CN111499570B - Synthesis method of AV-45 intermediate - Google Patents
Synthesis method of AV-45 intermediate Download PDFInfo
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- CN111499570B CN111499570B CN201910101176.9A CN201910101176A CN111499570B CN 111499570 B CN111499570 B CN 111499570B CN 201910101176 A CN201910101176 A CN 201910101176A CN 111499570 B CN111499570 B CN 111499570B
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
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Abstract
The invention provides a synthesis method of an AV-45 intermediate, which comprises the following steps: step (1): performing HECK reaction on tert-butyl-N-methyl-4-vinyl phenyl carbamate and 2-bromo-5-iodopyridine to obtain an intermediate A; step (2): condensing the intermediate A with triethylene glycol to obtain the target compound. The invention improves the synthesis method of (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate, has fewer reaction steps, avoids using an pungent odor reagent, and can directly purify the intermediate and the target compound by recrystallization, thereby having simple and convenient operation and high yield.
Description
Technical Field
The invention relates to the field of medical synthesis, in particular to a synthesis method of an AV-45 intermediate (namely (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridine-3-yl) vinyl) phenyl (methyl) carbamate).
Background
18 F-AV-45 (florbetapir), the first positron imaging agent approved by the U.S. Food and Drug Administration (FDA) for diagnosis of AD in 2012, developed by the U.S. Avid company. The imaging agent achieves the purpose of diagnosis by specific combination with Abeta, realizes the observation of Abeta deposition change in vivo in a noninvasive mode, and is widely applied to Abeta related disease research clinically. (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate is synthetic 18 F-AV-45 is prepared from the compound through sulfoation, fluoridation and deprotection 18 F-AV-45。
Currently, there are three main methods reported in the literature for the synthesis of (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate.
Patent documents CN102271716a, CN102432529a, non-patent document 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 A beta Plaques in Cerebral Amyloid Angiopathy (CAA), J.Med.chem.2011, 54, 8085-8098 all report synthetic route one.
The chemical equation of this synthetic route is shown below:
in the first synthetic route, 2-bromo-5-iodopyridine or 2-chloro-5-iodopyridine is used as a raw material, is reacted with triethylene glycol to prepare an intermediate 2- (2- (2- (5-iodopyridine-2-oxy) ethoxy) ethanol, and is reacted with tert-butyl-N-methyl-4-vinylphenyl carbamate to prepare (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate through HECK reaction. Although the route has few synthesis steps, the intermediates and the target compounds are purified by column chromatography, which is unfavorable for the scale-up production.
Non-patent literature Synthesis of TEG-Substituted 4- (N-Methyl-N-Boc-amino) styrylpyridine as Key Precursor for Monodentate and Multidentate Imaging Agents for Ab Plaques, synthetic Communications,2015, 45 (23), 2740-2747 reports synthetic route two.
The chemical equation of this synthetic route is shown below:
in scheme II, the (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate is prepared by a multi-step reaction starting from 4-nitrobenzyl bromide. The main problem of this route is 1) the number of reaction steps; 2) The 4-methylphenylsulfnol used in the fourth step has a pungent odor.
Non-patent documents Facile synthesis of TEG-subbistited 4- (N-methyl-N-Boc-amino) styrylpyridine and PET imaging agent [ F ] florbetapir ([ F ] AV-45), synthetic Communications,2018, 48 (4), 422-427 report synthetic route three.
The chemical equation of this synthetic route is shown below:
in the third synthetic route, 4-bromobenzyl bromide is used as a starting material, and (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate is prepared through a multi-step reaction, and the reaction steps are the biggest problems of the route.
Based on the above problems, there is a need for an improvement in the synthesis of (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate in the prior art to solve the above problems.
Disclosure of Invention
The invention aims to disclose a synthesis method of AV-105 with a structure shown in a formula (I), which is used for solving the problems of long reaction route, low yield, inconvenient use of pungent odor reagent and post-treatment in the existing synthesis route, and the like.
In order to achieve the above object, the present invention provides a method for synthesizing AV-105 having a structure represented by formula (I),
the method comprises the following steps:
step (1): performing HECK reaction on tert-butyl-N-methyl-4-vinyl phenyl carbamate and 2-bromo-5-iodopyridine to obtain an intermediate A;
step (2): condensing the intermediate A with triethylene glycol to obtain the target compound.
