CN111499544B - Synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by one-pot method - Google Patents

Synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by one-pot method Download PDF

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CN111499544B
CN111499544B CN201910100181.8A CN201910100181A CN111499544B CN 111499544 B CN111499544 B CN 111499544B CN 201910100181 A CN201910100181 A CN 201910100181A CN 111499544 B CN111499544 B CN 111499544B
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李祎亮
段玉清
贾建华
于江
宁洪鑫
毕常芬
魏会强
樊赛军
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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
    • 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
    • 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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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a synthesis method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method, which mainly solves the problems of expensive raw materials and high cost of the existing synthesis method of N-Boc-N-methyl-4-aminostyrene. The synthesis method comprises the steps of adding a substrate, a methylating agent, alkali and a dry organic solvent into a reactor for reaction, and obtaining the N-Boc-N-methyl-4-aminostyrene through a post-treatment step after the reaction is finished. The method has the advantages of cheap and easily obtained raw materials, simple reaction steps, high yield and low cost, and can complete methylation and elimination reactions simultaneously by one-pot reaction.

Description

Synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by one-pot method
Technical Field
The invention relates to a synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method
Background
N-Boc-N-methyl-4-aminostyrene is an important organic synthesis intermediate, and is a diagnostic reagent for Alzheimer's disease 18 F-AV-45 and analogues thereof.
Patent documents CN102271716A and CN102432529A report N-Boc-N-methyl-4-ammoniaMethod for synthesizing styrene, non-patent document 68 Ga-Bivalent Polypegylated Styrylpyridine Conjugates for Imaging AβPlaques in Cerebral Amyloid Angiopathy，Bioconjugate Chem.2016，27，1314-1323，Multidentate 18 The synthesis of N-Boc-N-methyl-4-aminostyrene was reported in F-grafted Styrylpyridines As Imaging Agents for A β plants in cereal analog adsorbed enzymes (CAA), J.Med.chem.2011, 54, 8085-8098.
The synthesis methods of the above documents are all obtained by using 4-aminostyrene as a raw material, protecting amino groups with BOC, and then carrying out methylation reaction. However, the preparation method of the raw material 4-aminostyrene in the route is complex, the conditions are harsh, the price of the commercialized 4-aminostyrene is high, and the cost for preparing the N-Boc-N-methyl-4-aminostyrene by the route is high.
Therefore, it is necessary to find a method for synthesizing N-Boc-N-methyl-4-aminostyrene, which is simple and has a high yield, using inexpensive and easily available raw materials.
Disclosure of Invention
The invention mainly solves the problems of expensive raw materials and high cost of the existing method for synthesizing N-Boc-N-methyl-4-aminostyrene, and provides a synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method.
The invention relates to a synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method, which comprises the following steps:
adding a substrate, a methylating agent, alkali and an organic solvent into a reactor for reaction, and obtaining N-Boc-N-methyl-4-aminostyrene through a post-treatment step after the reaction is finished, wherein the structural formula of the substrate is shown in the specification
Figure BDA0001965497170000011
The LG is a leaving group.
The reaction formula of the invention is as follows:
Figure BDA0001965497170000021
the invention discloses a synthesis method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method, which is characterized in that a leaving group is selected from-OTf, -OTs, -OMs and-I.
The invention relates to a synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method, which is characterized in that a methylating reagent is methyl iodide or dimethyl sulfate.
The invention relates to a synthesis method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method, which is characterized in that alkali is sodium hydride or potassium tert-butoxide.
The invention discloses a synthesis method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method.
The invention relates to a synthesis method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method, which is characterized in that the molar ratio of a substrate to alkali is 1: (2-5), the molar ratio of the substrate to the methylating agent is 1: (1-3).
The invention relates to a synthesis method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method, which is characterized in that the reaction is carried out under the protection of nitrogen, the reaction is carried out under the ice bath firstly, then the reaction is carried out at room temperature, and preferably, the reaction is carried out under the ice bath for 1 hour firstly, and then the reaction is carried out at room temperature for overnight.
The invention discloses a synthesis method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method, which is characterized in that the post-treatment step comprises the steps of adding distilled water into a reaction system to obtain a mixture, extracting with ethyl acetate to obtain an organic phase, washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and carrying out silica gel column chromatography separation and purification with an eluent to obtain the N-Boc-N-methyl-4-aminostyrene.
