CN104447679A - 2-thiopheneacetonitrile and 2-thiopheneethylamine preparing method - Google Patents

Abstract

The invention discloses a 2-thiopheneacetonitrile and 2-thiopheneethylamine preparing method. The method is characterized in that by using a palladium catalyst and an organic phosphine ligand, 2-bromothiophene and cyano-acetate are subject to decarboxylation coupling in an organic solvent to obtain 2-thiopheneacetonitrile; and from 2-thiopheneacetonitrile is reduced to obtain 2-thiopheneethylamine. By the method, the cost of production is greatly reduced; the reaction condition is mild, the process is simple, the pollution is less, and the method is conducive to industrial production; and the use of toxic substances is avoided, and the environmental pollution is greatly reduced.

Description

A kind of preparation method of 2-thiophenecetonitrile and 2-thiopheneethylamine

technical field

The invention relates to a preparation method of 2-thiophenecetonitrile and 2-thiopheneethylamine, belonging to the technical fields of medicine and chemical industry.

Background technique

2-Thienylethylamine is an intermediate of biologically active drugs such as blood lipid-lowering drugs, platelet aggregation inhibitors, cardiovascular relaxants, 5-lipoxygenase inhibitors and various antibacterial drugs, and is mainly used in the synthesis of cardiovascular and cerebrovascular diseases. The important drugs are ticlopidine hydrochloride and clopidogrel bisulfate. With the continuous development of downstream drugs, 2-thienylethylamine has become a fine chemical intermediate that has attracted much attention.

At present, there are mainly four routes for the known industrialization or application prospects of 2-thiopheneethylamine: the nitromethane method, the isopropyl chloroacetate method, the 2-thiophene acetonitrile method and the ethylene oxide method.

The nitromethane method is a two-step method of reducing 2-nitrothiophene to prepare 2-thiopheneethylamine. 2-thiophene formaldehyde is obtained from thiophene and dimethylformamide in the presence of phosphine oxychloride, and then 2-thiophene formaldehyde and nitromethane to prepare 2-nitrothiopheneethylene, and finally reduce 2-nitrothiopheneethylene to 2-thiopheneethylamine with various reducing agents (Journal of Wuhan Institute of Chemical Technology, 2002,24(3):14-16; US4806756; EP0522956 ; EP342118)). Both phosphine oxychloride and nitromethane used in this method have the disadvantages of high toxicity, high volatility or high price, large dosage, etc., and the process is tedious and the reaction time is long.

The isopropyl chloroacetate method is to obtain 2-thiophene formaldehyde by reacting dimethylformamide and thiophene in the presence of phosphine oxychloride, esterify chloroacetic acid and isopropanol to obtain isopropyl chloroacetate, 2-thiophene formaldehyde and chlorine Darzens reaction occurs in isopropyl acetate to obtain 2-thiophene acetaldehyde, then react with hydroxylamine hydrochloride to obtain 2-thiophene acetaldehyde oxime, and 2-thiophene acetaldehyde oxime reduction obtains 2-thiophene ethylamine (Fine Chemical Industry, 2001, 1 (1 ):53-55; EP465358). This method still needs to use highly toxic phosphine oxychloride, and the yield of the key step Darzens reaction is low, so it is not suitable for industrial production.

The 2-thiophene acetonitrile method is to synthesize 2-chloromethyl thiophene from thiophene, then react with sodium cyanide to obtain 2-thiophene acetonitrile, and then reduce it to prepare 2-thiopheneethylamine (Journal of the American Chemical Society, 77, 3529 -33, 1955; JP63107973; EP274324; JP03157382; WO2005009387). This method needs to use highly toxic sodium cyanide, and the environmental pollution is relatively large.

The ethylene oxide method uses thiophene as a raw material to prepare the intermediate 2-bromothiophene, and then reacts with magnesium chips to generate 2-thiophene magnesium bromide Grignard reagent, then reacts with ethylene oxide to generate 2-thiophenethanol, and then passes through the ester 2-thiopheneethylamine (CN101885720A; CN102432590A) was obtained by chemical reaction and ammonia solution. This method requires the use of highly toxic ethylene oxide, which is very harmful to the health of workers and the environment, and the risk of accidents is also high, and the cost of using ethylene oxide in industrial production is very high.

In addition, such as Chinese patent application CN102093333A, CN102020631A, CN101885770A and U.S. patent US4458086, US4970325 etc. all have the route is long, not easy to operate, some also have the use of highly toxic substances, and the disadvantages such as low yield, these have all limited in industrial large-scale application in production.

