CN109970527B - Continuous preparation method of aryl propionaldehyde compound - Google Patents
Continuous preparation method of aryl propionaldehyde compound Download PDFInfo
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Abstract
The invention discloses a continuous preparation method of aryl propionaldehyde compounds. The continuous preparation method of the aryl propionaldehyde compound comprises the following steps: in a solvent, under the action of a palladium catalyst, a ligand and an organic base, carrying out the following reaction on a compound shown in a formula A and a compound shown in a formula B in a tubular reactor to obtain a compound shown in a formula C; the preparation method of the invention shortens the reaction time, reduces the dosage of the catalyst, has good safety, ensures the product quality, reduces the cost, reduces the generation of byproduct tar, and is more suitable for industrial production.
Description
Technical Field
The invention relates to a continuous preparation method of aryl propionaldehyde compounds.
Background
The aryl propionaldehyde compounds are important intermediates for constructing drug molecules. For example, in 2001, the drug bimatoprost developed by eljian corporation for the treatment of glaucoma was approved by the FDA for marketing (formula 1); cinacalcet hydrochloride (formula 2) a drug for treating secondary hyperparathyroidism in Chronic Kidney Disease (CKD) patients undergoing dialysis and for treating hypercalcemia in parathyroid cancer patients, produced by Amgen corporation (NPS pharmaceutical company, a licensee of the product) approved for marketing by FDA in 2004; the clinical-stage new drugs, Efipladib (formula 3) and UK-447841 (formula 4), developed by the company pfeiri, all used arylpropionaldehyde compounds as intermediates, which were (formula 1-1), (formula 2-1), (formula 3-1) and (formula 4-1), respectively.
Currently, one type of synthetic methods for aryl propionaldehyde compounds is to use aryl propanol as a substrate to perform a selective oxidation reaction to obtain aryl propionaldehyde (Journal of Organic Chemistry,74(22),8510-&Medicinal Chemistry Letters,26(7), 1849-; 2016) or aryl propionaldehyde by selective reduction using aryl propionate as a substrate (European Journal of Organic Chemistry, (20), 4573-4577; 2006; catalysis Communications,50, 25-28; 2014). However, the raw materials of the method are not easy to obtain, the cost of the oxidant and the cost of the reducing agent are both high, the aryl propanol is easy to be oxidized into the aryl propionic acid in the reaction process, the aryl propionate is easy to be reduced into the aryl propanol, the reaction is not easy to control, the oxidation-reduction reactions are dangerous and are not suitable for industrial scale productionAnd (5) producing a mould. The other is aryl propionaldehyde prepared by Heck and Suzuki coupling reaction between aryl halide or boride and allyl alcohol or allyl aldehyde. Wherein the Heck reaction is a coupling reaction of halohydrocarbon and alkenyl compound to form carbon-carbon bond under the action of palladium catalyst, and is widely applied to the fields of organic synthesis and pharmacy (Green Chemistry,16 (5)), 2788-&Medicinal Chemistry Letters,27(2), 237-; 2017; journal of Medicinal Chemistry,56(23), 9427-; 2013; organic Letters,13(20), 5456-; 2011). However, the Heck reaction is very sensitive to air and moisture, the reaction time is usually long, the reaction efficiency is low, and the method adopts the traditional batch reaction at present. Therefore, the problems that the palladium catalyst is easy to inactivate, the dosage of the catalyst is large, the cost is high, the product quality is unstable, the industrial production is not facilitated, and the like exist. Organic Letters,13(20), 5456-; 2011 introduces Pd (dba) which takes bromobenzene and allyl alcohol as raw materials2The reaction is carried out at 100 ℃ for 1h by taking N, N-dicyclohexyl methylamine as a catalyst, N, N-dimethyl formamide as a solvent and a compound shown in the following formula 5 as a ligand, wherein the yield is 74%. Bromobenzene and Pd (dba)2The molar ratio of bromobenzene to organic base is 1:1.1, and the molar ratio of bromobenzene to ligand is 1: 0.06. The method has the advantages of large catalyst consumption, high ligand price shown in the following formula 5, long reaction time, intermittent reaction and unsuitability for industrial production.
Continuous preparation processes are more suitable for the production of bulk products, but continuous flow reactors are more suitable for reactions with shorter reaction times or reactions with stable products under recycle conditions. The conditions required during this operation are: a certain residence time is necessary to achieve a suitable degree of reaction completion under the conditions of desired temperature, flow rate and other key parameters. Continuous operation also lacks flexibility (anderson. a practical organic synthesis process research and development manual [ M ]. scientific press, 2011.). It can be seen that not all reactions can be carried out in a continuous reactor. And the continuous operation process has many drawbacks.
Therefore, there is a need in the art for a method with short reaction time, easy process control, low cost, safety, high efficiency, and low catalyst consumption, which ensures high activity of the catalyst during the reaction process, to solve the above technical problems.
