WO2009084827A2 - Synthetic intermediates, process for preparing pyrrolylheptanoic acid derivatives therefrom - Google Patents
Synthetic intermediates, process for preparing pyrrolylheptanoic acid derivatives therefrom Download PDFInfo
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- WO2009084827A2 WO2009084827A2 PCT/KR2008/007350 KR2008007350W WO2009084827A2 WO 2009084827 A2 WO2009084827 A2 WO 2009084827A2 KR 2008007350 W KR2008007350 W KR 2008007350W WO 2009084827 A2 WO2009084827 A2 WO 2009084827A2
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- derivative
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- fluorphenyl
- phenyl
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 20
- 239000000543 intermediate Substances 0.000 title abstract description 32
- RMFCNASGODHYAI-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)heptanoic acid Chemical class CCCCCC(C(O)=O)C1=CC=CN1 RMFCNASGODHYAI-UHFFFAOYSA-N 0.000 title abstract description 20
- -1 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carbonyl Chemical class 0.000 claims abstract description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims description 10
- 125000001769 aryl amino group Chemical group 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 6
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- XCLDSQRVMMXWMS-UHFFFAOYSA-N ethyl 4-methyl-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)C(C)C XCLDSQRVMMXWMS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 235000007715 potassium iodide Nutrition 0.000 claims description 2
- 229960004839 potassium iodide Drugs 0.000 claims description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract 2
- 239000008280 blood Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 abstract 1
- 235000012000 cholesterol Nutrition 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 101150041968 CDC13 gene Proteins 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 7
- 229940093499 ethyl acetate Drugs 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- ADHRFDCBLJVNFO-UHFFFAOYSA-N 4-methyl-3-oxo-n-phenylpentanamide Chemical compound CC(C)C(=O)CC(=O)NC1=CC=CC=C1 ADHRFDCBLJVNFO-UHFFFAOYSA-N 0.000 description 3
- OXVFDZPQWQRVBE-UHFFFAOYSA-N 5-(4-fluorophenyl)-4-phenyl-2-propan-2-yl-1h-pyrrole-3-carboxylic acid Chemical compound OC(=O)C1=C(C(C)C)NC(C=2C=CC(F)=CC=2)=C1C1=CC=CC=C1 OXVFDZPQWQRVBE-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- GBBJBUGPGFNISJ-YDQXZVTASA-N (4as,7r,8as)-9,9-dimethyltetrahydro-4h-4a,7-methanobenzo[c][1,2]oxazireno[2,3-b]isothiazole 3,3-dioxide Chemical compound C1S(=O)(=O)N2O[C@@]32C[C@@H]2C(C)(C)[C@]13CC2 GBBJBUGPGFNISJ-YDQXZVTASA-N 0.000 description 2
- DYTDDALWSRMTDA-UHFFFAOYSA-N 2-bromo-1-(4-fluorophenyl)-2-phenylethanone Chemical compound C1=CC(F)=CC=C1C(=O)C(Br)C1=CC=CC=C1 DYTDDALWSRMTDA-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- 0 CC1(C)O[C@@](CC*)C[C@](C*)O1 Chemical compound CC1(C)O[C@@](CC*)C[C@](C*)O1 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- HOFCRKOARYRLHG-UHFFFAOYSA-N ethyl 5-(4-fluorophenyl)-4-phenyl-2-propan-2-yl-1h-pyrrole-3-carboxylate Chemical class CCOC(=O)C1=C(C(C)C)NC(C=2C=CC(F)=CC=2)=C1C1=CC=CC=C1 HOFCRKOARYRLHG-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- VVWQXUVEGUGGOY-UHFFFAOYSA-N 5-(4-fluorophenyl)-n,4-diphenyl-2-propan-2-yl-1h-pyrrole-3-carboxamide Chemical class CC(C)C=1NC(C=2C=CC(F)=CC=2)=C(C=2C=CC=CC=2)C=1C(=O)NC1=CC=CC=C1 VVWQXUVEGUGGOY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- NYJYFSGMYHSTNZ-UHFFFAOYSA-N Cc(cc1)ccc1N=O Chemical compound Cc(cc1)ccc1N=O NYJYFSGMYHSTNZ-UHFFFAOYSA-N 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 102100030817 Liver carboxylesterase 1 Human genes 0.000 description 1
- 101710181187 Liver carboxylesterase 1 Proteins 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- XQKKWWCELHKGKB-UHFFFAOYSA-L calcium acetate monohydrate Chemical compound O.[Ca+2].CC([O-])=O.CC([O-])=O XQKKWWCELHKGKB-UHFFFAOYSA-L 0.000 description 1
- 229940067460 calcium acetate monohydrate Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- HWSHVKNLMBMKSR-GHMZBOCLSA-N tert-butyl 2-[(4r,6r)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1 HWSHVKNLMBMKSR-GHMZBOCLSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
Definitions
- the present invention relates to a novel synthetic intermediate that is used to prepare pyrrolylheptanoic acid derivatives including
- the preparation process has problems in that the final product may be produced in a low yield and a large amount of by-products may also be produced since it is necessary to conduct the reaction under the anhydrous condition, the chemical reactions in the preparation process should be carried out for a long-term period, for example, for 24 hours or more, and it is very difficult to prepare a pharmaceutical composition since it is necessary to use very expensive catalysts such as 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazonium bromide.
