TW201726648A - 製備４－（（６－（２－（２，４－二氟苯基）－１，１－二氟－２－羥基－３－（１ｈ－１，２，４－三唑－１－基）丙基）吡啶－３－基）氧基）苄腈之方法 - Google Patents
製備４－（（６－（２－（２，４－二氟苯基）－１，１－二氟－２－羥基－３－（１ｈ－１，２，４－三唑－１－基）丙基）吡啶－３－基）氧基）苄腈之方法 Download PDFInfo
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- difluorophenyl
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- 238000000034 method Methods 0.000 title claims abstract description 25
- JTCSEWBIRWUSAV-UHFFFAOYSA-N 4-[6-[2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1,2,4-triazol-1-yl)propyl]pyridin-3-yl]oxybenzonitrile Chemical compound FC1=C(C=CC(=C1)F)C(C(F)(F)C1=CC=C(C=N1)OC1=CC=C(C#N)C=C1)(CN1N=CN=C1)O JTCSEWBIRWUSAV-UHFFFAOYSA-N 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 18
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- GOTIICCWNAPLMN-UHFFFAOYSA-M trimethylsulfanium;bromide Chemical compound [Br-].C[S+](C)C GOTIICCWNAPLMN-UHFFFAOYSA-M 0.000 claims description 4
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- HQFQTTNMBUPQAY-UHFFFAOYSA-N cyclobutylhydrazine Chemical compound NNC1CCC1 HQFQTTNMBUPQAY-UHFFFAOYSA-N 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 claims description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 2
- HDBQZGJWHMCXIL-UHFFFAOYSA-N 3,7-dihydropurine-2-thione Chemical compound SC1=NC=C2NC=NC2=N1 HDBQZGJWHMCXIL-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
- SWBZRDVTDARPHO-UHFFFAOYSA-N 4-[6-[2-(2,4-difluorophenyl)-1,1-difluoro-2-oxoethyl]pyridin-3-yl]oxybenzonitrile Chemical compound FC1=CC(F)=CC=C1C(=O)C(F)(F)C(N=C1)=CC=C1OC1=CC=C(C#N)C=C1 SWBZRDVTDARPHO-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 150000002118 epoxides Chemical class 0.000 description 3
- 239000000417 fungicide Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- -1 1,1-difluoro-2-oxoethyl Chemical group 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- POYMFKJUYZDXAT-UHFFFAOYSA-N 1-(4-iodophenyl)pyrrolidine Chemical compound C1=CC(I)=CC=C1N1CCCC1 POYMFKJUYZDXAT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940125956 metalloenzyme inhibitor Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KEPJZBFFLDRKSF-UHFFFAOYSA-M trimethylsulfoxonium bromide Chemical compound [Br-].C[S+](C)(C)=O KEPJZBFFLDRKSF-UHFFFAOYSA-M 0.000 description 1