Disclosure of Invention
The invention aims to overcome the defects that the existing aryl propionaldehyde compound is easy to inactivate and has more consumption, long reaction time, high cost, inapplicability to industrial production and the like in the preparation process, and provides a continuous preparation method of the aryl propionaldehyde compound. The preparation method of the invention shortens the reaction time, reduces the dosage of the catalyst, has good safety, ensures the product quality, reduces the cost, reduces the generation of byproduct tar, and is more suitable for industrial production.
In the prior art, the method for preparing the aryl propionaldehyde compound by the Heck reaction generally has longer reaction time, and tar is easy to generate under the conditions of high temperature and long-time reaction; the continuous preparation method is also more suitable for chemical reactions with shorter reaction time or stable products under the circulating condition. The invention carries out Heck reaction in a tubular reactor, overcomes the technical prejudice through creative experiments, shortens the reaction time, reduces the dosage of catalyst and ligand, uses conventional ligand and reduces the reaction cost.
The invention mainly solves the technical problems through the following technical scheme.
The invention provides a continuous preparation method of aryl propionaldehyde compounds, which comprises the following steps: in a solvent, under the action of a palladium catalyst, a ligand and an organic base, carrying out the following reaction on a compound shown in a formula A and a compound shown in a formula B in a tubular reactor to obtain a compound shown in a formula C;
wherein X is Cl, Br, I or trifluoromethanesulfonate;
r is hydrogen, C1-C6Alkyl or cyano radicals
R1、R2、R3、R4And R5Each independently H, F, Cl, halogen substituted C1-C4Alkyl radical, C1-C4Alkyl, halogen substituted C1-C4Alkoxy radical, C1-C4Alkoxy radical, C2-C5Heteroaryl group, C6-C10Aryl, nitro radicals
Amino group
Cyano radical
Said RaIs H, halogen substituted C1-C4Alkyl or C1-C4An alkyl group; said C2-C5The hetero atom in the heteroaryl group is selected from N, O and S, and the number of the hetero atoms is 1-4.
In the present invention, the halogen is preferably Cl, Br or I.
In the present invention, said C1-C4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group.
In the present invention, the halogen is substituted for C1-C4Alkyl means C substituted by one or more halogens1-C4Alkyl, trifluoromethyl is preferred in the present invention.
In the present invention, the halogen is substituted for C1-C4Alkoxy means C substituted by one or more halogens1-C4Alkoxy, trifluoromethoxy being preferred in the present invention.
In the present invention, said C1-C4The alkoxy group is preferably a methoxy group.
In the present invention, said C2-C5Heteroaryl is preferably pyridyl, thienyl, thiazolyl, piperidinyl or piperazinyl.
In the present invention, said C6-C10Aryl is preferably phenyl.
The palladium catalyst may be a palladium catalyst conventional in the art for such reactions, with Pd being preferred in the present invention2(dba)3、Pd(OAc)2、Pd(PPh3)4、Pd(dba)2And PdCl2One or more of them, and Pd is further preferable2(dba)3。
The organic base may be an organic base conventional in such reactions in the art, and the present invention preferably uses an amine-based organic compound and/or a quaternary ammonium salt, and more preferably uses one or more of N, N-dicyclohexylmethylamine, triethylamine, tributylamine, diisopropylethylamine, tetrabutylammonium bromide, tetrabutylammonium chloride, pyridine, and bipyridine (e.g., one or more of 2,2 ' -bipyridine, 2,3 ' -bipyridine, and 4,4 ' -bipyridine), and more preferably uses N, N-dicyclohexylmethylamine.
The ligand may be a ligand conventional in such reactions in the art, and in the present invention, one or more of tri-tert-butylphosphine tetrafluoroborate, triphenylphosphine, tri-o-phenylphosphine and tricyclohexylphosphine are preferred, and tri-tert-butylphosphine tetrafluoroborate is further preferred.
The solvent can be a solvent which is conventional in the field for the reaction, so that the reaction is not influenced, and one or more of amide solvents, ether solvents, pyrrolidone solvents and aromatic hydrocarbon solvents are preferably selected in the invention; the amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide, and is more preferably N, N-dimethylformamide; the ether solvent is preferably 1, 4-dioxane; the pyrrolidone solvent is preferably N-methyl pyrrolidone; the aromatic hydrocarbon solvent is preferably toluene and/or xylene (e.g., one or more of o-xylene, m-xylene, and p-xylene).
The amounts of the compound represented by the formula a, the palladium catalyst, the ligand, and the organic base are not particularly limited. It is well known in the art that the use of the catalyst, the ligand and the organic base in the reaction of the present invention is increased, and the quality and yield of the reaction are not greatly affected except uneconomical increase of cost, as long as the lower limit of the use of the catalyst, the ligand and the organic base is controlled. The molar ratio of the compound of formula a according to the invention to the catalyst is preferably 1: 0.0001 to 1: 0.015, further preferably 1: 0.0003 to 1:0.01, more preferably 1:0.0004 to 1:0.008, e.g. 1: 0.004.
the molar ratio of the compound represented by formula a to the organic base is preferably 1: 0.5-1: 4, further preferably 1: 0.5-1: 2, more preferably 1: 0.9-1: 1.5, e.g. 1: 1.01, 1:1.1 or 1: 1.21.
