MXPA06008977A - Method for the separation of intermediates which may be used for the preparation of escitalopram - Google Patents
Method for the separation of intermediates which may be used for the preparation of escitalopramInfo
- Publication number
- MXPA06008977A MXPA06008977A MXPA/A/2006/008977A MXPA06008977A MXPA06008977A MX PA06008977 A MXPA06008977 A MX PA06008977A MX PA06008977 A MXPA06008977 A MX PA06008977A MX PA06008977 A MXPA06008977 A MX PA06008977A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- compound
- group
- enantiomer
- alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 74
- 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 title claims description 23
- 229960004341 escitalopram Drugs 0.000 title claims description 22
- 238000000926 separation method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title description 8
- 239000000543 intermediate Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 154
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 239000000203 mixture Substances 0.000 claims abstract description 40
- 239000011541 reaction mixture Substances 0.000 claims abstract description 16
- 239000002244 precipitate Substances 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 44
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 33
- 125000002252 acyl group Chemical group 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 238000005917 acylation reaction Methods 0.000 claims description 18
- 150000002009 diols Chemical class 0.000 claims description 18
- 230000002255 enzymatic effect Effects 0.000 claims description 18
- 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 claims description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims description 17
- 230000010933 acylation Effects 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 125000003282 alkyl amino group Chemical group 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 230000020176 deacylation Effects 0.000 claims description 10
- 238000005947 deacylation reaction Methods 0.000 claims description 10
- 150000008064 anhydrides Chemical class 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- -1 cyclic anhydride Chemical class 0.000 claims description 7
- 238000002955 isolation Methods 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 239000011347 resin Substances 0.000 claims description 6
- 229920005989 resin Polymers 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 150000003949 imides Chemical class 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000004957 naphthylene group Chemical group 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical group ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 229940014800 succinic anhydride Drugs 0.000 claims description 3
- ZTUKZULGOCFJET-UHFFFAOYSA-N 1-phenylpyrrolidine-2,5-dione Chemical group O=C1CCC(=O)N1C1=CC=CC=C1 ZTUKZULGOCFJET-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical group C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- 125000002843 carboxylic acid group Chemical group 0.000 abstract description 3
- GNULRNVWXYXBQY-FQEVSTJZSA-N 4-[(1s)-4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile Chemical class C1([C@@](O)(CCCN(C)C)C=2C(=CC(=CC=2)C#N)CO)=CC=C(F)C=C1 GNULRNVWXYXBQY-FQEVSTJZSA-N 0.000 abstract 3
- 102000004190 Enzymes Human genes 0.000 description 25
- 108090000790 Enzymes Proteins 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- 150000007524 organic acids Chemical class 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 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 6
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 229960001653 citalopram Drugs 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- 238000006798 ring closing metathesis reaction Methods 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical group OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- MEGHWIAOTJPCHQ-UHFFFAOYSA-N ethenyl butanoate Chemical compound CCCC(=O)OC=C MEGHWIAOTJPCHQ-UHFFFAOYSA-N 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 4
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000004157 Hydrolases Human genes 0.000 description 3
- 108090000604 Hydrolases Proteins 0.000 description 3
- 239000004367 Lipase Substances 0.000 description 3
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 3
- 102000043296 Lipoprotein lipases Human genes 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000589774 Pseudomonas sp. Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 3
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 2
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
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- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000012296 anti-solvent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 210000005056 cell body Anatomy 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-N isocaproic acid Chemical compound CC(C)CCC(O)=O FGKJLKRYENPLQH-UHFFFAOYSA-N 0.000 description 2
- 150000002540 isothiocyanates Chemical class 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
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- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 description 1
- JEUSDRLWFSRHSX-XUEDOEMRSA-N (z)-7-[(1s,2r,3r,4r)-3-[(e,3s)-4-(4-fluorophenoxy)-3-hydroxybut-1-enyl]-7-oxabicyclo[2.2.1]heptan-2-yl]hept-5-enoic acid Chemical compound C([C@@H](O)\C=C\[C@@H]1[C@H]([C@@H]2CC[C@H]1O2)C\C=C/CCCC(O)=O)OC1=CC=C(F)C=C1 JEUSDRLWFSRHSX-XUEDOEMRSA-N 0.000 description 1
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- FPIQZBQZKBKLEI-UHFFFAOYSA-N ethyl 1-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylate Chemical compound ClCCN(N=O)C(=O)NC1(C(=O)OCC)CCCCC1 FPIQZBQZKBKLEI-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- FCCDDURTIIUXBY-UHFFFAOYSA-N lipoamide Chemical compound NC(=O)CCCCC1CCSS1 FCCDDURTIIUXBY-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
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Abstract
The invention relates to a method of separating and isolating an acylated derivative of 4-[(S)-4-dimethylamino -1-(4-fluorophenyl)-1 -hydroxybutyl]-3- hydroxymethylbenzonitrile by reaction of a mixture of the 4-[(S)-4 -dimethylamino-1 -(4-fluorophenyl) -1-hydroxy-butyl]-3-hydroxymethylbenzonitrile and an acylated derivative thereof with a compound which form a derivative of the 4-[(S)-4 -dimethylamino -1-(4-fluorophenyl) -1-hydroxy-butyl]-3- hydroxymethylbenzonitrile containing a carboxylic acid group. The acylated derivative containing a carboxylic acid group precipitates once it is formed and may easily be separated from the reaction mixture.
Description
METHOD FOR THE SEPARATION OF INTERMEDIARIES THAT CAN BE USED FOR THE PREPARATION OF? SCITALOPRAM
The present invention relates to a new method for the preparation of optically active intermediates for the preparation of escitalopram.
BACKGROUND OF THE INVENTION
Citalopram is a well-known antidepressant drug that has been on the market for years. It is a central selective selective serotonin reuptake inhibitor (5-hydroxytryptamine, 5-HT), which consequently has antidepressant activities. Citalopram was first disclosed in DE 2,657,013, corresponding to US Pat. No. 4,136,193. This patent publication i. to . describes a process for the preparation of citalopram from the corresponding 5-bromo derivative by reaction with cuprous cyanide in a suitable solvent and by the alkylation of 5-bromo-phthalane. U.S. Patent No. 4,943,590 corresponding to patent EP-B1-347 066 describes two processes for the preparation of escitalopram (S enantiomer of citalopram). Both processes use the racemic diol that has the formula
as starting material. According to the first process, the diol of the formula (I) is reacted with an enantiomerically pure acid derivative, such as (+) or (-) -a-methoxy-α-trifluoromethyl-phenylacetyl * chloride to form a mixture of diastereoisomeric esters, which are separated by HPLC or fractional crystallization, so that the ester with the correct stereochemistry becomes enantioselectively in escitalopram. According to the second process, the diol of the formula (II) is separated into the enantiomers by stereoselective crystallization with an enantiomerically pure acid such as (+) - di-p-toluoyltartaric acid, whereby the S enantiomer of the diol of Formula (I) becomes enantioselectively in escitalopram. At present escitalopram has been developed as an antidepressant. Therefore, there is a need for an improved method for the preparation of escitalopram. It has been found that the S enantiomer of the diol of the above formula (I) as well as also its acylated derivatives can be prepared by selective enzymatic acylation of the primary hydroxyl group in the racemic diol to obtain the S-diol of the formula (I) or its acylated derivative with high optical purity and furthermore that the enantiomers obtained can be effectively separated by the reaction of the diol of the formula (I) with a compound forming a diol derivative of the formula (I) containing a carboxylic acid group. The formed derivative precipitates once it is formed and can be easily separated from the reaction mixture.