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
- PSZXPGFNGPBEFR-UHFFFAOYSA-N trisodium butan-1-olate Chemical compound [Na+].[Na+].[Na+].CCCC[O-].CCCC[O-].CCCC[O-] PSZXPGFNGPBEFR-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Engineering & Computer Science (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
本發明提供一種用於製備4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羥基-3-(1H-1,2,4-三唑-1-基)丙基)吡啶-3-基)氧基)苄腈之方法。
Description
本申請案主張2015年11月17日申請之美國臨時申請案第62/256,548號之優先權，該申請案之全文以引用的方式併入本文中。
本文提供4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羥基-3-(1H-1,2,4-三唑-1-基)丙基)吡啶-3-基)氧基)苄腈以及其製造方法。
美國發明專利申請案第13/527,387號、第13/527,426號及第13/528,283號尤其描述了某些金屬酶抑制劑化合物及其作為殺真菌劑之用途。每個申請案之揭示內容清楚地以引用的方式併入本文中。此等發明專利申請案各自描述了生成金屬酶抑制殺真菌劑之各種途徑。有利的是提供更
直接且有效的製備金屬酶抑制殺真菌劑及相關化合物之方法，例如，藉由使用提供經改良之時間及成本效率的試劑及/或化學中間體。
本文提供化合物4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羥基-3-(1H-1,2,4-三唑-1-基)丙基)吡啶-3-基)氧基)苄腈(I)以及其製備方法。在一實施例中，本文提供了一種製備式I化合物之方法。
該方法包括將式II化合物與鹵化三烷基硫鎓(trialkylsulfoxonium halide)、鹼及1H-1,2,4-三唑接觸。
術語「鹵素」或「鹵基」係指一或複數個鹵素原子，定義為F、Cl、Br及I。術語「羥基」係指-OH取代基。
術語「有機金屬」係指含有金屬之有機化合物，尤其是其中金屬原子直接鍵結至碳原子之化合物。
室溫(room temperature；RT)在本文中定義為約20℃至約25℃。
在整篇揭示內容中，提及式I化合物亦視為包括光學異構體(isomer)及鹽。具體言之，當式I化合物含有掌性碳時，應當理解該種化合物包括其光學異構體及外消旋體。示例性鹽可包括：鹽酸鹽、氫溴酸鹽、氫碘酸鹽及其類似物。
在此文件中揭示之某些化合物可以一或複數種異構體形式存在。熟習此項技術者應當理解一種異構體可比其他的異構體更有活性。為清楚起見，本揭示內容中所揭示之結構僅以一種幾何形式繪出，但旨在表示分子之所有幾何及互變異構形式。
上述實施例僅欲作為例示性的，且彼等熟習此項技術者將認識到或將能確定僅使用常規實驗、特定方法、材料及程序之許多等效者即可完成。所有這類等效者均被視為在本發明之範疇內且由隨附申請專利範圍所涵蓋。
本文提供了4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羥基-3-(1H-1,2,4-三唑-1-基)丙基)吡啶-3-基)氧基)苄腈(I)，並且可如實例1中所示由4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-氧代乙基)吡啶-3-基)氧基)苄腈(II)來製備。
實例1：製備4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羥基-3-(1H-1,2,4-三唑-1-基)丙基)吡啶-3-基)氧基)苄腈(I)
方法A：在低於5℃下將碳酸鉀(32.6g，236mmol)饋
