WO2024047657A1 - Process for the preparation of nitisinone - Google Patents
Process for the preparation of nitisinone Download PDFInfo
- Publication number
- WO2024047657A1 WO2024047657A1 PCT/IN2022/050879 IN2022050879W WO2024047657A1 WO 2024047657 A1 WO2024047657 A1 WO 2024047657A1 IN 2022050879 W IN2022050879 W IN 2022050879W WO 2024047657 A1 WO2024047657 A1 WO 2024047657A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- trifluoromethyl
- nitro
- benzoic acid
- nitisinone
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 46
- 230000008569 process Effects 0.000 title claims abstract description 39
- OUBCNLGXQFSTLU-UHFFFAOYSA-N nitisinone Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1C(=O)C1C(=O)CCCC1=O OUBCNLGXQFSTLU-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229960001721 nitisinone Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- MYSAXQPTXWKDPQ-UHFFFAOYSA-N 2-nitro-4-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O MYSAXQPTXWKDPQ-UHFFFAOYSA-N 0.000 claims abstract description 24
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000007822 coupling agent Substances 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical group CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-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 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- KNKRKFALVUDBJE-UHFFFAOYSA-N 1,2-dichloropropane Chemical compound CC(Cl)CCl KNKRKFALVUDBJE-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001718 carbodiimides Chemical class 0.000 claims description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 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-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 claims description 2
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229940086542 triethylamine Drugs 0.000 claims 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- -1 alkali metal bicarbonates Chemical class 0.000 description 14
- 239000008213 purified water Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 102000016680 Dioxygenases Human genes 0.000 description 1
- 108010028143 Dioxygenases Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100001010 corrosive Toxicity 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 235000020805 dietary restrictions Nutrition 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- CMESPBFFDMPSIY-UHFFFAOYSA-N n,n'-diphenylmethanediimine Chemical compound C1=CC=CC=C1N=C=NC1=CC=CC=C1 CMESPBFFDMPSIY-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 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
- 230000037361 pathway Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 201000011296 tyrosinemia Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to a process for the preparation of Nitisinone of formula 1.
- Nitisinone is a hydroxyphenyl-pyruvate dioxygenase inhibitor. It is indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1). Chemically, it is known as 2-(2-nitro-4- trifluoromethylbenzoyl) cyclohexane-1 ,3-dione.
- Nitisinone or salts thereof which can reduce the burden of isolating, crystallizing, and purifying the intermediate compound(s), and thus minimize production time, provide high yield and is convenient to operate on a commercial scale and also, a need for a process that leads to formation of Nitisinone with an improved yield and purity, and in particular by avoiding use of toxic, hazardous and corrosive chemicals such as phosphorus oxychloride, thionyl chloride etc.
- the present invention is associated with these advantages and enables practical and efficient manufacture of Nitisinone. Added advantages of the present invention are cost effectiveness, readily accessible raw materials, less hazardous reaction conditions, and simple work up procedures which all make the process more robust and cost-efficient.
- the impurities associated to nitisinone can be either derived from the starting materials themselves (i.e., Formula (2) and Formula (3)) or obtained as side products during the process of synthesis and/or under storage conditions (i.e., Formula (4)) and are the following:
- Impurities in nitisinone, or any active pharmaceutical ingredient (“API”) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
- the purity of an API produced in a manufacturing process is critical for commercialization.
- the product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the final product.
- it must be analyzed for purity, typically, by high performance liquid chromatography (“HPLC”) or thin-layer chromatography (“TLC”), to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product.
- HPLC high performance liquid chromatography
- TLC thin-layer chromatography
- nitisinone As known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways and by identifying the parameters that influence the amount of impurities in the final product. Extensive experimentation has been carried out by the present inventors. As a result, the present inventors found an improved method for the preparation of nitisinone which is substantially free of formula (2) and formula (4), by controlling critical process parameters.
- the nitisinone made by the process of the present invention is suitable for commercial scale production.
- the present invention provides a process for the preparation of Nitisinone of formula (1).
