CN113956268B - 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method - Google Patents
6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method Download PDFInfo
- Publication number
- CN113956268B CN113956268B CN202111402332.9A CN202111402332A CN113956268B CN 113956268 B CN113956268 B CN 113956268B CN 202111402332 A CN202111402332 A CN 202111402332A CN 113956268 B CN113956268 B CN 113956268B
- Authority
- CN
- China
- Prior art keywords
- bromo
- phenyl
- nitropyridine
- pyridine
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The invention discloses 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and a synthesis method, 2-methylthiophenylboronic acid and 4-chloro-3-nitropyridine are used as initial raw materials, suzuki coupling reaction is firstly carried out to obtain an intermediate 4- (2-methylthio) phenyl-3-nitropyridine, 4- (5-bromo- (2-methylthio) phenyl) -3-nitropyridine is synthesized through bromination reaction, 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine is obtained through reduction by a reducing agent, 6-bromobenzothiophene [2,3-c ] pyridine is prepared through diazotization reaction closed loop, a target compound 6-bromo-1-chlorobenzothiophene [2 ] is prepared through chlorination reaction at low temperature, 3-c ] pyridine.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, relates to a synthetic method of thiophene heterocyclic derivatives, and particularly relates to 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and a synthetic method thereof.
Background
Thiophene heterocyclic compounds have recently gained more and more application in the field of developing new photoelectric materials, and thiophene heterocyclic compounds have many applications as synthetic basic elements of dyes, medicines, pesticides or conductive polymers.
The benzothienopyridine compound contains two heterocyclic skeletons of thiophene and pyridine, so that the benzothienopyridine compound has rich potential drug and life activities. Such as anti-allergic, anti-inflammatory, antibacterial and analgesic activity, inhibitors of cyclin dependent protease kinases and topoisomerase inhibitors. Meanwhile, due to the existence of the pyridine ring, the pyridine ring can participate in the design and synthesis of a new catalyst in the form of a monodentate nitrogen ligand, in addition, different halogens are introduced into the 1 and 6 positions, so that the pyridine ring has good selectivity, a plurality of organic electroluminescent materials can be derived, and a good feedback effect is achieved on device evaluation.
The synthesis method of the compound mainly comprises the following steps:
the synthetic method of the compound is reported by Park, Ji Hui et al, Reub.Korean Kongkae Taeho Kongbo,2014079306 and 26Jun 2014, 2-chloro-4-aminopyridine is used as a raw material, iodination is firstly carried out, then coupling reaction is carried out on the raw material and p-bromothiophenol, and amino diazotization cyclization is carried out to obtain a target product, wherein the reaction route is as follows:
however, in the above synthesis method, the first step is based on Jose, Gilish et al, European Journal of Medicinal Chemistry,131, 275-; 2017, it is reported that there are three products in 2-chloro-4-aminopyridine at the time of iodination, mainly 2-chloro-5-iodo-4-aminopyridine, 2-chloro-3, 5-diiodo-4-aminopyridine, the ratio of the three products is 45: 45: 10, the separation of three compounds is very difficult, and is not suitable for large-scale industrial production.
The first iodination reaction route is as follows:
in the second step, the thiophenol is very active and has by-products
1, 2-bis (4-bromophenyl) disulfide
And the like.
The literature reports only one synthetic method, and the first step of the synthetic method has the defects of large isomer preparation, difficult separation, low yield, low atom utilization rate and unsuitability for industrial scale-up production, so that the development of a new synthetic method is necessary.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and a synthesis method thereof.
In order to solve the technical problem, the technical scheme of the invention is as follows: a synthetic method of 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine comprises the following steps:
step 1: carrying out coupling reaction by using 2-methylthio phenylboronic acid and 4-chloro-3-nitropyridine as initial raw materials to obtain an intermediate 4- (2-methylthio) phenyl-3-nitropyridine, wherein the molar ratio of the 2-methylthio phenylboronic acid to the 4-chloro-3-nitropyridine is 1: 0.9-1;
step 2: synthesizing 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine from the intermediate 4- (2-methylmercapto) phenyl-3-nitropyridine and bromine through bromination reaction, wherein the molar ratio of the 4- (2-methylmercapto) phenyl-3-nitropyridine to the bromine is 1: 1-1.2;
and step 3: reducing 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine by using a reducing agent to obtain 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine, wherein the molar ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine to the reducing agent is 1: 4-6;
and 4, step 4: carrying out diazotization reaction on 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine and a diazotization reagent to prepare 6-bromobenzothiophene [2,3-c ] pyridine, wherein the molar ratio of the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine to the diazotization reagent is 1: 1.6-2;
and 5: the 6-bromobenzothiophene [2,3-c ] pyridine and a chlorinated reagent are subjected to chlorination reaction to prepare a target compound 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, wherein the molar ratio of the 6-bromobenzothiophene [2,3-c ] pyridine to the chlorinated reagent is 1: 1-1.2.
Preferably, the step 1 specifically comprises: under the protection of inert gas, 2-methylthio phenylboronic acid and 4-chloro-3-nitropyridine are used as initial raw materials, the initial raw materials are dissolved in a mixed solvent of dioxane and water, and a suzuki coupling reaction is carried out in the presence of inorganic base and catalyst to prepare an intermediate 4- (2-methylthio) phenyl-3-nitropyridine, wherein the molar ratio of the 2-methylthio phenylboronic acid to the 4-chloro-3-nitropyridine to the catalyst to the inorganic base is (1: 0.9-1: 0.003-0.03): 2-3; the dosage ratio of the 2-methylthio phenylboronic acid to the dioxane to the water is 1g: 6 ml: 1.5ml, and the temperature of the suzuki coupling reaction is 85-95 ℃.
Preferably, the inert gas is nitrogen, the inorganic base is one of potassium carbonate, potassium phosphate or cesium carbonate, and the catalyst is palladium tetratriphenylphosphine or 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium.
Preferably, the molar ratio of the 2-methylthio phenylboronic acid to the 4-chloro-3-nitropyridine to the catalyst to the inorganic base is 1:0.95:0.01:2, and the temperature of the suzuki coupling reaction is 88 ℃.
