CN1989114A - 3-(4-哌啶基)-2,3,4,5-四氢-1,3-苯并二氮杂䓬-2(1h)-酮的制备方法 - Google Patents
3-(4-哌啶基)-2,3,4,5-四氢-1,3-苯并二氮杂䓬-2(1h)-酮的制备方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 4
- USOSUQZREODCRK-UHFFFAOYSA-N 3-piperidin-4-yl-4,5-dihydro-1h-1,3-benzodiazepin-2-one Chemical compound O=C1NC2=CC=CC=C2CCN1C1CCNCC1 USOSUQZREODCRK-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- 239000000725 suspension Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- YUBDLZGUSSWQSS-UHFFFAOYSA-N 1-benzylpiperidin-4-amine Chemical class C1CC(N)CCN1CC1=CC=CC=C1 YUBDLZGUSSWQSS-UHFFFAOYSA-N 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 4
- TZOIMAXWWXASDX-UHFFFAOYSA-N n-(1-benzylpiperidin-4-yl)-2-(2-nitrophenyl)acetamide Chemical class [O-][N+](=O)C1=CC=CC=C1CC(=O)NC1CCN(CC=2C=CC=CC=2)CC1 TZOIMAXWWXASDX-UHFFFAOYSA-N 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- MRCKRGSNLOHYRA-UHFFFAOYSA-N (2-nitrophenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1[N+]([O-])=O MRCKRGSNLOHYRA-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical class Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000005336 cracking Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003495 polar organic solvent Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical class NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims 1
- 238000007865 diluting Methods 0.000 claims 1
- 229940127597 CGRP antagonist Drugs 0.000 abstract description 2
- 208000019695 Migraine disease Diseases 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 206010027599 migraine Diseases 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- 239000000203 mixture Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- -1 N-methylpyrrole pyridine ketone Chemical class 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- FWARNCMTCYKUBS-UHFFFAOYSA-N ethyl n-(ethoxycarbonylcarbamoyl)carbamate Chemical compound CCOC(=O)NC(=O)NC(=O)OCC FWARNCMTCYKUBS-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000003735 calcitonin gene related peptide receptor antagonist Substances 0.000 description 1
- LUULLKSXBMRSPR-UHFFFAOYSA-N chloro(trimethyl)silane Chemical compound C[Si](C)(C)Cl.C[Si](C)(C)Cl LUULLKSXBMRSPR-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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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
