US20220259146A1 - Method for preparing intermediate of 4-methoxypyrrole derivative - Google Patents
Method for preparing intermediate of 4-methoxypyrrole derivative Download PDFInfo
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- US20220259146A1 US20220259146A1 US17/732,804 US202217732804A US2022259146A1 US 20220259146 A1 US20220259146 A1 US 20220259146A1 US 202217732804 A US202217732804 A US 202217732804A US 2022259146 A1 US2022259146 A1 US 2022259146A1
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- 238000000034 method Methods 0.000 title claims abstract description 25
- OTODBDQJLMYYKQ-UHFFFAOYSA-N 3-methoxy-1h-pyrrole Chemical class COC=1C=CNC=1 OTODBDQJLMYYKQ-UHFFFAOYSA-N 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 108
- 150000001875 compounds Chemical class 0.000 claims description 96
- 239000000126 substance Substances 0.000 claims description 93
- 239000002253 acid Substances 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 125000006242 amine protecting group Chemical group 0.000 claims description 10
- -1 magnesium halide Chemical class 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000011777 magnesium Substances 0.000 claims description 8
- 229910052749 magnesium Inorganic materials 0.000 claims description 8
- CYAXCSFTHFUALI-UHFFFAOYSA-N C(CC(=O)O)(=O)O.C[K] Chemical compound C(CC(=O)O)(=O)O.C[K] CYAXCSFTHFUALI-UHFFFAOYSA-N 0.000 claims description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 7
- 235000019270 ammonium chloride Nutrition 0.000 claims description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 7
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 7
- MLCMAFAGSNLWRZ-UHFFFAOYSA-N C[Na].C(CC(=O)O)(=O)O Chemical compound C[Na].C(CC(=O)O)(=O)O MLCMAFAGSNLWRZ-UHFFFAOYSA-N 0.000 claims description 6
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 6
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 29
- 238000002360 preparation method Methods 0.000 abstract description 15
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 abstract description 12
- 239000000543 intermediate Substances 0.000 abstract description 8
- 239000002360 explosive Substances 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 230000035484 reaction time Effects 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 230000002496 gastric effect Effects 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 159000000003 magnesium salts Chemical class 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 208000007882 Gastritis Diseases 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 208000025865 Ulcer Diseases 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
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- 231100000397 ulcer Toxicity 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 208000000689 peptic esophagitis Diseases 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
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- 239000000376 reactant Substances 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- STWYUDQLBORQDI-UHFFFAOYSA-N 2-(2,4-difluoroanilino)acetic acid Chemical compound OC(=O)CNC1=CC=C(F)C=C1F STWYUDQLBORQDI-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 241000590002 Helicobacter pylori Species 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 229940037467 helicobacter pylori Drugs 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- DMNUDNHYRCDZDC-UHFFFAOYSA-N COC(=O)c1c[nH]c(-c2ccc(F)cc2F)c1OC Chemical compound COC(=O)c1c[nH]c(-c2ccc(F)cc2F)c1OC DMNUDNHYRCDZDC-UHFFFAOYSA-N 0.000 description 2
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 2
- 108010083204 Proton Pumps Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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- 239000000908 ammonium hydroxide Substances 0.000 description 2
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
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- RWMKSKOZLCXHOK-UHFFFAOYSA-M potassium;butanoate Chemical compound [K+].CCCC([O-])=O RWMKSKOZLCXHOK-UHFFFAOYSA-M 0.000 description 2
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- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
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- 229960002626 clarithromycin Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- RHFZTBSULNJWEI-UHFFFAOYSA-N dimethyl 2-(methoxymethylidene)propanedioate Chemical compound COC=C(C(=O)OC)C(=O)OC RHFZTBSULNJWEI-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000011251 protective drug Substances 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000008096 xylene Substances 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
- C07D207/36—Oxygen or sulfur 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
- 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
- A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a method for preparing intermediates used in the preparation of 4-methoxypyrrole derivatives.
- Gastrointestinal track ulcers, gastritis, and reflux esophagitis occur while the balance between aggressive factors (e.g., gastric acid, Helicobacter pylori pepsin, stress, alcohol and tobacco) and protective factors (e.g., gastric mucosa, bicarbonate, prostaglandins, the degree of blood supply, etc.) is destroyed. Therefore, a therapeutic agent for gastrointestinal damage such as gastrointestinal track ulcer, gastritis and reflux esophagitis is divided into a drug for inhibiting the aggressive factors and a drug for enhancing the protective factors.
- aggressive factors e.g., gastric acid, Helicobacter pylori pepsin, stress, alcohol and tobacco
- protective factors e.g., gastric mucosa, bicarbonate, prostaglandins, the degree of blood supply, etc.
- H. pylori which is a bacteria present in the stomach, has been known to cause chronic gastritis, gastric ulcer, duodenal ulcer and the like, and a number of patients with gastrointestinal damages are infected with H. pylori . Therefore, these patients should take antibiotics such as clarithromycin, amoxicillin, metronidazole and tetracycline, together with anti-ulcer agents such as a proton pump inhibitor, or a gastric pump antagonist. Consequently, various side effects have been reported.
- antibiotics such as clarithromycin, amoxicillin, metronidazole and tetracycline
- Korean Patent No. 10-1613245 discloses that a 4-methoxypyrrole derivative or a pharmaceutically acceptable salt thereof has excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.) and disinfectant activity against H. pylori , and thus can be effectively used for the prevention and treatment of gastrointestinal damage due to gastrointestinal track ulcer, gastritis, reflux esophagitis or Helicobacter pylori.
- the intermediate is prepared from 2,4-difluorophenylglycine, and the preparation method consists of four steps in total (Steps (8-1) to (8-3) of Example 8 described in Korean Patent No. 10-1613245).
- the total yield is as low as 9.0%, a high-temperature reaction is required as a whole, and thus expensive equipment is required.
- (trimethylsilyl)diazomethane is used as a reactant, but this reagent is not only expensive but also explosive and thus is not suitable for industrial mass production.
- the present inventors have conducted intensive studies on a new preparation method capable of preparing the above intermediate. As a result, the inventors have found a preparation method in which a high-temperature reaction is not required as a whole as in the preparation method described later, and inexpensive, non-explosive reagent is used instead of (trimethylsilyl)diazomethane, and further, the yield is improved as a whole, thereby completing the present invention.
- the present invention provides a preparation method as shown in the following Reaction Scheme 1, and more specifically, the preparation method comprises the steps of:
- the step 1 relates to Strecker amino acid synthesis, which is a step of preparing an amino acid like a compound represented by the Chemical Formula 1-2 from the Chemical Formula 1-1.
- the reaction consists substantially of two reactions.
