HRP20020757A2 - Method for the preparation of 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofurans - Google Patents
Method for the preparation of 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofurans Download PDFInfo
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- HRP20020757A2 HRP20020757A2 HRP20020757A HRP20020757A2 HR P20020757 A2 HRP20020757 A2 HR P20020757A2 HR P20020757 A HRP20020757 A HR P20020757A HR P20020757 A2 HRP20020757 A2 HR P20020757A2
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- 238000000034 method Methods 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 6
- YXCRMKYHFFMNPT-UHFFFAOYSA-N 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical class C1=CC(F)=CC=C1C1C2=CC=C(C#N)C=C2CO1 YXCRMKYHFFMNPT-UHFFFAOYSA-N 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 79
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 229960001653 citalopram Drugs 0.000 claims description 18
- 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 claims description 17
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 10
- 239000012024 dehydrating agents Substances 0.000 claims description 10
- 230000018044 dehydration Effects 0.000 claims description 10
- 238000006297 dehydration reaction Methods 0.000 claims description 10
- -1 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran Chemical class 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 8
- 230000001430 anti-depressive effect Effects 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000935 antidepressant agent Substances 0.000 claims description 6
- 229940005513 antidepressants Drugs 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 5
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 5
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 claims description 3
- 229910006124 SOCl2 Inorganic materials 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000003999 initiator Substances 0.000 claims description 3
- 150000002978 peroxides Chemical class 0.000 claims description 3
- 150000003254 radicals Chemical class 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 238000006193 diazotization reaction Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000003544 oxime group Chemical group 0.000 claims description 2
- 150000002923 oximes Chemical class 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 229910006121 SOBr2 Inorganic materials 0.000 claims 1
- 239000013067 intermediate product Substances 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 150000003511 tertiary amides Chemical class 0.000 description 3
- 238000005979 thermal decomposition reaction Methods 0.000 description 3
- 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
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 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
- 239000000203 mixture Substances 0.000 description 2
- 150000002825 nitriles Chemical group 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient 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
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 150000003549 thiazolines Chemical class 0.000 description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UFBBMJWPPBNTGA-UHFFFAOYSA-N 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran Chemical compound C1=CC(F)=CC=C1C1C2=CC=CC=C2CO1 UFBBMJWPPBNTGA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- HCYFGRCYSCXKNQ-UHFFFAOYSA-N 2-(1,3-dimethyl-2,6-dioxo-7-purinyl)acetic acid Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC(O)=O)C=N2 HCYFGRCYSCXKNQ-UHFFFAOYSA-N 0.000 description 1
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 1
- DPZHKLJPVMYFCU-UHFFFAOYSA-N 2-(5-bromopyridin-2-yl)acetonitrile Chemical compound BrC1=CC=C(CC#N)N=C1 DPZHKLJPVMYFCU-UHFFFAOYSA-N 0.000 description 1
- OZDAOHVKBFBBMZ-UHFFFAOYSA-N 2-aminopentanedioic acid;hydrate Chemical compound O.OC(=O)C(N)CCC(O)=O OZDAOHVKBFBBMZ-UHFFFAOYSA-N 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
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 101710134784 Agnoprotein Proteins 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N Aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 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
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 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
- 239000002841 Lewis acid Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229950003769 acefylline Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 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
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000019568 aromas Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 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
- 239000002775 capsule Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ITMZWVBSKCMIHI-UHFFFAOYSA-N chlorosulfonyl cyanate Chemical compound ClS(=O)(=O)OC#N ITMZWVBSKCMIHI-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- HNEGQIOMVPPMNR-IHWYPQMZSA-N citraconic acid Chemical compound OC(=O)C(/C)=C\C(O)=O HNEGQIOMVPPMNR-IHWYPQMZSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 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
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 229910052748 manganese Inorganic materials 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
- WXHIJDCHNDBCNY-UHFFFAOYSA-N palladium dihydride Chemical compound [PdH2] WXHIJDCHNDBCNY-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 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
- 235000010288 sodium nitrite Nutrition 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- 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
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/10—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
Ovaj se izum odnosi na način priprave 5-cijano-1-(4-fluorofenil)-1,3-dihidroizobenzofurana, koji predstavlja intermedier pri proizvodnji poznatog antidepresiva citaloprama, 1-[3-(dimetilamino)propil]-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbonitrila.