BRIEF DESCRIPTION OF THE INVENTION
Accordingly, an object of the present invention relates to a method for the isolation and purification of a compound having the formula
in which R is cyano or a group that can be converted into a cyano group, the dotted line represents a single or double bond, Hal is halogen,. Z is a dimethylaminomethyl group or Z is a group that can be converted to a dimethylaminomethyl group, W is 0 or S, and Y is a bond, 0, S or NH and R1 is Ci-io alkyl, C2_? 0 alkenyl or alkynyl C2-? O, all of which may be optionally substituted with one or more substituents selected from C alco _ alco alkoxy, Cilt _ alqu alkylthio, hydroxyl, halogen, amino, nitro, cyano, Cila _? Alkylamino, di- (C 1 ι_) alkyl amino, aryl, aryloxy, arylthio and heteroaryl, or R 1 is aryl, wherein any of the aryl and heteroaryl groups may be optionally substituted one or more times with substituents selected from C alquilo-alkyl? or, C2_? 0 alkenyl, C2_? alkynyl, C? -? al alkoxy, alkylthio C? _?, hydroxyl, halogen, amino, nitro, cyano, alkylamino C? _? o and di- (C? _? alkyl? 0) amino, or a salt thereof and / or a diol of the formula
wherein R, Z, Hal and the dotted line are as defined above, or a salt thereof, of a mixture containing the compound of the formula (IV) and the diol of the formula (II), which it comprises: a) reacting said mixture containing the compound of the formula (IV) - and the diol of the formula (II) with a cyclic anhydride or an imide of the formula
(la) (Ib) (le)
where X is - (CHR "') n-, where n is 0-2;
and R, R and R "'are independently selected from hydrogen, C? -5 alkyl, Ci-e alkoxy, aryloxy, acyloxy C? e, aryl-CO-O, where each aryl may be substituted with Cn_6 alkyl, or R 'and R "in an anhydride of the formula, (the) together are -0-CR4R5-0-, where. R4 and R5 are independently hydrogen or Ct.sub.5 alkyl, or R 'and R "in an anhydride of the formula (Ib) are adjacent and together with the two carbon atoms to which they are attached form a benzene ring; of Q1 and Q2 is nitrogen and the other carbon, or both are carbon; A is C2_s aiquilene, phenylene, or naphthylene where
, C? -6 alkylene groups, phenylene, or naphthylene may be optionally substituted one or more times with alkyl
C? -6; to form a mixture of the compound of the formula (IV) and an ester having the formula
(V) in which R, Z and Hal is as defined above and V is -CHR '-X-CR "-C00H, -X-CHR" -C0-NH-A-COOH, -CHR "-X- CO-NH-A-COOH or
wherein R ', R ", X and A are as defined above: b) separating the compound of formula (IV) from the ester of formula (V) by a method selected from the group consisting of: i) allowing the acid of the formula (V) or a salt of the same precipitate of the reaction mixture, and separating the precipitate of the compound of the formula (V) or a salt thereof from the reaction mixture, optionally followed by isolation of the compound of the formula (IV) or a salt thereof of the reaction mixture, ii) dividing between an organic solvent and an aqueous solvent, whereby the compound of the formula (IV) will be dissolved in the organic phase while the compound of the formula (IV) will be dissolved in the organic phase. the formula (V) will dissolve in the aqueous phase, separating the phases and optionally isolating the compound of the formula (IV) or a salt thereof and / or isolating the compound of the formula (V) or a salt thereof; and iii) adsorbing the compound of the formula (V) on a basic resin, separating the sol Vente containing the compound of the formula (IV) of the resin, desorb the compound of the formula (V) of the basic resin, and optionally isolating the compound of the formula (IV) or a salt thereof and / or isolating the composed of the formula (V) or a salt thereof. A second objective of the invention relates to a method for making escitalopram comprising the method described above. According to a particular embodiment of the invention, an enantiomer of formula (II) is separated from
, a compound of the formula (IV) in the form of the other enantiomer. According to one embodiment of the invention, the S-enantiomer of the compound of the formula (V) or a mixture of enantiomers of the compound of the formula (V) comprising more than 50% of the S-enantiomer of the compound of the formula (V) is separated from the R enantiomer of the acyl derivative of the formula (IV) or a mixture of enantiomers of the acyl derivative of the formula (IV) comprising more than 50% of the R enantiomer of the acyl derivative of the formula (IV) . According to a particular embodiment of the invention, the S-enantiomer of the compound of the formula (V) is separated from the R-enantiomer of the acyl derivative of the formula (IV) or of a mixture of enantiomers of the acyl derivative of the formula ( IV) comprising more than 50% of the R-enantiomer of the acyl derivative of the formula (IV). According to a more particular embodiment of the invention, the S-enantiomer of the compound of the formula (V) is separated from the R-enantiomer of the acyl derivative of the formula (IV). According to another embodiment of the invention, the S-enantiomer of the acyl derivative of the formula (IV) or a mixture of enantiomers of the acyl derivative of the formula (IV) comprising more than 50% of the S-enantiomer of the acyl derivative of the formula (IV) is separated from the R-enantiomer of the compound of the formula (V) or a mixture of enantiomers of the compound of the formula (V) comprising more than 50% of the R-enantiomer of the compound of the formula (V) . According to a particular embodiment of the invention, the S-enantiomer of the acyl derivative of the formula (IV) is separated from the R-enantiomer of the compound of the formula (V) or a mixture of enantiomers of the compound of the formula (V) comprising more than 50% of the R-enantiomer of the compound of the formula (V).
According to a more particular embodiment, the S-enantiomer of the acyl derivative of the formula (IV) is separated from the R-enantiomer of the compound of the formula (V). According to a specific embodiment of the invention, the reagent used is a compound of the formula (Ia), suitably succinic anhydride or glutaric anhydride. According to another specific embodiment, the reagent used is a compound of the formula (Ib), conveniently phthalic anhydride. According to a third embodiment of the invention, the reagent is an imide of the formula (le), suitably N-phenyl-succinimide substituted on the phenyl ring with a carboxyl group. According to another embodiment of the invention, the group R in the compound of the formula (V) obtained in the form of the S-enantiomer is optionally converted to cyano, the group Z in the compound of the formula (V) obtained is optionally converted in a dimethylaminomethyl group, Hal is optionally converted to fluoro and / or a dotted line representing a double bond is optionally converted to a single bond, in any order; followed by conversion of the compound of the formula (V) into escitalopram or its derivative having the formula
wherein R, Z and Hal is as defined above by treatment with a base, optionally followed by, in any order, conversion of the R group into a cyano group, conversion of the Z group into a dimethylaminomethyl group, conversion of Hal into fluoro , and conversion of a dotted line representing a double bond into a single link; optionally followed by conversion of escitalopram or a derivative of the formula (VI) into a salt thereof. According to another embodiment of the invention, the group R in the compound of the formula (IV) obtained in the form of the S-enantiomer is optionally converted to cyano, the group Z in the compound of the formula IV obtained is optionally converted into a dimethylaminomethyl group, Hal is optionally converted to fluoro and / or a dotted line representing a double bond is optionally converted to a single bond, in any order;
followed by conversion of the compound of the formula (IV) into escitalopram or its derivative
wherein R, Z and Hal is as defined above by treatment with a base, optionally followed by, in any order, conversion of the R group into a cyano group, conversion of the Z group into a dimethyiaminomethyl group, conversion of Hal into fluoro , and conversion of a dotted line representing a double bond into a single link; optionally followed by conversion of escitalopram or a derivative of the formula (VI) into a salt thereof. According to the most preferred embodiment of the invention, a mixture of the compound of the formula (II) and (IV) where R is cyano, the dotted line is a single bond, Z is dimethylaminomethyl, Hal is fluoro, Y is a bond and R1 is -CH2-CH2-CH3 is reacted with a cyclic anhydride of the formula (la) where X is - (CH2) 0-? to form a mixture of the corresponding S-enantiomer of the formula (V) and the R-enantiomer of the formula (IV). The isolated compound of the formula (V) is then reacted with NaH to form the compound of the formula
(SAW) . The mixture of formula (II) and (IV) used as starting material is preferably prepared by enzymatic acylation of a compound of formula II where
R is cyano, the dotted line is a simple bond, Z is dimethylaminomethyl, Hal is fluoro, using vinyl butyrate as the acylating agent and the enzyme Candida antartica-lipase B.