Preferably, the step 2 specifically comprises: dissolving the intermediate 4- (2-methylmercapto) phenyl-3-nitropyridine obtained in the step 1 in dichloroethane solvent, dropwise adding bromine for bromination reaction, and then purifying to obtain the intermediate 4- (5-bromine- (2-methylmercapto) phenyl) -3-nitropyridine, wherein the molar ratio of the 4- (2-methylmercapto) phenyl-3-nitropyridine to the bromine is 1:1.1, the dosage ratio of the 4- (2-methylmercapto) phenyl-3-nitropyridine to the dichloroethane solvent is 1g:5ml, and the bromination reaction temperature is 30-50 ℃.
Preferably, the step 3 specifically comprises: dissolving the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine obtained in the step 2 in ethanol and water, and adding a reducing agent in batches for reduction reaction to prepare 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine, wherein the reducing agent is sodium hydrosulfite, the molar ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine to the sodium hydrosulfite is 1:5, and the dosage ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine to the ethanol and the water is 1g:5 ml: 9ml, and the temperature of the reduction reaction is 45-55 ℃.
Preferably, the step 4 specifically comprises: dissolving the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine obtained in the step 3 in a mixed solvent of acetic acid and tetrahydrofuran, dropwise adding a diazotization reagent, and continuing to perform a ring closing reaction after the dropwise adding is finished to prepare 6-bromobenzothiophene [2,3-c ] pyridine, wherein the diazotization reagent is tert-butyl nitrite or isoamyl nitrite, and the molar ratio of the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine to the diazotization reagent is 1: 1.8; the dosage ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine to the acetic acid and the tetrahydrofuran is 1g: 2 ml: 2ml, the temperature when the diazotization reagent is dripped is 0-5 ℃, the reaction temperature is 20-30 ℃ after the diazotization reagent is dripped, and the reaction time is 5-10h after the diazotization reagent is dripped.
Preferably, the step 5 specifically comprises: dissolving the 6-bromobenzothiophene [2,3-c ] pyridine obtained in the step 4 in tetrahydrofuran, wherein the dosage ratio of the 6-bromobenzothiophene [2,3-c ] pyridine to the tetrahydrofuran is 1g: 6ml, after being treated by organic alkali, the raw material is subjected to chlorination reaction with a chlorinating reagent to prepare a target product 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, wherein the organic alkali is 2,2,6, 6-tetramethyllithium piperidine or lithium diisopropylamide, the chlorinating reagent is hexachloroethane, the molar ratio of the 6-bromobenzothiophene [2,3-c ] pyridine to the organic alkali is 1:1.2-1.5, the molar ratio of the 6-bromobenzothiophene [2,3-c ] pyridine to the chlorinating reagent is 1:1.1, the organic alkali is treated by dropwise adding, the reaction treatment temperature of the organic alkali is-20-0 ℃, and the reaction time of the organic alkali is 2-3 h; the adding mode of the chlorinated reagent is dropwise adding, the dropwise adding temperature of the chlorinated reagent is-70 ℃ to-85 ℃, and the reaction time of the chlorinated reagent is 2-5 h.
Preferably, the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is used for organic photoelectric materials.
Preferably, the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is synthesized by the method for synthesizing 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine described in any one of the above.
Compared with the prior art, the invention has the advantages that:
(1) the invention provides a synthesis method of 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, raw materials are easy to obtain, five steps of reactions are simple in post-treatment, isomer-free, single in product, high temperature and high pressure are avoided in the five steps of reaction operation, dangerous operations such as severe heat release and severe air release are avoided, and the method is suitable for industrial amplification production;
(2) the main raw materials of the invention, namely the 2-methylthio phenylboronic acid and the 4-chloro-3-nitropyridine, are low in price, all auxiliary materials are sold in the market in large quantities, the operation and the post-treatment are simple, the purity of the prepared target product, namely the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, can reach more than 99 percent, and the invention is suitable for industrial production;
(3) the synthesis process has few side reactions, the prepared 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is a very important intermediate in the fields of organic photoelectric materials, medicines and the like, and a series of terminal derivative compounds can be prepared on the basis of the intermediate, and chlorine and bromine on the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine have good selectivity.
Drawings
FIG. 1 is a H spectrum of 4- (2-methylmercapto) phenyl-3-nitropyridine in example 1 of the present invention;
FIG. 2 is an H spectrum of 4- (5-bromo- (2-methylthio) phenyl) -3-nitropyridine in example 1 of the present invention;
FIG. 3 is an H spectrum of 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine in example 1 of the present invention;
FIG. 4 is an H spectrum of 6-bromobenzothiophene [2,3-c ] pyridine in example 1 of the present invention;
FIG. 5 is a H spectrum of 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine in example 1 of the present invention.
Detailed Description
The present invention is illustrated below by reference to specific examples, wherein the raw materials, solvents and catalysts are all conventional and commercially available products.
The invention discloses a synthetic method of 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, which comprises the following steps:
step 1: performing coupling reaction by using 2-methylthio phenylboronic acid and 4-chloro-3-nitropyridine as starting materials to obtain an intermediate 4- (2-methylthio) phenyl-3-nitropyridine, wherein the molar ratio of the 2-methylthio phenylboronic acid to the 4-chloro-3-nitropyridine is 1: 0.9-1;
step 2: synthesizing 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine from the intermediate 4- (2-methylmercapto) phenyl-3-nitropyridine and bromine through a bromination reaction, wherein the molar ratio of the 4- (2-methylmercapto) phenyl-3-nitropyridine to the bromine is 1: 1-1.2;
and step 3: reducing 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine by using a reducing agent to obtain 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine, wherein the molar ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine to the reducing agent is 1: 4-6;
and 4, step 4: the 6-bromobenzothiophene [2,3-c ] pyridine is prepared by 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine and a diazotization reagent through diazotization reaction closed-loop, wherein the molar ratio of the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine to the diazotization reagent is 1: 1.6-2.0;
and 5: the 6-bromobenzothiophene [2,3-c ] pyridine and a chlorinated reagent are subjected to chlorination reaction to prepare a target compound 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, wherein the molar ratio of the 6-bromobenzothiophene [2,3-c ] pyridine to the chlorinated reagent is 1: 1-1.2.
According to the synthetic method, reaction conditions (such as reaction temperature, solvent selection and product separation) of each step can be realized by adopting conventional available means in the field, and the method can be used for preparing the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine by realizing the reaction process.