Prethodno stanje struke
Citalopram je poznati antidepresiv koji se već nekoliko godina nalazi na tržištu i koji ima sljedeću strukturu:
[image]
To je selektivan, 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. Hytttel Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1982., 6, 277-295 i A. Gravem Acta Psychiatr.Scand. 1987., 75, 478-486. Osim toga se otkrilo da 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. Ta patentna objava opisuje pripravu citaloprama na jedan način i naznačuje daljnji način koji se može primijeniti za pripravu citaloprama.
Prema opisanom postupku, na odgovarajući 1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbonitril reagira se s 3-(N,N-dimetilamino)propil-kloridom uz prisutnost metilsulfinilmetida kao kondenzirajućeg agensa. Polazna supstanca pripravljena je iz odgovarajućeg 5-bromo derivata reakcijom s bakrenim cijanidom.
Međunarodna patentna prijava br. WO 98/019511 opisuje postupak za izradu citaloprama u kojem se spoj (4-(cijano, alkiloksikarbonil ili alkilaminokarbonil)-2-hidroksimetilfenil-(4-fluorofenil)metanola podvrgava zatvaranju prstena. Dobiveni 5-(alkiloksikarbonil ili alkilaminokarbonil)-1-(4-fluoreofenil)-1,3-dihidroizobenzo-furan 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, neočekivano, otkrilo da se citalopram može proizvoditi na novi, prikladan način pri kojemu se 5-supstituirani 1-(4-fluorofenil)-1,3-dihidroizobenzofuran prije alkilacije 3-dimetilaminopropilnom grupom konvertira u odgovarajući 5-cijano-1-(4-fluorofenil)-1,3-dihidroizobenzofuran.
Opis izuma
Dakle, ovaj se izum odnosi na novi način priprave intermediera u pripravi citaloprama koji ima formulu
[image]
konverzijom spoja formule
[image]
gdje je R halogen, grupa formula CF3-(CF2)n-SO2-O-, pri čemu je n 0-8, -OH, -CHO, -CH2OH, -CH2NH2, -CH2NO2, -CH2Cl, -CH2Br, -CH3, -NHR1, -COOR2, -CONR2R3, pri čemu su R2 i R3 odabrani iz vodikom opcionalno substituiranog alkila, aralkila ili arila, a R1 je vodik ili alkilkarbonil ili grupa formule
[image]
gdje X znači O ili S;
R4 - R5 su svaki za sebe neovisno odabrani iz vodika i C1-6 alkila ili R4 i R5 zajedno čine C2-5 alkilenski lanac tvoreći na taj način spiro prsten; R6 je odabran iz vodika i C1-6 alkila, R7 je odabran iz vodika, C1-6 alkila, karboksi grupe ili njezinog izvora ili R6 i R7 zajedno čine C2-5 alkilenski lanac tvoreći na taj način spiro prsten.
Taj se intermedier formule (II) može konvertirati u citalopram alkilacijom prema gornjem opisu.
U drugom aspektu, ovaj se izum odnosi na antidepresivnu farmaceutsku smjesu koja sadrži citalopram izrađen postupkom prema ovom izumu.
Prema jednoj izvedbi ovog izuma, u kojoj je R halogen, spoj formule (III) konvertira se u spoj formule (II) reakcijom s izvorom cijanida opcionalno uz prisutnost katalizatora.
Prema daljnjoj izvedbi ovog izuma, u kojoj je R troplošna grupa formule CF3-(CF2)n-SO2-O-, pri čemu je n 0, 1, 2, 3, 4, 5, 6, 7 ili 8, spoj formule (III) konvertira se u spoj formule (II) reakcijom s izvorom cijanida opcionalno uz prisutnost katalizatora.
Izvori cijana mogu prikladno biti odabrani iz grupe koja se sastoji od izvora cijanida poput NaCN, KCN, Zn(CN)2, Cu(CN) ili (R'')4NCN, pri čemu svaki R'' predstavlja C1-8 alkil ili opcionalno dva R'' zajedno s dušikom tvore prstenastu strukturu te kombinacije.
Izvor cijanida upotrebljava se u stehiometričkoj količini ili u suvišku, preferirano se rabe 1-2 ekvivalenta po ekvivalentu polazne supstance.
Kad je R halogen ili grupa formule CF3-(CF2)n-SO2-O-, pri čemu je n 0-8, reakcija prema ovom izumu provodi se uz prisutnost katalizatora ili bez njega. Katalizatori su tj. Ni (0), Pd (0) ili Pd(II) katalizatori prema opisu Sakakibare i sur. u Bull. Chem. Soc. Jpn. 1988., 61, 1985-1990. Preferirani katalizatori su Ni(PPh3)3 ili Pd(PPh3)4 ili Ni(PPh)2Cl ili Pd(PPh)2Cl2.