- the present invention is designed to solve the problems of the prior art, and therefore it is an object of the present invention to provide novel synthetic intermediate that is used to prepare pyrrolylheptanoic acid derivatives. [31] Also, it is another object of the present invention to provide a process for preparing pyrrolylheptanoic acid derivatives from the synthetic intermediate. [32] [33]
- a residue, R represents a residue selected from the group consisting of halogen-substituted or non-substituted alkyloxy, aryloxy and arylamino, all of which have 1 to 6 carbon atoms.
- the synthetic intermediate of Formula 2 is prepared by reacting a dion derivative represented by the following Formula 3 with a derivative represented by the following Formula 4 at the presence of either or both ammonium acetate or/and ammonium hydroxide at 0 to 13O 0 C under an acidic condition.
- the derivative of Formula 3 may be prepared from alkyl isobutyryl acetate, and particularly be prepared by reacting aniline with alkyl isobutyryl acetate using the known method (US Patent No. 5,124,482; and J. Org. Chem, 1978, 43, 2087) that has been widely used when a residue R is phenylamino, or prepared from a derivative, 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid.
- the l-(4-fluorphenyl)-2-hydroxy-2-phenylethanone derivative of Formula 4 used for the reaction according to one exemplary embodiment of the present invention may be prepared from a derivative, l-(4-fluorphenyl)-2-phenylethanone, represented by the following Formula 5, and the derivative of Formula 4 may be obtained by reacting the derivative of Formula 5 with lithium diisopropylamide and camphorsul- fonyloxaziridine at a sub-zero temperature.
- the derivative of Formula 5 may be prepared in a high yield from 2-phenylacetylchloride using the known method
- the present invention provides a process for preparing pyrrolylheptanoic acid derivatives from the novel synthetic intermediate
- a residue, R represents a residue selected from the group consisting of halogen-substituted or non-substituted alkyloxy, aryloxy and arylamino, all of which have 1 to 6 carbon atoms; and X is halogen.
- the Formula 1 derivative may be prepared using the process according to one exemplary embodiment of the present invention including: reacting a derivative, (4R-cis)-l,l-dimethylethyl-6-[2-haloethyl] - 2,2-dimethyl-l,3-dioxane-4-acetate, represented by the following Formula 6 with the derivative represented by Formula 2 and deesterifying a derivative represented by the following Formula 7 which is a main intermediate of the Formula 1 derivative.
- the derivative of Formula 2 and the derivative of Formula 6 react at a temperature of 50 to 12O 0 C at the presence of 18-crown-6 or potassiumiodide as a catalyst in a solvent selected from the group consisting of acetonitrile, toluene, heptane and dimethylfromamide.
- the derivative of Formula 6 was prepared from the intermediate, (4R-cis)- 1,1 -dimethylethyl-6- [2-hydroxyethyl] - 2,2-dimethyl-l,3-dioxane-4-acetate, using the known modified method, as shown in the following Scheme 6 (Tetrahedron Asymmetry, 1993, 4(5), 793-805).
- one aspect of the present invention provides a novel synthetic intermediate, 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carbonyl, represented by Formula 2, and a process for preparing a main intermediate, (4R-cis)-l,l-dimethylethyl-6-[2-[2-(4-fluorphenyl)-5-(l-methylethyl)-3-phenyl-4-[(ph enylamino)carbonyl]-lH-pyrrol-l-yl]ethyl]-2,2-dimethyl-l,3-dioxane-4-acetate, of the Formula 1 derivative, the process including a step of using the synthetic intermediate according to one exemplary embodiment of the present invention.
- the process for preparing pyrrolylheptanoic acid derivatives from the synthetic intermediate according to one exemplary embodiment of the present invention may be useful to prepare pyrrolylheptanoic acid derivatives since the process steps are simple to be performed, and the pyrrolylheptanoic acid derivatives may be easily prepared within a short time period under a moderate reaction condition.