Only in order to further improve the quality of the preparation route and better realize the purpose of the invention, the invention optimizes the specific conditions of the synthesis method as follows:
preferably, the step 1 specifically comprises: under the protection of inert gas, 2-methylthio phenylboronic acid and 4-chloro-3-nitropyridine are taken as initial raw materials and dissolved in a mixed solvent of dioxane and water, carrying out suzuki coupling reaction in the presence of inorganic base and catalyst to prepare an intermediate 4- (2-methylmercapto) phenyl-3-nitropyridine, the inert gas is nitrogen, the inorganic base is one of potassium carbonate, potassium phosphate or cesium carbonate, the inorganic base is preferably potassium phosphate, the catalyst is tetratriphenylphosphine palladium or 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride, the catalyst is preferably tetratriphenylphosphine palladium, the feeding molar ratio of the 2-methylthio phenylboronic acid to the 4-chloro-3-nitropyridine to the catalyst to the inorganic base is 1:0.9-1: 0.003-0.03: 2-3; the dosage ratio of the 2-methylthio phenylboronic acid to the dioxane to the water is 1g: 6 ml: 1.5ml, and the temperature of the suzuki coupling reaction is 85-95 ℃.
The catalyst is a common catalyst on the market, and the palladium tetratriphenylphosphine or 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (II) is a catalyst which is widely supplied on the market and is easy to obtain.
Preferably, the feeding molar ratio of the 2-methylthio phenylboronic acid to the 4-chloro-3-nitropyridine to the catalyst to the inorganic base is 1:0.95:0.01:2, and the temperature of the suzuki coupling reaction is 88 ℃.
The preferable post-treatment in the suzuki coupling reaction in the step 1 comprises the steps of recovering the solvent under reduced pressure, extracting toluene, washing an organic phase to be neutral, drying, removing the catalyst and mechanical impurities through a silica gel column, and recovering the solvent under reduced pressure.
Preferably, the step 2 specifically comprises: dissolving the intermediate 4- (2-methylmercapto) phenyl-3-nitropyridine obtained in the step 1 in dichloroethane solvent, dropwise adding bromine to carry out bromination reaction, and then purifying to obtain the intermediate 4- (5-bromine- (2-methylmercapto) phenyl) -3-nitropyridine, wherein the molar ratio of the 4- (2-methylmercapto) phenyl-3-nitropyridine to the bromine is 1:1.1, the dosage ratio of the 4- (2-methylmercapto) phenyl-3-nitropyridine to the dichloroethane solvent is 1g:5ml, and the bromination reaction temperature is 30-50 ℃, preferably 45 ℃.
In the bromination reaction in the step 2, the preferable post-treatment comprises washing the organic phase with an aqueous solution of sodium bisulfite, washing the organic phase with water until the organic phase is neutral, drying the organic phase, recovering the solvent under reduced pressure, and separating and purifying the organic phase through a silica gel column to obtain the intermediate 4- (5-bromo- (2-methylthio) phenyl) -3-nitropyridine.
Preferably, the step 3 specifically comprises: dissolving the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine obtained in the step 2 in ethanol and water, and adding a reducing agent in batches for reduction reaction to prepare 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine, wherein the reducing agent is sodium hydrosulfite, the molar ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine to the sodium hydrosulfite is 1:5, and the dosage ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine to the ethanol and the water is 1g:5 ml: 9ml, and the temperature of the reduction reaction is 45-55 ℃, preferably 50 ℃.
In the reduction reaction in the step 3, the preferable post-treatment comprises the steps of recovering ethanol under reduced pressure, extracting with dichloroethane, drying an organic phase, and recovering the solvent under reduced pressure to obtain the intermediate 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine.
Preferably, the step 4 specifically comprises: dissolving the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine obtained in the step 3 in a mixed solvent of acetic acid and tetrahydrofuran, dropwise adding a diazotization reagent, and continuing to perform a ring closing reaction after the dropwise adding is finished to prepare 6-bromobenzothiophene [2,3-c ] pyridine, wherein the diazotization reagent is tert-butyl nitrite or isoamyl nitrite, preferably tert-butyl nitrite, and the molar ratio of the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine to the diazotization reagent is 1: 1.8; the dosage ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine to the acetic acid and the tetrahydrofuran is 1g: 2 ml: 2ml, the temperature when the diazotization reagent is dripped is 0-5 ℃, preferably 2 ℃, the reaction temperature after the diazotization reagent is dripped is 20-30 ℃, preferably 25 ℃, and the reaction time after the diazotization reagent is dripped is 5-10 hours, preferably 6 hours.
In the diazotization ring-closure reaction in the step 4, the preferable post-treatment comprises adding water for dispersing, filtering a solid crude product, passing through a silica gel column, and boiling and washing with ethanol to obtain an intermediate 6-bromobenzothiophene [2,3-c ] pyridine.
Preferably, the step 5 specifically comprises: dissolving the 6-bromobenzothiophene [2,3-c ] pyridine obtained in the step 4 in tetrahydrofuran, wherein the dosage ratio of the 6-bromobenzothiophene [2,3-c ] pyridine to the tetrahydrofuran is 1g: 6ml, after being treated by organic alkali, the raw material is chlorinated with a chlorinating reagent to prepare the target product 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, wherein the organic alkali is 2,2,6, 6-tetramethyllithium piperidine or lithium diisopropylamide, preferably 2,2,6, 6-tetramethyllithium piperidine, the chlorinating reagent is hexachloroethane, the molar ratio of 6-bromobenzothiophene [2,3-c ] pyridine to the organic alkali is 1:1.2-1.5, preferably 1:1.3, the molar ratio of 6-bromobenzothiophene [2,3-c ] pyridine to the chlorinating reagent is 1:1.1, the organic alkali is dropwise added, the reaction treatment temperature of the organic alkali is-20 ℃ to 0 ℃, preferably-5 ℃, and the reaction time of the organic alkali is 2-3h, preferably for 2 h; the adding mode of the chlorinated reagent is dropwise adding, the dropwise adding temperature of the chlorinated reagent is-70 ℃ to-85 ℃, the preferable temperature is-75 ℃, and the reaction time of the chlorinated reagent is 2-5 hours, and the preferable time is 3 hours.