U posebno preferiranoj izvedbi, prije reakcije zamjene cijanida pripravlja se in situ kompleks niklja (0) redukcijom izvora niklja (II), kao što je NiCl2 ili NiBr2, metalom poput cinka, magnezija ili mangana uz prisutnost suviška kompleksnih liganda, preferirano trifenilfosfina.
Pd ili Ni-katalizator prikladno se rabi u količini od 0,5-10, preferirano 2-5 mol%.
U jednoj izvedbi ovog izuma, reakcija se provodi uz prisutnost katalitičke količine Cu+ ili Zn2+.
Katalitičke količine Cu+ odnosno Zn2+ znači substehiometrijske količine poput 0,5 - 5, preferirano 1 - 3 %. Prikladno se rabi oko 1⁄2 ekvivalenta po ekvivalentu Pd.
Može se upotrebljavati bilo koji prikladan izvor Cu+ ili Zn++. Cu+ se preferirano rabi u obliku CuI, a Zn2+ se prikladno rabi kao sol Zn(CN)2.
Reakcije se mogu provoditi u bilo kojem odgovarajućem otapalu prema opisu u Sakakibara i sur. u Bull. Chem. Soc. Jpn. 1988., 61, 1985-1990. Preferirana otapala su acetonitril, etilacetat, THF, DMF ili NMP.
U jednom aspektu ovog izuma, na spoj formule IV, u kojoj R znači Cl, reagira se s NaCN uz prisutnost Ni(PPh3)3, koji se preferirano pripravlja in situ prema gornjem opisu.
U drugom aspektu ovog izuma, na spoj formule IV, u kojoj R znači Br ili I, reagira se s KCN, NaCN, CuCN ili Zn(CN)2 uz prisutnost Pd(PPh3)4. U posebnom aspektu ovog izuma, dodaju se substehiometrijske količine Cu(CN) i Zn(CN)2 kao reciklirajući izvori cijanida.
U još jednom aspektu ovog izuma, spoj formule IV, u kojoj R znači Br ili I, konvertira se u odgovarajući cijano spoj reakcijom s Cu(CN) bez katalizatora. U preferiranoj izvedbi, ta se reakcija provodi na povišenoj temperaturi.
U posebnom aspektu ovog izuma, reakcija zamjene cijanida provodi se kao reakcija na suho, tj. bez dodavanja otapala.
U još jednom aspektu ovog izuma, reakcija zamjene cijanida provodi se u ionskoj tekućini opće formule (R')4N+, X-, pri čemu su R' alkilne grupe ili dvije od R' grupa zajedno tvore prsten, a X- je indikator iona. U jednoj izvedbi ovog izuma (R')4N+X- predstavlja
[image]
U drugom posebnom aspektu ovog izuma, reakcija izmjene cijanida provodi se s apolarnim otapalima poput benzena, ksilena ili mesitilena i pod utjecajem mikrovalova pomoću uređaja Sinthewave 1000TM proizvođača Prolabo. U posebnom aspektu ovog izuma, reakcija se provodi bez dodavanja otapala.
Temperatura ovisi o vrsti reakcije. Ako nema katalizatora, preferirane temperature kreću se od 100-200°C. Međutim, ako se reakcija provodi pod utjecajem mikrovalova, temperatura u reakcijskoj mješavini može se popeti iznad 300°C. Više preferirana temperatura kreće se između 120-170°C. Najviše preferirana se kreće između 130-150°C.
Ako postoji katalizator, preferirana temperatura kreće se između 0 i 100°C. Više preferirana temperatura iznosi 40-90°C. Najviše preferirani raspon temperature je između 60-90°C.
Drugi uvjeti reakcije, otapala itd. su uobičajeni uvjeti za takve reakcije i stručnjak ih može lako odrediti.
U još jednoj izvedbi ovog izuma, u kojoj je R oksazolin ili tiazolinska grupa formule
[image]
gdje su X, R4, R5, R6 i R7 prema gornjoj definiciji, konverzija u cijano grupu može se provesti pomoću dehidracijskog agensa ili alternativno, ako X znači S, termalnim cijepanjem tiazolinskog prstena ili tretiranjem s radikalnim inicijatorom poput peroksida ili sa svjetlom.
Dehidrirajući agens može biti bilo koji prikladan dehidrirajući agens koji struka uobičajeno rabi, poput fosforoksitriklorida, tionilklorida, fosforpentaklorida, PPA (polifosforna kiselina) i P4O10. Reakcija se može provesti uz prisutnost organske baze poput piridina ili katalitičke količine tercijarnog amida.
