WO2006082452A1 - Optically active diaryl acetic acid derivatives and process for their preparation - Google Patents
Optically active diaryl acetic acid derivatives and process for their preparation Download PDFInfo
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- WO2006082452A1 WO2006082452A1 PCT/HU2006/000003 HU2006000003W WO2006082452A1 WO 2006082452 A1 WO2006082452 A1 WO 2006082452A1 HU 2006000003 W HU2006000003 W HU 2006000003W WO 2006082452 A1 WO2006082452 A1 WO 2006082452A1
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- Prior art keywords
- chloro
- general formula
- ethyl
- straight
- alkyl group
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 24
- 238000002360 preparation method Methods 0.000 title claims description 3
- -1 diaryl acetic acid derivatives Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 40
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 38
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910052799 carbon Inorganic materials 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
- 229940093499 ethyl acetate Drugs 0.000 claims description 22
- 235000019439 ethyl acetate Nutrition 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 13
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 claims description 7
- 125000000180 D-prolyl group Chemical class N1[C@@H](C(=O)*)CCC1 0.000 claims description 5
- 125000000174 L-prolyl group Chemical class [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims description 5
- 230000005526 G1 to G0 transition Effects 0.000 claims description 4
- 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 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 229930182820 D-proline Natural products 0.000 claims description 2
- 229930182821 L-proline Natural products 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- NQYNBKGUDUARBJ-SFHVURJKSA-N methyl 4-chloro-3-[(2r)-2-(5-chloro-2-nitrophenyl)-1-methoxy-1-oxopropan-2-yl]benzoate Chemical compound COC(=O)C1=CC=C(Cl)C([C@](C)(C(=O)OC)C=2C(=CC=C(Cl)C=2)[N+]([O-])=O)=C1 NQYNBKGUDUARBJ-SFHVURJKSA-N 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 229960002429 proline Drugs 0.000 claims description 2
- VXUVAKHUSWHNAN-KRWDZBQOSA-N (2r)-2-(2-chloro-5-methoxycarbonylphenyl)-2-(5-chloro-2-nitrophenyl)propanoic acid Chemical compound COC(=O)C1=CC=C(Cl)C([C@](C)(C(O)=O)C=2C(=CC=C(Cl)C=2)[N+]([O-])=O)=C1 VXUVAKHUSWHNAN-KRWDZBQOSA-N 0.000 claims 1
- LQCSYTYXOJHFSL-MRXNPFEDSA-N 3-[(1s)-1-carboxy-1-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid Chemical compound C1([C@](C(O)=O)(C)C=2C(=CC=C(Cl)C=2)[N+]([O-])=O)=CC(C(O)=O)=CC=C1Cl LQCSYTYXOJHFSL-MRXNPFEDSA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 2
- 239000000460 chlorine Substances 0.000 description 56
- 239000007787 solid Substances 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical class CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 229960004592 isopropanol Drugs 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 description 1
- 0 *c1cc(Cl)ccc1[N+]([O-])=O Chemical compound *c1cc(Cl)ccc1[N+]([O-])=O 0.000 description 1
- QUIMTLZDMCNYGY-UHFFFAOYSA-N 2,4-dichloro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1Cl QUIMTLZDMCNYGY-UHFFFAOYSA-N 0.000 description 1
- KQOOFMWRLDRDAX-UHFFFAOYSA-N 2-chloro-4-fluoro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1Cl KQOOFMWRLDRDAX-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- HIJBIFCQDHMEPI-UHFFFAOYSA-N [2-(3-nitrophenyl)-2-oxoethyl] 2-(2,4-dichlorophenoxy)acetate Chemical compound [O-][N+](=O)C1=CC=CC(C(=O)COC(=O)COC=2C(=CC(Cl)=CC=2)Cl)=C1 HIJBIFCQDHMEPI-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- NQYNBKGUDUARBJ-GOSISDBHSA-N methyl 4-chloro-3-[(2s)-2-(5-chloro-2-nitrophenyl)-1-methoxy-1-oxopropan-2-yl]benzoate Chemical compound COC(=O)C1=CC=C(Cl)C([C@@](C)(C(=O)OC)C=2C(=CC=C(Cl)C=2)[N+]([O-])=O)=C1 NQYNBKGUDUARBJ-GOSISDBHSA-N 0.000 description 1
- NQYNBKGUDUARBJ-UHFFFAOYSA-N methyl 4-chloro-3-[2-(5-chloro-2-nitrophenyl)-1-methoxy-1-oxopropan-2-yl]benzoate Chemical compound COC(=O)C1=CC=C(Cl)C(C(C)(C(=O)OC)C=2C(=CC=C(Cl)C=2)[N+]([O-])=O)=C1 NQYNBKGUDUARBJ-UHFFFAOYSA-N 0.000 description 1
- 150000005181 nitrobenzenes Chemical class 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/07—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms
- C07C205/11—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings
- C07C205/12—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings the six-membered aromatic ring or a condensed ring system containing that ring being substituted by halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/58—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- This invention relates to the optically active compounds of the general formula (I)
- R means a hydrogen atom or a straight or branched alkyl group containing
- R 1 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms
- R 2 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms - and their salts.
- this invention relates to a process for the production of above compounds.
- These optically active compounds of the general formula/I/ are useful intermediates during the synthesis of the compounds, which are described in the US-6 673790 and in J. Pharmacol. Exp. Ther. , 309, p 414 /2004/. Content of these citations is hereby incorporated by reference.
