of reaction pressure and temperature thereby high chances of explosion. Further, the disclosed processes involves preparation of benzyl caronic amide of Formula V in two steps, which involves first cyclization of caronic acid of Formula III to form caronic anhydride followed by amide formation. The two step process disclosed under
the prior literatures not only lengthy but also requires additional step of isolation and drying process of caronic anhydride, which leads to operational inconvenience and burden on equipment occupancy. In order to overcome the difficulties associated with the prior processes, the present inventors have found that below modifications can be improved the process of getting Formula III and/or Formula V with high yields and high purity: 1) oxidation reaction may be carried out at corresponding acid compound of Formula II as a salt instead of alkyl ester as disclosed in the prior art, which process makes the reaction homogeneous thereby complete conversion of starting material without need of any excess quantity of oxidizing agent. 2) The use of acid compound of Formula II is not only advantage in making homogeneous but also avoids the necessity of ester formation and subsequent hydrolysis step, as these steps are necessary when the process utilizes alkyl ester of Formula II as a starting material, 3) Oxidation reaction may be carried out with part-wise addition of both the starting material and oxidizing agent sequentially one after another. This modification substantially reduces the chances of pressure shoot up and temperature build up in the reaction thereby there is no any safety concern, and 4) For making compound of formula V, prior literature proposes two-step process, where in which isolation of caronic anhydride as intermediate is mandatory whereas the present invention bypass the formation of caronic anhydride as intermediate therefore the present invention is advantage in commercial scale. In another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof. In another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising:
a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III or a salt thereof, and
b) reacting the compound of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI. In another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising: reacting a caronic acid of Formula III or a salt thereof with a suitable source of amine to obtain caronic amide of Formula VI.
The compound of Formula III, which is used herein as a starting material is known in the art and can be prepared by any known methods. For example, can be prepared as per the process disclosed in the above embodiments or can be prepared by following the process disclosed in WO2004/113295. Reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine may be carried out either in neat reaction or in a suitable solvent, wherein the suitable solvent is selected from the group consisting of but not limited to amides, sulfoxides, aromatic hydrocarbons and the like, water and mixtures thereof. The amides include, but are not limited to dimethylacetamide, dimethylformamide, N- methylpyrrolidone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene, diphenyl ether and the like and mixture thereof; preferably dimethyl sulfoxide, toluene, xylene, water and mixtures thereof; more preferably xylene, water and mixtures thereof. The source of amine is selected from the group consisting of but not limited to urea, ammonia, formamide and the like and mixtures thereof.
Optionally reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine may be carried out in presence of a suitable catalyst, wherein the suitable catalyst is selected from the group consisting of but not limited to 1,8-Diazabicyclo[5.4.0]undec- 7-ene (DBU), triethylamine, trimethylamine, dimethylamine, diethylamine, dibenzoyl peroxide, toluene-4-sulfonic acid, hydrogen peroxide, pyridine, dimethylaminopyridine, acetic acid, tetrabutyl ammonium bromide, azobisisobutyronitrile, copper(I)/DBU catalyst, copper(II) acetate, copper(I) bromide, iron(III) acetylacetonate, ruthenium based catalysts, molecular sieves, tetra methyl guanidine, 7-methyl-1,5,7- triazabicyclo[4.4.0]dec-5-ene, triazabicyclo[4.4.0]dec-5-ene, 1,5-diazabicyclo[4.3.0] non-5-ene, proton sponge, 1,4-diazabicyclo[2.2.2]octane/tri ethylene diamine and the like and mixture thereof; preferably 1,8-Diazabicyclo[5.4.0]undec-7-ene, triethylamine, dimethylamine, pyridine, dimethylaminopyridine and mixture thereof; more preferably 8-Diazabicyclo[5.4.0]undec-7-ene, triethylamine, dimethylaminopyridine and mixture thereof. In another embodiment, the reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine is carried out in presence of a suitable catalyst. In another embodiment, the reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine is carried out in presence of a suitable catalyst and a suitable solvent. In another embodiment, the reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine is carried out in presence of a suitable solvent. The reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine is carried out at a temperature of about 50°C to about 200°C; preferably at about 100°C to about 150°C; more preferably at about 135°C to about 145°C. Then the compound of Formula VI may be isolated from the reaction mass by conventional techniques such as solvent extraction, solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably isolated by cooling the reaction mass and filtering the solids. In another embodiment, preparation of caronic amide of Formula VI or a salt thereof by reaction of caronic acid of Formula III or a salt thereof with a suitable source of amine is