The chemical equation of the synthesis method is as follows:
the invention relates to a synthesis method of (E) -tert-butyl-4- (2- (6- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate shown in a formula (I), which is characterized in that the catalyst in the step (1) is PdCl 2 ,Pd(OAc) 2 . The catalyst may be used alone or with the addition of a ligand such as dppf, PCy3, preferably Pd (OAc) 2 。
The invention relates to a synthesis method of (E) -tert-butyl-4- (2- (6- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate shown in a formula (I), which is characterized in that the reaction temperature of the step (1) is 60-100 ℃, preferably 65 ℃.
The invention relates to a synthesis method of (E) -tert-butyl-4- (2- (6- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate shown in a formula (I), which is characterized in that the mol ratio of the tert-butyl-N-methyl-4-vinylphenyl carbamate to the 2-bromo-5-iodopyridine in the step (1) is 1.0-1.5:1, preferably 1.1:1.
The invention relates to a synthesis method of (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridine-3-yl) vinyl) phenyl (methyl) carbamate shown in a formula (I), which is characterized in that DMF, NMP, DMA and dioxane are selected as solvents in the step (1), and DMF is preferred.
The invention relates to a synthesis method of (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridine-3-yl) vinyl) phenyl (methyl) carbamate shown in a formula (I), which is characterized in that the alkali used in the step (2) is sodium methoxide, sodium ethoxide, potassium tert-butoxide and cesium carbonate, preferably potassium tert-butoxide.
The invention relates to a synthesis method of (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridine-3-yl) vinyl) phenyl (methyl) carbamate shown in a formula (I), which is characterized in that the solvent used in the step (2) is DMF, NMP, DMA and dioxane, and DMF is preferable.
The invention relates to a synthesis method of (E) -tert-butyl-4- (2- (6- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate shown in a formula (I), which is characterized in that the reaction temperature of the step (2) is 60-100 ℃, preferably 65 ℃.
The invention also provides a synthetic method of the tert-butyl-N-methyl-4-vinyl phenyl carbamate, which comprises the following steps: adding a substrate, a methylating agent, alkali and an organic solvent into a reactor for reaction, and after the reaction is finished, obtaining the tert-butyl-N-methyl-4-vinyl phenyl carbamate through a post-treatment step, wherein the structural formula of the substrate isThe LG is a chain-offAnd (5) removing groups.
The chemical equation of the synthesis method is as follows:
the synthesis method of the tert-butyl-N-methyl-4-vinylphenyl carbamate is characterized in that the leaving group is selected from-OTf, -OTs, -OMs, -I.
The invention relates to a method for synthesizing tert-butyl-N-methyl-4-vinyl phenyl carbamate, which is characterized in that the methylation reagent is methyl iodide or dimethyl sulfate.
The invention relates to a synthesis method of tert-butyl-N-methyl-4-vinyl phenyl carbamate, which is characterized in that the alkali is sodium hydride or potassium tert-butoxide.
The synthesis method of the tert-butyl-N-methyl-4-vinylphenyl carbamate is characterized in that the organic solvent is acetonitrile, DMF, THF, DMA or NMP.
The synthesis method of the tert-butyl-N-methyl-4-vinyl phenyl carbamate is characterized in that the molar ratio of the substrate to the alkali is 1: (2-5), the molar ratio of the substrate to the methylating agent is 1: (1-3).
The synthesis method of the tert-butyl-N-methyl-4-vinylphenyl carbamate is characterized in that the reaction is carried out under the protection of nitrogen, firstly in an ice bath, then in a room temperature, preferably in the ice bath for 1 hour, and then in the room temperature overnight.
The invention relates to a method for synthesizing tert-butyl-N-methyl-4-vinylphenyl carbamate, which is characterized in that distilled water is added into a reaction system to obtain a mixture, ethyl acetate is used for extraction to obtain an organic phase, the organic phase is washed with saturated saline water, dried and concentrated by anhydrous sodium sulfate, and then silica gel column chromatography separation and purification are carried out by using an eluent to obtain tert-butyl-N-methyl-4-vinylphenyl carbamate.
Compared with the prior art, the invention has the beneficial effects that: the synthesis method of the (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate disclosed by the invention has fewer reaction steps, avoids using an pungent odor reagent, and can directly purify an intermediate and a target compound prepared by the route through recrystallization.
The synthesis method of tert-butyl-N-methyl-4-vinyl phenyl carbamate disclosed by the invention has the advantages that the cost of raw materials is low, the methylation and elimination reactions are finished simultaneously by adopting a one-pot method, the operation is simple and convenient, and the yield can reach more than 90%.