- Example 2 was dissolved in 50 ml of acetic acid, and 3.3 g of the l-(4-fluorphenyl)-2-hydroxy-2-phenylethanone derivative (14.6 mmol)prepared in Example 1 was then added to the resulting mixture. Also, 12 g of ammonium acetate (146 mmol) was added to the mixture, and the resulting mixture was refluxed at a temperature of 110 to 12O 0 C for 2 hours. When the reaction was completed, the resulting reaction solution was cooled, diluted with distilled water, and extracted three times with ethylacetate. The extracted reaction solution was washed with distilled water and saturated saline, and concentrated under a reduced pressure. The resulting derivative was purified with column chromatography to obtain 4.7 g of a white solid title derivative (Yield: 81%).
Abstract
There are provided intermediates used to prepare a derivative, (3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl]-3,5-di hydroxyheptanoic acid, which has an effect to suppress cholesterol in blood, and a process for preparing pyrrolylheptanoic acid derivatives therefrom. In accordance with the present invention, the 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carbonyl derivative is provided as one of the novel synthetic intermediates that are used to prepare pyrrolylheptanoic acid derivatives including a derivative, (3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl]-3,5-di hydroxyheptanoic acid. Therefore, the (3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl]-3,5-di hydroxyheptanoic acid derivative may be prepared from the carbonyl derivative in a high yield for a short time period under a moderate condition.
Description
Description
SYNTHETIC INTERMEDIATES, PROCESS FOR PREPARING PYRROLYLHEPTANOIC ACID DERIVATIVES THEREFROM
Technical Field
[1] The present invention relates to a novel synthetic intermediate that is used to prepare pyrrolylheptanoic acid derivatives including
(3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l- yl]-3,5-dihydroxyheptanoic acid, which show their therapeutic effect to treat hyper- lipidemia, and a process for preparing pyrrolylheptanoic acid derivatives therefrom.
[2]
Background Art
[3] The derivative,
(3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l- yl]-3,5-dihydroxyheptanoic acid, (hereinafter, referred to as 'Formula 1 derivative') is disclosed in US Patent Nos. 4,681,893 and 5,273,995, and has been widely used to treat hyperlipidemia since it has effects to suppress functions of HMG-CoA reductase and acyl-coenzyme A: cholesterol acyltransferase (ACAT). Also, the derivative is a medicine that has been commercially available in the form of calcium salt that has a chemical structure represented by the following Formula 1.
[4] [5] <Formula 1>
[7] [8] The process for preparing the Formula 1 derivative is disclosed in many patents and documents such as US Patent Nos. 4,681,893, 5,124,482 and 5,216,174, and Korean Patent Publication No. 2006-8015, etc. In general, an intermediate, (4R-cis)-l,l-dimethylethyl-6-[2-[2-(4-fluorphenyl)-5-(l-methylethyl)-3-phenyl-4-[(ph enylamino)carbonyl]-lH-pyrrol-l-yl]ethyl]-2,2-dimethyl-l,3-dioxane-4-acetate, was prepared by the pyrolization between the derivatives, 4-(4-fluorphenyl)-2-isobutylyl-3-phenyl-4-oxo-N-phenyl-butylamide and (4R-cis)- 1 , 1 -dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3-dioxane-4-acetate, and
then deesterified, and reacted with calcium acetate monohydrate to prepare the Formula 1 derivative, as shown in the following Scheme 1.
[9] <Scheme 1>
[H] [12] In the Scheme 1, a derivative,
4-(4-fluorphenyl)-2-isobutylyl-3-phenyl-4-oxo-N-phenyl-butylamide, used as a starting material to prepare the Formula 1 derivative may be synthesized according to the following Scheme 2.
[13] <Scheme 2>
[15] [16] However, the preparation process has problems in that the final product may be produced in a low yield and a large amount of by-products may also be produced since it is necessary to conduct the reaction under the anhydrous condition, the chemical reactions in the preparation process should be carried out for a long-term period, for example, for 24 hours or more, and it is very difficult to prepare a pharmaceutical composition since it is necessary to use very expensive catalysts such as 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazonium bromide.
[17] [18] Also, another process for preparing a derivative
4-(4-fluorphenyl)-2-isobutylyl-3-phenyl-4-oxo-N-phenyl-butylamide derivative used as a starting material to prepare the Formula 1 derivative, as shown in the Scheme 1, is disclosed in International Publication No. 03/004457 and Korean Patent Publication No. 2004-1435, and presented by the following Scheme 3.
[19] <Scheme 3>
[21] [22] In the Scheme 3, a derivative, 2-bromo-l-(4-fluorphenyl)-2-phenylethan-l-one, is used as a reactant to prepare a starting material,
4-(4-fluorphenyl)-2-isobutylyl-3-phenyl-4-oxo-N-phenyl-butylamide, which is used to prepare the Formula 1 derivative as shown in the Scheme 1. However, the 2-bromo-l-(4-fluorphenyl)-2-phenylethan-l-one derivative used as the reactant has problems in that it is difficult to be mass-produced since its preparation process is carried out for a long-term period, for example, for 24 hours or more, and the use of toxic bromine may be detrimental to the environment as well as workers.