入碘化三甲基硫鎓(trimethylsulfoxonium iodide)(26.5g，118mmol)於N-甲基-2-吡咯啶酮(N-methyl-2-pyrrolidone；NMP)(190mL)中的懸浮液中，並且在20℃下攪拌反應2h以得到白色懸浮液。一次性添加4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-氧代乙基)吡啶-3-基)氧基)苄腈(II)(38g，94mmol)，並且在N2下，在35℃下攪拌反應18h，此時高效液相層析(high-performance liquid chromatography；HPLC)分析指示起始物料經充分轉化為環氧化物中間體(Ia)。添加1H-1,2,4-三唑(8.56g，123mmol)，並且在60℃下攪拌反應18h，此時HPLC分析顯示剩餘約10%環氧化物中間體(Ia)。在80℃下進一步攪拌反應1h，此時，HPLC分析指示反應完成。使混合物冷卻至20℃並且傾入冰水(1200mL)中。將所得懸浮液過濾，並且將固體溶於二氯甲烷(dichloromethane；DCM)(1200mL)中。將溶液用鹽水(2×300mL)洗滌並將有機層濃縮至約200mL。將所得溶液藉由使用乙酸乙酯(EtOAc)/己烷作為溶離劑之管柱層析(750g矽石)純化以得到呈淡黃色發泡體之所要產物(39.2g，85%產率)。1H NMR(400MHz,CDCl3)δ 8.36(d,J=2.7Hz,1H),8.15(d,J=1.0Hz,1H),7.74(s,1H),7.73-7.67(m,2H),7.58(dd,J=8.7,0.6Hz,1H),7.51-7.44(m,1H),7.42(dd,J=8.7,2.8Hz,1H),7.15-7.03(m,2H),6.81-6.68(m,2H),6.27(s,1H),5.40(d,J=14.4Hz,1H),4.93-4.82(m,1H)；ESIMS m/z 470.0([M+H]+)。
方法B：向100mL、3頸圓底燒瓶中饋入碘化三甲基硫鎓(0.356g，1.618mmol)及NMP(5mL)。在低於25℃下添加第三丁醇鈉(NaOt-Bu)(0.143g，1.488mmol)，並且在20℃下攪拌反應1h。將反應冷卻至低於-15℃並且添加4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-氧代乙基)吡啶-3-基)氧基)苄腈(II)(0.5g，1.294mmol)。將反應在低於-10℃下攪拌1h，此後HPLC分析指示起始物料經充分轉化為環氧化物中間體(Ia)。添加1H-1,2,4-三唑(0.103g，1.488mmol)及NaOt-Bu(0.143g，1.488mmol)，並且將反應在40℃下加熱6h。將反應冷卻至20℃並且添加水(20mL)。將混合物用EtOAc(2×20mL)萃取。將有機層濃縮至乾燥並且藉由管柱層析(40g矽石，0-60% EtOAc/己烷，經5管柱體積，保持5個體積)純化。濃縮含有純產物之溶離份以得到無色油狀物(400mg，66%產率)。分析數據與先前獲得之樣品的分析數據一致。
方法C：向100mL、3頸圓底燒瓶中饋入溴化三甲基硫鎓(trimethylsulfoxonium bromide)(0.560g，3.24mmol)及NMP(5mL)。在低於25℃下添加K2CO3(1.073g，7.77mmol)，並且在20℃下攪拌反應1h。添加4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-氧代乙基)吡啶-3-基)氧基)苄腈(II)(1.0g，2.59mmol)，並且在20℃下攪拌反應18h，之後HPLC分析指示反應未完成。將其在35℃下進一步攪拌4
h，之後HPLC分析指示起始物料經消耗。添加1H-1,2,4-三唑(0.215,3.11mmol)，並且在20℃下攪拌反應18h，此時HPLC分析指示反應未完成。將其在35℃下進一步加熱4h，並且冷卻至20℃。添加水(20mL)，並且攪拌反應混合物30min以得到黏性沉澱，藉由傾析掉溶劑將其分離。將粗產物藉由管柱層析(40g矽石，0-50% EtOAc/己烷，經10min，保持15min)純化。濃縮含有純產物之溶離份以得到白色發泡體(0.89g，73%產率)。分析數據與先前獲得之樣品的分析數據一致。
方法D：向100mL、3頸圓底燒瓶中饋入氯化三甲基硫鎓(trimethylsulfoxonium chloride)(0.832g，6.48mmol)及NMP(10mL)。在低於25℃下添加K2CO3(2.146g，15.554mmol)，並且在20℃下攪拌反應1h。添加4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-氧代乙基)吡啶-3-基)氧基)苄腈(II)(2.0g，5.18mmol)，並且在20℃下攪拌反應18h，之後HPLC分析指示起始物料經充分消耗。添加1H-1,2,4-三唑(0.43g，6.11mmol)，並且在20℃下攪拌反應18h，此時HPLC分析指示反應完成。添加水(25mL)，並且攪拌反應混合物30min以得到黏性沉澱，藉由傾析掉溶劑將其分離。將粗產物藉由管柱層析(80g矽石，0-50% EtOAc/己烷，經10min，保持15min)純化。濃縮含有純產物之溶離份以得到白色發泡體(1.5g，62%產率)。分析數據與先前獲得之樣品的分析數據一致。
