HRP20020742A2 - Method for the preparation of citalopram - Google Patents
Method for the preparation of citalopram Download PDFInfo
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- HRP20020742A2 HRP20020742A2 HR20020742A HRP20020742A HRP20020742A2 HR P20020742 A2 HRP20020742 A2 HR P20020742A2 HR 20020742 A HR20020742 A HR 20020742A HR P20020742 A HRP20020742 A HR P20020742A HR P20020742 A2 HRP20020742 A2 HR P20020742A2
- Authority
- HR
- Croatia
- Prior art keywords
- formula
- citalopram
- compound
- followed
- reaction
- Prior art date
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- 229960001653 citalopram Drugs 0.000 title claims description 37
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 title claims description 36
- 238000000034 method Methods 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical group 0.000 claims description 10
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 8
- 238000006268 reductive amination reaction Methods 0.000 claims description 8
- 230000001430 anti-depressive effect Effects 0.000 claims description 7
- -1 sulfonyl ester Chemical class 0.000 claims description 7
- 239000000935 antidepressant agent Substances 0.000 claims description 6
- 229940005513 antidepressants Drugs 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 238000002955 isolation Methods 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 5
- 230000011987 methylation Effects 0.000 claims description 5
- 238000007069 methylation reaction Methods 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 150000001540 azides Chemical class 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- 229910044991 metal oxide Inorganic materials 0.000 claims description 2
- 150000004706 metal oxides Chemical class 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
- 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 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- WSEQXVZVJXJVFP-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 WSEQXVZVJXJVFP-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 150000003891 oxalate salts Chemical class 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- KTGRHKOEFSJQNS-UHFFFAOYSA-N Citalopram Oxalate Chemical compound OC(=O)C(O)=O.O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 KTGRHKOEFSJQNS-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- JIKYAUBJQSVFAE-UHFFFAOYSA-N 1-(3-azidopropyl)-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile Chemical compound C1=CC(F)=CC=C1C1(CCCN=[N+]=[N-])C2=CC=C(C#N)C=C2CO1 JIKYAUBJQSVFAE-UHFFFAOYSA-N 0.000 description 2
- YXCRMKYHFFMNPT-UHFFFAOYSA-N 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical compound C1=CC(F)=CC=C1C1C2=CC=C(C#N)C=C2CO1 YXCRMKYHFFMNPT-UHFFFAOYSA-N 0.000 description 2
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 2
- RKUKMUWCRLRPEJ-UHFFFAOYSA-N Didemethylcitalopram Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCN)C1=CC=C(F)C=C1 RKUKMUWCRLRPEJ-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229940052303 ethers for general anesthesia Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- SKTFQHRVFFOHTQ-UHFFFAOYSA-N 8-bromo-1,3-dimethyl-7h-purine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Br)=N2 SKTFQHRVFFOHTQ-UHFFFAOYSA-N 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- PTJADDMMFYXMMG-UHFFFAOYSA-N Demethylcitalopram Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCNC)C1=CC=C(F)C=C1 PTJADDMMFYXMMG-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N methylsulphonylmethane Natural products CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical class O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
Ovaj se izum odnosi na način priprave dobro poznatog antidepresiva citaloprama, 1-[3-(dimetilamino)propil]-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbonitrila.
Prethodno stanje struke
Citalopram je dobro poznati antidepresiv koji se već nekoliko godina nalazi na tržištu i koji ima sljedeću strukturu:
[image]
To je selektivni, centralno djelujući inhibitor ponovne pohrane serotonina (5-hidroksitriptamin; 5-HT), pa prema tome ima antidepresivno djelovanje. Antidepresivno djelovanje tog spoja opisano je u nekoliko publikacija, npr. J. Hyttel Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1982., 6, 277-295 i A. Gravem Acta Psychiatr. Scand. 1987., 75, 478-486. Osim toga, pokazalo se da taj spoj ima učinka u liječenju demencije i cerebrovaskularnih poremećaja, EP-A-474580.
Citalopram je prvi put opisan u DE 2,657,013, što odgovara US 4,136,193. Objava tog patenta opisuje pripravu citaloprama na jedan način i naznačuje daljnji način koji se može koristiti za pripravu citaloprama.
Prema opisanom postupku, na odgovarajući 1-(4-fluorofenil)-1,3-dihidro-5-izobenzofuran-karbonitril reagira se s 3-(N,N-dimetilamino)propil-kloridom uz prisutnost metilsulfinilmeti-da kao kondenzirajućeg agensa. Početni materijal pripravljen je iz odgovarajućeg 5-bromo derivata reakcijom s bakrenim cijanidom.
Međunarodna patentna prijava br. WO 98/019511 opisuje postupak za proizvodnju citaloprama u kojem se (4-(cijano, alkiloksikarbonil ili alkilaminokarbonil)-2-hidroksimetil-fenil-(4-fluorofenil)metanol podvrgava zatvaranju prstena. Dobiveni 5-(alkiloksi-karbonil ili alkilaminokarbonil)-1-(4-fluorofenil)-1,3-dihidroizobenzofuran konvertira se u odgovarajući 5-cijano derivat, a taj se 5-cijano derivat zatim alkilira s (3-dimetilamino) propilhalogenidom kako bi se dobio citalopram.
