CN114539250B - Preparation method of Alzheimer's disease PET-tau tracer - Google Patents
Preparation method of Alzheimer's disease PET-tau tracer Download PDFInfo
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Abstract
The invention provides a preparation method of a PET-tau tracer for Alzheimer's disease, belonging to the technical field of compound preparation. The invention takes the compound I as the initial raw material, has easily available raw materials and low price, and is favorable for reducing the production cost of the target compound; the method provided by the invention has a short reaction route, the core route has only three steps, the palladium catalyst is used in the third step, and the step is synthesized by using a one-pot method, so that the cost is further reduced. Meanwhile, compared with the prior art, the method provided by the invention has the advantages that the product yield is obviously improved, and the results of examples show that the highest product yield can reach 73.2 percent by adopting the method provided by the invention.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a preparation method of a PET-tau tracer for Alzheimer's disease.
Background
Alzheimer's disease (Alzheimer disease, AD) is one of the most common, irreversible, age-related neurodegenerative brain diseases that can lead to slow loss of memory and induction of other mental disorders in patients. With the increasing global aging, the number of AD incidents increases year by year. Early discovery, early diagnosis, early intervention are important measures to improve patient prognosis, improve quality of life, and therefore development of pathology-specific diagnostic tools for AD has been receiving attention from scientists worldwide.
Aggregated tau protein is the major neuropathological substrate of the pathophysiology of neurodegenerative diseases such as AD. 7- (6-fluoropyridin-3-yl) -5H-pyridinyl [4,3-b ] indole (denoted compound T807) is an indole drug with high affinity and selectivity for tau protein and suitable in vivo pharmacokinetic characteristics, and is widely used as a highly selective and specific PET-tau tracer for AD.
Compound T807 was reported (Bioorganic & Medicinal Chemistry Letters (2015) 2953-2957) using the following route:
however, when the compound T807 is prepared by the method, the compound T807 is prepared by taking the compound 3 as a raw material, wherein the raw material is not easy to obtain, dangerous goods such as hydrogen peroxide, nitric acid and sulfuric acid are required to be prepared through a plurality of steps, and when the compound T807 is prepared, palladium catalysts are required to be used in three steps, so that the production cost of the compound T807 is high. In addition, compound T807 was prepared in the above method in a lower yield with a total yield of only 29.76%.
Disclosure of Invention
The invention aims to provide a preparation method of an Alzheimer disease PET-tau tracer, raw materials of the method are easy to obtain, a palladium catalyst is used in one step, and a target compound is low in production cost and high in yield.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of an Alzheimer's disease PET-tau tracer, wherein the Alzheimer's disease PET-tau tracer is 7- (6-fluoropyridine-3-yl) -5H-pyridinyl [4,3-b ] indole, and the preparation method comprises the following steps:
mixing the compound I, the compound II and the catalyst with a first organic solvent, and carrying out condensation reaction in a protective atmosphere to obtain a compound III; the catalyst is p-toluenesulfonic acid or glacial acetic acid;
mixing the compound III with polyphosphoric acid, and condensing to form a ring reaction in a protective atmosphere to obtain a compound IV;
mixing the compound IV, the bisboronic acid pinacol ester, potassium acetate, tris (dibenzylidene-BASE acetone) dipalladium, 2-dicyclohexylphosphine-2 ',4',6' -triisopropyl biphenyl and a second organic solvent, and carrying out a first coupling reaction in a protective atmosphere to obtain an intermediate product system; combining said intermediate system, a second organic solvent solution of 5-chloro-2-fluoropyridine with K 3 PO 4 Carrying out a second coupling reaction in a protective atmosphere to obtain the PET-tau tracer for Alzheimer's disease;
the structural formulas of the compound I, the compound II, the compound III and the compound IV are shown in the formula I, the formula II, the formula III and the formula IV in sequence:
wherein the R is 1 is-Cl, -Br or-I;
the R is 2 And R is 3 Independently selected from C1-C20 aliphatic hydrocarbonsA base.