方法E：向夾套設定在25℃下之250mL夾套反應器中添加溴化三甲基硫鎓(6.16g，35.6mmol)、碳酸鉀(11.18g，81mmol)及DMSO(37.5mL)。將漿料攪拌30min，接著添加4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-氧代乙基)吡啶-3-基)氧基)苄腈(II)(12.5g，32.4mmol)並且將夾套加熱至55℃。1h之後，添加1H-1,2,4-三唑(2.458g，35.6mmol)並且在55℃下攪拌混合物5h。使夾套降至25℃並且添加125mL甲基第三丁基醚(methyl tert-butyl ether；MTBE)至反應中，隨後添加125mL水。劇烈地攪拌混合物30min，接著使其沉降。移除水層並且將125mL水添加至有機層中並且將兩者混合15min。添加25mL MTBE及10mL飽和鹽水並且將各層混合2分鐘，隨後使其沉降。將水層自反應器中移除。反應器配備有蒸餾頭並且夾套設定為65℃。將82g溶劑塔頂常壓蒸餾(約115mL)，接著添加甲醇(53g，約70mL)。繼續蒸餾直至塔頂溫度為65℃並且總共130g溶劑已經塔頂蒸餾(約110g MTBE及約20g MeOH；33g甲醇殘留在反應器中)。將夾套冷卻至60℃並且逐滴添加水(3.4g)。隨後將混合物用化合物I接種。緩慢添加額外的水(3.2g)，造成更多固體沉澱。將漿料經4h冷卻至20℃。在20℃下攪拌1h之後，將固體藉由過濾分離並且用母液洗滌反應容器以清除出固體。將固體用2：1甲醇/水w/w(2×10mL)洗滌。將固體風乾至恆重，得到呈棕褐色固體之4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羥基
-3-(1H-1,2,4-三唑-1-基)丙基)吡啶-3-基)氧基)苄腈(I)(10.08g，20.40mmol，63.0%產率)。分析數據與先前獲得之樣品的分析數據一致。
方法F：向夾套設定在25℃下之250mL夾套反應器中添加溴化三甲基硫鎓(6.16g，35.6mmol)、碳酸鉀(11.18g，81mmol)、四氫呋喃(tetrahydrofuran；THF)(62.6mL)及水(12.51mL)。將漿料在25℃下攪拌15min，接著添加4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-氧代乙基)吡啶-3-基)氧基)苄腈(II)(12.5g，32.4mmol)並且將混合物在60℃下攪拌隔夜。將夾套冷卻至25℃，添加水(37.5mL)並且混合各層5min。將水層自反應器中移除。在85℃下的夾套下常壓蒸餾有機層。塔頂蒸餾掉40mL之後，添加37.5mL二甲基亞碸(dimethyl sulfoxide；DMSO)。繼續蒸餾，僅有5mL多的溶劑來到塔頂。將夾套冷卻至55℃，在反應混合物中留下約20mL THF。添加碳酸鉀(11.18g，81mmol)，接著添加1H-1,2,4-三唑(2.458g，35.6mmol)。將反應在55℃下攪拌5h，接著添加MTBE(125mL)及水(125mL)並且混合15min。分離各層。將有機層用125mL水與20mL鹽水之混合物洗滌。將留在夾套反應器中之有機層常壓蒸餾。67g溶劑塔頂蒸餾之後，添加55.7g甲醇並且繼續蒸餾直至多於47g的溶劑來到塔頂。將深棕色溶液冷卻至60℃，接著緩慢添加3.02g水，並且接種混合物。添加額外的8.5g水，得到約3：1甲醇/水w/w。將混合物經2h
冷卻至20℃並且將漿料保持在20℃下隔夜。將所形成之固體藉由過濾分離，用母液洗滌反應器。將固體用3：1甲醇/水w/w(20g)洗滌並且風乾至恆重，得到呈棕褐色固體之4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羥基-3-(1H-1,2,4-三唑-1-基)丙基)吡啶-3-基)氧基)苄腈(I)(11.62g，24.76mmol，77%產率)。1H NMR(400MHz,DMSO-d 6)δ 8.47(d,J=2.7Hz,1H),8.36(s,1H),7.99-7.89(m,2H),7.71(s,1H),7.69(dd,J=8.7,2.8Hz,1H),7.51(d,J=8.7Hz,1H),7.30-7.19(m,3H),7.13(ddd,J=12.0,9.2,2.6Hz,1H),7.05(s,1H),6.88(td,J=8.5,2.6Hz,1H),5.35(d,J=14.6Hz,1H),4.83(d,J=14.6Hz,1H)。19F NMR(376MHz,DMSO-d 6)δ-102.83(td,J=22.5,21.9,9.2Hz),-107.66(dd,J=21.7,13.5Hz),-110.46(d,J=9.4Hz)。ESIMS m/z 470.2[(M+H)+]。
本文所述之製程可在約-20℃至約100℃，或約20℃至約80℃範圍內之溫度下進行。
可使用於本文所述之製程中的溶劑可包括以下中的至少一者：二甲基亞碸(DMSO)、二甲基甲醯胺(dimethylformamide；DMF)、四氫呋喃(THF)、環丁碸、水、及N-甲基-2-吡咯啶酮(NMP)。