Sada se, nenadano, pokazalo da se citalopram može proizvesti novim, pogodnim postupkom.
Postupak alkilacije prema ovom izumu ima posebnih prednosti, jer je izbjegnuto stvaranje nusproizvoda zbog polimerizacije alkilirajućeg agensa, čime je omogućeno smanjenje količine alkilirajućeg agensa koji će se koristiti. Postupak prema ovom izumu također omogućuje visoko iskorištenje.
Sažetak izuma
Dakle, ovaj se izum odnosi na način priprave citaloprama, koji sadrži reakciju spoja formule
[image]
sa spojem koji ima formulu
[image]
gdje je R halogen ili -O-SO2-X, pri čemu je X alkil, alkenil, alkinil ili opcionalno alkilom supstituirani aril ili aralkil, a R1 je dimetilamino, halogen ili -O-SO2-X, pri čemu je X prema gornjoj definiciji, pod uvjetom da R nije halogen kad je R1 dimetilamino;
te ako je R1 dimetilamino nakog čega slijedi izolacija baze citaloprama ili njezine farmaceutski prihvatljive soli,
te ako je R1 halogen ili -O-SO2-X, pri čemu je X prema gornjoj definiciji, nakon čega slijedi konverzija dobivenog spoja formule
[image]
gdje je R2 halogen ili grupa formule -O-SO2-X, a X prema gornjoj definiciji, u citalopram, nakon čega slijedi izolacija baze citaloprama ili njezine farmaceutski prihvatljive soli.
Tako se u jednoj izvedbi ovaj izum odnosi na način u kojem se na spoj formule (II) reagira spojem formule (III) gdje R znači -O-SO2-X, pri čemu je X prema gornjoj definiciji, a R1 je dimetilamino iz kojega direktno nastaje citalopram.
U drugoj izvedbi ovaj se izum odnosi na način u kojem se na spoj formule (II) reagira spojem formule (III), gdje su R i R1 neovisno odabrani iz halogena i -O-SO2-X. Dobiveni spoj formule (IV), u kojem je R2 halogen ili grupa formule -O-SO2-X, pri čemu je X prema gornjoj definiciji, zatim se konvertira u citalopram reakcijom s
a) dimetilaminom ili njegovom metalnom soli,
b) metilaminom, nakon čega slijedi reduktivna aminacija ili
c) azidom nakon čega slijedi redukcija radi stvaranja odgovarajućeg amino spoja, a nakon toga metilacija ili reduktivna aminacija.
U drugom aspektu, ovaj izum nudi nove intermediere opće formule (IV).
U još jednom aspektu, ovaj izum odnosi se na antidepresivnu farmaceutsku smjesu koja sadrži citalopram proizveden postupkom prema ovom izumu.
Faza alkilacije u kojoj se na spoj formule (II) reagira spojem formule (III) prikladno se obavlja tretiranjem spoja formule (II) bazom kao npr. LDA (litijev diizopropilamin), LiHMDS (litijev heksametildisilazan), NaH, NaHMDS (natrijev heksametildisilazan) ili metaloksidima poput NaOMe, KOMe, LiOMe, NaOtertBu, KotertBu i LiOtertBu u aprotičkom organskom otapalu poput THF (tetrahidrofuran), DMF (dimetilformamid), NMP (N-metilpirolidon), etera poput dietiletera ili dioksalana, toluena, benzena ili alkana i njihovih mješavina. Na nastali anion zatim se reagira spojem formule (III) u kojem se grupa formule -CH2-CH2-CH2-R2 ili grupa formule -CH2-CH2-CH2-N(CH3)2 uvodi na položaj 1 sustava izobentofuranilskog prstena.
Na spoj formule (IV) zatim se reagira dimetilaminom ili njegovom metalnom soli, poput M+, N(CH3)2, pri čemu M+ predstavlja Li+ ili Na+. Reakcija se prikladno obavlja u aprotičkom organskom otapalu poput THF (tetradihrofuran), DMF (dimetilformamid), NMP (N-metil pirolidon), etera poput dietiletera ili dioksalana, toluena, benzena ili alkana i njihovih mješavina. Spoj formule (IV) može se također konvertirati u citalopram preko reakcije s dimetilamonijevim kloridom.
Uvjeti reakcije, otapala itd. primijenjeni za gore opisane reakcije predstavljaju uobičajene uvjete za takve reakcije i stručnjak ih može lako odrediti.
Alternativno, na spoj formule (IV) reagira se azidom, poput natrijevog azida, nakon čega slijedi redukcija u kojoj Pd/C služi kao katalizator, kako bi nastao odgovarajući amin formule
[image]
a zatim metilacija ili reduktivna aminacija radi stvaranja citaloprama.
