JP2008515879A - アリピプラゾールの製造方法、並びに対応する中間体及びそれらの製造 - Google Patents
アリピプラゾールの製造方法、並びに対応する中間体及びそれらの製造 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 44
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 34
- 239000000543 intermediate Substances 0.000 title claims abstract description 33
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- DXEOJRJYNSFSFL-UHFFFAOYSA-N 6-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-2,3-dihydroinden-1-one Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4C(=O)CCC4=CC=3)CC2)=C1Cl DXEOJRJYNSFSFL-UHFFFAOYSA-N 0.000 claims abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 235000011181 potassium carbonates Nutrition 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- MQAYPFVXSPHGJM-UHFFFAOYSA-M trimethyl(phenyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)C1=CC=CC=C1 MQAYPFVXSPHGJM-UHFFFAOYSA-M 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 2
- 229940106681 chloroacetic acid Drugs 0.000 claims description 2
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- MOANRQDXNNXOLW-UHFFFAOYSA-N 6-hydroxyindanone Natural products OC1=CC=C2CCC(=O)C2=C1 MOANRQDXNNXOLW-UHFFFAOYSA-N 0.000 abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- -1 2,3-dichlorophenyl Chemical group 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- UDQMXYJSNNCRAS-UHFFFAOYSA-N 2,3-dichlorophenylpiperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1Cl UDQMXYJSNNCRAS-UHFFFAOYSA-N 0.000 description 3
- IXYSVHVGZZIRNC-UHFFFAOYSA-N 6-(4-chlorobutoxy)-2,3-dihydroinden-1-one Chemical compound ClCCCCOC1=CC=C2CCC(=O)C2=C1 IXYSVHVGZZIRNC-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- KJDRSWPQXHESDQ-UHFFFAOYSA-N 1,4-dichlorobutane Chemical compound ClCCCCCl KJDRSWPQXHESDQ-UHFFFAOYSA-N 0.000 description 2
- GMCKRZZXDSWMTP-UHFFFAOYSA-N 6-(4-bromobutoxy)-2,3-dihydroinden-1-one Chemical compound BrCCCCOC1=CC=C2CCC(=O)C2=C1 GMCKRZZXDSWMTP-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000000561 anti-psychotic effect Effects 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- ZZIANJABSBSRBK-UHFFFAOYSA-N 1-(2,3-dichlorophenyl)piperazine;hydrobromide Chemical compound Br.ClC1=CC=CC(N2CCNCC2)=C1Cl ZZIANJABSBSRBK-UHFFFAOYSA-N 0.000 description 1
