CN111499544B - A kind of synthetic method of N-Boc-N-methyl-4-aminostyrene prepared by one-pot method - Google Patents
A kind of synthetic method of N-Boc-N-methyl-4-aminostyrene prepared by one-pot method Download PDFInfo
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- NNEVIHMHALMUSB-UHFFFAOYSA-N tert-butyl n-(4-ethenylphenyl)-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)C1=CC=C(C=C)C=C1 NNEVIHMHALMUSB-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 16
- 238000010189 synthetic method Methods 0.000 title claims description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 238000001308 synthesis method Methods 0.000 claims abstract description 11
- 239000000758 substrate Substances 0.000 claims abstract description 9
- 239000012022 methylating agents Substances 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 239000012153 distilled water Substances 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 238000010898 silica gel chromatography Methods 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000007069 methylation reaction Methods 0.000 abstract description 3
- 238000003379 elimination reaction Methods 0.000 abstract description 2
- 230000011987 methylation Effects 0.000 abstract description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- LBSXSAXOLABXMF-UHFFFAOYSA-N 4-Vinylaniline Chemical compound NC1=CC=C(C=C)C=C1 LBSXSAXOLABXMF-UHFFFAOYSA-N 0.000 description 3
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 230000001035 methylating effect Effects 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BIAWAXVRXKIUQB-UHFFFAOYSA-N 2-(2-phenylethenyl)pyridine Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=N1 BIAWAXVRXKIUQB-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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Abstract
Description
技术领域technical field
本发明涉及一种一锅法制备N-Boc-N-甲基-4-氨基苯乙烯的合成方法The invention relates to a synthetic method for preparing N-Boc-N-methyl-4-aminostyrene in one pot
背景技术Background technique
N-Boc-N-甲基-4-氨基苯乙烯是重要的有机合成中间体，是阿尔茨海默病诊断试剂18F-AV-45及其类似物的必要原料。N-Boc-N-methyl-4-aminostyrene is an important intermediate in organic synthesis and a necessary raw material for Alzheimer's disease diagnostic reagent 18 F-AV-45 and its analogues.
专利文献CN102271716A，CN102432529A报道了N-Boc-N-甲基-4-氨基苯乙烯的合成方法，非专利文献68Ga-Bivalent Polypegylated Styrylpyridine Conjugates forImaging AβPlaques in Cerebral Amyloid Angiopathy，Bioconjugate Chem.2016，27，1314-1323，Multidentate 18F-Polypegylated Styrylpyridines As Imaging Agents forAβPlaques in Cerebral Amyloid Angiopathy(CAA)，J.Med.Chem.2011，54，8085-8098报道了N-Boc-N-甲基-4-氨基苯乙烯的合成方法。Patent literature CN102271716A, CN102432529A report the synthesis method of N-Boc-N-methyl-4-aminostyrene, non-patent literature 68 Ga-Bivalent Polypegylated Styrylpyridine Conjugates for Imaging AβPlaques in Cerebral Amyloid Angiopathy, Bioconjugate Chem.2016, 27, 1314 -1323, Multidentate 18 F-Polypegylated Styrylpyridines As Imaging Agents for AβPlaques in Cerebral Amyloid Angiopathy (CAA), J.Med.Chem.2011, 54, 8085-8098 reported N-Boc-N-methyl-4-aminostyrene synthetic method.
上述文献的合成方法均是为以4-氨基苯乙烯为原料，先用BOC保护氨基，然后再进行甲基化反应得到。但该路线的原料4-氨基苯乙烯的制备方法复杂，条件苛刻，商品化的4-氨基苯乙烯价格昂贵，以该路线制备N-Boc-N-甲基-4-氨基苯乙烯成本高。The synthesis methods of the above-mentioned documents are all obtained by using 4-aminostyrene as a raw material, first protecting the amino group with BOC, and then performing a methylation reaction. But the preparation method of the raw material 4-aminostyrene of this route is complicated, and the conditions are harsh, and the commercialized 4-aminostyrene is expensive, and the cost of preparing N-Boc-N-methyl-4-aminostyrene with this route is high.
因此，使用廉价易得的原料，寻求一种简便且具有高产率的N-Boc-N-甲基-4-氨基苯乙烯的合成方法非常必要。Therefore, it is very necessary to seek a simple and high-yield synthesis method of N-Boc-N-methyl-4-aminostyrene using cheap and easily available raw materials.
