TWI387577B - 非對稱性合成 - Google Patents
非對稱性合成 Download PDFInfo
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- TWI387577B TWI387577B TW096102355A TW96102355A TWI387577B TW I387577 B TWI387577 B TW I387577B TW 096102355 A TW096102355 A TW 096102355A TW 96102355 A TW96102355 A TW 96102355A TW I387577 B TWI387577 B TW I387577B
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- Taiwan
- Prior art keywords
- group
- compound
- acid
- added
- palmitic
- Prior art date
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- 238000011914 asymmetric synthesis Methods 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 79
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 33
- 150000002902 organometallic compounds Chemical class 0.000 claims abstract description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229960004341 escitalopram Drugs 0.000 claims abstract description 17
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims description 90
- 150000002009 diols Chemical class 0.000 claims description 60
- 239000011541 reaction mixture Substances 0.000 claims description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 239000004327 boric acid Substances 0.000 claims description 37
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 36
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 34
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 claims description 30
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- -1 diisopropyl butyl Chemical group 0.000 claims description 22
- 239000000460 chlorine Substances 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 239000000047 product Substances 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 229940126062 Compound A Drugs 0.000 claims description 13
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- 229910052796 boron Inorganic materials 0.000 claims description 12
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 12
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 11
- 239000006227 byproduct Substances 0.000 claims description 11
- 239000011777 magnesium Substances 0.000 claims description 11
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 10
- 229940073569 n-methylephedrine Drugs 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229960000541 cetyl alcohol Drugs 0.000 claims description 9
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 229910052749 magnesium Inorganic materials 0.000 claims description 9
- GBBSAMQTQCPOBF-UHFFFAOYSA-N 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane Chemical compound CB1OB(C)OB(C)O1 GBBSAMQTQCPOBF-UHFFFAOYSA-N 0.000 claims description 8
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 8
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 claims description 8
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- FMCGSUUBYTWNDP-GXSJLCMTSA-N (+)-N-methylpseudoephedrine Chemical compound CN(C)[C@@H](C)[C@@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-GXSJLCMTSA-N 0.000 claims description 6
- FMCGSUUBYTWNDP-UHFFFAOYSA-N N-Methylephedrine Natural products CN(C)C(C)C(O)C1=CC=CC=C1 FMCGSUUBYTWNDP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 5
- 150000002901 organomagnesium compounds Chemical class 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000005619 boric acid group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 229960000948 quinine Drugs 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 4
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 claims description 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 3
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical class C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical class C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical class C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 claims description 3