Spoj formule (IV) može se također konvertirati u citalopram preko reakcije s metilaminom kako bi nastao spoj formule
[image]
nakon čega slijedi metilacija ili reduktivna aminacija radi stvaranja citaloprama.
Amino grupe u spojevima formula (V) i (VI) mogu se metilirati metilirajućim agensima poput MeI i Me2SO4, u kojima je Me metil. Metilacija se provodi primjenom uobičajenih postupaka za obavljanje takvih reakcija.
Reduktivnom aminacijom u spojeve formula (V) i (VI) mogu se uvesti i metilne grupe. Prema tom postupku, na spojeve formule (V) ili (VI) reagira se spojevima poput formaldehida, paraformaldehida ili trioksana uz prisutnost reducirajućeg agensa poput NaBH4 ili NaBH3CN. Reduktivna aminacija provodi se primjenom uobičajenog postupka za obavljanje takvih reakcija.
Početni materijal formule (II) može se pripraviti prema opisu u SAD patentu br. 4,136,193 ili prema opisu u WO 98/019511.
Spojevi formule (III) poznati su ili se mogu pripraviti iz poznatih spojeva na uobičajene načine.
Citalopram se na tržištu nalazi kao antidepresiv u obliku racemata. Međutim, uskoro će se na tržištu pojaviti i aktivni S-enantiomer citaloprama.
S-citalopram se može pripraviti kromatografskom separacijom optički aktivnih izomera.
U specifikacijama i patentnim zahtjevima izraz alkil odnosi se na razgranatu ili nerazgranatu grupu koja ima jedan do uključivo šest atoma ugljika, poput metila, etila, 1-propila, 2-propila, 1-butila, 2-butila, 2-metil-2-propila, 2,2-dimetil-1-etila i 2-metil-1-propila.
Slično tome, alkenil odnosno alkinil označavaju grupe koje imaju od dva do šest atoma ugljika, uključujući jednu dvostruku odnosno trostruku vezu, poput etenila, propenila, butenila, etinila, propinila i butinila.
Izraz aril odnosi se na mono- ili bicikličku karbocikličku aromatsku grupu, poput fenila i naftila, posebno fenila.
Izraz aralkil odnosi se na aril-alkil, pri čemu su aril i alkil prema gornjoj definiciji.
Opcionalno, arilom supstituirani aril i aralkil odnosi se na grupe arila i aralkila koje mogu opcionalno biti supstituirane s jednom ili više alkilnih grupa.
Halogen znači klor, brom ili jod.
Spoj opće formule I može se koristiti kao slobodna baza, posebno kao baza citaloprama u kristalnom obliku, ili kao njezina farmaceutski prihvatljiva kiselinska sol. Kao kiselinske soli mogu se koristiti soli nastale s organskim ili anorganskim kiselinama. Primjeri takvih organskih soli su one s maleinskom, fumarnom, benzojevom, askorbinskom, jantarnom, oksalnom, bimetilensalicilnom, metansulfonskom, etandisulfonskom, octenom, propion-skom, vinskom, salicilnom, limunskom, glukonskom, mliječnom, jabučnom, bademovom, cinaminskom, citrakonskom, asparaginskom, stearinskom, palmitinskom, itakonskom, gli-kolnom, p-aminobenzojevom, glutaminskom, benzen sulfonskom i teofilinskom kiselinom, kao i 8-haloteofilini, npr. 8-bromoteofilin. Primjeri takvih anorganskih soli su one sa solnom, hidrobromnom, sumpornom, sulfaminskom, fosfornom i dušičnom kiselinom.
Kiselinske soli spojeva mogu se pripraviti na način poznat struci. Na bazu se reagira bilo izračunatom količinom kiseline u otapalu koje se miješa s vodom, poput acetona ili etanola, nakon čega slijedi izolacija soli koncentracijom i hlađenjem, bilo suviškom kiseline u otapalu koje se ne miješa s vodom, poput etiletera, etilacetata ili diklorometana, pri čemu se sol taloži sama od sebe.
Farmaceutske smjese prema ovom izumu mogu se primjenjivati na bilo koji odgovarajući način ili u bilo kojem odgovarajućem obliku, npr. oralno u obliku tableta, kapsula, prašaka ili sirupa ili parenteralno u obliku uobičajenih sterilnih otopina za ubrizgavanje.
Farmaceutske formulacije prema ovom izrazu mogu se pripraviti na načine uobičajene u struci. Na primjer, tablete se mogu pripraviti miješanjem aktivnih tvari s uobičajenim pomoćnim sredstvima i/ili razrjeđivačima i zatim komprimiranjem mješavine u konvencionalnom stroju za tabletiranje. Primjeri pomoćnih sredstava ili razrjeđivača: škrobno brašno, krumpirovo škrobno brašno, talk, magnezijev stearat, želatina, laktoza, vezivna sredstva i slično. Mogu se koristiti bilo koja druga pomoćna sredstva ili aditivi, boje, arome, konzervansi itd. pod uvjetom da su kompatibilni s aktivnim tvarima.