发明内容Contents of the invention
本发明主要解决现有合成N-Boc-N-甲基-4-氨基苯乙烯的方法原料昂贵，成本高的问题，提供一种一锅法制备N-Boc-N-甲基-4-氨基苯乙烯的合成方法。The present invention mainly solves the problem of expensive raw materials and high cost in the existing method for synthesizing N-Boc-N-methyl-4-aminostyrene, and provides a one-pot method for preparing N-Boc-N-methyl-4-aminostyrene Synthesis of styrene.
本发明的一种一锅法制备N-Boc-N-甲基-4-氨基苯乙烯的合成方法，包括以下步骤：A kind of one-pot method of the present invention prepares the synthetic method of N-Boc-N-methyl-4-aminostyrene, comprises the following steps:
将底物，甲基化试剂，碱和有机溶剂加入到反应器中反应，反应结束后经过后处理步骤得到N-Boc-N-甲基-4-氨基苯乙烯，所述的底物结构式为
本发明的反应式如下：Reaction formula of the present invention is as follows:
本发明的一种一锅法制备N-Boc-N-甲基-4-氨基苯乙烯的合成方法，其特征在于，所述的离去基团选自-OTf，-OTs，-OMs，-I。A kind of one-pot method of the present invention prepares the synthetic method of N-Boc-N-methyl-4-aminostyrene, is characterized in that, described leaving group is selected from -OTf, -OTs, -OMs, - I.
本发明的一种一锅法制备N-Boc-N-甲基-4-氨基苯乙烯的合成方法，其特征在于，所述的甲基化试剂为碘甲烷或硫酸二甲酯。A one-pot synthesis method for preparing N-Boc-N-methyl-4-aminostyrene of the present invention is characterized in that the methylating agent is methyl iodide or dimethyl sulfate.
本发明的一种一锅法制备N-Boc-N-甲基-4-氨基苯乙烯的合成方法，其特征在于，所述的碱为氢化钠或叔丁醇钾。A one-pot synthesis method of the present invention for preparing N-Boc-N-methyl-4-aminostyrene is characterized in that the base is sodium hydride or potassium tert-butoxide.
本发明的一种一锅法制备N-Boc-N-甲基-4-氨基苯乙烯的合成方法，其特征在于，所述的有机溶剂为乙腈，DMF，THF，DMA或NMP。A one-pot synthesis method of the present invention for preparing N-Boc-N-methyl-4-aminostyrene is characterized in that the organic solvent is acetonitrile, DMF, THF, DMA or NMP.
本发明的一种一锅法制备N-Boc-N-甲基-4-氨基苯乙烯的合成方法，其特征在于，所述的底物与碱的摩尔比为1：(2～5)，底物与甲基化试剂的摩尔比为1：(1～3)。A kind of one-pot method of the present invention prepares the synthetic method of N-Boc-N-methyl-4-aminostyrene, is characterized in that, the molar ratio of described substrate and alkali is 1: (2～5), The molar ratio of substrate to methylating reagent is 1: (1-3).
本发明的一种一锅法制备N-Boc-N-甲基-4-氨基苯乙烯的合成方法，其特征在于，所述的反应是在氮气保护下，先在冰浴下反应，然后转至室温反应，优选先在冰浴下反应1小时，然后转至室温反应过夜。A kind of one-pot method of the present invention prepares the synthetic method of N-Boc-N-methyl-4-aminostyrene, is characterized in that, described reaction is under the protection of nitrogen, first reacts under ice bath, then turns to React at room temperature, preferably in an ice bath for 1 hour, then turn to room temperature for overnight reaction.
本发明的一种一锅法制备N-Boc-N-甲基-4-氨基苯乙烯的合成方法，其特征在于，所述的后处理步骤是向反应体系中加入蒸馏水，得到混合物，再以乙酸乙酯萃取，得到有机相，有机相后以饱和食盐水洗涤，无水硫酸钠干燥并浓缩，再以洗脱剂进行硅胶柱层析分离纯化，得到N-Boc-N-甲基-4-氨基苯乙烯。A kind of one-pot method of the present invention prepares the synthetic method of N-Boc-N-methyl-4-aminostyrene, is characterized in that, described post-processing step is to add distilled water in reaction system, obtain mixture, then with Extracted with ethyl acetate to obtain an organic phase, which was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography with an eluent to obtain N-Boc-N-methyl-4 -Aminostyrene.