Preferably, the molar ratio of compound I to compound II is 1: (1-2), the dosage ratio of the catalyst to the compound I is (0.01-1.00) g: (20-200) mmol.
Preferably, the temperature of the condensation reaction is 100-130 ℃ and the time is 3-6 h.
Preferably, the ratio of the amount of polyphosphoric acid to compound I is 1mmol: (1.0-1.5) g.
Preferably, the temperature of the condensation cyclization reaction is 120-160 ℃ and the time is 1-3 h.
Preferably, the molar ratio of compound IV to pinacol diboronate is 1: (1.8-2.2), wherein the molar ratio of the potassium acetate to the compound IV is (1.8-2.2): 1, the mole ratio of the (dibenzylidene-BASE acetone) dipalladium, the 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl and the compound IV is (0.18-0.22): (0.38-0.42): 10.
preferably, the temperature of the first coupling reaction is 90-130 ℃ and the time is 2-5 h.
Preferably, the molar ratio of the 5-chloro-2-fluoropyridine to the compound IV is (0.8-1.2): 1, said K 3 PO 4 The molar ratio of the compound IV is (4-6): 1.
preferably, the temperature of the second coupling reaction is 90-130 ℃ and the time is 4-8 h.
Preferably, the aliphatic hydrocarbon group is an alkyl group.
The invention provides a preparation method of an Alzheimer disease PET-tau tracer, which takes a compound I as a starting material, has easily available raw materials and low price, and is beneficial to reducing the production cost of a target compound; the method provided by the invention has a short reaction route, the core route has only three steps, the palladium catalyst is used in the third step, and the step is synthesized by using a one-pot method, so that the cost is further reduced. Meanwhile, compared with the prior art, the method provided by the invention has the advantages that the product yield is obviously improved, and the results of examples show that the highest product yield can reach 73.2 percent by adopting the method provided by the invention.
Drawings
FIG. 1 is an embodiment1 prepared 7-bromo-5H-pyridine [4,3-b ]]Indole compounds 1 H NMR chart;
FIG. 2 is a diagram of compound T807 prepared in example 1 1 H NMR chart.
Detailed Description
The invention provides a preparation method of an Alzheimer's disease PET-tau tracer, which is 7- (6-fluoropyridine-3-yl) -5H-pyridinyl [4,3-b ] indole, and comprises the following steps:
mixing the compound I, the compound II and the catalyst with a first organic solvent, and carrying out condensation reaction in a protective atmosphere to obtain a compound III; the catalyst is p-toluenesulfonic acid or glacial acetic acid;
mixing the compound III with polyphosphoric acid, and condensing to form a ring reaction in a protective atmosphere to obtain a compound IV;
mixing the compound IV, the bisboronic acid pinacol ester, potassium acetate, tris (dibenzylidene-BASE acetone) dipalladium, 2-dicyclohexylphosphine-2 ',4',6' -triisopropyl biphenyl and a second organic solvent, and carrying out a first coupling reaction in a protective atmosphere to obtain an intermediate product system; combining said intermediate system, a second organic solvent solution of 5-chloro-2-fluoropyridine with K 3 PO 4 Carrying out a second coupling reaction in a protective atmosphere to obtain the PET-tau tracer for Alzheimer's disease;
the structural formulas of the compound I, the compound II, the compound III and the compound IV are shown in the formula I, the formula II, the formula III and the formula IV in sequence:
wherein the R is 1 is-Cl, -Br or-I;
the R is 2 And R is 3 Independently selected from C1-C20 aliphatic hydrocarbon groups.