The invention has the beneficial effects that: the method has the advantages of low cost of the used raw materials, simple and convenient operation and high yield of over 90 percent, and adopts a one-pot method to simultaneously complete methylation and elimination reaction.
Detailed Description
The technical solutions in the embodiments of the present invention are described below in a clear and complete manner, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Figure BDA0001965497170000031
Sodium hydride (60%, 5.11g, 128mmol) was added to 200mL of dry DMF under nitrogen, the temperature was lowered to 0 ℃ in an ice bath, 200mL of a DMF solution containing Compound 1 (20.0g, 51.1mmol) and methyl iodide (8.7g, 61.3mmol) was added dropwise, and the temperature was maintained at 0 ℃. After the dropwise addition, the mixture was stirred for 1 hour in an ice bath, and then allowed to react overnight at room temperature, after the completion of the reaction, 1L of distilled water was added to the reaction system to obtain a mixture, which was then extracted with ethyl acetate (1L. Times.3) to obtain organic phases, and the organic phases were combined, washed with 2L of saturated brine, dried over anhydrous sodium sulfate and concentrated, and then subjected to separation and purification by silica gel column chromatography using an eluent to obtain N-Boc-N-methyl-4-aminostyrene (10.8g, 90.6%).
Example 2
Figure BDA0001965497170000032
Sodium hydride (60%, 6.34g, 158mmol) was added to 200mL of dry DMF under nitrogen, the temperature was lowered to 0 ℃ in an ice bath, 200mL of a DMF solution containing Compound 2 (20.0g, 63.4 mmol) and methyl iodide (10.8g, 76.1mmol) was added dropwise, and the temperature was maintained at 0 ℃. After the completion of the dropwise addition, the mixture was stirred for 1 hour under ice bath, and then allowed to react overnight at room temperature, and after the completion of the reaction, 1L of distilled water was added to the reaction system to obtain a mixture, which was further extracted with ethyl acetate (1L. Times.3) to obtain organic phases, which were combined and washed with 2L of saturated saline, dried over anhydrous sodium sulfate and concentrated, and then subjected to separation and purification by silica gel column chromatography with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (14.1g, 95.3%).
Example 3
Figure BDA0001965497170000033
Sodium hydride (60%, 5.76g, 144mmol) was added to 200mL of dry DMF under nitrogen, the temperature was lowered to 0 ℃ in an ice bath, 200mL of a DMF solution containing Compound 3 (20.0 g,57.6 mmol) and methyl iodide (9.81g, 69.1 mmol) was added dropwise, and the temperature was maintained at 0 ℃. After the completion of the dropwise addition, the mixture was stirred for 1 hour in an ice bath, and then allowed to react overnight at room temperature, after the completion of the reaction, 1L of distilled water was added to the reaction system to obtain a mixture, which was further extracted with ethyl acetate (1L. Times.3) to obtain organic phases, which were combined and washed with 2L of saturated saline, dried over anhydrous sodium sulfate and concentrated, and then subjected to separation and purification by silica gel column chromatography using an eluent to obtain N-Boc-N-methyl-4-aminostyrene (12.6 g, 93.8%).
Example 4
Figure BDA0001965497170000041
Sodium hydride (60%, 5.41g, 135mmol) was added to 200mL of dry DMF under nitrogen, the temperature was reduced to 0 ℃ in an ice bath, 200mL of a DMF solution containing Compound 4 (20.0 g, 54.2mmol) and methyl iodide (9.22g, 65.0 mmol) was added dropwise, and the temperature was maintained at 0 ℃. After the completion of the dropwise addition, the mixture was stirred for 1 hour under ice bath, and then allowed to react overnight at room temperature, after the completion of the reaction, 1L of distilled water was added to the reaction system to obtain a mixture, which was further extracted with ethyl acetate (1L. Times.3) to obtain organic phases, which were combined and washed with 2L of saturated saline, dried over anhydrous sodium sulfate and concentrated, and then subjected to separation and purification by silica gel column chromatography using an eluent to obtain N-Boc-N-methyl-4-aminostyrene (11.4g, 90.3%).
Example 5
Figure BDA0001965497170000042
Sodium hydride (60%, 5.11g, 128mmol) was added to 200mL of dry DMF under nitrogen, the temperature was lowered to 0 ℃ in an ice bath, 200mL of a DMF solution containing Compound 5 (20.0 g, 51.1mmol) and dimethyl sulfate (7.73g, 61.3 mmol) was added dropwise, and the temperature was maintained at 0 ℃. After the completion of the dropwise addition, the mixture was stirred in an ice bath for 1 hour, and then allowed to react overnight at room temperature, after the completion of the reaction, 1L of distilled water was added to the reaction system to obtain a mixture, which was further extracted with ethyl acetate (1L. Times.3) to obtain organic phases, the organic phases were combined, washed with 2L of saturated saline, dried over anhydrous sodium sulfate and concentrated, and further subjected to separation and purification by silica gel column chromatography using an eluent to obtain N-Boc-N-methyl-4-aminostyrene (11.1g, 93.1%).
The above-listed detailed description is only a specific description of a possible embodiment of the present invention, and they are not intended to limit the scope of the present invention, and all equivalent embodiments or modifications that do not depart from the technical spirit of the present invention should be included in the scope of the present invention.

