EP3110795A1 - Novel economic process for vildagliptin - Google Patents
Novel economic process for vildagliptinInfo
- Publication number
- EP3110795A1 EP3110795A1 EP15754784.5A EP15754784A EP3110795A1 EP 3110795 A1 EP3110795 A1 EP 3110795A1 EP 15754784 A EP15754784 A EP 15754784A EP 3110795 A1 EP3110795 A1 EP 3110795A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- acid
- group
- process according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 58
- 230000008569 process Effects 0.000 title claims abstract description 49
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 title claims abstract description 39
- 229960001254 vildagliptin Drugs 0.000 title claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims description 135
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 133
- 150000001875 compounds Chemical class 0.000 claims description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 84
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 51
- 239000002904 solvent Substances 0.000 claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 44
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 16
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- 229910021529 ammonia Inorganic materials 0.000 claims description 13
- 239000012024 dehydrating agents Substances 0.000 claims description 13
- 150000002367 halogens Chemical group 0.000 claims description 13
- 229940086542 triethylamine Drugs 0.000 claims description 13
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 239000000654 additive Substances 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 claims description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 9
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 claims description 9
- 235000011054 acetic acid Nutrition 0.000 claims description 9
- 239000012535 impurity Substances 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
- 229910052710 silicon Inorganic materials 0.000 claims description 7
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 6
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 235000015165 citric acid Nutrition 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 238000011065 in-situ storage Methods 0.000 claims description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-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
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 4
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- KZVLNAGYSAKYMG-UHFFFAOYSA-N pyridine-2-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=N1 KZVLNAGYSAKYMG-UHFFFAOYSA-N 0.000 claims description 4
- NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 3
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 3
- 229930182821 L-proline Natural products 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 239000000908 ammonium hydroxide Substances 0.000 claims description 3
- 229940117389 dichlorobenzene Drugs 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 229960002429 proline Drugs 0.000 claims description 3
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- UJZBSAONPRVEIJ-UHFFFAOYSA-N 2,2,2-trifluoroethyl carbonochloridate Chemical compound FC(F)(F)COC(Cl)=O UJZBSAONPRVEIJ-UHFFFAOYSA-N 0.000 claims description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 241000723346 Cinnamomum camphora Species 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 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
- 239000004280 Sodium formate Substances 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Inorganic materials [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 229960000846 camphor Drugs 0.000 claims description 2
- 229930008380 camphor Natural products 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000003444 phase transfer catalyst Substances 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- FKXLDNQJUBQUIY-UHFFFAOYSA-N N1C=NC=C1.N12CCCN=C2CCC1 Chemical compound N1C=NC=C1.N12CCCN=C2CCC1 FKXLDNQJUBQUIY-UHFFFAOYSA-N 0.000 claims 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 claims 2