always possibility to formation of mono amide and/or diamide impurities along with unreacted starting material and these impurities mostly separated through the mother liquors. The mono amide and diamide impurities specifically represents as following compounds:
The present inventors have surprisingly found that the mother liquors which contain unwanted impurities such as unreacted caronic acid and/or mono amide and/or diamide impurities are utilized as solvent source for the additional batches of the process of the above embodiments. The reuse of mother liquors as solvent source is advantageously increases the overall product yield as the unwanted impurities accumulated in the mother liquors are converted into compound of Formula VI in each batch of the process. In another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising reacting a caronic acid of Formula III or a salt thereof with a suitable source of amine and mother liquors containing unwanted impurities selected from unreacted caronic acid and/or mono amide and/or diamide impurities obtained from the above embodiments. In another embodiment, the present invention provides a process for preparation of caronic amide of Formula VI or a salt thereof, comprising reacting a caronic acid of Formula III or a salt thereof with a suitable source of amine and mother liquors containing unwanted impurities selected from unreacted caronic acid and/or mono amide and/or diamide impurities obtained from the above embodiments; wherein the source of amine, reaction temperature and other process conditions are same as the process as described just as above. The present invention provides a compound of Formula VI or a salt thereof prepared by the process described as above having a purity of at least about 97%, as measured by HPLC, preferably at least about 99% as measured by HPLC; and having less than 0.5%,
preferably less than 0.2% each of unreacted starting material caronic acid and/or mono amide and/or diamide impurities as measured by HPLC. In another embodiment, the caronic amide of Formula VI or a salt thereof prepared by the process of the present invention or prepared by any other processes is further purified to remove impurities such as mono amide and/or diamide impurities along with unreacted starting material by solvent purification. In another embodiment, the present invention provides a process for purification of caronic amide of Formula VI or a salt thereof, comprising:
a) suspending or dissolving caronic amide of Formula VI or a salt thereof in a suitable solvent at a suitable temperature, and b) isolating the pure caronic amide of Formula VI or a salt thereof. The step a) process may be involve suspending or dissolving a compound of Formula VI having unreacted caronic acid and/or mono amide and/or diamide impurities more than 0.5% by HPLC in a suitable solvent at a temperature of about ambient temperature to reflux temperature; preferably at about 50°C to about 60°C. The suitable solvent used to suspend or dissolve compound of Formula VI having about more than 0.5% unreacted caronic acid and/or mono amide and/or diamide impurities by HPLC is selected from the group consisting of but is not limited to esters, ethers, ketones, nitriles, halogenated hydrocarbons, aliphatic or alicyclic hydrocarbons, aromatic hydrocarbons and the like, water and mixtures thereof. The esters include, but are not limited to ethyl acetate, methyl acetate and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aliphatic or alicyclic hydrocarbons include, but are not limited to hexane, heptane, pentane, cyclohexane,
cycloheptane, cyclopentane and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture thereof; preferably ethyl acetate, acetonitrile, water and mixture thereof; more preferably water. Then the pure compound of Formula VI having unreacted caronic acid and/or mono amide and/or diamide impurities less than 0.5% by HPLC may be isolated from the reaction mass by conventional techniques such as solvent extraction, solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably isolated by cooling the reaction mass and filtering the solids. In another embodiment, the compound of Formula VI obtained by the processes described as above, having purity of at least about 99% as measured by HPLC, preferably at least about 99.5% as measured by HPLC and less than 0.5%, preferably less than 0.2% as measured by HPLC of each of unreacted starting material caronic acid and/or mono amide and/or diamide impurities. Compound of Formula VI is the key cost contributor in the preparation of certain antiviral compounds for example boceprevir and nirmatrelvir. The disclosed processes involve preparation of caronic amide of Formula VI in three steps, which involves first cyclization of caronic acid of Formula III to form caronic anhydride, amide formation to obtain protected caronic amide and followed by de-protection. These three step process disclosed under the prior literatures not only lengthy but also requires additional step of isolation and drying process of caronic anhydride and protected caronic amide, which leads to operational inconvenience and burden on equipment occupancy. The present invention encompasses an improved process for the preparation of compound of Formula VI with high yields and high purity by direct reaction of caronic acid of Formula III with a source of amine, without involving formation of caronic anhydride, protected caronic amide and subsequent deprotection steps using hazardous deprotecting agents. The term "catalyst" as used in this application means a substance that increases reaction rate by altering the reaction mechanism.