Contents of the invention

The problem to be solved by the present invention is to provide a preparation method with simple process, low cost, safe operation and suitable for industrial production of 2-thiopheneacetonitrile and 2-thiopheneethylamine in view of the deficiencies of the prior art.

The present invention solves technical problem, adopts following technical scheme:

The preparation method of 2-thiophene acetonitrile of the present invention is characterized in that: under the action of palladium catalyst and organic phosphine ligand, 2-thiophene acetonitrile is prepared by decarboxylation coupling of 2-bromothiophene and cyanoacetate in an organic solvent, The specific steps are: mix 2-bromothiophene, cyanoacetate, palladium catalyst and organic phosphine ligand, then add an organic solvent to it under the protection of an inert gas, and stir the reaction at 120-160°C for 8- After 24 hours, the organic solvent was removed after cooling, and then collected by vacuum distillation or column chromatography to obtain the product 2-thiopheneacetonitrile.

Preferably, the amount of the palladium catalyst is 0.05% to 1% of the amount of the substance of the 2-bromothiophene in terms of palladium; the ratio of the amount of the substance of the organophosphine ligand to the palladium catalyst is 1: 1-3:1; the ratio of the cyanoacetate to the 2-bromothiophene is 1.1:1-2:1.

The palladium catalyst is palladium acetate, palladium chloride, bis(acetonitrile)palladium dichloride, palladium trifluoroacetate, tris(dibenzylideneacetone)dipalladium, dipolyallylpalladium chloride, bis(dibenzylideneacetone)dipalladium, At least one of benzylacetone) palladium;

The organic phosphine ligands are triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, 2-bicyclohexylphosphine-2 ',6'-dimethoxybiphenyl, 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphine-2-(N,N -Dimethylamino)biphenyl, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 9,9-dimethyl-4,5-bis(di-t- Butylphosphino)xanthene, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, (±)-2,2'-bis-(diphenyl Phosphino)-1,1'-binaphthyl, (±)-2,2'-bis-(xylylphosphino)-1,1'-binaphthyl and 1,1'-bis(diphenyl At least one of phosphino) ferrocenes;

The cyanoacetate is at least one of sodium 2-cyanoacetate and potassium 2-cyanoacetate;

Described organic solvent is benzene, toluene, xylene, mesitylene, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethylene glycol dimethyl ether, diethylene glycol At least one of alcohol diethyl ether, triethylene glycol dimethyl ether, and dipropylene glycol diethyl ether.

The method for preparing 2-thiopheneethylamine in combination with the above-mentioned preparation method of 2-thiophenecetonitrile is characterized in that: firstly, under the action of a palladium catalyst and an organic phosphine ligand, decarboxylation of 2-bromothiophene and cyanoacetate in an organic solvent Coupling is obtained 2-thiophenecetonitrile, and then 2-thiopheneethylamine is obtained by reduction of 2-thiopheneacetonitrile, and the specific steps are:

(1) Mix 2-bromothiophene, cyanoacetate, palladium catalyst and organic phosphine ligand, then add an organic solvent to it under the protection of an inert gas, and stir the reaction at 120-160°C for 8-24 hour, after cooling, the organic solvent was removed, and then collected by vacuum distillation or column chromatography to obtain the product 2-thiophene acetonitrile; % to 1%; the ratio of the amount of the organic phosphine ligand to the palladium catalyst is 1:1 to 3:1; the ratio of the amount of the cyanoacetate to the 2-bromothiophene The ratio is 1.1:1～2:1;

(2) Add tetrahydrofuran THF into the reaction vessel, then add 2-thiophenecetonitrile and sodium borohydride, then add the ether solution of boron trifluoride dropwise. Cool the reaction solution to room temperature, then pour it into the same volume of hydrochloric acid with a mass concentration of 8-12%, stir evenly, then adjust the pH to 9-10 with a lye with a mass concentration of 25-35%, and then use toluene Extract 2-4 times, wash the organic layer with saturated brine and concentrate to dryness under reduced pressure to obtain 2-thiopheneethylamine; tetrahydrofuran THF, 2-thiophene acetonitrile, sodium borohydride and boron trifluoride ether solution volume mass The ratio is 500mL: 210-215g: 40-45g: 85-90g.

Therefore, when using 2-bromothiophene as a raw material to prepare 2-thienylethylamine, only two steps are required:

(1) 2-thiophene acetonitrile is prepared according to the above steps by 2-bromothiophene;

(2) 2-bromothiophene was prepared from 2-thiophene acetonitrile according to the above steps.

The above ether solution of boron trifluoride is commercially available, wherein the boron trifluoride content is 47%.