Preferirano, derivat oksazolina ili tiazolina formule (IV) tretira se sa SOCl2 kao dehidrirajućim agensom, a reakcija se provodi u toluenu koji sadrži katalitičku količinu N,N-dimetilformamida.
Alternativno, dehidrirajući agens može biti Vilmeierov reagens, tj. spoj koji nastaje reakcijom klorirajućeg agensa, preferirano kiselog klorida, npr. fozgena, oksalil klorida, tionil klorida, fosforoksiklorida, fosforpentaklorida, triklorometil kloroformata, koji je također poznat pod kraticom "difozgen", ili bi(klorometil) karbonata, koji je također poznat kod kraticom "trifozgen", s tercijarnim amidom poput N,N-dimetilformamida ili N,N-dialkilalkanamida, npr. N,N-dimetilacetamida. Klasični Vilsmeyerov je klorometilendimetiliminij klorid. Virsmeierov reagens preferirano se pripravlja in situ dodavanjem klorirajućeg agensa mješavini koja sadrži polazni derivat oksazolina ili tiazolina formule (IV) i tercijarni amid.
Kad X znači S, konverzija tiazolinske grupe formule (IV) u cijano grupu obavlja se termalnom transformacijom, termalno raspadanje tiazolinske grupe preferirano se provodi u bezvodnom organskom otapalu, još bolje u aprotičkom polarnom otapalu poput N,N-dimetilformamida, N,N-dimetilacetamida, dimetilsulfoksida ili acetonitrila. Temperatura na kojoj termalno raspadanja pretvara 2-tiazolilnu grupu u cijano grupu iznosi između 60°C i 140°C. Termalno raspadanje može se prikladno provesti refluksom u odgovarajućem otapalu, preferirano acetonitrilu. Termalno se cijepanje može prikladno provesti uz prisutnost kisika ili nekog oksidirajućeg agensa. Tiazolinska grupa formule (IV), u kojoj X znači S, a R7 je karboksi grupa ili izvor karboksi grupe, može se također konvertirati u cijano grupu tretiranjem s radikalnim inicijatorom poput svjetla ili peroksidā.
Prema još jednoj izvedbi ovog izuma, u kojoj je R formaldehidna grupa, spoj formule (III) konvertira se u spoj formule (II) konverzijom aldehidne grupe u oksim, nakon čega slijedi dehidracija oksimske grupe.
Konverzija formilne grupe u cijano grupu može se provesti reakcijom s reagensom R8-V-NH2, pri čemu je R8 vodik, niži alkil, aril ili heteroaril, a V je O, N ili S, nakon čega slijedi dehidracija s uobičajenim dehidrirajućim agensom, na primjer tionilkloridom, octenim anhidridom/piridinom, piridinom/HCl ili fosfornim pentakloridom. Preferirani reagensi R8-V-NH2 su hidroksilamin i spojevi u kojima je R8 alkil ili aril, a V je N ili O.
Prema još jednoj izvedbi ovog izuma, u kojoj R predstavlja -COOH grupu, spoj formule (III) konvertira se u spoj formule (II) konverzijom amida preko odgovarajućeg kiselog klorida ili njegovog estera, nakon čega slijedi dehidracija amida.
Kiseli klorid prikladno se dobiva tretiranjem kiseline s POCl3, PCl5 ili SOCl2 na suho ili u odgovarajućem otapalu, poput toluena ili toluena koji sadrži katalitičku količinu N,N-dimetilformamida. Ester se dobiva tretiranjem karboksilne kiseline s alkoholom, uz prisutnost neke kiseline, preferirano mineralne kiseline ili Lewisove kiseline, poput HCl, H2SO4, POCl3, PCl5 ili SOCl2. Alternativno, ester se može dobiti iz kiselog klorida reakcijom s alkoholom. Ester kiselog klorida zatim se amidacijom s amonijakom ili C1-6 alkilaminom, preferirano butil aminom, konvertira u amid.
Konverzija u amid može se postići i reakcijom estera s amonijakom ili alkilaminom pod tlakom i uz grijanje.
Amidna grupa zatim se dehidracijom konvertira u cijano grupu. Dehidrirajući agens može biti bilo koji prikladan dehidrirajući agens, a stručnjak može lako odrediti optimalni agens. Primjeri prikladnog dehidrirajućeg agensa su SOCl2, POCl3 i PCl5, preferirano SOCl2.
