CN1033581C - 5-氯代羟基吲哚的制备方法 - Google Patents
5-氯代羟基吲哚的制备方法 Download PDFInfo
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- WWJLCYHYLZZXBE-UHFFFAOYSA-N 5-chloro-1,3-dihydroindol-2-one Chemical compound ClC1=CC=C2NC(=O)CC2=C1 WWJLCYHYLZZXBE-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims description 8
- 238000000034 method Methods 0.000 claims abstract description 24
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- -1 monochloroacetic acid alkane ester Chemical class 0.000 claims description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000003610 charcoal Substances 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 229940106681 chloroacetic acid Drugs 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- MVFCKEFYUDZOCX-UHFFFAOYSA-N iron(2+);dinitrate Chemical compound [Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MVFCKEFYUDZOCX-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- MYTGFBZJLDLWQG-UHFFFAOYSA-N 5-chloro-1h-indole Chemical class ClC1=CC=C2NC=CC2=C1 MYTGFBZJLDLWQG-UHFFFAOYSA-N 0.000 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 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- PTXVSDKCUJCCLC-UHFFFAOYSA-N 1-hydroxyindole Chemical compound C1=CC=C2N(O)C=CC2=C1 PTXVSDKCUJCCLC-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- VCRYGHPVKURQMM-UHFFFAOYSA-N methane;platinum Chemical compound C.[Pt] VCRYGHPVKURQMM-UHFFFAOYSA-N 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 239000010970 precious metal Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- CPKMACHMITVCAU-UHFFFAOYSA-N 1-bromo-5-chloro-3h-indol-2-one Chemical class ClC1=CC=C2N(Br)C(=O)CC2=C1 CPKMACHMITVCAU-UHFFFAOYSA-N 0.000 description 1
- PRQZENXGVVLPIF-UHFFFAOYSA-N 1-chloro-3h-indol-2-one Chemical compound C1=CC=C2N(Cl)C(=O)CC2=C1 PRQZENXGVVLPIF-UHFFFAOYSA-N 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- CZGCEKJOLUNIFY-UHFFFAOYSA-N 4-Chloronitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1 CZGCEKJOLUNIFY-UHFFFAOYSA-N 0.000 description 1
- FADJBVVVZBOWCI-UHFFFAOYSA-N C(C)(=O)OCC.ClC1=C(C=CC=C1)[N+](=O)[O-] Chemical compound C(C)(=O)OCC.ClC1=C(C=CC=C1)[N+](=O)[O-] FADJBVVVZBOWCI-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000004690 nonahydrates Chemical class 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940099204 ritalin Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Catalysts (AREA)
Abstract
本专利描述一种从氯硝基苯制备5-氯羟基吲哚的新的方法。第一步骤是在碱存在下将结构式为II的氯硝基苯