DETAILED DESCRIPTION OF THE INVENTION
When used in connection with the compounds of the formula (II), (IV), (V) and (VI), the terms "enantiomer", "R enantiomer", "S enantiomer", "R form", "form S "," R-diol "and" S-diol "refer to the orientation of the groups around the carbon atom to which the 4-Hal-phenyl group is attached. As used herein, the term "alkyl" refers to a branched or unbranched alkyl group having from one to ten carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl, pentyl, hexyl and heptyl. Alkyl C? ~ 6 refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2- methyl-2-propyl, 2-methyl-1-propyl, pentyl and hexyl. Alkyl C? _4 refers to a branched or unbranched alkyl group having from one to four carbon atoms inclusive, such as methyl, ethyl, 1-pro? Yl, 2-propyl, 1-butyl, 2-butyl, -methyl-2-propyl and 2-methyl-1-propyl. Alkyl C? _3 refers to a branched or unbranched alkyl group having from one to three carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl. Similarly, C2-? O alkenyl and C2-? Alkynyl or refer to branched or unbranched alkynyl and alkynyl groups, respectively, having. from two to ten carbon atoms, including a double bond and a triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl. C2-6 alkenyl and C2-6 alkynyl refer to alkenyl and alkynyl-branched or unbranched groups, respectively, having from two to six carbon atoms, including a double bond and a triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl. C 4 alkenyl and C 2-4 alkynyl refer to branched or unbranched alkenyl and alkynyl groups, respectively, having from two to four carbon atoms, including a double bond and a triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl , propynyl and butynyl. C2-3 alkenyl and C2_3 alkynyl refer to branched or unbranched alkenyl and alkynyl groups, respectively, having from two to three carbon atoms, including a double bond and a triple bond respectively, such as ethenyl, propenyl, ethynyl and propynyl . The terms alkoxy C? _? O, alkylthio C? _? O, alkylamino C? _? _ O and di- (alkyl C? _? 0) amino etc. they refer to such groups in which the alkyl group is C alquilo _ ?alkyl or as defined above. The terms alkoxy C? -g, alkylthio C? _6, alkylamino C? _6 and di- (C? _6 alkyl) amino etc. they refer to such groups in which the alkyl group is C alquilo _s alkyl as defined above. The terms C 1 -4 alkoxy, C 4 alkylthio, C 1 alkylamino, and di- (C 4 alkyl) amino etc. they refer to groups in which the alkyl group is C? _4 alkyl as defined above. The terms alkoxy C? _3, alkylthio Cj._3, alkylamino Cx_3 and di- (C? _3 alkyl) amino etc. they refer to such groups in which the alkyl group is C? _3 alkyl as defined above. Halogen means fluoro, chloro, bromo or iodo.
As used herein, the term "anti-solvent" refers to a liquid that when added to a solute system in solvent reduces the solubility of the solute. In a particular embodiment of the invention, the separation of the compound of the formula (IV) from the ester of the formula (V) is carried out by allowing the acid of the formula (V) to precipitate out of the reaction mixture, and separating the precipitate of the compound of the formula (V) of the reaction mixture, optionally followed by isolation of the compound of the formula (IV) or a salt thereof from the reaction mixture. In a particular embodiment of the invention, R ', R "and R"' are independently selected from hydrogen and C alquilo _ alkyl, and Q1 and Q2 are both carbon. In a particular embodiment of the invention, the mixture of enantiomers of the compound of the formula (V) comprises more than 60% of the S-enantiomer of the compound of the formula (V), such as more than 70%, more than 80%, more 90%, more than 95%, more than 98% or more than 99%. In another equally particular embodiment of the invention, the mixture of enantiomers of the compound of the formula (V) comprises more than 60% of the R enantiomer of the compound of the formula (V), such as more than 70%, more than 80%, more than 90%, more than 95%, more than 98% or more than 99%.
In yet another particular embodiment of the invention, the mixture of enantiomers of the acyl derivative of the formula (IV) comprises more than 60% of the S-enantiomer of the compound of the formula (V), such as more than 70%, more than 80%, more than 90%, more than 95%, more than 98% or more than 99%. In yet another particular embodiment of the invention, the enantiomer mixture of the acyl derivative of the formula (IV) comprises more than 60% of the R enantiomer of the compound of the formula (V), such as more than 70%, more than 80%, more than 90%, more than 95%, more than 98% or more than 99%. In a preferred embodiment of the invention, R is halogen or cyano, more preferably cyano. In another preferred embodiment of the invention, Hal is fluoro. In another preferred embodiment of the invention, the dotted line in formula (II), (IV) and (V) is a single bond. In yet another preferred embodiment, Z is dimethylaminomethyl or a group that can be converted to dimethylaminomethyl. In a preferred embodiment, Z is dimethylaminomethyl.