- the process comprises: reacting 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) with cyclohexane- 1,3-dione of formula (3)
- the present invention provides a process for the preparation of nitisinone substantially free of 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2), and 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4) in an amount of 0.001% or less as determined by HPLC method.
- the present invention provides a process for the preparation of nitisinone substantially free of 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2), and 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4) undetectable as determined by HPLC method.
- FIG. 1 SHOWS AN X-RAY POWDER DIFFRACTION PATTERN (XRPD) OF NITISINONE AS OBTAINED BY THE PROCESS ACCORDING TO THE PRESENT INVENTION, AS DISCLOSED HEREIN IN EXAMPLE 1.
- the present invention provides a process for the preparation of Nitisinone of formula (1)
- Formula (1) which comprises: reacting 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) with cyclohexane- 1,3-dione of formula (3)
- the 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) may be obtained by any of the methods known in the art including those described in U.S. Patent No. 4,868,333.
- the base includes, for example an amine, an inorganic base or ammonia.
- amines examples include triethylamine, N-methyl morpholine, N,N- dimethyl benzyl amine, pyridine, picoline, and lutidine.
- the inorganic base may be an alkali metal carbonate, bicarbonate or hydroxide.
- alkali metal carbonates include lithium carbonate, potassium carbonate and sodium carbonate.
- alkali metal bicarbonates include potassium bicarbonate and sodium bicarbonate.
- alkali metal hydroxides include potassium hydroxide and sodium hydroxide.
- the base is an amine. More preferably, the base is triethylamine.
- the amount of base used with respect to 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) is between 0.9 to 4 molar equivalents, more preferably between 1 to 2 molar equivalents, even more preferably between 1.1 to 1.3 molar equivalents, and most preferably about 1.2 molar equivalents.
- the coupling agent includes, for example a carbodiimide, a 1,1 '-carbonyl compound, or a mixture thereof.
- the coupling agent is selected from 1,3 -di cyclohexylcarbodiimide (DCC); 1,1'- carbonyldiimidazole (GDI); N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC . HC1); 1,3 -diisopropylcarbodiimide (DIC); or a mixture thereof.
- the coupling agent is N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDC . HC1)
- the amount of coupling agent used with respect to 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) is between 0.5 to 5 molar equivalents, more preferably between 0.9 to 2 molar equivalents, even more preferably between 0.95 to 1.25 molar equivalents, and most preferably about 1.05 molar equivalents.
- the reaction may be carried out in the presence of a catalyst.
- the reaction may be carried out in the presence of a catalytic amount of a source of cyanide.
- the cyanide sources are cyanohydrins of methyl alkyl ketones having from C1-C4 carbon atoms in the alkyl groups, such as acetone or methyl isobutyl ketone cyanohydrins; cyanohydrins of benzaldehyde or of C2-C5 aliphatic aldehydes such as acetaldehyde, propionaldehyde; alkali metal cyanides such as sodium and potassium cyanide; zinc cyanide; trimethyl silyl cyanide.
- the preferred cyanide source is acetone cyanohydrin.
- the cyanide source may be used in as little as about 0.1 mole equivalent to produce an acceptable rate of reaction on a small scale. Larger scale reactions give more reproducible results with slightly higher catalyst levels of about 0.12 to about 1 mole equivalent. Generally, about 0.001 to 1.5 mole % of the cyanide source is preferred.
- the reaction may be carried out in the presence of a solvent.
- a solvent includes, for example, water, alcohols, such as, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol; aromatic hydrocarbon, such as, benzene, toluene, and xylene, substituted toluenes, substituted xylenes; halogenated hydrocarbons, such as, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, chloroform, carbon tetrachloride; ethers, such as, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran;
- the solvent is halogenated hydrocarbon. More preferably, the solvent is dichloromethane.
- 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) and cyclohexane- 1,3-dione of formula (3) can be taken in the mole ratio of about 1:0.9 to about 1: 1.5, preferably, about 1: 1 to about 1:1.2, more preferably, about 1 :1.05.
