US20200262788A1 - Process for preparation of molindone - Google Patents
Process for preparation of molindone Download PDFInfo
- Publication number
- US20200262788A1 US20200262788A1 US16/791,169 US202016791169A US2020262788A1 US 20200262788 A1 US20200262788 A1 US 20200262788A1 US 202016791169 A US202016791169 A US 202016791169A US 2020262788 A1 US2020262788 A1 US 2020262788A1
- Authority
- US
- United States
- Prior art keywords
- compound
- ethyl
- cyclohexane
- molindone
- dione
- 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.)
- Granted
Links
- KLPWJLBORRMFGK-UHFFFAOYSA-N Molindone Chemical compound O=C1C=2C(CC)=C(C)NC=2CCC1CN1CCOCC1 KLPWJLBORRMFGK-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 35
- 229960004938 molindone Drugs 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- RZUQNFAPFIHYCR-UHFFFAOYSA-N 3-ethyl-2-methyl-1,5,6,7-tetrahydroindol-4-one Chemical compound C1CCC(=O)C2=C1NC(C)=C2CC RZUQNFAPFIHYCR-UHFFFAOYSA-N 0.000 claims abstract description 40
- ARKVGTXSIMNYRN-UHFFFAOYSA-N 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione Chemical compound O=C(C)C(CC)C1C(CCCC1=O)=O ARKVGTXSIMNYRN-UHFFFAOYSA-N 0.000 claims abstract description 29
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 24
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 claims abstract description 16
- -1 ethyl halide Chemical class 0.000 claims abstract description 13
- 150000004820 halides Chemical class 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical group CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-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
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 6
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 6
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 6
- 229940090181 propyl acetate Drugs 0.000 claims description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 6
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 5
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical group CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 claims description 3
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 235000019743 Choline chloride Nutrition 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 2
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 2
- 229960003178 choline chloride Drugs 0.000 claims description 2
- 229960003750 ethyl chloride Drugs 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 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 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
- 235000013877 carbamide Nutrition 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000002798 polar solvent Substances 0.000 description 14
- 229940093499 ethyl acetate Drugs 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 10
- 239000012454 non-polar solvent Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 5
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 229940043232 butyl acetate Drugs 0.000 description 5
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 229940093858 ethyl acetoacetate Drugs 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 5
- 229940086542 triethylamine Drugs 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- CKSIBFLEDRJUTN-UHFFFAOYSA-N 3-chloropentan-2-one Chemical compound CCC(Cl)C(C)=O CKSIBFLEDRJUTN-UHFFFAOYSA-N 0.000 description 3
- 150000004982 aromatic amines Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- 0 *OC(=O)C(C)(CC)C(C)=O.*OC(=O)CC(C)=O Chemical compound *OC(=O)C(C)(CC)C(C)=O.*OC(=O)CC(C)=O 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 2
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 2
- ARUZEPPBKBYBJL-UHFFFAOYSA-N CCC(C(C)=O)C1C(=O)CCCC1=O.CCC(C)C(C)=O.O=C1CCCC(=O)C1 Chemical compound CCC(C(C)=O)C1C(=O)CCCC1=O.CCC(C)C(C)=O.O=C1CCCC(=O)C1 ARUZEPPBKBYBJL-UHFFFAOYSA-N 0.000 description 2
- GQWNECFJGBQMBO-UHFFFAOYSA-N Molindone hydrochloride Chemical compound Cl.O=C1C=2C(CC)=C(C)NC=2CCC1CN1CCOCC1 GQWNECFJGBQMBO-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- NCAPIWDYXGDHIK-UHFFFAOYSA-L [Li+].[K+].OC([O-])=O.OC([O-])=O Chemical compound [Li+].[K+].OC([O-])=O.OC([O-])=O NCAPIWDYXGDHIK-UHFFFAOYSA-L 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- ZMCUDHNSHCRDBT-UHFFFAOYSA-M caesium bicarbonate Chemical compound [Cs+].OC([O-])=O ZMCUDHNSHCRDBT-UHFFFAOYSA-M 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- 229910000103 lithium hydride Inorganic materials 0.000 description 2
- YVSZXUQSNXUQGI-UHFFFAOYSA-N methyl 2-chloro-2-ethyl-3-oxobutanoate Chemical compound CCC(Cl)(C(C)=O)C(=O)OC YVSZXUQSNXUQGI-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229960004684 molindone hydrochloride Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- MMRXSDODKLLOLN-UHFFFAOYSA-N C=C(C)C(CC)C1C(=O)CCCC1=O Chemical compound C=C(C)C(CC)C1C(=O)CCCC1=O MMRXSDODKLLOLN-UHFFFAOYSA-N 0.000 description 1
- 241000694440 Colpidium aqueous Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 239000003875 Wang resin Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- IPILPUZVTYHGIL-UHFFFAOYSA-M tributyl(methyl)azanium;chloride Chemical compound [Cl-].CCCC[N+](C)(CCCC)CCCC IPILPUZVTYHGIL-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
- C07C49/403—Saturated compounds containing a keto group being part of a ring of a six-membered ring
Definitions
- the present invention provides novel process for preparation of Molindone and its salts.
