TWI430999B - 有機化合物之合成方法 - Google Patents
有機化合物之合成方法 Download PDFInfo
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- TWI430999B TWI430999B TW095120302A TW95120302A TWI430999B TW I430999 B TWI430999 B TW I430999B TW 095120302 A TW095120302 A TW 095120302A TW 95120302 A TW95120302 A TW 95120302A TW I430999 B TWI430999 B TW I430999B
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- group
- lower alkyl
- phenyl
- compound
- methyl
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- 238000000034 method Methods 0.000 title claims description 19
- 230000015572 biosynthetic process Effects 0.000 title description 5
- 238000003786 synthesis reaction Methods 0.000 title description 5
- 150000002894 organic compounds Chemical class 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 19
- -1 5-(4-methyl-1 H -imidazol-1-yl)-3-(trifluoromethyl)-phenyl Chemical group 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- WWTGXYAJVXKEKL-UHFFFAOYSA-N 3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)aniline Chemical compound C1=NC(C)=CN1C1=CC(N)=CC(C(F)(F)F)=C1 WWTGXYAJVXKEKL-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- NESWUFFSSGAALZ-UHFFFAOYSA-N N-decyl-10,10-dimethylundecan-1-amine Chemical compound CC(CCCCCCCCCNCCCCCCCCCC)(C)C NESWUFFSSGAALZ-UHFFFAOYSA-N 0.000 claims 1
- JGFFTJDJHXLDNJ-UHFFFAOYSA-L [O-]OOO[O-].[K+].[K+] Chemical compound [O-]OOO[O-].[K+].[K+] JGFFTJDJHXLDNJ-UHFFFAOYSA-L 0.000 claims 1
- 238000005815 base catalysis Methods 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 description 11
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- TUTXBKLGUMBWGR-UHFFFAOYSA-N CC(CCCCCCCCCN(CCCCCCCCCC)CCCCCCCCCC(C)(C)C)(C)C Chemical compound CC(CCCCCCCCCN(CCCCCCCCCC)CCCCCCCCCC(C)(C)C)(C)C TUTXBKLGUMBWGR-UHFFFAOYSA-N 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical group NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- DYVOLUUJJDFBFC-UHFFFAOYSA-N tripotassium butan-1-olate Chemical compound [K+].