Otopine za ubrizgavanje mogu se pripraviti otapanjem aktivnih tvari i eventualnih aditiva u dijelu otapala za ubrizgavanje, preferirano sterilnoj vodi, uz podešavanje otopine na željeni volumen, sterilizacijom otopine i njezinim punjenjem u odgovarajuće ampule ili bočice. Može se dodati bilo koji odgovarajući aditiv uobičajen u struci, poput agensa toniciteta, konzervansa, antioksidansa itd.
Ovaj izum u nastavku ilustriraju sljedeći primjeri.
Primjer 1
Otopina 1-(4-fluorofenil)-1,3-dihidroizobenzofuran-5-karbonitrila (4,8 g, 0,02 mol) u THF (50 ml) kao po kap je dodana otopini LDA (butil litij 1,6 M (15 mL), diizopropilamin (2,6 g)) na -30°C u atmosferi dušika. Nakon 10 min miješanja na -30°C kap po kap je dodana otopina alkil halida/sulfonata (0,01 mol) u THF (25 mL) i ostavljena da se zagrije na sobnu temperaturu, a zatim miješana daljnjih 60 minuta. Reakcija je zatim ugašena ledom, ekstrahirana toluenom (3 x 50 mL), isprana vodom (50 mL) i koncentrirana pod smanjenim tlakom. Talog je pročišćen kromatografijom na silika gelu pomoću mješavina n-heptana/EtOAc kao eluenta. Dobiveni anion je reakcija sa spojem formule (III).
Primjer 2
Priprava 1-[3-(N,N-dimetilamino)propil]-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofuran-karboninitrila (citaloprama, oksalata):
Otopini 1-(4-fluorofenil)-1-[(3-p-toluensulfoniloksi)propil]-1,3-dihidro-5-izobenzofurankar-bonitrila (0,10 g, 0,4 mol) u DNF (10 mL) dodan je trietilamin (1,4 mL, 7,0 mol) i dimetilamonijev klorid (0,41 g, 5,0 mol). Reakcijska mješavina miješana je preko noći na 70°C, zatim ohlađena na sobnu temperaturu, ulivena u ledenu vodu i ekstrahirana pomoću Et2O (3 x 3 mL). Organski ekstrakti su isprani vodom i matičnim lugom te upareni. Talog je pročišćen silika gel kromatografijom (heptan, EtOAc, trietilamin 1:3:4%) i kristaliziran iz acetona i soli oksalata (0,12 g, 70%). DSC (otvorena komora), Tonset = 158,96, Tpeak = 162,14. 1H NMR (DMSO-d6) δ 1,42 (1H, m); 1,51 (1H, m); 2,22 (2H, t, J = 8,0 Hz); 2,62 (6H, s); 2,95 (2H, t, J = 8,0 Hz); 5,15 (1H, d, J = 14,0 Hz); 5,23 (1H, d, J = 14,0 Hz); 7,18 (2H, t, J = 9,0 Hz); 7,59 (2H, d.d., J = 5,0 i 8,0 Hz); 7,74 (1H, d, J = 7,5 Hz); 7,79 (1H, d, J = 7,0 Hz); 7,80 (1H, br s). 13C NMR (DMSO-d6) δ 19,3; 37,0; 42,3; 56,7; 71,2; 90,3; 110,7; 115,2; 115,3; 118,8; 123,2; 125,8; 127,0; 132,1; 139,9; 140,0; 148,161,4; 164,3. Analitički (C20H21N2O, C2H2O4) izračun C:63,76; H:5,59; N: 6,67. Nađeno C: 63,50; H:5,78; N: 6,63.
Primjer 3
Priprava 1-[3-(N,N-dimetilamino)propil]-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofuran-karbonitrila (citaloprama, oksalata):
Otopini 1-(4-fluorofenil)-1-[(3-metansulfoniloksi)propil]-1,3-dihidro-5-izobenzofurankarbo- nitrila (1,0 g, 2,7 mmol) u etanolu (10 mL) i THF (20 mL) dodan je dimetilamin (18 mL; 100 mmol, 33% u etanolu). Dobivena mješavina 1 sat je miješana na sobnoj temperaturi i 3 sata na 60°C. Nakon hlađenja reakcijska je mješavina uparena. Talogu je dodan 1 M NaOH (70 mL) i talog je ekstrahiran s Et2O (100 mL). Organski ekstrakt ispran je matičnim lugom, osušen i uparen. Talog je profiltriran kroz silika gel (EtOAc, heptan, trietilamin 75:25:1) i kristaliziran iz acetona i soli oksalata (0,72g, 65%). DSC (otvorena komora), Tonset = 158,56, Tpeak = 161, 59. NMR spektri bili su identični onima dobivenim iz citaloprama oksalata pripravljenog u primjeru 2. Analitički (C20H21N2O, C2H2O4) izračun C: 63,76; H: 5,59;N: 6,76. Nalaz C: 63,57; H: 5,51; N: 6,77.