- the present invention also provides novel intermediate for preparation of Molindone.
- Molindone is chemically known as4H-Indol-4-one, 3-ethyl-1,5,6,7- tetrahydro- 2-methyl-5-(4-morpholinylmethyl) and represented by formula I. Molindone is indicated for management of schizophrenia and is under clinical trial for alternate therapies.
- the present invention provides process for preparation of molindone (I) comprising:
- the present invention further provides process for preparation of compound (2) comprising:
- the present invention provides process for preparation of molindone (I) or its pharmaceutically salts thereof, comprising
- the present invention provides process for preparation of molindone (I) or its pharmaceutically salts thereof, comprising
- the present invention provides novel compound 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4).
- the compound (4) is useful as an intermediate for preparation of molindone.
- the compound (4) was isolated in a purity of above 95%.
- 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) is characterized by 1 H NMR (500 MHz, CDCl 3 ), ⁇ 5.14; (S 1H), ⁇ 4.37; (d 1H), ⁇ 2.50-2.55; (m 2H) ⁇ 2.35-2.38; (m 2H), ⁇ 2.16; (s 3H), ⁇ 2.00-2.05; (m 2H) ⁇ 1.88-1.90; (m 2H), ⁇ 1.00-1.02; (m 3H); 13 C NMR (500 MHz, CDCl 3 ),206.04,199.34,176.63,103.70,77.12,36.62,28.88,25.44,21.00,16.55,9.41 ppm; Dept135 NMR(500 MHz, CDCl 3 ): 103.70,83.78,36.62,28.87,28.65,25.45,24.69,21.00,9.41ppm
- the present invention provides process for preparation of 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4), comprising
- the present invention provides process for preparation of molindone (I) or its pharmaceutically salts thereof, comprising
- the present invention provides process for preparation of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) comprising reacting compound (2) with cyclohexane-1,3-dione (3) in presence of R-NH 2 , base, solvent and catalyst, wherein R is H, alkyl or aryl.
- the present invention provides process for preparation of molindone (I) or its pharmaceutically salts thereof, comprising
- the present invention provides process for preparation of compound (2) comprising:
- the reaction of compound (1′) with ethyl halide can be carried out in presence of base and a solvent .
- R is alkyl selected from straight chain or branched like methyl, ethyl, propyl, butyl and the like.
- ethyl halide can be selected from ethyl iodide, ethyl bromide , ethyl chloride.
- the reaction can be carried out at a temperature of about 40 to 100° C. for 12 to 16 hours.
- further reaction with another halide source can be carried out in presence of a solvent at a temperature of about 0 to 100° C. for 30 minutes to 6 hours.
- Another halide source can be selected from N-chlorosuccimide, N-bromosuccinimde, N-Iodosuccinimide, sulfuryl chloride and the like.
- compound (2′) is converted to compound (2) by treating compound (2′) with acid in presence of water or aqueous solvent or a solvent.
- the acid can be selected from inorganic acid or organic acid.