- FMCGSUUBYTWNDP-ONGXEEELSA-N (1R,2S)-2-(dimethylamino)-1-phenyl-1-propanol Chemical compound CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-N 0.000 claims description 2
- FUKFNSSCQOYPRM-UHFFFAOYSA-N 2-(dimethylamino)-1-phenylethanol Chemical compound CN(C)CC(O)C1=CC=CC=C1 FUKFNSSCQOYPRM-UHFFFAOYSA-N 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000003574 free electron Substances 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000001979 organolithium group Chemical group 0.000 claims description 2
- 125000002734 organomagnesium group Chemical group 0.000 claims description 2
- 150000002916 oxazoles Chemical class 0.000 claims description 2
- 125000003544 oxime group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- FWEOQOXTVHGIFQ-UHFFFAOYSA-N 8-anilinonaphthalene-1-sulfonic acid Chemical group C=12C(S(=O)(=O)O)=CC=CC2=CC=CC=1NC1=CC=CC=C1 FWEOQOXTVHGIFQ-UHFFFAOYSA-N 0.000 claims 1
- 125000002877 alkyl aryl group Chemical group 0.000 claims 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 abstract description 17
- 230000008569 process Effects 0.000 abstract description 15
- 238000005804 alkylation reaction Methods 0.000 abstract description 14
- 230000029936 alkylation Effects 0.000 abstract description 9
- 150000001642 boronic acid derivatives Chemical class 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000000935 antidepressant agent Substances 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 230000000707 stereoselective effect Effects 0.000 abstract description 4
- 238000011915 stereoselective alkylation Methods 0.000 abstract description 3
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 abstract description 2
- PQMFVUNERGGBPG-UHFFFAOYSA-N (6-bromopyridin-2-yl)hydrazine Chemical compound NNC1=CC=CC(Br)=N1 PQMFVUNERGGBPG-UHFFFAOYSA-N 0.000 abstract 4
- 125000005621 boronate group Chemical class 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 255
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- 239000000243 solution Substances 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 50
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 48
- 239000010410 layer Substances 0.000 description 40
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 37
- 239000002904 solvent Substances 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 30
- 238000003756 stirring Methods 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- BHOFOFKBMGVFSG-UHFFFAOYSA-N methyl-di(propan-2-yloxy)borane Chemical compound CC(C)OB(C)OC(C)C BHOFOFKBMGVFSG-UHFFFAOYSA-N 0.000 description 20
- NGPAITITALWALP-UHFFFAOYSA-M magnesium;n,n-dimethylpropan-1-amine;chloride Chemical compound [Mg+2].[Cl-].CN(C)CC[CH2-] NGPAITITALWALP-UHFFFAOYSA-M 0.000 description 19
- LJWYBBIKAYVUCA-UHFFFAOYSA-N C1=CC(=CC=C1C=C2C=CC(=CC2CO)C#N)F Chemical compound C1=CC(=CC=C1C=C2C=CC(=CC2CO)C#N)F LJWYBBIKAYVUCA-UHFFFAOYSA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 17
- 239000011159 matrix material Substances 0.000 description 17
- GNULRNVWXYXBQY-FQEVSTJZSA-N 4-[(1s)-4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile Chemical compound C1([C@@](O)(CCCN(C)C)C=2C(=CC(=CC=2)C#N)CO)=CC=C(F)C=C1 GNULRNVWXYXBQY-FQEVSTJZSA-N 0.000 description 16
- 239000012298 atmosphere Substances 0.000 description 16
- 238000000926 separation method Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- GNULRNVWXYXBQY-HXUWFJFHSA-N 4-[(1r)-4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile Chemical compound C1([C@](O)(CCCN(C)C)C=2C(=CC(=CC=2)C#N)CO)=CC=C(F)C=C1 GNULRNVWXYXBQY-HXUWFJFHSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 150000001414 amino alcohols Chemical class 0.000 description 14
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical class CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000002671 adjuvant Substances 0.000 description 10