- reaction can be carried out in one-pot.
- the temperature at which the reaction of 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) with cyclohexane- 1, 3-dione of formula (3) may be carried out may range from about -20°C to about 120°C, for example from about 0°C to about 40°C or from about 20°C to about 35°C. In particular, it may be carried out at a temperature from about 25 °C to about 30°C.
- the process involves addition of 2- nitro-4-(trifluoromethyl)benzoic acid of formula (2), cyclohexane- 1,3-dione of formula (3), triethylamine (base), in dichloromethane (solvent) in optional order of succession at a temperature of about 25°C to 30°C, optionally under stirring, and maintaining at a temperature of about 25 to 30°C for about 0.5 hours, followed by the addition of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [EDC .
- HC1] (coupling agent), and acetone cyanohydrin (catalyst), in optional order of succession at a temperature of about 25°C to 30°C, optionally under stirring, and maintaining at a temperature of about 25 to 30°C for about 2 to 3 hours, to obtain nitisinone, and the isolation of the nitisinone involves common isolation techniques such as one or more of washing, crystallization, precipitation, cooling, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
- the Nitisinone obtained may be further or additionally dried to achieve the desired moisture values.
- the product may be further or additionally dried in a tray drier, dried under vacuum, dried at 50-55°C in hot air oven and/or in a Fluid Bed Drier.
- the Nitisinone of formula (1) obtained may have X- Ray powder diffraction (XRPD) pattern as shown in FIG. 1 and the 2 theta values
- the present invention provides a process for the preparation of nitisinone substantially free of 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2), and 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4) in an amount of 0.001% or less as determined by HPLC method.
- the present invention provides a process for the preparation of nitisinone substantially free of 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2), and 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4) as determined by HPLC method.
- EXAMPLE 1 PROCESS FOR THE PRERPATIN OF NITISINONE
- Purified water (50 ml) was charged at 25-30°C. The mixture was stirred and settled for 15 minutes. The aqueous layer was separated, and washed with methylene dichloride (25 ml). The aqueous layer was cooled to 15-20°C and concentrated hydrochloric acid (5 ml) was charged slowly over 15-20 minutes. The mixture was maintained at 25-30°C for 30 minutes and distilled below 40°C under vacuum to completely remove methylene dichloride. Acetonitrile (25 ml) was added with the residue at 25-30°C and heated at 45-50°C for 30 minutes. Purified water (30 ml) was added at 45-50°C, slowly over 30 minutes. The mixture was maintained at 45-50°C for 30 minutes and then cooled to 25-30°C for 2 hours. The solid obtained was filtered, washed with purified water (5 ml), suck dried under vacuum and dried at 50-55°C in hot air oven.
- the aqueous layer was separated, and washed with methylene dichloride (25 ml).
- the aqueous layer was cooled to 15-20°C and concentrated hydrochloric acid (5 ml) was charged slowly over 15-20 minutes.
- the mixture was maintained at 25-30°C for 30 minutes and distilled below 40°C under vacuum to completely remove methylene dichloride.
- Acetonitrile (25 ml) was added with the residue at 25-30°C and heated at 45-50°C for 30 minutes.
- Purified water (30 ml) was added at 45-50°C, slowly over 30 minutes.
- the mixture was maintained at 45-50°C for 30 minutes and then cooled to 25-30°C for 2 hours.
- the solid obtained was filtered, washed with purified water (5 ml), suck dried under vacuum and dried at SO- 55 °C in hot air oven.
- the aqueous layer was separated, and washed with methylene dichloride (25 ml).
- the aqueous layer was cooled to 15-20°C and concentrated hydrochloric acid (5 ml) was charged slowly over 15-20 minutes.
- the mixture was maintained at 25-30°C for 30 minutes and distilled below 40°C under vacuum to completely remove methylene dichloride.
- Acetonitrile (25 ml) was added with the residue at 25-30°C and heated at 45-50°C for 30 minutes.