The term "Neat reaction" as used in this application means a step forward in the direction of solvent free reactions and an alternative approach that eliminates the use of a solid support as well as solvent from the reaction. The term "one-pot" as used in this application means a process uses a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one solvent/reactor. This is much desired by chemists because avoiding a lengthy separation process and purification of the intermediate chemical compounds can save time and resources, improves the efficiency of a chemical reaction, and offers better chemical yield. The present invention encompasses an improved process for the preparation of intermediates of azabicyclo [3.1.0] hexane of Formula I with high product yield and quality by the following scheme:
In accordance with another embodiment, the present invention provides an improved process for the preparation of compound of Formula I, comprising preparing the compound of Formula V and/or compound of Formula VI as process described above, and converting the compound of Formula V and/or compound of Formula VI in to compound of Formula I by any process known in the art for example WO2004/113295, CN101020680A, CN101863866B, WO2007/075790, WO2010/08828, WO2012/049688 and WO2014/061034.
In accordance with another embodiment, the present invention provides use of compound of Formula V and/or compound of Formula VI prepared as process described above, as an intermediate in the preparation of certain antiviral compounds for example boceprevir or nirmatrelvir. EXAMPLES The following non-limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way. EXAMPLE-1: Preparation of compound of Formula III (addition of both Formula IIa and oxidizing agent - in part wise one after another sequentially) Compound of Formula IIa (100 g), water (500 mL) were added in to a round bottom flask at 20-30°C. To the reaction mass was added aqueous sodium hydroxide (26 mL) at 20- 30°C and stir for 10 min at same temperature. Then the solution was divided in to 4 equivalent parts and kept a side (4×150 mL). In another round bottom flask was added water (500 mL) and first part of potassium permanganate (37.8 g) at 20-30°C and stir for 10 min. To the reaction mass was added first part of solution of Formula IIa (150 mL) for a period of 1.5 to 2 hrs at 20-30°C. To the reaction mass was added second part of potassium permanganate (37.8 g) at 20-30°C and followed by addition of second part of solution of Formula IIa (150 mL) for a period of 1.5 to 2 hrs at same temperature and repeat the addition of potassium permanganate and Formula IIa in another three lots at same temperature. Reaction mass was heated to 35-40°C and stir for 2-4 hrs at same temperature. After completion of the reaction by TLC, cool the reaction mass to 10°C and was added sodium metabisulfite solution at below 30°C and stir for 60 min at same temperature. Reaction mass pH was adjusted to less than 2.0 with sulphuric acid (187 g) and stir for 60 min. To the reaction mass was added ethyl acetate (600 mL), filtered and washed the wet cake with water (100 mL). Then the product containing organic layer was separated and concentrated under vacuum at below 55°C. To the obtained solid was added water (100 mL) and cool to 5°C and stir for 2-3 hrs at same temperature. Filtered the solids and washed the wet cake with chilled water and dry the wet material at 60-70°C to obtain title compound. Wt.: 70 g. Purity by HPLC: 99%.