Detailed Description
The following description of the embodiments of the present invention will be provided to illustrate some, but not all embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. Unless specifically indicated in the specification, the components and materials used in the various examples herein are all of analytical grade.
Step (1): HECK reaction between tert-butyl-N-methyl-4-vinyl phenyl carbamate and 2-bromo-5-iodopyridine to obtain intermediate A
Example 1
tert-butyl-N-methyl-4-vinylphenylcarbamate (5.13 g,22 mmol), 2-bromo-5-iodopyridine (5.66 g,20 mmol), TBAB (12.9 g,40 mmol), K under nitrogen 2 CO 3 (6.91g,50mmol),Pd(OAc) 2 (224 mg,1.0 mmol) was suspended in 150mL DMF and reacted at 65℃for 3 hours. Cooling to room temperature, adding 300mL of water, extracting with ethyl acetateTake (300 mL. Times.3). The organic phases were combined and washed with saturated brine (500 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was recrystallized from methylene chloride/n-hexane to give 6.43g of a white solid in 82.6% yield.
Example 2
tert-butyl-N-methyl-4-vinylphenylcarbamate (5.13 g,22 mmol), 2-bromo-5-iodopyridine (5.68 g,20 mmol), pdCl under nitrogen 2 (177mg,1.0mmol),TBAB(645mg,2mmol),K 2 CO 3 (2.76 g,20 mmol) was suspended in 100mL DMF and reacted at 65℃for 3 hours. Cooled to room temperature, 200mL of water was added, and extraction was performed with ethyl acetate (200 mL. Times.3). The organic phases were combined and washed with saturated brine (500 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was recrystallized from acetonitrile to give 6.03g of a white solid in 77.4% yield.
Example 3
tert-butyl-N-methyl-4-vinylphenylcarbamate (5.13 g,22 mmol), 2-bromo-5-iodopyridine (5.68 g,20 mmol), pd (OAc) under nitrogen 2 (224mg,1.0mmol),TBAB(645mg,2mmol),K 2 CO 3 (2.76 g,20 mmol) was suspended in 100mL DMF and reacted at 65℃for 3 hours. Cooled to room temperature, 200mL of water was added, and extraction was performed with ethyl acetate (200 mL. Times.3). The organic phases were combined and washed with saturated brine (500 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was recrystallized from acetonitrile to give 5.87g of a white solid in 75.4% yield.
Step (2): condensing the intermediate A with triethylene glycol to obtain the compound of the formula (I)
Example 4
Intermediate A (6 g,15.4 mmol), triethylene glycol (11.6 g,77.1 mmol), potassium tert-butoxide (8.65 g,77.1 mmol) were mixed in 100mL dry DMF under nitrogen, heated to 65℃and reacted for 3 hours. Cooled to room temperature, 200mL of water was added, and extraction was performed with ethyl acetate (200 mL. Times.3). The organic phases were combined and washed with saturated brine (200 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was recrystallized from methylene chloride/n-hexane to give 5.8g of a white solid in 82.1% yield.
Example 5
Intermediate A (6 g,15.4 mmol), triethylene glycol (11.6 g,77.1 mmol), sodium methoxide (4.16 g,77.1 mmol) were mixed in 150mL dry DMF under nitrogen, heated to 65℃and reacted for 3 hours. Cooled to room temperature, 300mL of water was added, and extraction was performed with ethyl acetate (300 mL. Times.3). The organic phases were combined and washed with saturated brine (500 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was recrystallized from t-butyl methyl ether to give 5.16g of a white solid in 73.1% yield.
Example 6
Intermediate A (6 g,15.4 mmol), triethylene glycol (11.6 g,77.1 mmol), potassium tert-butoxide (8.65 g,77.1 mmol) were mixed in 150mL dry DMF under nitrogen, heated to 90℃and reacted for 3 hours. Cooled to room temperature, 300mL of water was added, and extraction was performed with ethyl acetate (300 mL. Times.3). The organic phases were combined and washed with saturated brine (500 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was recrystallized from t-butyl methyl ether to give 4.93g of a white solid in 69.8% yield.