- Inorganic acid may be selected from hydrochloric acid, sulfuric acid, and the like.
- Organic acid may be selected from acetic acid, para toluene sulfonic acid and the like.
- the reaction can be carried out at a temperature of about 20 to 100° C. for about 24 hours.
- the solvent can be selected from organic polar or non-polar solvent.
- Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers like tetrahydrofuran, dioxane, dimethoxyethane; dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane; acids like acetic acid; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl
- Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like
- chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- the base can be selected from inorganic bases or organic base
- the inorganic base can be selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate lithium bicarbonate, cesium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia; and the organic base can be selected fromalkyl and aryl amines such as
- preparation of compound (2) can be carried out in stepwise manner, by isolation of the intermediates or can be carried out in-situ.
- the reaction of pentan-2-one (1) with a halide source can be carried out in presence of a solvent.
- the solvent can be selected from organic polar or non-polar solvent.
- Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers like tetrahydrofuran, dioxane, dimethoxyethane; dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane
- Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- the halide source can be selected from N-chlorosuccimide, N-bromosuccinimde, N-Iodosuccinimide, sulfuryl chloride and the like.
- the reaction can be optionally carried out in presence of catalyst selected from sodium iodide, sodium bromide and the like.
- the compound (2) may be isolated by techniques known in art or may be used in-situ for further reactions. The reaction can be carried out at a temperature of 0-5° C. to reflux temperature of the solvent over a period 30 minutes to 24 hours.
- the reaction of compound (2) with cyclohexane-1,3-dione (3) can be carried out in presence of a solvent and a base and optionally in presence of catalyst.
- the solvent can be selected from organic polar or non-polar solvent.
- Polar solvent can be selected from nitriles like acetonitrile, propionitrile, butyronitrile; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers like tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; other
- Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like
- chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- the base can be selected from inorganic bases or organic base
- the inorganic base can be selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate lithium bicarbonate, cesium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia; and the organic base can be selected fromalkyl and aryl amines such as
- the catalyst can be selected from quaternary ammonium salts, like tetra-n-butylammonium bromide, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride and the like.
- the reaction can be carried out at a temperature of 25-30° C. to reflux temperature of the solvent over a period 30 minutes to 24 hours.
- the product 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) can be isolated by techniques known in art or may be used in-situ for further reactions.
- the cyclization of 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) can be carried out in presence of suitable reagent selected from urea/choline chloride, ammonium acetate, aqueous ammonia, methanolic ammonia, ammonium chloride or the like in presence of solvent.
- suitable reagent selected from urea/choline chloride, ammonium acetate, aqueous ammonia, methanolic ammonia, ammonium chloride or the like in presence of solvent.
- the solvent can be selected from organic polar or non-polar solvent, water or mixtures thereof.
- Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ether solvents such as ethers like tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like; acids like acetic acid and the like; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl
- Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like
- chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- the product 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) can be isolated by techniques known in art.
- reaction of compound (2) with cyclohexane-1,3-dione (3) to give 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) can be carried out in presence of R-NH 2 , base, solvent and catalyst, wherein R is H, alkyl or aryl.
- the base is organic base selected from alkyl and aryl amines such as methylamine, ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine or mixtures thereof.
- the catalyst is preferably sulphonic acids on Wang resins, like Wang sulfonic acid and the like.
- the solvent can be selected from organic polar, organic non-polar or water.
- Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers like tetrahydrofuran, dioxane, dimethoxyethane; dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane; acids like acetic acid; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl
- Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like
- chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- the reaction of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with morpholine and formaldehyde can be carried out in presence of solvent selected fromalcohols like methanol, ethanol, butanol, propanol.
- solvent selected fromalcohols like methanol, ethanol, butanol, propanol.
- the reaction can be carried out at a temperature of 25-30° C. to reflux temperature of the solvent over a period 30 minutes to 24 hours.
- the product molindone can be isolated by techniques known in art.
- the compound molindone can be optionally converted into pharmaceutically acceptable salt.