Primjer 4
Priprava 1-(3-azidopropil)-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbonitrila:
Otopini 1-(4-fluorofenil)-1-[(3-metansulfoniloksi)propil]-1,3-dihidro-5-izobenzofurankarbo-nitrila (4,0 g, 10,6 mmol) u DMF (100 mL) dodan je natrijev azid (5,5 g, 80,5 mmol). Dobivena mješavina 3 sata je miješana na 40°C, a zatim 2 sata refluksirana. Nakon hlađenja reakcijska je mješavina ulivena u H2O i ektrahirana s Et2O (4 x 200 mL). Organski ekstrakti isprani su s H2O i matičnim lugom, osušeni i upareni kako bi nastao sirovi proizvod u obliku smeđeg ulja (1,3 g, 45%). 1H NMR (DMSO-d6) δ 1,40 (2H, m); 2,22 (2H, m); 3,30 (2H, t, J = 6,6 HZ); 5,10 (1H, d, J = 13,7 Hz); 5,21 (1H, d, J = 13,7 Hz); 7,18 (2H, t, J = 8,5 Hz); 7,59 (2H, dd, J = 5,2 i 8,5 Hz); 7,78 (3H, s + d, J = 8,1 Hz).
Priprava 1-(3-aminopropil)-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbonitrila:
Mješavina 1-(3-azidopropil)-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbonitrila (1,3 g, 4,4 mmol) i paladija na ugljiku (0,6 g, 5%) u etanolu (50 mL) hidrogenizirana je 2 sata. Zatim je mješavina profiltrirana kroz Celit i uparena kako bi nastao sirovi proizvod u obliku smeđeg ulja (0,8 g, 66%). 1H NMR (DMSO-d6) δ 1,11 (1H, m); 2,12 (2H, m); 2,48 (2H, t, J = 7,1 Hz); 5,15 (1H, d, J = 13,7 Hz); 5,19 (1H, d, J = 13,7 Hz); 7,15 (2H, t, J = 8,9 Hz);
7,58 (2H, dd, J = 5,2 i 8,5 Hz); 7,72 (1H, d, J = 8,4 Hz); 7,78 (2H, s + d, J = 8,1 Hz).
Priprava 1-[3-(N,N-dimetilamino)propil]-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbo-nitrila (citaloprama, oksalata):
Mješavini 1-(3-aminopropil)-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbonitrila (0,80 g, 2,7 mmol) i formaldehida (o,44 mL, 5,4 mmol, 37% u H2O) u metanolu (10 mL) dodan je natrijev cijanoborohidrid (0,34 g, 5,4 mmol). Dobivena mješavina je 3 sata miješana na sobnoj temperaturi, zatim joj je dodano još natrijevog cijanoborohidrida (0,17 g, 2,7 mmol) i formaldehida (0,22 mL, 2,7 mmol). Nakon 1 sata miješanja na sobnoj temperaturi mješavina je ugašena s H2O i ekstrahirana s Et2O. Organski ekstrakti su osušeni i upareni. Silika gel kromatografija (EtOAc, heptan, trietilamin 75:25:1) taloga dala je sirovi proizvod koji je izoliran kao sol oksalata iz acetona (0,31 g, 0,8 mmol, 30%). NMR spektri bili su identični onima dobivenim iz citaloprama oksalata pripravljenog u primjeru 2. Analitički (C20H21N2O, C2H2O4, 1⁄2 H2O) izračun C: 63,06; H: 5,67;N: 6,69. Nalaz C: 63,28; H: 5,64; N: 6,67.
Primjer 5
Priprava 1-(4-fluorofenil)-1-[3-(N-metilamino)propil]-1,3-dihidro-5-izobenzofurankarbo-nitrila, soli oksalata:
Spoj je pripravljen iz metilamina (60 mL, 120 mmol, 2M otopine u THF) na način opisan u primjeru 3. Iskorištenje: 760 mg, 36%. 1H NMR (DMSO-d6) δ 1,40 (1H, m); 1,41 (1H, m); 2,25 (2H, t); 2,47 (3H,s); 2,83 (2H, t, J = 8,0 Hz); 5,15 (1H, d, J = 13,2 Hz); 5,21 (1H, d, J = 13,2 Hz); 7,18 (2H, t, J = 9,0 Hz); 7,59 (2H, dd, J = 5,6 i 7,5 Hz); 7,73 (1H, d, J = 8,1 Hz); 7,81 (3H, d + s, J = 8,1 Hz).
Priprava 1-[3-(N,N-dimetilamino)propil]-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbo-nitrila (citaloprama, oksalata):
Otopina 1-[3-(N-metil-amonijak)propil]-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbo-nitrila (0,70 g, 2,24 mmol) i formaldehida (0,5 mL, 6,7 mmol, 35% vodene otopine) u 98%-tnoj mravljoj kiselini refluksirano je 4 sata. Nakon hlađenja dodano je 4M HCl (2 mL) i dobivena mješavina je uparena. Talogu je dodan 1 M NaOH (50 mL) i talog je ekstrahiran s Et2O (3 x 100 mL). Organski ekstrakt ispran je matičnim lugom, osušen i uparen.