[23] [24] As described above, the conventional processes for preparing an intermediate, 4-(4-fluorphenyl)-2-isobutylyl-3-phenyl-4-oxo-N-phenyl-butylamide, that has been used to prepare the Formula 1 derivative have problems in that the intermediate is produced in a low yield and the by-products are also produced in a large amount. Also, the conventional processes have problems in that it is necessary to conduct the reaction for a long-term period, many complicated reaction processes should be carried out under the anhydrous condition, and it is difficult to makes them commercially available since they are detrimental to the environment.
[25] [26] Therefore, in order to solve the problems associated with the
4-(4-fluorphenyl)-2-isobutylyl-3-phenyl-4-oxo-N-phenyl-butylamide intermediate used to prepare the known Formula 1 derivative, there have been demands for a preparation process using new intermediates that may be used to prepare the pyrrolylheptanoic acid derivatives.
[27] [28] Accordingly, the present inventors have found that a novel intermediate used to prepare pyrrolylheptanoic acid derivatives was developed to solve the problems associated with the
4-(4-fluorphenyl)-2-isobutylyl-3-phenyl-4-oxo-N-phenyl-butylamide intermediate used to prepare the known Formula 1 derivative, for example, the problems associated with the production of the intermediate in a low yield and a large amount of by-products
and the demand for the fastidious reaction conditions such as the anhydrous condition, and the pyrrolylheptanoic acid derivatives were prepared from the intermediate.
Therefore, the present invention was completed on the basis of the above facts. [29]
Disclosure of Invention
Technical Problem [30] The present invention is designed to solve the problems of the prior art, and therefore it is an object of the present invention to provide novel synthetic intermediate that is used to prepare pyrrolylheptanoic acid derivatives. [31] Also, it is another object of the present invention to provide a process for preparing pyrrolylheptanoic acid derivatives from the synthetic intermediate. [32] [33]
Technical Solution [34] According to an aspect of the present invention, there is provided a novel synthetic intermediate represented by the following Formula 2, the synthetic intermediate being used to prepare pyrrolylheptanoic acid derivatives: [35] <Formula 2>
[37]
[38] wherein, a residue, R, represents a residue selected from the group consisting of halogen-substituted or non-substituted alkyloxy, aryloxy and arylamino, all of which have 1 to 6 carbon atoms. [39] [40] Hereinafter, exemplary embodiments of the present invention will be described in detail. [41] The present invention provides a derivative,
5-(4-fluorphenyl)-2-isopropyl-4-phenyl- lH-pyrrole-3-carbonyl, represented by
Formula 2, that is a novel synthetic intermediate that may be useful to prepare pyrrolylheptanoic acid derivatives. [42] The schematic process for preparing a novel synthetic intermediate of Formula 2 according to one exemplary embodiment of the present invention is described in the
following Scheme 4.
[43] <Scheme 4>
[45] [46] The synthetic intermediate of Formula 2 according to one exemplary embodiment of the present invention is prepared by reacting a dion derivative represented by the following Formula 3 with a derivative represented by the following Formula 4 at the presence of either or both ammonium acetate or/and ammonium hydroxide at 0 to 13O0C under an acidic condition.
[47] <Formula 3>
[49]
[50] <Formula 4>
[52] [53] The derivative of Formula 3 may be prepared from alkyl isobutyryl acetate, and particularly be prepared by reacting aniline with alkyl isobutyryl acetate using the known method (US Patent No. 5,124,482; and J. Org. Chem, 1978, 43, 2087) that has been widely used when a residue R is phenylamino, or prepared from a derivative, 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid.
[54] [55] Also, the l-(4-fluorphenyl)-2-hydroxy-2-phenylethanone derivative of Formula 4 used for the reaction according to one exemplary embodiment of the present invention may be prepared from a derivative, l-(4-fluorphenyl)-2-phenylethanone, represented by the following Formula 5, and the derivative of Formula 4 may be obtained by reacting the derivative of Formula 5 with lithium diisopropylamide and camphorsul- fonyloxaziridine at a sub-zero temperature. The derivative of Formula 5 may be
prepared in a high yield from 2-phenylacetylchloride using the known method
(International Publication No. 03/4457). [56] <Formula 5>
[58]
[59] Also, the present invention provides a process for preparing pyrrolylheptanoic acid derivatives from the novel synthetic intermediate,
5-(4-fluorphenyl)-2-isopropyl-4-phenyl- lH-pyrrole-3-carbonyl, represented by
Formula 2, which is used to prepare the Formula 1 derivative. [60] [61] The schematic process for preparing pyrrolylheptanoic acid derivatives from the novel synthetic intermediate,
5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carbonyl, of Formula 2 according to one exemplary embodiment of the present invention was shown in the following Scheme 5. [62] <Scheme 5>
[64]
[65] wherein, a residue, R, represents a residue selected from the group consisting of halogen-substituted or non-substituted alkyloxy, aryloxy and arylamino, all of which have 1 to 6 carbon atoms; and X is halogen.