In the chlorination reaction in the step 5, the preferable post-treatment comprises the steps of recovering the solvent under reduced pressure, extracting dichloroethane, washing the organic phase with water, drying, recovering the solvent under reduced pressure, and then separating and purifying through a silica gel column to obtain the intermediate 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine.
Preferably, the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is used for organic photoelectric materials.
Preferably, the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is synthesized by the method for synthesizing 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine described in any one of the above.
Example 1
The embodiment provides a synthesis method of 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, and specifically, the method comprises the following steps:
adding 95g (molecular weight 168.02, 0.565mol) of 2-methylthio phenylboronic acid, 85.1g (molecular weight 158.54,0.537mol) of 4-chloro-3-nitropyridine, 239.8g (molecular weight 212.27,1.13mol) of potassium phosphate, 570ml of dioxane and 143ml of water into a reaction bottle with a stirring pipe, a condensing pipe and a thermometer, continuously carrying out nitrogen protection after three times of nitrogen replacement, heating to 40 ℃, quickly adding 6.53g (molecular weight 1155.56,0.00565mol) of palladium tetratriphenylphosphine into the system, and heating to 88 ℃ for reflux reaction; the reaction is stopped by tracking and monitoring the raw material 4-chloro-3-nitropyridine LC (LC) to be less than 1 percent, 500ml of solvent is concentrated from the reaction solution under reduced pressure, 600ml of toluene is added, the organic phase is washed to be neutral by water, drying is carried out by 50g of anhydrous sodium sulfate, then the drying agent is filtered, a normal-temperature column filled with 100g of silica gel is passed, and the column solution is concentrated under reduced pressure to be dried to obtain a brown yellow oily substance 4- (2-methylthio) phenyl-3-nitropyridine 125.1g with the content of 95.8 percent, wherein the yield of the step is 89.8 percent.
As shown in fig. 1, the nuclear magnetic spectrum data is consistent with the product structure,1H NMR(500MHz,Chloroform)δ9.43(d,J＝0.6Hz,1H),9.36(d,J＝15.0Hz,1H),7.91(d,J＝14.8Hz,1H),7.67(dd,J＝14.9,3.1Hz,1H),7.55(dd,J＝14.9,3.2Hz,1H),7.42(tt,J＝17.0,8.4Hz,1H),7.26(td,J＝14.9,3.2Hz,1H),2.46(s,3H)。
reacting 125.1g (molecular weight of 246.28, 0.508mol) of 4- (2-methylmercapto) phenyl-3-nitropyridine with 625ml of dichloroethane, heating to 45 ℃, starting to dropwise add 89.5g (molecular weight of 160,0.559mol) of bromine, and keeping the temperature at 45 ℃ for reacting for 24 hours after the dropwise addition; the Liquid Chromatography (LC) is utilized to track and monitor that the content of the 4- (2-methylmercapto) phenyl-3-nitropyridine LC is less than 5 percent, the reaction is stopped, the organic phase of the reaction solution is washed once by 300ml of 5 percent sodium bisulfite aqueous solution, the organic phase is washed to be neutral by water again, the drying agent is filtered after being dried by 50g of anhydrous sodium sulfate, the solvent is removed by decompression, the column is filtered by n-heptane and ethyl acetate, and the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine is obtained by separation and purification, wherein the content is 97.1 percent, and the yield of the step is 78.05 percent.
As shown in fig. 2, the nuclear magnetic spectrum data is consistent with the structure of the product,1H NMR(500MHz,Chloroform)δ9.43(d,J＝0.6Hz,1H),9.36(d,J＝15.0Hz,1H),7.97–7.85(m,2H),7.44(d,J＝15.0Hz,1H),7.35(d,J＝3.0Hz,1H),2.46(s,3H)。
128g (molecular weight 325.18, 0.393mol) of 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine, 640ml of ethanol and 1150ml of water are stirred uniformly, 342g (molecular weight 174.1, 1.965mol) of sodium hydrosulfite (sodium dithionate) is added in batches when the temperature is raised to 50 ℃, and the mixture is stirred and reacted at the temperature after the addition is finished; the reaction was stopped by following the Liquid Chromatography (LC) until the content of 4- (5-bromo- (2-methylthio) phenyl) -3-nitropyridine was < 0.5%, ethanol was removed under reduced pressure by about 600ml, the system was extracted with dichloroethane, the organic phase was washed with water, dried over 50g of anhydrous sodium sulfate and then the drying agent was filtered off, and the solvent was removed under reduced pressure to give 110.4g of 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine with a purity of 94.9% and a yield of 95.1% in this step.
As shown in fig. 3, the nmr spectrum data was consistent with the product structure,1H NMR(500MHz,Chloroform)δ8.61(d,J＝15.0Hz,1H),8.23(s,1H),7.91(dd,J＝15.0,2.9Hz,1H),7.67(d,J＝15.0Hz,1H),7.44(d,J＝15.0Hz,1H),7.35(d,J＝3.0Hz,1H),3.62(s,2H),2.46(s,3H)。
stirring 92.5g (with the molecular weight of 295.2 and 0.313mol) of 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine 185ml and 185ml of acetic acid and tetrahydrofuran, uniformly mixing the system, cooling to 2 ℃, dropwise adding 58.1g (with the molecular weight of 103.12 and 0.563mol) of tert-butyl nitrite, and heating to 25 ℃ after dropwise adding to react for 6 hours; after the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine is reacted completely by utilizing Liquid Chromatography (LC) tracking monitoring, 200ml of water is added into a reaction solution, solid is directly filtered and precipitated, the solid is washed to be neutral by water and is drained, 1400ml of toluene is used for dissolving the solid, then the solid is filtered through a normal-temperature (25 ℃) silica gel column, concentration is stopped when column-passing liquid is collected and concentrated to about the residual 120ml of a system under negative pressure, the solid is filtered and drained when the temperature is reduced to 0 ℃ under stirring, 68g of a solid product is obtained, the solid is washed for 30min by refluxing with 102ml of ethanol, then the solid is stirred and cooled to 0 ℃, filtered and dried, 62g of yellow solid 6-bromobenzothiophene [2,3-c ] pyridine is obtained, the content is 98.2%, and the yield of the step is 75%.