- C07D401/04—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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明是关于一种制备式(I)的化合物3-(4-哌啶基)-2,3,4,5-四氢-1,3-苯并二氮杂䓬-2(1H)-酮的方法,发现该化合物是尤其适用于口服治疗偏头痛的CGRP-拮抗剂的结构元素。
Description
发明所属的技术领域
本发明是关于一种制备式(I)的化合物3-(4-哌啶基)-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮的方法,
可发现该化合物在主要适用于口服治疗偏头痛的CGRP拮抗剂中作为结构元素(structural element)。
国际专利申请案PCT/EP97/04862、PCT/EP 00/02004、PCT/EP 00/13236、PCT/EP 03/02417、PCT/EP 03/11762及PCT/EP 03/11763中描述含有作为结构元素的式(I)化合物并具有CGRP-拮抗特性的化合物的实例。
可使用2-硝基苯基乙酸作为式(I)化合物的起始物质。在第一步骤中,在至少1当量,优选1.1至1.5当量,尤其优选1.1当量诸如羰基二咪唑、羰基二(三唑)、正丙基膦酸酐、二环己基碳二亚胺、亚硫酰氯、四氟硼酸O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲_(TBTU)或1-乙基-3-(3’-二甲氨基丙基)-碳二亚胺的缩合剂的存在下,使其与4-氨基-N-苯甲基哌啶的等摩尔溶液反应以形成2-硝基-N-[1-(苯甲基)-4-哌啶基]-苯基乙酰胺。适宜溶剂为极性非质子性溶剂,诸如四氢呋喃、二甲氧基乙烷、甲苯、二甲基甲酰胺或N-甲基吡咯啶酮。可(例如)通过用水稀释使产物结晶且通过过滤或离心及干燥加以处理。
在随后的关键步骤中,首先将2-硝基-N-[1-(苯甲基)-4-哌啶基]-苯乙酰胺溶解于诸如(例如)四氢呋喃或二甲氧基乙烷的极性非质子性有机溶剂中,并通过添加至少1当量,优选2.0至4.0当量的还原剂将羰基转化成亚甲基。适宜的还原剂(例如)为硼烷、硼氢化锂或硼氢化钠,任选地添加至少0.5当量,优选2.0至4.0当量的路易斯酸、酸或卤素,例如添加硫酸、三甲基氯硅烷(chlorotrimethylsilane)或碘。可在20至70℃,优选60至70℃的温度下进行该还原作用。
接着在阮尼(Raney)镍催化剂存在下,将因此获得的中间产物N-[2-(2-硝基苯基)乙基]-1-(苯甲基)-4-氨基-哌啶的硝基氢化。对于该氢化作用,将起始物质置于二甲基甲酰胺中,且添加呈水性悬浮液的催化剂。对于该氢化作用而言,有利条件为20至60℃的温度及至多3巴的过氢压(excesshydrogen pressure)。将催化剂过滤出来后,可通过蒸馏该溶剂来浓缩氢化产物。接着通过将因此获得的粗产物添加至至少1当量,优选1.1至1.75当量,尤其优选1.1当量诸如(例如)羰基二咪唑或羰基二(三唑)的缩合剂的悬浮液中来进行环化作用。适宜溶剂为极性非质子性溶剂,诸如四氢呋喃、乙酸乙酯、2-甲基四氢呋喃、二甲基甲酰胺或N-甲基吡咯啶酮。可(例如)通过用水或例如甲醇、乙醇或异丙醇,优选为甲醇的醇稀释来使3-[1-(苯甲基)-4-哌啶基]-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮沉淀,且通过过滤或离心及干燥加以处理。
若需要,可通过添加至少2当量的强酸水溶液使中间产物N-[2-(2-硝基苯基)乙基]-1-(苯甲基)-4-氨基-哌啶以盐的形式沉淀并将其分离。适宜酸的实例为盐酸、氢溴酸或硫酸,尤其为盐酸,因而获得二盐酸盐。为达成此目的,将反应混合物冷却至周围温度并与诸如(例如)甲醇、乙醇或异丙醇,优选为甲醇的醇组合。添加过量的酸水溶液后,再回流该混合物,并接着再次将其冷却。以例如氢氧化锂、氢氧化钠、氨或氢氧化钾的碱的水溶液使该反应混合物呈碱性,并在相分离后,将有机相与过量的酸水溶液组合,由此结晶出所要的盐。接着可通过过滤或离心及干燥处理产物。
在第三步骤中,裂解3-[1-(苯甲基)-4-哌啶基]-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮的苄基保护基。为达成此目的,将起始物质溶解于诸如(例如)甲醇、乙醇、水、丙酮、四氢呋喃、二甲基甲酰胺或丙醇的极性溶剂中,并于加压反应器中将其氢化。可(例如)使用Pd/C或Pd(OH)2作为氢化剂。对于该氢化作用而言的有利条件为40至80℃的温度及至多3巴的过氢压。将催化剂过滤出来后,可通过浓缩溶剂,并随后添加丙酮或水来使氢化产物式(I)的3-(4-哌啶基)-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮结晶,接着将其过滤出来并进行干燥。
实施方式
实施例1:2-硝基-N-[1-(苯甲基)-4-哌啶基]-苯乙酰胺:
于20℃下取11.81kg(72.87mol,1.1当量)1,1-羰基二咪唑(CDI)并添加18L四氢呋喃。接着在15分钟内添加12.00kg(66.24mol,1.0当量)溶解于24L四氢呋喃中的2-硝基苯基乙酸。用9L四氢呋喃冲洗给料容器并将该反应混合物搅拌30分钟(排出气体:CO2)。接着施加300毫巴的真空两次以除去过量CO2。
于20℃下将6L四氢呋喃中的12.61kg(66.24mol,1.0当量)4-氨基-N-苯甲基哌啶添加至该溶液(放热性)。反应混合物添加完之后,于20℃下将所得混合物另搅拌2小时。接着添加144L水,并在添加1/4量的水后,用2-硝基-N-[1-(苯甲基)-4-哌啶基]-苯基乙酰胺培育(inoculate)该溶液。将所得悬浮液冷却至0到5℃并另外搅拌1小时以完成该结晶作用。接着通过离心移除产物,将其用冷的160L水与9L四氢呋喃的混合物洗涤,并于45℃下在惰性化干燥橱中干燥。
产量:18.21kg(为理论产量的77.8%)
根据HPLC的化学纯度:99.8%
实施例2:N-[2-(2-硝基苯基)乙基]-1-(苯甲基)-4-氨基-哌啶二盐酸盐:
将10.00kg(28.29mol,1.0当量)来自实施例1的2-硝基-N-[1-(苯甲基)-4-哌啶基]-苯基乙酰胺置于60L四氢呋喃中并将其加热至60℃。于60至65℃下在15分钟内量入11.06kg(101.84mol,3.6当量)三甲基氯硅烷及14.79kg(67.90mol,2.4当量)10%硼氢化锂于THF中的溶液(排出气体)。将该反应混合物搅拌4小时,接着冷却至20℃并与7L甲醇组合。添加14.80kg(121.65mol,4.3当量)30%工业级盐酸后,将该反应混合物回流搅拌2.5小时,冷却至20℃并用8.38kg(104.67mol,3.7当量)50%工业级氢氧化钠溶液将pH值调节至9.2。分离出水相,组合有机相与6.89kg(56.58mol,2.0当量)30%工业级盐酸(pH值为1.5)并回流搅拌1小时。在3小时内将所得悬浮液冷却至0℃。于0℃下将该混合物搅拌1小时以完成结晶过程。接着通过离心移除产物,将其用20L四氢呋喃洗涤并于50℃下在惰性化干燥橱中干燥。
产量:7.78kg(为理论产量的66.7%)
根据HPLC的化学纯度:99.3%
实施例3:3-[1-(苯甲基)-4-哌啶基]-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮
将10.00kg(24.25mol,1.0当量)来自实施例2的N-[2-(2-硝基苯基)乙基]-1-(苯甲基)-4-氨基-哌啶-二盐酸盐置于甲苯及水各30L中。量入5.82kg(72.75mol,3.0当量)50%工业级氢氧化钠溶液并于50℃下将该两相混合物搅拌1小时。分离出水相,用12L水洗涤有机相并接着在真空中进行蒸发。将残余物与50L甲醇组合。蒸馏出一些所用的甲醇。于50℃下在860g阮尼镍存在下将剩余的溶液氢化。将催化剂过滤出来并用16L甲醇洗涤。将溶剂蒸馏出来并将残余物与30L四氢呋喃组合。将所用四氢呋喃的一半量蒸馏出来并于20℃下在1.5小时内将剩余溶液量入6.88kg(42.44mol,1.75当量)1,1-羰基二咪唑于15L四氢呋喃中的悬浮液中。在此温度下将混合物搅拌1小时。接着添加20L水,培育混合物并另外添加17L水。将所得悬浮液冷却至0℃。于0℃下将该混合物搅拌1.5小时以完成该结晶过程。接着通过离心移除产物,将其用30L水洗涤并于45℃下在惰性化干燥橱中干燥。
产量:6.38kg(为理论产量的78.4%)
根据HPLC的化学纯度:98.5%
实施例4:3-[1-(苯甲基)-4-哌啶基]-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮
将17.00kg(48.10mol,1.0当量)来自实施例1的2-硝基-N-[1-(苯甲基)-4-哌啶基]-苯基乙酰胺悬浮于170L乙二醇二甲醚中并将其冷却至0至5℃。在此温度下,分批添加7.28kg(192.40mol,4.0当量)硼氢化钠及(接着)9.91kg(101.01mol,2.1当量)工业级硫酸于17L乙二醇二甲醚中的溶液。添加结束后,用6.8L乙二醇二甲醚冲洗该混合物。在1小时内将反应混合物加热至70℃且在此温度下搅拌4小时。
冷却到55℃后,量入29L水和11.69kg(96.20mol,2.0当量)30%工业级盐酸的溶液。添加结束后,混合物用5L水冲洗。然后在70℃再继续搅拌1.5小时。然后将反应混合物冷却到20℃并与30.0kg(375.18mol,7.8当量)50%工业级氢氧化钠溶液以及17L水组合。相分离后,真空蒸发有机相得到油,然后其与43L二甲基甲酰胺合并。
将上述得到的溶液从反应器中排出进入容器中并转移入氢化反应器中。将预先与3L二甲基甲酰胺合并三次并倾出的1.35kg阮尼镍催化剂悬浮液悬浮于3L二甲基甲酰胺中,并抽滤。将该混合物在3巴并且内温50℃下氢化,直到没有进一步的氢吸收被检测到。将催化剂滤出并用17L二甲基甲酰胺洗涤。然后真空蒸馏出至少46L溶剂。在这样的蒸馏量后,蒸馏物中的水含量不低于1%,继续蒸馏直到得到所希望的值。
取8.58kg(52.91mol,1.1当量)1,1-羰基二咪唑并且与32L二甲基甲酰胺组合。然后在20℃温度下,在2小时内量入氢化剂溶液(Hydrierl_sung)(来自前述反应步骤)。在30分钟搅拌后,检测反应物以判断反应是否完全。然后加热至50℃,并且在35分钟内量入34L甲醇和136L水的混合物。为了完成结晶,于50℃再加入34L水,并将该悬浮液在1小时内冷却到10℃,并在该温度下搅拌30分钟。接着通过离心移除沉淀物,将其用85L水洗涤并于50℃下在干燥橱中干燥。
产量:12.73kg(为理论产量的78.9%)
根据HPLC的化学纯度:96.0%
实施例5:3-(4-哌啶基)-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮
将10.00kg(29.81mol,1.0当量)来自实施例3的3-[1-(苯甲基)-4-哌啶基]-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮溶解于100L甲醇中,与1.00kg10%Pd/C组合并于70℃及3巴下在加压反应器中将其氢化。氢吸收结束后,将催化剂过滤出来并用30L甲醇洗涤。将滤液在真空中浓缩并将残余物悬浮于100L丙酮中。接着将其回流,于回流下将该悬浮液搅拌15分钟并在常压下蒸馏出一半量的丙酮。蒸馏结束后,将该混合物冷却至0℃并另外搅拌1小时。抽气过滤产物,将其用20L丙酮洗涤并于50℃下干燥。
产量:6.17kg(为理论产量的84.3%)
根据HPLC的化学纯度:99.8%。
Claims (7)
1.一种制备式(I)的化合物的方法
其特征在于:
(a)在缩合剂的存在下,使2-硝基苯基乙酸与4-氨基-N-苯甲基哌啶反应;
(b)通过添加还原剂将所得的2-硝基-N-[1-(苯甲基)-4-哌啶基]-苯基乙酰胺的羰基转化成亚甲基;
(c)在阮尼镍催化剂的存在下将硝基还原后,通过添加缩合剂将所得的中间产物N-[2-(2-硝基苯基)乙基]-1-(苯甲基)-4-氨基-哌啶环化以获得3-[1-(苯甲基)-4-哌啶基]-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮及
(d)通过裂解苄基保护基将3-[1-(苯甲基)-4-哌啶基]-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮转化为式(I)化合物。
2.如权利要求1所述的方法,其特征在于在步骤(a)中,加入呈溶液形式的4-氨基-N-苯甲基哌啶且通过用水稀释使该反应中所获得的产物结晶。
3.如权利要求1所述的方法,其特征在于在步骤(b)中将2-硝基-N-[1-(苯甲基)-4-哌啶基]-苯基乙酰胺溶解于极性非质子性有机溶剂中且于20至70℃的温度下进行该还原作用,任选地添加路易斯酸、酸或卤素。
4.如权利要求1所述的方法,其特征在于步骤(c)中的起始化合物置于二甲基甲酰胺中,加入呈水性悬浮液的该催化剂且于20至60℃的温度及至多3巴的过氢压下进行该氢化作用。
5.如权利要求1所述的方法,其特征在于步骤(d)中的起始物质溶解于极性溶剂中且在添加氢化剂后,于40至80℃的温度及至多3巴的过氢压下在加压反应器中将其氢化。
6.如权利要求1所述的方法,其特征在于通过添加强酸的水溶液使自步骤(b)获得的该中间产物N-[2-(2-硝基苯基)乙基]-1-(苯甲基)-4-氨基-哌啶以盐的形式沉淀并将其分离。
7.如权利要求4所述的方法,其特征在于通过用水及醇稀释来使所得的产物3-[1-(苯甲基)-4-哌啶基]-2,3,4,5-四氢-1,3-苯并二氮杂_-2(1H)-酮沉淀。
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EP04017424A EP1619187A1 (de) | 2004-07-23 | 2004-07-23 | Verfahren zur Herstellung von 3-(4-Piperidinyl)- 2,3,4,5-tetrahydro-1,3-benzodiazepin-2(1H)-on |
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CNA2005800242298A Pending CN1989114A (zh) | 2004-07-23 | 2005-07-16 | 3-(4-哌啶基)-2,3,4,5-四氢-1,3-苯并二氮杂䓬-2(1h)-酮的制备方法 |
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US7473778B2 (en) | 2005-12-24 | 2009-01-06 | Boehringer Ingelheim International Gmbh | 3-(4-piperidinyl)-2,3,4,5-tetrahydro-1,3-benzodiazepin-2(1H)-one |
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EP1773789A1 (de) | 2007-04-18 |
IL180848A0 (en) | 2007-07-04 |
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CA2572811A1 (en) | 2006-02-02 |
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