The method comprises the steps of mixing a compound I, a compound II and a catalyst with a first organic solvent, and carrying out condensation reaction in a protective atmosphere to obtain a compound III; the catalyst is p-toluenesulfonic acid or glacial acetic acid. In the invention, the structural formula of the compound I is shown as formula I, wherein R in the formula I 1 is-Cl, -Br or-I, preferably-Br, in which case the compound I is 6-bromoindole-3-carbaldehyde. In the invention, the structural formula of the compound II is shown as a formula II, wherein R in the formula I 2 And R is 3 Independently selected from C1-C20 aliphatic hydrocarbon groups, wherein the C1-C20 aliphatic hydrocarbon groups are preferably C1-C20 alkyl groups, more preferably C1-C10 alkyl groups, even more preferably C1-C5 alkyl groups, and even more preferably methyl or ethyl groups, and in this case, the compound II is aminoacetaldehyde dimethyl acetal or aminoacetaldehyde diethyl acetal.
In the present invention, the molar ratio of compound I to compound II is preferably 1: (1-2), more preferably 1: (1.2-1.7). In the present invention, the ratio of the catalyst to the compound I is preferably (0.01 to 1.00) g: (20-200) mmol; specifically, when the catalyst is p-toluenesulfonic acid, the dosage ratio of p-toluenesulfonic acid to compound I is preferably (0.1 to 1.0) g:22.3mmol, more preferably 0.1g:22.3mmol; when the catalyst is glacial acetic acid, the ratio of glacial acetic acid to compound I is preferably (0.01 to 0.10) g:200mmol, more preferably 0.1g:200mmol. In the present invention, the first organic solvent preferably includes benzene or toluene, more preferably toluene; the amount of the first organic solvent is used to ensure that the condensation reaction proceeds smoothly, which is not particularly limited in the present invention; the first organic solvent is preferably dried before use. The mixing mode of the compound I, the compound II, the catalyst and the first organic solvent is not particularly limited, and the components can be sufficiently mixed.
The kind of the protective gas for providing the protective atmosphere is not particularly limited, and may be specifically nitrogen. In the invention, the temperature of the condensation reaction is preferably 100-130 ℃, more preferably 110-120 ℃, and particularly can be the reflux temperature of the system; the time of the condensation reaction is preferably 3 to 6 hours, more preferably 3 to 4 hours; the condensation reaction is preferably carried out under stirring. In the embodiment of the invention, the condensation reaction is carried out in a three-neck flask with mechanical stirring and a water separator until the organic phase in the water separator is clear, and the reaction is stopped.
After the condensation reaction, the obtained product system is preferably concentrated under reduced pressure while the product system is hot to obtain a brownish black oily substance which is a crude product of the compound III, and the next reaction is directly carried out without purification.
After the compound III is obtained, the compound III is mixed with polyphosphoric acid, and condensation ring reaction is carried out in a protective atmosphere to obtain the compound IV. In the present invention, the polyphosphoric acid (PPA) is preferably anhydrous polyphosphoric acid; the polyphosphoric acid functions as dehydration. In the present invention, the ratio of the amount of polyphosphoric acid to compound I is preferably 1mmol: (1.0 to 1.5) g, more preferably 1mmol: (1.2-1.4) g. In the invention, the mixing of the compound III and the polyphosphoric acid is preferably to add the compound III into the polyphosphoric acid in batches, specifically to stop heating after heating the polyphosphoric acid to 80-100 ℃, and to add the compound III (specifically, the crude product of the compound III) in batches, wherein the temperature of the system is controlled to 80-110 ℃ in the whole feeding process of the compound III, and the condensation cyclization reaction is started by heating after the feeding is completed.
In the present invention, the temperature of the condensation cyclization reaction is preferably 120 to 160 ℃, more preferably 150 to 160 ℃; the time of the condensation cyclization reaction is preferably 1 to 3 hours, more preferably 2 to 3 hours; the condensation cyclization reaction is preferably carried out under stirring. In embodiments of the invention, the condensation cyclization reaction is specifically carried out in a four-necked flask with mechanical agitation. The progress of the reaction is preferably monitored by TLC.