the molar ratio of the compound of formula a to the ligand is preferably 1: 0.0003 to 1:0.5, further preferably 1: 0.0003 to 1: 0.1, more preferably 1:0.0008 to 1:0.06, most preferably 1: 0.001 to 1: 0.03, e.g. 1: 0.0011, 1: 0.005 or 1: 0.011.
the molar ratio of the compound represented by the formula a to the compound represented by the formula B is preferably 1: 1-1: 5, more preferably 1: 1.17-1: 4, more preferably 1: 1.5-1: 4, most preferably 1: 1.7-1: 3.4, e.g. 1: 2.5.
the amount of the solvent may be not particularly limited so as not to affect the reaction; the mass ratio of the solvent to the compound represented by the formula a is preferably 1: 1-10: 1, more preferably 1: 1-4: 1, more preferably 2.5: 1-3.1: 1, e.g. 2.9: 1.
the reaction time of the reaction may be 0.1min to 30min, preferably 0.1min to 10min, and more preferably 0.5min to 8min, for example, 1min, 2.9min, 4.5min, or 5 min.
The reaction temperature of the reaction is a temperature conventional in such reactions in the art, and the temperature is preferably 10 ℃ to 200 ℃, more preferably 30 ℃ to 150 ℃, even more preferably 110 ℃ to 140 ℃, and most preferably 120 ℃ to 130 ℃ in the present invention.
The reaction of the present invention does not require additional control of the anhydrous and anaerobic conditions, since the tubular reactor itself can provide an anhydrous and anaerobic environment.
In a preferred embodiment of the present invention, R is H, and R is1、R2、R3、R4And R5Is hydrogen, and X is Cl, Br or I, preferably Br.
When R is H, R is1、R2、R3、R4And R5When the X is Cl, Br or I, the organic base is preferably an amine organic compound. The molar ratio of the compound of formula a to the catalyst is preferably 1: 0.0003 to 1: 0.01. the molar ratio of the compound of formula a to the ligand is preferably 1:0.0008 to 1: 0.06. the molar ratio of the compound represented by the formula a to the compound represented by the formula B is preferably 1: 1.5-1: 4. the reaction time of the reaction is preferably 0.1min to 10 min. The reaction temperature of the reaction is preferably 110 ℃ to 140 ℃. The rest conditions are the same as the above.
In a preferred embodiment of the present invention, R is H, and R is1、R2、R4And R5Is hydrogen, said R3Is F or Cl, preferably Cl, and the X is Cl, Br or I, preferably I.
When R is H, R is1、R2、R4And R5Is hydrogen, said R3When the compound is F or Cl and the X is Cl, Br or I, the organic base is preferably an amine organic compound. The molar ratio of the compound of formula a to the catalyst is preferably 1: 0.0003 to 1: 0.01. the molar ratio of the compound represented by formula a to the organic base is preferably 1: 0.9-1: 1.5. the molar ratio of the compound of formula a to the ligand is preferably 1:0.0008 to 1: 0.06. the molar ratio of the compound represented by the formula a to the compound represented by the formula B is preferably 1: 1.5-1: 4. the mass ratio of the solvent to the compound represented by the formula a is preferably 1: 1-4: 1. the reaction time of the reaction is preferably 0.1min to 10 min. The reaction temperature of the reaction is preferably 110 ℃ to 140 ℃. The rest conditions are the same as the above.
In a preferred embodiment of the invention, R is H, and R is HR of (A) to (B)1、R2、R4And R5Is hydrogen, said R3Is as described in
Preference is given to
And X is Cl, Br or I, preferably Br.
When R is H, R is1、R2、R4And R5Is hydrogen, said R3Is as described in
When X is Cl, Br or I, the organic alkali is preferably an amine organic compound. The molar ratio of the compound of formula a to the catalyst is preferably 1: 0.0003 to 1: 0.01. the molar ratio of the compound represented by formula a to the organic base is preferably 1: 0.9-1: 1.5. the molar ratio of the compound of formula a to the ligand is preferably 1:0.0008 to 1: 0.06. the molar ratio of the compound represented by the formula a to the compound represented by the formula B is preferably 1: 1.5-1: 4. the mass ratio of the solvent to the compound represented by the formula a is preferably 1: 1-4: 1. the reaction time of the reaction is preferably 0.1min to 10 min. The reaction temperature of the reaction is preferably 110 ℃ to 140 ℃. The rest conditions are the same as the above.
The continuous preparation method of the aryl propionaldehyde compound preferably comprises the following steps of:
(1) forming a mixed solution 1 of the compound represented by the formula a, the palladium catalyst, the organic base, the ligand and the solvent;
(2) when the compound shown in the formula B is a solid, forming a mixed solution 2 by the compound shown in the formula B and the solvent; respectively feeding the mixed solution 1 and the mixed solution 2 into a tubular reactor through a metering pump to carry out the reaction; the concentration of the mixed solution 2 is not particularly limited, and the mixed solution 2 does not block the pipeline of the tubular reactor.