[K+].[K+].CCCC[O-].CCCC[O-].CCCC[O-] DYVOLUUJJDFBFC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07D401/14—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 three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Steroid Compounds (AREA)
Description
本發明提供一種製備式(I)化合物之新穎方法：
其中R1係單或多取代芳基；R2係氫、低碳烷基或芳基；且R4係氫、低碳烷基或鹵素。
式(I)之化合物已在W.Breitenstein等人於2004年1月15日公開之WO 04/005281中揭示，該案之揭示內容以引用之方式併入。式(I)之較佳化合物係4－甲基－3－[[4－(3－吡啶基)－2－嘧啶基]胺基]－N
－[5－(4－甲基－1H
－咪唑－1－基)－3－(三氟甲基)苯基]苯甲醯胺(Ia)。式(I)之化合物已顯示能抑制一或多種酪胺酸激酶，諸如c－Abl、Bcr－Abl；受體酪胺酸激酶PDGF－R、Flt3、VEGF－R、EGF－R及c－Kit。同樣，式(I)之化合物可用於治療某些贅生性疾病，諸如白血病。
如流程1所示，式(I)(且特定言之(Ia))之化合物之先前合成包括將乙基酯水解為羧酸，接著使其與苯胺反應，且採用二乙基氰基膦酸酯作為偶合劑。
該方法產生低且不一致之產率。此外，二乙基氰基膦酸酯係一種昂貴的試劑。因此，需要一種廉價、一致。有效的且以高產率生產化合物(I)的替代性方法。
本發明之一目標係提供一種以高且一致之產率有效製備式(I)之化合物的替代性方法。
本發明之另一目標係自較低成本之試劑製備式(I)之化合物。
本發明之又一目標係提供一種採用較安全之試劑製備式(I)之化合物的方法。
本發明克服流程1所述之先前合成中所遇到的問題且通常產生自54－86%之提高之總產率。
本發明提供一種製備式(I)之化合物的新穎方法：
其包含以下反應：
其中R1係經取代或未經取代芳基；R2係氫、低碳烷基或芳基；R4係氫、低碳烷基或鹵素；且R3係低碳烷基、苯基、苯基－低碳烷基或經取代苯基。
酯(II
)與苯胺(IV
)之直接縮合藉由如第三丁氧化鉀之鹼催化以製備式(I)之化合物。該方法在－50℃至50℃之間的溫度下在四氫呋喃、二甲基甲醯胺、甲苯或N
－甲基吡咯啶酮之有機溶劑中進行。
本發明之通用反應流程可如下說明：
其中R1係經取代或未經取代芳基；R2係氫、低碳烷基或芳基；R4係氫、低碳烷基或鹵素；且R3係低碳烷基、苯基、苯基－低碳烷基或經取代苯基。
酯(II
)與苯胺(IV
)之直接縮合可藉由諸如第三丁氧化鉀之強鹼催化以在不進行任何層析或再結晶的情況下製備高產率及高純度之式(I)之化合物，。亦可使用其他鹼，諸如金屬氫化物、大烷基鋰(bulky alkyl lithium)、金屬醇鹽、金屬雙(三甲基矽烷基)醯胺或二烷基醯胺鋰。該金屬可係鋰、鈉或鉀。該方法在－50℃至50℃之間的溫度下在四氫呋喃、二甲基甲醯胺、甲苯或N
－甲基吡咯啶酮之有機溶劑中進行。
在一較佳實施例中，該方法包含以下反應：
其中R3係低碳烷基、苯基、苯基－低碳烷基或經取代苯基。
式(IVa
)之化合物可採用美國專利申請案第SN 60/688,920與SN 60/688,976號中揭示之方法製備，兩案之標題皆為"Process for the Synthesis of Organic Compounds"，與此同時提出申請專利。彼等申請案之揭示內容以引用的方式併入本文中。
在最佳實施例中，該方法包含以下反應：
如在本申請案中所用，除本文另外特別規定外，以下各術語均應具以下所述之涵義。
低碳烷基包含1－6碳原子，且係直鏈或支鏈的，較佳低碳烷基部分係丁基，諸如正丁基、第二丁基、異丁基、第三丁基；丙基，諸如正丙基或異丙基；乙基或甲基。尤其較佳之低碳烷基部分係甲基、乙基、正丙基或第三丁基。