The raw material 2-bromothiophene used for preparing 2-thiophene acetonitrile can be purchased in the market, and can also be prepared according to the following method:

In the presence of an organic solvent, add a brominating agent dropwise to thiophene at -10-10°C, and continue the heat preservation reaction for 60 minutes after the dropwise addition is completed, then add water to separate the oil phase to recover the oil phase, precipitate it, and then collect it by distillation under reduced pressure 58 ℃ ~ 62 ℃ (7.33kPa) fraction, namely 2-bromothiophene; the bromination agent is one of N-succinimide, pyridine hydrobromide, bromine or hydrobromic acid or multiple; the molar ratio of the thiophene to the brominating agent is 1:2 to 3; the organic solvent is glacial acetic acid, carbon tetrachloride, dichloroethane, toluene or acetonitrile;

Compared with the prior art, the beneficial effects of the present invention are reflected in:

The invention greatly reduces the production cost; the reaction condition is mild, the process is simple, and the pollution is small, which is beneficial to the realization of industrial production; the use of highly toxic substances is avoided, and the pollution to the environment is greatly reduced.

detailed description

Embodiment 1: Synthesis of 2-bromothiophene

Place the 500mL three-neck flask in an ice bath, and install a condenser, a stirring rod, and a thermometer. The upper port of the condenser tube is connected to the hydrogen bromide gas absorption device. Add thiophene 79mL (84g, 1.0mol) and carbon tetrachloride 160mL (250g), control the temperature at 0-5°C, start stirring, add dropwise bromine 48mL (150g, 1.15mol) and hydrobromic acid (40%) 190mL (235g, 1.16mol), after adding dropwise within 80min, stir for another 60min, at this time the hydrogen bromide has escaped completely. After washing with water and drying, the solvent was recovered by atmospheric distillation. Transfer the product into a 250mL distillation bottle, distill under reduced pressure, collect the fraction at 58-62°C/7.33KPa to obtain 85mL (143g) of colorless liquid, which is 2-bromothiophene, with a yield of 88.1% and a content of 98.4%.

Embodiment 2: Synthesis of 2-thiophenecetonitrile

Example 2-1

Dipolyallylpalladium chloride (0.0059g, 0.016mmol), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl ( 0.0197g, 0.048mmol), 2-bromothiophene (2.61g, 16mmol), sodium 2-cyanoacetate (1.88g, 17.6mmol). The cover is coated with a vacuum grease grinding plug, connected to the Schrank vacuum line, the air in the container is drained and filled with nitrogen, repeat 3 times, and 16mL xylene is added under the backflow of nitrogen. After the addition, cover the stopper, put it into a 140°C oil pan after clamping, and stir and react for 16 hours. After cooling, xylene was distilled off under reduced pressure, and the 87-90°C/3mmHg fraction was collected to obtain the product 2-thiophenecetonitrile with a yield of 84%.

Example 2-2

In an oven-dried 100 mL Schlenk bottle equipped with a magnet, were added dipolyallylpalladium chloride (0.0146 g, 0.040 mmol), 9,9-dimethyl-4,5-bis(di tert-butylphosphino)xanthene (0.0693 g, 0.120 mmol), 2-bromothiophene (6.52 g, 40 mmol) and potassium 2-cyanoacetate (5.90 g, 48 mmol). The lid is coated with a vacuum grease grinding plug, connected to the Schrank vacuum line, the air in the container is drained and filled with nitrogen, repeat 3 times, and 40mL of mesitylene is added under the reverse flow of nitrogen. After the addition, cover with a stopper, put it into a 140°C oil pan after clamping, and stir for 20 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the 87-90°C/3mmHg fraction was collected to obtain the product 2-thiopheneacetonitrile with a yield of 92%.

Example 2-3

Add tris(dibenzylideneacetone)dipalladium (0.0183g, 0.020mmol), tri-tert-butylphosphine (0.0242g, 0.120mmol), 2-Bromothiophene (6.52 g, 40 mmol) and potassium 2-cyanoacetate (5.41 g, 44 mmol). The lid is coated with a vacuum grease grinding plug, connected to the Schrank vacuum line, the air in the container is drained and filled with nitrogen, repeat 3 times, and 35mL of N-methylpyrrolidone is added under the backflow of nitrogen. After the addition, cover the stopper, put it into a 160°C oil pan after clamping, and stir for 12 hours. After the reaction, the solvent was distilled off under reduced pressure, and the product 2-thiopheneacetonitrile was obtained by column chromatography with a yield of 56%.