- Purified water (30 ml) was added at 45-50°C, slowly over 30 minutes.
- the mixture was maintained at 45-50°C for 30 minutes and then cooled to 25-30°C for 2 hours.
- the solid obtained was filtered, washed with purified water (5 ml), suck dried under vacuum and dried at SO- 55 °C in hot air oven.
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Abstract
Disclosed herein is a process for the preparation of Nitisinone of formula (1) which comprises reacting 2-nitro-4-(trifluoromethyl) benzoic acid of formula (2) with cyclohexane-1,3-dione of formula (3) in the presence of a base, and a coupling agent.
Description
PROCESS FOR THE PREPARATION OF NITISINONE
FIELD OF THE INVENTION
Formula (1)
BACKGROUND OF THE INVENTION
Nitisinone is a hydroxyphenyl-pyruvate dioxygenase inhibitor. It is indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1). Chemically, it is known as 2-(2-nitro-4- trifluoromethylbenzoyl) cyclohexane-1 ,3-dione.
Several processes have been reported for the preparation of Nitisinone for example, in U.S. Patent No. 4,695,673; 4,774,360; 5,006,158 5,550,165; 5,728,889; 9,783,485; 10,328,029; U.S. Patent Publication No. 2016/0324785; Indian Patent Application No. 201611023671; 201841016377, the contents of which are hereby incorporated as reference in their entirety. These processes require multiple steps or complicated purification processes such as chromatography and therefore inevitably lead to poorer yields or purity.
There is still a need for an improved and simplified process for the preparation of Nitisinone or salts thereof, which can reduce the burden of isolating, crystallizing, and purifying the intermediate compound(s), and thus minimize production time, provide high yield and is convenient to operate on a commercial scale and also, a
need for a process that leads to formation of Nitisinone with an improved yield and purity, and in particular by avoiding use of toxic, hazardous and corrosive chemicals such as phosphorus oxychloride, thionyl chloride etc.
The present invention is associated with these advantages and enables practical and efficient manufacture of Nitisinone. Added advantages of the present invention are cost effectiveness, readily accessible raw materials, less hazardous reaction conditions, and simple work up procedures which all make the process more robust and cost-efficient.
The impurities associated to nitisinone can be either derived from the starting materials themselves (i.e., Formula (2) and Formula (3)) or obtained as side products during the process of synthesis and/or under storage conditions (i.e., Formula (4)) and are the following:
2-nitro-4-(trifluoromethyl)benzoic acid of formula (2), cyclohexane- 1, 3-dione of formula (3), and 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4).
Formula (2) Formula (3) Formula
(4)
Impurities in nitisinone, or any active pharmaceutical ingredient (“API”), are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The purity of an API produced in a manufacturing process is critical for commercialization. The product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the final product. At certain stages during processing of an API, it must be analyzed for purity, typically, by high performance liquid chromatography (“HPLC”) or thin-layer chromatography (“TLC”), to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product.
As known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways and by identifying the parameters that influence the amount of impurities in the final product. Extensive experimentation has been carried out by the present inventors. As a result, the present inventors found an improved method for the preparation of nitisinone which is substantially free of formula (2) and formula (4), by controlling critical process parameters. The nitisinone made by the process of the present invention is suitable for commercial scale production.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of Nitisinone of formula (1).
Formula (1)
The process comprises: reacting 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) with cyclohexane- 1,3-dione of formula (3)
Formula (2) Formula (3) in the presence of a base, and a coupling agent to obtain Nitisinone of formula
(1).
In another general aspect, the present invention provides a process for the preparation of nitisinone substantially free of 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2), and 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4) in an amount of 0.001% or less as determined by HPLC method.
In yet another general aspect, the present invention provides a process for the preparation of nitisinone substantially free of 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2), and 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4) undetectable as determined by HPLC method.