[66]
[67] As shown in the Scheme 5, the Formula 1 derivative may be prepared using the process according to one exemplary embodiment of the present invention including: reacting a derivative, (4R-cis)-l,l-dimethylethyl-6-[2-haloethyl] - 2,2-dimethyl-l,3-dioxane-4-acetate, represented by the following Formula 6 with the derivative represented by Formula 2 and deesterifying a derivative represented by the following Formula 7 which is a main intermediate of the Formula 1 derivative.
[68] <Formula 6>
[70]
[73] [74] In accordance with the present invention, the derivative of Formula 2 and the derivative of Formula 6 react at a temperature of 50 to 12O0C at the presence of 18-crown-6 or potassiumiodide as a catalyst in a solvent selected from the group consisting of acetonitrile, toluene, heptane and dimethylfromamide.
[75] [76] The (4R-cis)- 1 , 1 -dimethylethyl-6- [2-haloethyl]-2,2-dimethyl- 1 ,3-dioxane-4-acetate derivative of Formula 6, which is required for the preparation of the pyrrolylheptanoic acid derivatives according to one exemplary embodiment of the present invention, has been studied well and may be prepared from the commercially available intermediates. In accordance with the present invention, the derivative of Formula 6 was prepared from the intermediate, (4R-cis)- 1,1 -dimethylethyl-6- [2-hydroxyethyl] - 2,2-dimethyl-l,3-dioxane-4-acetate, using the known modified method, as shown in the following Scheme 6 (Tetrahedron Asymmetry, 1993, 4(5), 793-805).
[77] <Scheme 6>
[79] [80] The intermediates of the pyrrolylheptanoic acid derivative according to one exemplary embodiment of the present invention, and the process for preparing the intermediates including the above-mentioned steps may be useful to prepare a therapeutic agent for treating hyperlipidemia due to the simple reaction processes and the high reaction yield.
Advantageous Effects
[81] As described above, one aspect of the present invention provides a novel synthetic intermediate, 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carbonyl,
represented by Formula 2, and a process for preparing a main intermediate, (4R-cis)-l,l-dimethylethyl-6-[2-[2-(4-fluorphenyl)-5-(l-methylethyl)-3-phenyl-4-[(ph enylamino)carbonyl]-lH-pyrrol-l-yl]ethyl]-2,2-dimethyl-l,3-dioxane-4-acetate, of the Formula 1 derivative, the process including a step of using the synthetic intermediate according to one exemplary embodiment of the present invention. Therefore, the process for preparing pyrrolylheptanoic acid derivatives from the synthetic intermediate according to one exemplary embodiment of the present invention may be useful to prepare pyrrolylheptanoic acid derivatives since the process steps are simple to be performed, and the pyrrolylheptanoic acid derivatives may be easily prepared within a short time period under a moderate reaction condition.
[82]
Best Mode for Carrying out the Invention
[83] Hereinafter, exemplary embodiments of the present invention are described in more detail. Although the exemplary embodiments of the present invention have been disclosed for illustrative purposes, it is considered that various modifications, additions and substitutions can be made without departing from the scope of the present invention.
[84]
[85] <Example 1> Preparation of 1- (4-fluorphenyl) -2-hvdroxy-2-phenylethanone
[86] 0.5 g of l-(4-fluorphenyl)-2-phenylethanone (2.3 mmol) was dissolved in 50 ml of tetrahydrofurane, and then cooled to a temperature below O0C. 1.8 ml of lithium diiso- propylamide (3.5 mmol) was dissolved in 5 ml of tetrahydrofurane, and then added dropwise to the l-(4-fluorphenyl)-2-phenylethanone solution cooled to a temperature below O0C. 30 minutes after the dropwise addition, 1 g of camphorsulfonyloxaziridine (4.7 mmol) was dissolve in 5 ml of tetrahydrofurane, added to the l-(4-fluorphenyl)-2-phenylethanone solution cooled to a temperature below O0C, and then kept at a room temperature. After 30 minutes, the reaction of the resulting mixture was stopped with a saturated ammonium chloride solution, and then extracted by adding ethylacetate to the mixture. The extracted ethylacetate was washed with water and saturated saline, and then concentrated under a reduced pressure. Then, the resulting concentrate was purified with column chromatography to obtain 0.38 g of white crystals (Yield: 71%).