Note: Each lot of potassium permanganate addition is slightly exothermic; the Maximum Temperature of the Synthesis Reaction (MTSR) during KMnO4 lots addition in worst case is 28ºC. Oxygen gas liberation observed during KMnO4 lots addition at 25ºC and digestion at 38ºC with peak gas flow rate of 4.75L/min/kg was observed. EXAMPLE-2: Preparation of compound of Formula V Compound of Formula III (100 g), o-xylene (400 mL) were added in to a round bottom flask with dean stark condenser at 20-30°C. Reaction mass heated to 135-140°C and was added benzyl amine solution (68 g was dissolved in 100 mL o-xylene) in 3-4 hrs at same temperature. Reaction mass was stir for 2-3 hrs at 140-145°C (water was collected by azeotropically). Reaction mass was allowed to cool to 30-35°C and was added acetic anhydride (13 g) at same temperature. Reaction mass was heated to 140-145°C and stir for 2-3 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80°C and concentrated under vacuum and co-distilled with isopropyl alcohol (100 mL) at below 80°C. To the obtained residue was added isopropyl alcohol (150 mL) at 25-30°C and stir for 2-3 hrs at same temperature. Reaction mass was cool to 0-5°C, filtered the solids and washed the wet cake with chilled isopropyl alcohol (100 mL) and dry the wet material at 60-65°C to obtain title compound. Wt.: 120 g. Purity by HPLC: 99.5%. EXAMPLE-3: One pot process of compound of Formula V Compound of Formula IIa (100 g), water (500 mL) were added in to a round bottom flask at 20-30°C. To the reaction mass was added aqueous sodium hydroxide (26 mL) at 20- 30°C and stir for 10 min at same temperature. Then the solution was divided in to 4 equivalent parts and kept a side (4×150 mL). In another round bottom flask was added water (500 mL) and first part of potassium permanganate (37.8 g) at 20-30°C and stir for 10 min. To the reaction mass was added first part of solution of Formula IIa (150 mL) for a period of 1.5 to 2 hrs at 20-30°C. To the reaction mass was added second part of potassium permanganate (37.8 g) at 20-30°C and followed by addition of second part of solution of Formula IIa (150 mL) for a period of 1.5 to 2 hrs at same temperature and repeat the addition of potassium permanganate and Formula IIa in another three lots at same temperature. To the reaction mass was added third part of potassium permanganate (37.8 g) at 20-30°C and followed by addition of third part of solution of Formula IIa (150 mL) for a period of 1.5 to 2 hrs at same temperature. To the reaction mass was added fourth part of potassium permanganate (37.8 g) at 20-30°C and followed by addition of
fourth part of solution of Formula IIa (150 mL) for a period of 1.5 to 2 hrs at same temperature. To the reaction mass was added fifth part of potassium permanganate (37.8 g) at 20-30°C and stir for 1-2 hrs at same temperature. Reaction mass was heated to 35- 40°C and stir for 2-4 hrs at same temperature. After completion of the reaction by TLC, cool the reaction mass to 10°C and was added sodium metabisulfite solution at below 30°C and stir for 60 min at same temperature. Reaction mass pH was adjusted to below 2.0 with sulphuric acid (187 g) at below 30°C and stir for 60 min at same temperature. To the reaction mass was added ethyl acetate (600 mL), filtered and washed the wet cake with water (100 mL). Then the product containing organic layer was separated and concentrated under vacuum at below 55°C. To the reaction mass was added o-xylene (400 mL) and transferred into a round bottom flask with dean stark condenser at 20-30°C. Reaction mass was heated to 135-140°C and was added benzyl amine solution (68 g in 100 mL o-xylene) in 3-4 hrs at same temperature. Reaction mass was stirred for 2-3 hrs at 140-145°C (19-20 mL of water was collected by azeotropically). Reaction mass was allowed to cool to 30-35°C and was added acetic anhydride (13 g) at same temperature. Reaction mass was heated to 140-145°C and stir for 2-3 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80°C and concentrated under vacuum and co-distilled with isopropyl alcohol (100 mL) at below 80°C. To the obtained residue was added isopropyl alcohol (150 mL) at 25-30°C and stir for 2-3 hrs at same temperature. Reaction mass was cool to 0-5°C, filtered the solids and washed the wet cake with chilled isopropyl alcohol (100 mL) and dry the wet material at 60-65°C to obtain title compound. Wt.: 124 g. Purity by HPLC: 99.2%. EXAMPLE-4: Preparation of compound of Formula III (from ethyl ester of compound of Formula II) Water (250 mL) was added in to a round bottom flask and heated to at 50-55°C. To the reaction mass was added potassium permanganate (20×3.14 g) and compound of Formula II ethyl ester (20×1.41 g) in part wise one after another sequentially at 50-55°C (observed heterogeneous reaction mass). After 2 hr of stirring, reaction was not completed by TLC. To the reaction mass was added additional potassium permanganate (2×9.4 g) and stirred for 1 hr. The heterogeneous reaction mass was allowed to cool to 10°C and was added sodium metabisulfite solution at below 30°C and stir for 60 min at same temperature. To the reaction mass was added sulphuric acid (94.5 g) at below 30°C and stir for 60 min at same temperature. To the heterogeneous reaction mass was added toluene (55 mL) and