After the condensation cyclization reaction, the invention preferably reduces the temperature of the obtained product system to 50-80 ℃, dropwise adds a first sodium hydroxide aqueous solution under the stirring condition until the pH value of the system is 8-10, filters, and washes the obtained filter cake with water to obtain a crude product of the compound IV; mixing the crude product of the compound IV with hydrochloric acid for salifying reaction, extracting with dichloromethane, mixing an aqueous phase obtained after extraction with a second sodium hydroxide aqueous solution for neutralization reaction, filtering, washing the obtained filter cake with methanol, and drying to obtain a light brown yellow solid, namely 7-bromo-5H-pyridine [4,3-b ] indole. In the present invention, the concentration of the first aqueous sodium hydroxide solution is preferably 20 to 50wt%, more preferably 40 to 50wt%. In the invention, the concentration of the hydrochloric acid is preferably 1-2 mol/L, and the use amount of the hydrochloric acid is based on the condition that the compound IV is fully salified; the temperature of the salification reaction is preferably 80-110 ℃, more preferably 90-100 ℃; the time of the salt formation reaction is preferably 2 to 6 hours, more preferably 3 to 4 hours. In the present invention, the concentration of the second aqueous sodium hydroxide solution is preferably 20 to 50wt%, more preferably 40 to 50wt%; the invention preferably adds crushed ice into the extracted water phase, and drops the second sodium hydroxide aqueous solution under the condition of stirring at 0-5 ℃ until the pH value of the system is 9-10, and performs neutralization reaction; the neutralization reaction time is preferably 2 to 5 hours, more preferably 2 to 3 hours. The invention preferably salifies the compound IV by using hydrochloric acid, so that the compound IV can be dissolved in water, and the dichloromethane is convenient for back extraction, and impurities and byproducts are extracted; and then neutralizing the hydrochloride of the compound IV in the water phase by using a sodium hydroxide aqueous solution, and separating out the compound IV in a free state from the water to achieve the purification effect.
After the compound IV is obtained, the compound IV, the bispinacol ester, the potassium acetate, the tris (dibenzylidene-BASE acetone) dipalladium, the 2-dicyclohexylphosphine-2 ',4',6' -triisopropyl biphenyl and a second organic solvent are mixed, and a first coupling reaction is carried out in a protective atmosphere to obtain an intermediate product system. In the present invention, the molar ratio of the compound IV to pinacol diboronate (BPIN) is preferably 1: (1.8 to 2.2), more preferably 1:2. in the present invention, the potassium acetate acts as a catalyst, and the molar ratio of the potassium acetate to the compound IV is preferably (1.8 to 2.2): 1, more preferably 2:1. in the present invention, the tris (dibenzylidene-BASE acetone) dipalladium (Pd 2 dba 3 ) 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (X-PHOS) as ligand catalyst for improving Pd 2 dba 3 Is a catalyst activity of (a); the Pd is 2 dba 3 The molar ratio of X-PHOS to compound IV is preferably (0.18-0.22): (0.38-0.42): 10, more preferably 0.1:0.4:10. in the present invention, the second organic solvent preferably includes dioxane, benzene or toluene, more preferablyIs dioxane; the amount of the second organic solvent is not particularly limited as long as the first coupling reaction is smoothly performed. The method for mixing the compound IV, the bispinacol ester, the potassium acetate, the tris (dibenzylidene-BASE acetone) dipalladium and the 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl with the second organic solvent is not particularly limited, and the components are fully mixed.
In the invention, the temperature of the first coupling reaction is preferably 90-130 ℃, more preferably 100-110 ℃, and particularly can be the reflux temperature of the system; the time of the first coupling reaction is preferably 2 to 5 hours, more preferably 3 to 4 hours. In the present invention, compound IV is coupled with BPIN to form a pinacol borate intermediate in the first coupling reaction. The progress of the reaction is preferably monitored by TLC.