And when the compound shown in the formula B is liquid, respectively feeding the mixed solution 1 and the compound shown in the formula B into a tubular reactor through a metering pump to carry out the reaction.
The flow rate of the mixed liquid 1 is within the allowable range of the flow rate of the tubular reactor itself, and may be a flow rate conventionally used in the art for carrying out such a reaction using the tubular reactor, and is preferably 0.01mL/min to 50L/min, more preferably 1mL/min to 10L/min, and still more preferably 30mL/min to 50mL/min, for example, 32.9mL/min, 34.5mL/min, 36.8mL/min, 37.6mL/min, 40mL/min, 41.4mL/min, or 50 mL/min.
When the compound represented by the formula B is a solid, the flow rate of the mixed solution 2 is within the range allowed by the flow rate of the tubular reactor itself, and may be the flow rate conventionally used in the art for carrying out such a reaction using the tubular reactor, and is preferably 0.01mL/min to 50L/min, more preferably 1mL/min to 10L/min, even more preferably 2mL/min to 15mL/min, and most preferably 3.6mL/min to 10.5mL/min, such as 5.2mL/min, 5.7mL/min, or 7 mL/min.
When the compound of formula B is a liquid, the flow rate of the compound of formula B is within the range allowed by the flow rate of the tubular reactor itself, and may be the flow rate conventionally used in the art for carrying out such reactions using the tubular reactor, preferably 0.01mL/min to 50L/min, further preferably 1mL/min to 10L/min, more preferably 2mL/min to 15mL/min, most preferably 3.6mL/min to 10.5mL/min, such as 5.2mL/min, 5.7mL/min or 7 mL/min.
When R is H, R is1、R2、R3、R4And R5When the X is Cl, Br or I, the flow rate of the mixed solution 1 is preferably 30mL/min to 50 mL/min. The flow rate of the compound represented by the formula B is preferably 2mL/min to 15 mL/min.
When R is H, R is1、R2、R4And R5Is hydrogen, said R3When the X is Cl, Br or I, the flow rate of the mixed solution 1 is preferably 30mL/min to 50 mL/min. The flow rate of the compound represented by the formula B is preferably 2mL/min to 15 mL/min.
When said R isH, said R1、R2、R4And R5Is hydrogen, said R3Is as described in
When X is Cl, Br or I, the flow rate of the mixed solution 1 is preferably 30mL/min to 50 mL/min. The flow rate of the compound represented by the formula B is preferably 2mL/min to 15 mL/min.
In the present invention, the tubular reactor is preferably a tubular reactor equipped with a T-type mixer, and more preferably a tubular reactor disclosed in the patent application No. 201720662235.6.
The preparation method of the aryl propionaldehyde compound further comprises a post-treatment operation after the preparation of the aryl propionaldehyde compound is finished. The work-up procedure may be carried out using conventional work-up procedures for such reactions in the art, and the present invention preferably comprises the steps of: and continuously flowing a crude product obtained after the reaction is finished out of the tubular reactor with the T-shaped mixer to a receiver, cooling to 0-60 ℃, adding ethyl acetate, adding water to wash an organic layer, evaporating a solvent, and distilling or recrystallizing to obtain the aryl propionaldehyde compound.
In the present invention, the letter min in the description of time refers to minutes.
The above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: 1. the reaction process is a continuous flow reaction, compared with an intermittent reaction, the reaction time is shortened, the reaction temperature can be increased, the difficulty of generating tar when the temperature is increased in the intermittent reaction is overcome, and the yield is increased by the reaction process; 2. the raw materials are continuously added into a tubular reactor with a T-shaped mixer, and the reaction liquid continuously flows out to a receiver, so that potential safety hazards caused by heat accumulation in the intermittent reaction are avoided; 3. compared with the intermittent reaction, the phenomenon that the catalyst is inactivated at high temperature for a long time is avoided, the activity of the catalyst is improved, and the using amount of the catalyst in the process is reduced to 1/50-1/5 in the prior art; 4. the process reduces the generation of byproduct tar, has simple separation and purification steps, and is suitable for industrial production; 5. the process overcomes the technical prejudice that Heck reaction with generally long reaction time can not be carried out in a tubular reactor.
Drawings
FIG. 1 is a schematic process flow diagram of a tubular reactor with a T-type mixer used in the present invention.
Wherein 1 and 2 denote raw material tanks, 3 and 4 denote metering pumps, 5 and 6 denote shut-off valves, 7 denotes a tubular reactor with a T-type mixer, and 8 denotes a holding tank.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed and dissolved in N, N-dimethylformamide solvent (206g), and Pd was added2(dba)3(1.7g, 0.0018mol, 0.004eq), tri-tert-butylphosphine tetrafluoroborate (1.4g, 0.0049mol, 0.011eq) and N, N-dicyclohexylmethylamine (87.6g, 0.45mol, 1.01eq), stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 1.0g/mL, and placing the mixed solution 1 in a raw material tank 1; weighing allyl alcohol (44.4g, 0.76mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 40mL/min and 5.7mL/min respectively by the metering pump 3 and the metering pump 4, setting the temperature of the tubular reactor 7 with the T-shaped mixer to be 120 ℃, and setting the reaction retention time to be 2.9 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 99.3% (HPLC analysis); after purification of the crude product, the product purity was 97.5% and the yield was 82% (GC-MS analysis).