- the first reaction is to react a compound represented by the Chemical Formula 1-1 with ammonium chloride, and sodium cyanide, or potassium cyanide.
- the molar ratio of the compound represented by the Chemical Formula 1-1 to ammonium chloride is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1:3.
- the molar ratio of the compound represented by the Chemical Formula 1-1 to sodium cyanide or potassium cyanide is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1:3.
- an alcohol having from 1 to 4 carbon atoms, and ammonium hydroxide or ammonium carbonate are used as a solvent for the first reaction. More preferably, the alcohol having 1 to 4 carbon atoms is methanol, ethanol, propanol, iso-propanol, butanol, or tert-butanol.
- the first reaction is carried out at 0° C. to 40° C.
- the reaction temperature is less than 0° C., there is a problem that the production yield is lowered.
- the reaction temperature exceeds 40° C., the production yield does not substantially increase.
- the first reaction is carried out for 1 to 48 hours.
- the reaction time is less than 1 hour, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered.
- the reaction time exceeds 48 hours, the production yield does not substantially increase.
- a step of purifying the product may be included, if necessary.
- the purification is carried out by crystallizing a cyanamide compound from the product of the reaction.
- the crystallization solvent water and an alcohol having 1 to 4 carbon atoms can be used.
- the alcohol having 1 to 4 carbon atoms is methanol, ethanol, propanol, iso-propanol, butanol, or tert-butanol.
- water is added to the reaction product and cooled to 10 to 15° C. Then, an alcohol having 1 to 4 carbon atoms is added thereto and stirred for 10 minutes to 2 hours.
- a second reaction is carried out in which the product of the first reaction is reacted with an acid.
- acetic acid or hydrochloric acid can be mentioned.
- acetic acid and hydrochloric acid are used together.
- the acid not only acts as a reactant in the second reaction, but also acts as a solvent. Therefore, it is preferable to use the acid in an amount sufficient to dissolve the first product.
- the second reaction is carried out at 80 to 120° C.
- the reaction temperature is less than 80° C., there is a problem that the production yield is lowered.
- the reaction temperature exceeds 120° C., the production yield does not substantially increase.
- the second reaction is carried out for 1 to 10 hours.
- the reaction time is less than 1 hour, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered.
- the reaction time exceeds 10 hours, the production yield does not substantially increase.
- a step of purifying the product may be included, if necessary.
- the step 2 is a step of protecting a compound represented by the Chemical Formula 1-2 with an amine protecting group (P), which is a step of preparing a compound represented by the Chemical Formula 1-3 by reacting a compound represented by the Chemical Formula 1-2 with a compound capable of introducing an amine protecting group (P).
- P an amine protecting group
- the amine protecting group (P) is tert-butoxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), Tosyl, or Acyl.
- the compound capable of introducing an amine protecting group (P) refers to various compounds used in the art for introducing the protecting group.
- the compound capable of introducing the amine protecting group includes di-tert-butyl dicarbonate.
- the molar ratio of the compound represented by the Chemical Formula 1-2 to the compound capable of introducing the amine protecting group (P) is 10:1 to 1:10, and more preferably 3:1 to 1:5.
- the reaction is carried out in the presence of a base.
- a base triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, potassium butyrate, or cesium carbonate can be used, and preferably, sodium hydrogencarbonate is used.
- the molar ratio of the compound represented by the Chemical Formula 1-2 to the base is 1:1 to 1:10, and more preferably 1:1 to 1:5.
- water, tetrahydrofuran, dioxane, methylene chloride, butyl alcohol, tetrahydrofuran, or a mixture thereof may be used.
- water and tetrahydrofuran are used together.
- the reaction is carried out at 10 to 40° C.
- the reaction temperature is less than 10° C., there is a problem that the production yield is lowered.
- the reaction temperature exceeds 40° C., the production yield does not substantially increase. More preferably, the reaction is carried out at 20 to 30° C.
- the above reaction is carried out for 1 to 48 hours.
- the reaction time is less than 1 hour, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered.
- the reaction time exceeds 48 hours, the production yield does not substantially increase. More preferably, the reaction is carried out for 6 to 24 hours.
- a step of purifying the product may be included, if necessary.
- the step 3 is a reaction for substituting a carboxyl group of the compound represented by the Chemical Formula 1-3, wherein the reaction consists substantially of two reactions.
- the first reaction is a reaction for preparing a compound of the following Chemical Formula, which is a magnesium salt of the compound represented by the
- the second reaction is a reaction for preparing the magnesium salt of the compound represented by the Chemical Formula 1-4 by dissociating the magnesium salt of the compound represented by the Chemical Formula 1-4
- the compound represented by the Chemical Formula 1-4 is difficult to crystallize. Therefore, in the present invention, it is prepared by first preparing a magnesium salt thereof and then purifying it through crystallization.
- the first reaction is a reaction of reacting a compound represented by the Chemical Formula 1-3 with (i) methylpotassium malonate or methylsodium malonate, (ii) carbonyldiimidazole, and (iii) magnesium halide.
- magnesium halide magnesium chloride or magnesium bromide may be used, and more preferably, magnesium chloride is used.
- the molar ratio of the compound represented by the Chemical Formula 1-3 to methylpotassium malonate or methylsodium malonate is 10:1 to 1:10, more preferably from 5:1 to 1:5, most preferably 3:1 to 1:3.
- the molar ratio of the compound represented by the Chemical Formula 1-3 to carbonyldiimidazole is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1:3.
- the molar ratio of the compound represented by the Chemical Formula 1-3 to magnesium halide is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1:3.
- the first reaction is carried out in the presence of triethylamine.
- the molar ratio of the compound represented by the Chemical Formula 1-3 to triethylamine is 10:1 to 1:10, more preferably 5:1 to 1:5 and most preferably 3:1 to 1:3.
- acetonitrile or tetrahydrofuran is used, and more preferably, acetonitrile is used.
- the first reaction is carried out at 50 to 100° C.
- the reaction temperature is less than 50° C., there is a problem that the production yield is lowered.
- the reaction temperature exceeds 100° C., a side reaction occurs, which is not preferable.
- the first reaction is carried out for 10 minutes to 10 hours.
- the reaction time is less than 10 minutes, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered.
- the reaction time exceeds 10 hours, a side reaction occurs, which is not preferable. More preferably, the reaction is carried out for 10 minutes to 5 hours.
- a second reaction is performed in which the product of the first reaction is reacted with an acid.
- hydrochloric acid nitric acid, sulfuric acid, or phosphoric acid, preferably hydrochloric acid.
- ethyl acetate As the solvent for the second reaction, ethyl acetate, water, methylene chloride, or a mixture thereof may be used. Preferably, ethyl acetate and water are used together.