芳基係經由位於該基團之芳族環碳原子的鍵與分子結合的芳族基團。在一較佳實施例中，芳基係具6－14個碳原子之芳族基團，尤其為苯基、萘基、四氫萘基、茀基或菲基，且其未經取代或經一或多個、較佳多達三個、尤其一或兩個取代基取代，其中該等取代基係包含一、二、三個環氮原子、一個氧原子或一個硫原子之雜環基團；芳基上之其他取代基包括雙取代之胺基、鹵素、低碳烷基、經取代低碳烷基、低碳烯基、低碳炔基、苯基、醚化羥基、酯化羥基、硝基、氰基、羧基、酯化羧基、烷醯基、苯甲醯基、胺甲醯基，N
－單或N,N
－雙取代胺甲醯基、甲脒基、胍基、脲基、巰基、磺酸基、低碳烷硫基、苯硫基、苯基－低碳烷硫基、低碳烷基苯硫基、低碳烷基亞磺醯基、苯基亞磺醯基、苯基－低碳烷基亞磺醯基、低碳烷基苯基亞磺醯基、低碳烷基磺醯基、苯基磺醯基、苯基－低碳烷基磺醯基、低碳烷基苯基磺醯基、鹵素－低碳烷基巰基、鹵素－低碳烷基磺醯基(諸如尤其為三氟甲磺醯基)、雜環基、單或雙環雜芳基或在環之相鄰C－原子處結合之低碳伸烷基二氧基，諸如亞甲基二氧基。根據較佳實施例，芳基係苯基、萘基或四氫萘基，在各情況下，其未經取代或獨立地經一或兩個選自由以下各基團組成之群的取代基取代：鹵素，尤其為氟、氯或溴；藉由例如甲基之低碳烷基、例如三氟甲基之鹵素－低碳烷基或苯基醚化之羥基；結合至兩個相鄰C－原子之低碳伸烷基二氧基，例如亞甲基二氧基；低碳烷基，例如甲基或丙基；鹵素－低碳烷基，例如三氟甲基；羥基－低碳烷基，例如羥甲基或2－羥基－2－丙基；低碳烷氧基－低碳烷基，例如甲氧基甲基或2－甲氧基乙基；低碳烷氧基羰基－低碳烷基，例如甲氧基－羰基甲基；低碳炔基，諸如1－丙炔基；酯化羧基，尤其為低碳烷氧基羰基，例如甲氧基羰基、正丙氧基羰基或異丙氧基羰基；N
－單取代胺甲醯基，詳言之經例如甲基、正丙基或異丙基之低碳烷基單取代之胺甲醯基；二－低碳烷胺基，例如二甲胺基或二乙胺基；低碳伸烷基－胺基，例如吡咯啶酮基或哌啶基；低碳氧雜伸烷基－胺基，例如嗎啉基；低碳氮雜伸烷基－胺基，例如哌嗪基、例如乙醯胺基或苯甲醯胺基之醯胺基；低碳烷基磺醯基，例如甲基磺醯基、胺磺醯基及苯基磺醯基。
鹵素係氟、氯、溴或碘，尤其為氟、氯或溴。
以下實例更特定地說明本發明，而並非以任何方式限制本發明。
式(Ia)之化合物的合成
在氮氣氛下於23℃向裝有機械攪拌器、溫度感應器、回流冷凝器、加料漏斗及氮氣出入口之1－L燒瓶中饋入化合物(IIc
)(16 g)、(IVa
)(12 g)及THF(300 ml)。在23℃下將混合物攪拌15分鐘且冷卻至－20℃至－15℃。在－20℃至－10℃下添加1 M第三丁氧化鉀於THF(275 ml)中之溶液。添加之後，將混合物溫至18－23℃。當根據HPLC指示反應完成時，將混合物冷卻至5℃。將15%氯化鈉水溶液(500 ml)添加至混合物中，保持溫度在15℃以下。將產物萃取至乙酸異丙酯(500 ml)中且依次用15%氯化鈉水溶液(500 ml)及水(500 ml)洗滌。在大氣壓下75－85℃之內部溫度下將有機相蒸餾直至殘餘體積為約200 ml。將所得懸浮液冷卻至70±5℃且饋入乙醇(250 ml)及水(30 ml)。將混合物加熱至回流(78℃)歷時1小時且接著將其冷卻至－10℃至－15℃。在－10℃至－15℃下將懸浮液另外攪拌30分鐘。藉由過濾收集所有固體，將其用冷(5℃)乙醇(85 ml)沖洗且在真空(10－20托)中55－60℃下在氮氣排放(8~16小時)的情況下進行乾燥以獲得白色固體狀之AMN107(17.4 g，產量67%)。
1
H NMR(300 MHz,DMSO－d6
),δ 10.5(s,1H),9.15(s,1H),9.05(s,1H),8.60(s,1H),8.45(d,1H),8.35(d,1H),8.22(d,2H),8.10(d,2H),7.65(m,2H),7.45(m,4H),2.25(s,3H),2.05(s,3H)。
Claims (5)
- 一種用於製備式(I)之化合物的方法，
- 如請求項1之方法，其中R4係甲基。
- 如請求項1或2之方法，其中該金屬係選自由鋰、鈉及鉀組成之群。
- 如請求項1或2之方法，其中該鹼係第三丁氧化鉀。
- 如請求項1或2之方法，其中該有機溶劑係選自由四氫呋喃、二甲基甲醯胺、甲苯及N -甲基吡咯啶酮組成之群。
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