More preferably, Hal is fluoro, R is cyano, the dotted line is a single bond and Z is dimethylaminomethyl. According to one embodiment of the invention, Y in the compound of the formula (IV) is 0 or S. According to another embodiment of the invention, Y in the compound of the formula (IV) is NH. However, according to a preferred embodiment of the invention, Y in the compound of the formula (IV) is a bond. Conveniently, the substituent R1 in the compound of the formula (IV) as defined in any of the foregoing embodiments, is as follows: R1 is C5-alkyl, C2-6 alkenyl or C2_6 alkynyl, all of which may optionally being substituted one or more times with substituents selected from C6_6alkoxy, C6_6alkyl, hydroxyl, halogen, amino, nitro, cyano, C4_4alkylamino and di- (Ci_g_alkyl) amino, more convenient R1 is C C4 alkyl, C2- alkenyl or C2_4 alkynyl, all of which may be optionally substituted one or more times with substituents selected from C alco _ alkoxy, C? _4 alkylthio, hydroxyl, halogen, amino, nitro, cyano, alkylamino C ? 4 and di- (C 1 -4 alkyl) amino, preferably R 1 is C 3-3 alkyl, C 2-3 alkenyl or C 2 - 3 alkynyl, all of which may be optionally substituted one or more times with C 3 alkoxy, alkylthio Ca_3, hydroxyl, halogen, amino, nitro, cyano, alkylamino C? _3 and di- (C? _ 3 alkyl) amino, with greater preference R1 is C3_3alkyl, C3_alkenyl or C2_3alkynyl, and more conveniently R1 is C3_3alkyl, in particular unbranched C3_3alkyl, such as methyl, ethyl or propyl. The present invention is particularly useful for the separation of compounds of the formula (II) in the form of the R or S enantiomer and the compound of the formula (IV) in the form of the Opponent enantiomer obtained by enzymatic resolution in accordance with the processes described in the patent application WO No. PCT / DK / 0300537 published "as WO2004 / 014821. In this way, according to one embodiment of the invention, the mixture of a compound of formula (II) and (IV) used in the process is prepared by selective enzymatic acylation or selective enzymatic deacylation. A particular advantage of the present invention is that following the formation, the compound of the formula (V) precipitates from the reaction mixture and is then easily isolated. Another particular advantage of the present invention is that (depending on the particular reagent of the formula
(Ia) - (Ic) used) results in the separation and isolation of a product that may be enclosed in a ring directly to form escitalopram or its derivative by treatment with a base. The reaction of the mixture of a compound of the formula (II) in the form of an enantiomer with a compound of the formula (Ia), (Ib) or (le) can be carried out in an inert organic solvent, such as tetrahydrofuran, preferably a solvent in which the acid of the formula
(V) forms a precipitate and in a quantity of the particular solvent where the acid of the formula (V) forms a precipitate. Those skilled in the art can identify the appropriate solvents. Alternatively, the reaction is carried out in
- a solvent, of which the acid of the formula (V) does not form a precipitate and an antisolvent is added after the formation of the compound of the formula (V), whereby the acid of the formula (V) forms a precipitate . The reaction can be carried out conveniently at or around room temperature (25 ° C). The compound of formula V is conveniently separated from the compound of formula (IV) by filtration or decantation, or by any other suitable manner of separation of a solid and a liquid. When the compound of formula V, which is isolated, is an S-enantiomer it can be enclosed in a ring directly by treatment with a base in a suitable organic solvent. The enantioselective ring closure of an S-enantiomer of the formula (V) to form escitalopram or another compound of the formula (VI) can be conveniently carried out by treating the compound of the formula (V) with a base such as KOC ( CH3) 3 or other alkoxides, NaH or other hydrides, or amines such as triethylamine, ethyldiisopropylamine or pyridine, at low temperatures in an inert organic solvent, such as tetrahydrofuran, toluene, DMSO, DMF, tert-butyl methyl ester, dimethoxyethane, dimethoxymethane, dioxane,
- acetonitrile or dichloromethane. This process can be carried out analogously to that described in U.S. Patent No. 4,943,590. In the same way, a compound of the formula
(IV) in the form of the S-enantiomer and separated from the reaction mixture, can be subjected to ring closure by treatment with a base. In some cases, it may be advantageous to exchange the group CW-Y-R1 in the compound of the formula IV or the group -CO-V in the compound of the formula
(V) for a more labile group, before the closure of the ring is carried out. Said leaving groups (leaving groups) could typically be a selected group of methanesulfonyloxy, p-toluenesulfonyloxy, 10-camphorsulfonyloxy, trifluoroacetyloxy and
. trifluoromethanesulfonyloxy or halogen. Typically, the compound of the formula (IV) or (V) is then subjected to hydrolysis to form the compound of the formula (II) with an aqueous base, such as NaOH, KOH or LiOH in water or alcohol or a mixture thereof. and then an activated leaving group is reacted, such as a group -0-S02-A where A is C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl or optionally alkyl-substituted aryl
C? -6 or aryl- (C? -6 alkyl), particularly mesyl chloride or tosyl chloride, or trifluoroacetyl chloride, chloride
* of acetyl or a formic acid form such as a mixture of formic acid and acetic anhydride in an organic solvent in the presence of an organic base. Preferably, the substituent V in the compound of the formula (V) is a substituent that allows the closure of the direct ring of the compound of the formula V by treatment with a base. More preferably, V is -CH2-CH2-COOH or -CH2-CH2-CH2-COOH. The optical purity of the escitalopram product may have to be improved after the closure of the ring. The improvement in optical purity can be obtained by chromatography on a chiral stationary phase or by crystallization of a racemic citalopram base according to the methods described in WO 03/000672. The R-enantiomer of the compounds of the formula
(V) and (IV) obtained according to the invention can be used to prepare racemic citalopram and escitalopram by ring closure in an acid medium according to the method described in WO 03/000672. Suitable acids for carrying out the ring-acid closure are a mineral acid, a carboxylic acid, a sulfonic acid, or sulfonic acid derivative, more conveniently H2SO4 or H3P04. The starting mixture used for the method of
* separation according to the invention can be prepared by enzymatic acylation or deacylation using a hydrolase, such as a lipase, an esterase, an acylase or a protease, as described in the Application
WO Patent No. PCT / DK / 0300537 published as WO2004 / 014821. It has been found that the enzymatic acylation according to the invention can be carried out using Novozyme®435, from Candida antartica, LipoZyme ™ TL-IM from
Thermomyces lanuginosus both available from the company
Novozymes A / S or Lipoprotein Lipase pseudomonas sp.
(isolated from Pseudomonas Cepacia and obtained from Fluka), and particularly good results have been found when using Novozyme 435, Candida antartica or Lipoprotein Lipase pseudomonas sp. The "enzyme" or "hydrolase" can be immobilized as the enzyme itself or as a cell body by known techniques, and can be used in immobilized form. The immobilization can be carried out by methods known to those skilled in the art, said methods include, for example, carrier binding, crosslinking, encapsulation and the like. Thus, the hydrolase can be used in the form of an immobilized enzyme or enzymes of cross-linked enzymatic crystals (CLEC). The aforementioned enzymes can also be used in the form of cultured products containing the enzyme, such as culture fluid containing a cell body, or a cultured cell body, a processed product of the cultured product and any immobilized form of these enzymes. cultivated products. In addition, mutations, variants or any equivalent of the enzymes specifically mentioned above can be used, which are capable of performing selective acylation or deacylation. Variants or equivalents thereof can be isolated from various strains of Pseudomonas, Candida or Thermomyces, or any other source, or they can be prepared by mutation of the DNA encoding the aforementioned enzymes, leading to variations in the amino acid composition of the enzyme Conveniently the mutations or variants of the enzymes mentioned above. they are variants and mutations where the simple amino acids have been eliminated or replaced by other amino acids, and the appropriate amino acid sequence of the variant or mutation is more than 60% identical, preferably more than 80% and more preferably more than 99% identical to the enzymes mentioned above. The preferred reaction conditions for enzymatic acylation / deacylation differ depending on
* the particular enzyme used, whether immobilized or not, etc. A suitable temperature for the reaction is between 0-80 ° C, more preferably between 20-60 ° C, or more preferably between 30-50 ° C. The amount of enzyme to be used is normally not restricted, but is usually 0.01-1.0, preferably 0.02-0.5 and more preferably 0.02-0.3, as a weight ratio to the substrate. The reaction can be carried out as a batch process or it can be carried out in the form of a continuous process. The enzyme can be used in a plurality of batches repeatedly or continuously.