stir for 10 min at 30°C. Then the product containing organic layer was separated and concentrated under vacuum at below 65°C. The obtained residue was cool to 10°C and was added sodium hydroxide solution (22.5 g dissolved in 75 mL water) at same temperature. Reaction mass was heated to 50°C and stir for 2 hr at same temperature. After completion of the reaction, reaction mass was cool to 10°C and pH was adjusted to 1.0-2.0 with HCl (43 mL) and stir for 10 min at same temperature. Then the product was extracted with ethyl acetate (2×85 mL) and concentrated to obtain the title compound. Wt.: 8.1 g. Purity by HPLC: 92.1%. EXAMPLE-5: Preparation of compound of Formula III (from ethyl ester of compound of Formula II) Water (300 mL) and acetone (75 mL) was added in to a round bottom flask and heated to at 25-30°C. To the reaction mass was added potassium permanganate (128.5 g) at 25- 30°C and stir for 10 min at same temperature. To the reaction mass was added slowly compound of Formula II ethyl ester (56.5 g) in 7-8 hr at 25-30°C (observed heterogeneous reaction mass). Reaction mass was heated to 35-40°C. After 4 hr of stirring, reaction was not completed by TLC. To the reaction mass was added potassium permanganate (2×7.6 g) and stir for 1 hr. The heterogeneous reaction mass was allowed to cool to 10°C and was added sodium metabisulfite solution at below 30°C and stir for 60 min at same temperature. To the reaction mass was added sulphuric acid (189 g) at below 30°C and stir for 60 min at same temperature. To the heterogeneous reaction mass was added toluene (220 mL) and stir for 10 min at 30°C. Then the product containing organic layer was separated and concentrated under vacuum at below 65°C. The obtained residue was cool to 10°C and was added sodium hydroxide solution (45 g dissolved in 150 mL water) at same temperature. Reaction mass was heated to 50°C and stir for 2 hr at same temperature. After completion of the reaction, reaction mass was cool to 10°C and pH was adjusted to 1.0-2.0 with HCl (85 mL) and stir for 10 min at same temperature. Then the product was extracted with ethyl acetate (2×300 mL) and concentrated to obtain the title compound. Wt.: 20.5 g. Purity by HPLC: 93.5%. EXAMPLE-6: Preparation of compound of Formula VI Compound of Formula III (100 g), Urea (43.7 g) and water (200 mL) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 135-145°C and stir for 2-3 hrs at same temperature. Reaction mass was cool to 70-75°C and was added 1,8-
diazabicyclo[5.4.0]undec-7-ene (10 g) at same temperature. Reaction mass was heated to 135-145°C and stir for 3-4 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added water (200 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 86 g. Purity by HPLC: 99.8%; Formula III by HPLC: Not detected; mono amide by HPLC: 0.1% and di amide by HPLC: 0.05%. EXAMPLE-7: Preparation of compound of Formula VI Compound of Formula III (100 g), Urea (43.7 g) and water (200 mL) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 135-145°C and stir for 24 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80- 85°C and was added water (200 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 79 g. Purity by HPLC: 99.7%; Formula III by HPLC: Not detected; mono amide by HPLC: 0.13% and di amide by HPLC: 0.06%. Taken mother liquors and tested for content of purity and impurity and the results are as follows: Formula VI by HPLC: 59.31%, Formula III by HPLC: 8.7%; mono amide by HPLC: 27.9% and di amide by HPLC: 3.7%. EXAMPLE-7a: Compound of Formula III (100 g), Urea (43.7 g) and mother liquors (200 mL) obtained from Ex-2 were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 135-145°C and stir for 24 hrs at same temperature. After completion of the reaction, reaction mass was allowed to cool to 80-85°C and was added water (200 mL) and stir for 30 min at same temperature. Then, reaction mass was further allowed to cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 84 g. Purity by HPLC: 99.62%; Formula III by HPLC: 0.08%; mono amide by HPLC: 0.25% and di amide by HPLC: 0.05%.