In the present invention, after the first coupling reaction, the resulting intermediate system is directly combined with a second organic solvent solution of 5-chloro-2-fluoropyridine and K without any post-treatment 3 PO 4 And (3) carrying out a second coupling reaction in a protective atmosphere to obtain the PET-tau tracer for Alzheimer's disease. In the present invention, the molar ratio of the 5-chloro-2-fluoropyridine to the compound IV is preferably (0.8 to 1.2): 1, more preferably 1:1, a step of; the concentration of the second organic solvent solution of 5-chloro-2-fluoropyridine is preferably 0.8 to 1.2mmol/mL, more preferably 1.0mmol/mL. In the present invention, the K 3 PO 4 As a catalyst, said K 3 PO 4 The molar ratio to compound IV is preferably (4 to 6): 1, more preferably 5:1, a step of; the K is 3 PO 4 The concentration of the aqueous solution of (2) is preferably 4 to 6mol/L, more preferably 5mol/L. The invention relates to the intermediate product system, a second organic solvent solution of 5-chloro-2-fluoropyridine and K 3 PO 4 The mode of mixing the aqueous solution of (a) is not particularly limited, and the components are ensured to be fully mixed.
In the present invention, the temperature of the second coupling reaction (suzuki reaction) is preferably 90 to 130 ℃, more preferably 100 to 110 ℃, and may specifically be the reflux temperature of the system; the time of the second coupling reaction is preferably 4 to 8 hours, more preferably 5 to 6 hours. The progress of the reaction is preferably monitored by TLC.
After the second coupling reaction, the solvent is preferably removed by reduced pressure distillation after the obtained product system is cooled, the remainder is extracted by dichloromethane after water washing, the obtained organic phase is dried by anhydrous magnesium sulfate and filtered, the obtained filtrate is removed by reduced pressure distillation, the remainder is recrystallized by a methanol-dichloromethane mixed solvent, and the obtained white solid is the Alzheimer disease PET-tau tracer (compound T807). In the invention, the volume ratio of the methanol to the dichloromethane in the methanol-dichloromethane mixed solvent is preferably 2: 8-4: 6, more preferably 2:8.
the technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the 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.
Example 1
(1) Preparation of N- ((6-bromo-1H-indol-3-yl) methylene) -2, 2-dimethoxyethylamine according to the following reaction formula:
a three-necked flask equipped with a mechanical stirrer and a water separator was charged with 40mL of dry toluene, 5.0g (22.3 mmol) of 6-bromoindole-3-carbaldehyde, 4.0g (38.1 mmol) of aminoacetaldehyde dimethyl acetal and 0.1g of p-toluenesulfonic acid in N 2 Under the protection, refluxing and water diversion is carried out for 3 hours at 110 ℃, at the moment, the organic phase in the water diversion device is clarified, and the reaction is stopped; the resulting product system was concentrated under reduced pressure while hot to give a tan oil, which was crude N- ((6-bromo-1H-indol-3-yl) methylene) -2, 2-dimethoxyethylamine, which was directly subjected to the next reaction without purification.
(2) Preparing 7-bromo-5H-pyridine [4,3-b ] indole, wherein the reaction formula is as follows:
into a four-necked flask with mechanical stirring, 30g of anhydrous polyphosphoric acid (PPA) was added to N 2 Heating to 80 ℃ under protection, stopping heating, adding the brown-black oily matter in batches, controlling the system temperature to be 100-110 ℃ (the reaction is violently exothermic, so that no additional heating is needed in the feeding process), starting heating after the feeding is finished, condensing the system into a ring reaction for 3 hours at 150-160 ℃, and monitoring the reaction to be complete by TLC;
after the reaction is finished, the temperature of the obtained product system is reduced to 80 ℃, 50wt% sodium hydroxide aqueous solution is added dropwise under the condition of stirring speed of 72rpm until the pH value of the system is 9, the mixture is filtered, and the obtained filter cake is washed 3 times by deionized water to obtain a crude product of 7-bromo-5H-pyridine [4,3-b ] indole;
adding the crude 7-bromo-5H-pyridine [4,3-b ] indole into 200mL of hydrochloric acid with the concentration of 1mol/L, stirring for 4H at 90 ℃ to salify the 7-bromo-5H-pyridine [4,3-b ] indole, extracting with dichloromethane for 3 times (100 mL multiplied by 3), and recovering an extracted organic phase, wherein the residual solid in the organic phase is a small amount of unreacted 6-bromoindole-3-formaldehyde, and the organic phase can be recovered for use; adding crushed ice into the extracted water phase, dropwise adding a 50wt% sodium hydroxide aqueous solution at 0-5 ℃ under stirring until the pH value of the system is 9, continuously stirring for 2 hours, filtering, washing the obtained filter cake with methanol for 3 times, and drying to obtain a light brown yellow solid which is 7-bromo-5H-pyridine [4,3-b ] indole, wherein the yield is 4.3g and the purity is 98.6%; the total yield of step (1) and step (2) was 78.0%.