The reaction time is not particularly restricted, and will depend on the enzyme used and the scale and type of production method (batch or continuous). According to the patent application WO No. PCT / DK / 0300537 published as WO2004 / 014821, the acylating agent used for the enzymatic acylation can be a reagent of the formula
(Illb) (Ule) (Illa)
or an isocyanate having the formula R1-N = C = 0 or an isothiocyanate having the formula R1-N = C = S; where X is 0 or S; W is O or S; U is O or S, V is halogen; R ° is Cx-io alkyl, C2-? O alkenyl C2_? O alkynyl, all of which may be optionally substituted one or more times with substituents selected from C? -? Alkoxy, alkylthio C? -? Or, hydroxyl, halogen , amino, nitro, cyano, alkylamino C? _? o, di- (alkyl Cx_? o) amino, aryl, aryloxy, arylthio and heteroaryl, or R ° is aryl, where any of the aryl and heteroaryl groups may be optionally substituted one or more times with substituents selected from Ci-io alkyl, C2-io alkenyl, or C2_ alkynyl.
Alkoxy C? _? o, alkylthio Ci-io, hydroxyl, halogen, amino, nitro, cyano, alkylamino C? _? 0 and di- (C? _ 0 alkyl) amino; R1 is as defined for R °; R2 is as defined for R °, or R2 is an appropriate irreversible acyl donor group; or R ° and R1 together form a chain of 3 to 5 carbon atoms; with the proviso that W and U are not S when X is S. Preferably, ü is O in the compound of the formula (Illa). Preferably, W is O in any of the aforementioned acylating agents. Preferably, X is O in any of the aforementioned acylating agents. Preferably, R1? R ° is C¿-3 alkyl, in particular unbranched C? _3 alkyl, such as methyl, ethyl or propyl, and preferably R 2 is C? _3 alkyl substituted one or more times with halogen or R 2 is C 2 al 3 alkenyl, and more preferred R2 is C2_3 alkenyl, such as vinyl. A preferred acylating agent is vinyl butyrate. Deacylation can be carried out using a compound of the formula
where R, Z, W, Y, Hal, dotted line and R1 is 5. as defined above, as starting material. - Conveniently, R 1 is C 0 alquilo 0 alkyl, preferably unbranched Ci-io alkyl and more preferably R 1 is C 4? Or unbranched alkyl in the starting material used for enzymatic deacylation. 0 Selective enzymatic acylation is carried out under conditions that substantially suppress hydrolysis. The hydrolysis, which is the reverse reaction of the acylation reaction, takes place if the water is present in the reaction system. Thus, the selective enzymatic acylation is preferably carried out in an anhydrous organic solvent or an almost anhydrous organic solvent (the enzymes usually require the presence of some water to be active). The percentage of water allowed in a particular reaction system can be determined by one skilled in the art. The organic solvent, which can be used for the acylation reaction, is not particularly important insofar as it does not deactivate the enzyme used. Suitable solvents include hydrocarbons such as hexane, heptane, benzene and toluene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether and dimethoxyethane; ketones such as acetone, diethyl ketone, butanone, and methyl ethyl ketone; esters such as methyl acetate, ethyl acetate, ethyl butyrate, vinyl butyrate.
- ethyl benzoate; halogenated hydrocarbons such as methylene chloride, chloroform and 1,1,1-trichloroethane; secondary and tertiary alcohols, such as tert-butanol; nitrogen-containing solvents such as dimethylformamide, acetamide, formamide, acetonitrile and propionitrile; and polar aprotic solvents such as dimethyl sulfoxide, N-methylpyrrolidone and hexamethylphosphorustriamide. Among them, hydrocarbons such as hexane, heptane, benzene and toluene are preferred, ethers such as diethyl ether, diisopropyl ether, 1,4-dioxane and tert-butyl methyl ether and esters such as vinyl butyrate. For an enzyme, the most preferred solvents may be ethers and aromatic hydrocarbons such as benzene or toluene, more preferably toluene and for another enzyme the most preferred solvents may be ethers such as 1,4-dioxane. The above solvents can be used alone or in combination of two or more solvents. The concentration of racemic diol of the formula
(II) and the acylating agent should not be too high, since a high concentration of reagents in the solvent can lead to non-selective acylation of the racemic diol of the formula (II). The appropriate concentration of the racemic diol of the formula (II) and the acylation reagent is below 1.0 M, more convenient below 0.5
* M, even more convenient below 0.2 M or even more convenient below 0.1 M. A person skilled in the art will be able to determine the optimum concentration of racemic diol of formula (II) and the acylating agent. Selective enzymatic deacylation is preferably carried out in water or a mixture of water and an organic solvent, in the presence of a buffer. The organic solvent, which can be used in the reaction, is not particularly important insofar as it does not deactivate the enzyme used. Suitable organic solvents are water-miscible solvents such as alcohols, acetonitrile, DMF, DMSO, dioxane, DME and diglyme. The person skilled in the art will be able to identify other suitable solvents. An expert will be able to determine the optimum concentration of the racemic compound of the formula (IV) used in the reaction. The stereoselectivity of the enzyme used can be increased by carrying out the acylation or deacylation in the presence of an organic acid and / or an organic base. In particular, enzymatic acylation or enzymatic deacylation is carried out in the presence of an organic acid, conveniently an organic carboxylic acid. Conveniently the aforementioned organic acid > previously it is an aromatic carboxylic acid or an aliphatic carboxylic acid. Suitable organic acids, which can be used in the reaction are alkylcarboxylic acids, cycloalkylcarboxylic acids, cycloalkylalkylcarboxylic acids, optionally substituted phenylalkylcarboxylic acids and optionally substituted phenylcarboxylic acids. Suitable aliphatic carboxylic acids are carboxylic acids such as formic acid, acetic acid, propionic acid, n-butyric acid, iso-butyric acid, 2-ethylbutyric acid, n-valeric acid, iso-valeric acid, pivalic acid, n-acid caproic, iso-caproic acid, decanoic acid, crotonic acid, palmitic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, phenyl (C3-4 alkylcarboxylic acids) such as 3-phenylpropionic acid, 4-phenylbutyric acid, oxalic acid, malonic acid and tartaric Suitable aromatic carboxylic acids include acids such as benzoic acid, p-chlorobenzoic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, p-toiuic acid, o-toluic acid, f-toluic acid, naphthoic acid, phthalic acid and terephthalic acid, salicylic acid, hydrocinnamic acid for example. Preferably, the organic acid used for
- improving the stereoselectivity of the enzyme is selected from n-propionic acid, iso-propionic acid, n-butyric acid, iso-butyric acid, iso-valeric acid, 2-ethylbutyric acid, crotonic acid, palmitic acid, cyclohexanecarboxylic acid, acid Pivalic, benzoic acid and p-toluic acid, salicylic acid and 3-phenylpropionic acid. The most preferred carboxylic acid used is pivalic acid. The amount of the organic acid to be used is not particularly restricted, but the molar ratio with respect to a substrate is usually 0.1 to 10, preferably 1.0 to 3.0, and more preferably 1.0 to 2.0.