Example 2
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed and dissolved in N, N-dimethylformamide solvent (206g), and Pd was added2(dba)3(0.17g, 0.18mmol, 0.0004eq), tri-tert-butylphosphine tetrafluoroborate (0.14g, 0.49mmol, 0.0011eq) and N, N-dicyclohexylmethylamine (87.6g, 0.45mol, 1.01eq) by stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 1.0g/mL, and the mixed solution 1 is placed in a raw material tank 1; weighing allyl alcohol (44.4g, 0.76mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 40mL/min and 5.7mL/min respectively by using a metering pump 3 and a metering pump 4, setting the temperature of a tubular reactor 7 with a T-shaped mixer to be 130 ℃, and setting the reaction retention time to be 4.5 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 96.5% (HPLC analysis); after purification of the crude product, the product purity was 97.1% and the yield was 78% (GC-MS analysis).
Example 3
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed out and dissolved in N, N-dimethylformamide solvent (206g), Pd (OAc) was added2(1g, 4.45mmol, 0.01eq), triphenylphosphine (0.58g, 2.21mmol, 0.005eq) and tributylamine (90.73g, 0.49mol, 1.1eq) by stirring to mix them uniformly to obtain a mixed solution 1, the density of the mixed solution 1 is 1.0g/mL, and the mixed solution 1 is placed in a stock tank 1; weighing allyl alcohol (44.4g, 0.76mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 36.8mL/min and 5.2mL/min respectively by using a metering pump 3 and a metering pump 4, setting the temperature of a tubular reactor 7 with a T-shaped mixer to be 130 ℃, and keeping the reaction time for 5 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 92% (HPLC analysis); after purification of the crude product, the product purity was 97.1% and the yield was 78.5% (GC-MS analysis).
Example 4
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed and dissolved in N, N-dimethylformamide solvent (206g), and Pd was added2(dba)3(4.07g, 4.45mmol, 0.01eq), tri-tert-butylphosphine tetrafluoroborate (0.65g, 2.24mmol, 0.005eq) and N, N-dicyclohexylmethylamine (95.72g, 0.49mol, 1.1eq), stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 1.0g/mL, and placing the mixed solution 1 in a raw material tank 1; weighing allyl alcohol (44.4g, 0.76mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 37.6mL/min and 5.2mL/min respectively by the metering pump 3 and the metering pump 4, setting the temperature of the tubular reactor 7 with the T-shaped mixer to be 130 ℃, and setting the reaction residence time to be 5 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 100% (HPLC analysis); after purification of the crude product, the product purity was 98.2% and the yield was 82.1% (GC-MS analysis).
Example 5
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed out and dissolved in N, N-dimethylformamide solvent (206g), Pd (dba) was added2(2.56g, 4.45mmol, 0.01eq), tri-o-methylphenyl phosphine (0.68g, 2.23mmol, 0.005eq) and triethylamine (49.58g, 0.49mol, 1.1eq), stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 1.0g/mL, and placing the mixed solution 1 in a raw material tank 1; weighing allyl alcohol (44.4g, 0.76mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 32.9mL/min and 5.2mL/min respectively by using a metering pump 3 and a metering pump 4, setting the temperature of a tubular reactor 7 with a T-shaped mixer to be 130 ℃, and keeping the reaction time for 5 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 88% (HPLC analysis); after purification of the crude product, the product purity was 97.1% and the yield was 72.2% (GC-MS analysis).
Example 6
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed and dissolved in N, N-dimethylformamide solvent (206g), and Pd (PPh) was added3)4(5.14g, 4.45mmol, 0.01eq), tricyclohexylphosphorus (0.63g, 2.25mmol, 0.005eq) and diisopropylethylamine (63.32g, 0.49mol, 1.1eq), stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 1.0g/mL, placing the mixed solution 1 in a raw material tank 1; weighing allyl alcohol (88.8g, 1.52mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 34.5mL/min and 10.5mL/min respectively by the metering pump 3 and the metering pump 4, setting the temperature of the tubular reactor 7 with the T-shaped mixer to be 130 ℃, and setting the reaction residence time to be 5 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 81% (HPLC analysis); after purification of the crude product, the product purity was 96.8% and the yield was 60.4% (GC-MS analysis).
Example 7
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed and dissolved in N, N-dimethylformamide solvent (206g), and Pd was added2(dba)3(1.7g, 0.0018mol, 0.004eq), tri-tert-butylphosphine tetrafluoroborate (1.4g, 0.0049mol, 0.011eq) and N, N-dicyclohexylmethylamine (87.6g, 0.45mol, 1.01eq), stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 1.0g/mL, and placing the mixed solution 1 in a raw material tank 1;weighing allyl alcohol (44.4g, 0.76mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 40mL/min and 5.7mL/min respectively by using a metering pump 3 and a metering pump 4, setting the temperature of a tubular reactor 7 with a T-shaped mixer to be 130 ℃, and setting the reaction retention time to be 0.5 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 98.2% (HPLC analysis); after purification of the crude product, the product purity was 97.6% and the yield was 75% (GC-MS analysis).