- the second reaction is adjusted to pH 4 to 8 with an acid at 0 to 40° C.
- the reaction temperature is less than 0° C. or higher than 40° C., there is a problem that the production yield is lowered.
- it is adjusted to pH 6 to 8.
- the pH is 8 or more, the magnesium salt is not completely dissociated, and the production yield is lowered.
- the step 4 is a step of preparing a pyrrole derivative from a compound represented by the Chemical Formula 1-4, which is a step of reacting a compound represented by the Chemical. Formula 1-4 with N,N-dimethylformamide dimethylacetal to prepare a compound represented by the Chemical Formula 1-5.
- the molar ratio of the compound represented by the Chemical Formula 1-4 to N,N-dimethylformamide dimethylacetal is 1:1 to 1:10, and more preferably 1:1 to 1:5.
- toluene or xylene may be used, and more preferably, toluene is used.
- the reaction is carried out at 20 to 70° C.
- the reaction temperature is less than 20° C., there is a problem that the production yield is lowered.
- the reaction temperature exceeds 70° C., the production yield does not substantially increase.
- the reaction is carried out for 30 minutes to 12 hours.
- the reaction time is less than 30 minutes, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered.
- the reaction time exceeds 12 hours, the production yield does not substantially increase.
- the step 5 is a reaction of substituting a hydroxy group of the compound represented by the Chemical Formula 1-5 with methoxy, which is a step of reacting a compound represented by the Chemical Formula 1-5 with dimethyl sulfate to prepare a compound represented by the Chemical Formula 1-6.
- the molar ratio of the compound represented by the Chemical Formula 1-5 to dimethyl sulfate is 10:1 to 1:10, more preferably from 5:1 to 1:5, most preferably from 3:1 to 1:3.
- the reaction is preferably carried out in the presence of a base.
- a base triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methylate, potassium butyrate, or cesium carbonate can be used, and preferably, potassium carbonate is used.
- the reaction can be carried out using methyl iodide in the presence of a base.
- the molar ratio of the compound represented by the Chemical Formula 1-5 to the base is 1:1 to 1:5, and more preferably 1:1 to 1:3.
- the solvent for the reaction an alcohol having 1 to 4 carbon atoms or a ketone having 3 to 6 carbon atoms is used. More preferably, the solvent for the reaction is methanol, ethanol, propanol, butanol, tert-butanol, acetone, methyl ethyl ketone, or isobutyl ketone.
- the reaction is carried out at 20. to 60° C.
- the reaction temperature is less than 20° C., there is a problem that the production yield is lowered.
- the reaction temperature exceeds 60° C., a side reaction occurs, which is not preferable.
- the reaction is carried out for 1 to 24 hours. If the reaction time is less than 1 hour, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered. When the reaction time exceeds 24 hours, a side reaction occurs, which is not preferable.
- a step of purifying the product may be included, if necessary.
- the step 6 is a step of removing a protecting group of the compound represented by the Chemical Formula 1-6, which is a step of reacting the compound represented by the Chemical Formula 1-6 with an acid to prepare a compound represented by the Chemical Formula 1.
- trifluoroacetic acid As the acid that can be used, there may be mentioned trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid, preferably trifluoroacetic acid.
- the molar ratio of the compound represented by the Chemical Formula 1-6 to the acid is 1:1 to 1:30, and more preferably 1:5 to 1:20.
- methylene chloride ethyl acetate, methanol, toluene, diethyl ether, tetrahydrofuran, or water
- methylene chloride ethyl acetate, methanol, toluene, diethyl ether, tetrahydrofuran, or water
- methylene chloride ethyl acetate, methanol, toluene, diethyl ether, tetrahydrofuran, or water
- methylene chloride ethyl acetate, methanol, toluene, diethyl ether, tetrahydrofuran, or water
- the reaction is carried out at 10 to 40° C. If the reaction temperature is less than 10° C., there is a problem that the production yield is lowered. If the reaction temperature exceeds 40° C., a side reaction occurs, which is not preferable.
- the reaction is carried out for 1 to 24 hours.
- the reaction time is less than 1 hour, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered.
- the reaction time exceeds 24 hours, the production yield does not substantially increase.
- a step of purifying the product may be included, if necessary.
- the preparation method according to the present invention has advantages that the production cost can be lowered by using inexpensive starting materials, a high-temperature reaction is not required as a whole, inexpensive and non-explosive reagents are used instead of (trimethylsilyl)diazomethane, and further an intermediate of 4-methoxypyrrole derivatives can be prepared as a whole at a high yield.
- the preparation method was carried out as follows in the same manner as in steps 8-1 to 8-3 of Example 8 of Korean. Patent No. 10-1613245.
- Acetic anhydride (1731.2 ml) and triethylamine (577.1 ml) were added to the compound represented by the Chemical Formula 2-3 (190.0 g, 577.1 mmol) prepared in step 1.
- the reaction mixture was refluxed at 140° C. for 30 minutes and then cooled to 0° C.
- ice water (577.1 ml) was added at 0° C., stirred at room temperature for 1 hour and then extracted with ethyl acetate.
- the obtained extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.
- the resulting compound was filtered using a silica gel to remove a solid, and then concentrated under reduced pressure to prepare the compound represented by the Chemical Formula 2-4, which was then used in the following step 3.
- Tetrahydrofuran (140.0 ml) and water (120.0 ml) were added to the resulting residue, cooled to 0° C., followed by addition of sodium hydroxide (46.17 g, 1154.2 mmol).
- the reaction mixture was stirred at 0° C. for 30 minutes, neutralized using IN hydrochloric acid aqueous solution and then extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
- Example according to the present invention could not only reduce the production cost by using inexpensive aldehyde as a starting material but also improve the yield by about 5.4 times as compared with the Comparative Example.
- step 2 of Example according to the present invention and step 1 of Comparative Example used 2,4-difluorophenylglycine as a starting material. Comparing the methods for preparing the compound represented by the Chemical Formula 1 from the above step, Example according to the present invention showed a yield of about 50%, whereas Comparative Example showed a yield of 9%, thereby confirming that the yield according to the present invention was remarkably improved.
- Example according to the present invention the relatively low temperature was applied in the entire steps, whereas in step 2 of Comparative Example, the reaction temperature of about 140° C. was applied.
- the preparation method according to the present invention has an advantage that a relatively low reaction temperature can be applied.
- step 4 of Comparative Example used (trimethylsilyl)diazomethane which is an explosive reaction material, whereas Example according to the present invention has the advantage that such a reactant was not used.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a method for preparing intermediates of 4-methoxypyrrole derivatives. The preparation method according to the present invention has advantages that the production cost can be lowered by using inexpensive starting materials, a high-temperature reaction is not required as a whole, inexpensive and non-explosive reagents are used instead of (trimethylsilyl)diazomethane, and further an intermediate of 4-methoxypyrrole derivatives can be prepared as a whole at a high yield.