U posebno preferiranoj izvedbi, na karboksilnu kiselinu se reagira s alkoholom, preferirano etanolom, uz prisutnost POCl3, kako bi se dobio odgovarajući ester, na koji se zatim reagira s amonijakom, što daje odgovarajući amid, na koji se potom reagira sa SOCl2 u toluenu koji sadrži katalitičku količinu N,N-dimetilformamida.
Alternativno, na spoj u kojem R znači -COOH može se reagirati s klorosulfonil cijanatom, kako bi se dobio nitril, ili se taj spoj može tretirati s dehidrirajućim agensom i sulfonamidom prema opisu u WO 00/44738.
Na taj se način spoj formule (III) u kojem R znači -COOR2 grupu može konvertirati u spoj formule (II) konverzijom u amid te potom dehidracijom.
Nadalje, spoj formule (III) u kojem R predstavlja -CONR2R3 grupu može se dehidracijom konvertirati u spoj formule (II) i tako stvoriti cijano grupu.
U još jednoj izvedbi ovog izuma, u kojoj R predstavlja –NHR1 grupu, spoj formule (III) konvertira se u spoj formule (II) hidrolizom radi dobivanja slobodne amino grupe te potom diazotacijom slobodne amino grupe i reakcijom s izvorom cijanida.
Kao korišteni izvor cijanida najviše se preferiraju NaNO2, CuCN i/ili NaCN. Kad R1 znači C1-6 alkilkarbonil, on se najprije podvrgava hidrolizi, čime se dobiva odgovarajući spoj u kojem R1 predstavlja H, koji se potom konvertira prema gornjem opisu. Hidroliza se može provesti bilo u kiselom bilo u lužnatom okolišu.
Spojevi formule (III) u kojima R znači -CH2NO2 mogu se konvertirati u spoj formule (II) tretiranjem s TMSI kako bi se dobila cijano grupa.
Spojevi formule (III) u kojima R predstavlja -CH2NH2 grupu mogu se konvertirati u spoj formule (II) oksidacijom uz prisutnost bakrenog(I)klorida kako bi se dobila cijano grupa.
Spojevi formule (III) u kojima R znači -CH2Cl grupu mogu se konvertirati u spoj formule (II) reakcijom s AgNO2 radi dobivanja odgovarajuće -CH2NO2 grupe te potom tretiranjem s TMSI kako bi se dobila cijano grupa.
Spojevi formule (III) u kojima R predstavlja -CH2Br grupu mogu se konvertirati u spoj formule (II) reakcijom s AgNO2 radi dobivanja odgovarajuće -CH2NO2 grupe i zatim tretiranjem s TMSI kako bi se dobila cijano grupa; ili tretiranjem s NH3 radi stvaranja odgovarajuće -CH2NH2 grupe i potom oksidacijom uz prisutnost bakrenog(I)klorida kako bi se dobila cijano grupa.
Spojevi formule (III) u kojima R znači -CH3 grupu mogu se konvertirati u spoj formule (II) tretiranjem s bazom i nakon toga s R9ONO2, pri čemu R9 znači C1-6 alkil, kako bi se dobila odgovarajuća -CH2NO2 grupa, a zatim tretiranjem s TMSI kako bi nastala cijano grupa.
Spojevi formule (III) u kojima R znači -CH2OH grupu mogu se konvertirati u spoj formule (II) tretiranjem sa SOCl2 ili SOBr2 radi dobivanja odgovarajuće -CH2Cl grupe ili –CH2Br grupe, nakon čega slijedi konverzija u cijano prema gornjem opisu.
Polazna supstanca formule (III) u kojoj je R halogen može se pripraviti prema opisu u GB 1526331, spojevi formule IV u kojoj R znači -O-SO2-(CF2)-CF3 i -OH mogu se pripraviti analogno kao spojevi opisani u WO 00/13648, spojevi formule IV u kojoj je R oksazolin ili tiazolinska grupa mogu se pripraviti analogno kao spojevi opisani u WO 00/23431, spojevi formule IV u kojoj R znači -CH2OH grupu mogu se pripraviti kao spojevi opisani u PCT/DK/0100123, spojevi formule IV u kojoj je R formaldehid mogu se pripraviti analogno kao spojevi opisani u WO 99/30548, spojevi formule IV u kojoj R znači -COOH te odnosne estere i amide mogu se pripraviti analogno kao spojevi opisani u WO 98/19513, a spojevi formule IV u kojoj R znači -NHR1 mogu se pripraviti analogno kao spojevi opisani u WO 98/19512.
Citalopram se nalazi na tržištu kao antidepresiv u obliku racemata. Međutim, uskoro će se na tržište uvesti i aktivni S-enantiomer citaloprama.