Sol oksalata je izolirana iz acetona (0,22 g, 30%) DCS (otvorena komora), Tonset = 157,73, Tpeak = 160,80. NMR spektri bili su identični onima dobivenim iz citaloprama, okslata pripravljenog u primjeru 2. Analitički (C20H21N20, C2H204, 1⁄2 H2O) izračun C: 63,06; H: 5,67; N: 6,69. Nalaz C: 63,24; H: 5.65; N: 6,62.
Claims (5)
1. Način priprave citaloprama naznačen time da sadrži reakciju spoja formule II
[image]
sa spojem koji ima formulu
[image]
gdje je R halogen ili -O-SO2-X, pri čemu je X alkil, alkenil, alkinil ili opcionalno alkilom supstituirani aril ili aralkil, a R1 je dimetilamino, halogen, -O-SO2-X, gdje je X prema gornjoj definiciji, pod uvjetom da R nije halogen kad je R1 dimetilamino;
a ako je R1 dimetilamino nakon čega slijedi izolacija baze citaloprama ili njezine farmaceutski prihvatljive kiselinske soli,
te ako je R1 halogen ili -O-SO2-X, gdje je X prema gornjoj definiciji, nakon čega slijedi konverzija dobivenog spoja formule
[image]
gdje je R2 halogen ili grupa formule -O-SO2-X, a X prema gornjoj definiciji, u citalopram, nakon čega slijedi izolacija baze citaloprama ili njezine farmaceutski prihvatljive kiselinske soli.
2. Način za pripravu citaloprama prema patentom zahtjevu 1, naznačen time da sadrži reakciju spoja formule II sa sulfonil esterom koji ima formulu
[image]
gdje je X prema definiciji u patentnom zahtjevu 1, nakon čega slijedi izolacija baze citaloprama ili njezine farmaceutski prihvatljive kiselinske soli.
3. Način priprave citaloprama prema patentnom zahtjevu 1, naznačen time da sadrži reakciju spoja formule (II) sa spojem koji ima formulu
[image]
gdje su R i R2 prema definiciji u patentnom zahtjevu 1, nakon čega slijedi reakcija dobivenog spoja formule (IV) s
a) dimetilaminom ili njegovom metalnom soli,
b) metilaminom, nakon čega slijedi reduktivna aminacija, ili
c) azidom nakon čega slijedi redukcija radi stvaranja odgovarajućeg amino spoja i nakon toga metilacija ili reduktivna aminacija,
kako bi nastao citalopram.
4. Način prema patentnim zahtjevima 1-3, naznačen time da se reakcija spoja formule (II) sa spojem formule (III) odvija uz prisutnost baze odabrane iz LDA (litijev diizopropilamin), LiHMDS (heksametildisilasan litij), NaH, NaHMDS (heksametildisilasan natrij) i metaloksida poput NaOMe, KOMe, LiOMe, NaOtertBu, KotertBu i LiOtertBu.
5. Antidepresivna farmaceutska smjesa naznačena time da sadrži citalopram proizveden postupkom prema bilo kojem od patentnih zahtjeva 1-4.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200000353 | 2000-03-03 | ||
| PCT/DK2001/000140 WO2001051478A1 (en) | 2000-03-03 | 2001-03-01 | Method for the preparation of citalopram |
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| Publication Number | Publication Date |
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| HRP20020742A2 true HRP20020742A2 (en) | 2004-02-29 |
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| HR20020742A HRP20020742A2 (en) | 2000-03-03 | 2002-09-10 | Method for the preparation of citalopram |
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| US (1) | US6768011B2 (hr) |
| EP (1) | EP1263750A1 (hr) |
| JP (1) | JP2003519692A (hr) |
| KR (1) | KR20020080450A (hr) |
| CN (1) | CN1411454A (hr) |
| AR (1) | AR027559A1 (hr) |
| AU (1) | AU2001240469A1 (hr) |
| BE (1) | BE1011481A6 (hr) |
| BG (1) | BG107050A (hr) |
| BR (1) | BR0109022A (hr) |
| CA (1) | CA2401374A1 (hr) |
| EA (1) | EA005491B1 (hr) |
| FR (1) | FR2805814A1 (hr) |
| GR (1) | GR1003795B (hr) |
| HR (1) | HRP20020742A2 (hr) |
| HU (1) | HUP0300060A3 (hr) |
| IE (1) | IES20010157A2 (hr) |
| IL (1) | IL151467A0 (hr) |
| IS (1) | IS6526A (hr) |
| IT (1) | ITMI20010444A1 (hr) |
| MX (1) | MXPA02008634A (hr) |
| NL (1) | NL1017417C1 (hr) |
| NO (1) | NO20024180L (hr) |
| NZ (1) | NZ521200A (hr) |
| PL (1) | PL358543A1 (hr) |
| SK (1) | SK14152002A3 (hr) |