[87] IH-NMR (CDC13)δ: 5.9 (d, IH), 7.05 (m, 2H), 7.28-7.40 (m, 5H), 7.92-8.20 (m,
2H)
[88] Mass (M+l): 231
[89]
[90] <Example 2> Preparation of 4-methyl-3-oxo-N-phenylpentaneamide
[91] 10 g of ethylisobutyrylacetate (63.2 mmol) was dissolved in 30 ml of toluene, and
6.5 g of aniline (70 mmol) was added to the resulting mixture and refluxed for 3 hours. When the reaction was completed, 50 ml of IN HCl was added to the resulting reaction mixture, and stirred to separate an organic phase. The organic phase was diluted with 50 ml of ethylacetate, washed with distilled water and saturated saline, and then concentrated under a reduced pressure to obtain brown oil. The resultant brown oil was washed with nucleic acid to obtain 10.5 g of brown oil (Yield: 81%).
[92] IH-NMR (CDC13)δ: 1.14 (d, 6H), 2.71 (m, IH), 3.58 (s, 2H), 7.09 (m, IH),
7.24-7.31 (m, 2H), 7.53 (d, 2H), 9.20 (b, IH)
[93] Mass (M+l): 206
[94]
[95] <Example 3> Preparation of
5-(4-fluorphenylV2-isopropyl-N.4-diphenyl-lH-pyrrole-3-carboxamide
[96] 3 g of the 4-methyl-3-oxo-N-phenylpentaneamide derivative (14.6 mmol) prepared in
Example 2 was dissolved in 50 ml of acetic acid, and 3.3 g of the l-(4-fluorphenyl)-2-hydroxy-2-phenylethanone derivative (14.6 mmol)prepared in Example 1 was then added to the resulting mixture. Also, 12 g of ammonium acetate (146 mmol) was added to the mixture, and the resulting mixture was refluxed at a temperature of 110 to 12O0C for 2 hours. When the reaction was completed, the resulting reaction solution was cooled, diluted with distilled water, and extracted three times with ethylacetate. The extracted reaction solution was washed with distilled water and saturated saline, and concentrated under a reduced pressure. The resulting derivative was purified with column chromatography to obtain 4.7 g of a white solid title derivative (Yield: 81%).
[97] IH-NMR (CDC13)δ: 1.40 (d, 6H), 4.08 (m, IH), 6.90-7.23 (m, 10H), 7.38-7.51 (m,
5H), 8.38 (b, IH),
[98] Mass (M+l): 399
[99]
[100] <Example 4> Preparation of ethvl-
5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-3-carboxylate
[101] 1 g of ethyl isobutyryl acetate (6.3 mmol) was dissolved in 50 ml of acetic acid, 1.6 g of the l-(4-fluorphenyl)-2-hydroxy-2-phenylethanone (7 mmol) prepared in Example 1 was then added to the resulting mixture. Also, 4.8 g of ammonium acetate (63 mmol) was added to the mixture, and the resulting mixture was refluxed for 2 hours. When the reaction was completed, the resulting reaction solution was cooled, diluted with distilled water, and extracted three times with ethylacetate. The extracted reaction solution was washed with distilled water and saturated saline, and concentrated under a reduced pressure. The resulting derivative was purified with column chromatography
to obtain 1.6 g of a white solid title derivative (Yield: 71%).
[102] IH-NMR (CDC13)δ: 1.01 (t, 3H), 1.38 (d, 6H), 3.85 (m, IH), 4.08 (q, 2H), 6.90-6.98 (m, 2H), 7.03-7.12 (m, 2H), 7.21-7.35 (m, 5H)
[103] Mass (M+l): 352
[104]
[105] <Example 5> Preparation of
5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid
[106] 1 g of the ethyl 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylate derivative (2.8 mmol) prepared in Example 4 was dissolved in 20 ml of methanol, and 1.2 g of an aqueous sodium hydroxide solution (28 mmol) was added to the resulting mixture, and then refluxed for 24 hours. When the reaction was completed, the resulting reaction solution was cooled, neutralized with IN HCl, and then extracted three times with ethylacetate. The extracted reaction solution was washed with distilled water and saturated saline, and concentrated under a reduced pressure. The resulting derivative was purified with column chromatography to obtain 0.5 g of a white solid title derivative (Yield: 55%).
[107] IH-NMR (CDC13)δ: 1.41 (d, 6H), 3.90 (m, IH), 6.91-7.12 (m, 4H), 7.20~7.35(m, 5H)
[108] Mass (M+l): 324
[109]
[110] <Example 6> Preparation of
5-(4-fluorphenyl)-2-isopropyl-N.4-diphenyl-lH-pyrrole-3-carboxamide
[111] 0.5 g of the 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid derivative (1.5 mmol) prepared in Example 5 was dissolved 10 ml of tetrahydrofurane, and the resulting mixture was cooled to O0C. 0.65 ml of triethylamine (4.6 mmol) was added, and 0.274 ml of diethylchlorophosphate (3 mmol) was added dropwise to the cooled mixture. 30 minutes after the dropwise addition, 0.22 g of aniline (2.3 mmol) was added to the resulting mixture, and then stirred at a room temperature for 4 hours. When the reaction was completed, the resulting reaction solution was stirred to separate an organic phase. The organic phase was diluted with 50 ml of ethylacetate, washed with distilled water and saturated saline, and then concentrated under a reduced pressure to obtain a derivative. The resultant derivative was purified with column chromatography to obtain 0.52 g of a white solid title derivative (Yield: 85%).