与结构通式为III的氯醋酸烷酯，
反应生成氯硝基苯醋酸烷酯，其结构通式为
第二步骤以氢进行催化氢化反应生成相应的胺，其结构通式为
第三步骤再将此产物在一种酸存在下进行环化反应生成最终产品，其结构式为
Description
本发明涉及一种从氯硝基苯制取结构式为I的5-氯代羟基吲哚
的新的方法。
5-氯代羟基吲哚是制造药品的重要的中间产物，例如制造1，3-二取代基的2-羟吲哚(US专利4′721′712)。
至今已知许多制备5-氯代羟基吲哚的方法。例如US专利4′761′485中所述从5-氯代吲哚制取5-氯代羟基吲哚的方法。该法为首先通过吡啶溴化物过溴化物将5-氯代吲哚转化成3，3-二溴-5-氯代羟基吲哚，然后用铂载于炭(钯炭)作催化剂通过催化氢化反应将其转化成5-氯代羟基吲哚。此方法的缺点是离析物(5-氯代吲哚)很难处理，并且5-氯代羟基吲哚的得率也差。
另一个US专利4′730′004描述一种从5-氯靛红制备5-氯代羟基吲哚的方法是先用水合肼将氯靛红转化为5-氯-3-腙-2-羟吲哚，然后再用甲醇钠将其转化为5-氯代羟基吲哚。
这一方法也有缺点，即离析物5-氯靛红较难处理，并且所期望的产物得率也较低。
本发明的任务是提供一种经济效益好又简便的方法制备5-氯代羟基吲哚，产品的得率也好。
此任务是通过用按照本发明的新的方法来解决。
按本发明，此制备结构式为I的5-氯代羟基吲哚
的方法是这样进行的：第一阶段将结构式II的氯硝基苯，为
与结构通式为III的氯醋酸烷酯，其中R表示直链或支链的C1-C7烷基，在碱存在下转化为氯硝基苯醋酸烷酯，结构通式为其中R如前述，然后第二阶段将其用氢进行催化氢化反应生成相应的胺，其结构通式为
其中R为已表示的；第三阶段在一种酸的存在下将其环化成按照结构式I的最终产品。第一步是用结构式II的氯硝基苯，并用结构式III的氯醋酸-C1-C7烷酯进行的。作为氯醋酸-C1-C7烷酯可使用的合适的代表物，其中C1-C7是甲基、乙基、丙基、异丙基、叔丁基或叔戊基。最好C1-C7是一个乙基基团。
氯醋酸-C1-C7-烷酯的用量要过量于氯硝基苯，对于1mol氯硝基苯最好用1.3-1.7mol氯醋酸-C1-C7烷酯。对于这两个反应体可使用非极性溶剂，例如甲苯、乙醚、四氢呋喃或叔丁基甲基醚，最好是使用甲苯。第一阶段是在碱存在下进行的，作为碱可用碱金属氨化物或碱金属氢氧化物。作为碱金属氢氧化物可用氢氧化钠或氢氧化钾。而作为碱金属氨化物则可用氨基钠或氨基钾。
适宜的碱是用液态氨中的碱金属氨化物，最好是氨基钠，它特别是在液态氨中与相应的元素金属在原位上(需要时，在催化剂存在下)形成的。
第一阶段的最佳实施方案是使用在醇存在下(其结构通式为
R-OH VI其中R如前述在原位上形成的碱金属氨化物。作为醇的合适代表，可使用下列一些，其中R代表甲基、乙基、丙基、异丙基、叔丁基或叔戊基，最好是用叔丁基。最好是用等分子的醇和碱金属氨化物。第一阶段的反应温度为-30℃～-40℃。一般在反应0.1-2小时后加入氯化铵，用专业通用的方法分离出氯硝基苯醋酸烷酯，结构式为
第二阶段用氢将氯硝基苯醋酸烷酯(结构式IV)进行催化氢化反应成相应的胺(结构式V)。可以用贵金属、贵金属氧化物或Raney(阮内)镍催化剂作氢化反应的催化剂，需要时可将其置于合适的载体材料上。例如可用阮内镍或铂置于炭上的作氢化反应催化剂。适宜用铂炭作氢反应催化剂。最好用0.5-5重量％铂炭。氢化催化剂的用量相对于氯硝基苯醋酸烷酯为0.1-20重量％，最好用5-10重量％。适宜在加压下进行氢化反应。最好在5-10巴的H2压力下。
第二阶段适宜在非极性溶剂，如甲苯或在极性溶剂中，如醇或酯中进行反应，作为酯可以用醋酸甲酯或醋酸乙酯，作为醇，可以用甲醇、乙醇或丙醇，最好用乙醇。第二阶段的反应在0-55℃温度下进行，最佳反应温度为10-20℃。
一般在反应1-20小时后，或用专业通用的方法分离出胺(结构通式V)，或在去除催化剂后直接用于第三阶段，最佳方案是胺不经分离直接用于第三阶段。在第三阶段胺(结构通式V)在酸存在下环化生成5-氯代羟基吲哚(结构式I)。可以将甲苯-4-磺酸，甲磺酸或其水合物用作酸，最好是用甲苯-4-磺酸或其水合物。酸的用量每克分子胺为0.0005-0.1mol，最佳用量为0.05-0.1mol。第三阶段所用的溶剂同于第二阶段。第三阶段的反应温度为50℃至溶剂回流温度，最佳温度为70℃至溶剂回流温度。
一般在反应1-20小时后，可用专业通用的方法分离出得率较好的5-氯羟基吲哚。实例5-氯羟基吲哚的制备方法
(a)第一步骤
氯硝基苯醋酸乙酯的制备
将250ml NH3放入经干燥的并用氩冲洗过的烧瓶(低温温度为-40℃)内冷凝，加入一小块钠使成蓝色溶液，在加入250mg硝酸铁(III)一九水合物后溶溶即脱色，在15分钟内再加入一小块钠5.75g(250mmol)，接着搅拌10分钟；然后在15分钟内滴加溶于3ml甲苯的叔丁醇18.53g(250mmol)，并搅动35分钟，使成灰色悬浮液。然后再在15分钟内滴入15.76g(100mmol)4-氯硝基苯和18.38g(150mmol)氯醋酸乙酯溶于20ml甲苯的的混合物(反应混合物呈蓝色)，加好后继续搅动1小时，然后小心地加入26.75g(500mmol)固体氯化铵。接着取去干冰冷却器，将悬浮液在约30分钟内加热至10℃(除去NH3)，然后在20分钟内滴加200ml甲苯(低温温度：10℃)，30分钟后将此反应混合物通过一GB-玻璃滤器(带有硅藻土)进行过滤。将滤液用旋转蒸发器，在35℃、25毫巴压力下浓缩，并于高真空状态下干燥30分钟。可得到27.14g产品，含量(HPLC法)：78.8％，相当于得率为87.8％，也即相当于投入离析物量。
(b)氯苯胺醋酸乙酯的制备