- optically active compounds of the general formula (I) and their salts may be produced by the resolution of the racemic compounds of the general formula
- R means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms
- R 1 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms
- R 2 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms - carried out by using one of the following procedures a) the racemic compound of the general formula (Ia) - wherein R means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms, R 1 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms, R 2 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms - is separated by chromatography using chiral stationary phase and optically active product thus obtained if desired is partially or totally hydrolized to optically active compounds of the general formula (I) - wherein the meaning of R and
- the chiral stationary phase may be a derivatized polysaccharide and the mobile phase may be a mixture of a polar solvent and an apolar solvent.
- Suitable polar solvent may be isopropanol and the apolar solvent may be n-hexane.
- R and R 1 mean a hydrogen atom
- R 2 is a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms, may be deliberated from their salts by addition of acids, for example hydrochloric acid.
- Racemic compounds of the general formula (Ia) may be prepared according to the above patent applications by the following synthesis route:
- R stands for nitro group or -COOR 1 group, wherein R 1 stands for hydrogen atom or C 1-4 straight or branched alkyl group, R 2 stands for hydrogen atom, C 1-4 straight or branched alkyl group and R 3 stands for a -COOR group or -CN group, wherein R 4 stands for hydrogen atom or C 1-4 straight or branched alkyl group, may be prepared by reacting a compound of the general formula (II),
- R 5 stands for nitro group or -COOR 6 group, wherein R 6 stands for a straight or branched C 1-4 alkyl group, R 7 stands for a -COOR 8 or -CN group, wherein R 8 stands for a straight or branched C 1-4 alkyl group, with a nitrobenzene derivative of the formula (III),
- X stands for a fluorine atom or a chlorine atom, in the presence of solid sodium hydride, alkali metal hydroxide, alkali metal alkoxylate, alkali metal carbonate or bicarbonate in a solvent at low temperature, and if desired reacting a compound of the general formula (IV),
- R 5 and R 7 have the same meaning as defined above, with an alkylating compound of the formula (R 9 ) n Y, wherein R 9 stands for C 1-4 straight or branched alkyl group, Y stands for halogen atom, sulphate, sulphonate or phosphate group and n stands for 1, 2 or 3, if desired hydrolyzing the ester groups of a compound of the formula (V), wherein R 2 and R 5 have the same meaning as defined above and R 7 stands for
- R stands for straight or branched C 1-4 alkyl group in one or two steps and if desired hydrolyzing the -CN group of a compound of the formula (V), wherein R 7 stands for -CN group and R 2 and R 5 are as defined above, and if desired transforming the substituents of the compound of the general formula (I) into each other by known methods.
- sodium hydroxide or potassium hydroxide might be used as alkali metal hydroxide; sodium methoxide or potassium tertiary butoxide, as alkali metal alkoxylate; potassium carbonate, as alkali metal carbonate; sodium bicarbonate, as alkali metal bicarbonate; dimethylformamide, N-methylpyrrolidone, toluene, tetrahydrofurane, acetone, tertiary-butylalcohol, as solvent.
- the X leaving group preferably means fluorine or chlorine atom.
- the hydrolysis of the group -COOR 6 might be carried out in a protic solvent, preferably methanol in the presence of a base, preferably benzyltrimethylammonium-hydroxide
- the hydrolysis of the groups -C00R6 and -COOR8 together is preferably performed in a protic solvent, preferably isopropanol in the presence of a base, preferably alkali hydroxide, preferably potassium hydroxide.
- a protic solvent preferably isopropanol
- a base preferably alkali hydroxide, preferably potassium hydroxide.
- the arylation with 2,4-dichloro-nitrobenzene is preferably carried out at a temperature between (-20 °C) and 0 °C, preferably (-10 0 C) and (-8 0 C), while using 2-chloro-4-fluoro- nitrobenzene the preferable temperature is between (-10 °C) and (+20 °C).
- Example 2 (18.94 g), obtained in Example 2 was added to water (270 niL) and concentrated hydrochloric acid (8 niL) was dropwise added to the solution at 5O 0 C. The mixture was stirred for 1 hour at room temperature and the precipitate was filtered and washed with water (3x130 mL) to give (i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4- chlorobenzoic acid (14.0 g), yield 26.6 %.
- Example 4 The filtrate of Example 4 was evaporated and the residue was dissolved in hot ethanol (23 ml). The solution was diluted with water (23 ml) and it was acidified with concentrated hydrochloric acid (10 ml). The reaction mixture was cooled to room temperature and the crystals were collected by filtration and washed with aqueous ethyl alcohol (50 v%, 10 niL) and dried to give racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4- chlorobenzoic acid (10.85 g, mp.: 241-246 0 C, ee: 3.4).
- Example 10 The mother liquid of Example 10 was concentrated in vacuum to give pale yellow foam of (li?,2 1 S)-(-)-ephedrine salt of(i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4- chlorobenzoic acid (15.4 g). This salt (15.3 g) was converted to the corresponding (R)-3- [l-carboxy-l-(5-chloro-2-nitro-phenyl)ethyl]-4-chlorobenzoic acid with diluted hydrochloric acid (18.5 mL). The obtained white powder was 10.5 g (98 % yield).
- EXAMPLE 16 (i?)-3-[l-methoxycarbonyl-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid methyl ester (2.5 g) (obtained in Example 1) and Triton B(benzyl-trimethyl-ammonium hydroxide) (7.5 mL) in methanol (25 mL) are refluxed for 4 hours. The solvent is removed in vacuum. The residue is diluted with water (25 mL), acidified with hydrochloric acid. - The solution is poured off from the separated oil. The residue is treated with methanol (7.5 mL) the precipitated is filtered off, washed and dried.