S-citalopram se može pripraviti kromatografskom separacijom optički aktivnih izomera.
U svim specifikacijama i patentnim zahtjevima izraz alkil odnosi se na razgranatu ili nerazgranatu alkilnu 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 takve 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.
Halogen znači klor, brom ili jod.
Citalopram se može upotrebljavati kao slobodna baza, posebno kao slobodna baza u kristalnom obliku, ili kao njezina farmaceutski prihvatljiva kiselinska sol. Kao kiselinske soli mogu se koristiti soli nastale iz organskih ili anorganskih kiselina. Primjeri takvih organskih soli su one s maleinskom, fumarnom, benzojevom, askorbinskom, jantarnom, oksalnom, bimetilensalicilnom, metansulfonskom, etandisulfonskom, octenom, propionskom, vinskom, salicilnom, limunskom, glukonskom, mliječnom, jabučnom, bademovom, cinamičnom, citrakonskom, asparaginskom, stearinskom, palmitinskom, itakonskom, glikolnom, p-aminobenzojevom, glutaminskom, benzen sulfonskom i teofilinskom octenom kiselinom, kao i s 8-haloteofilinima, na primjer s 8-bromoteofilinom. Primjeri takvih anorganskih soli su one sa solnom, hidrobromnom, sumpornom, sulfaminskom, fosfornom i dušičnom kiselinom.
Kiselinske soli spojeva mogu se pripravljati prema načinima poznatima u struci. Na bazu se reagira bilo izračunatom količinom kiseline u otapalu koje se miješa s vodom, poput acetona ili etanola, nakon čega se koncentracijom i hlađenjem izolira sol, ili suviškom kiseline u otapalu koje se ne miješa s vodom, poput etiletera, etilacetata ili diklorometana, pri čemu se sol separira sama od sebe.
Farmaceutske smjese prema ovom izumu mogu se primjenjivati na bilo koji prikladan način i u bilo kojem prikladnom obliku, na primjer oralno u obliku tableta, kapsula, prašaka ili sirupa, ili parenteralno u obliku uobičajenih sterilnih otopina za ubrizgavanje.
Farmaceutske formulacije prema ovom izumu mogu se pripravljati na načine uobičajene u struci. Na primjer, tablete se mogu pripravljati miješanjem aktivne tvari s uobičajenim pomoćnim tvarima i/ili razrjeđivačima i potom komprimiranjem te mješavine u konvencionalnom stroju za tabletiranje. Primjeri pomoćnih tvari ili razrjeđivača su: škrobno brašno, krumpirovo škrobno brašno, talk, magnezijev stearat, želatina, laktoza, vezivna sredstva i slično. Mogu se koristiti i bilo koje druge pomoćne tvari ili aditivi, boje, aroma, konzervansi itd. pod uvjetom da su kompatibilni s aktivnom tvari.
Otopine za ubrizgavanje mogu se pripravljati otapanjem aktivne tvari i eventualnih aditiva u dijelu otapala za ubrizgavanje, preferirano sterilnoj vodi, uz podešavanje otopine na željeni volumen, sterilizaciju otopine i njezino punjenje u prikladne ampule ili bočice. Mogu se dodati bilo koji prikladni aditivi koji se uobičajeno rabe u struci, poput tonizirajućih agensa, konzervansa, antioksidansa itd.
Claims (19)
1. Način priprave 5-cijano-1-(4-fluorofenil)-1,3-dihidroizobenzofurana
[image]
naznačen time da uključuje konverziju 5-supstituiranog derivata 1-(4-fluorofenil)-1,3-dihidroizobenzofurana formule
[image]
gdje R predstavlja halogen, grupu formule CF3-(CF2)n-SO2-O-, pri čemu je n 0-8, -OH, -CHO, -CH2OH, -CH2NH2, -CH2NO2, -CH2Cl, -CH2Br, -CH3, -NHR1, -COOR2, -CONR2R3, u kojima su R2 i R3 odabrani iz vodikom opcionalno supstituiranog alkila, aralkila ili arila, a R1 je vodik ili alkilkarbonil, ili grupu formule
[image]
u kojoj X predstavlja O ili S;
R4 - R5 su svaki neovisno odabrani iz vodika i C1-6 alkila ili R4 i R5 zajedno čine C2-5 alkilenski lanac i tako tvore spiro prsten; R6 je odabran iz vodika i C1-6 alkila, R7 je odabran iz vodika, C1-6 alkila, karboksi grupe ili njezinog izvora ili R6 i R7 zajedno čine C2-5 alkilenski lanac i tako tvore spiro prsten.