Description
- The present invention relates to a method for preparing intermediates used in the preparation of 4-methoxypyrrole derivatives.
- Gastrointestinal track ulcers, gastritis, and reflux esophagitis occur while the balance between aggressive factors (e.g., gastric acid, Helicobacter pylori pepsin, stress, alcohol and tobacco) and protective factors (e.g., gastric mucosa, bicarbonate, prostaglandins, the degree of blood supply, etc.) is destroyed. Therefore, a therapeutic agent for gastrointestinal damage such as gastrointestinal track ulcer, gastritis and reflux esophagitis is divided into a drug for inhibiting the aggressive factors and a drug for enhancing the protective factors.
- Meanwhile, it is reported that gastrointestinal track ulcers, gastritis and reflux esophagitis occur ulcers even without an increase in secretion of gastric acid. Thus, as much as the aggressive factor increases, a reduction in protective factors due to a pathological change of the gastric mucosa is thought to play an important role in the occurrence of gastric ulcers. Therefore, in addition to drugs for inhibiting the aggressive factor, drugs for enhancing the protective factors are used for the treatment of gastrointestinal ulcer and gastritis. As the drugs for enhancing protective factors, mucosal protective drugs which are attached to the ulcer site to form a physicochemical membrane, drugs that promote the synthesis and secretion of mucus have been known.
- On the other hand, Helicobacter pylori (H. pylori), which is a bacteria present in the stomach, has been known to cause chronic gastritis, gastric ulcer, duodenal ulcer and the like, and a number of patients with gastrointestinal damages are infected with H. pylori. Therefore, these patients should take antibiotics such as clarithromycin, amoxicillin, metronidazole and tetracycline, together with anti-ulcer agents such as a proton pump inhibitor, or a gastric pump antagonist. Consequently, various side effects have been reported.
- Therefore, there is a need to develop anti-ulcer drugs which inhibit the secretion of gastric acid (e.g., proton pump inhibitory activity) and enhance protective factors (e.g., an increase in mucus secretion) and at the same time have disinfectant activity against H pylori.
- In this connection, Korean Patent No. 10-1613245 discloses that a 4-methoxypyrrole derivative or a pharmaceutically acceptable salt thereof has excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.) and disinfectant activity against H. pylori, and thus can be effectively used for the prevention and treatment of gastrointestinal damage due to gastrointestinal track ulcer, gastritis, reflux esophagitis or Helicobacter pylori.
- In the preparation of the 4-methoxypyrrole derivative described in the above patent, the following compound is prepared as an intermediate.
- According to the description of the above patent, the intermediate is prepared from 2,4-difluorophenylglycine, and the preparation method consists of four steps in total (Steps (8-1) to (8-3) of Example 8 described in Korean Patent No. 10-1613245). However, according to the preparation method of the above patent, the total yield is as low as 9.0%, a high-temperature reaction is required as a whole, and thus expensive equipment is required. Especially, (trimethylsilyl)diazomethane is used as a reactant, but this reagent is not only expensive but also explosive and thus is not suitable for industrial mass production.
- Given the above circumstances, the present inventors have conducted intensive studies on a new preparation method capable of preparing the above intermediate. As a result, the inventors have found a preparation method in which a high-temperature reaction is not required as a whole as in the preparation method described later, and inexpensive, non-explosive reagent is used instead of (trimethylsilyl)diazomethane, and further, the yield is improved as a whole, thereby completing the present invention.
- It is an object of the present invention to provide a method for preparing an intermediate which can be usefully used in the preparation of 4-methoxypyrrole derivatives.
- In order to achieve the above object, the present invention provides a preparation method as shown in the following Reaction Scheme 1, and more specifically, the preparation method comprises the steps of:
- 1) reacting a compound represented by the following Chemical Formula 1-1 with ammonium chloride, sodium cyanide, or potassium cyanide, followed by reaction with an acid to prepare a compound represented by the following Chemical Formula 1-2;
- 2) protecting a compound represented by the following Chemical Formula 1-2 with an amine protecting group (P) to prepare a compound represented by the following Chemical Formula 1-3;
- 3) reacting a compound represented by the following Chemical Formula 1-3 with (i) methylpotassium malonate or methylsodium malonate, (ii) carbonyldiimidazole, and (iii) magnesium halide, followed by reaction with an acid to prepare a compound represented by the following Chemical Formula 1-4;
- 4) reacting a compound represented by the following Chemical Formula 1-4 with N,N-dimethylformamide dimethylacetal to prepare a compound represented by the following Chemical Formula 1-5;
- 5) reacting a compound represented by the following Chemical Formula 1-5 with dimethyl sulfate to prepare a compound represented by the following Chemical Formula 1-6; and 6) reacting a compound represented by the following Chemical Formula 1-6 with an acid via deprotection to prepare a compound represented by the following Chemical Formula 1.
- Hereinafter, the present invention will be described in detail for each step.
- (Step 1)
- The step 1 relates to Strecker amino acid synthesis, which is a step of preparing an amino acid like a compound represented by the Chemical Formula 1-2 from the Chemical Formula 1-1.
- The reaction consists substantially of two reactions. First, the first reaction is to react a compound represented by the Chemical Formula 1-1 with ammonium chloride, and sodium cyanide, or potassium cyanide.
- Preferably, the molar ratio of the compound represented by the Chemical Formula 1-1 to ammonium chloride is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1:3. Preferably, the molar ratio of the compound represented by the Chemical Formula 1-1 to sodium cyanide or potassium cyanide is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1:3.
- Preferably, as a solvent for the first reaction, an alcohol having from 1 to 4 carbon atoms, and ammonium hydroxide or ammonium carbonate are used. More preferably, the alcohol having 1 to 4 carbon atoms is methanol, ethanol, propanol, iso-propanol, butanol, or tert-butanol.
- Preferably, the first reaction is carried out at 0° C. to 40° C. When the reaction temperature is less than 0° C., there is a problem that the production yield is lowered. When the reaction temperature exceeds 40° C., the production yield does not substantially increase.
- Preferably, the first reaction is carried out for 1 to 48 hours. When the reaction time is less than 1 hour, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered. When the reaction time exceeds 48 hours, the production yield does not substantially increase.