Abstract
The application relates to optically active compounds of the general formula (I): Formula (I) wherein R means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms, R1 means a hydrogen atom or a straight or branched alkyi group containing 1-4 carbon atoms, R2 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms- and their salts. Compounds of the general formula (I) are useful intermediates of the therapeutically active compounds described in US-6673790 and in J. Pharmacol. Exp. Ther. 309 p 414 (2004).
Description
New compounds
This invention relates to the optically active compounds of the general formula (I)
1-4 carbon atoms, R1 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms, R2 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms - and their salts. Furthermore this invention relates to a process for the production of above compounds. These optically active compounds of the general formula/I/ are useful intermediates during the synthesis of the compounds, which are described in the US-6 673790 and in J. Pharmacol. Exp. Ther. , 309, p 414 /2004/. Content of these citations is hereby incorporated by reference.
It has been found that the optically active compounds of the general formula (I) and their salts may be produced by the resolution of the racemic compounds of the general formula
wherein R means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms, R1 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms, R2 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms - carried out by using one of the following procedures a) the racemic compound of the general formula (Ia) -
wherein R means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms, R1 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms, R2 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms - is separated by chromatography using chiral stationary phase and optically active product thus obtained if desired is partially or totally hydrolized to optically active compounds of the general formula (I) - wherein the meaning of R and/or R1 is hydrogen, R2 is as defined above - and optionally their salts are formed or b) to the racemic compound of the general formula (Ia) - wherein R and R1 mean hydrogen atoms, R2 has the meaning as defined above - D-Proline is added and the received D-Proline salt of the (i?)-enantiomer of compound of the general formula (I) is separated and the (R) -enantiomer is optionally deliberated or
L-Proline is added and the received L-Proline salt of the (6)-enantiomer of compound of the general formula (I) separated and the (>S)-enantiomer is optionally deliberated or c) to the racemic compound of the general formula (Ia) - wherein R and R1 mean hydrogen atoms, R2 has the meaning as defined above - (IS, 2i?)-(+)ephedrine is added and the received (1>$, 2i?)-(+)-ephedrine salt of the (i?)-enantiomer of compound of the general formula (I) is separated and optionally the (i?)-enantiomer is deliberated or - (Ii?, 2iS)-(-)-ephedrine is added and the received (Ii?, 26)-(-)-ephedrine salt of the (S)- enantiomer of compound of the general formula (I) is separated and optionally the (S)- enantiomer is deliberated, and in case of processes Ib) and Ic) the (R) or the (S) enantiomer is partially or totally esterifϊed to optically active compounds of the general formula (I) wherein R and/or R1 mean a straight or branched alkyl group containing 1-4 carbonatoms and R2 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms.
In case of the procedure a) the chiral stationary phase may be a derivatized polysaccharide and the mobile phase may be a mixture of a polar solvent and an apolar solvent. Suitable polar solvent may be isopropanol and the apolar solvent may be n-hexane.
In case of the procedure b) methanol is used as solvent and ethyl-acetate is used for dilution of the reaction mixture. During procedure c) anhydrous ethyl-acetate is the suitable solvent. All the three procedures can be carried out preferably between +1O0C and +6O0C.
During the resolution processes b) and c) the (R) or (S) enantiomers of the general formula
(I) - wherein R and R1 mean a hydrogen atom, R2 is a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms, may be deliberated from their salts by addition of acids, for example hydrochloric acid.
The (R) or (S) enantiomer of the compounds of the general formula (I) - wherein R and R1 mean a straight or branched alkyl group containing 1-4 carbon atoms - is transformed into the (R) or (S) enantiomer of the compounds of the general formula (I) - wherein R is a hydrogen atom and R1 is a straight or branched alkyl group containing 1-4 carbon atoms, R2 is as defined above, by using of benzyl trimethyl-ammonium hydroxide and a solvent during the procedure a.
The (R) or (S) enantiomer of the compound of the general formula (I) - wherein R and R1 mean a hydrogen atom, R2 is as defined above - is treated firstly with thionyl chloride and subsequently with an alkanol -containing 1-4 carbonatoms - and thus the (R) or (S) enantiomer of the compound of the formula (I) wherein R means a straight or branched alkyl group alkyl group containing 1-4 carbon atoms and R1 means a hydrogen atom, R2 is as defined above, is obtained during the procedures b and c. Preparation of the racemic starting materials of the general formula (Ia) is described in the Hungarian Patent Application No P0500126 filed on 26 January 2005 and in the corresponding Patent Application No ... filed on ... and they are hereby incorporated by reference. Racemic compounds of the general formula (Ia) may be prepared according to the above patent applications by the following synthesis route:
The compounds of the general formula (Ic), which group of compounds contain the group of racemic compounds of the general formula (Ia)
-COOR , wherein R stands for straight or branched C1-4 alkyl group in one or two steps and if desired hydrolyzing the -CN group of a compound of the formula (V), wherein R7 stands for -CN group and R2 and R5 are as defined above, and if desired transforming the substituents of the compound of the general formula (I) into each other by known methods.