FIG. 1 is a diagram of the product 1 HNMR plot, characterized by the following data:
1 H NMR(DMSO-d 6 ):d 7.41(dd,J＝2.0,8.5Hz,1H,Ar-H),7.50(dd,J＝1.0,5.5Hz,1H,Ar-H),7.77(d,J＝2.0Hz,1H,Ar-H),8.1(d,J＝8.5Hz,1H,Ar-H),8.4(d,J＝5.5Hz,1H,Ar-H),9.36(s,1H,Ar-H),11.82(s,1H,NH)。
(3) Preparation of 7- (6-fluoropyridin-3-yl) -5H-pyridinyl [4,3-b ] indole (Compound T807) is described in the following formula:
sequentially adding 7-bromo-5H-pyridine [4,3-b ] into a three-neck flask]Indole (2.47 g,10 mmol), pinacol diboronate (BPIN, 5.1g,20 mmol), potassium acetate (1.96 g,20 mmol), tris (dibenzylidene-BASE acetone) dipalladium (0) (Pd) 2 dba 3 91.5mg,0.1 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (X-PHOS, 0.19g,0.4 mmol) and 40mL dioxane at N 2 Reflux-reacting for 3h at 110 ℃ under protection, and monitoring the reaction to be complete by TLC;
after the reaction was completed, a solution of 5-chloro-2-fluoropyridine (1.31 g,10 mmol) in dioxane (10 mL) and 10mL of K at a concentration of 5mol/L were introduced via syringe 3 PO 4 Adding the aqueous solution into the obtained reaction system, carrying out reflux reaction for 6 hours at 110 ℃, and monitoring the reaction to be complete by TLC;
after the reaction is finished, the obtained product system is cooled and then depressurized to remove dioxane, the remainder is washed 3 times with distilled water, then extracted 3 times with dichloromethane (30 mL multiplied by 3), the extracted organic phase is dried with anhydrous magnesium sulfate, a drying agent is filtered off, dichloromethane is recovered from the obtained filtrate through reduced pressure distillation, and the remainder is recrystallized by using a methanol-dichloromethane mixed solvent (the volume ratio of methanol to dichloromethane is 2:8), so that the obtained white solid is compound T807, the yield is 2.47g, the purity is 99.3%, and the yield is 93.8%; the total yield of step (1), step (2) and step (3) was 73.2%.