- CYQFNNSFAGXCEC-UHFFFAOYSA-N 1-(2,3-dichlorophenyl)piperazine;hydrochloride Chemical compound [Cl-].ClC1=CC=CC(N2CC[NH2+]CC2)=C1Cl CYQFNNSFAGXCEC-UHFFFAOYSA-N 0.000 description 1
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical compound NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 description 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- MYDQBNQZWOOKDG-UHFFFAOYSA-N 6-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-2,3-dihydroinden-1-one;hydrochloride Chemical compound Cl.ClC1=CC=CC(N2CCN(CCCCOC=3C=C4C(=O)CCC4=CC=3)CC2)=C1Cl MYDQBNQZWOOKDG-UHFFFAOYSA-N 0.000 description 1
- ZPOARNXSPFNVTK-UHFFFAOYSA-N 7-hydroxy-3H-quinolin-2-one Chemical compound OC=1C=CC2=CCC(N=C2C=1)=O ZPOARNXSPFNVTK-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000006085 Schmidt reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229960004319 trichloroacetic acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0239—Quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Materials Engineering (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
- Quinoline Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
の1,4−ジハロブタンと塩基及び溶媒の存在下で90から110度Cの範囲の温度にて反応させて式3の新規中間体を形成させることを含む方法を提供する。
(i)式11の化合物を式12(ここで、XはCl又はBrを表す)の1,4−ジハロブタンと塩基及び溶媒の存在下で90から110度Cの範囲の温度にて反応させて式3の新規中間体を形成させ、そして
(ii)工程(i)において得られた式3の新規化合物を式9
ことを含む方法も提供される。
(i)式11の化合物を式12(ここで、XはCl又はBrを表す)の1,4−ジハロブタンと塩基及び溶媒の存在下で90から110度Cの範囲の温度にて反応させて式3の新規中間体を形成させ、
(ii)工程(i)において得られた式3の新規化合物を式9の化合物と塩基並びに相間移動触媒及び溶媒の存在下で80から120度Cの範囲の温度にて反応させて式2の新規中間体を形成させ、そして
(iii)式2の生じた新規化合物をアジ化ナトリウム又はトリメチルシリルアジドと酸の存在下で50から90度Cの間の温度にて反応させて(シュミット反応)式1の化合物を得る
ことを含む方法が提供される。
工程1
式3の新規中間体6−(4−クロロブトキシ)−インダン−1−オンの製造方法
IR(cm-1): 1697.88、1616.31、1492.71、1296.57、1055.33、837.51、720.75。
PMR: δ:1.96(m,4H)、2.70(m,2H)、3.06(t,2H)、3.61(t,2H)、4.02(t,2H)、7.18(m,2H)、7.36(d,1H)。
CMR: δ:24.99(t)、26.45(t)、29.19(t)、36.87(t)、44.54(t)、67.31(t)、105.56(d)、124.12(d)、127.30(d)、138.11(s)、147.84(s)、158.49(s)、206.75(s)。
質量スペクトル: m/z(%)=[M+1]239(100)、197.1(15.7)、161.2(48.8)、149.0(22.8)、107.1(27.8)。
式2の新規6−[4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]−ブトキシ]−インダン−1−オンの製造方法
IR(cm-1):1711.81、1576.39、1474.07、1448.34、1292.80、1274.96、1240.72、994.75、963.85、775.15、712.75。
MR: δ:1.72(m,2H)、1.84(m,2H)、2.48(t,2H)、2.65(m,2H)、2.71(t,2H)、3.06(m,2H)、4.02(t,2H)、6.95(q,2H)、7.14〜7.37(m,5H)。