- the salt can be selected from hydrochloride, hydro bromide, sulfuric, nitric, phosphoric, oxalic, tartaric, citric, acetic, succinic, maleic and the like.
- the salt formation can be carried out by techniques known in the art.
- the compounds and intermediates can be isolated by techniques known in the art like filtration, concentration, crystallization, removal of solvent by evaporation, distillation, centrifugation, cooling etc.
- Example 7 preparation of molindone hydrochloride.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Indole Compounds (AREA)
Abstract
The present invention provides process for preparation of molindone (I) comprising: a) reacting compound with cyclohexane-1,3-dione to form 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione wherein X is Cl, Br or I, b) cyclizing 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione to 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole, c) reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole with morpholine and formaldehyde to give molindone (I), and d) optionally converting molindone (I) to its salt. The present invention further provides process for preparation of compound comprising: a) reacting compound with ethyl halide and another halide source to form compound wherein R is alkyl and X is Cl, Br or I; b)converting compound to compound.
Description
- The present invention provides novel process for preparation of Molindone and its salts. The present invention also provides novel intermediate for preparation of Molindone.
- Molindone is chemically known as4H-Indol-4-one, 3-ethyl-1,5,6,7- tetrahydro- 2-methyl-5-(4-morpholinylmethyl) and represented by formula I. Molindone is indicated for management of schizophrenia and is under clinical trial for alternate therapies.
- The compound molindone, process for its preparation and its pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 3,491,09. Another application WO 2014042688 discloses methods of producing molindone. Since there are very limited methods for preparation of molindone reported in literature there exist a need for alternate process for preparation of molindone. The present invention provides novel process for preparation of Molindone (I) and its salts.
- The present invention provides process for preparation of molindone (I) comprising:
-
- a) reacting compound (2) with cyclohexane-1,3-dione (3) to form 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4)
-
-
- wherein X is Cl, Br or I,
- b) cyclizing 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5),
-
-
- c) reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with morpholine and formaldehyde to give molindone (I), and
- d) optionally converting molindone (I) to its salt.
- The present invention further provides process for preparation of compound (2) comprising:
-
- a) reacting compound (1′) with ethyl halide and another halide source to form compound (2′) wherein R is alkyl and X is Cl, Br or I
-
- b) converting compound (2′) to compound (2).
- In the first embodiment, the present invention provides process for preparation of molindone (I) or its pharmaceutically salts thereof, comprising
-
- a) reacting pentan-2-one (1) with a halide source to form compound (2), wherein X is Cl, Br or I
- b) reacting compound (2) with cyclohexane-1,3-dione (3) to form 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4),
- c) cyclizing 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5),
- d) reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with morpholine and formaldehyde to give molindone, and
- e) optionally converting molindone to its salt.
- In the second embodiment, the present invention provides process for preparation of molindone (I) or its pharmaceutically salts thereof, comprising
-
- a) reacting compound (2) with cyclohexane-1,3-dione (3) to form 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4), wherein X is Cl, Br or I,
- b) cyclizing 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5),
- c) reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with morpholine and formaldehyde to give molindone, and
- d) optionally converting molindone to its salt.
- In the third embodiment, the present invention provides novel compound 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4). The compound (4) is useful as an intermediate for preparation of molindone. The compound (4) was isolated in a purity of above 95%. 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) is characterized by 1H NMR (500 MHz, CDCl3), δ 5.14; (S 1H), δ 4.37; (d 1H), δ 2.50-2.55; (m 2H) δ 2.35-2.38; (m 2H), δ 2.16; (s 3H), δ 2.00-2.05; (m 2H) δ 1.88-1.90; (m 2H), δ 1.00-1.02; (m 3H); 13C NMR (500 MHz, CDCl3),206.04,199.34,176.63,103.70,77.12,36.62,28.88,25.44,21.00,16.55,9.41 ppm; Dept135 NMR(500 MHz, CDCl3): 103.70,83.78,36.62,28.87,28.65,25.45,24.69,21.00,9.41ppm; Mass: [M+1]=197.