According to the invention sodium hydroxide or potassium hydroxide might be used as alkali metal hydroxide; sodium methoxide or potassium tertiary butoxide, as alkali metal alkoxylate; potassium carbonate, as alkali metal carbonate; sodium bicarbonate, as alkali metal bicarbonate; dimethylformamide, N-methylpyrrolidone, toluene, tetrahydrofurane, acetone, tertiary-butylalcohol, as solvent.
The X leaving group preferably means fluorine or chlorine atom.
The hydrolysis of the group -COOR6 might be carried out in a protic solvent, preferably methanol in the presence of a base, preferably benzyltrimethylammonium-hydroxide
(Triton B).
The hydrolysis of the groups -C00R6 and -COOR8 together is preferably performed in a protic solvent, preferably isopropanol in the presence of a base, preferably alkali hydroxide, preferably potassium hydroxide.
The arylation with 2,4-dichloro-nitrobenzene is preferably carried out at a temperature between (-20 °C) and 0 °C, preferably (-10 0C) and (-8 0C), while using 2-chloro-4-fluoro- nitrobenzene the preferable temperature is between (-10 °C) and (+20 °C).
Compounds of the general formula (II) are new compounds, which may be prepared according to methods known per se, e.g. by methods given in reaction schemes 1 and 2. The used resolution agents and reagents are commercial products.
Further details of this invention are illustrated by the following examples without limitation of the scope of claims to the content of these examples.
1. Reaction scheme 2. Reaction scheme
DMF, Cs2CO3
NBS, CCI4 C1-V1 alkyliodide
NaCN, 1,4-dioxane, water
NaCN, 1,4-dioxane, water lcanol, HCI
EXAMPLE 1 Separation of the enantiomers of 3-[l -methoxycarbonyl- l-(5-chloro-2- nitrophenyl)ethyl]-4-chlorobenzoic acid methyl ester was done using a Chiralpak® AD
(Product of Daicel Chem. Corp.) 20 (m preparative column (250 x 50 mm) (Chiral
Technologies Europe, France) and isocratic mobile phase consisting of n-hexane - 2- propanol (v/v 900 : 100) and UV detection at 240 nm. Racemic 3-[ 1 -methoxycarbonyl- 1 -(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid methyl ester (10 g) was dissolved in chloroform (150 ml) and the solution was diluted by the eluent to 1000 ml. Prior the injection of the solution to the preparative column it should be degassed. Each time 100 mL of the above mentioned solution was injected into the column. Running time was 30 min in each case. The (R)-3-[ 1 -methoxycarbonyl- 1 -(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid methyl ester was obtained from the eluent collected between 7 and 13 min running time, by evaporation of the combined eluent. Yield: 4.95 g
Mp.: 97-99 0C, [Q20589 = +32.59° (c=l, MeOH )
Anal. Calcd for C18H15CI2NO6: C, 52.45; H, 3.67; N, 3.40; Cl, 17.20. Found: C, 52.66; H, 3.45; N, 3.30; Cl, 17.37.
The (S)-3-[ 1 -methoxycarbonyl- 1 -(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid methyl ester was obtained from the eluent collected between 14 and 22 min running time, by evaporation of the combined eluent. Yield: 4.23 g. Mp.: 100-101°C, [Q20589 = -32.67° (c=l, MeOH)
Anal. Calcd for C18H15CI2NO6: C, 52.45; H, 3.67; N, 3.40; Cl, 17.20. Found: C, 52.56; H, 3.50; N, 3.37; Cl, 17.17.
EXAMPLE 2 Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (50.7 g), D- proline (15.2 g) in methanol (255 mL) were heated at 50 °C with vigorous stirring. This reaction mixture was then diluted with ethyl acetate (306 mL). After cooling to room temperature the reaction mixture was stirred overnight. The precipitated solid was filtered off and the cake was washed with a 5 : 6 mixture of methanol and ethyl acetate (3x25 mL),
and dried to give 18.94g (28.6 %) of D-proline salt of (i?)-3-[l-carboxy-l-(5-chloro-2- nitrophenyl)ethyl]-4-chlorobenzoic acid as a white crystalline solid. Mp.: 184-187 0C5 [α]20 589 = +6.96° (c=l, MeOH) Anal. Calcd for C2IH20Cl2N2O8: C, 50.52; H, 4.04; N, 5.61; Cl, 14.20. Found: C, 50.46; H, 4.10; N, 5.47; Cl, 14.15.
EXAMPLE 3
D-Proline salt of (/?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid
(18.94 g), obtained in Example 2 was added to water (270 niL) and concentrated hydrochloric acid (8 niL) was dropwise added to the solution at 5O0C. The mixture was stirred for 1 hour at room temperature and the precipitate was filtered and washed with water (3x130 mL) to give (i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4- chlorobenzoic acid (14.0 g), yield 26.6 %.
Mp.: 199-201 0C, [α]20 589 = -6.97° (c=l, MeOH) Anal. Calcd for Ci6H11Cl2NO6: C, 50.02; H, 2.89; N, 3.65; Cl, 18.46. Found: C, 50.06; H, 2.80; N, 3.57; Cl, 18.37.
EXAMPLE 4
Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (20 g), L- proline (6 g) in methanol (100 mL) were heated at 50 °C with vigorous stirring. This reaction mixture was then diluted with ethyl acetate (120 mL). After cooling to room temperature the reaction mixture was stirred overnight. The precipitated solid was filtered off and the cake was washed with a 5:6 mixture of methanol and ethyl acetate (3x15 mL), and dried to give 5.76g (28.6 %) of L-proline salt of (,S)-3-[l-carboxy-l-(5-chloro-2- nitrophenyl)ethyl]-4-chlorobenzoic acid as a white crystalline solid. Mp.: 182-184 °C, [α]20 589 = -6.47° (c=l, MeOH) Anal. Calcd for C21H20Cl2N2O8: C, 50.52; H, 4.04; N, 5.61; Cl, 14.20. Found: C, 50.39; H, 4.10; N, 5.53; Cl5 14.09.