As shown in fig. 4, the nmr spectrum data was consistent with the product structure,1H NMR(500MHz,Chloroform)δ8.84(s,1H),8.61(d,J＝7.5Hz,1H),7.92(d,J＝1.4Hz,1H),7.86(d,J＝7.5Hz,1H),7.70(d,J＝7.5Hz,1H),7.45(dd,J＝7.5,1.4Hz,1H)。
under the protection of nitrogen, 58g (molecular weight of 264.14, 0.22mol) of 6-bromobenzothiophene [2,3-c ] pyridine and 350ml of tetrahydrofuran are added into a reaction bottle, stirred until the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is dissolved, the temperature is reduced to minus 5 ℃,2,6, 6-tetramethylpiperidine lithium 286ml (1.0mol/L n-hexane solution, 0.286mol) is added dropwise, after dropping, the reaction is carried out at 5 ℃ for 2h, the temperature is reduced to minus 75 ℃, 57.3g (molecular weight of 236.74, 0.242mol) of tetrahydrofuran (60ml) solution is added dropwise, after dropping, the reaction is carried out at minus 75 ℃ for 3h, after the reaction is finished, the solvent is removed under reduced pressure, dichloroethane is used for extraction, the organic phase is washed to be neutral, 30g of anhydrous magnesium sulfate is used for drying, a drying agent is filtered out, the organic phase is used for removing the solvent, a mixed solvent of n-heptane and ethyl acetate is used for passing through a silica gel column, after the solvent is removed by the injection liquid, 40.6g of the target compound 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is obtained by dispersing with 50ml of ethanol, and the product is a white solid with the purity of 99.35 percent and the yield of 62 percent.
As shown in fig. 5, the nmr spectrum data was consistent with the product structure,1H NMR(500MHz,Chloroform)δ8.72(s,1H),8.35(s,1H),7.92(s,1H),7.86(s,1H),7.45(s,1H)。
example 2
The embodiment provides a synthesis method of 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, and specifically, the method comprises the following steps:
adding 40g (molecular weight of 168.02, 0.238mol) of 2-methylthio phenylboronic acid, 33.9g (molecular weight of 158.54,0.214mol) of 4-chloro-3-nitropyridine, 110g (molecular weight of 212.27,0.476mol) of potassium phosphate, 240ml of dioxane and 60ml of water into a reaction bottle with a stirring pipe, a condensing pipe and a thermometer, continuously carrying out nitrogen protection after three times of nitrogen replacement, heating to 40 ℃, quickly adding 1.74g (molecular weight of 731.7,0.00238mol) of 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) into the system, and heating to 88 ℃ for reflux reaction; the reaction is stopped by tracking and monitoring the content of 4-chloro-3-nitropyridine LC < 1% by using Liquid Chromatography (LC), the reaction solution is decompressed and concentrated to remove 200ml of solvent, 200ml of toluene is added, the organic phase is washed to be neutral by water, drying is carried out by 20g of anhydrous sodium sulfate, then a drying agent is filtered out, the mixture is filtered through a normal temperature column filled with 35g of silica gel, and the column filtrate is decompressed, concentrated and dried to obtain a brown yellow oily matter 4- (2-methylmercapto) phenyl-3-nitropyridine 50.42g with the content of 96.3%, and the yield of the step is 86.02%.
Reacting 50g (molecular weight of 246.28, 0.203mol) of 4- (2-methylmercapto) phenyl-3-nitropyridine with 250ml of dichloroethane, heating to 45 ℃, dropwise adding 38.9g (molecular weight of 160,0.243mol) of bromine, and keeping the temperature at 45 ℃ for reacting for 24 hours; the Liquid Chromatography (LC) is utilized to track and monitor that the content of the 4- (2-methylmercapto) phenyl-3-nitropyridine LC is less than 5 percent, the reaction is stopped, the organic phase of the reaction solution is washed once by 150ml of 5 percent sodium bisulfite aqueous solution, the organic phase is washed to be neutral by water again, after being dried by 25g of anhydrous sodium sulfate, a drying agent is filtered, after the solvent is removed by decompression, 53.9g of 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine is obtained by separation and purification by passing through a column by n-heptane and ethyl acetate, the content is 96.7 percent, and the yield of the step is 81.7 percent.
50g (molecular weight 325.18, 0.154mol) of 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine, 250ml of ethanol and 450ml of water are uniformly stirred, 160g (molecular weight 174.1, 0.924mol) of sodium hydrosulfite (sodium dithionate) is added in batches when the temperature is raised to 50 ℃, and the mixture is stirred and reacted at the temperature after the addition is finished; the reaction was stopped by Liquid Chromatography (LC) until the content of 4- (5-bromo- (2-methylthio) phenyl) -3-nitropyridine was < 0.5%, ethanol was removed under reduced pressure by 200ml, the system was extracted with dichloroethane, the organic phase was washed with water, dried over 25g anhydrous sodium sulfate and then the drying agent was filtered off, and the solvent was removed under reduced pressure to give 42.8g of 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine with a purity of 95.5% and a yield of 94.2% in this step.
Starting stirring 40g (molecular weight is 295.2,0.135mol) of 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine, 90ml of acetic acid and 80ml of tetrahydrofuran, uniformly mixing the system, cooling to 2 ℃, dropwise adding 20.8g (molecular weight is 103.12, 0.202mol) of tert-butyl nitrite, and heating to 25 ℃ after dropwise adding for reacting for 6 h; after the completion of the reaction of 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine by Liquid Chromatography (LC) tracking monitoring, adding 80ml of water into the reaction solution, directly filtering to separate out a solid, washing the solid with water to neutrality, draining, dissolving the solid with 600ml of toluene, passing through a normal-temperature (25 ℃) silica gel column, collecting the column liquid, concentrating under negative pressure until about the remaining 40ml of the system is obtained, cooling to 0 ℃ under stirring, filtering, draining to obtain 68g of a solid product, washing the solid with 102ml of ethanol under reflux for 30min, cooling to 0 ℃ under stirring, filtering, and drying to obtain 28.2g of yellow solid 6-bromobenzothiophene [2,3-c ] pyridine with the content of 97.5%, wherein the yield in the step is 79%.