Example 8
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed and dissolved in N, N-dimethylformamide solvent (206g), PdCl was added2(0.79g, 4.45mmol, 0.01eq), tricyclohexylphosphorus (0.63g, 2.25mmol, 0.005eq) and tetrabutylammonium chloride (136.18g, 0.49mol, 1.1eq), stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 1.0g/mL, and placing the mixed solution 1 in a raw material tank 1; weighing allyl alcohol (30.4g, 0.52mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2; )
2. With the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 41.4mL/min and 3.6mL/min respectively by the metering pump 3 and the metering pump 4, setting the temperature of the tubular reactor 7 with the T-shaped mixer to be 130 ℃, and setting the reaction residence time to be 5 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 71% (HPLC analysis); after purification of the crude product, the product purity was 96.5% and the yield was 43.6% (GC-MS analysis).
Example 9
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed and dissolved in N, N-dimethylformamide solvent (206g), and Pd was added2(dba)3(1.7g, 0.0018mol, 0.004eq), tri-tert-butylphosphine tetrafluoroborate (1.4g, 0.0049mol, 0.011eq) and N, N-dicyclohexylmethylamine (87.6g, 0.45mol, 1.01eq), stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 1.0g/mL, and placing the mixed solution 1 in a raw material tank 1; weighing allyl alcohol (44.4g, 0.76mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 40mL/min and 5.7mL/min respectively by the metering pump 3 and the metering pump 4, setting the temperature of the tubular reactor 7 with the T-shaped mixer to be 200 ℃, and setting the reaction residence time to be 8 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 99.8% (HPLC analysis); after purification of the crude product, the product purity was 96.5% and the yield was 41% (GC-MS analysis).
Example 10
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed and dissolved in N, N-dimethylformamide solvent (206g), and Pd was added2(dba)3(0.085g, 0.09mmol, 0.0002eq), tri-tert-butylphosphine tetrafluoroborate (0.07g, 0.25mmol, 0.00056eq) and N, N-dicyclohexylmethylamine (87.6g, 0.45mol, 1.01eq) were mixed by stirring to obtain a mixed solution 1, the density of the mixed solution 1 was 1.0g/mL, and the mixed solution 1 was placed in a stock tank 1; weighing allyl alcohol (44.4g, 0.76mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 40mL/min and 5.7mL/min respectively by using a metering pump 3 and a metering pump 4, setting the temperature of a tubular reactor 7 with a T-shaped mixer to be 130 ℃, and keeping the reaction time for 1 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 43.9% (HPLC analysis); after purification of the crude product, the product purity was 98.2% and the yield was 28% (GC-MS analysis).
Example 11
1. Preparing raw materials: bromobenzene (70g, 0.445mol) was weighed and dissolved in N, N-dimethylformamide solvent (206g), and Pd was added2(dba)3(1.7g, 0.0018mol, 0.004eq), tri-tert-butylphosphine tetrafluoroborate (1.4g, 0.005mol, 0.011eq) and N, N-dicyclohexylmethylamine (87.6g, 0.45mol, 1.01eq), stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 1.0g/mL, and placing the mixed solution 1 in a raw material tank 1; weighing allyl alcohol (44.4g, 0.76mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 40mL/min and 5.7mL/min respectively by the metering pump 3 and the metering pump 4, setting the temperature of the tubular reactor 7 with the T-shaped mixer to be 30 ℃, and setting the reaction retention time to be 2.9 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. Bromobenzene conversion was 9.8% (HPLC analysis); after purification of the crude product, the product purity was 98.5% and the yield was 5% (GC-MS analysis).
Example 12
1. Preparing raw materials: 3-chloro-iodobenzene (81g, 0.34mol) was weighed out and dissolved in N, N-dimethylformamide solvent (240g), Pd was added2(dba)3(2.6g,0.0028mol, 0.008eq), tri-tert-butylphosphine tetrafluoroborate (3.0g, 0.01mol, 0.03eq) and N, N-dicyclohexylmethylamine (80g, 0.41mol, 1.21eq), stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 1.0g/mL, and placing the mixed solution 1 in a raw material tank 1; weighing allyl alcohol (49g, 0.84mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 50mL/min and 7.0mL/min respectively by the metering pump 3 and the metering pump 4, setting the temperature of the tubular reactor 7 with the T-shaped mixer to be 130 ℃, and setting the reaction residence time to be 5 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. The conversion of 3-chloro-iodobenzene was 99.5% (HPLC analysis result); after purification of the crude product, the product purity was 98.2% and the yield was 69% (GC-MS analysis).