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 10
- 239000002808 molecular sieve Substances 0.000 description 10
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 9
- 239000003480 eluent Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000010533 azeotropic distillation Methods 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 125000002524 organometallic group Chemical group 0.000 description 7
- 229940095064 tartrate Drugs 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000005191 phase separation Methods 0.000 description 6
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- 229910004298 SiO 2 Inorganic materials 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 229960002179 ephedrine Drugs 0.000 description 5
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical group [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 4
- 229960003908 pseudoephedrine Drugs 0.000 description 4
- 229960001404 quinidine Drugs 0.000 description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- USSSGFJRIUUWBB-UHFFFAOYSA-N 1-n,1-n'-dimethylprop-2-yne-1,1-diamine Chemical compound CNC(NC)C#C USSSGFJRIUUWBB-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000157855 Cinchona Species 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000003960 organic solvent 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
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- KTGRHKOEFSJQNS-BDQAORGHSA-N (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;oxalic acid Chemical compound OC(=O)C(O)=O.C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 KTGRHKOEFSJQNS-BDQAORGHSA-N 0.000 description 2
- ZWVHTXAYIKBMEE-UHFFFAOYSA-N 2-hydroxyacetophenone Chemical compound OCC(=O)C1=CC=CC=C1 ZWVHTXAYIKBMEE-UHFFFAOYSA-N 0.000 description 2
- RNKGDBXXIBUOTR-UHFFFAOYSA-N 3,6-dioxocyclohexa-1,4-diene-1-carbonitrile Chemical compound O=C1C=CC(=O)C(C#N)=C1 RNKGDBXXIBUOTR-UHFFFAOYSA-N 0.000 description 2
- JOWBVIAXILQDHG-UHFFFAOYSA-N 4-[(4-fluorophenyl)-hydroxymethyl]-3-(hydroxymethyl)benzonitrile Chemical compound OCC1=CC(C#N)=CC=C1C(O)C1=CC=C(F)C=C1 JOWBVIAXILQDHG-UHFFFAOYSA-N 0.000 description 2
- OVMZZDSKRLPDPU-UHFFFAOYSA-N 4-[1-(4-fluorophenyl)-1-hydroxy-3-methylbutyl]-3-(hydroxymethyl)benzonitrile Chemical compound C=1C=C(C#N)C=C(CO)C=1C(O)(CC(C)C)C1=CC=C(F)C=C1 OVMZZDSKRLPDPU-UHFFFAOYSA-N 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
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- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- 238000003109 Karl Fischer titration Methods 0.000 description 2
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- 230000001430 anti-depressive effect Effects 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 239000003849 aromatic solvent Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
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- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229960005086 escitalopram oxalate Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 229910001629 magnesium chloride Chemical group 0.000 description 2
- QUXHCILOWRXCEO-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CCC[CH2-] QUXHCILOWRXCEO-UHFFFAOYSA-M 0.000 description 2
- BRKADVNLTRCLOW-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=[C-]C=C1 BRKADVNLTRCLOW-UHFFFAOYSA-M 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
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- 230000003287 optical effect Effects 0.000 description 2
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- 239000012071 phase Substances 0.000 description 2
- 229950010765 pivalate Drugs 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- FUKFNSSCQOYPRM-JTQLQIEISA-N (1r)-2-(dimethylamino)-1-phenylethanol Chemical compound CN(C)C[C@H](O)C1=CC=CC=C1 FUKFNSSCQOYPRM-JTQLQIEISA-N 0.000 description 1