本发明的有益效果是：本发明所用原料成本低廉，采用一锅法同时完成甲基化和消除反应，操作简单方便，产率可达90％以上。The beneficial effects of the invention are: the cost of raw materials used in the invention is low, the methylation and elimination reactions are simultaneously completed by a one-pot method, the operation is simple and convenient, and the yield can reach more than 90%.
具体实施方式Detailed ways
下面对本发明实施例中的技术方案进行清除、完整的描述，显然，所描述的实施例仅仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Apparently, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.
实施例1Example 1
在氮气保护下，将氢化钠(60％，5.11g，128mmol)加入到200mL干燥DMF中，冰浴降温至0℃，滴加含有化合物1(20.0g，51.1mmol)和碘甲烷(8.7g，61.3mmol)的DMF溶液200mL，保持温度在0℃。滴加完毕后，冰浴下搅拌1小时，转至室温反应过夜，反应结束后，向反应体系中加入1L蒸馏水，得到混合物，再以乙酸乙酯萃取(1L×3)，得到有机相，合并有机相后以2L饱和食盐水洗涤，无水硫酸钠干燥并浓缩，再以洗脱剂进行硅胶柱层析分离纯化，得到N-Boc-N-甲基-4-氨基苯乙烯(10.8g，90.6％)。Under nitrogen protection, sodium hydride (60%, 5.11g, 128mmol) was added to 200mL dry DMF, cooled to 0°C in an ice bath, and compound 1 (20.0g, 51.1mmol) and iodomethane (8.7g, 61.3 mmol) in 200 mL of DMF, keeping the temperature at 0°C. After the dropwise addition was completed, stir for 1 hour under ice bath, then turn to room temperature and react overnight. After the reaction, add 1 L of distilled water to the reaction system to obtain the mixture, then extract with ethyl acetate (1 L × 3) to obtain the organic phase, and combine The organic phase was washed with 2L saturated brine, dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (10.8g, 90.6%).
实施例2Example 2
在氮气保护下，将氢化钠(60％，6.34g，158mmol)加入到200mL干燥DMF中，冰浴降温至0℃，滴加含有化合物2(20.0g，63.4mmol)和碘甲烷(10.8g，76.1mmol)的DMF溶液200mL，保持温度在0℃。滴加完毕后，冰浴下搅拌1小时，转至室温反应过夜，反应结束后，向反应体系中加入1L蒸馏水，得到混合物，再以乙酸乙酯萃取(1L×3)，得到有机相，合并有机相后以2L饱和食盐水洗涤，无水硫酸钠干燥并浓缩，再以洗脱剂进行硅胶柱层析分离纯化，得到N-Boc-N-甲基-4-氨基苯乙烯(14.1g，95.3％)。Under nitrogen protection, sodium hydride (60%, 6.34g, 158mmol) was added to 200mL dry DMF, cooled to 0°C in an ice bath, and compound 2 (20.0g, 63.4mmol) and iodomethane (10.8g, 76.1 mmol) in 200 mL of DMF, keeping the temperature at 0°C. After the dropwise addition was completed, stir for 1 hour under ice bath, then turn to room temperature and react overnight. After the reaction, add 1 L of distilled water to the reaction system to obtain the mixture, then extract with ethyl acetate (1 L × 3) to obtain the organic phase, and combine The organic phase was washed with 2L saturated brine, dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (14.1 g, 95.3%).