EXAMPLE 5
The filtrate of Example 4 was evaporated and the residue was dissolved in hot ethanol (23 ml). The solution was diluted with water (23 ml) and it was acidified with concentrated hydrochloric acid (10 ml). The reaction mixture was cooled to room temperature and the crystals were collected by filtration and washed with aqueous ethyl alcohol (50 v%, 10
niL) and dried to give racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4- chlorobenzoic acid (10.85 g, mp.: 241-2460C, ee: 3.4).
The filtrate was evaporated until crystallization was observed. The reaction mixture was cooled to room temperature and the crystals were collected by filtration to give (R)-3-[l- carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (3.3 g.). Mp.: 204-210°C, [α]20 589 = -7.0° (c=l, MeOH) Anal. Calcd for Ci6H11Cl2NO6: C, 50.02; H, 2.89; N, 3.65; Cl, 18.46. Found: C, 50.06; H, 2.80; N, 3.57; Cl, 18.37.
EXAMPLE 6
L-Proline salt of (S)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (5.76 g), obtained in Example 4 was added to water (80 rnL) and concentrated hydrochloric acid (2.5 mL) was dropwise added to the solution at 5O0C. The mixture was stirred for 1 hour at room temperature and the precipitate was filtered and washed with water (3x40 mL) to give (6)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (3.1 g), yield 26.6 %,.
Mp.: 202-208°C, [α]20 589 = +7.0° (c=l, MeOH) Anal. Calcd for C16Hi1Cl2NO6: C, 50.02; H, 2.89; N, 3.65; Cl, 18.46. Found: C, 50.21; H, 2.50; N, 3.37; Cl, 17.17.
EXAMPLE 7
Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (70 g), (l.S',2i?)-(+)-ephedrine (31.5 g) in ethyl acetate (700 mL) were heated at 55°C with stirring. After cooling to room temperature the reaction mixture was stirred overnight. The precipitated solid was filtered off and the cake was washed with ethyl acetate (2x50 mL), and dried to give 44.93g (45 %) of (lS,2i?)-(+)-ephedrine salt of (i?)-3-[l-carboxy-l-(5- chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid as a white crystalline solid. Mp.: 1510C, [α]20 589= -45.0° (c=l, MeOH) Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.50; H, 4.59; N, 5.02; Cl, 12.80.
EXAMPLE 8
Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (50 g), (15,2Λ)-(+)-ephedrine (21.5 g) in ethyl acetate (IL) were heated to 550C with stirring. The solution was seeded with a small amount of the desired (i?)-acid ephedrine salt, and the reaction mixture was stirred overnight at the same temperature. The solid was filtered off and the cake was washed with ethyl acetate (2x40 mL) and dried to give 22.64 g (31 %) of (15',2i?)-(+)-eρhedrine salt of (i?)-3-[l-carboxy-l-(5-chloro-2-nitroρhenyl)ethyl]-4- chlorobenzoic acid as a white crystalline solid. Mp.: 154-155°C, [α]20 589= -46.0° (c=l, MeOH) Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.61; H, 4.81; N, 5.05; Cl, 12.81.
EXAMPLE 9
Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (20 g), (l.Sr,2i?)-(+)-ephedrine (4.5 g) in ethyl acetate (200 mL) were heated to 550C. The suspension was stirred for 3 hours at this temperature. The solid formed was filtered off and the cake was washed with ethyl acetate (2x50 mL), and dried to give 8.2 g (37 %) of
(liSr,2i?)-(+)-ephedrine salt of (i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)-ethyl]-4- chlorobenzoic acid as white crystalline solid. Mp.: 155-1560C, [α]20 589= -45.0° (c=l, MeOH)
Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.51; H, 4.62; N, 5.00; Cl, 12.8.
EXAMPLE 10 Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (20 g), (li?,25)-(-)-ephedrine (9,08 g) in ethyl acetate (100 mL) were heated to 550C with stirring. The solution was seeded with a small amount of pure (<S)-acid ephedrine salt, the mixture allowed to crystallize overnight while stirring was maintained for 18 hours at room temperature. The solid was filtered off and the cake was washed with ethyl acetate (2x25 mL), and dried to give 13.3 g (46.5 %) of (li?,26)-(-)-ephedrine salt of (_3)-3-[l-carboxy-l- (5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid as white crystalline solid. Mp.: 156-157°C, [α]20 589= +43.0° (c=l, MeOH) Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.47; H, 4.59; N, 5.07; Cl, 12.8.
EXAMPLE I l
The mother liquid of Example 10 was concentrated in vacuum to give pale yellow foam of (li?,21S)-(-)-ephedrine salt of(i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4- chlorobenzoic acid (15.4 g). This salt (15.3 g) was converted to the corresponding (R)-3- [l-carboxy-l-(5-chloro-2-nitro-phenyl)ethyl]-4-chlorobenzoic acid with diluted hydrochloric acid (18.5 mL). The obtained white powder was 10.5 g (98 % yield). Mp.: 201-202°C, [α]20 589= - 7.0° (c=l, MeOH) Anal. Calcd for Ci6H11Cl2NO6: C, 50.02; H, 2.89; N, 3.65; Cl, 18.46. Found: C, 49.56; H, 2.75; N, 3.6; Cl, 18.28.