Characterization data of (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate prepared by the present synthetic method are
1H NMR(400MHz,CDCl 3 )δ8.18(d,J=2.3Hz,1H),7.80(dd,J=8.7,2.4Hz,1H),7.45(d,J=8.5Hz,2H),7.23(d,J=8.4Hz,2H),6.97(d,J=1.9Hz,2H),6.81(d,J=8.7Hz,1H),4.54-4.48(m,2H),3.91-3.85(m,2H),3.77-3.69(m,6H),3.65-3.60(m,2H),3.27(s,3H),1.47(s,9H).
13C NMR(100MHz,CDCl 3 )δ163.0,154.6,145.6,143.1,135.4,134.1,127.3,126.7,126.4,125.4,124.4,111.4,80.4,77.3,77.0,76.7,72.5,70.6,70.3,69.7,65.1,61.7,37.2,28.3.
Example 7: synthesis of tert-butyl-N-methyl-4-vinylphenylcarbamate
Sodium hydride (60%, 5.11g,128 mmol) was added to 200mL of dry DMF under nitrogen, ice-cooled to 0deg.C, 200mL of DMF solution containing compound 1 (20.0 g,51.1 mmol) and methyl iodide (8.7 g,61.3 mmol) was added dropwise, and the temperature was maintained at 0deg.C. After the completion of the dropwise addition, stirring was carried out for 1 hour under ice bath, and the mixture was 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, followed by extraction with ethyl acetate (1L. Times.3) to obtain an organic phase, the organic phases were combined, washed with 2L of saturated saline solution, dried over anhydrous sodium sulfate and concentrated, and then subjected to silica gel column chromatography separation and purification with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (10.8 g, 90.6%).
Example 8: synthesis of tert-butyl-N-methyl-4-vinylphenylcarbamate
Sodium hydride (60%, 6.34g,158 mmol) was added to 200mL of dry DMF under nitrogen, ice-cooled to 0deg.C, 200mL of DMF solution containing compound 2 (20.0 g,63.4 mmol) and methyl iodide (10.8 g,76.1 mmol) was added dropwise, and the temperature was maintained at 0deg.C. After the completion of the dropwise addition, stirring was carried out for 1 hour under ice bath, and the mixture was 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, followed by extraction with ethyl acetate (1L. Times.3) to obtain an organic phase, the organic phases were combined, washed with 2L of saturated saline solution, dried over anhydrous sodium sulfate and concentrated, and then subjected to silica gel column chromatography separation and purification with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (14.1 g, 95.3%).
Example 9: synthesis of tert-butyl-N-methyl-4-vinylphenylcarbamate
Sodium hydride (60%, 5.76g,144 mmol) was added to 200mL of dry DMF under nitrogen, ice-cooled to 0deg.C, 200mL of DMF solution containing compound 3 (20.0 g,57.6 mmol) and methyl iodide (9.81 g,69.1 mmol) was added dropwise, and the temperature was maintained at 0deg.C. After the completion of the dropwise addition, stirring was carried out for 1 hour under ice bath, and the mixture was 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, followed by extraction with ethyl acetate (1L. Times.3) to obtain an organic phase, the organic phases were combined, washed with 2L of saturated saline solution, dried over anhydrous sodium sulfate and concentrated, and then subjected to silica gel column chromatography separation and purification with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (12.6 g, 93.8%).
Example 10
Sodium hydride (60%, 5.41g,135 mmol) was added to 200mL of dry DMF under nitrogen, ice-cooled to 0deg.C, 200mL of DMF solution containing compound 4 (20.0 g,54.2 mmol) and methyl iodide (9.22 g,65.0 mmol) was added dropwise, and the temperature was maintained at 0deg.C. After the completion of the dropwise addition, stirring was carried out for 1 hour under ice bath, and the mixture was 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, followed by extraction with ethyl acetate (1L. Times.3) to obtain an organic phase, the organic phases were combined, washed with 2L of saturated saline solution, dried over anhydrous sodium sulfate and concentrated, and then subjected to silica gel column chromatography separation and purification with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (11.4 g, 90.3%).
Example 11
Sodium hydride (60%, 5.11g,128 mmol) was added to 200mL of dry DMF under nitrogen, ice-cooled to 0deg.C, and 200mL of DMF solution containing compound 5 (20.0 g,51.1 mmol) and dimethyl sulfate (7.73 g,61.3 mmol) was added dropwise, maintaining the temperature at 0deg.C. After the completion of the dropwise addition, stirring was carried out for 1 hour under ice bath, and the mixture was 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, followed by extraction with ethyl acetate (1L. Times.3) to obtain an organic phase, the organic phases were combined, washed with 2L of saturated saline solution, dried over anhydrous sodium sulfate and concentrated, and then subjected to silica gel column chromatography separation and purification with an eluent to obtain N-Boc-N-methyl-4-aminostyrene (11.1 g, 93.1%).