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 35
- 239000010410 layer Substances 0.000 description 32
- 239000000243 solution Substances 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- 235000019439 ethyl acetate Nutrition 0.000 description 27
- 239000012043 crude product Substances 0.000 description 19
- 238000004809 thin layer chromatography Methods 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 238000010992 reflux Methods 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 10
- 230000018044 dehydration Effects 0.000 description 9
- 238000006297 dehydration reaction Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- -1 3-hydroxy-l-adamantyl Chemical group 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- IUJJPEBUSBVYIP-FBXIQOIYSA-N (2s)-1-[2-[(3-hydroxy-1-adamantyl)amino]acetyl]pyrrolidine-2-carboxamide Chemical compound NC(=O)[C@@H]1CCCN1C(=O)CNC1(C2)CC(O)(C3)CC2CC3C1 IUJJPEBUSBVYIP-FBXIQOIYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZWFIQWGKGUOCHX-JPVBRBBMSA-N COC(=O)[C@H]1N(CCC1)C(CNC12CC3(CC(CC(C1)C3)C2)O)=O Chemical compound COC(=O)[C@H]1N(CCC1)C(CNC12CC3(CC(CC(C1)C3)C2)O)=O ZWFIQWGKGUOCHX-JPVBRBBMSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000004296 chiral HPLC Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 210000003739 neck Anatomy 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- FSZTVAMKEHAGGP-UHFFFAOYSA-N 2-[(3-hydroxy-1-adamantyl)amino]acetic acid Chemical compound C1C(C2)CC3CC2(O)CC1(NCC(=O)O)C3 FSZTVAMKEHAGGP-UHFFFAOYSA-N 0.000 description 3
- ILOBSLACVDHHLE-UHFFFAOYSA-N 3-(benzylamino)adamantan-1-ol Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC1=CC=CC=C1 ILOBSLACVDHHLE-UHFFFAOYSA-N 0.000 description 3
- DWPIPTNBOVJYAD-UHFFFAOYSA-N 3-aminoadamantan-1-ol Chemical compound C1C(C2)CC3CC1(N)CC2(O)C3 DWPIPTNBOVJYAD-UHFFFAOYSA-N 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- YYUKRFPRBNDTQF-LURJTMIESA-N methyl (2s)-1-(2-chloroacetyl)pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1C(=O)CCl YYUKRFPRBNDTQF-LURJTMIESA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- NDGYOVVMRWXIHB-XZDGRMCRSA-N tert-butyl N-[2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]-N-(3-hydroxy-1-adamantyl)carbamate Chemical compound C(C)(C)(C)OC(N(C12CC3(CC(CC(C1)C3)C2)O)CC(=O)N2[C@@H](CCC2)C#N)=O NDGYOVVMRWXIHB-XZDGRMCRSA-N 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- SKLSSRXCKJINHO-YFKPBYRVSA-N (2s)-n-(2-chloroacetyl)pyrrolidine-2-carboxamide Chemical compound ClCC(=O)NC(=O)[C@@H]1CCCN1 SKLSSRXCKJINHO-YFKPBYRVSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HQEXJDIJALSAJV-UHFFFAOYSA-N C(C)OC(CN(C12CC3(CC(CC(C1)C3)C2)O)CC2=CC=CC=C2)=O Chemical compound C(C)OC(CN(C12CC3(CC(CC(C1)C3)C2)O)CC2=CC=CC=C2)=O HQEXJDIJALSAJV-UHFFFAOYSA-N 0.000 description 2
- XTSJVQRQDIHMME-UHFFFAOYSA-N C(C1=CC=CC=C1)N(C12CC3(CC(CC(C1)C3)C2)O)CC(=O)O Chemical compound C(C1=CC=CC=C1)N(C12CC3(CC(CC(C1)C3)C2)O)CC(=O)O XTSJVQRQDIHMME-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- PVICRJVBAUWNQK-UHFFFAOYSA-N OC12CC3(CC(CC(C1)C3)C2)NCC#N Chemical compound OC12CC3(CC(CC(C1)C3)C2)NCC#N PVICRJVBAUWNQK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229960003805 amantadine Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000002027 dichloromethane extract Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- ZFSLODLOARCGLH-UHFFFAOYSA-N isocyanuric acid Chemical compound OC1=NC(O)=NC(O)=N1 ZFSLODLOARCGLH-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BHRSEPVINGDQAC-LGABGLQWSA-N methyl (2S)-1-[2-[(3-hydroxy-1-adamantyl)-[(2-methylpropan-2-yl)oxycarbonyl]amino]acetyl]pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@H]1N(CCC1)C(CN(C12CC3(CC(CC(C1)C3)C2)O)C(=O)OC(C)(C)C)=O BHRSEPVINGDQAC-LGABGLQWSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000000802 nitrating effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- BNNMDMGPZUOOOE-UHFFFAOYSA-N 4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1 BNNMDMGPZUOOOE-UHFFFAOYSA-N 0.000 description 1