Example 13
1. Preparing raw materials: 4-bromo-benzoic acid ethyl ester (78g, 0.34mol) was weighed out and dissolved in N, N-dimethylformamide solvent (240g), and Pd was added2(dba)3(2.6g,0.0028mol, 0.008eq), tri-tert-butylphosphine tetrafluoroborate (3.0g, 0.01mol, 0.03eq) and N, N-dicyclohexylmethylamine (80g, 0.41mol, 1.21eq), stirring to mix them uniformly to obtain a mixed solution 1, wherein the density of the mixed solution 1 is 0.97g/mL, and placing the mixed solution 1 in a raw material tank 1; weighing allyl alcohol (49g, 0.84mol) with the density of 0.85g/mL, and placing the allyl alcohol into a raw material tank 2;
2. with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed solution 1 in the raw material tank 1 enters a tubular reactor 7 with a T-shaped mixer through a metering pump 3, and the allyl alcohol in the raw material tank 2 enters the tubular reactor 7 with the T-shaped mixer through a metering pump 4; (2) setting the flow rates of the mixed solution 1 and the allyl alcohol to be 50mL/min and 7.0mL/min respectively by the metering pump 3 and the metering pump 4, setting the temperature of the tubular reactor 7 with the T-shaped mixer to be 130 ℃, and setting the reaction residence time to be 5 min; (3) the reaction channel is provided with a stop valve 5 and a stop valve 6 to prevent the backflow of materials; (4) after the mixture is mixed and reacted in a tubular reactor 7 with a T-shaped mixer, the crude product is continuously discharged and collected in a collecting tank 8, and the crude product is analyzed by HPLC; (4) the crude product was cooled to 25 ℃, ethyl acetate (700g) was added to the crude product, the resulting salt and the palladium catalyst were removed by filtration, water (200g x 3) was added to wash the organic layer, the solvent was distilled off, and the product was analyzed by GC-MS after distillation or recrystallization.
3. The 4-bromo-ethyl benzoate conversion was 99.5% (HPLC analysis); after purification of the crude product, the product purity was 98.2% and the yield was 89% (GC-MS analysis).
Claims (11)
1. A continuous preparation method of aryl propionaldehyde compounds is characterized by comprising the following steps: in a solvent, under the action of a palladium catalyst, a ligand and an organic base, carrying out the following reaction on a compound shown in a formula A and a compound shown in a formula B in a tubular reactor to obtain a compound shown in a formula C;
wherein X is Cl, Br or I;
r is hydrogen;
R1、R2、R3、R4and R5Each independently is H, F, Cl or
Said RaIs C1-C4An alkyl group;
the ligand is one or more of tri-tert-butylphosphine tetrafluoroborate, triphenylphosphine and tri-o-phenylphosphine;
the palladium catalyst is Pd2(dba)3、Pd(OAc)2、Pd(PPh3)4、Pd(dba)2And PdCl2One or more of the above;
the organic alkali is an amine organic compound and/or a quaternary ammonium salt;
the solvent is one or more of amide solvents, ether solvents, pyrrolidone solvents and aromatic hydrocarbon solvents;
the molar ratio of the compound shown in the formula A to the ligand is 1: 0.0008-1: 0.06;
the molar ratio of the compound shown in the formula A to the catalyst is 1: 0.0004-1: 0.01;
the molar ratio of the compound shown in the formula A to the compound shown in the formula B is 1: 1.5-1: 4;
the reaction time is 0.1 min-10 min;
the reaction temperature of the reaction is 110-140 ℃.
2. A continuous process for the preparation of arylpropionaldehyde as claimed in claim 1, wherein: said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
3. A continuous process for the preparation of arylpropionaldehyde as claimed in claim 2, wherein: the palladium catalyst is Pd2(dba)3；
And/or the organic base is one or more of N, N-dicyclohexyl methylamine, triethylamine, tributylamine, diisopropylethylamine, tetrabutylammonium bromide, tetrabutylammonium chloride, pyridine and bipyridyl;
and/or the ligand is tri-tert-butylphosphine tetrafluoroborate;
and/or the amide solvent is N, N-dimethylformamide and/or N, N-dimethylacetamide;
and/or the ether solvent is 1, 4-dioxane;
and/or the pyrrolidone solvent is N-methyl pyrrolidone;
and/or the aromatic hydrocarbon solvent is toluene and/or xylene.
4. A continuous process for the preparation of arylpropionaldehyde as claimed in claim 3, wherein: the organic alkali is N, N-dicyclohexyl methylamine;
or the amide solvent is N, N-dimethylformamide.
5. A process for the continuous preparation of arylpropionaldehyde compounds according to any one of claims 1 to 4, wherein:
the molar ratio of the compound shown in the formula A to the organic base is 1: 0.5-1: 4;
and/or the mass ratio of the solvent to the compound shown in the formula A is 1: 1-10: 1.
6. A continuous process for the preparation of arylpropionaldehyde as claimed in claim 5, wherein:
the molar ratio of the compound shown in the formula A to the organic base is 1: 0.5-1: 2;
and/or the mass ratio of the solvent to the compound shown in the formula A is 1: 1-4: 1.