EXAMPLE 12
Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (2.0 g), (15',2i?)-(+)-eρhedrine (0.45 g) and ethyl acetate (25 mL) were heated to 60°C with stirring to dissolve the solids. Stirring was maintained for 3 hours at this temperature then the precipitated solid was filtered off and the cake was washed with cold ethyl acetate (2x5 mL) and dried to give 0.41 g (29 %) of (l1S,2i?)-(+)-ephedrine salt of (i?)-3-[l-carboxy-l-(5- chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid as white, crystalline solid. Mp.: 156-157°C, [α]20 589= -45.0° (c=l, MeOH) Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.66; H, 4.57; N, 5.05; Cl, 12.8.
EXAMPLE 13
(i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)-emyl]-4-chlorobenzoic acid (2.0 g), (1S,2R)-
(+)-ephedrine (0.45 g) and ethyl acetate (20 mL) were heated at 55°C with stirring to dissolve the solids. The solution was seeded with a small amount of title compound. After being allowed to cool to room temperature and stirring overnight the solid was filtered off and the cake was washed with ethyl acetate (2x5 mL), and dried to give 1.35 g (47 %) of (li-,2S)-(+)-ephedrine salt of (i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)-ethyl]-4- chlorobenzoic acid ephedrine salt as a white, crystalline solid. Mp.: 148-149°C, [α]20 589= -46.0° (c=l, MeOH)
Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.75; H, 4.65; N, 5.05; Cl, 12.80.
EXAMPLE 14
(,S)-3-[l-carboxy-l-(5-chloro-2-nitroplienyl)-ethyl]-4-clilorobenzoic acid (2.0 g), (1.5,2/2)- (+)-ephedrine (0.45 g) and ethyl acetate (20 mL) were heated at 55°C with stirring to dissolve the solids. The solution was seeded with a small amount of title compound. After being allowed to cool to room temperature and stirred overnight the solid was filtered off and the cake was washed with ethyl acetate (2x5 mL), and dried to give 1.4 Ig (48 %) of (15,2R)-(+)-eρhedrine salt of (S)-3-[l-carboxy~l-(5-chloro-2-nitrophenyl)-ethyl]-4- chlorobenzoic acid as a white, crystalline and vaxy solid , [α]20 589=+ 45.0° (c=l, MeOH) Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.78; H, 4.70; N5 5.,00; Cl, 12.80.
EXAMPLE 15
(15,2i?)-Ephedrine salt of (i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4- chlorobenzoic acid (31.73 g), obtained in Example 7 was added to a diluted hydrochloric acid (37 mL) at room temperature. The mixture was stirred for 2 hours then the resulting precipitate was collected by filtration to give (i?)-3-[l-carboxy-l-(5-chloro-2- nitrophenyl)ethyl]-4-chlorobenzoic acid 21.78 g (yield 98 %).
Mp.: 199-201 °C, [α]20 589= -8.0° (c=l, MeOH) Anal. Calcd for C16H11Cl2NO6: C, 50.02; H, 2.89; N, 3.65; Cl, 18.46. Found: C, 49.75; H, 2.81; N, 3.60; C.,18.36.
EXAMPLE 16 (i?)-3-[l-methoxycarbonyl-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid methyl ester (2.5 g) (obtained in Example 1) and Triton B(benzyl-trimethyl-ammonium hydroxide) (7.5 mL) in methanol (25 mL) are refluxed for 4 hours. The solvent is removed in vacuum. The residue is diluted with water (25 mL), acidified with hydrochloric acid. - The solution is poured off from the separated oil. The residue is treated with methanol (7.5 mL) the precipitated is filtered off, washed and dried. It yields 2.01 g (83 %) of (R)-3-[l- methoxy-carbonyl-l-(5-chloro-2-nitrophenyl)-ethyl]-4-chloro-benzoic acid. Mp.: 174-175°C, [α]20 589 = +61,5° (c=l, DMSO) Anal. Calcd for C17H13Cl2NO6: C, 51.28; H, 3.29; N, 3.52; Cl, 17.81. Found: C, 51.18; H, 3.27; N, 3.4; Cl, 17.80.
EXAMPLE 17
(5)-3-[l-methoxycarbonyl-l~(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid methyl ester (2.5 g) (obtained in Example 1) and Triton B (7.5 mL) in methanol (25 mL) were refluxed for 4 hours. The solvent was removed in vacuum. The residue was diluted with water (25 mL), acidified with hydrochloric acid. The solution was poured off from the separated oil. The residue was treated with methanol (7.5 mL) the precipitated was filtered off, washed and dried. It yielded 0.6 g (79%) of (S)-3-[l-methoxy-carbonyl-l-(5-chloro-2- nitrophenyl)-ethyl]-4-chloro-benzoic acid. Mp.: 172-174°C, [α]20 589 = -63.0° (c=l, DMSO) Anal. Calcd for C17Hi3Cl2NO6: C, 51.28; H, 3.29; N, 3.52; Cl, 17.81. Found: C, 52.03; H, 3.39; N, 3.44; Cl, 17.64.