- DNHXLKLIEIPCFV-QTFKPMJZSA-N COC(=O)[C@H]1N(CCC1)C(CN(C12CC3(CC(CC(C1)C3)C2)O)CC2=CC=CC=C2)=O Chemical compound COC(=O)[C@H]1N(CCC1)C(CN(C12CC3(CC(CC(C1)C3)C2)O)CC2=CC=CC=C2)=O DNHXLKLIEIPCFV-QTFKPMJZSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- XLZCIXFPTHCUFB-UHFFFAOYSA-N dmf pocl3 Chemical compound CN(C)C=O.ClP(Cl)(Cl)=O XLZCIXFPTHCUFB-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 description 1
- HQEIPVHJHZTMDP-JEDNCBNOSA-N methyl (2s)-pyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CCCN1 HQEIPVHJHZTMDP-JEDNCBNOSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- UBWDBGWGZCHPHO-UHFFFAOYSA-N n,n'-dicyclohexylmethanediimine;n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.C1CCCCC1N=C=NC1CCCCC1 UBWDBGWGZCHPHO-UHFFFAOYSA-N 0.000 description 1
- FDRVTDDJHPPAGK-UHFFFAOYSA-N n,n-dimethylformamide;thionyl dichloride Chemical compound ClS(Cl)=O.CN(C)C=O FDRVTDDJHPPAGK-UHFFFAOYSA-N 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- SAQIYCRIAKCKIQ-CKOCOWKSSA-N tert-butyl N-[2-[(2S)-2-carbamoylpyrrolidin-1-yl]-2-oxoethyl]-N-(3-hydroxy-1-adamantyl)carbamate Chemical compound C(C)(C)(C)OC(N(C12CC3(CC(CC(C1)C3)C2)O)CC(=O)N2[C@@H](CCC2)C(N)=O)=O SAQIYCRIAKCKIQ-CKOCOWKSSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C07C255/25—Aminoacetonitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Definitions
- the present invention relates to a commercially viable novel process for manufacturing Vildagliptin in high yield with hi h chemical and chiral purity.
- Vildagliptin is chemically known as l-[ ⁇ (3-hydroxy-l-adamantyl)amino ⁇ acetyl]-2-cyano(s)- pyrrolidine, which is a dipeptidylpeptidase IV (DPP-IV) inhibitor and found usefulness in the treatment of diabetes mellitus.
- DPP-IV dipeptidylpeptidase IV
- PCT Patent Publication WO 01/96295A2 the method described involve chloroacetylation in THF followed by dehydration with TFAA.
- PCT Patent Publication WO 2006/10.0181 a process for the synthesis of l-(haloacetyl)-2- cyano pyrroloine is described wherein the proline amide was coupled with chloroacetyl chloride followed by dehydration of amide using Vilsmeier reagent and its variants e.g., POCl 3 -DMF, SOCl 2 -DMF, cyanuric chloride-DMF etc).
- the main object of the present invention is to provide an improved process for the preparation of a compound of formula (I), which is simple, economical, user- friendly and commercially viable.
- Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s), which makes the present invention eco-friendly as well.
- Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a greater yield with higher chemical purity.
- Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the byproduct formed during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.
- the present invention provides an improved process for the preparation of Vildagliptin of formula (I),
- R 2 is H using a suitable dehydrating agent in a suitable solvent
- the substituent Ri is considered to constitute C[-C 3 linear, cyclic or branched chain or C7-C 1 0 alkyl aryl group;
- R 2 is defined as H, C 2 -C 6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C 7 -C 1 0 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc.
- R 3 is defined as CpC 6 alkyl group optionally substituted with one or more atoms selected from among halogen (such as F, CI etc), S, O, Si or a group containing C 7 -C 15 alkyl aryl (monocyclic or polycyclic) both the types are optionally substituted by one or more atom(s) selected from N, O, S, halogen Si etc.
- halogen such as F, CI etc
- R4 is chosen from C 6 -C] 0 aryl or heteroaryl group optionally substituted with F, CI, N0 2 and the like;
- X is halogen (CI, Br, I), CH 3 S0 2 , PhS0 2 , 4-Me- PhS0 2 and the like.