实施例3Example 3
在氮气保护下，将氢化钠(60％，5.76g，144mmol)加入到200mL干燥DMF中，冰浴降温至0℃，滴加含有化合物3(20.0g，57.6mmol)和碘甲烷(9.81g，69.1mmol)的DMF溶液200mL，保持温度在0℃。滴加完毕后，冰浴下搅拌1小时，转至室温反应过夜，反应结束后，向反应体系中加入1L蒸馏水，得到混合物，再以乙酸乙酯萃取(1L×3)，得到有机相，合并有机相后以2L饱和食盐水洗涤，无水硫酸钠干燥并浓缩，再以洗脱剂进行硅胶柱层析分离纯化，得到N-Boc-N-甲基-4-氨基苯乙烯(12.6g，93.8％)。Under nitrogen protection, sodium hydride (60%, 5.76g, 144mmol) was added to 200mL dry DMF, cooled to 0°C in an ice bath, and compound 3 (20.0g, 57.6mmol) and methyl iodide (9.81g, 69.1 mmol) in 200 mL of DMF, keeping the temperature at 0°C. After the dropwise addition was completed, stir for 1 hour under ice bath, then turn to room temperature and react overnight. After the reaction, add 1 L of distilled water to the reaction system to obtain the mixture, then extract with ethyl acetate (1 L × 3) to obtain the organic phase, and combine The organic phase was washed with 2L saturated brine, dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (12.6 g, 93.8%).
实施例4Example 4
在氮气保护下，将氢化钠(60％，5.41g，135mmol)加入到200mL干燥DMF中，冰浴降温至0℃，滴加含有化合物4(20.0g，54.2mmol)和碘甲烷(9.22g，65.0mmol)的DMF溶液200mL，保持温度在0℃。滴加完毕后，冰浴下搅拌1小时，转至室温反应过夜，反应结束后，向反应体系中加入1L蒸馏水，得到混合物，再以乙酸乙酯萃取(1L×3)，得到有机相，合并有机相后以2L饱和食盐水洗涤，无水硫酸钠干燥并浓缩，再以洗脱剂进行硅胶柱层析分离纯化，得到N-Boc-N-甲基-4-氨基苯乙烯(11.4g，90.3％)。Under nitrogen protection, sodium hydride (60%, 5.41g, 135mmol) was added to 200mL dry DMF, cooled to 0°C in an ice bath, and compound 4 (20.0g, 54.2mmol) and methyl iodide (9.22g, 65.0 mmol) in 200 mL of DMF, keeping the temperature at 0°C. After the dropwise addition was completed, stir for 1 hour under ice bath, then turn to room temperature and react overnight. After the reaction, add 1 L of distilled water to the reaction system to obtain the mixture, then extract with ethyl acetate (1 L × 3) to obtain the organic phase, and combine The organic phase was washed with 2L saturated brine, dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (11.4 g, 90.3%).
实施例5Example 5
在氮气保护下，将氢化钠(60％，5.11g，128mmol)加入到200mL干燥DMF中，冰浴降温至0℃，滴加含有化合物5(20.0g，51.1mmol)和硫酸二甲酯(7.73g，61.3mmol)的DMF溶液200mL，保持温度在0℃。滴加完毕后，冰浴下搅拌1小时，转至室温反应过夜，反应结束后，向反应体系中加入1L蒸馏水，得到混合物，再以乙酸乙酯萃取(1L×3)，得到有机相，合并有机相后以2L饱和食盐水洗涤，无水硫酸钠干燥并浓缩，再以洗脱剂进行硅胶柱层析分离纯化，得到N-Boc-N-甲基-4-氨基苯乙烯(11.1g，93.1％)。Under nitrogen protection, sodium hydride (60%, 5.11g, 128mmol) was added to 200mL dry DMF, cooled to 0°C in an ice bath, and compound 5 (20.0g, 51.1mmol) and dimethyl sulfate (7.73 g, 61.3 mmol) in 200 mL of DMF, keeping the temperature at 0°C. After the dropwise addition was completed, stir for 1 hour under ice bath, then turn to room temperature and react overnight. After the reaction, add 1 L of distilled water to the reaction system to obtain the mixture, then extract with ethyl acetate (1 L × 3) to obtain the organic phase, and combine The organic phase was washed with 2L saturated brine, dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (11.1 g, 93.1%).
上文所列出去的一系列的详细说明仅仅是针对本发明的可行性可行性实施方式的具体说明，它们并非用以限制本发明的保护范围，凡为脱离本发明技艺精神所作的等效实施方式或变更均应包含在本发明的保护范围内。The series of detailed descriptions listed above are only specific descriptions of the feasible and feasible implementation modes of the present invention, and they are not intended to limit the protection scope of the present invention. All equivalent implementations that deviate from the technical spirit of the present invention Ways or changes should be included in the protection scope of the present invention.
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