- In the fourth embodiment, the present invention provides process for preparation of 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4), comprising
-
- a) reacting pentan-2-one (1) with a halide source to form compound (2), and wherein X is Cl Br or I
- b) reacting compound (2) with cyclohexane-1,3-dione (3) to form 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4)
- In the fifth embodiment, the present invention provides process for preparation of molindone (I) or its pharmaceutically salts thereof, comprising
-
- a) converting 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5),
- b) reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with morpholine and formaldehyde to give molindone (I), and
- c) optionally converting molindone (I) to its salt.
- In the sixth embodiment, the present invention provides process for preparation of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) comprising reacting compound (2) with cyclohexane-1,3-dione (3) in presence of R-NH2, base, solvent and catalyst, wherein R is H, alkyl or aryl.
- In the seventh embodiment, the present invention provides process for preparation of molindone (I) or its pharmaceutically salts thereof, comprising
-
- a) reacting compound (2) with cyclohexane-1,3-dione (3) in presence of R-NH2, base, solvent and catalyst, wherein R is H, alkyl or aryl to give 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) and
- b) reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with morpholine and formaldehyde to give molindone (I), and
- c) optionally converting molindone (I) to its salt.
- In aneight embodiment, the present invention provides process for preparation of compound (2) comprising:
-
- a) reacting compound (1′) with ethyl halide and another halide source to form compound (2′) wherein R is alkyl and X is Cl, Br or I
- b) converting compound (2′) to compound (2)
- In the present invention, the reaction of compound (1′) with ethyl halide can be carried out in presence of base and a solvent . In the compound (1′), R is alkyl selected from straight chain or branched like methyl, ethyl, propyl, butyl and the like. In the reaction ethyl halide can be selected from ethyl iodide, ethyl bromide , ethyl chloride. The reaction can be carried out at a temperature of about 40 to 100° C. for 12 to 16 hours.
- In the present invention, further reaction with another halide source can be carried out in presence of a solvent at a temperature of about 0 to 100° C. for 30 minutes to 6 hours. Another halide source can be selected from N-chlorosuccimide, N-bromosuccinimde, N-Iodosuccinimide, sulfuryl chloride and the like.
- In the present invention, compound (2′) is converted to compound (2) by treating compound (2′) with acid in presence of water or aqueous solvent or a solvent. The acid can be selected from inorganic acid or organic acid. Inorganic acid may be selected from hydrochloric acid, sulfuric acid, and the like. Organic acid may be selected from acetic acid, para toluene sulfonic acid and the like. The reaction can be carried out at a temperature of about 20 to 100° C. for about 24 hours.
- In the above reactions the solvent can be selected from organic polar or non-polar solvent. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers like tetrahydrofuran, dioxane, dimethoxyethane; dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane; acids like acetic acid; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- The base can be selected from inorganic bases or organic base, the inorganic base can be selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate lithium bicarbonate, cesium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia; and the organic base can be selected fromalkyl and aryl amines such as methylamine, ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine or mixtures thereof.
- In the present invention, preparation of compound (2) can be carried out in stepwise manner, by isolation of the intermediates or can be carried out in-situ.
- In the present invention, the reaction of pentan-2-one (1) with a halide source can be carried out in presence of a solvent. The solvent can be selected from organic polar or non-polar solvent. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers like tetrahydrofuran, dioxane, dimethoxyethane; dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane; acids like acetic acid; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof. The halide source can be selected from N-chlorosuccimide, N-bromosuccinimde, N-Iodosuccinimide, sulfuryl chloride and the like. The reaction can be optionally carried out in presence of catalyst selected from sodium iodide, sodium bromide and the like. The compound (2) may be isolated by techniques known in art or may be used in-situ for further reactions. The reaction can be carried out at a temperature of 0-5° C. to reflux temperature of the solvent over a period 30 minutes to 24 hours.