- On the other hand, after the first reaction is completed, a step of purifying the product may be included, if necessary. Preferably, the purification is carried out by crystallizing a cyanamide compound from the product of the reaction. As the crystallization solvent, water and an alcohol having 1 to 4 carbon atoms can be used. Preferably, the alcohol having 1 to 4 carbon atoms is methanol, ethanol, propanol, iso-propanol, butanol, or tert-butanol. Preferably, water is added to the reaction product and cooled to 10 to 15° C. Then, an alcohol having 1 to 4 carbon atoms is added thereto and stirred for 10 minutes to 2 hours.
- After the first reaction is completed, a second reaction is carried out in which the product of the first reaction is reacted with an acid.
- As the acid that can be used, acetic acid or hydrochloric acid can be mentioned. Preferably, acetic acid and hydrochloric acid are used together. The acid not only acts as a reactant in the second reaction, but also acts as a solvent. Therefore, it is preferable to use the acid in an amount sufficient to dissolve the first product.
- Preferably, the second reaction is carried out at 80 to 120° C. When the reaction temperature is less than 80° C., there is a problem that the production yield is lowered. When the reaction temperature exceeds 120° C., the production yield does not substantially increase.
- Preferably, the second reaction is carried out for 1 to 10 hours. When the reaction time is less than 1 hour, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered. When the reaction time exceeds 10 hours, the production yield does not substantially increase.
- On the other hand, after the second reaction is completed, a step of purifying the product may be included, if necessary.
- (Step 2)
- The step 2 is a step of protecting a compound represented by the Chemical Formula 1-2 with an amine protecting group (P), which is a step of preparing a compound represented by the Chemical Formula 1-3 by reacting a compound represented by the Chemical Formula 1-2 with a compound capable of introducing an amine protecting group (P).
- Preferably, the amine protecting group (P) is tert-butoxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), Tosyl, or Acyl. In addition, the compound capable of introducing an amine protecting group (P) refers to various compounds used in the art for introducing the protecting group. For example, when the amine protecting group (P) is a tert-butoxycarbonyl (Boc), the compound capable of introducing the amine protecting group includes di-tert-butyl dicarbonate.
- Preferably, the molar ratio of the compound represented by the Chemical Formula 1-2 to the compound capable of introducing the amine protecting group (P) is 10:1 to 1:10, and more preferably 3:1 to 1:5.
- Preferably, the reaction is carried out in the presence of a base. As the base, triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, potassium butyrate, or cesium carbonate can be used, and preferably, sodium hydrogencarbonate is used. Preferably, the molar ratio of the compound represented by the Chemical Formula 1-2 to the base is 1:1 to 1:10, and more preferably 1:1 to 1:5.
- Preferably, as a solvent for the above reaction, water, tetrahydrofuran, dioxane, methylene chloride, butyl alcohol, tetrahydrofuran, or a mixture thereof may be used. Preferably, water and tetrahydrofuran are used together.
- Preferably, the reaction is carried out at 10 to 40° C. When the reaction temperature is less than 10° C., there is a problem that the production yield is lowered. When the reaction temperature exceeds 40° C., the production yield does not substantially increase. More preferably, the reaction is carried out at 20 to 30° C.
- Preferably, the above reaction is carried out for 1 to 48 hours. When the reaction time is less than 1 hour, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered. When the reaction time exceeds 48 hours, the production yield does not substantially increase. More preferably, the reaction is carried out for 6 to 24 hours.
- On the other hand, after the reaction is completed, a step of purifying the product may be included, if necessary.
- (Step 3)
- The step 3 is a reaction for substituting a carboxyl group of the compound represented by the Chemical Formula 1-3, wherein the reaction consists substantially of two reactions.
- First, the first reaction is a reaction for preparing a compound of the following Chemical Formula, which is a magnesium salt of the compound represented by the
- Chemical Formula 1-4 to be prepared. The second reaction is a reaction for preparing the magnesium salt of the compound represented by the Chemical Formula 1-4 by dissociating the magnesium salt of the compound represented by the Chemical Formula 1-4
- The compound represented by the Chemical Formula 1-4 is difficult to crystallize. Therefore, in the present invention, it is prepared by first preparing a magnesium salt thereof and then purifying it through crystallization.
- First, the first reaction is a reaction of reacting a compound represented by the Chemical Formula 1-3 with (i) methylpotassium malonate or methylsodium malonate, (ii) carbonyldiimidazole, and (iii) magnesium halide. Preferably, as the magnesium halide, magnesium chloride or magnesium bromide may be used, and more preferably, magnesium chloride is used.
- Preferably, the molar ratio of the compound represented by the Chemical Formula 1-3 to methylpotassium malonate or methylsodium malonate is 10:1 to 1:10, more preferably from 5:1 to 1:5, most preferably 3:1 to 1:3. Preferably, the molar ratio of the compound represented by the Chemical Formula 1-3 to carbonyldiimidazole is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1:3. Preferably, the molar ratio of the compound represented by the Chemical Formula 1-3 to magnesium halide is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1:3.
- Preferably, the first reaction is carried out in the presence of triethylamine. Preferably, the molar ratio of the compound represented by the Chemical Formula 1-3 to triethylamine is 10:1 to 1:10, more preferably 5:1 to 1:5 and most preferably 3:1 to 1:3.
- Preferably, as a solvent for the first reaction, acetonitrile or tetrahydrofuran is used, and more preferably, acetonitrile is used.
- Preferably, the first reaction is carried out at 50 to 100° C. When the reaction temperature is less than 50° C., there is a problem that the production yield is lowered. When the reaction temperature exceeds 100° C., a side reaction occurs, which is not preferable.
- Preferably, the first reaction is carried out for 10 minutes to 10 hours. When the reaction time is less than 10 minutes, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered. When the reaction time exceeds 10 hours, a side reaction occurs, which is not preferable. More preferably, the reaction is carried out for 10 minutes to 5 hours.
- After the first reaction is completed, a second reaction is performed in which the product of the first reaction is reacted with an acid.
- As the acid that can be used, there may be mentioned hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid, preferably hydrochloric acid.
- As the solvent for the second reaction, ethyl acetate, water, methylene chloride, or a mixture thereof may be used. Preferably, ethyl acetate and water are used together.
- The second reaction is adjusted to pH 4 to 8 with an acid at 0 to 40° C. When the reaction temperature is less than 0° C. or higher than 40° C., there is a problem that the production yield is lowered. Preferably it is adjusted to pH 6 to 8. When the pH is 8 or more, the magnesium salt is not completely dissociated, and the production yield is lowered.
- On the other hand, after the second reaction is completed, a step of purifying the product can be included, if necessary.
- (Step 4)
- The step 4 is a step of preparing a pyrrole derivative from a compound represented by the Chemical Formula 1-4, which is a step of reacting a compound represented by the Chemical. Formula 1-4 with N,N-dimethylformamide dimethylacetal to prepare a compound represented by the Chemical Formula 1-5.