[112] IH-NMR (CDC13)δ: 1.40 (d, 6H), 4.08 (m, IH), 6.90-7.23 (m, 10H), 7.38-7.51 (m, 5H), 8.38 (b, IH)
[113] Mass (M+l): 399
[114]
[115] <Example 7> Preparation of (4R-cisVl.l-dimethylethyl-6-r2-iodoethyll -
2.2-dimethyl- 1.3-dioxane-4-acetate
[116] 5 g of the (4R-cis)-l,l-dimethylethyl-6-[2-hydroxyethyl] -
2,2-dimethyl-l,3-dioxane-4-acetate derivative (18 mmol) was dissolved in 100 ml of dimethylfromamide, and 5.3 g of triphenylphosphine (20 mmol) was added to the resulting mixture, and then stirred. 5.2 g of iodine (20 mmol) dissolved in dimethylfromamide was added to the reaction mixture, and the resulting reaction solution was stirred at a room temperature for 6 hours. When the reaction was completed, the resulting reaction solution was washed with an aqueous sodium bicarbonate solution and saturated saline. The washed reaction solution was concentrated under a reduced pressure, and then purified with column chromatography to obtain 0.98 g of a colorless oil derivative (Yield: 70%).
[117] IH-NMR (CDC13)δ: 1.37 (s, 3H), 1.42 (s, 9H), 1.49 (s, 3H), 1.05-1.58 (m, 2H), 1.85 (m, 2H), 2.23-2.48 (m, 2H), 3.26 (m, 2H), 3.97 (m, IH), 4.25 (m, IH)
[118] Mass (M+Na): 407
[119]
[120] <Example 8> Preparation of
(4R-cisVl.l-dimethylethyl-6-r2-r2-(4-fluorphenylV5-α-methylethylV3-phenyl-4-r(ph enylaminos)carbonyll-lH-pyrrol-l-yllethyll-2.2-dimethyl-1.3-dioxane-4-acetate
[121] 1 g of the 5-(4-fluorphenyl)-2-isopropyl-N,4-diphenyl-lH-pyrrole-3-carboxamide derivative (2.5 mmol) prepared in Example 3 or 6 was dissolved in 10 ml of ace- tonitrile, and 0.69 g of potassium carbonate (K CO ) (5 mmol) and 0.33 g of 18-crown-6 (0.12 mmol) were added to the resulting mixture, and stirred. Also, 1.2 g of the (4R-cis)- 1 , 1 -dimethylethyl-6- [2-iodoethyl]-2,2-dimethyl- 1 ,3-dioxane-4-acetate (3 mmol) prepared in Example 7 was added to the resulting reaction mixture, and then refluxed overnight while stirring. When the reaction was completed, the resulting reaction solution was cooled to a room temperature, and then washed with an aqueous saturated citric acid solution, an aqueous sodium bicarbonate solution and saturated saline. The washed reaction solution was concentrated under a reduced pressure to obtain brown oil. The brown oil was purified with column chromatography to obtain 1.1 g of a white solid title derivative (Yield: 65%).
[122] IH-NMR (CDC13)δ: 1.30 (s, 3H), 1.35 (s, 3H), 1.43 (s, 9H), 1.53 (d, 6H), 1.05-1.70 (m, 4H), 2.20-2.44 (m, 2H), 3.57 (m, IH), 3.68 (m, IH), 3.85 (m, IH), 4.07 (m, IH), 4.15 (m, IH), 6.80-7.30 (m, 14H)
[123] Mass (M+Na): 677
[124]
[125] <Example 9> Preparation of ethyll-(2-α4R.6RV6-(2-t-butoxi-2-oxoethylV2.2-dimethyl-1.3-dioxan-4-vDethylV5-(4 -fluorphenylV2-isopropyl-4-phenyl-lH-pyrrole-3-carboxvlate
[126] 0.1 g of the ethyl 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylate derivative (0.28 mmol) was dissolved in 5 ml of acetonitrile, and 0.079 g of potassium carbonate (K CO ) (0.57 mmol) and 0.037 g of 18-crown-6 (0.14 mmol) were added to the resulting mixture, and stirred. Also, 0.13 g of the
(4R-cis)- 1 , 1 -dimethylethyl-6-[2-iodoethyl] -2,2-dimethyl- 1 ,3-dioxane-4-acetate derivative (0.3 mmol) prepared in Example 7 was added to the resulting reaction mixture, and then refluxed overnight while stirring. When the reaction was completed, the resulting reaction solution was cooled to a room temperature, and then washed with an aqueous saturated citric acid solution, an aqueous sodium bicarbonate solution and saturated saline. The washed reaction solution was concentrated under a reduced pressure to obtain oil. The oil was purified with column chromatography to obtain 0.11 g of a white solid title derivative (Yield: 62%).