EXAMPLE 18
(i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (1.0 g) (obtained in Example 3) was stirred with thionyl chloride (2.0 mL). After the completion of the acyl chloride formation the excess of reagent was evaporated under reduced pressure. The residue was treated with methanol (5 mL) and was refluxed for one hour. The precipitated solid material was filtered off, washed with hot methanol and dried. It yielded (R)-3-[l- carboxy-l-(5-chloro-2-nitrophenyl)-ethyl]-4-chloro-benzoic acid-methyl-ester (0.77 g). Mp.: 243-245°C, [α]20 589 = +21,78 °(c=l, DMSO)
Anal. Calcd for C17H13Cl2NO6: C, 51.28, H, 3.29; N, 3.52; Cl, 17.81. Found: C, 51.10; H, 3.17; N, 3.48; Cl, 17.79.
EXAMPLE 19 (iS)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (1.0 g) (obtained in Example 4) was stirred with thionyl chloride (2 mL). After the completion of the acyl chloride formation the excess of reagent was evaporated under reduced pressure. The residue was treated with methanol (5 mL) and was refluxed for one hour. The precipitated solid material was filtered off, washed with hot methanol and dried. It yielded (S)-3-[l- carboxy-l-(5-chloro-2-nitrophenyl)-ethyl]-4-chloro-benzoic acid-methyl-ester (0.81 g). Mp.: 245-246°C, [α]20 589 = -21,78 °(c=l, DMSO) Anal. Calcd for C17H13Cl2NO6: C, 51.28; H, 3.29; N, 3.52; Cl, 17.81. Found: C, 51.19; H, 3.14; N, 3.40; Cl, 17.69.
Claims
1. Optically active compounds of the general formula (I)
2. (i?)-enantiomers of the compounds of the general formula (I) - wherein R, R1 and R2 independently from each other mean hydrogen atom or a straight or branched alkyl group alkyl group containing 1-4 carbon atoms - and their salts.
3. (5)-enantiomers of the compounds of the general formula (I) - wherein R, R1 and R2 independently from each other mean a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms - and their salts.
4. A compound or its diastereoisomeric salt according to any of claims 1 to 3 selected from the group consisting of
Methyl (R)-3 - [ 1 -methoxycarbonyl- 1 -(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoate;
Methyl (.S)-3-[l-methoxycarbonyl-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoate;
(li?,2S>Ephedrme salt of (R)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4- chlorobenzoic acid;
(l1Sr,2i?)-Ephedrine salt of (5)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4- chlorobenzoic acid;
L-proline salt of (S)-3 - [ 1 -carboxy- 1 -(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid;.
D-proline salt of (J?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid;
(»S)-3-[ 1 -carboxy- 1 -(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid;
(i?)-3-[ 1 -carboxy- 1 -(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid;
(i?)-3-[l-methoxy-carbonyl-l-(5-chloro-2-nitrophenyl)-ethyl]-4-chloro-benzoic acid;
(iS)-3-[l-methoxy-carbonyl-l-(5-chloro-2-nitrophenyl)etliyl]-4-chloro-benzoic acid;
(R)-3-[ 1 -carboxy- 1 -(5-chloro-2-nitrophenyl)-ethyl]-4-chloro-benzoic acid-methylester;
(S)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)-ethyl]-4-chloro-benzoic acid-methyl ester;
A process for the preparation of the optically active compounds of the general formula (I)
wherein R, R1 and R2 independently from each other mean a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms - characterized in that a) the racemic compound of the general formula (Ia) - wherein R and R1 mean a straight or branched alkyl groups containing 1-4 carbonatoms, R2 means a hydrogen atom or a straight or branched alkyl group containing 1-4 carbon atoms - is separated by chromatography using chiral stationary phase and optically active product thus obtained if desired is partially or totally hydrolized to optically active compounds of the general formula (I) - wherein the meaning of R and/or R1 is hydrogen and R2 has the above mentioned meaning - and optionally their salts are formed or b) r' to the racemic compound of the general formula (Ia) - wherein R and R1 mean hydrogen atoms, R2 means a hydrogen atom or a straight or branched alkyl grooup containing 1-4 carbon atoms - D-Proline is added and the received D-Proline salt of the
(i?)-enantiomer of compound of the general formula (I) is separated and the (R) - enantiomer is optionally deliberated or
L-Proline is added and the received L-Proline salt of the
(5)-enantiomer of compound of the general formula (I) separated and the (ιS)-enantiomer is optionally deliberated or c) to the racemic compound of the general formula (Ia) - wherein R and R1 mean hydrogen atoms and R2 has the above meaning - (IS, 2i?)-(+)ephedrine is added and the received (IS, 2i?)-(+)-ephedrine salt of the (i?)-enantiomer of compound of the general formula (I) is separated and optionally the (i?)-enantiomer is deliberated or - (Ii?, 2S)-(-)-ephedrine is added and the received (Ii?, 25)-(-)-ephedrine salt of the (S)- enantiomer of compound of the general formula (I) is separated and optionally the (S)- enantiomer is deliberated, and in case of processes Ib) and Ic) the (R) or the (S) enantiomer is partially or totally esterifϊed to optically active compounds of the general formula (I) wherein R and/or R1
mean a straight or branched alkyl group containing 1-4 carbon atoms and R2 has the above meaning.
6. A process according to claim Ia), characterized in that, the chiral stationary phase is a derivatized polysaccharide and the mobile phase is a mixture of a polar solvent and an apolar solvent.
7. A process according to claim Ib), characterized in that, methanol is used as solvent and ethyl-acetate is used for dilution of the reaction mixture.
8. A process according to claim Ic), characterized in that, anhydrous ethyl-acetate is used as solvent.
9. A process according to claim Ia) or Ib) or Ic), characterized in that, the process is carried out between +100C and +6O0C.