Claims (6)

1. A synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by a one-pot method is characterized by comprising the following steps:
adding a substrate, a methylating agent, alkali and an organic solvent into a reactor for reaction, and obtaining N-Boc-N-methyl-4-aminostyrene through a post-treatment step after the reaction is finished, wherein the structural formula of the substrate is shown in the specification
Figure FDA0003896475360000011
LG is a leaving group selected from-OTf, -OTs, -OMs, -I, the methylating agent is methyl iodide or dimethyl sulfate, the base is sodium hydride or potassium tert-butoxide,
the reaction formula is as follows:
Figure FDA0003896475360000012
2. the synthesis method for preparing N-Boc-N-methyl-4-aminostyrene according to claim 1, wherein the organic solvent is acetonitrile, DMF, THF, DMA or NMP.
3. The synthesis method for preparing N-Boc-N-methyl-4-aminostyrene according to claim 1 or 2, characterized in that the molar ratio of substrate to base is 1: (2-5), the molar ratio of the substrate to the methylating agent is 1: (1-3).
4. The synthesis method for preparing N-Boc-N-methyl-4-aminostyrene according to claim 1, wherein the reaction is performed in a one-pot method under the protection of nitrogen, and the reaction is performed in an ice bath and then is carried out at room temperature.
5. The synthesis method for preparing N-Boc-N-methyl-4-aminostyrene according to claim 4, wherein the reaction in ice bath is performed for 1 hour in ice bath.
6. The synthesis method of N-Boc-N-methyl-4-aminostyrene according to claim 1, wherein the post-treatment step comprises adding distilled water to the reaction system to obtain a mixture, extracting with ethyl acetate to obtain an organic phase, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate and concentrating, and separating and purifying with silica gel column chromatography using an eluent to obtain N-Boc-N-methyl-4-aminostyrene.
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CN102271716A (en) * 2008-12-31 2011-12-07 阿维德放射性药品公司 Synthesis of 18f-radiolabeled styrylpyridines from tosylate precursors and stable pharmaceutical compositions thereof
CN102432529A (en) * 2011-11-14 2012-05-02 江苏省原子医学研究所 Styryl pyridine disulfide dinitrogen derivative and preparation method thereof

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CN102432529A (en) * 2011-11-14 2012-05-02 江苏省原子医学研究所 Styryl pyridine disulfide dinitrogen derivative and preparation method thereof

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