Example 2-4

In an oven-dried 50 mL Schlenk flask equipped with a magnet, add bis(acetonitrile)palladium dichloride (0.0259 g, 0.10 mmol), (±)-2,2'-bis-(diphenylphosphine base)-1,1'-binaphthyl (0.0748g, 0.120mmol), 2-bromothiophene (3.26g, 20mmol) and sodium 2-cyanoacetate (2.35g, 22mmol). The cover is coated with a vacuum grease grinding plug, connected to the Schrank vacuum line, the air in the container is drained and filled with nitrogen, repeat 3 times, and 40mL of triethylene glycol dimethyl ether is added under the backflow of nitrogen. After the addition, cover the stopper, put it into a 120°C oil pan after clamping, and stir for 24 hours. After the reaction, the solvent was distilled off under reduced pressure, and the product 2-thiopheneacetonitrile was obtained by column chromatography with a yield of 63%.

Example 2-5

Add palladium trifluoroacetate (0.0166g, 0.050mmol), 2-(dicyclohexylphosphino)biphenyl (0.0525g, 0.150mmol), 2-Bromothiophene (3.26 g, 20 mmol) and sodium 2-cyanoacetate (2.35 g, 22 mmol). The lid is coated with a vacuum grease grinding plug, connected to the Schrank vacuum line, the air in the container is drained and filled with nitrogen, repeat 3 times, and 40 mL of dimethyl sulfoxide is added under the backflow of nitrogen. After the addition, cover the stopper, put it into a 150°C oil pan after clamping, and stir for 24 hours. After the reaction was cooled, 200 mL of water was added, and extracted three times with ethyl acetate, 100 mL each time. The ethyl acetates were combined, dried and concentrated. The residue was distilled under reduced pressure, and the 87-90°C/3mmHg fraction was collected to obtain the product 2-thiopheneacetonitrile with a yield of 74%.

Embodiment 3: Synthesis of 2-thienylethylamine

Add 500mL tetrahydrofuran (THF) into a 1L four-neck flask, then add 210-215g 2-thiophene acetonitrile, 40-45g sodium borohydride, and then slowly add 85-90g boron trifluoride ether solution dropwise. After the dropwise addition, raise the temperature to 45-50°C and keep it warm for 4-8h. After the heat preservation is over, cool the reaction liquid to room temperature, then pour it into the same volume of hydrochloric acid with a mass concentration of 8-12%, stir evenly, and then use a mass concentration of 25-35% % NaOH solution, adjust the pH=9-10, then extract 2-4 times with an appropriate amount of toluene, wash the organic layer with saturated brine and concentrate under reduced pressure to remove the toluene, to dryness to obtain 220g of 2-thienylethylamine, the yield is 98% , purity 98.3% (GC).

The descriptions of the above embodiments are only used to help understand the method and core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, some improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

The above description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the present invention will not be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (7)

1. a preparation method for 2 thiophene acetonitrile, is characterized in that: under palladium catalyst and organophosphorus ligand effect, obtains 2 thiophene acetonitrile in organic solvent by 2-bromothiophene and cyano-acetate decarboxylation coupling.

2. the preparation method of 2 thiophene acetonitrile according to claim 1, is characterized in that carrying out as follows:

2-bromothiophene, cyano-acetate, palladium catalyst and organophosphorus ligand are mixed; then under protection of inert gas; add organic solvent wherein; and at 120-160 DEG C of temperature stirring reaction 8-24 hour; organic solvent is sloughed after cooling; collected by underpressure distillation or column chromatography again, obtain product 2 thiophene acetonitrile.

3. the preparation method of 2 thiophene acetonitrile according to claim 1 and 2, is characterized in that: the consumption of described palladium catalyst counts 0.05% ~ 1% of the amount of substance of described 2-bromothiophene with palladium; Described organophosphorus ligand is 1:1 ~ 3:1 with the ratio of the amount of substance of described palladium catalyst; Described cyano-acetate is 1.1:1 ~ 2:1 with the ratio of the amount of substance of described 2-bromothiophene.