Adding 25g (molecular weight is 264.14, 0.094mol) of 6-bromobenzothiophene [2,3-c ] pyridine and 150ml of tetrahydrofuran into a reaction bottle under the protection of nitrogen, stirring until the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is dissolved, cooling to-5 ℃ at first, dropwise adding 131ml (1.0mol/L of n-hexane solution and 0.131mol) of 2,2,6, 6-tetramethylpiperidine lithium, reacting at 5 ℃ for 2h, cooling to-75 ℃, dropwise adding 22.5g (molecular weight is 236.74 and 0.095mol) of tetrahydrofuran (25ml) solution, reacting at-75 ℃ for 3h after dropwise adding, removing the solvent under reduced pressure after the reaction is finished, extracting with dichloroethane, washing the organic phase to be neutral, drying with 15g of anhydrous magnesium sulfate, filtering to remove the solvent, passing through a silica gel column with a mixed solvent of n-heptane and ethyl acetate after the organic phase is removed, after the solvent is removed by the injection liquid, 19.5g of the target compound 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is obtained by dispersing with 20ml of ethanol, and the product is a white solid with the purity of 99.18 percent and the yield of the step is 69 percent.
Example 3
The embodiment provides a synthesis method of 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, and specifically, the method comprises the following steps:
adding 185.0g (molecular weight 168.02, 1.101mol) of 2-methylthio phenylboronic acid, 174.4g (molecular weight 158.54, 1.1mol) of 4-chloro-3-nitropyridine, 467g (molecular weight 212.27, 2.2mol) of potassium phosphate, 1110ml of dioxane and 270ml of water into a reaction bottle with a stirring pipe, a condensing pipe and a thermometer, continuously carrying out nitrogen protection after three times of nitrogen replacement, heating to 40 ℃, quickly adding 8.05g (molecular weight 731.7,0.011mol) of 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) into the system, and heating to 88 ℃ for reflux reaction; the reaction is stopped by monitoring the content of the 4-chloro-3-nitropyridine LC < 1% by utilizing Liquid Chromatography (LC), 900ml of solvent is concentrated from the reaction solution under reduced pressure, 900ml of toluene is added, the organic phase is washed to be neutral by water, drying is carried out by 80g of anhydrous sodium sulfate, then a drying agent is filtered out, the mixture is passed through a normal-temperature column filled with 150g of silica gel, and the column-passing solution is concentrated under reduced pressure to be dried to obtain 222.9g of brown yellow oily matter 4- (2-methylmercapto) phenyl-3-nitropyridine with the content of 97.1%, wherein the yield of the step is 82.2%.
Reacting 200g (molecular weight 246.28, 0.812mol) of 4- (2-methylmercapto) phenyl-3-nitropyridine with 1000ml of dichloroethane, heating to 45 ℃, dropwise adding 131.2g (molecular weight 160,0.820mol) of bromine, and reacting for 24h at 45 ℃ after dropwise adding; the Liquid Chromatography (LC) is utilized to track and monitor that the 4- (2-methylmercapto) phenyl-3-nitropyridine LC < 5% stops reacting, the organic phase of the reaction solution is washed once by 600ml of 5% sodium bisulfite aqueous solution, the organic phase is washed to be neutral by water again, the drying agent is filtered after being dried by 100g of anhydrous sodium sulfate, after the solvent is removed by decompression, the organic phase is filtered by n-heptane and ethyl acetate, and the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine 225.5g with the content of 95.1% is obtained by separation and purification, and the yield of the step is 85.4%.
200g (molecular weight 325.18, 0.615mol) of 4- (5-bromine- (2-methylmercapto) phenyl) -3-nitropyridine, 1000ml of ethanol and 1800ml of water are stirred uniformly, when the temperature is raised to 50 ℃, 428g (molecular weight 174.1, 2.46mol) of sodium hydrosulfite (sodium dithionate) is added in batches, and after the addition is finished, the stirring reaction is carried out at the temperature; the reaction was stopped by Liquid Chromatography (LC) followed until the content of 4- (5-bromo- (2-methylthio) phenyl) -3-nitropyridine was < 0.5%, ethanol was removed under reduced pressure by about 800ml, the system was extracted with dichloroethane, the organic phase was washed with water, dried over 100g anhydrous sodium sulfate and then the drying agent was filtered off, and the solvent was removed under reduced pressure to give 168.5g of 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine with a purity of 95.8% and a yield of 92.8% in this step.
160g (molecular weight is 295.2,0.54mol) of 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine, 360ml of acetic acid and 320ml of tetrahydrofuran are stirred, the system is uniformly mixed, the temperature is reduced to 2 ℃, 107.2g (molecular weight is 103.12, 1.04mol) of tert-butyl nitrite is dropwise added, and the temperature is increased to 25 ℃ after the dropwise addition for reaction for 6 hours; the method comprises the following steps of tracking and monitoring by using a Liquid Chromatography (LC) until 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine is reacted, adding 320ml of water into a reaction solution, directly filtering to separate out a solid, washing the solid with water to be neutral, draining, dissolving the solid by using 2400ml of toluene, then passing through a normal-temperature (25 ℃) silica gel column, collecting column-passing liquid, concentrating until about 160ml of a residual system is obtained under negative pressure, cooling to 0 ℃ under stirring, filtering, draining to obtain 285g of a solid product, boiling and washing the solid with 410ml of ethanol for 30min under reflux, then cooling to 0 ℃ under stirring, filtering, and drying to obtain 99.6g of yellow solid 6-bromobenzothiophene [2,3-c ] pyridine with the content of 98.4%, wherein the yield of the step is 69.8%.
Adding 75g (molecular weight 264.14, 0.282mol) of 6-bromobenzothiophene [2,3-c ] pyridine and 450ml of tetrahydrofuran into a reaction bottle under the protection of nitrogen, stirring until 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is dissolved, cooling to-5 ℃ at first, dropwise adding 393ml (1.0mol/L n-hexane solution, 0.131mol) of 2,2,6, 6-tetramethylpiperidine lithium, reacting at 5 ℃ for 2h after dropwise adding, cooling to-75 ℃, dropwise adding 78.2g (molecular weight 236.74, 0.33mol) of tetrahydrofuran (75ml) solution of hexachloroethane, reacting at-75 ℃ for 3h after dropwise adding, removing the solvent under reduced pressure after the reaction is finished, extracting with dichloroethane, washing an organic phase to be neutral, drying with 50g of anhydrous magnesium sulfate, filtering out a drying agent, removing the solvent from the organic phase, passing through a silica gel column by using a mixed solvent of n-heptane and ethyl acetate, after the solvent is removed by the injection liquid, 64.2g of the target compound 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is obtained by dispersing with 50ml of ethanol, and the product is white solid with the purity of 99.32 percent and the yield of 76.2 percent.