CMR: δ:23.16(t)、24.86(t)、26.89(t)、36.74(t)、51.09(t)、53.05(t)、57.88(t)、67.82(t)、105.32(d)、118.36(t)、124.06(d)、124.21(d)、127.11(d)、127.22(d)、133.69(s)、137.93(s)、147.54(s)、151.07(s)、158.49(s)、206.62(s)。
質量スペクトル: m/z(%):[m+1]=433.5(36.7)、285.3(20.5)、161.6(100)。
式1の7−[4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]−ブトキシ]−3,4−ジヒドロ−1(H)−キノリン−2−オン(アリピプラゾール)の製造方法
IR(cm-1): 1677.95、1626.97、1595.06、1521.51、1447.24、1376.84、1172.27、960.70、778.54。
PMR: δ:1.69(m,2H),1.81(m,2H)、2.48(t,2H)、2.62(m,6H)、2.89(t,2H)、3.07(m,4H)、3.95(t,2H)、6.31(d,1H)、6.53(dd,1H)、6.96(q,1H)、7.02(d,1H)、7.14(m,2H)、8.00(s,1H)。
CMR: δ:23.34(t)、24.49(t)、27.20(t)、31.00(t)、51.26(t)、53.20(t)、58.10(t)、67.81(t)、102.25(d)、108.68(d)、115.55(s)、118.50(d)、124.41(d)、127.34(d)、127.40(d)、128.45(d)、133.91(s)、138.21(s)、151.25(s)、158.62(s)、172.31(s)。
質量スペクトル: m/z(%):[M+1]=448.2(100)、285.5(74.2)、218.5(22.8)、176.5(20.0)。
工程1
式3の6−(4−ブロモブトキシ)−インダン−1−オンの製造方法
IR(cm-1): 1705.61、1610.51、1488.19、1294.21、1021.54、836.60、558.98。
PMR: δ:1.94(m,2H)、2.06(m,2H)、2.71(m,2H)、3.06(t,2H)、3.47(t,2H)、4.01(t,2H)、7.17(m,2H)、7.36(d,1H)。
CMR: δ:25.01(t)、27.69(t)、29.35(t)、33.18(t)、36.01(t)、67.19(t)、105.57(d)、124.16(d)、127.31(d)、138.13(s)、147.87(s)、158.50(s)、206.77(s)。
質量スペクトル: m/z(%)=[M+1]283.4(55.1)、161.1(66.1)、149.4(40.4)、135.4(100)、106.9(38.2)。
6−[4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]−ブトキシ]−インダン−1−オンの製造方法
上記の工程1において記載された方法により製造された6−(4−ブロモブトキシ)−インダン−1−オン(100g,0.282mol,80%純度)とヨウ化ナトリウム(42g,0.28mol)との混合物をアセトニトリル中で30分間還流し、そして次いで室温に冷却した。この混合物に1−(2,3−ジクロロフェニル)−ピペラジン塩酸塩(68g,0.294mol)及びトリエチルアミン(77g,0.761mol)を添加し、そして生じた混合物を4〜6hr還流した。溶媒を除去した後、かくして得られた残渣をクロロホルム中に溶解し、水で洗浄し、そしてクロロホルム及び及び塩酸で処理すると、140gの6−[4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]−ブトキシ]−インダン−1−オン塩酸塩が得られた。クロロホルム溶液におけるこれを水酸化アンモニウムでpH9.5まで塩基性にし、そしてクロロホルムで2回(2×500ml)抽出した。クロロホルム層を一緒にし、減圧下で回転蒸発器を用いて濃縮して残渣を得、そしてこの残渣をメタノールで精製すると、85gの式2の6−[4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]−ブトキシ]−インダン−1−オン(実施例1の工程2について得られた生成物と同一の特性を有する)が得られた。
7−[4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]−ブトキシ]−3,4−ジヒドロ−1(H)−キノリン−2−オン(アリピプラゾール)の製造方法