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 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 description 1
- BFAQNLRAFSBFGU-UHFFFAOYSA-N 1-amino-1-phenylethanol Chemical compound CC(N)(O)C1=CC=CC=C1 BFAQNLRAFSBFGU-UHFFFAOYSA-N 0.000 description 1
- OWXTVVMIMIRMLL-UHFFFAOYSA-N 1-hydrazinylpropan-2-ol Chemical compound CC(O)CNN OWXTVVMIMIRMLL-UHFFFAOYSA-N 0.000 description 1
- BSNCDZRIFUUQEW-UHFFFAOYSA-N 2,3-dihydroxy-4-(2-methylphenoxy)-4-oxobutanoic acid Chemical compound CC1=CC=CC=C1OC(=O)C(O)C(O)C(O)=O BSNCDZRIFUUQEW-UHFFFAOYSA-N 0.000 description 1
- DTBDAFLSBDGPEA-UHFFFAOYSA-N 3-Methylquinoline Natural products C1=CC=CC2=CC(C)=CN=C21 DTBDAFLSBDGPEA-UHFFFAOYSA-N 0.000 description 1
- QMSFXFWDRYGFFN-HXUWFJFHSA-N 4-[(1s)-4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybut-2-ynyl]-3-(hydroxymethyl)benzonitrile Chemical compound C1([C@](O)(C#CCN(C)C)C=2C(=CC(=CC=2)C#N)CO)=CC=C(F)C=C1 QMSFXFWDRYGFFN-HXUWFJFHSA-N 0.000 description 1
- IDVCWZLASJEQHV-UHFFFAOYSA-N 4-[1-(4-fluorophenyl)-1-hydroxypentyl]-3-(hydroxymethyl)benzonitrile Chemical compound C=1C=C(C#N)C=C(CO)C=1C(O)(CCCC)C1=CC=C(F)C=C1 IDVCWZLASJEQHV-UHFFFAOYSA-N 0.000 description 1
- GNULRNVWXYXBQY-UHFFFAOYSA-N 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile Chemical compound C=1C=C(C#N)C=C(CO)C=1C(O)(CCCN(C)C)C1=CC=C(F)C=C1 GNULRNVWXYXBQY-UHFFFAOYSA-N 0.000 description 1
- LVSQXDHWDCMMRJ-UHFFFAOYSA-N 4-hydroxybutan-2-one Chemical compound CC(=O)CCO LVSQXDHWDCMMRJ-UHFFFAOYSA-N 0.000 description 1
- IOBKNZNXFXTQNC-UHFFFAOYSA-N 5-(dimethylamino)-2-phenylpentane-1,2-diol Chemical compound CN(C)CCCC(O)(CO)C1=CC=CC=C1 IOBKNZNXFXTQNC-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 235000021513 Cinchona Nutrition 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
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- 230000027832 depurination Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- RXOBWFMXPDQMAQ-UHFFFAOYSA-N dimethoxymethylboron Chemical compound COC([B])OC RXOBWFMXPDQMAQ-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical group [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Chemical group 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- YSMZEMQBSONIMJ-UHFFFAOYSA-M magnesium;2-methanidylpropane;chloride Chemical compound [Mg+2].[Cl-].CC(C)[CH2-] YSMZEMQBSONIMJ-UHFFFAOYSA-M 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000010955 niobium Substances 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical compound [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
- C07C215/32—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton containing hydroxy groups and carbon atoms of two six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (1)
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|---|---|---|---|
| GBGB0601286.8A GB0601286D0 (en) | 2006-01-23 | 2006-01-23 | Asymmetric synthesis |
Publications (2)
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|---|---|
| TW200800858A TW200800858A (en) | 2008-01-01 |
| TWI387577B true TWI387577B (zh) | 2013-03-01 |
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| TW096102355A TWI387577B (zh) | 2006-01-23 | 2007-01-22 | 非對稱性合成 |
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| EP (1) | EP1966127B1 (enExample) |
| JP (1) | JP5081163B2 (enExample) |
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| CN (1) | CN101460448B (enExample) |
| AT (1) | ATE504558T1 (enExample) |
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| EA (1) | EA016650B1 (enExample) |
| ES (1) | ES2364502T3 (enExample) |
| GB (1) | GB0601286D0 (enExample) |
| HR (1) | HRP20110492T1 (enExample) |
| IL (1) | IL192628A (enExample) |
| PL (1) | PL1966127T3 (enExample) |
| SI (1) | SI1966127T1 (enExample) |