可用於本文所述之製程中的鹼可包括金屬碳酸鹽，諸
如碳酸鉀及碳酸鈉；金屬醇鹽，諸如第三丁醇鉀；或金屬碳酸氫鹽，諸如碳酸氫鈉及碳酸氫鉀。
Claims (8)
- 一種製備式I化合物之方法，包括將式II化合物與鹵化三烷基硫鎓、鹼及1H-1,2,4-三唑接觸之步驟：
- 如請求項1所記載之製備式I化合物之方法，其中前述鹵化三烷基硫鎓為以下中之一者：碘化三甲基硫鎓、溴化三甲基硫鎓及氯化三甲基硫鎓。
- 如請求項1所記載之製備式I化合物之方法，其中前述鹼可選自包括以下之群：金屬碳酸鹽、金屬醇鹽及金屬碳酸氫鹽。
- 如請求項1所記載之製備式I化合物之方法，其中前述鹼可為碳酸鉀與第三丁醇鈉中之一者。
- 如請求項1所記載之製備式I化合物之方法，進一步包含溶劑之使用，前述溶劑選自包括以下之群：二甲基亞碸、二甲基甲醯胺、環丁碸、四氫呋喃、水、 N-甲基-2-吡咯啶酮、及其混合物。
- 如請求項1所記載之製備式I化合物之方法，進一步包含溶劑之使用，前述溶劑選自包括以下之群：四氫呋喃、水、二甲基亞碸、及其混合物。
- 如請求項1所記載之製備式I化合物之方法，其中前述接觸在約-20℃至約100℃下進行。
- 如請求項1所記載之製備式I化合物之方法，其中前述接觸在約20℃至約80℃下進行。
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2016
- 2016-11-17 EP EP16867089.1A patent/EP3377480A4/en not_active Withdrawn
- 2016-11-17 TW TW105137625A patent/TWI637948B/zh not_active IP Right Cessation
- 2016-11-17 CA CA3005743A patent/CA3005743A1/en not_active Abandoned
- 2016-11-17 JP JP2018545126A patent/JP2018533635A/ja active Pending
- 2016-11-17 CN CN201680078989.5A patent/CN108473463A/zh active Pending
- 2016-11-17 WO PCT/US2016/062398 patent/WO2017087592A1/en not_active Ceased
- 2016-11-17 KR KR1020187017049A patent/KR20180100313A/ko not_active Withdrawn
- 2016-11-17 BR BR112018009915A patent/BR112018009915A2/pt not_active Application Discontinuation
- 2016-11-17 US US15/776,615 patent/US20180354928A1/en not_active Abandoned
- 2016-11-17 AR ARP160103516A patent/AR106730A1/es unknown
-
2018
- 2018-05-16 IL IL259410A patent/IL259410A/en unknown
- 2018-06-06 ZA ZA2018/03745A patent/ZA201803745B/en unknown
-
2019
- 2019-07-10 US US16/507,443 patent/US20190330185A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20190330185A1 (en) | 2019-10-31 |
| CA3005743A1 (en) | 2017-05-26 |
| EP3377480A4 (en) | 2019-04-10 |
| KR20180100313A (ko) | 2018-09-10 |
| IL259410A (en) | 2018-07-31 |
| ZA201803745B (en) | 2019-03-27 |
| JP2018533635A (ja) | 2018-11-15 |
| BR112018009915A2 (pt) | 2018-11-13 |
| WO2017087592A1 (en) | 2017-05-26 |
| AR106730A1 (es) | 2018-02-14 |
| US20180354928A1 (en) | 2018-12-13 |
| CN108473463A (zh) | 2018-08-31 |
| EP3377480A1 (en) | 2018-09-26 |
| TWI637948B (zh) | 2018-10-11 |
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