工程2により製造された6−[4−[4−(2,3−ジクロロフェニル)−1−ピペラジニル]−ブトキシ]−インダン−1−オン(15g,34.63mmol)及び90mlのトリフルオロ酢酸を添加し、そしてアジ化ナトリウム(9g,138.46mmol)を65℃にて少しずつ添加した。この反応混合物を65℃に8〜10hr維持した。維持期間が終わった後、この反応混合物を100gの粉砕氷中へ急冷し、クロロホルムで抽出し、そしてこのクロロホルムをアンモニア水溶液で塩基性にしそして有機層を分離した。有機層を無水硫酸ナトリウムで乾燥しそして減圧下で濃縮して残渣19gを得、そしてこの残渣をメタノール/トルエン及びアセトンで結晶化すると、式1の純粋なアリピプラゾールが得られた。
1.製造されたアリピプラゾールは、高純度(99%より大)を有する。
2.問題のある除去不能な不純物の形成が回避される。
3.式2及び3の新規中間体が提供される。
Claims (17)
- 式1のアリピプラゾールの改良製造方法であって、
(i)式11の化合物を式12(ここで、XはCl又はBrを表す)の1,4−ジハロブタンと塩基及び溶媒の存在下で90から110度Cの範囲の温度にて反応させて式3の新規中間体を形成させ、
(ii)工程(i)において得られた式3の新規化合物を式9の化合物と塩基並びに相間移動触媒及び溶媒の存在下で80から120度Cの範囲の温度にて反応させて式2の新規中間体を得、そして
(iii)式2の生じた新規化合物をアジ化ナトリウム又はトリメチルシリルアジドと酸の存在下で50から70度Cの間の温度にて反応させて式1の化合物を得、そして所望されるならば式1の化合物を再結晶する
ことを含む方法。 - 水素化ナトリウム、ナトリウムメトキシド、トリエチルアミン、炭酸カリウム、重炭酸ナトリウム及び炭酸ナトリウムのような塩基、好ましくはトリエチルアミン最も好ましくは炭酸カリウムを工程(i)において用いる、請求項3〜5のいずれか一項に記載の方法。
- 工程(i)において用いられる溶媒が、アセトン、クロロホルム、メチレンクロライド、エチレンジクロライド、ジメチルホルムアミド、ジメチルスルホキシド、アセトニトリル、等、好ましくはアセトンそして最も好ましくは1,4−ジハロブタンから選択される、請求項3〜6のいずれか一項に記載の方法。
- 工程(i)において用いられる温度が、90〜110°の間そして最も好ましくは100〜110°の間にある、請求項3〜7のいずれか一項に記載の方法。
- 工程(ii)において用いられる塩基が、炭酸ナトリウム、炭酸カリウム、重炭酸ナトリウム、重炭酸カリウム、水素化ナトリウム、水素化カリウム及びトリエチルアミン、最も好ましくは炭酸ナトリウムを包含する、請求項3〜8のいずれか一項に記載の方法。
- 工程(ii)において用いられる溶媒が、アセトニトリル、アセトン、ジメチルホルムアミド、ジメチルスルホキシド、エタノール、メタノール、n−ブタノール及び水、好ましくはアセトン及び水そして最も好ましくは水から選択される、請求項3〜9のいずれか一項に記載の方法。
- 工程(ii)において用いられる温度が、80〜120℃の間そして最も好ましくは100〜120℃の間にある、請求項3〜10のいずれか一項に記載の方法。
- 工程(i)及び(ii)において用いられる相間移動触媒が、テトラブチルアンモニウムクロライド、テトラブチルアンモニウムブロマイド、ベンジルトリエチルアンモニウムクロライド、フェニルトリメチルアンモニウムクロライドである、請求項3〜11のいずれか一項に記載の方法。
- 工程(iii)において用いられる酸が、硫酸、塩化アルミニウム、ホウ素トリフルオロエーテラート、トリフルオロ酢酸、メタンスルホン酸、クロロ酢酸、ジクロロ酢酸及びトリフルオロメタンスルホン酸、好ましくはトリフルオロ酢酸及びメタンスルホン酸そして最も好ましくはトリフルオロ酢酸を包含する、請求項3〜12のいずれか一項に記載の方法。
- 工程(iii)において用いられる反応剤アジ化物が、トリメチルシリルアジド及びアジ化ナトリウム、好ましくはアジ化ナトリウムである、請求項3〜13のいずれか一項に記載の方法。
- 工程(iii)において用いられる温度が、50〜90℃の間そして最も好ましくは60〜70℃の間にある、請求項3〜14のいずれか一項に記載の方法。
- 工程(iii)において用いられるアジ化ナトリウムの量が、用いられる式2の化合物に対して1〜5モル当量、好ましくは1.5〜4モル当量の間にある、請求項3〜15のいずれか一項に記載の方法。
- 工程(iii)において再結晶のために用いられる溶媒が、アセトン、クロロホルム、メチレンクロライド、エチレンジクロライド、ジメチルホルムアミド、ジメチルスルホキシド、アセトニトリル、等、好ましくはアセトンそして最も好ましくはメタノールから選択される、請求項3〜16のいずれか一項に記載の方法。
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RU2497819C2 (ru) | 2007-05-21 | 2013-11-10 | Ривайва Фармасьютикалс, Инк. | Композиции, синтез и способы применения атипичных нейролептиков на основе хинолина |
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