- the present invention provides an improved process for the preparation of Vildagliptin of formula (I) via novel synthetic approach.
- step (a) step (c) and step (f) are preferably selected from the group consisting of ethyl acetate, isopropyl acetate, dichloro methane, chloroform, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, dioxane, dimethyl formamide, acetone and the like or the mixture thereof; more preferably dichloro methane or ethyl acetate or dimethyl formamide or acetone.
- step (a), step (d), step (1) and step (m) are preferably selected from organic base or an inorganic base, which are selected from the group consisting of triethyl amine, diisopropylethyl amine, pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, more preferably is potassium carbonate or sodium carbonate or triethyl amine.
- the said catalyst in step (a) and step (m) is a phase transfer catalyst and or alkali metal iodides such as sodium iodide or potassium iodide and the like to accelerate the said reaction.
- step (a) is carried out preferably at ambient temperature to reflux temperature, more preferably at reflux temperature, whilest most preferably at 40 °C to 80°C.
- step (b) wherein the solvent used in step (b) are preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol or a mixture thereof, more preferably water or methanol or a mixture thereof.
- the said reaction of step (b) are carried out preferably at ambient temperature to 120°C, more preferably at 45°C to 1 10°C, most preferably at reflux temperature of the solvent.
- step (b) are preferably selected from hydrochloric acid, sulfuric acid, nitric acid and the like, more preferably is hydrochloric acid.
- the said base in step (b) are preferably selected from alkali or alkaline earth metal hydroxides selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, C C 5 quaternary ammonium hydroxide and the like, more preferably is sodium hydroxide.
- the reagent for N protection in step (d) are preferably selected from the group consisting of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, carbobenzoxy chloride, di-t-butyl dicarbonate, 2,2,2- trifluoroethyl chloroformate, aryl sulfonyl chloride and the like, more preferably di-t-butyl dicarbonate under the standard reaction condition known for those skilled in the art.
- the solvent used in step (d) are preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, dichloro methane, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or a mixture thereof, more preferably water or methanol or dichloro methane or isopropyl alcohol or a mixture thereof.
- step (c) and step (f) can be selected from the prior knowledge which is well understood by those skilled in the organic synthesis. More preferably in step (c) and step (f) is propylphosphonic anhydride is used.
- step (c) and step (f) are carried out preferably at the temperature in the range between - 20°C to 100°C.
- the said ammonia is either liquid ammonia or 10 to 50 % alcoholic solution of ammonia.
- step (e) and step (g) are preferably selected from the alcoholic solvent and group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and the like or a mixture thereof, more preferably methanol.
- step (e) and step (g) are carried out preferably at the temperature in the range of ambient to 100°C.
- step (h) and step (j) are preferably selected from the group consisting of phosphorus pentoxide, phosphoryl chloride, thionyl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid-N,N-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, polyphosphoric acid, propylphosphonic anhydride and the like optionally in combination with additives selected from the group consisting of pyridine, triethylamine, ⁇ , ⁇ -diisopropylethylamine, l,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5-Diazabicyclo[4.3.0] non-5-ene, l,5-Diazabicyclo[4.3.0]non-5-ene imidazole, dimethyl sulfoxide, 4- dimethylamino
- step (h), step (i) step (j), step (k) and step (1) are preferably selected from the group consisting of acetone, dichloro methane, chloroform, esters, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl formamide, methyl isobutyl ketone, acetone, acetonitrile, toluene, cyclohexane, tert butyl methyl ether, 1 ,4-dioxane, dimethyl sulfoxide and the like or combination thereof, more preferably selected from the group consisting of dichloro methane, tetrahydrofuran, 2-methyl tetrahydrofuran or combination thereof.
- step (h) and step (j) are carried out preferably at 0°C to 100°C, more preferably at ambient to 50°C.