| TR (1) | TR200202096T2 (hr) |
| WO (1) | WO2001051478A1 (hr) |
| ZA (1) | ZA200206846B (hr) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR200102957T2 (tr) | 1999-04-14 | 2004-12-21 | H. Lundbeck A/S | Sitalopram hazırlanması için metod. |
| IES20010157A2 (en) | 2000-03-03 | 2002-03-06 | Lundbeck & Co As H | Method for the preparation of citalopram |
| GB0005477D0 (en) | 2000-03-07 | 2000-04-26 | Resolution Chemicals Limited | Process for the preparation of citalopram |
| NZ521201A (en) | 2000-03-13 | 2004-02-27 | H | Method for the preparation of citalopram |
| IES20010206A2 (en) | 2000-03-13 | 2002-03-06 | Lundbeck & Co As H | Method for the preparation of citalopram |
| CN1427835A (zh) * | 2000-03-13 | 2003-07-02 | H·隆德贝克有限公司 | 5－取代的1－(4－氟苯基)－1,3－二氢异苯并呋喃的分步烷基化 |
| ATE257832T1 (de) | 2000-03-14 | 2004-01-15 | Lundbeck & Co As H | Verfahren zur herstellung von citalopram |
| AR032455A1 (es) | 2000-05-12 | 2003-11-12 | Lundbeck & Co As H | Metodo para la preparacion de citalopram, un intermediario empleado en el metodo, un metodo para la preparacion del intermediario empleado en el metodo y composicion farmaceutica antidepresiva |
| NZ532478A (en) * | 2001-11-08 | 2007-02-23 | Sepracor Inc | Methods for treating depression and other CNS disorders using enantiomerically enriched desmethyl- and didesmethyl-metabolites of citalopram |
| TWI306846B (en) | 2002-08-12 | 2009-03-01 | Lundbeck & Co As H | Method for the separation of intermediates which may be used for the preparation of escitalopram |
| US20050154052A1 (en) * | 2003-03-24 | 2005-07-14 | Hetero Drugs Limited | Novel crystalline forms of (s)-citalopram oxalate |
| TWI339651B (en) | 2004-02-12 | 2011-04-01 | Lundbeck & Co As H | Method for the separation of intermediates which may be used for the preparation of escitalopram |
| GB0601286D0 (en) | 2006-01-23 | 2006-03-01 | Sandoz Ag | Asymmetric synthesis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1143702A (hr) | 1965-03-18 | |||
| GB1526331A (en) * | 1976-01-14 | 1978-09-27 | Kefalas As | Phthalanes |
| GB8419963D0 (en) | 1984-08-06 | 1984-09-12 | Lundbeck & Co As H | Intermediate compound and method |
| GB8814057D0 (en) | 1988-06-14 | 1988-07-20 | Lundbeck & Co As H | New enantiomers & their isolation |
| US5296507A (en) | 1990-09-06 | 1994-03-22 | H.Lundbeck A/S | Treatment of cerbrovascular disorders |
| DE19626659A1 (de) | 1996-07-03 | 1998-01-08 | Basf Ag | Verfahren zur Herstellung von Phthaliden |
| DE19627697A1 (de) | 1996-07-10 | 1998-01-15 | Basf Ag | Verfahren zur Herstellung von Phthaliden |
| PT1015416E (pt) | 1997-07-08 | 2002-03-28 | Lundbeck & Co As H | Metodo para a producao de citalopram |
| UA62985C2 (en) * | 1997-11-10 | 2004-01-15 | Lunnbeck As H | A method for the preparation of citalopram |
| AU738359B2 (en) | 1997-11-11 | 2001-09-13 | H. Lundbeck A/S | Method for the preparation of citalopram |
| HU228576B1 (en) | 1998-10-20 | 2013-04-29 | Lundbeck & Co As H | Method for the preparation of citalopram |
| CA2356188C (en) | 1998-12-23 | 2006-05-23 | H. Lundbeck A/S | Method for the preparation of 5-cyanophthalide |
| AR022329A1 (es) | 1999-01-29 | 2002-09-04 | Lundbeck & Co As H | Metodo para la preparacion de 5-cianoftalida |
| TR200102957T2 (tr) | 1999-04-14 | 2004-12-21 | H. Lundbeck A/S | Sitalopram hazırlanması için metod. |
| ITMI991581A1 (it) | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
| ITMI991579A1 (it) | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
| ITMI991486A1 (it) | 1999-07-06 | 2001-01-06 | Vis Farmaceutici S P A | Processo per la sintesi di citalopram |
| ES2169709A1 (es) | 1999-10-25 | 2002-07-01 | Lundbeck & Co As H | Metodo para la preparacion de citalopram |
| AR026063A1 (es) | 1999-11-01 | 2002-12-26 | Lundbeck & Co As H | Metodo para la preparacion de 5-carboxiftalida. |