BRIEF DESCRIPTION OF THE DRAWINGS
A SKILLED PERSON WILL UNDERSTAND THAT THE DRAWINGS, DESCRIBED BELOW, ARE FOR ILLUSTRATION PURPOSES ONLY. THE DRAWINGS ARE NOT INTENDED TO LIMIT THE SCOPE OF THE PRESENT INVENTION IN ANY WAY.
FIG. 1 SHOWS AN X-RAY POWDER DIFFRACTION PATTERN (XRPD) OF NITISINONE AS OBTAINED BY THE PROCESS ACCORDING TO THE PRESENT INVENTION, AS DISCLOSED HEREIN IN EXAMPLE 1.
DETAILED DESCRIPTION OF THE INVENTION
The term “about”, as used herein, when used along with values assigned to certain measurements and parameters means a variation of up to 10% from such values, or in case of a range of values, means up to a 10% variation from both the lower and upper limits of such ranges.
Use of exemplary language, such as “for example”, “such as”, and the like, is merely intended to better illustrate the invention and does not indicate a limitation on the scope of the invention unless so claimed.
In one aspect, the present invention provides a process for the preparation of Nitisinone of formula (1)
Formula (1) which comprises: reacting 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) with cyclohexane- 1,3-dione of formula (3)
Formula (2) Formula (3)
in the presence of a base, and a coupling agent to obtain Nitisinone of formula
(1).
The 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) may be obtained by any of the methods known in the art including those described in U.S. Patent No. 4,868,333.
In one embodiment of this aspect, the base includes, for example an amine, an inorganic base or ammonia.
Examples of amines include triethylamine, N-methyl morpholine, N,N- dimethyl benzyl amine, pyridine, picoline, and lutidine.
The inorganic base may be an alkali metal carbonate, bicarbonate or hydroxide. Examples of alkali metal carbonates include lithium carbonate, potassium carbonate and sodium carbonate. Examples of alkali metal bicarbonates include potassium bicarbonate and sodium bicarbonate. Examples of alkali metal hydroxides include potassium hydroxide and sodium hydroxide.
Preferably, the base is an amine. More preferably, the base is triethylamine.
In another embodiment of this aspect, the amount of base used with respect to 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) is between 0.9 to 4 molar equivalents, more preferably between 1 to 2 molar equivalents, even more preferably between 1.1 to 1.3 molar equivalents, and most preferably about 1.2 molar equivalents.
In another embodiment of this aspect, the coupling agent includes, for example a carbodiimide, a 1,1 '-carbonyl compound, or a mixture thereof. Preferably, the coupling agent is selected from 1,3 -di cyclohexylcarbodiimide (DCC); 1,1'- carbonyldiimidazole (GDI); N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC . HC1); 1,3 -diisopropylcarbodiimide (DIC); or a mixture thereof.
Preferably, the coupling agent is N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDC . HC1)
In another embodiment of this aspect, the amount of coupling agent used with respect to 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) is between 0.5 to 5 molar equivalents, more preferably between 0.9 to 2 molar equivalents, even more preferably between 0.95 to 1.25 molar equivalents, and most preferably about 1.05 molar equivalents.
In another embodiment of this aspect, the reaction may be carried out in the presence of a catalyst. In another embodiment, the reaction may be carried out in the presence of a catalytic amount of a source of cyanide. Preferably, the cyanide sources are cyanohydrins of methyl alkyl ketones having from C1-C4 carbon atoms in the alkyl groups, such as acetone or methyl isobutyl ketone cyanohydrins; cyanohydrins of benzaldehyde or of C2-C5 aliphatic aldehydes such as acetaldehyde, propionaldehyde; alkali metal cyanides such as sodium and potassium cyanide; zinc cyanide; trimethyl silyl cyanide. Among cyanohydrins, the preferred cyanide source is acetone cyanohydrin.
The cyanide source may be used in as little as about 0.1 mole equivalent to produce an acceptable rate of reaction on a small scale. Larger scale reactions give more reproducible results with slightly higher catalyst levels of about 0.12 to about 1 mole equivalent. Generally, about 0.001 to 1.5 mole % of the cyanide source is preferred.