4. the preparation method of 2 thiophene acetonitrile according to claim 1 and 2, is characterized in that:

Described palladium catalyst is at least one in acid chloride, Palladous chloride, two (acetonitrile) palladium chloride, palladium trifluoroacetate, three (dibenzalacetone) two palladium, dimerization allyl palladium chloride, two (dibenzalacetone) palladium;

Described organophosphorus ligand is triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2-dicyclohexylphosphontetrafluoroborate-2, 4, 6-tri isopropyl biphenyl, 2-dicyclohexyl phosphine-2', 6'-dimethoxy-biphenyl, 2-(di-t-butyl phosphino-) biphenyl, 2-(dicyclohexyl phosphino-) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2-(N, N-dimethyl amido) biphenyl, 9, 9-dimethyl-4, 5-bis-(diphenylphosphino) xanthene, 9, 9-dimethyl-4, 5-bis-(di-t-butyl phosphino-) xanthene, 2-dicyclohexylphosphontetrafluoroborate-2', 6'-diisopropoxy-1, 1'-biphenyl, (±)-2, 2'-pair-(diphenyl phosphine)-1, 1'-dinaphthalene, (±)-2, 2'-pair-(di-p-tolyl phosphino-)-1, 1'-dinaphthalene and 1, at least one in two (diphenylphosphino) ferrocene of 1'-,

Described cyano-acetate is at least one in 2-cyanoacetic acid sodium and 2-cyanoacetic acid potassium;

Described organic solvent is at least one in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, TRIGLYME and dipropylene glycol diethyl ether.

5. prepare the method for 2 thiophene ethyl amine in conjunction with the preparation method of 2 thiophene acetonitrile described in claim 1 for one kind, it is characterized in that: first under palladium catalyst and organophosphorus ligand effect, obtain 2 thiophene acetonitrile by 2-bromothiophene and cyano-acetate decarboxylation coupling in organic solvent, then obtain 2 thiophene ethyl amine by 2 thiophene acetonitrile by reduction.

6. method according to claim 5, is characterized in that carrying out as follows:

(1) 2-bromothiophene, cyano-acetate, palladium catalyst and organophosphorus ligand are mixed, then under protection of inert gas, add organic solvent wherein, and at 120-160 DEG C of temperature stirring reaction 8-24 hour, organic solvent is sloughed after cooling, collected by underpressure distillation or column chromatography again, obtain product 2 thiophene acetonitrile; The consumption of described palladium catalyst counts 0.05% ~ 1% of the amount of substance of described 2-bromothiophene with palladium; Described organophosphorus ligand is 1:1 ~ 3:1 with the ratio of the amount of substance of described palladium catalyst; Described cyano-acetate is 1.1:1 ~ 2:1 with the ratio of the amount of substance of described 2-bromothiophene;

(2) in reaction vessel, tetrahydrofuran THF is added, then 2 thiophene acetonitrile and sodium borohydride is added, then the diethyl ether solution of boron trifluoride is dripped, drip and finish, be warming up to 45-50 DEG C of insulation 4-8h, after reaction terminates, reaction solution is cooled to room temperature, then the mass concentration being poured into same volume is in the hydrochloric acid of 8-12%, stir, pH to 9-10 is regulated again with the alkali lye that mass concentration is 25-35%, then with toluene extraction 2-4 time, be evaporated to dry after the water washing of organic layer saturated common salt, obtain 2 thiophene ethyl amine;

Tetrahydrofuran THF, 2 thiophene acetonitrile, sodium borohydride are 500mL:210-215g:40-45g:85-90g with the volume mass ratio of the diethyl ether solution of boron trifluoride.

7. method according to claim 6, is characterized in that: described palladium catalyst is at least one in acid chloride, Palladous chloride, two (acetonitrile) palladium chloride, palladium trifluoroacetate, three (dibenzalacetone) two palladium, dimerization allyl palladium chloride, two (dibenzalacetone) palladium;

Described organophosphorus ligand is triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2-dicyclohexylphosphontetrafluoroborate-2, 4, 6-tri isopropyl biphenyl, 2-dicyclohexyl phosphine-2', 6'-dimethoxy-biphenyl, 2-(di-t-butyl phosphino-) biphenyl, 2-(dicyclohexyl phosphino-) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2-(N, N-dimethyl amido) biphenyl, 9, 9-dimethyl-4, 5-bis-(diphenylphosphino) xanthene, 9, 9-dimethyl-4, 5-bis-(di-t-butyl phosphino-) xanthene, 2-dicyclohexylphosphontetrafluoroborate-2', 6'-diisopropoxy-1, 1'-biphenyl, (±)-2, 2'-pair-(diphenyl phosphine)-1, 1'-dinaphthalene, (±)-2, 2'-pair-(di-p-tolyl phosphino-)-1, 1'-dinaphthalene and 1, at least one in two (diphenylphosphino) ferrocene of 1'-,

Described cyano-acetate is at least one in 2-cyanoacetic acid sodium and 2-cyanoacetic acid potassium;

Described organic solvent is at least one in benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, TRIGLYME and dipropylene glycol diethyl ether.