FIG. 2 is a diagram of the product 1 H NMR chart; characterization data are as follows:
R f ＝0.34(1:12MeOH/CH 2 Cl 2 ),mp>300℃；
1 H NMR(DMSO-d 6 ):d 7.33(dd,J＝2.8,8.4Hz,1H,Ar-H),7.50(d,J＝5.2Hz,1H,Ar-H),7.61(dd,J＝1.2,8.4Hz,1H,Ar-H),7.85(d,1H,Ar-H),8.33–8.46(m,3H,Ar-H),8.66(d,J＝5.6Hz,1H,Ar-H),9.39(s,1H,Ar-H),11.88(brs,1H,NH)。
example 2
(1) Preparation of N- ((6-bromo-1H-indol-3-yl) methylene) -2, 2-diethoxyethylamine according to the following reaction formula:
600mL of dry toluene, 44.8g (0.2 mol) of 6-bromoindole-3-carbaldehyde, 32.0g (0.24 mol) of aminoacetaldehyde diethyl acetal and 0.1g of glacial acetic acid were placed in a three-necked flask equipped with a mechanical stirrer and a water separator, and the mixture was stirred under N 2 Under the protection, refluxing and water diversion is carried out for 4 hours at 110 ℃, at the moment, the organic phase in the water diversion device is clarified, and the reaction is stopped; the resulting product system was concentrated under reduced pressure while hot to give a tan oil, which was crude N- ((6-bromo-1H-indol-3-yl) methylene) -2, 2-diethoxyethylamine, which was directly subjected to the next reaction without purification.
(2) Preparing 7-bromo-5H-pyridine [4,3-b ] indole, wherein the reaction formula is as follows:
into a four-necked flask with mechanical stirring, 250g of anhydrous polyphosphoric acid (PPA) was added to N 2 Heating to 80 ℃ under protection, stopping heating, adding the brown-black oily matter in batches, controlling the system temperature to be 100-110 ℃ (the reaction is violently exothermic, so that no additional heating is needed in the feeding process), starting heating after the feeding is finished, condensing the system into a ring reaction for 3 hours at 150-160 ℃, and monitoring the reaction to be complete by TLC;
after the reaction is finished, the temperature of the obtained product system is reduced to 80 ℃, 50wt% sodium hydroxide aqueous solution is added dropwise under the condition of rapid stirring (the stirring speed is 70 rpm) until the pH value of the system is 9, the mixture is filtered, and the obtained filter cake is washed 3 times by deionized water to obtain a crude 7-bromo-5H-pyridine [4,3-b ] indole product;
adding the crude 7-bromo-5H-pyridine [4,3-b ] indole into 1L hydrochloric acid with the concentration of 2mol/L, stirring for 3 hours at 90 ℃ to salify the 7-bromo-5H-pyridine [4,3-b ] indole, extracting with dichloromethane for 3 times (300 mL multiplied by 3), and recovering an extracted organic phase, wherein the residual solid in the organic phase is a small amount of unreacted 6-bromoindole-3-formaldehyde, and the organic phase can be recovered for use; adding crushed ice into the extracted water phase, dropwise adding a 50wt% sodium hydroxide aqueous solution at 0-5 ℃ under stirring until the pH value of the system is 9, continuously stirring for 3 hours, filtering, washing the obtained filter cake with methanol for 3 times, and drying to obtain a light brown yellow solid which is 7-bromo-5H-pyridine [4,3-b ] indole, wherein the yield is 36.4g and the purity is 98.3%; the total yield of step (1) and step (2) was 73.7%.