| TW (1) | TWI387577B (enExample) |
| WO (1) | WO2007082771A1 (enExample) |
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| US20110130591A1 (en) * | 2009-06-03 | 2011-06-02 | Boehringer Ingelheim International Gmbh | Steroselective synthesis of certain trifluoromethyl-substituted alcohols |
| MX351657B (es) * | 2012-03-14 | 2017-10-23 | Merck Sharp & Dohme | Sales de alcaloide de cinchona bis-cuaternarias como catalizadores de transferencia de fase asimétrica. |
| HUE040244T2 (hu) * | 2013-06-26 | 2019-02-28 | Syngenta Participations Ag | Eljárás pirazol-karboxamid sztereoszelektív elõállítására |
| US10287240B2 (en) | 2014-11-14 | 2019-05-14 | Zhejiang Hushai Pharmaceuticals Co., Ltd. | Method for resolution of citalopram intermediate 5-cyano diol |
| KR20160109083A (ko) | 2015-03-09 | 2016-09-21 | 엔팩토리주식회사 | 휴대용 앱세서리를 이용한 공기품질 정보제공 시스템 및 방법 |
| US10111356B2 (en) | 2016-03-31 | 2018-10-23 | Oracle International Corporation | System for electrical connection of printed circuit boards and backplanes in server enclosure |
| CN106892837A (zh) * | 2017-03-23 | 2017-06-27 | 浙江师范大学 | 4‑[4‑(二甲氨基)‑1‑(4‑氟苯基)‑1‑羟丁基]‑3‑羟甲基苯腈的合成 |
| CN108947869A (zh) * | 2017-05-25 | 2018-12-07 | 万全万特制药江苏有限公司 | 一种艾司西酞普兰工艺杂质的制备方法 |
| CN108640856B (zh) * | 2018-06-11 | 2021-06-25 | 淮阴工学院 | 一种依地普仑中间体的不对称合成方法及其中间体 |
| CN108640855A (zh) * | 2018-06-11 | 2018-10-12 | 中南林业科技大学 | 一种依地普仑中间体的合成方法及其中间体 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| UA62985C2 (en) | 1997-11-10 | 2004-01-15 | Lunnbeck As H | A method for the preparation of citalopram |
| WO2000012044A2 (en) * | 1999-10-25 | 2000-03-09 | H. Lundbeck A/S | Method for the preparation of citalopram |
| FR2805812A1 (fr) | 2000-02-24 | 2001-09-07 | Lundbeck & Co As H | Procede de preparation du citalopram |
| IES20010157A2 (en) | 2000-03-03 | 2002-03-06 | Lundbeck & Co As H | Method for the preparation of citalopram |
| CA2402388A1 (en) | 2000-03-13 | 2001-09-20 | Hans Petersen | Method for the preparation of citalopram |
| AR034759A1 (es) | 2001-07-13 | 2004-03-17 | Lundbeck & Co As H | Metodo para la preparacion de escitalopram |
| EP1522539B1 (en) | 2001-07-31 | 2007-01-24 | H. Lundbeck A/S | Crystalline composition containing escitalopram |
| PT1281707E (pt) | 2001-08-02 | 2005-04-29 | Infosint Sa | Processo para a preparacao de isobenzofuranos 5-substituidos |
| 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 |
| WO2005066185A1 (en) | 2004-01-12 | 2005-07-21 | Jubilant Organosys Limited | Process for preparing 5-substituted -1-(4-fluorophenyl) -1,3-dihydroisobenzofurans |
| JP2005247710A (ja) * | 2004-03-01 | 2005-09-15 | Sumitomo Chemical Co Ltd | 光学活性シタロプラムの製造方法、その中間体およびその製造方法 |
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|---|---|
| IL192628A (en) | 2013-04-30 |
| PL1966127T3 (pl) | 2011-10-31 |
| DE602007013690D1 (de) | 2011-05-19 |
| JP2009523749A (ja) | 2009-06-25 |
| AU2007207103B2 (en) | 2011-01-06 |
| ATE504558T1 (de) | 2011-04-15 |
| WO2007082771A1 (en) | 2007-07-26 |
| US8288569B2 (en) | 2012-10-16 |
| IL192628A0 (en) | 2009-02-11 |
| SI1966127T1 (sl) | 2011-08-31 |
| US20110009648A1 (en) | 2011-01-13 |
| GB0601286D0 (en) | 2006-03-01 |
| KR101379154B1 (ko) | 2014-04-11 |
| CN101460448B (zh) | 2013-05-15 |
| JP5081163B2 (ja) | 2012-11-21 |
| EA200801673A1 (ru) | 2009-02-27 |
| AU2007207103A1 (en) | 2007-07-26 |
| ES2364502T3 (es) | 2011-09-05 |
| CA2636256C (en) | 2014-04-29 |
| BRPI0706735B1 (pt) | 2016-11-22 |
| EP1966127B1 (en) | 2011-04-06 |
| KR20080090444A (ko) | 2008-10-08 |
| CN101460448A (zh) | 2009-06-17 |
| TW200800858A (en) | 2008-01-01 |
| HRP20110492T1 (hr) | 2011-07-31 |
| BRPI0706735A2 (pt) | 2011-04-05 |
| CA2636256A1 (en) | 2007-07-26 |
| EP1966127A1 (en) | 2008-09-10 |
| EA016650B1 (ru) | 2012-06-29 |
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