- The reaction of compound (2) with cyclohexane-1,3-dione (3) can be carried out in presence of a solvent and a base and optionally in presence of catalyst. The solvent can be selected from organic polar or non-polar solvent. Polar solvent can be selected from nitriles like acetonitrile, propionitrile, butyronitrile; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers like tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- The base can be selected from inorganic bases or organic base, the inorganic base can be selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate lithium bicarbonate, cesium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia; and the organic base can be selected fromalkyl and aryl amines such as methylamine, ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine or mixtures thereof.
- The catalyst can be selected from quaternary ammonium salts, like tetra-n-butylammonium bromide, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride and the like. The reaction can be carried out at a temperature of 25-30° C. to reflux temperature of the solvent over a period 30 minutes to 24 hours. The product 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) can be isolated by techniques known in art or may be used in-situ for further reactions.
- The cyclization of 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) can be carried out in presence of suitable reagent selected from urea/choline chloride, ammonium acetate, aqueous ammonia, methanolic ammonia, ammonium chloride or the like in presence of solvent. The solvent can be selected from organic polar or non-polar solvent, water or mixtures thereof. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ether solvents such as ethers like tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like; acids like acetic acid and the like; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof. The product 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) can be isolated by techniques known in art.
- The reaction of compound (2) with cyclohexane-1,3-dione (3) to give 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) can be carried out in presence of R-NH2, base, solvent and catalyst, wherein R is H, alkyl or aryl.
- The base is organic base selected from alkyl and aryl amines such as methylamine, ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine or mixtures thereof. The catalyst is preferably sulphonic acids on Wang resins, like Wang sulfonic acid and the like.
- The solvent can be selected from organic polar, organic non-polar or water. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers like tetrahydrofuran, dioxane, dimethoxyethane; dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane; acids like acetic acid; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.
- The reaction of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5) with morpholine and formaldehyde can be carried out in presence of solvent selected fromalcohols like methanol, ethanol, butanol, propanol. The reaction can be carried out at a temperature of 25-30° C. to reflux temperature of the solvent over a period 30 minutes to 24 hours. The product molindone can be isolated by techniques known in art.
- The compound molindone can be optionally converted into pharmaceutically acceptable salt. The salt can be selected from hydrochloride, hydro bromide, sulfuric, nitric, phosphoric, oxalic, tartaric, citric, acetic, succinic, maleic and the like. The salt formation can be carried out by techniques known in the art.
- In the present invention, the compounds and intermediates can be isolated by techniques known in the art like filtration, concentration, crystallization, removal of solvent by evaporation, distillation, centrifugation, cooling etc.
- The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.
- A mixture of methyl acetoacetate (100 g), potassium tertiary butoxide (101.5 g) and tetrahydrofuran (400 ml) was stirred and a solution of ethyliodide (141 g) in tetrahydrofuran (200 ml) was added to it. The reaction mixture was stirred at 60° C. for about 15 hours. Water (250 ml) was added to the reaction mixture at 25° C. followed by addition of dichloromethane (500 ml). The organic layer was separated and concentrated. To the concentrate was added dichloromethane (1000 ml) and sulfuryl chloride (93.7 g) and the solution was stirred for about 18 hours at 25-30° C. Water (500 ml) was added to the reaction mixture. The organic layer was separated and concentrated to give the title compound.
- A mixture of methyl 2-chloro-2-ethyl-3-oxobutanoate (98.8 g) and water (240 ml) was treated with sulfuric acid (260 g) and stirred for 90 minutes at 75-80° C. The reaction mixture was poured into water (500 ml) and dichloromethane (500 ml). The organic layer was separated and concentrated. The concentrate was subjected to fractional distillation and pure compound was collected.
- A mixture of petane-2-one (15 g), acetic acid (60 ml) and N-chlorosuccinimide (24.4 g) was stirred for about 18 hours at 80-85° C. The reaction mixture was cooled and dichloromethane (100 ml) was added to it. The mixture was treated with sodium bicarbonate solution. The organic layer was separated and concentrated to give the title compound (2).