Taken mother liquors and tested for content of purity and impurity and the results are as follows: Formula VI by HPLC: 77.03%, Formula III by HPLC: 9.76%; mono amide by HPLC: 9.7% and di amide by HPLC: 2.98%. EXAMPLE-7b: Compound of Formula III (100 g), Urea (43.7 g) and mother liquors (200 mL) obtained from Ex-2a were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 135-145°C and stir for 24 hrs at same temperature. After completion of the reaction, reaction mass was allowed to cool to 80-85°C and was added water (200 mL) and stir for 30 min at same temperature. Then, reaction mass was further allowed to cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 87 g. Purity by HPLC: 99.5%; Formula III by HPLC: 0.26%; mono amide by HPLC: 0.55% and di amide by HPLC: 0.12%. Taken mother liquors and tested for content of purity and impurity and the results are as follows: Formula VI by HPLC: 67.23%, Formula III by HPLC: 9.46%; mono amide by HPLC: 18.9% and di amide by HPLC: 3.83%. EXAMPLE-8: Preparation of compound of Formula VI Compound of Formula III (10 g) and Urea (4.3 g) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 135-145°C and collected the water during the heating and stir for 12 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added water (15 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 2 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (5 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 83 g. Purity by HPLC: 99.9%; Formula III by HPLC: 0.1%; mono amide by HPLC: 0.02% and di amide by HPLC: 0.03%. EXAMPLE-9: Preparation of compound of Formula VI Compound of Formula III (50 g) and ammonia solution (150 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 160-165°C and collected the water during the heating and stir for 8-9 hrs at same temperature. After completion of the
reaction, reaction mass was cool to 80-85°C and was added a mixture of cyclohexane and water (100 mL) and stir for 15 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled a mixture of cyclohexane and water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 83 g. Purity by HPLC: 99.4%; Formula III by HPLC: 0.5%; mono amide by HPLC: 0.1% and di amide by HPLC: 0.02%. EXAMPLE-10: Preparation of compound of Formula VI Compound of Formula III (10 g), Formamide (3.7 mL) and 4-Dimethylaminopyridine (0.7 g) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 135-145°C and collected the water during the heating and stirred for 20 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added water (15 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 2 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (5 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 7.9 g. Purity by HPLC: 99.6%; Formula III by HPLC: 0.06%; mono amide by HPLC: 0.13% and di amide by HPLC: 0.01%. EXAMPLE-11: Preparation of compound of Formula VI Compound of Formula III (50 g), Urea (21.8 g) and O-xylene (50 mL) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 130-140°C and collected the water during the heating and stirred for 24 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added water (150 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 2 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (25 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 39.5 g. Purity by HPLC: 99.8%; Formula III by HPLC: Not detected; mono amide by HPLC: 0.04% and di amide by HPLC: 0.2%. EXAMPLE-12: Preparation of compound of Formula VI Compound of Formula II (10 g), Urea (4.36 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 eq) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 130-140°C and stir for 4-8 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added water (20 mL) and stir for 30 min at
same temperature. Then, reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (5 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 7.4 g. EXAMPLE-13: Preparation of compound of Formula VI Compound of Formula III (10 g), Urea (4.36 g) and triethylamine (0.1 eq) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 130-140°C and stir for 4-8 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added water (20 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (5 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 7.1 g. EXAMPLE-14: Preparation of compound of Formula VI Compound of Formula III (100 g), Urea (43.7 g) and triethylamine (70 gr) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 80-90°C and stir for 2- 3 hrs. Reaction mass was heated to 135-145°C and stir for 4-6 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added water (200 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 86 g. Purity by HPLC: 99.8%; Formula III by HPLC: Not detected; mono amide by HPLC: 0.1% and di amide by HPLC: 0.05%. EXAMPLE-15: Purification of compound of Formula VI Compound of Formula VI (20 g; HPLC Purity: 97.5%; Formula III by HPLC: 0.9%; mono amide by HPLC: 0.5% and di amide by HPLC: 0.4%) and water (40 mL) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 50-60°C and stir for 2 hrs at same temperature. Reaction mass was cool to 25-30°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with water (10 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 39.5 g. Purity by HPLC: 99.9%; Formula III by HPLC: Not detected; mono amide by HPLC: 0.05% and di amide by HPLC: 0.05%.
EXAMPLE-16: Preparation of compound of Formula VI Compound of Formula III (50 g), Urea (21.8 g) and mother liquors obtained from Ex-10; 100 mL) were added in to a round bottom flask at 25-30°C. Reaction mass was heated to 135-145°C and stir for 10-12 hrs at same temperature. After completion of the reaction, reaction mass was cool to 80-85°C and was added water (100 mL) and stir for 30 min at same temperature. Then, reaction mass was further cool to 25-35°C and stir for 4 hr at same temperature. Filtered the solids and washed the wet cake with chilled water (50 mL) and dry the wet material at 55-60°C to obtain title compound. Wt.: 41 g. Purity by HPLC: 99.6%; Formula III by HPLC: 0.15%; mono amide by HPLC: 0.1% and di amide by HPLC: 0.1%. It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.