In yet another embodiment of this aspect, the reaction may be carried out in the presence of a solvent. There are no specific limitations with respect to the organic solvent employed in the reaction, so far as the solvent does not participate in the reaction. The solvent includes, for example, water, alcohols, such as, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol; aromatic hydrocarbon, such as, benzene, toluene, and xylene, substituted toluenes, substituted xylenes; halogenated
hydrocarbons, such as, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, chloroform, carbon tetrachloride; ethers, such as, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran; ketones, such as, acetone, methyl ethyl ketone, methyl isobutyl ketone; alkyl acetate, such as, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; alkyl nitriles, such as, acetonitrile, propionitrile; amides, such as, N,N- dimethylformamide; dimethyl sulfoxide. The solvents may be employed singly or in combination.
Preferably, the solvent is halogenated hydrocarbon. More preferably, the solvent is dichloromethane.
In yet another embodiment of this aspect, 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) and cyclohexane- 1,3-dione of formula (3) can be taken in the mole ratio of about 1:0.9 to about 1: 1.5, preferably, about 1: 1 to about 1:1.2, more preferably, about 1 :1.05.
In yet another embodiment of this aspect, the reaction can be carried out in one-pot.
In yet another embodiment of this aspect, the temperature at which the reaction of 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) with cyclohexane- 1, 3-dione of formula (3) may be carried out may range from about -20°C to about 120°C, for example from about 0°C to about 40°C or from about 20°C to about 35°C. In particular, it may be carried out at a temperature from about 25 °C to about 30°C.
In yet another embodiment of this aspect, the process involves addition of 2- nitro-4-(trifluoromethyl)benzoic acid of formula (2), cyclohexane- 1,3-dione of formula (3), triethylamine (base), in dichloromethane (solvent) in optional order of succession at a temperature of about 25°C to 30°C, optionally under stirring, and
maintaining at a temperature of about 25 to 30°C for about 0.5 hours, followed by the addition of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [EDC . HC1] (coupling agent), and acetone cyanohydrin (catalyst), in optional order of succession at a temperature of about 25°C to 30°C, optionally under stirring, and maintaining at a temperature of about 25 to 30°C for about 2 to 3 hours, to obtain nitisinone, and the isolation of the nitisinone involves common isolation techniques such as one or more of washing, crystallization, precipitation, cooling, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
In yet another embodiment of this aspect, the Nitisinone obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum, dried at 50-55°C in hot air oven and/or in a Fluid Bed Drier.
In another embodiment, the Nitisinone of formula (1) obtained may have X- Ray powder diffraction (XRPD) pattern as shown in FIG. 1 and the 2 theta values
In another general aspect, the present invention provides a process for the preparation of nitisinone substantially free of 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2), and 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4) in an amount of 0.001% or less as determined by HPLC method.
In yet another general aspect, the present invention provides a process for the preparation of nitisinone substantially free of 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2), and 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4) as determined by HPLC method.
While the present invention has been described in terms of its specific aspect, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
In the following section, the aspect is described by way of examples to illustrate the processes of the invention. However, these do not limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLES
EXAMPLE 1 : PROCESS FOR THE PRERPATIN OF NITISINONE
2-Nitro-4-(trifhroromethyl)benzoic acid (5.0 g), Triethylamine (2.57 g) and then, Cyclohexane- 1, 3-dione (2.50 g) were added into Dichloromethane (50 ml) at 25-30°C and maintained at 25-30°C for 30 minutes. N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride [EDC. HC1] (3.46 g) was added to the mixture at 25-30°C in one lot. Acetone cyanohydrin (0.18 g) was added at 25-30°C, and the mixture was maintained at 25-30°C for 2-3 hours. Purified water (50 ml) was charged at 25-30°C. The mixture was stirred and settled for 15 minutes. The aqueous layer was separated, and washed with methylene dichloride (25 ml). The aqueous layer was cooled to 15-20°C and concentrated hydrochloric acid (5 ml) was charged slowly over 15-20 minutes. The mixture was maintained at 25-30°C for 30 minutes and distilled below 40°C under vacuum to completely remove methylene dichloride. Acetonitrile (25 ml) was added with the residue at 25-30°C and heated at 45-50°C for 30 minutes. Purified water (30 ml) was added at 45-50°C, slowly over 30 minutes. The mixture was maintained at 45-50°C for 30 minutes and then cooled to 25-30°C for 2 hours. The solid obtained was filtered, washed with purified water (5 ml), suck dried under vacuum and dried at 50-55°C in hot air oven.