2. Način prema patentnom zahtjevu 1, naznačen time da se međuproizvod formule (II) alkilacijom konvertira u citalopram; potom slijedi izolacija citaloprama ili njegove farmaceutski prihvatljive soli.
3. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da je u njemu R halogen, a spoj formule (III) se konvertira u spoj formule (II) reakcijom s izvorom cijanida opcionalno uz prisutnost katalizatora.
4. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da je R troplošna grupa formule CF3-(CF2)n-SO2-O-, pri čemu je n 0, 1, 2, 3, 4, 5, 6, 7 ili 8, a spoj formule (III) konvertira se u spoj formule (II) reakcijom s izvorom cijanida opcionalno uz prisutnost katalizatora.
5. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da je R oksazolin ili tiazolinska grupa formule (IV), a spoj formule (III) konvertira se u spoj formule (II) tretiranjem s dehidrirajućim agensom ili alternativno, ako X znači S, termalnim cijepanjem tiazolinskog prstena ili tretiranjem s radikalnim inicijatorom, poput peroksida, ili sa svjetlom.
6. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da je R formaldehidna grupa, a spoj formule (III) konvertira se u spoj formule (II) konverzijom aldehidne grupe u oksim, a potom dehidracijom te oksimne grupe.
7. Način prema bilokojem od patentnih zahtjeva 1-2, naznačen time da R predstavlja -COOH grupu, a spoj formule (III) konvertira se u spoj formule (II) konverzijom amida preko odgovarajućeg kiselog klorida ili njegovog estera i potom dehidracijom amida.
8. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da u njemu R znači -COOR2 grupu, a spoj formule (III) konvertira se u spoj formule (II) konverzijom -COOR2 grupe u amid nakon čega slijedi dehidracija.
9. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da u njemu R znači -CONR2R3 grupu, a spoj formule (III) konvertira se u spoj formule (II) dehidracijom -CONR2R3 grupe radi stvaranja cijano grupe.
10. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da u njemu R znači -NHR1 grupu, a spoj formule (III) konvertira se u spoj formule (II) hidrolizom radi stvaranja slobodne amino grupe, te potom diazotacijom slobodne amino grupe i reakcijom s izvorom cijanida.
11. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da u njemu R znači -CH2NO2 grupu, a spoj formule (III) konvertira se u spoj formule (II) tretiranjem s TMSI radi stvaranja cijano grupe.
12. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da u njemu R znači -CH2NH2 grupu, a spoj formule (III) konvertira se u spoj formule (II) oksidacijom uz prisutnost bakrenog(I)klorida radi stvaranja cijano grupe.
13. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da u njemu R znači -CH2Cl grupu, a spoj formule (III) konvertira se u spoj formule (II) reakcijom s AgNO2 radi stvaranja odgovarajuće -CH2NO2 grupe i zatim tretiranjem s TMSI radi stvaranja cijano grupe.
14. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da u njemu R znači -CH2Br grupu, a spoj formule (III) konvertira se u spoj formule (II) reakcijom s AgNO2 radi stvaranja odgovarajuće -CH2NO2 grupe i zatim tretiranjem s TMSI radi stvaranja cijano grupe;
ili tretiranjem s NH3 radi stvaranja odgovarajuće -CH2NH2 grupe i zatim oksidacijom uz prisutnost bakrenog(I)klorida radi stvaranja cijano grupe.
15. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da u njemu R znači -CH3 grupu, a spoj formule (III) konvertira se u spoj formule (II) tretiranjem s bazom i zatim s R9ONO2, pri čemu R9 znači C1-6 alkil, radi stvaranja odgovarajuće -CH2NO2 grupe, nakon čega slijedi tretiranje s TMSI radi stvaranja cijano grupe.
16. Način prema bilo kojem od patentnih zahtjeva 1-2, naznačen time da u njemu R znači -CH2OH grupu, a spoj formule (III) konvertira se u spoj formule (II) tretiranjem sa SOCl2 ili SOBr2 radi stvaranja odgovarajuće -CH2Cl grupe ili –CH2Br grupe, nakon čega slijedi
i) reakcija s AgNO2 radi stvaranja odgovarajuće -CH2NO2 grupe i potom tretiranje s TMSI radi stvaranja cijano grupe ili
ii) tretiranje s NH3 radi stvaranja odgovarajuće -CH2NH2 grupe i potom oksidacija uz prisutnost bakrenog(I)klorida radi stvaranja cijano grupe.