The above list of detailed descriptions is only specific to practical and feasible embodiments of the present invention, and they are not intended to limit the scope of the present invention, but all equivalent embodiments or modifications that deviate from the spirit of the present invention are included in the scope of the present invention.
Claims (7)
1. A process for the synthesis of (E) -tert-butyl-4- (2- (6- (2- (2- (2-hydroxyethoxy) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate of formula (I),
the method comprises the following steps:
step (1): performing HECK reaction on tert-butyl-N-methyl-4-vinyl phenyl carbamate and 2-bromo-5-iodopyridine to obtain an intermediate A;
step (2): condensing the intermediate A with triethylene glycol to obtain a target compound; the chemical equation of the synthesis method is as follows:
the synthesis method of the tert-butyl-N-methyl-4-vinylphenyl carbamate in the step (1) is also included: adding a substrate, a methylating agent, alkali and an organic solvent into a reactor for reaction, and after the reaction is finished, obtaining the tert-butyl-N-methyl-4-vinyl phenyl carbamate through a post-treatment step, wherein the structural formula of the substrate isLG is a leaving group, the leaving group is selected from-OTf, -OTs, -OMs, -I, the methylating agent is methyl iodide or dimethyl sulfate, the base is sodium hydride or potassium tert-butoxide, and the chemical equation of the synthesis method is shown as follows:
2. the method according to claim 1, wherein the catalyst in step (1) is PdCl 2 ,Pd(OAc) 2 The reaction temperature is 60-100 ℃, the mol ratio of the tert-butyl-N-methyl-4-vinyl phenyl carbamate to the 2-bromo-5-iodopyridine is 1.0-1.5:1, and DMF, NMP, DMA and dioxane are selected as solvents.
3. The method according to claim 2, wherein the catalyst in step (1) is Pd (OAc) 2 The reaction temperature is 65 ℃, the mol ratio of the tert-butyl-N-methyl-4-vinyl phenyl carbamate to the 2-bromo-5-iodopyridine is 1.1:1, and DMF is selected as a solvent.
4. The synthesis method according to claim 1, wherein the base used in the step (2) is sodium methoxide, sodium ethoxide, potassium tert-butoxide, cesium carbonate, the solvent used is DMF, NMP, DMA, dioxane, and the reaction temperature is 60-100 ℃.
5. The method according to claim 4, wherein the base used in the step (2) is potassium t-butoxide, the solvent used is DMF, and the reaction temperature is 65 ℃.
6. The method of claim 1, wherein the organic solvent is acetonitrile, DMF, THF, DMA or NMP.
7. The method of claim 1, wherein 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).
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011141515A1 (en) * | 2010-05-14 | 2011-11-17 | Bayer Pharma Aktiengesellschaft | Diagnostic agents for amyloid beta imaging |
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 |
CN111499544A (en) * | 2019-01-31 | 2020-08-07 | 中国医学科学院放射医学研究所 | Synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by one-pot method |
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US20140079635A1 (en) * | 2011-03-30 | 2014-03-20 | Case Western Reserve University | Molecular probes for detecting lipid composition |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
WO2011141515A1 (en) * | 2010-05-14 | 2011-11-17 | Bayer Pharma Aktiengesellschaft | Diagnostic agents for amyloid beta imaging |
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 |
CN111499544A (en) * | 2019-01-31 | 2020-08-07 | 中国医学科学院放射医学研究所 | Synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by one-pot method |
Non-Patent Citations (3)
Title |
---|
68 Ga-Bivalent Polypegylated Styrylpyridine Conjugates for Imaging A β Plaques in Cerebral Amyloid Angiopathy;Zhihao Zha et al.;《Bioconjugate Chem.》;20160404;第27卷;第1314-1323页 * |
Jianhua Jia et al..An Improved Synthesis of the Triethylene Glycol-Substituted 4 ‑( N‑Methyl ‑N‑Boc-Amino)Styrylpyridine.《ACS Omega》.2020,第5卷第19446-19452页. * |
Multidentate 18 F-Polypegylated Styrylpyridines As Imaging Agents for Aβ Plaques in Cerebral Amyloid Angiopathy (CAA);Zhihao Zha et al.;《J. Med. Chem.》;20111019;第54卷;第8085-8098页 * |
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