- Preferably, the molar ratio of the compound represented by the Chemical Formula 1-4 to N,N-dimethylformamide dimethylacetal is 1:1 to 1:10, and more preferably 1:1 to 1:5.
- Preferably, as a solvent for the reaction, toluene or xylene may be used, and more preferably, toluene is used.
- Preferably, the reaction is carried out at 20 to 70° C. When the reaction temperature is less than 20° C., there is a problem that the production yield is lowered. When the reaction temperature exceeds 70° C., the production yield does not substantially increase.
- Preferably, the reaction is carried out for 30 minutes to 12 hours. When the reaction time is less than 30 minutes, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered. When the reaction time exceeds 12 hours, the production yield does not substantially increase.
- On the other hand, since the compound represented by the Chemical Formula 1-5, which is a product of the reaction, is chemically unstable, it is preferable to continuously perform the subsequent reaction of step 5 without further purification.
- (Step 5)
- The step 5 is a reaction of substituting a hydroxy group of the compound represented by the Chemical Formula 1-5 with methoxy, which is a step of reacting a compound represented by the Chemical Formula 1-5 with dimethyl sulfate to prepare a compound represented by the Chemical Formula 1-6.
- Preferably, the molar ratio of the compound represented by the Chemical Formula 1-5 to dimethyl sulfate is 10:1 to 1:10, more preferably from 5:1 to 1:5, most preferably from 3:1 to 1:3.
- Further, the reaction is preferably carried out in the presence of a base. As the base, triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methylate, potassium butyrate, or cesium carbonate can be used, and preferably, potassium carbonate is used. In addition, the reaction can be carried out using methyl iodide in the presence of a base. Preferably, the molar ratio of the compound represented by the Chemical Formula 1-5 to the base is 1:1 to 1:5, and more preferably 1:1 to 1:3.
- Preferably, as the solvent for the reaction, an alcohol having 1 to 4 carbon atoms or a ketone having 3 to 6 carbon atoms is used. More preferably, the solvent for the reaction is methanol, ethanol, propanol, butanol, tert-butanol, acetone, methyl ethyl ketone, or isobutyl ketone.
- Preferably, the reaction is carried out at 20. to 60° C. When the reaction temperature is less than 20° C., there is a problem that the production yield is lowered. When the reaction temperature exceeds 60° C., a side reaction occurs, which is not preferable.
- Preferably, the reaction is carried out for 1 to 24 hours. If the reaction time is less than 1 hour, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered. When the reaction time exceeds 24 hours, a side reaction occurs, which is not preferable.
- On the other hand, after the reaction is completed, a step of purifying the product may be included, if necessary.
- (Step 6)
- The step 6 is a step of removing a protecting group of the compound represented by the Chemical Formula 1-6, which is a step of reacting the compound represented by the Chemical Formula 1-6 with an acid to prepare a compound represented by the Chemical Formula 1.
- As the acid that can be used, there may be mentioned trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid, preferably trifluoroacetic acid.
- Preferably, the molar ratio of the compound represented by the Chemical Formula 1-6 to the acid is 1:1 to 1:30, and more preferably 1:5 to 1:20.
- Preferably, as a solvent for the reaction, methylene chloride, ethyl acetate, methanol, toluene, diethyl ether, tetrahydrofuran, or water may be used, and preferably, methylene chloride is used.
- Preferably, the reaction is carried out at 10 to 40° C. If the reaction temperature is less than 10° C., there is a problem that the production yield is lowered. If the reaction temperature exceeds 40° C., a side reaction occurs, which is not preferable.
- Preferably, the reaction is carried out for 1 to 24 hours. When the reaction time is less than 1 hour, there is a problem that the reaction does not proceed sufficiently and thus the production yield is lowered. When the reaction time exceeds 24 hours, the production yield does not substantially increase.
- On the other hand, after the reaction is completed, a step of purifying the product may be included, if necessary.
- As described above, the preparation method according to the present invention has advantages that the production cost can be lowered by using inexpensive starting materials, a high-temperature reaction is not required as a whole, inexpensive and non-explosive reagents are used instead of (trimethylsilyl)diazomethane, and further an intermediate of 4-methoxypyrrole derivatives can be prepared as a whole at a high yield.
- Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention thereto. On the other hand, in the example and comparative example, the compounds prepared in each step are used in the next steps, and each step can produce more products than those described below for the next step.
-
- (Step 1)
- 35.8 g of ammonium chloride and 26.9 g of sodium cyanide were added to a flask, and 716.0 mL of ammonium hydroxide (25 to 28%) was added and then stirred for 10 minutes. The mixture was cooled to 0 to 5° C., stirred for 10 minutes, then heated to room temperature, and stirred for 15 minutes. After cooling to 0 to 5° C., 100.0 g of the prepared 2,4-difluorobenzaldehyde (Chemical Formula 1-1) and 770.0 mL of methanol-containing solution was slowly added to another flask for 15 to 20 minutes. The temperature was raised to room temperature, and the mixture was stirred for 22 hours to complete the first reaction. After concentration under reduced pressure at 50° C., 983.0 mL of acetic acid and 983.0 mL of conc.HCl were added, and refluxed at 100 to 105° C. (internal temperature) for 5 hours to complete the second reaction. It was concentrated under reduced pressure at 75° C., and the solvent was removed until a solid was precipitated. After purified water was added, the crystals were precipitated by stirring. The pH was adjusted to 6.5 using 5M-NaOH solution at internal temperature of 25° C. or less. Ethanol was added thereto and stirred at 10 to 15° C. for 1 hour. After filtration under reduced pressure, the filtrate was washed with ethanol. The resulting solid was dried under reduced pressure to obtain 78.4 g of the compound represented by the Chemical Formula 1-2 (yield: 59.5%).
- (Step 2)
- 100.0 g of the compound represented by the Chemical Formula 1-2 prepared in step 1, 1.5 L of THF and 1.5 L of purified water were added to a flask, and then stirred at room temperature for 10 minutes. The internal temperature was cooled to 0 to 5° C., and 134.6 g of sodium hydrogencarbonate and 139.5 g of di-tert-butyl dicarbonate were added thereto. The mixture was stirred at an internal temperature of 20 to 30° C. for 12 hours to complete the reaction, followed by concentration under reduced pressure at 45° C. After ethyl acetate was added, the internal temperature was cooled to 10° C. or lower. The pH was adjusted to 2.5 using 6N—HCl. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at 45° C. to obtain 151.2 g of the compound represented by the Chemical Formula 1-3 (yield: 98.5%).