10. A process according to claim Ib) or Ic), characterized in that, the deliberation of the (R) or (S) enantiomers of the compounds of the general formula (I) - wherein R and Ri mean a hydrogen atom, R2 has the same meaning as it is defined in claim 1 - from their salts - is carried out by addition of hydrochloric acid.
11. A process according to claim Ia), characterized in that, the (R) or (S) enantiomer of the compounds of the general formula (I) - wherein R and Ri mean a straight or branched alkyl group containing 1-4 carbon atoms, R2 has the same meaning as it is defined in claim 1 - is transformed into the (R) or (S) enantiomer of the compounds of the general formula (I) - wherein R is hydrogen atom and Ri is a straight or branched alkyl group containing 1-4 carbonatoms, R2 has the same meaning as it is defined in claim 1, by using of benzyl trimethyl-ammonium hydroxide and a solvent.
12. A process according to claim Ib) or Ic), characterized in that, the (R) or (S) enantiomer of the compound of the general formula (I) - wherein R and Ri mean hydrogen atom and R2 has the same meaning as it is defined in claim 1 - is treated firstly with thionyl chloride and subsequently with an alkanol -containing 1-4 carbon atoms - and thus the (R) or (S) enantiomer of the compound of the formula (I) wherein
R means a straight or branched alkyl group alkyl group containing 1-4 carbonatoms, R1 means hydrogenatom and R2 has the same meaning as it is defined in claim 1, is obtained.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP0500157 | 2005-02-01 | ||
| HU0500157A HU0500157D0 (en) | 2005-02-01 | 2005-02-01 | New compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006082452A1 true WO2006082452A1 (en) | 2006-08-10 |
Family
ID=89985786
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2006/000003 WO2006082452A1 (en) | 2005-02-01 | 2006-01-17 | Optically active diaryl acetic acid derivatives and process for their preparation |
Country Status (5)
| Country | Link |
|---|---|
| AR (1) | AR055848A1 (en) |
| HU (1) | HU0500157D0 (en) |
| TW (1) | TW200640834A (en) |
| UY (1) | UY29355A1 (en) |
| WO (1) | WO2006082452A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995005879A1 (en) * | 1993-08-27 | 1995-03-02 | The Dow Chemical Company | Process for the separation of enantiomers |
| US5602169A (en) * | 1995-06-07 | 1997-02-11 | Bristol-Myers Squibb Company | 3-substituted oxindole derivatives as potassium channel modulators |
| WO2002032878A1 (en) * | 2000-10-13 | 2002-04-25 | Eli Lilly And Company | Resolution process for preparation of substantially pure (r) and (s) enantiomers of 2-(4-nitroimidazolyl)-4-methoxyphenylpropionic acid and salts thereof |
| US6673790B1 (en) * | 2000-04-03 | 2004-01-06 | Sanofi-Synthelabo | Indolin-2-one derivatives, preparation and their use as ocytocin receptor ligands |
-
2005
- 2005-02-01 HU HU0500157A patent/HU0500157D0/en unknown
-
2006
- 2006-01-17 WO PCT/HU2006/000003 patent/WO2006082452A1/en not_active Application Discontinuation
- 2006-01-27 TW TW095103233A patent/TW200640834A/en unknown
- 2006-01-30 AR ARP060100325A patent/AR055848A1/en not_active Application Discontinuation
- 2006-02-01 UY UY29355A patent/UY29355A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995005879A1 (en) * | 1993-08-27 | 1995-03-02 | The Dow Chemical Company | Process for the separation of enantiomers |
| US5602169A (en) * | 1995-06-07 | 1997-02-11 | Bristol-Myers Squibb Company | 3-substituted oxindole derivatives as potassium channel modulators |
| US6673790B1 (en) * | 2000-04-03 | 2004-01-06 | Sanofi-Synthelabo | Indolin-2-one derivatives, preparation and their use as ocytocin receptor ligands |
| WO2002032878A1 (en) * | 2000-10-13 | 2002-04-25 | Eli Lilly And Company | Resolution process for preparation of substantially pure (r) and (s) enantiomers of 2-(4-nitroimidazolyl)-4-methoxyphenylpropionic acid and salts thereof |
Non-Patent Citations (3)
| Title |
|---|
| HEWAWASAM P ET AL: "The synthesis and characterization of BMS-204352 (MaxiPostTM) and related 3-fluorooxindoles as openers of maxi-K potassium channels", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 12, no. 7, 8 April 2002 (2002-04-08), pages 1023 - 1026, XP002380786, ISSN: 0960-894X * |
| LAWRENCE N J ET AL: "Synthesis of Diaryl Acetates and Oxoindoles via a Sequential VNSAR-SNAR Three-Component Coupling reaction", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 6, no. 26, 24 November 2004 (2004-11-24), pages 4957 - 4960, XP002380787, ISSN: 1523-7060 * |
| RAMANATHAN C R ET AL: "Resolution of C2-symmetric 9,10-dihydro-9,10-ethanoanthracene-11,12-d icarboxylic acid and 2,3-diphenylsuccinic acid using (S)-proline", TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 9, no. 15, 7 August 1998 (1998-08-07), pages 2651 - 2656, XP004132760, ISSN: 0957-4166 * |
Also Published As
| Publication number | Publication date |
|---|---|
| TW200640834A (en) | 2006-12-01 |
| AR055848A1 (en) | 2007-09-12 |
| UY29355A1 (en) | 2006-08-31 |
| HU0500157D0 (en) | 2005-04-28 |
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