7. A continuous process for the preparation of arylpropionaldehyde as claimed in claim 1, wherein: the molar ratio of the compound shown in the formula A to the catalyst is 1: 0.0004-1: 0.008;
and/or the molar ratio of the compound shown in the formula A to the organic base is 1: 0.9-1: 1.5;
and/or the molar ratio of the compound shown in the formula A to the compound shown in the formula B is 1: 1.7-1: 3.4;
and/or the mass ratio of the solvent to the compound shown in the formula A is 2.5: 1-3.1: 1;
and/or the reaction time of the reaction is 0.5 min-8 min.
8. A continuous process for the preparation of arylpropionaldehyde as claimed in claim 1, wherein: r is H, R1、R2、R3、R4And R5Is hydrogen, and X is Cl, Br or I;
in this case, the organic base is an amine-based organic compound; the molar ratio of the compound shown in the formula A to the catalyst is 1: 0.0004-1: 0.01; the molar ratio of the compound shown in the formula A to the ligand is 1: 0.0008-1: 0.06; the molar ratio of the compound shown in the formula A to the compound shown in the formula B is 1: 1.5-1: 4; the reaction time is 0.1 min-10 min; the reaction temperature of the reaction is 110-140 ℃.
9. A continuous process for the preparation of arylpropionaldehyde as claimed in claim 1, wherein: r is H, R1、R2、R4And R5Is hydrogen, said R3Is F or Cl, and X is Cl, Br or I;
in this case, the organic base is an amine-based organic compound; the molar ratio of the compound shown in the formula A to the catalyst is 1: 0.0004-1: 0.01; the molar ratio of the compound shown in the formula A to the organic base is 1: 0.9-1: 1.5; the molar ratio of the compound shown in the formula A to the ligand is 1: 0.0008-1: 0.06; the molar ratio of the compound shown in the formula A to the compound shown in the formula B is 1: 1.5-1: 4; the mass ratio of the solvent to the compound shown in the formula A is 1: 1-4: 1; the reaction time is 0.1 min-10 min; the reaction temperature of the reaction is 110-140 ℃.
10. A continuous process for the preparation of arylpropionaldehyde as claimed in claim 1, wherein: r is H, R1、R2、R4And R5Is hydrogen, said R3Is as described in
X is Cl, Br or I;
in this case, the organic base is an amine-based organic compound; the molar ratio of the compound shown in the formula A to the catalyst is 1: 0.0004-1: 0.01; the molar ratio of the compound shown in the formula A to the organic base is 1: 0.9-1: 1.5; the molar ratio of the compound shown in the formula A to the ligand is 1: 0.0008-1: 0.06; the molar ratio of the compound shown in the formula A to the compound shown in the formula B is 1: 1.5-1: 4; the mass ratio of the solvent to the compound shown in the formula A is 1: 1-4: 1; the reaction time is 0.1 min-10 min; the reaction temperature of the reaction is 110-140 ℃.
11. A continuous process for the preparation of arylpropionaldehyde as claimed in claim 1, wherein: comprises the following steps:
(1) forming a mixed solution 1 of the compound represented by the formula a, the palladium catalyst, the organic base, the ligand and the solvent;
(2) when the compound shown in the formula B is a solid, forming a mixed solution 2 by the compound shown in the formula B and the solvent; respectively feeding the mixed solution 1 and the mixed solution 2 into a tubular reactor through a metering pump to carry out the reaction;
when the compound shown in the formula B is liquid, respectively feeding the mixed solution 1 and the compound shown in the formula B into a tubular reactor through a metering pump to perform the reaction;
the flow rate of the mixed solution 1 is 0.01mL/min to 50L/min;
when the compound shown in the formula B is liquid, the flow rate of the compound shown in the formula B is 0.01 mL/min-50L/min;
the tubular reactor is a tubular reactor with a T-shaped mixer.
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| US3862236A (en) * | 1969-11-28 | 1975-01-21 | Bayer Ag | Production of propionaldehyde |
| CN105175235A (en) * | 2015-09-10 | 2015-12-23 | 常州大学 | Method of preparing aromatic aldehyde and ketone through continuously oxidizing aromatic alcohol by adopting tubular reactor |
| CN109438205A (en) * | 2018-10-12 | 2019-03-08 | 西北大学 | A kind of synthetic method of 2- methyl -2,3- diaryl propionic aldehyde derivative |
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| US3862236A (en) * | 1969-11-28 | 1975-01-21 | Bayer Ag | Production of propionaldehyde |
| CN105175235A (en) * | 2015-09-10 | 2015-12-23 | 常州大学 | Method of preparing aromatic aldehyde and ketone through continuously oxidizing aromatic alcohol by adopting tubular reactor |
| CN109438205A (en) * | 2018-10-12 | 2019-03-08 | 西北大学 | A kind of synthetic method of 2- methyl -2,3- diaryl propionic aldehyde derivative |
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| Double Arylation of Allyl Alcohol via a One-Pot Heck Arylation Isomerization Acylation Cascade;Paul Colbon etal;《Organic letters》;20110920;第13卷(第20期);5457-5458 * |
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