Claims
WE CLAIM: 1. A process for preparation of compound of Formula V, comprising:
a) reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III,
b) reacting the compound of Formula III or a salt thereof with benzyl amine to obtain a compound of Formula IV or a salt thereof, and
c) cyclizing the compound of Formula IV or a salt thereof in presence of a suitable cyclizing agent to obtain compound of Formula V.
2. The process as claimed in claim 1, wherein R represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, bromo, chloro or Iodo.
3. The process as claimed in claim 1, wherein the suitable oxidizing agent is selected from the group comprising bromine, hydrogen peroxide, Potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate, sodium monopersulfate, potassium permanganate, sodium permanganate and mixture thereof.
5. The process as claimed in claim 1, wherein the oxidizing agent is potassium permanganate.
6. The process as claimed in claim 1, wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity.
7. The process as claimed in claim 1, wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity in a sequential manner one after another.
8. The process as claimed in claim 1, wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 3 to about 10 parts of the total quantity in a sequential manner one after another at a temperature of about 20°C to about 30°C.
9. The process as claimed in claim 6, wherein both the compound of Formula II or a salt thereof and the oxidizing agent are added in about 4 to about 5 equal parts of the total quantity.
10. The process as claimed in claim 1, wherein the step a) reaction is carried out at a temperature of about 35°C to about 40°C.
11. The process as claimed in claim 1, wherein the step a) is carried out in presence of a base and a solvent.
12. The process as claimed in claim 11, wherein the base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium-butoxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, triethyl amine, diisopropyl ethyl amine and mixtures thereof; and
wherein the solvent is selected from tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane; ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate; ketones include but are not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform; aprotic organic solvent, include but are not limited to N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, l,3-dimethyl-2-imidazolidinone, acetonitrile; water and mixture thereof.
13. The process as claimed in claim 12, wherein the base is sodium hydroxide and the solvent is water.
14. The process as claimed in claim 1, wherein the suitable cyclizing agent is selected from the group comprising acetic anhydride, sulfuric acid, para toluene sulfonic acid and mixture thereof.
15. The process as claimed in claim 1, wherein the step b) is carried out in a suitable solvent; wherein the suitable solvent is selected from the group comprising dimethylacetamide, dimethylformamide, N- methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, toluene, xylene and mixture thereof.
16. The process as claimed in claim 1, wherein the suitable cyclizing agent is acetic anhydride.
17. The process as claimed in claim 1, wherein the step b) and step c) are carried out at a temperature of about 135°C to about 145°C.
18. The process as claimed in claim 1, wherein the steps a) to c) are carried out in one- pot reaction.
19. A process for preparation of compound of Formula V, comprising:
Formula V a) reacting a compound of Formula III or salt thereof with benzamine to obtain a compound of Formula IV or salt thereof, and
b) cyclizing the compound of Formula IV or salt thereof in presence of a suitable cyclizing agent to obtain a compound of Formula V.
20. The process as claimed in claim 19, wherein the suitable cyclizing agent is selected from the group comprising acetic anhydride, sulfuric acid, para toluene sulfonic acid and mixture thereof.
21. The process as claimed in claim 19, wherein the step a) is carried out in a suitable solvent; wherein the suitable solvent is selected from the group comprising dimethylacetamide, dimethylformamide, N- methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, toluene, xylene and mixture thereof.
22. The process as claimed in claim 20, wherein the cyclizing agent is acetic anhydride.
23. The process as claimed in claim 21, wherein the solvent is xylene.
24. The process as claimed in claim 19, wherein the steps a) and b) are carried out in one-pot reaction.
25. The process as claimed in claim 19, wherein the step a) and step b) are carried out at a temperature of about 135°C to about 145°C.
27. The process as claimed in claim 26, wherein the suitable source of amine is selected from the group comprising urea, ammonia, formamide and mixtures thereof.
28. The process as claimed in claim 26, wherein the reaction is carried out in presence of a suitable catalyst selected from the group comprising 1,8- Diazabicyclo[5.4.0]undec-7-ene, triethylamine, trimethylamine, dimethylamine, diethylamine, dibenzoyl peroxide, toluene-4-sulfonic acid, hydrogen peroxide, pyridine, dimethylaminopyridine, acetic acid, tetrabutyl ammonium bromide, azobisisobutyronitrile, copper(I)/DBU catalyst, copper(II) acetate, copper(I) bromide, iron(III) acetylacetonate, ruthenium based catalysts, molecular sieves, tetra methyl guanidine, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, triazabicyclo[4.4.0]dec-5-ene, 1,5-diazabicyclo[4.3.0] non-5-ene, proton sponge, 1,4-diazabicyclo[2.2.2]octane/tri ethylene diamine and mixture thereof.