| US6310222B1 (en) | 1999-11-01 | 2001-10-30 | Sumika Fine Chemicals Co., Ltd. | Production method of 5-phthalancarbonitrile compound, intermediate therefor and production method of the intermediate |
| SI1246812T1 (en) | 1999-12-28 | 2004-08-31 | H. Lundbeck A/S | Method for the preparation of citalopram |
| PT1246813E (pt) | 1999-12-30 | 2004-02-27 | Lundbeck & Co As H | Metodo para a preparacao de citalopram |
| EA005134B1 (ru) | 2000-01-14 | 2004-12-30 | Х.Лундбекк А/С | Способ получения 5-цианофталида |
| IT1317729B1 (it) | 2000-01-18 | 2003-07-15 | Norpharma S P A | Procedimento per la preparazione della 5-carbossiftalide. |
| US6433196B1 (en) | 2000-02-17 | 2002-08-13 | Sumika Fine Chemicals Co., Ltd. | Production method of citalopram, intermediate therefor and production method of the intermediate |
| FR2805812A1 (fr) * | 2000-02-24 | 2001-09-07 | Lundbeck & Co As H | Procede de preparation du citalopram |
| IES20010143A2 (en) | 2000-02-24 | 2001-07-25 | Lundbeck & Co As H | Method for the preparation of citalopram |
| IES20010157A2 (en) | 2000-03-03 | 2002-03-06 | Lundbeck & Co As H | Method for the preparation of citalopram |
| GB0005477D0 (en) | 2000-03-07 | 2000-04-26 | Resolution Chemicals Limited | Process for the preparation of citalopram |
| CN1427835A (zh) | 2000-03-13 | 2003-07-02 | H·隆德贝克有限公司 | 5－取代的1－(4－氟苯基)－1,3－二氢异苯并呋喃的分步烷基化 |
| IES20010206A2 (en) | 2000-03-13 | 2002-03-06 | Lundbeck & Co As H | Method for the preparation of citalopram |
| GB2357762B (en) | 2000-03-13 | 2002-01-30 | Lundbeck & Co As H | Crystalline base of citalopram |
| NZ521201A (en) | 2000-03-13 | 2004-02-27 | H | Method for the preparation of citalopram |
| ATE257832T1 (de) | 2000-03-14 | 2004-01-15 | Lundbeck & Co As H | Verfahren zur herstellung von citalopram |
| WO2001068632A1 (en) | 2000-03-16 | 2001-09-20 | H. Lundbeck A/S | Method for the preparation of 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofurans |
| AR032455A1 (es) | 2000-05-12 | 2003-11-12 | Lundbeck & Co As H | Metodo para la preparacion de citalopram, un intermediario empleado en el metodo, un metodo para la preparacion del intermediario empleado en el metodo y composicion farmaceutica antidepresiva |
| WO2002004435A1 (en) | 2000-07-06 | 2002-01-17 | H. Lundbeck A/S | Method for the preparation of citalopram |
| IL144817A0 (en) | 2000-08-18 | 2002-06-30 | Lundbeck & Co As H | Method for the preparation of citalopram |
| EP1181713B1 (en) | 2000-12-22 | 2004-09-29 | H. Lundbeck A/S | Method for the preparation of pure citalopram |
| PT1181272E (pt) | 2000-12-28 | 2003-01-31 | Lundbeck & Co As H | Processo para a preparacao de citalopram puro |
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| HUP0300060A3 (en) | 2005-02-28 |
| KR20020080450A (ko) | 2002-10-23 |
| HUP0300060A2 (en) | 2003-05-28 |
| NO20024180D0 (no) | 2002-09-02 |
| SK14152002A3 (sk) | 2003-03-04 |
| CA2401374A1 (en) | 2001-07-19 |
| CN1411454A (zh) | 2003-04-16 |
| WO2001051478A1 (en) | 2001-07-19 |
| BE1011481A6 (fr) | 2001-07-03 |
| EP1263750A1 (en) | 2002-12-11 |
| IES20010157A2 (en) | 2002-03-06 |
| ITMI20010444A1 (it) | 2002-09-05 |
| AR027559A1 (es) | 2003-04-02 |
| IS6526A (is) | 2002-08-27 |
| NL1017417C1 (nl) | 2001-03-16 |
| ZA200206846B (en) | 2003-08-27 |
| GR1003795B (el) | 2002-02-08 |
| PL358543A1 (en) | 2004-08-09 |
| FR2805814A1 (fr) | 2001-09-07 |
| EA005491B1 (ru) | 2005-02-24 |
| AU2001240469A1 (en) | 2001-07-24 |
| JP2003519692A (ja) | 2003-06-24 |
| BR0109022A (pt) | 2003-06-03 |
| NO20024180L (no) | 2002-09-02 |
| NZ521200A (en) | 2004-03-26 |
| TR200202096T2 (tr) | 2003-01-21 |
| US6768011B2 (en) | 2004-07-27 |
| MXPA02008634A (es) | 2003-02-24 |
| BG107050A (en) | 2003-05-30 |
| IL151467A0 (en) | 2003-04-10 |
| EA200200939A1 (ru) | 2003-02-27 |
| US20030092761A1 (en) | 2003-05-15 |
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