- 1H-NMR (500 MHz, CDCl3): 8.13-8.14; (d, 1H), 7.37-7.42; (m, 1H), 6.82-6.89; (m, 2H), 5.46-5.47; (d, 1H), 1.23; (s, 9H)
- (Step 3)
- 100.0 g of the compound represented by the Chemical. Formula 1-3 prepared in step 2, 61.9 g of carbonyldiimidazole and 1.0 L of acetonitrile were added to a flask, and then stirred at room temperature for 1 hour. 59.8 g of methyl potassium malonate, 36.4 g of anhydrous magnesium chloride, 1.0 L of acetonitrile and 38.8 g of triethylamine were added to another flask and then stirred at 20 to 30° C. for 1 hour. The reactants of the two flasks were mixed and refluxed at an external temperature of 80° C. for 1 hour to complete the reaction. After cooling to room temperature, purified water was added. After cooling the internal temperature to 5 to 10° C., stirring was carried out for 1 hour. The obtained solid was filtered under reduced pressure and washed with purified water. Since the obtained crystal is a magnesium salt, the following salt dissociation process was carried out.
- The magnesium salt prepared above, 1.5 L of ethyl acetate and 1.0 L of purified water were added to a flask and stirred for 10 minutes. The pH was adjusted to 7.0 using 6N—HCl. The organic layer was extracted, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at 45° C. to prepare 97.3 g of the compound represented by the Chemical Formula 1-4 (yield: 81.4%).
- 1H-NMR (500 MHz, CDCl3): 7.26-7.30; (m, 1H), 6.85-6.92; (m, 2H), 5.83; (s, 1H), 5.64-5.65; (d, 1H), 3.67; (s, 3H), 3.38-3.52; (dd, 2H), 1.41; (s, 9H)
- (Step 4)
- 100.0 g of the compound represented by the Chemical Formula 1-4 prepared in step 3, and 2.0 L of toluene were added to a flask, and then stirred at room temperature for 10 minutes. 104.1 g of N,N-dimethylformamide dimethylacetal was added and stirred at 40° C. for 4 hours to complete the reaction. After concentration under reduced pressure at 45° C., ethyl acetate and purified water were added to the concentrated residue, and then stirred for 10 minutes. The pH was adjusted to 7.0 using 1N—HCl. The organic layer was extracted, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure at 45° C. to produce 79.2 g of the compound represented by the Chemical Formula 1-5 (yield: 77.0%). On the other hand, the compound represented by the Chemical Formula 1-5 was unstable (aerial oxidation occurred), the following step 5 was continuously carried out by an in-situ process.
- 1H-NMR (500 MHz, CDCl3): 7.73 (s, 1H), 7.48; (s, 1H), 7.38-7.43; (q, 1H), 6.83-6.95; (tt, 2H), 3.90; (s, 3H), 1.39; (s, 9H)
- (Step 5)
- 100.0 g of the compound represented by the Chemical Formula 1-5 prepared in step 4, and 1.5 L of acetone were added to a flask, and then stirred at room temperature for 10 minutes. 78.2 g of potassium carbonate, and 42.9 g of dimethyl sulfate were added thereto, and then stirred at 40° C. for 6 hours to complete the reaction. After cooling to room temperature, purified water and ethyl acetate were added and stirred for 10 minutes. The pH was adjusted to 7.0 using 6N-HCl. The organic layer was extracted, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure at 45° C. to obtain 90.6 g of the compound represented by the Chemical Formula 1-6 (yield: 87.1%). Then, the following step 6 was carried out by an in-situ process without further purification.
- 1H-NMR (500 MHz, CDCl3): 7.87; (s, 1H), 7.31-7.36; (q, 1H), 6.84-6.95; (tt, 2H), 3.86; (s, 3H), 3.68; (s, 311), 1.38; (s, 91-1)
- (Step 6)
- 100.0 g of the compound represented by the Chemical Formula 1-6 prepared in step 5, and 500.0 mL of methylene chloride were added to a flask, and then stirred at room temperature for 10 minutes. 310.4 g of trifluoroacetic acid was added and stirred at room temperature for 6 hours to complete the reaction. After cooling to 0 to 5° C., purified water was slowly added at 15° C. or lower. The pH was adjusted to 7.0 using a 50.0% NaOH solution at 15° C. or lower. Ethyl acetate was added and stirred for 10 minutes. The organic layer was extracted and dried over anhydrous magnesium sulfate. The celite washed with ethyl acetate was placed on a filter, and the organic layer was filtered under reduced pressure and then concentrated under reduced pressure at 45° C. Ethyl acetate was added to the concentrated residue and suspended by stirring. n-Hexane was added thereto, the internal temperature was cooled to 0 to 5° C., and the mixture was stirred for 1 hour. The obtained solid was filtered under reduced pressure. The filtrate was washed with n-hexane, and then dried under reduced pressure to obtain 65.5 g of the compound represented by the Chemical Formula 1 (yield: 90.0%).
- 1H-NMR (500 MHz, CDCl3): 8.78; (s, 1H), 8.12; (m, 1H), 7.30; (d, 1H), 6.95; (t, 1H), 6.88; (t, 1H), 3.87; (s, 3H), 3.85; (s, 3H)
-
- The preparation method was carried out as follows in the same manner as in steps 8-1 to 8-3 of Example 8 of Korean. Patent No. 10-1613245.
- (Step 1)
- 2,4-Difluorophenylglycine (Chemical Formula 2-1, 150.0 g, 801.5 mmol), dimethyl 2-(methoxymethylene)malonate (Chemical Formula 2-2, 126.9 g, 728.6 mmol), and sodium acetate (65.8 g, 801.5 mmol) were added to methanol (800.0 ml), and then refluxed at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to remove about 70% of methanol, and then filtered. The resulting solid was dried under reduced pressure to produce 190.0 g of the compound represented by the Chemical Formula 2-3 (yield:
- 79.2%).
- 1H-NMR (500 MHz, CDCl3): 8.02-7.99; (m, 1H), 7.45-7.40; (m, 1H), 7.00-6.95; (m, 2H), 5.16; (s, 1H), 3.74; (s, 3H), 3.76; (s, 3H)
- (Step 2)
- Acetic anhydride (1731.2 ml) and triethylamine (577.1 ml) were added to the compound represented by the Chemical Formula 2-3 (190.0 g, 577.1 mmol) prepared in step 1. The reaction mixture was refluxed at 140° C. for 30 minutes and then cooled to 0° C. To the reaction mixture, ice water (577.1 ml) was added at 0° C., stirred at room temperature for 1 hour and then extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting compound was filtered using a silica gel to remove a solid, and then concentrated under reduced pressure to prepare the compound represented by the Chemical Formula 2-4, which was then used in the following step 3.