29. The process as claimed in claim 28, wherein the suitable catalyst is 1,8- Diazabicyclo[5.4.0]undec-7-ene, triethylamine, dimethylaminopyridine and mixture thereof.
30. The process as claimed in claim 26, wherein the reaction is carried out in a suitable solvent; wherein the solvent is selected from amides, sulfoxides, aromatic hydrocarbons, water and mixtures thereof.
31. The process as claimed in claim 30, wherein the solvent is selected from the group comprising dimethylacetamide, dimethylformamide, N- methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, toluene, xylene, diphenyl ether and mixture thereof.
32. The process as claimed in claim 30, wherein the solvent is xylene, water and mixtures thereof.
33. The process as claimed in claim 26, wherein the step b) is carried out at a temperature of about 100°C to about 150°C.
35. The process as claimed in claim 34, wherein the solvent is selected from the group comprising dimethylacetamide, dimethylformamide, N- methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, toluene, xylene, diphenyl ether and mixture thereof.
36. The process as claimed in claim 34, wherein the suitable source of amine is selected from the group comprising urea, ammonia, formamide and mixtures thereof.
37. A process for purification of caronic amide of Formula VI or a salt thereof, comprising: a) suspending or dissolving caronic amide of Formula VI or a salt thereof in a suitable solvent at a suitable temperature, and b) isolating the pure caronic amide of Formula VI or a salt thereof.
38. The process as claimed in claim 37, wherein the suitable solvent is selected from the group comprising ethyl acetate, methyl acetate, tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, propionitrile, methylene chloride, ethylene chloride, chloroform, hexane, heptane, pentane, cyclohexane, cycloheptane, cyclopentane, toluene, xylene, and water and mixture thereof.
39. The process as claimed in claim 38, wherein the suitable solvent is ethyl acetate, acetonitrile, water or mixtures thereof.
40. The process as claimed in claim 38, wherein the step a) is carried out at a temperature of about 50°C to about 60°C.
41. A process for preparation of compound of Formula III or a salt thereof, comprising: reacting a compound of Formula II or a salt thereof with a suitable oxidizing agent to obtain a compound of Formula III.
42. The process as claimed in claim 41, wherein the R is selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, bromo, chloro or Iodo. 43. The process as claimed in claim 41, wherein the suitable oxidizing agent is selected from the group comprising bromine, hydrogen peroxide, Potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate, sodium monopersulfate, potassium permanganate, sdoium permanganate and mixture thereof. 44. The process as claimed in claim 41, wherein the R is chloro and wherein the suitable oxidizing agent is potassium permanganate. 45. The process as claimed in claim 41, wherein the reaction is carried out at a temperature of about 35°C to about 40°C. 46. A process for preparation of nirmatrelvir or boceprevir, comprising: preparing the compound of Formula III, compound of Formula V and /or compound of Formula VI according to claims-1 to 45; and converting the compound of Formula III, compound of Formula V and /or compound of Formula VI into nirmatrelvir or boceprevir.
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WO2004113295A1 (en) * | 2003-06-17 | 2004-12-29 | Schering Corporation | Process and intermediates for the preparation of (1r,2s,5s)-6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylates or salts thereof |
WO2007075790A1 (en) * | 2005-12-22 | 2007-07-05 | Schering Corporation | Process for the preparation of 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds and enantiomeric salts thereof |
CN104163759A (en) * | 2011-08-24 | 2014-11-26 | 南通雅本化学有限公司 | New synthesis methods of caronic acid and caronic anhydride |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2004113295A1 (en) * | 2003-06-17 | 2004-12-29 | Schering Corporation | Process and intermediates for the preparation of (1r,2s,5s)-6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylates or salts thereof |
WO2007075790A1 (en) * | 2005-12-22 | 2007-07-05 | Schering Corporation | Process for the preparation of 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds and enantiomeric salts thereof |
CN104163759A (en) * | 2011-08-24 | 2014-11-26 | 南通雅本化学有限公司 | New synthesis methods of caronic acid and caronic anhydride |
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