将26.73g从第一步骤中得到的粗制品放入135ml乙醇中室温溶解，在加入1.0g Pt/c后将压热器用H2冲洗3次，然后5巴H2加压，并于于室温下搅动7.5小时，接着将反应混合物进行过滤，用25ml乙醇洗涤滤渣。如此得到的滤液直接用于第三步骤处理。
(c)氯代羟基吲哚的制备
给从第二步骤中来的滤液加入1.90g(10mmol)甲苯-4-磺酸-一水合物，接着回流加热30分钟，然后馏去总量为125ml乙醇，其上形成一层悬浮液，反应混合物冷却至室温并过滤，用总共60ml乙醇(3×20ml)洗涤滤渣，接着于35℃和40毫巴压力下干燥12小时。
得到的产品为12.07g玫瑰红-紫色固体物，含量(HPLC)：94.3％，相当于得率为67.9％，也即相当于所投入的氯硝基苯量(第一步骤中)。
Claims (10)
1.结构式为的5-氯代羟基吲哚的制备方法，其特征在于，在第一步骤中将结构式为II的氯硝基苯
与结构通式为III的氯醋酸烷酯，
其中R表示直链或支键的C1-C7烷基，在碱存在下反应生成氯硝基苯醋酸烷酯，其结构通式为其中R如前述，第二步骤将此产物用氢进行催化氢化反应生成相应的胺，结构通式为其中R如前述，然后进行第三步骤，将此产物在酸存在条件下环化生成如结构式I的最终产品。
2.按照权利要求1所述的方法，其特征在于，在第一步骤中用液态氨中的碱金属氨化物作碱。
3.按照权利要求2所述的方法，其特征在于，在第一步骤中，在醇存在下，其结构通式为
R-OH VI其中R如前述，使用碱金属氨化物。
4.按照权利要求3所述的方法，其特征在于，在第一步骤中用叔丁醇作为醇，用氨基钠作碱金属氨化物。
5.按照权利要求1所述的方法，其特征在于，在第一步骤中所进行反应的温度为-30～-40℃。
6.按照权利要求1所述的方法，其特征在于，在第二步骤中使用铂载于炭上作氢化催化剂。
7.按照权利要求1所述的方法，其特征在于，在第二步骤中进行氢化反应的压力为5-10巴，温度为0-55℃。
8.按照权利要求1所述的方法，其特征在于，在第三步骤中用甲苯-4-磺酸，甲磺酸或其水合物作为酸。
9.按照权利要求1所述的方法，其特征在于，第三步骤中的环化反应在温度为50℃至回流温度下进行。
10.按照权利要求1所述的方法，其特征在于，反应时不分离结构式为V的胺。
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| US5679799A (en) * | 1994-11-04 | 1997-10-21 | K-I Chemical Industry Co., Ltd. | Method for producing oxyindoles |
| US6469181B1 (en) | 1995-01-30 | 2002-10-22 | Catalytica, Inc. | Process for preparing 2-oxindoles and N-hydroxy-2-oxindoles |
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| US4060626A (en) * | 1972-01-26 | 1977-11-29 | Boehringer Mannheim G.M.B.H. | Indole-carboxylic carbon compounds and pharmaceutical compositions containing them |
| US4160032A (en) * | 1973-11-21 | 1979-07-03 | Sandoz, Inc. | Oxindoles as sleep-inducers |
| US3882236A (en) * | 1973-12-26 | 1975-05-06 | Lilly Co Eli | Pharmaceutical compositions containing substituted 2-oxo-indolines and the use thereof to treat anxiety and tension |
| US4476315A (en) * | 1982-04-30 | 1984-10-09 | Ethyl Corporation | Nucleophilic substitution process |
| US4721712A (en) * | 1984-06-12 | 1988-01-26 | Pfizer Inc. | 1,3-disubstituted 2-oxindoles as analgesic and anti-inflammatory agents |
| US4659862A (en) * | 1984-05-03 | 1987-04-21 | E. I. Du Pont De Nemours And Company | Process of preparing nitrodihydroaryl carbonyl compounds |
| US4730004A (en) * | 1986-01-22 | 1988-03-08 | Pfizer Inc. | Analgesic and anti-inflammatory 1-acyl-2-oxindole-3-carboxamides |
| US4761485A (en) * | 1987-03-11 | 1988-08-02 | Pfizer Inc. | Synthetic method for indol-2(3H)-ones |
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