(3) Preparation of 7- (6-fluoropyridin-3-yl) -5H-pyridinyl [4,3-b ] indole (Compound T807) is described in the following formula:
sequentially adding 7-bromo-5H-pyridine [4,3-b ] into a three-neck flask]Indole (24.7 g,0.1 mol), pinacol diboronate (BPIN, 51g,0.2 mol), potassium acetate (19.6 g,0.2 mol), tris (dibenzylidene-BASE acetone) dipalladium (0) (Pd) 2 dba 3 0.92g,1.0 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (X-PHOS, 1.9g,4 mmol) and 500mL dioxane in N 2 Reflux-reacting for 4h at 110 ℃ under the protection, and monitoring the reaction to be complete by TLC;
after the completion of the reaction, a solution of 5-chloro-2-fluoropyridine (13.1 g,0.1 mol) in dioxane (100 mL) and 80mL of K at a concentration of 5mol/L were introduced via syringe 3 PO 4 Adding the aqueous solution into the obtained reaction system, and carrying out reflux reaction for 5h at 110 ℃ (TLC monitoring reaction is complete;
after the reaction is finished, the obtained product system is cooled and then depressurized to remove dioxane, the remainder is washed 3 times with distilled water, then extracted 3 times with dichloromethane (200 mL multiplied by 3), the extracted organic phase is dried with anhydrous magnesium sulfate, a drying agent is filtered off, dichloromethane is recovered from the obtained filtrate by reduced pressure distillation, and the remainder is recrystallized by a methanol-dichloromethane mixed solvent (the volume ratio of methanol to dichloromethane is 2:8), so that the obtained white solid is compound T807, the yield is 25.48g, the purity is 99.1%, and the yield is 96.8%; the total yield of step (1), step (2) and step (3) was 71.3%.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (3)
1. The preparation method of the Alzheimer's disease PET-tau tracer is characterized by comprising the following steps of:
mixing the compound I, the compound II and the catalyst with a first organic solvent, and carrying out condensation reaction in a protective atmosphere to obtain a compound III; the catalyst is p-toluenesulfonic acid or glacial acetic acid; the mol ratio of the compound I to the compound II is 1 (1-2), and the dosage ratio of the catalyst to the compound I is (0.01-1.00) g (20-200) mmol;
mixing the compound III with polyphosphoric acid, and condensing to form a ring reaction in a protective atmosphere to obtain a compound IV; the dosage ratio of the polyphosphoric acid to the compound I is 1mmol (1.0-1.5 g);
mixing the compound IV, the bisboronic acid pinacol ester, potassium acetate, tris (dibenzylidene-BASE acetone) dipalladium, 2-dicyclohexylphosphine-2 ',4',6' -triisopropyl biphenyl and a second organic solvent, and carrying out a first coupling reaction in a protective atmosphere to obtain an intermediate product system; combining said intermediate system, a second organic solvent solution of 5-chloro-2-fluoropyridine with K 3 PO 4 The aqueous solution of the organic phase is dried by anhydrous magnesium sulfate and then filtered, the solvent is removed by reduced pressure distillation, and the remainder is recrystallized by a methanol-dichloromethane mixed solvent to obtain the PET-tau tracer for Alzheimer's disease; the molar ratio of the compound IV to the pinacol diboronate is 1: (1.8-2.2), the potassium acetate and the chemical reactionThe molar ratio of the compound IV is (1.8-2.2): 1, and the molar ratio of the tri (dibenzylidene-BASE acetone) dipalladium, the 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl and the compound IV is (0.18-0.22): (0.38-0.42): 10; the molar ratio of the 5-chloro-2-fluoropyridine to the compound IV is (0.8-1.2): 1, the K 3 PO 4 The molar ratio of the compound IV is (4-6) 1;
the temperature of the first coupling reaction is 90-130 ℃ and the time is 2-5 h; the temperature of the second coupling reaction is 90-130 ℃ and the time is 4-8 h;
the structural formulas of the compound I, the compound II, the compound III and the compound IV are shown in the formula I, the formula II, the formula III and the formula IV in sequence:
wherein the R is 1 is-Cl, -Br or-I;
the R is 2 And R is 3 Independently methyl or ethyl.
2. The method according to claim 1, wherein the condensation reaction is carried out at a temperature of 100 to 130 ℃ for a time of 3 to 6 hours.
3. The method according to claim 1, wherein the condensation cyclization reaction is carried out at a temperature of 120 to 160 ℃ for a time of 1 to 3 hours.
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| CN102083830A (en) * | 2008-03-24 | 2011-06-01 | 梅迪维新技术公司 | Pyrido [3, 4-b] indoles and methods of use |
| CN104781234A (en) * | 2012-05-22 | 2015-07-15 | 伊莱利利公司 | Carboline and carbazole based imaging agents for detecting neurological dysfunction |
| CN105579454A (en) * | 2013-09-26 | 2016-05-11 | 伊莱利利公司 | Compounds and their use for preparation of Tau imaging agents and Tau imaging formulations |
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