Alternatively, an organic base can be used to improve the selectivity of the enzyme, either alone or together with any organic acid mentioned above. Suitable organic base can be mentioned, triethylamine, pyridine and 4-dimethylamino-pyridine, and pyridine is preferred. Suitable combinations of the organic acid and the organic base are benzoic acid and pyridine for example. The amount of the organic base to be used is not particularly restricted, but the molar ratio with respect to a substrate is usually 0.5 to 3.0., and preferably 0.5 to 2.0. As mentioned above, the group R means cyano or any other group that can be converted into a cyano group. Groups which can be converted to a cyano group include halogen such as chlorine, bromine, iodine or fluorine, preferably chlorine or bromine. Other groups that can be converted to cyano include CF3- (CF2) n-S02-0-, where n is 0-8, -OH, -CHO, -CH2OH, -CHNH2, -CH2N02, -CH2C1, -CH2Br, -CH3 , -NHR5, -CHNOH, -COOR6, -CONR6R7 wherein R5 is hydrogen or C6-C6 alkylcarbonyl, and R6 and R7 are selected from hydrogen, optionally substituted Ci-e alkyl, aryl (C? -d alkyl) or aryl and, a group of the formula (VII) where Z is 0 or S; Rs-R9 are each independently selected from hydrogen and alkylC? ~ G or R3 and R9 together form a C2_5 alkylene chain thereby forming a spiro ring; R10 is selected from hydrogen and C6_6 alkyl, R11 is selected from hydrogen, C1_6 alkyl, therefore a carboxyl group or a precursor group, or R10 and R1 together form a C2-5 alkylene chain thereby forming a Spiro ring. When R is halogen, in particular bromine or chlorine, the conversion to a cyano can be carried out as described in US Patents 4,136,193, WO 00/13648, WO 00/11926 and WO 01/02383. According to US Pat. No. 4,136,193, the conversion of a bromine group to a cyano group is carried out by the reaction with CuCN. WO 00/13648 and WO 00/11926 describe the conversion of a halogen group or a triflate in a cyano group by cyanation with a cyanide source in the presence of a Pd or Ni catalyst. The compounds wherein the group R is a group of the formula (VII) can be converted into the corresponding 3Sg > sesto cyano by methods analogous to those described in WO 11 31. The compounds wherein R is OH, -CH 2 OH, -CH 2 NH 2,
- jS k, -CH2C1, -CH23r, -CH3 or any of the groups
£ "jjjgcato is, you can convert them into corresponding ones
• S & stGS cyano by methods analogous to those described in
Zf fzte WO 01/68632. The racemic compounds of the formula (II) are gsgÉs & prepare by the methods described in the S-j s $? is mentioned above or by the method of the invention described in US Pat. 4,136,193 or the double grignard solution described in the patent EP 171 -S? Ér by analogous methods. The racemic compounds of the Sfeatóta (IV) can be prepared from MÍ-SS? SSECOS compounds of the formula (II) by non-acylation. aeSakr iva using anhydrides, esters, carbonates, iissEnates or isothiocyanates as defined by the formulas PSfiB? X (Illb), (IIIc), R1-M = C = 0 and R1-N = C = S above. In some cases the racemic compound of the (II) may be available in the form of a gs-addition salt of acid, such as the sulfate salt, and in this as? F-: a base may be obtained free of the compound of the
-i'ZÉ, ~ La (II) treating the salt with a base in a mixture or ^ gs¿ and an organic solvent, to transfer the compound l & e: S: formula (II) to the orsanic phase.
Preferably, R is cyano. If R is not cyano, the conversion of the R group into a cyano group is conveniently carried out after ring closure to form a compound of the formula (V). Preferably, Hal is fluoro. If Hal is not fluoro, the conversion of the Hal group into a fluoro is conveniently carried out after ring closure to form a compound of the formula (V). A procedure for carrying out this conversion is described in Speciali ty Chemicals Magazine, April 2003, pages 36-38. The Z groups that can be converted to dimethylaminomethyl are groups such as -CH2-L, -CH2-N02,
- -MgHal, cyano, aldehyde, -CH2-0-Pg, -CH2-NPg? Pg2,
-CH2 ~ NMePg ?, -CH2CH3, -CH2-NH2, -CO-N (CH3) 2, - CH ^ R12) (A3 ^ 13), - (A ^ -R14) (A2R15) (A3R16), -COOR17 , -CH2-CO-NH2, - CH = CH-R18 or -CONHR19, where Pg is a protection group for an alcohol group, Pgi and Pg2 are protective groups for an amino group, R12 and R13 are selected independently of alkyl C6-6, C2-6 alkenyl, C2-5 alkynyl and optionally aryl substituted with alkyl or aralkyl groups or R12 and R13 together form a chain of 2 to 4 carbon atoms, each of R14-R18 are selected from C6_6 alkyl, C2_6 alkenyl, C5_3 alkenyl and optionally aryl substituted with C6_6 alkyl or aryl (Ca_6 alkyl), R19 is hydrogen or methyl and A1, A2 and A3 are selected from O and S; L is a leaving group, such as halogen or -0-S02-A where A is alkyl Ct.s, alkenyl
C2_6, C2_6 alkynyl or optionally aryl substituted with C? _6 alkyl or C? _6 arylalkyl. The alcohol protection group, Pg, can be a trialkylsilyl group, a benzyl group or a tetrahydropyranyl group (THP). Suitable groups Pgx and Pg2 are aralkyl or groups -S02-R ° where R ° is alkyl, aralkyl, aryl or aryl substituted with alkyl, typically methyl, benzyl or tosyl, or Pgi and Pg2 together with the N atom to which they are - units form an optionally substituted phthalimide group. - Compounds where Z is -CH2-0-Pg can be converted into the corresponding compounds where Z is dimethylaminomethyl as described in WO Patents
01/43525, WO 01/51478 or WO 01/68631 or by analogous methods. The compounds wherein Z is -CH2-L, where L is a leaving group, can be converted to a dimethylaminomethyl group in the same manner. The compounds wherein Z is -CO-N (CH3) 2 and -CO-NHR19, where R19 is hydrogen or methyl, can be converted to the corresponding compounds where Z is dimethylaminomethyl as described in WO 01/43525 or WO 01 / 68631 or by analogous methods.
Compounds where Z is -CH2-NMe (Pgi) or -CH2-N (Pgl) (Pg2) can be converted into the corresponding compound where Z is dimethylamine methyl as described in WO 01/43525 or WO 01/68631 or by analogous methods. The compounds wherein Z is -CH (A1R12) (A2R13) can be converted to the corresponding compounds wherein Z is dimethylaminomethyl as described in WO 01/43525 or WO 01/68631 or by analogous methods. The compounds wherein Z is -C (A ^ -R14) (A2R15) (A3R16) can be converted into the corresponding compounds wherein Z is dimethylaminomethyl as described in WO 01/68631 or by analogous methods. Compounds where Z is -COOR17 can be converted into the corresponding compounds where Z is dimethylaminomethyl as described above, starting with him. ester of the carboxylic acid. The compounds wherein Z is -CH2-CONH2 can be converted to the corresponding compound wherein Z is as described in WO 01/43525 or WO 01/68631 or by analogous methods. The compounds wherein Z is -CH = CHR18 can be converted to the corresponding compound wherein Z is dimethylaminomethyl as described in WO 01/43525 or WO 01/68631 or by analogous methods.
The compounds wherein Z is cyano or -CH2-M02 can be converted into the corresponding compound where Z is dimethylaminomethyl as described in WO 01/68629 or by analogous methods. Compounds where Z is -MgHal can be converted to the corresponding compound where Z is dimethylaminomethyl as described in WO 01/68629 or by analogous methods. Preferably, Z is dimethylaminomethyl. If Z is not dimethylaminomethyl, the conversion of Z to a dimethylaminomethyl group is conveniently carried out after ring closure. Compounds where the dotted line represents a double bond can be converted into the corresponding compound where the dotted line is a single bond by the methods described in WO 01/68630 or by analogous methods. Preferably the reduction is carried out after the closure of the ring.