[127] IH-NMR (CDC13)δ: 0.98 (t, 3H), 1.30 (s, 3H), 1.35 (s, 3H), 1.43 (s, 9H), 1.53 (d, 6H), 1.0-1.70 (m, 4H), 2.20-2.44 (m, 2H), 3.57 (m, IH), 3.68 (m, IH), 3.85 (m, IH), 4.05 (m, 3H), 4.15 (m, IH), 6.91-7.15 (m, 9H)
[128] Mass (M+Na): 630
Claims
[1] A carbonyl derivative represented by the following Formula 2: <Formula 2>
[2] The carbonyl derivative according to claim 1, wherein the R residue comprises phenylamino and ethyloxy.
[3] A process for preparing a carbonyl derivative represented by the following
Formula 2, the process comprising: reacting a derivative represented by the following Formula 3 with a derivative represented by the following Formula 4:
<Formula 2>
<Formula 3>
[4] The process for preparing a carbonyl derivative according to claim 3, wherein the derivative of Formula 3 is prepared from ethylisobutyryl acetate.
[5] The process for preparing a carbonyl derivative according to claim 3, wherein the derivative of Formula 4 is prepared from a derivative represented by the following Formula 5:
<Formula 5>
[6] A process for preparing a derivative represented by the following Formula 7, the process comprising: reacting a derivative represented by the following Formula 2 with a derivative represented by the following Formula 6:
<Formula 2>
<Formula 6>
X is halogen.
[7] The process for preparing a derivative represented by the following Formula 7
according to claim 6, wherein the derivative of Formula 2 is prepared by reacting a derivative represented by the following Formula 3 with a derivative represented by the following Formula 4: <Formula 3>
[8] The process for preparing a derivative represented by the following Formula 7 according to claim 6, wherein either or both 18-crown-6 or/and potassiumiodide are used as a catalyst.
[9] A derivative represented by the following Formula 6:
<Formula 6>
wherein, a residue, X, is halogen.
[10] The derivative represented by the following Formula 6 according to claim 9, wherein the X residue is iodine (I).
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| CN102617440A (en) * | 2012-03-07 | 2012-08-01 | 湖南欧亚生物有限公司 | Method for preparing atorvastatin calcium |
| CN102702014A (en) * | 2012-05-28 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for preparing atorvastatin calcium intermediate |
| CN104151286A (en) * | 2014-04-10 | 2014-11-19 | 湖北益泰药业有限公司 | Atorvastatin calcium intermediate preparation method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050182125A1 (en) * | 2003-05-16 | 2005-08-18 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
| WO2006110918A1 (en) * | 2005-04-13 | 2006-10-19 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
| EP1834944A1 (en) * | 2006-03-17 | 2007-09-19 | Ratiopharm GmbH | Process for preparing C7 intermediates and their use in the preparation on N-substituted pyrrole derivatives |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050182125A1 (en) * | 2003-05-16 | 2005-08-18 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
| WO2006110918A1 (en) * | 2005-04-13 | 2006-10-19 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
| EP1834944A1 (en) * | 2006-03-17 | 2007-09-19 | Ratiopharm GmbH | Process for preparing C7 intermediates and their use in the preparation on N-substituted pyrrole derivatives |
Non-Patent Citations (1)
| Title |
|---|
| PRAMOD. S. PANDEY ET AL.: 'An efficient synthesis ofN3,4-diphenyl-5-(4- fluorophenyl)-2-isopropyl-1H-3-pyrrolecarbo xamide, a key intermediate for atorvastatin synthesis.' BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. vol. 14, no. 1, 2004, ISSN 0960-894X pages 129 - 131 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617440A (en) * | 2012-03-07 | 2012-08-01 | 湖南欧亚生物有限公司 | Method for preparing atorvastatin calcium |
| CN102702014A (en) * | 2012-05-28 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for preparing atorvastatin calcium intermediate |
| CN104151286A (en) * | 2014-04-10 | 2014-11-19 | 湖北益泰药业有限公司 | Atorvastatin calcium intermediate preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2011507947A (en) | 2011-03-10 |
| WO2009084827A3 (en) | 2009-08-27 |
| KR20090070233A (en) | 2009-07-01 |
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