The reaction principle of the invention is as follows:
the method comprises the steps of taking 2-methylthiophenylboronic acid and 4-chloro-3-nitropyridine as initial raw materials, carrying out a suzuki coupling reaction in a system with dioxane and water as solvents under the protection of inert gas and in the presence of inorganic base and a catalyst to obtain an intermediate 4- (2-methylthio) phenyl-3-nitropyridine, synthesizing 4- (5-bromo- (2-methylthio) phenyl) -3-nitropyridine through bromination of bromine, and reducing the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine in a system with ethanol and water through sodium hydrosulfite (sodium dithionate). Then the diazotization reagent is used for attacking coupling reaction and ring closing to prepare 6-bromobenzothiophene [2,3-c ] pyridine, and the target compound 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is prepared through chlorination reaction at low temperature.
The invention provides a synthesis method of 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, which has the advantages of easily available raw materials, simple post-treatment in all five steps, no isomer, single product, no high temperature and high pressure in all five steps of reaction operation, no dangerous operation such as severe heat release and severe air release and the like, and is suitable for industrial amplification production.
The main raw materials of the invention, namely the 2-methylthio phenylboronic acid and the 4-chloro-3-nitropyridine, are low in price, a large amount of auxiliary materials are sold in the market, the operation and the post-treatment are simple, the purity of the prepared target product, namely the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, can reach more than 99 percent, and the invention is suitable for industrial production.
The synthesis process has few side reactions, the prepared 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is a very important intermediate in the fields of organic photoelectric materials, medicines and the like, and a series of terminal derivative compounds can be prepared on the basis of the intermediate, and chlorine and bromine on the 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine have good selectivity.
While the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.
Many other changes and modifications can be made without departing from the spirit and scope of the invention. It is to be understood that the invention is not to be limited to the specific embodiments, but only by the scope of the appended claims.
Claims (7)
1. A synthetic method of 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine is characterized by comprising the following steps:
step 1: performing coupling reaction by using 2-methylthio phenylboronic acid and 4-chloro-3-nitropyridine as starting materials to obtain an intermediate 4- (2-methylthio) phenyl-3-nitropyridine, wherein the molar ratio of the 2-methylthio phenylboronic acid to the 4-chloro-3-nitropyridine is 1: 0.9-1;
and 2, step: synthesizing 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine from the intermediate 4- (2-methylmercapto) phenyl-3-nitropyridine and bromine through a bromination reaction, wherein the molar ratio of the 4- (2-methylmercapto) phenyl-3-nitropyridine to the bromine is 1: 1-1.2;
and 3, step 3: reducing 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine by using a reducing agent to obtain 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine, wherein the molar ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine to the reducing agent is 1: 4-6;
and 4, step 4: the 6-bromobenzothiophene [2,3-c ] pyridine is prepared by 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine and a diazotization reagent through diazotization reaction closed-loop, wherein the molar ratio of the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine to the diazotization reagent is 1: 1.6-2;
and 5: dissolving the 6-bromobenzothiophene [2,3-c ] pyridine obtained in the step 4 in tetrahydrofuran, wherein the dosage ratio of the 6-bromobenzothiophene [2,3-c ] pyridine to the tetrahydrofuran is 1g: 6ml, after being treated by organic alkali, the raw materials and a chlorinated reagent are subjected to chlorination reaction to prepare a target product 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine, the molar ratio of the 6-bromobenzothiophene [2,3-c ] pyridine to the chlorinated reagent is 1:1-1.2, the organic base is 2,2,6, 6-tetramethyl lithium piperidine or lithium diisopropylamide, the chlorination reagent is hexachloroethane, the mol ratio of 6-bromobenzothiophene [2,3-c ] pyridine to organic alkali is 1:1.2-1.5, the mol ratio of the 6-bromobenzothiophene [2,3-c ] pyridine to the chlorinated reagent is 1:1.1, the organic alkali is treated in a dropwise manner, the reaction treatment temperature of the organic alkali is-20-0 ℃, and the reaction time of the organic alkali is 2-3 h; the adding mode of the chlorinated reagent is dropwise adding, the dropwise adding temperature of the chlorinated reagent is minus 70 ℃ to minus 85 ℃, and the reaction time of the chlorinated reagent is 2-5 h.
2. The method for synthesizing 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine according to claim 1, wherein the step 1 specifically comprises: under the protection of nitrogen gas, 2-methylthio phenylboronic acid and 4-chloro-3-nitropyridine are used as starting materials, the starting materials are dissolved in a mixed solvent of dioxane and water, and a suzuki coupling reaction is carried out in the presence of inorganic base and a catalyst to prepare an intermediate 4- (2-methylthio) phenyl-3-nitropyridine, wherein the molar ratio of the 2-methylthio phenylboronic acid to the 4-chloro-3-nitropyridine to the catalyst to the inorganic base is 1:0.9-1: 0.003-0.03: 2-3; the dosage ratio of the 2-methylthio phenylboronic acid to the dioxane to the water is 1g: 6 ml: 1.5ml, and the temperature of the suzuki coupling reaction is 85-95 ℃.
3. The method for synthesizing 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine according to claim 2, wherein the inorganic base is one of potassium carbonate, potassium phosphate or cesium carbonate, and the catalyst is palladium tetratriphenylphosphine or 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium.
4. The synthesis method of 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine according to claim 2, characterized in that the molar ratio of the 2-methylthiophenylboronic acid to the 4-chloro-3-nitropyridine to the catalyst to the inorganic base is 1:0.95:0.01:2, and the temperature of the suzuki coupling reaction is 88 ℃.
5. The method for synthesizing 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine according to claim 1, wherein the step 2 is specifically: dissolving the intermediate 4- (2-methylmercapto) phenyl-3-nitropyridine obtained in the step 1 in dichloroethane solvent, dropwise adding bromine for bromination reaction, and then purifying to obtain the intermediate 4- (5-bromine- (2-methylmercapto) phenyl) -3-nitropyridine, wherein the molar ratio of the 4- (2-methylmercapto) phenyl-3-nitropyridine to the bromine is 1:1.1, the dosage ratio of the 4- (2-methylmercapto) phenyl-3-nitropyridine to the dichloroethane solvent is 1g:5ml, and the bromination reaction temperature is 30-50 ℃.