Experiments In the following examples the% conversion and optical purity were measured and calculated as described below: HPLC analysis condition (for conversion ratio):
Column: column A Lichrospher RP-8, 250 x 4 mm (particle size 5 μm) Eluent: MeOH / water buffer prepared as follows: 1.1 ml of Et3N added to 150 ml of water, 10% of H3PO4 (aqueous ) is added to pH = 7 and water is added to a total of 200 ml. The mixture is added to 1.8 liters of MeOH. Temperature: 35 ° C Flow rate: 1 ml / min Pressure: 16.0 MPa Detection: ÜV 254 nm Injection volume: 10 microL Conversion ratio (%) = P / (S + P) x 100, (P: amount of product, S: amount of residual substrate). Supercritical fluid chromatography. Analysis condition (for optical purity) Column: Daicel AD column with the dimensions 250 x 4.6 mm (particle size 5 μm) Mobile phase: carbon dioxide Modifier: Methanol with diethylamine (0.5%) and trifluoroacetic acid (0.5%). Gradient of the modifier: 1-2% in 4 minutes 2-4% in 4 minutes 4-8% in 4 minutes 8-16% in 4 minutes 16-32% in 4 minutes 32-45% in 1.62 minutes
Temperature: ambient temperature Flow rate: 2 ml / min Pressure: 20 mPa Detection: UV 230 nm and 254 nm Injection volume: 10 microL Optical purity (% ee) = (AB) / (A + B) x 100, ( A and B represent the corresponding stereoisomer, A > B)
E-value = In ((lc / 100) x (l-En / 100)) / ln ((lc / 100) x (l +? S / 100)) (c: conversion ratio, Es: optical purity of the substrate residual)
Example 1 (S) -1- (3-dimethylamino-propyl) -1- (4-fluoro-phenyl) -1,3-dihydro-isobenzofuran-5-carbonitrile acid oxalate
To a mixture of 3.7 g of 4- [(S) -4-dimethylamino-1- (4 '-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile and 6.3 g of 5-cyano-2- [4-dimethylamino] ester -l- (4-fluorophenyl) -1-hydroxybutyl] -benzyl of butyric acid (R / S = 3: 1) in 50 ml of tetrahydrofuran was added 1.2 g (1.1 eq.) of succinic anhydride. The entire night was allowed to stir at room temperature. The mono- ester. { 5-Cyano-2- [(S) -4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -benzyl} of the precipitated succinic acid was filtered and washed with cold tetrahydrofuran to obtain 3.1 g of 98% pure ester. The crystals were dried in an oven and then dissolved in 50 ml of anhydrous dimethylformamide. To the solution was added 1.1 g of NaH (60% suspension in oil) and stirred overnight at room temperature. The mixture was quenched with water and extracted 3 times with 50 ml of diethyl ether. The combined organic phases were washed with 50 ml of water and dried with Na 2 SO 4 and evaporated in vacuo. The remaining oil was dissolved in 14 ml of acetone and 630 mg was added
, of oxalic acid. After 1 hour of stirring at room temperature, the precipitated crystals were filtered and washed with cold acetone to obtain 2.02 g of oxitalic acid of escitalopram (ee-value 95%)
Example 2 (Preparation of the mixture used in Example 1) (S) -4- [4-dimethylamino-1- (4'-fluoro-phenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile
To a stirred solution of racemic 4- [4-dimethylamino-l- (4-fluorophenyl) -1-hydroxy-butyl] -3-hydroxymethylbenzonitrile (29 mmol, 10 g) and vinyl butyrate (58 mmol, 7.5 ml) in anhydrous 1,4-dioxane (142.5 ml) was added lipoprotein-lipase pseudomonas sp. (160 U, 250 mg). The reaction was heated to 50 ° C and continued with HPLC. After 192 hours at a conversion of 41%, another 250 mg of lipase was added. After 504 hours, at a conversion of 63% the reaction was stopped. The enzyme was filtered and washed with a small amount of 1,4-dioxane. The combined organic phases were evaporated in vacuo and then analyzed on supercritical fluid chromatography. An ee-value ((S-diol) = 95% (S-diol / R-diol = 40: 1) was obtained.
Claims (32)
1. Method for the isolation and purification of the compound that has a formula where R is cyano or a group that can become a cyano group; the dotted line represents a single or double bond; Hal is halogen; Z is a dimethylaminomethyl group or Z is a group that can be converted to a dimethylaminomethyl group; W is O or S; And it is a link, 0, S or NH; and R1 is C alquilo _? alquiloalkyl, C2-o o alkenyl or C C-alqu alqu alkynyl, all of which may be optionally substituted with one or more substituents selected from Ci-io alkoxy, Cilt-o alqu alkylthio, hydroxyl, halogen , amino, nitro, cyano, alkylamino C? -? o, di- (alkyl C? _? o) amino, aryl, aryloxy, arylthio and heteroaryl, or R1 is aryl, where any of the aryl and heteroaryl groups may be optionally substituted one or more times with substituents selected from Ci-io alkyl, C2-? alkenyl, C2.10 alkynyl, C? _0 alkoxy, Ci -io alkylthio, hydroxyl, halogen, amino, nitro, cyano, Ci-alkylamino -io and di- (alkyl C? _? o) amino, or a salt thereof; and / or a diol of formula wherein R, Z, Hal and the dotted line are as defined above, or a salt thereof, of a mixture containing the compound of formula (IV) and the diol of formula (II), which it comprises: a) reacting said mixture containing the compound of the formula (IV) and the diol of the formula (II) with a cyclic anhydride or an imide of the formula (la) (Ib) (le) in which X is - (CHR "') n-, where n is 0-2, and R', R" and R "'are independently selected from hydrogen, alkyl C ? 6, C? -6 alkoxy, aryloxy, C? _6 acyloxy, aryl-CO-O, wherein each aryl may be substituted with Ci-e alkyl, or R 'and R "in an anhydride of the formula (la) together are -0-CR4RD-0-, where R4 and R5 are independently hydrogen or C alquilo _s alkyl, or R 'and R "in an anhydride of the formula (Ib) are adjacent and together with the two carbon atoms to the which are bonded form a benzene ring, one of Q1 and Q2 is nitrogen and the other carbon, or both are carbon, A is C6-6 alkylene, phenylene, or naphthylene where the C6-6 alkylene, phenylene, or naphthylene groups they may be optionally substituted one or more times with C ?5 alkyl, to form a mixture of the compound of the formula (IV) and an ester having the formula wherein R, Z and Hal is as defined above and V is -CHR '-X-CR "-COOH, -X-CHR" -CO-NH-A-COOH, -CHR "-X-CO-NH -A-COOH, where R ', R ", X and A are as defined above, b) separating the compound of formula (IV) from the ester of formula (V) by a method selected from the group consisting of: iv) allowing the acid of the formula (V) or a salt thereof of the precipitate of the reaction mixture, and separating the precipitate of the compound of the formula (V) or a salt thereof from the reaction mixture, optionally followed by isolation of the compound of the formula (IV) or a salt thereof of the reaction mixture; v) dividing between an organic solvent and an aqueous solvent, whereby the compound of the formula (IV) will dissolve in the organic phase while the compound of the formula (V) will dissolve in the aqueous phase-, separate the phases , and optionally isolating the compound of the formula (IV) or a salt thereof and / or isolating the compound of the formula (V) or a salt thereof; and vi) adsorbing the compound of the formula (V) on a basic resin, separating the solvent containing the compound of the formula (IV) from the resin, desorbing the compound of the formula (V) from the basic resin, and optionally isolating the compound of the formula (IV) or a salt thereof and / or isolating the compound of the formula (V-) or a salt thereof.