- the said dehydrating agent used in step (i) is preferably selected from the group consisting of phosphorus pentoxide, phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid-N,N- dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, polyphosphoric acid, propylphosphonic anhydride and the like optionally in combination with additives selected from pyridine, triethylamine, ⁇ , ⁇ -diisopropylethylamine, l,8-Diazabicyclo[5.4.0]undec-7- ene, l,5-Diazabicyclo[4.3.0]non-5-ene, l,5-Diazabicyclo[4.3.0]non-5-ene imidazole, pyridine, sodium acetate, potassium acetate, sodium formate, more preferably the preferred dehydrating rea
- step (i) is carried out preferably at 0°C to 100°C, more preferably at ambient to 60°C.
- the said reagent used in step (k) and (1) are preferably selected in suitable molar ratios from the group consisting of hydrochloric acid, hydrobromic acid, boron tribromide, formic acid, acetic acid, para toluene sulfonic acid, trifluoro acetic acid, trifluoromethan sulfonic acid, piperidine, pyridine, thioanisole, zinc, zinc chloride, alumunium chloride nBu 4 N + F ⁇ , N-bromosuccinimide, N-chlorosuccinimide, hydrogen/nickel, hydrogen / palladium on carbon, Rhodium on carbon, hydrogen/palladium- barium sulfate, hydrogen/palladium-calcium carbonate and the like or in suitable, combination thereof.
- the solvent used in step (m) is preferably selected from the group consisting of water, alcohols, acetone, ethyl acetate, isopropyl acetate, dichloro methane, chloroform, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, dioxane, dimethyl formamide, toluene, cyclohexane, cyclohexane, chlorobenzene, dichlorobenzene and the like or combination thereof, more preferably selected from the group consisting of dichloro methane, tetrahydrofuran, 2 -methyl tetrahydrofuran or combination thereof, more preferably dichloro methane, toluene or ethyl acetate.
- step (m) is carried out preferably at ambient temperature to 100°C or reflux temperature, more preferably at ambient to 80°C.
- present inventor have surprisingly found an impurity of a compound of formula (16), wherein the definition of Ri is defined earlier. Moreover the removal process of the said impurity is also suggested by the present invention.
- the said impurity is characterized by the known methods in the prior art.
- the acid used is selected from the group consisting of acetic acid, formic acid, citric acid, tartaric acid, para toluene sulfonic acid, methanesulfonic acid and the like, more preferably acetic acid.
- step (n) is carried out by procedure described for step (d).
- step (o) is carried out by procedure described for step (1).
- TP In a clean and dry 5.0 L 4 necks RBF equipped with liquid addition funnel, TP. Charged cone, sulphuric acid (300 mL, 2 V) and cooled the reaction mass to 5-10 °C. To the cooled mass 1-adamantyl amine (150 g, 1 eq.) was added lot wise at 5-10 °C. After complete addition, stirred the reaction mass to get clear (slightly hazy) solution and maintained the reaction mass at 5-15 °C. Meanwhile a nitrating mixture was prepared by adding 150 mL of 65-70 % nitric acid to 450 mL cone, sulphuric acid maintaining temperature at 0-10 °C).
- the nitrating mixture was added to the reaction mass maintaining reaction temperature at 20 ⁇ 5 °C. After the addition was over, stirred the reaction mass at 20 ⁇ 5°C for 3 to 5 h. Completion of the reaction was confirmed by GC.
- the reaction mass was cooled to 0 - 5 °C and added water (150 mL, I V) to the reaction mass maintaining 0-20 °C and again cooled reaction mass to 5-10 °C. Second lot of water (300 mL, 2 V) was added to the reaction mass maintaining 5-20 °C. The reaction mass was cooled again to 5-10 °C and added third lot of water (1050 mL, 7 V) to the reaction mass maintaining 5-20 °C.