6. The method for synthesizing 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine according to claim 1, wherein the step 3 specifically comprises: dissolving the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine obtained in the step 2 in ethanol and water, and adding a reducing agent in batches for reduction reaction to prepare 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine, wherein the reducing agent is sodium hydrosulfite, the molar ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine to the sodium hydrosulfite is 1:5, and the dosage ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-nitropyridine to the ethanol and the water is 1g:5 ml: 9ml, and the temperature of the reduction reaction is 45-55 ℃.
7. The method for synthesizing 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine according to claim 1, wherein the step 4 is specifically: dissolving the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine obtained in the step 3 in a mixed solvent of acetic acid and tetrahydrofuran, dropwise adding a diazotization reagent, and continuing to perform a ring closing reaction after the dropwise adding is finished to prepare 6-bromobenzothiophene [2,3-c ] pyridine, wherein the diazotization reagent is tert-butyl nitrite or isoamyl nitrite, and the molar ratio of the 4- (5-bromo- (2-methylthio) phenyl) -3-aminopyridine to the diazotization reagent is 1: 1.8; the dosage ratio of the 4- (5-bromo- (2-methylmercapto) phenyl) -3-aminopyridine to the acetic acid and the tetrahydrofuran is 1g: 2 ml: 2ml, the temperature when the diazotization reagent is dripped is 0-5 ℃, the reaction temperature is 20-30 ℃ after the diazotization reagent is dripped, and the reaction time is 5-10h after the diazotization reagent is dripped.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111402332.9A CN113956268B (en) | 2021-11-19 | 2021-11-19 | 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111402332.9A CN113956268B (en) | 2021-11-19 | 2021-11-19 | 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113956268A CN113956268A (en) | 2022-01-21 |
| CN113956268B true CN113956268B (en) | 2022-07-15 |
Family
ID=79471731
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111402332.9A Active CN113956268B (en) | 2021-11-19 | 2021-11-19 | 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113956268B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2004298453A1 (en) * | 2003-12-19 | 2005-06-30 | Altana Pharma Ag | Intermediates for the preparation of tricyclic dihydropyrano -imidazo -pyridines derivatives |
| CN101838275A (en) * | 2010-04-30 | 2010-09-22 | 温州大学 | Method for synthesizing 6-methyl-dibenzothienophridine |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2079739A2 (en) * | 2006-10-04 | 2009-07-22 | Pfizer Products Inc. | Pyrido[4,3-d]pyrimidin-4(3h)-one derivatives as calcium receptor antagonists |
| US9067947B2 (en) * | 2009-01-16 | 2015-06-30 | Universal Display Corporation | Organic electroluminescent materials and devices |
| KR102191780B1 (en) * | 2012-12-18 | 2020-12-16 | 에스에프씨 주식회사 | An electroluminescent compound and an electroluminescent device comprising the same |
| CN110981895B (en) * | 2018-12-17 | 2023-08-25 | 广州华睿光电材料有限公司 | Transition metal complexes, polymers, mixtures, compositions and organic electronic devices |
| KR102342781B1 (en) * | 2019-01-04 | 2021-12-23 | 주식회사 엘지화학 | Novel compound and organic light emitting device comprising the same |
-
2021
- 2021-11-19 CN CN202111402332.9A patent/CN113956268B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2004298453A1 (en) * | 2003-12-19 | 2005-06-30 | Altana Pharma Ag | Intermediates for the preparation of tricyclic dihydropyrano -imidazo -pyridines derivatives |
| CN101838275A (en) * | 2010-04-30 | 2010-09-22 | 温州大学 | Method for synthesizing 6-methyl-dibenzothienophridine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113956268A (en) | 2022-01-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108047198B (en) | Method for preparing polyaryl substituted naphthalene derivative by reaction of aryl ketone and tolane under catalysis of ruthenium | |
| CN110183445A (en) | The synthetic method of Moxifloxacin and its derivative | |
| CN110294730B (en) | Difluoromethyl sulfuration flavonoid compound and preparation method thereof | |
| CN113956268B (en) | 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method | |
| CN110845401B (en) | Synthesis method of 2-fluoro-3, 6-dihydroxypyridine | |
| CN113912609B (en) | Preparation method of natural alkaloid tryptanthrin and derivatives thereof | |
| CN115215814A (en) | Synthetic method of isoxazolidine compounds | |
| CN105198806B (en) | A kind of method using aromatic amine, diketone synthesis of quinoline derivatives | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN115697970A (en) | Process for producing aromatic ether compound | |
| CN107573301B (en) | Preparation method of tricyclazole intermediate | |
| CN107935913B (en) | Carbazole compound and synthesis method and application thereof | |
| CN116836107B (en) | Carbazol eight-membered ring large conjugated structure OLED material and preparation method thereof | |
| CN112479993A (en) | Synthetic method applied to KRAS inhibitor drug heterocyclic intermediate | |
| CN111747923A (en) | Crown ether carboxylic acid compound-containing BPDC-12-C-4 and preparation method and application thereof | |
| CN113816912B (en) | Preparation method of phenazine | |
| CN114874127B (en) | Preparation method of difluoro carbonyl indolone compound | |
| CN115974879B (en) | Preparation method of polysubstituted imidazo heterocyclic compound | |
| CN113754606B (en) | Phenoxazine diamine derivative and/or phenothiazine diamine derivative and preparation method thereof | |
| CN104418805B (en) | Dabigatran etexilate intermediate as well as preparation method and application thereof | |
| CN110396094B (en) | Quinolinone heteroaromatic ring compound and derivative and synthetic method thereof | |
| CN110372718B (en) | Difluoromethane thiochromanonthiophene compound and preparation method thereof | |
| JP2003231659A (en) | Purification method for optically active 1,1'-bi-2-naphthol | |
| CN108822060B (en) | 3-aryl substituted oxetane and preparation method thereof | |
| CN107417501B (en) | Preparation method of pinaverium bromide intermediate 2-bromo-4, 5-dimethoxy benzyl bromide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |