CN101970434A - 制备2,3,4,9-四氢-1H-β-咔啉-3-羧酸酯的工艺 - Google Patents
制备2,3,4,9-四氢-1H-β-咔啉-3-羧酸酯的工艺 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 10
- 238000000034 method Methods 0.000 title abstract description 3
- FSNCEEGOMTYXKY-UHFFFAOYSA-N 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid Chemical class N1C2=CC=CC=C2C2=C1CNC(C(=O)O)C2 FSNCEEGOMTYXKY-UHFFFAOYSA-N 0.000 title 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims abstract description 25
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims abstract description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 37
- 238000005516 engineering process Methods 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 229960004799 tryptophan Drugs 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 abstract description 13
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract 1
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- 150000001299 aldehydes Chemical class 0.000 description 8
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- 239000000543 intermediate Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- KCUNTYMNJVXYKZ-SNVBAGLBSA-N methyl (2r)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-SNVBAGLBSA-N 0.000 description 4
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
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- XNFNGGQRDXFYMM-UHFFFAOYSA-N hydron;methyl 2-amino-3-(1h-indol-3-yl)propanoate;chloride Chemical compound [Cl-].C1=CC=C2C(CC([NH3+])C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-UHFFFAOYSA-N 0.000 description 3
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- VGKZBAMIYUHSMU-UHFFFAOYSA-N 4-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylic acid Chemical compound OC(=O)C1CCC(NC(=O)N(CCCl)N=O)CC1 VGKZBAMIYUHSMU-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
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- 125000005599 alkyl carboxylate group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- BFAKENXZKHGIGE-UHFFFAOYSA-N bis(2,3,5,6-tetrafluoro-4-iodophenyl)diazene Chemical compound FC1=C(C(=C(C(=C1F)I)F)F)N=NC1=C(C(=C(C(=C1F)F)I)F)F BFAKENXZKHGIGE-UHFFFAOYSA-N 0.000 description 1
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- 125000005843 halogen group Chemical group 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
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Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及通过一步法由外消旋型色氨酸和/或其对映体以及3,4-(亚甲基二氧)苯甲醛制备通式(I)的1位取代2,3,4,9-四氢-1H-β-咔啉-3-羧酸酯。
Description
技术领域:
本发明涉及合成在1位取代的2,3,4,9-四氢-1H-β-咔啉-3-羧酸酯的工艺。
背景技术:
结构式(I)的化合物
被广泛用于合成例如生物碱和药物的活性成分。最被了解的中间体是顺式非对映异构体形式的2,3,4,9-四氢-1-(3,4-苯并间二氧杂环戊烯基)-β-咔啉-3-羧酸甲酯,其被用于合成药物(6R,12aR)-2,3,6,7,12,12a-esahydro-2-甲基-6-(3,4-亚甲基二氧苯基)-哌嗪-[2′,1′:6,1]吡啶并[3,4-b]吲哚-1,4-二酮,也就是已知的他拉达非。
通式(I)化合物具有两个手性中心,其中在非对称碳原子上的非氢取代基可以是顺式或反式的。已知含有至少一个非对称原子的化合物的生物活性基于其他们的立体异构体而不同,一个立体异构体比另一个更具有活性。
已知通式(I)的适宜的顺式或反式结构产物可以通过由适宜的结构的D或L色氨酸与3,4-(亚甲基二氧)-苯甲醛经皮克特-施彭格勒反应而得,如下面所述:
特别是,已有大量关于合成顺式2,3,4,9-四氢-1-(3,4-苯并间二氧杂环戊烯基)-β-咔啉-3-羧酸甲酯(制备他拉达非的中间体)的描述。
US5859006描述通过D-色氨酸甲酯和3,4-苯并间二氧杂环戊烯基-1-甲醛(胡椒醛)在二氯甲中且存在三氟乙酸条件下反应合成他拉达非及其中间体顺式2,3,4,9-四氢-1-(3,4-苯并间二氧杂环戊烯基)-β-咔啉-3-羧酸甲酯。
在这一情况下,得到所有非对映异构体,其中顺式异构体通过制备色谱与反式异构体分离开。前述工艺色谱分离法具有缺陷,其使用高腐蚀性三氟乙酸,反应时间长(4-5天),顺式异构体产率低(37-42%)。
在专利申请WO2004/011463中,合成他拉达非以及合成顺式2,3,4,9-四氢-1-(3,4-苯并间二氧杂环戊烯基)-β-咔啉-3-羧酸甲酯是通过D-色氨酸甲酯盐酸盐和胡椒醛在无水异丙醇中反应而得。
这一工艺的缺点是使用无水异丙醇而不易于工业化。专利申请WO2005/068464描述的制备工艺中D-色氨酸甲酯和胡椒醛在三氟乙酸存在下在适宜溶剂中缩聚,且有分子筛去吸附反应产生的水。所得顺式和反式非对映异构体由盐酸水溶液处理,顺式异构体盐酸盐在反应介质中沉淀后被分离后再与适宜的反应物反应以得到他拉达非。上述工艺的缺点是使用分子筛,这很难在工业上规模使用,事实上反应分两步走,需要分离中间体。
US6143746描述了一个制备工艺,其中D-色氨酸甲酯和胡椒醛在三氟乙酸在无水二氯甲中缩聚。浓缩溶剂并过滤得到反式异构体。主要含有顺式异构体的母液被进一步浓缩,通过添加作为助溶剂的异丙醚结晶得到顺式异构体。前述工艺的缺点是使用氯化溶剂,强腐蚀性酸三氟乙酸,反应时间长,且通过部分结晶分离。
US 6143757描述一种制备他拉达非的工艺,该工艺起始于D-色氨酸甲酯盐酸盐,通过皮克特-施彭格勒反应,在氯化溶剂(三氟乙酸)的存在下与胡椒醛反应,得到2,3,4,9-四氢-1-(3.4-苯并间二氧杂环戊烯基)-β-咔啉-3-羧酸甲酯,为顺式和反式非对映异构体。顺式结构通过制备色谱被分离,所得非对映异构体与适宜的异氰酸酯反应得到他拉达非。所述工艺的缺点是使用高腐蚀性三氟乙酸,并需要制备色谱分离两种非对映异构体。
专利申请WO2006/110893描述制备他达拉非及其前体(顺式2,3,4.9-四氢-1-(3.4-苯并间二氧杂环戊烯基)-β-咔啉-3-羧酸甲酯)的工艺。后者是通过D-色氨酸甲酯和/或适宜的盐在选自羧酸烷基酯(例如乙酸乙酯)的溶剂中,在三氟乙酸存在下,在室温或50℃长时间反应(7天)而得。然后通过过滤得到顺式非对映异构体,产率波动在32%-75%。所述工艺的缺点在于使用高腐蚀性三氟乙酸已经反应时间长(7天)。
专利申请US2006/0258865描述制备他拉达非及其前体顺式2,3,4,9-四氢-1-(3,4-苯并间二氧杂环戊烯基)-β-咔啉-3-羧酸甲酯的工艺。后者的制备是通过D-色氨酸甲酯盐酸盐与胡椒醛在高沸点疏质子偶极溶剂(例如N,N-二甲基乙酰胺(DMA))在大量脱水剂(例如无水硫酸钠)存在下,加热30-35小时反应而得。所得非对映异构体混合物然后与盐酸水溶液再加热6-10小时以差向异构反式非对映异构体,酸性水溶液有机萃取后顺式异构体通过结晶从甲苯/环己胺混合物中分离出来。所述工艺的缺点是使用高沸点疏质子偶极溶剂,例如DMA,其很难被恢复,以及使用大量的脱水剂,例如硫酸钠,然后与盐酸反应得到顺式异构体,水性酸溶液萃取后结晶化。
Herraiz T.等人在J.Agric.Food Chemistry,2003,51,2168-2173,中提到,L-色氨酸与适宜的醛在硫酸存在下长时间反应(9天)得到相应的四氢-β-咔啉-3-羧酸非对映异构体混合物。这一方法直接起始于氨基酸,所得产物只表现为咔啉-羧酸而非其酯。而且反应需要长时间,无需分离不同非对映异构体。
Lopez-Rodriguez M.等人在J.Org.Chem.1994,59,1583-1585描述了一个工艺用于得到适宜的1位取代的2,3,4,9-四氢-1H-β-咔啉-3-羧酸,工艺是通过L-色氨酸和苯甲醛在稀释的硫酸中反应7小时。这样所得产物是外消旋的,该产物然后用于同异氰酸酯或异硫氰酸酯反应。没有关于从色氨酸得到羧酸酯的报道。
综述,现有技术没有报道任何由单一反应(一锅法反应)得到适宜的1位取代的2,3,4,9-四氢-1H-β-咔啉-3-羧酸酯非对映异构体的教导。事实上,其直接起始于适宜的D-或L-色氨酸酯或者起始于相应的氨基酸,合成停止在1位取代的2,3,4,9-四氢-1H-β-咔啉-3-羧酸。
而且,制备1位取代2,3,4,9-四氢-1H-β-咔啉-3-羧酸酯的不利因素可以总结为反应时间长(数天),需要色谱分离,使用脱水剂(例如分子筛或硫酸钠一类的化学品),分离非对映异构体混合物随后差向异构化以得到所需异构体,使用无水溶剂。
发明内容:
现在发现一个新的工艺用于制得结构式(I)的1位取代的2,3,4,9-四氢-1H-β-咔啉-3-羧酸酯
优选的非对映异构体直接起始于色氨酸(D-、L或外消旋),这是一种易得且不昂贵的氨基酸,通过一锅法反应与3,4-(亚甲基二氧)苯甲醛(胡椒醛)在适宜的醇溶剂中在存在质子酸的情况下反应。在所提及的结构式(I)中,R′代表烷基、环烷基、含杂原子环烷基、芳基、芳烷基、杂芳基或者杂芳烷基取代基。
优选R′中,烷基和芳烷基取代基是C1-C8烷基,C1-C8芳烷基;环烷基取代基是指3-8元环;含杂原子的取代基为含1-3个选自O,N,S原子的4-8元环;而且所有的环取代基可被随意地取代,特别是被C1-C8烷基、羟基、C1-C8烷氧基、硝基和卤素基团取代。
本发明的一个目标是如方案1所示的由一步合成法在酸催化条件下起始于色氨酸(II)合成产物(I)的工艺:
方案1
反应的进行是在适宜的醇溶剂R′OH(提供R′基团)中,在无机质子酸存在下,相对于色氨酸(II)摩尔数所述质子酸的化学计量是过量的。优选所用质子酸相对于色氨酸(II)摩尔数过量可达50%;优选过量5%-30%;更优选过量10%-30%。
方案1中所示工艺中两个反应发生在相同反应器中无需任何中间体分离。第一个是将醛(IV)添加到色氨酸(II)的吲哚环的2位上,然后闭合哌啶环(皮克特-施彭格勒反应);第二个是CO2H基团酯化。
工艺所用的是易得廉价无机酸,在工业上可用且不难处理,这样的酸例如盐酸。
而且该工艺可以制备1位取代的2,3,4,9-四氢-1H-β-咔啉-3-羧酸酯,这是基于优选的非对映异构体通过原位转换非预期的非对映异构体为预期的异构体。
具体实施方式:
在本发明的工艺中,起始材料色氨酸(II)可使用外消旋型、对映体富集型或者纯对映体型(L-或D-)。
色氨酸(II)和化合物(IV)(3,4-(亚甲基二氧)苯甲醛)优选摩尔比为0.8-1.5;更优选的摩尔比是0.9-1.3;再优选的摩尔比是0.9-1.1;最优选摩尔比是1.0。
所述无机质子酸选自盐酸、硫酸、硝酸。盐酸和硫酸为优选;盐酸最优选。盐酸是指浓盐酸水溶液,所述盐酸浓度为30%-37%(%w/w)。浓度33%-37%(%w/w)是优选的;浓度37%(%w/w)更优选。
质子酸(例如盐酸)和色氨酸(II)的摩尔比是1.0-1.5;优选摩尔比是1.05-1.3;更优选摩尔比是1.1-1.2。
溶剂R′OH的选择基于将要引入化合物(I)的取代基R′。非限制性示例包括甲醇、乙醇、正丙醇、异丙醇、正丁醇及其异构体、正戊醇及其异构体、正己醇及其异构体、正庚醇及其异构体、正辛醇及其异构体、环戊醇、环己醇、环庚醇,羟基哌啶、苯基醇,苯甲醇、甲基苯甲醇、4-甲氧苄基醇、3-甲氧苄基醇、2-甲氧苄基醇、4-硝基苄基醇,四氢呋喃甲醇。
甲醇、乙醇、正丙醇、异丙醇、正丁醇、仲丁醇、异丁醇是优选的;甲醇是最优选的。
反应是在溶剂回流温度反应12-36小时,例如24小时。在反应过程中形成水会改变纯溶剂的沸点,所形成的水醇溶液被蒸馏掉,加入新溶剂到反应溶液中,直到溶剂沸点被维持。
在反应结束时,混合物被真空蒸发,进入同一反应器中,恢复外消旋和粗化合物(I)(为固体)。从这一化合物(I),单一纯非对映异构体(顺式和/或反式)可通过色谱或使用其他已知分离非对映异构体系统恢复,如果需要,可在处理前进行适当的差向异构化反应以增加所需形式的非对映异构体的产量。
基于所述优选的差向异构化程序,固体粗化合物(I)由稀释的盐酸水溶液处理,再加热到40℃-70℃(例如50℃-60℃)40-100小时(例如60-80小时)。
所用盐酸摩尔数过量(相对于起始色氨酸(II))5%-50%,优选5%-30%,更优选10%-20%。所得沉淀物是化合物(I)盐酸盐,为顺式非对映异构体结构,过滤分离,由适宜醇或醚溶剂(例如异丙醇或异丙醚)清洗,干燥。
盐酸盐沉淀后的母液中含有残余顺式-化合物(I),剩余的反式化合物(I),少量非酯型同一化合物,以及少量未反应的醛(IV)或色氨酸(I)。这些母液很容易地用已知系统处理后被恢复。
特别的,所述醛(IV)可由有机溶剂,例如乙醚或异丙醚,萃取恢复;通式(I)的化合物可通过与适宜的碱(例如NaHCO3)沉淀恢复;被恢复的化合物可被循环用于随后的皮克特-施彭格勒反应,酯化反应和差向异构化(再循环)以增加所需型式对映体并进一步恢复所需型式对映体的量。
下面给出本发明非限制性示例
实验部分
例1
向D-色氨酸(10.20g;50.0mm)甲醇(45ml)悬浮液中加入HCl 37%(5ml)水溶液。
然后将胡椒醛(7.50g;50.0mm)加入上述所得溶液,在回流温度反应25小时。蒸馏移除溶剂,连续用新鲜甲醇进行替换,体量达到400ml的总蒸馏量。溶剂被蒸发后,HCl 0.3M(183ml)水溶液被加入残留物中,所得溶液被保温在55℃72小时。沉淀物被过滤,由二异丙醚清洗,真空干燥,得到顺式盐酸酯(10.79g;27.82mm),产率为56%。水性溶液由二异丙醚(2x90ml)清洗以恢复未反应的胡椒醛,并由固体NaHCO3(6.80g)中和。所得沉淀被过滤,二异丙醚清洗,真空干燥,得到固体残余(6.18g)。从水层恢复的固体用色谱分析,结果显示如下组分:顺式酯(1.90g;5.41mm);反式酯(1.45g;4.13mm);顺式酸(1.58g;4.68mm);反式酸(1.25g;3.71mm)。
工艺总产率是92%(酯的总产率是:75%;顺式酯总产率是67%)
1H NMR(200MHz,DMSO-d6)δ(ppm):10.84(s,NH,1H),7.54(d,J6.7Hz,1H),7.29(d,J 7.4Hz,1H),7.17-6.99(m,5H),6.10(s,OCH2O,2H),5.87(s br,CHAr1 1H),4.73(s br,CHCO2CH3,1H),3.84(s,CO2CH3,3H),3.38-3.26(m,CH2CHCO2CH3,2H).
13C NMR(50.33MHz,DMSO-d6)δ(ppm):168.5(s),148.5(s),147.1(s),136.7(s),128.9(s),127.0(s),125.4(s),125.0(d),122.0(d),119.2(d),118.2(d),111.6(d),110.4(d),108.3(d),106.3(s),101.5(t),57.6(d),55.2(d),53.0(q),22.2(t).
例2
向例1所述所恢复的固体残余物(6.18g)和D-色氨酸(10.20g;50.0mm)甲醇(61ml)悬浮液中加入HCl 37%(6.6ml)。想所得溶液中加入胡椒醛(7.50g;50.0mm),在回流温度反应25小时。蒸馏移除溶剂,连续用新鲜甲醇进行替换,体量达到680ml的总蒸馏量。溶剂蒸发后向残余物中加入HCl 0.3M(183ml)水溶液,所得溶液被保温在55℃72小时。沉淀物被过滤,二异丙醚清洗,真空干燥,得到顺式盐酸酯(12.90g;33.26mm),产率为66.7%。水溶液由二异丙醚(2x90ml)清洗以恢复未反应胡椒醛,用NaHCO3(9.10g)中和。所得沉淀被过滤,由二异丙醚清洗,真空干燥,得到固体残余物(10.60g)。沉淀物由色谱分析,结果显示如下组分:
顺式酯(2.58g;7.34mm);反式酯(2.36g;6.72mm);顺式酸(3.09g;9.16mm);反式酸(2.55g;7.59mm).顺式酯总产率:81.4%。
Claims (12)
2.如权利要求1所述的工艺,其中色氨酸是D-色氨酸、L-色氨酸或其混合物。
3.如权利要求1-2所述的工艺,其中所述酸是盐酸、硫酸或硝酸。
4.如权利要求1-3所述的工艺,其中所述质子酸相对于色氨酸摩尔数过量达到50%。
5.如权利要求4所述工艺,其中所述质子酸相对于色氨酸摩尔数过量5%-30%。
6.如权利要求5所述的工艺,其中所述质子酸相对于色氨酸摩尔数过量10%-30%。
7.如权利要求1-6所述工艺,其中所用色氨酸和3,4-(亚甲基二氧)苯甲醛克分子数相等。
8.如权利要求1-7所述工艺,其中溶剂R′OH选自甲醇、乙醇、正丙醇、异丙醇、正丁醇及其异构体、正戊醇及其异构体、正己醇及其异构体、正庚醇及其异构体、正辛醇及其异构体、环戊醇、环己醇、环庚醇,羟基哌啶、苯基醇、苯甲醇、甲基苯甲醇、4-甲氧苄基醇、3-甲氧苄基醇、2-甲氧苄基醇、4-硝基苄基醇,四氢呋喃甲醇。
9.如权利要求1-8所述工艺,其中色氨酸、3,4-(亚甲基二氧)苯甲醛和R′OH的反应是在R′OH回流温度进行,反应时长12-36小时。
10.如权利要求1-9所述工艺,其中所得产物(I)随后进行差向异构化反应以增加其非对映异构体中一个的富集。
11.如权利要求10所述的工艺,其中所述非对映异构体是顺式非对映异构体。
12.如权利要求11所述的工艺,其中所述差向异构化是化合物(I)在40℃-70℃与相对于起始色氨酸摩尔数过量的盐酸水溶液反应40-100小时。
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CN111116583A (zh) * | 2019-12-23 | 2020-05-08 | 平光制药股份有限公司 | 一种他达拉非中间体的制备方法 |
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CN110437228B (zh) * | 2019-07-22 | 2022-06-14 | 山东省药学科学院 | 一种他达拉非及其中间体的制备方法 |
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