17. Način prema bilo kojem od patentnih zahtjeva 3-4 i 10, naznačen time da je u njemu izvor cijanida odabran iz KCN, NaCN, Zn(CN)2, CuCN (R'')4NCN, pri čemu svaki R'' predstavlja C1-8 alkil, opcionalno dva R'' zajedno s dušikom tvore strukturu prstena ili njihove kombinacije.
18. Način prema bilo kojem od patentnih zahtjeva 3-4 i 10, naznačen time da se u njemu Zn2+ i Cu+ dodaju u substehiometrijskim količinama u kombinaciji s drugim izvorom cijanida.
19. Antidepresivna farmaceutska smjesa, naznačena time da sadrži citalopram proizveden na način prema bilo kojem od patentnih zahtjeva 1 do 18.
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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 |
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IES20010157A2 (en) | 2000-03-03 | 2002-03-06 | Lundbeck & Co As H | Method for the preparation of citalopram |
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EP1265883A1 (en) | 2000-03-13 | 2002-12-18 | H. Lundbeck A/S | Method for the preparation of citalopram |
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DE60101786T2 (de) | 2000-03-14 | 2004-07-15 | H. Lundbeck A/S, Valby | 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 |
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UA62985C2 (en) * | 1997-11-10 | 2004-01-15 | Lunnbeck As H | A method for the preparation of citalopram |
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ITMI991579A1 (it) * | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
ITMI991581A1 (it) * | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
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IES20010143A2 (en) * | 2000-02-24 | 2001-07-25 | Lundbeck & Co As H | Method for the preparation of citalopram |
FR2805812A1 (fr) * | 2000-02-24 | 2001-09-07 | Lundbeck & Co As H | Procede de preparation du citalopram |
AU2001272368A1 (en) * | 2000-07-06 | 2002-01-21 | H. Lundbeck, A/S | Method for the preparation of citalopram |
FI20011622A (fi) * | 2000-08-18 | 2002-02-19 | Lundbeck & Co As H | Menetelmä sitalopraamin valmistamiseksi |
TR200201166T1 (tr) * | 2000-12-22 | 2002-10-21 | H.Lundbecks A/S | Saf sitalopram hazırlanması için yöntem |
TR200200018T1 (tr) * | 2000-12-28 | 2002-06-21 | H. Lundbeck A/S | Saf sitalopram hazırlanması için yöntem. |
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2001
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- 2001-03-16 CN CN01806598A patent/CN1418206A/zh active Pending
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- 2001-03-16 NZ NZ521059A patent/NZ521059A/en unknown
- 2001-03-16 CH CH00866/01A patent/CH692148A5/de not_active IP Right Cessation
- 2001-03-16 KR KR1020027011955A patent/KR20020080483A/ko not_active Application Discontinuation
- 2001-03-16 SK SK1481-2002A patent/SK14812002A3/sk unknown
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- 2001-03-16 JP JP2001567724A patent/JP2003527388A/ja not_active Withdrawn
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Also Published As
Publication number | Publication date |
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CH692148A5 (de) | 2002-02-28 |
CZ20023406A3 (cs) | 2003-01-15 |
EA200200982A1 (ru) | 2003-02-27 |
ZA200206802B (en) | 2003-11-26 |
MXPA02008652A (es) | 2003-02-24 |
IS6522A (is) | 2002-08-23 |
KR20020080483A (ko) | 2002-10-23 |
US20030060640A1 (en) | 2003-03-27 |
HUP0300134A2 (en) | 2003-05-28 |
EP1274699A1 (en) | 2003-01-15 |
BR0109180A (pt) | 2003-05-27 |
NO20024197L (no) | 2002-09-03 |
TR200202168T2 (tr) | 2002-12-23 |
WO2001068632A1 (en) | 2001-09-20 |
AU2001244086A1 (en) | 2001-09-24 |
NO20024197D0 (no) | 2002-09-03 |
ES2159271A1 (es) | 2001-09-16 |
BG107049A (en) | 2003-05-30 |
PL360115A1 (en) | 2004-09-06 |
NZ521059A (en) | 2004-04-30 |
JP2003527388A (ja) | 2003-09-16 |
AT5093U1 (de) | 2002-03-25 |
ES2159271B1 (es) | 2002-05-01 |
CA2402869A1 (en) | 2001-09-20 |
IL151487A0 (en) | 2003-04-10 |
CN1418206A (zh) | 2003-05-14 |
SK14812002A3 (sk) | 2003-02-04 |
DE10190485T1 (de) | 2002-03-21 |
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