- A mixture of3-bromopentan-2-one (17 g), cyclohexane-1,3-dione (11.5 g), triethyl amine (15.6 g) and acetonitrile (100 ml)) was stirred for about 2 hours at 55-60° C. The reaction mixture was concentrated and ethyl acetate (170 ml) and water (85 ml) was added. The organic layer separated and concentrated. The residue was subjected to column chromatography (ethylacetate: cyclohexane). The title compound was obtained. 1H NMR (500 MHz, CDCl3), δ 5.14; (S 1H), δ 4.37; (d 1H), δ 2.50-2.55; (m 2H) δ 2.35-2.38; (m 2H), δ 2.16; (s 3H), δ 2.00-2.05; (m 2H) δ 1.88-1.90; (m 2H), δ 1.00-1.02; (m 3H); 13C NMR (500 MHz, CDCl3),206.04,199.34,176.63,103.70,77.12,36.62,28.88,25.44,21.00,16.55,9.41 ppm; Dept135 NMR(500 MHz, CDCl3): 103.70,83.78,36.62,28.87,28.65,25.45,24.69,21.00,9.41ppm; Mass: [M+1]=197.
- A mixture of 2-(2-oxopentan-3-yl)cyclohexane-1, 3-dione (10g), acetic acid (40 ml) and ammonium acetate (19.6 g) was stirred for about 3 hours at 95-100° C. The reaction mixture was cooled and concentrated. To the residue a mixture of ethyl acetate (60 ml) and water (50 ml) was added. The organic layer separated and concentrated to give the title compound.
- Example 6: preparation of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5)
- A mixture of cyclohexane-1,3-dione (3 g), dimethyl sulfoxide (15 ml), triethyl amine (2.7 g) and 3-chloropentan-2-one (3.2 g) was stirred for about 24 hours at 40-45° C. Aqueous ammonia (15 ml) was added to the mixture and stirred for about 10 hours at 25-30° C. A mixture of water (60 ml) and ethyl acetate (30 ml) was added to it. The organic layer separated and concentrated. The residue was subjected to column chromatography (ethyl acetate/n-hexane). The title compound was obtained.
- Example 7: preparation of molindone hydrochloride.
- A mixture of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5 g), morpholine (4.42 g), paraformaldehyde (1.52 g) and ethanol (70 ml) was stirred for about 24 hours at 75-80° C. The reaction mixture was concentrated and water (50 ml) was added to the residue. The mixture was treated with concentrated hydrochloric acid followed by aqueous ammonia in presence of ethyl acetate. The organic layer was separated and concentrated to obtain molindone as a residue. Isopropanol hydrochloride was added to the residue and stirred for 30 minutes at 25-30° C. The solution was concentrated and ethyl acetate (15 ml) was added. The solid was filtered, washed with ethyl acetate and dried to obtain molindone hydrochloride.
Claims (11)
1. A process for the preparation of molindone (I) comprising:
a) reacting compound (2) with cyclohexane-1,3-dione (3) to form 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4)
wherein X is Cl, Br or I,
b) cyclizing 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4) to 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5),
4. The process according to claim 1 , wherein the cyclization process of step (b) is carried out in presence of reagent selected from ammonium acetate, aqueous ammonia, methanolic ammonia, ammonium chloride or urea and choline chloride.
5. The process according to claim 2 , wherein ethyl halide is selected from ethyl iodide, ethyl bromide or ethyl chloride.
6. The process according to claim 2 , wherein halide source is selected from N-chlorosuccimide, N-bromosuccinimde, N-Iodosuccinimide orsulfuryl chloride.
7. The process according to claim 2 , wherein compound (2′) is converted to compound (2) by treating with acid selected from hydrochloric acid, sulfuric acid, acetic acid or para toluene sulfonic acid.
8. The process according to claim 1 , wherein molindone salt is hydrochloride salt.
9. The process according to claim 1 , wherein the reaction of compound (2) and cyclohexane-1,3-dione is carried out in presence of solvent and base.
10. The process according to claim 9 , wherein the solvent is selected fromacetonitrile, propionitrile, butyronitrile, ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate, tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, dimethylformamide, toluene, dichloro methane or ethylene dichloride.
11. The process according to claim 9 , wherein the base is selected from ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine or 4-dimethylaminopyridine.
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