Yield (%): 48.6%
Purity (%): 99.98% (by HPLC)
2-nitro-4-(trifluoromethyl)benzoic acid of formula (2): ND (by HPLC) 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4): ND (by HPLC)
(ND = Not Detected)
EXAMPLE 2: PROCESS FOR THE PRERPAHON OF NITISINONE
2-Nitro-4-(trifluoromethyl)benzoic acid (5.0 g), Triethylamine (2.57 g) and then, Cyclohexane- 1, 3-dione (2.50 g) were added into Dichloromethane (50 ml) at 25-30°C and maintained at 25-30°C for 30 minutes. N,N'-Dicyclohexylcarbodiimide- [DCC] (4.6 g) was added to the mixture at 25-30°C in one lot. Acetone cyanohydrin (0.18 g) was added at 25-30°C, and the mixture was maintained at 25-30°C for 2-3 hours. Purified water (50 ml) was charged at 25-30°C. The mixture was stirred and settled for 15 minutes. The aqueous layer was separated, and washed with methylene dichloride (25 ml). The aqueous layer was cooled to 15-20°C and concentrated hydrochloric acid (5 ml) was charged slowly over 15-20 minutes. The mixture was maintained at 25-30°C for 30 minutes and distilled below 40°C under vacuum to completely remove methylene dichloride. Acetonitrile (25 ml) was added with the residue at 25-30°C and heated at 45-50°C for 30 minutes. Purified water (30 ml) was added at 45-50°C, slowly over 30 minutes. The mixture was maintained at 45-50°C for 30 minutes and then cooled to 25-30°C for 2 hours. The solid obtained was filtered, washed with purified water (5 ml), suck dried under vacuum and dried at SO- 55 °C in hot air oven.
Yield (%): 46.4%
Purity (%): 99.97% (by HPLC)
2-nitro-4-(trifluoromethyl)benzoic acid of formula (2): ND (by HPLC) 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4): ND (by HPLC)
(ND = Not Detected)
EXAMPLE 3: PROCESS FOR THE PRERPATIN OF NITISINONE
2-Nitro-4-(trifhroromethyl)benzoic acid (5.0 g), Triethylamine (2.57 g) and then, Cyclohexane- 1, 3-dione (2.50 g) were added into Dichloromethane (50 ml) at
25-30°C and maintained at 25-30°C for 30 minutes. N,N'-carbonyldiimidazole-[CDI] (3.61 g) was added to the mixture at 25-30°C in one lot. Acetone cyanohydrin (0.18 g) was added at 25-30°C, and the mixture was maintained at 25-30°C for 2-3 hours. Purified water (50 ml) was charged at 25-30°C. The mixture was stirred and settled for 15 minutes. The aqueous layer was separated, and washed with methylene dichloride (25 ml). The aqueous layer was cooled to 15-20°C and concentrated hydrochloric acid (5 ml) was charged slowly over 15-20 minutes. The mixture was maintained at 25-30°C for 30 minutes and distilled below 40°C under vacuum to completely remove methylene dichloride. Acetonitrile (25 ml) was added with the residue at 25-30°C and heated at 45-50°C for 30 minutes. Purified water (30 ml) was added at 45-50°C, slowly over 30 minutes. The mixture was maintained at 45-50°C for 30 minutes and then cooled to 25-30°C for 2 hours. The solid obtained was filtered, washed with purified water (5 ml), suck dried under vacuum and dried at SO- 55 °C in hot air oven.