- (Step 3)
- Tetrahydrofuran (140.0 ml) and water (120.0 ml) were added to the resulting residue, cooled to 0° C., followed by addition of sodium hydroxide (46.17 g, 1154.2 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, neutralized using IN hydrochloric acid aqueous solution and then extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane =1:4 (v/v)) to produce 22.0 g of the compound represented by the Chemical Formula 2-5 (yield: 15.1%) (including steps 2 and 3).
- 1H-NMR (500 MHz, CDCl3): 8.80; (s, 1H), 8.17-8.12; (m, 2H), 7.13; (d, 1H), 6.95; (t, 1H), 6.86-6.83; (m, 1H), 3.88; (s, 3H)
- (Step 4)
- The compound represented by the Chemical Formula 2-5 (22.0 g, 86.9 mmol) prepared in step 3 was dissolved in tetrahydrofuran (434.5 ml) and methanol (173.9 ml). (Trimethylsilyl)diazomethane (2.0M diethyl ether solution, 173.8 ml) was added to the reaction mixture and then stirred at room temperature for 48 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane=1:4 (v/v)) to produce 18.1 g of the compound represented by the Chemical Formula 1 (yield: 75.3%).
- 1H-NMR (500 MHz, CDCl3): 8.78; (s, 1H), 8.12; (m, 1H), 7.30; (d, 1H), 6.95; (t, 1H), 6.88; (t, 1H), 3.87; (s, 3H), 3.85; (s, 3H)
- The yields of the preparation methods of the Example and Comparative Example are shown in Table 1 below.
-
TABLE 1 Example Comparative Example Total yield 28.8% 9.0% Total yield from 2,4-ditluoroph- 48.4% 9.0% enylglycine to Chemical Formula I - As shown Table 1, it was confirmed that the Example according to the present invention could not only reduce the production cost by using inexpensive aldehyde as a starting material but also improve the yield by about 5.4 times as compared with the Comparative Example.
- In particular, both step 2 of Example according to the present invention and step 1 of Comparative Example used 2,4-difluorophenylglycine as a starting material. Comparing the methods for preparing the compound represented by the Chemical Formula 1 from the above step, Example according to the present invention showed a yield of about 50%, whereas Comparative Example showed a yield of 9%, thereby confirming that the yield according to the present invention was remarkably improved.
- In addition, in Example according to the present invention, the relatively low temperature was applied in the entire steps, whereas in step 2 of Comparative Example, the reaction temperature of about 140° C. was applied. Thus, the preparation method according to the present invention has an advantage that a relatively low reaction temperature can be applied. Furthermore, step 4 of Comparative Example used (trimethylsilyl)diazomethane which is an explosive reaction material, whereas Example according to the present invention has the advantage that such a reactant was not used.
Claims (17)
1. A method for preparing a compound represented by the following Chemical Formula 1, comprising the steps of:
1) reacting a compound represented by the following Chemical Formula 1-1 with ammonium chloride, and sodium cyanide, or potassium cyanide, followed by reaction with an acid to prepare a compound represented by the following Chemical Formula 1-2;
2) protecting a compound represented by the following Chemical Formula 1-2 with an amine protecting group (P) to prepare a compound represented by the following Chemical Formula 1-3;
3) reacting a compound represented by the following Chemical Formula 1-3 with (i) methylpotassium malonate, or methylsodium malonate, (ii) carbonyldiimidazole, and (iii) magnesium halide, followed by reaction with an acid to prepare a compound represented by the following Chemical Formula 1-4;
4) reacting a compound represented by the following Chemical Formula 1-4 with N,N-dimethylformamide dimethylacetal to prepare a compound represented by the following Chemical Formula 1-5;
5) reacting a compound represented by the following Chemical Formula 1-5 with dimethyl sulfate to prepare a compound represented by the following Chemical Formula 1-6; and
6) reacting a compound represented by the following Chemical Formula 1-6 with an acid to prepare a compound represented by the following Chemical Formula 1:
2. The method according to claim 1 , wherein
in the step 1, the molar ratio of the compound represented by the Chemical Formula 1-1 to ammonium chloride is 10: 1 to 1:10, and
the molar ratio of the compound represented by the Chemical Formula 1-1 to sodium cyanide or potassium cyanide is 10:1 to 1:10.
3. The method according to claim 1 , wherein
in the step 1, the reaction with the compound represented by the Chemical Formula 1-1, ammonium chloride, and sodium cyanide or potassium cyanide is carried out at 0 to 40° C., and the reaction with an acid is carried out at 80 to 120° C.
4. The method according to claim 1 , wherein
the acid in the step 1 is acetic acid or hydrochloric acid.
5. The method according to claim 1 , wherein,
the amine protecting group (P) in the step 2 is tert-butoxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), Tosyl, or Acyl.
6. The method according to claim 1 , wherein
the reaction of the step 2 is carried out at 10 to 40° C.
7. The method according to claim 1 , wherein
the magnesium halide in the step 3 is magnesium chloride or magnesium bromide.
8. The method according to claim 1 , wherein
in the step 3, the molar ratio of the compound represented by the Chemical Formula 1-3 to methylpotassium malonate or methylsodium malonate is 10:1 to 1:10,
the molar ratio of the compound represented by the Chemical Formula 1-3 to carbonyldiimidazole is 10:1 to 1:10, and
the molar ratio of the compound represented by the Chemical Formula 1-3 to the magnesium halide is 10:1 to 1:10.
9. The method according to claim 1 , wherein
the acid in the step 3 is hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid.
10. The method according to claim 1 , wherein
the reaction between the compound represented by the Chemical. Formula 1-3 and (i) methylpotassium malonate or methylsodium malonate, (ii) carbonyldiimidazole, and (iii) magnesium halide in the step 3 is carried out at 50 to 100° C., and the reaction with the acid is carried out at 0 to 40° C.
11. The method according to claim 1 , wherein
the molar ratio of the compound represented by the Chemical Formula 1-4 to N,N-dimethylformamide dimethylacetal in the step 4 is 1:1 to 1:10.
12. The method according to claim 1 , wherein
the reaction of the step 4 is carried out at 20 to 70° C.
13. The method according to claim 1 , wherein
the molar ratio of the compound represented by the Chemical Formula 1-5 to dimethylsulfate in the step 5 is 10:1 to 1:10.
14. The method according to claim 1 , wherein
the reaction of the step 5 is carried out at 20 to 60° C.
15. The method according to claim 1 , wherein
the molar ratio of the compound represented by the Chemical Formula 1-6 to trifluoroacetic acid in the step 6 is 1:1 to 1:30.
16. The method according to claim 1 , wherein
the reaction of the step 6 is carried out at 10 to 40° C.
17. The method according to claim 1 , wherein
the acid of the step 6 is trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid.
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