2. The method according to claim 1, wherein the separation of the compound of the formula (IV) from the ester of the formula (V) is carried out by allowing the acid of the formula (V) to precipitate out of the reaction mixture, and separating the precipitate of the compound of the formula (V) of the reaction mixture, optionally followed by isolation of the compound of the formula (IV) or a salt thereof from the reaction mixture.
3. Method according to any of claims 1 or 2, wherein R ', R "and R"' are independently selected from hydrogen and C6-alkyl, and Q1 and Q2 are both carbon.
. The method according to any of claims 1-3, wherein the S-enantiomer of the compound of the formula (V) or a mixture of enantiomers of the compound of the formula (V) comprising more than 50% of the S-enantiomer of the compound of the formula (V) is separated from the R-enantiomer of the acyl derivative of the formula (IV) or a mixture of enantiomers of the acyl derivative of the , formula (IV) comprising more than 50% of the R enantiomer of the acyl derivative of the formula (IV).
5. The method according to claim 4, wherein the S-enantiomer of the compound of the formula (V) is separated from the R-enantiomer of the acyl derivative of the formula (IV) or a mixture of enantiomers of the acyl derivative of the formula (IV) comprising more than 50% of the R-enantiomer of the acyl derivative of the formula (IV).
6. The method according to claim 5, wherein the S-enantiomer of the compound of the formula (V) is separated from the R-enantiomer of the acyl derivative of the formula (IV).
7. The method according to any of claims 1-3, wherein the S-enantiomer of the acyl derivative of the formula (IV) or a mixture of enantiomers of the acyl derivative of the formula (IV) comprising more than 50% of the S-enantiomer of the Acyl derivative of the formula (IV), is separated from the R-enantiomer of the compound of the formula (V) or a mixture of enantiomers of the compound of the formula (V) comprising more than 50% of the R-enantiomer of the compound of the formula (V).
8. The method according to claim 7, wherein the S-enantiomer of the acyl derivative of the formula (IV) , is separated from the R-enantiomer of the compound of the formula (V) or a mixture of enantiomers of the compound of the formula (V) comprising more than 50% of the R-enantiomer of the compound of the formula (V).
9. The method according to claim 8, wherein the S-enantiomer of the acyl derivative of the formula (IV) is separated from the R-enantiomer of the compound of the formula (V).
10. The method according to any of claims 4-6, wherein the group R in the compound of the formula (V) obtained in the form of the S-enantiomer is optionally converted to cyano, the group Z in the compound of the formula V obtained becomes optionally in a dimethylaminomethyl group, Hal is optionally converted to fluoro, and / or a dotted line representing a double bond is optionally converted to a single bond, in any order, followed by conversion of the compound of the formula (V) to escitalopram or its derivative that has the formula wherein R, Z and Hal is as defined above by treatment with a base, optionally followed by, in any order, the conversion of the R group into a cyano group, the conversion of the Z group into a dimethylaminomethyl group, the conversion of Hal in fluoro, and the conversion of a dotted line representing a double bond into a single bond; optionally followed by conversion of escitalopram or a derivative of the formula (VI) into a salt thereof.
11. The method according to any of claims 7-9, wherein the R group in the compound of the formula (IV), the one obtained in the form of the S-enantiomer is optionally converted to cyano, the group Z in the compound of the formula-IV obtained is optionally converted to a dimethylaminomethyl group, Hal is optionally converted to fluoro and / or a dotted line representing a double bond is optionally converted to a single bond, in any order, followed by The conversion of the compound of the formula (IV) into escitalopram or its derivative wherein R, Z and Hal is as defined above by treatment with a base, optionally followed by, in any order, the conversion of the R group into a cyano group, the conversion of the Z group into a dimethylaminomethyl group, the conversion of Hal in fluoro, and the conversion of a dotted line representing a double bond in a single bond; optionally followed by the conversion of escitalopram or a derivative of the formula (VI) into a salt thereof.
12. The method according to any of claims 10 or 11, wherein the closure of the basic ring is carried out by treatment with a base such as KOC (CH3) or other alkoxides, NaH or other hydrides, or amines such as triethylamine, ethyldiisopropylamine or pyridine. .
13. The method according to any of claims 1-12, wherein Hal is fluoro and R is halogen or cyano, preferably R is cyano.
14. Method according to any of claims 1-13, wherein the dotted line represents a simple link.
15. The method according to any of claims 1-14, wherein Z is dimethylaminomethyl or a group that can be converted to a dimethylaminomethyl group, preferably Z is a dimethylaminomethyl group.
16. Method according to any of claims 1-15, wherein the anhydride is a compound of the formula (la).
17. The method according to claim 16, wherein the anhydride is succinic anhydride or glutaric anhydride.
18. Method according to claims 1-17, wherein the anhydride is a compound of the formula (Ib).
19. The method according to claim 18, wherein the anhydride is phthalic acid anhydride.
20. Method according to claims 1-15, wherein the reagent is an imide of the formula (le).
21. The method according to claim 20, wherein the imide is N-phenyl-succinimide substituted on the phenyl ring with a carboxyl group.
22. The method according to any of claims 1-21, wherein Y in the compound of the formula (IV) is a bond.
23. The method according to any of claims 1-21, wherein Y in the compound of the formula (IV) is O or S.
24. Method according to claim 23, wherein And in the compound of the formula (IV) is 0.
25. Method according to any of claims 1-21, wherein Y in the compound of the formula (IV) is NH.
26. The method according to any of claims 22-25, wherein R1 is selected from C ?4 alkyl, C2-4 alkenyl and C2- alkynyl, all of which may be optionally substituted one or more times with substituents selected from C? _ Alkoxy. , alkylthio C? _, hydroxyl, halogen, amino, nitro, cyano, C? -4 alkylamino and di- (C? _4 alkyl) amino.
27. Method according to claim 26, wherein R1 is selected from C3_3alkyl, C2_3alkenyl and C2_3alkynyl, all of which may be optionally substituted one or more times with substituents selected from C3_3alkoxy, C3_3alkyloxy, hydroxyl, halogen, amino, nitro, cyano, alkylamino C? _3 and di- (C? _3) alkyl amino.
28. Method according to claim 26, wherein R is Ci-
29. Method according to claim 27, wherein R1 is C3-C3 alkyl.
30. The method according to claim 29, wherein R 1 is methyl, ethyl or propyl, preferably propyl.
31. The method according to any of claims 1-30, wherein the mixture of a compound of the formula (II) and (IV) is prepared by selective enzymatic acylation * or selective enzymatic deacylation. "
32. Method for making escitalopram comprising the method according to any of claims 1-31.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/544,970 | 2004-02-12 | ||
| PAPA200400217 | 2004-02-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA06008977A true MXPA06008977A (en) | 2007-04-10 |
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