Yield (%): 47.1%
Purity (%): 99.96% (by HPLC)
2-nitro-4-(trifluoromethyl)benzoic acid of formula (2): ND (by HPLC) 6-(trifluoromethyl)-3,4-dihydro-lH-xanthene-l,9(2H)-dione of formula (4): ND (by HPLC)
(ND = Not Detected)
Claims
Formula (1) which comprises: reacting 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) with cyclohexane- 1,3- dione of formula (3)
Formula (2) Formula (3) in the presence of a base, and a coupling agent to obtain Nitisinone of formula (1).
2. The process as claimed in claim 1, wherein the base is selected from a group comprising an amine, an inorganic base or mixtures thereof.
3. The process as claimed in claim 1, wherein the base is tri ethylamine.
4. The process as claimed in claim 1, wherein the coupling agent is selected from a group comprising a carbodiimide, a l,l'-carbonyl compound, or a mixture thereof.
5. The process as claimed in claim 1, wherein the coupling agent is N-(3-Dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (EDC.HC1).
6. The process as claimed in claim 1, wherein the reaction is carried out in the presence of a catalyst.
7. The process as claimed in claim 6, wherein the catalyst is acetone cyanohydrin.
8. The process as claimed in claim 1, wherein the reaction is carried out in the presence of a solvent selected from a group comprising of water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, benzene, toluene, and xylene, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, chloroform, carbon tetrachloride, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; acetonitrile, propionitrile, N,N-dimethylformamide; dimethyl sulfoxide or any mixtures thereof.
9. The process as claimed in claim 8, wherein the solvent is dichloromethane.
10. The process as claimed in claim 1, wherein the reaction is carried out at a temperature of about -20°C to about 120°C.
11. The process as claimed in claim 10, wherein the reaction is carried out at a temperature of about 20°C to about 35°C.
12. The process as claimed in claim 1, the process comprises addition of 2-nitro-4- (trifluoromethyl)benzoic acid of formula (2), cyclohexane- 1,3 -di one of formula (3), triethylamine, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [EDC . HC1], and acetone cyanohydrin, in dichloromethane at a temperature of about 25 °C to 30°C, wherein, the amount of triethylamine used with respect to 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) is about 1.2 molar equivalent, the amount of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [EDC . HC1] used with respect to 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) is about 1.05 molar equivalent, the amount of acetone cyanohydrin used with respect to 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) is about 0.1 molar equivalent,
the mole ratio between 2-nitro-4-(trifluoromethyl)benzoic acid of formula (2) and cyclohexane- 1, 3-dione is about 1 : 1.05 molar equivalent.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993000080A1 (en) * | 1991-06-24 | 1993-01-07 | Zeneca Ltd. | Use of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione in the treatment of tyrosinaemia and pharmaceutical compositions |
CN102976948A (en) * | 2012-11-28 | 2013-03-20 | 郑州大明药物科技有限公司 | Method for preparing nitisinone |
US9783485B1 (en) * | 2016-11-30 | 2017-10-10 | Dipharma S.A. | Crystalline inhibitor of 4-hydroxyphenylpyruvate dioxygenase, and a process of synthesis and crystallization thereof |
IN201841016377A (en) * | 2018-05-01 | 2020-09-11 |
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- 2022-10-03 WO PCT/IN2022/050879 patent/WO2024047657A1/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993000080A1 (en) * | 1991-06-24 | 1993-01-07 | Zeneca Ltd. | Use of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione in the treatment of tyrosinaemia and pharmaceutical compositions |
CN102976948A (en) * | 2012-11-28 | 2013-03-20 | 郑州大明药物科技有限公司 | Method for preparing nitisinone |
US9783485B1 (en) * | 2016-11-30 | 2017-10-10 | Dipharma S.A. | Crystalline inhibitor of 4-hydroxyphenylpyruvate dioxygenase, and a process of synthesis and crystallization thereof |
IN201841016377A (en) * | 2018-05-01 | 2020-09-11 |
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