- reaction mass Cooled reaction mass to 35-40°C under N 2 and applied vacuum slowly. Methanol was distilled completely under reduced pressure. After complete removal of methanol, heated reaction mass (stirable thick oil) at 45 °C under reduced pressure for 30 min. Charged above crude product into 2 L RBF and rinsed with water (700 mL, 7 V) and stirred to dissolve. The reaction mass was cooled to 10-15°C and potassium bicarbonate (260.50 g, 3.0 eq.) was added carefully. After complete addition of potassium bicarbonate, stirred reaction mass for 5-10 min. Charged chloroacetyl chloride (103.6 mL, 1.50 eq.) slowly maintaining below 10°C.
- acetic acid (30.2 mL, 3.1 eq.) in water (175 mL, 5 V) was added to above reaction mass. The reaction mass was stirred for 30 min. at 20-25°C. The organic layer and aq. Layer were separated. The organic layer was kept aside. The aqueous layer was extracted with dichloromethane (70 mL x 4, 2V x 4). [Collectively organic layers were concentrated to get a compound of formula (16) wherein the Rl is specifically methyl]. After dichloromethane wash, adjusted the pH of aqueous layer using aq. ammonia (3V). The aqueous layer was extracted with dichloromethane (70 mL ⁇ 4, 2V ⁇ 4).
- Example 12.2 (S)-l-[2-(3-Hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2- carboxylic acid amide.
- Examplel4 [2-((S)-2-Carbamoyl-pyrrolidine-l-yl)-2-oxo-ethyI]-(3-hydroxy-damantan-l- yl)-carbamic acid tert butyl ester
- the crude was further purified by crystallization by dissolving under reflux with ethyl acetate (255 mL, 6V w.r.t to crude wt.) and IPA (85 mL, 2V) and crude compound (42.4 g) under stirring It was allowed to cool to 20-25°C and then to 0-5°C and stirred for 1 h at 0-5°C. Filtered the solid formed and washed with chilled ethyl acetate (42.5 mL, 1 V).
- the 2-Me THF layer was concentrated to isolate crude product.
- aqueous citric acid solution citric acid - 98 g, 3.0 eq; water - 6V
- DCM DCM extract obtained above
- DCM-3 DCM extract obtained above
- DCM DCM
- the crude material (26.4 g) was dissolved by refluxing in ethyl acetate (158.4 mL, 6 V w.r.t to crude wt.) and IPA (52.8 mL, 2V) under stirring maintaining for 2 h. Cooled the reaction mass to 20-25°C and then to 0-5 °C and stirred for 1 h. Filtered the solid formed and wash with chilled ethyl acetate (26.4 mL, IV) dried the solid obtained for 3-4 h at 50°C in tray dryer. Unload the solid and weighed.
Abstract
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CN107033054A (en) * | 2017-06-19 | 2017-08-11 | 河北富格药业有限公司 | A kind of synthetic method of vildagliptin |
CN107325010A (en) * | 2017-08-14 | 2017-11-07 | 四川众邦制药有限公司 | The safe preparation method and device of a kind of adamantanol |
WO2021116897A1 (en) * | 2019-12-10 | 2021-06-17 | Optimus Drugs (P) Ltd | Process for the preparation of vildagliptin |
WO2022003405A1 (en) | 2020-07-03 | 2022-01-06 | Savoi Guilherme | One-pot process to obtain a pyrrolidine-2-carbonitrile intermediate compound and industrial scale telescopic process to prepare (2s)-1-[n-(3-hydroxyadamantan-1-yl)glycyl]-2-pyrrolidinecarbonitrile (vildagliptin) using same |
CN112279809A (en) * | 2020-09-23 | 2021-01-29 | 山东省海洋化工科学研究院 | Preparation method of 2-cyano-4-fluoropyridine |
CN112939837B (en) * | 2021-02-03 | 2022-07-19 | 海南通用三洋药业有限公司 | Method for preparing vildagliptin through multiphase compound continuous production |
CN115108939A (en) * | 2021-03-17 | 2022-09-27 | 成都施贝康生物医药科技有限公司 | Intermediate of trans-4- [ (2-amino-3, 5-dibromo benzyl) amino ] -adamantan-1-ol and preparation method thereof |
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