Method for preparing substituted aryl propionic acid by decarboxylating substituted aryl malonic acid

Abstract

The invention discloses a method for preparing substituted aryl propionic acid by decarboxylating substituted aryl malonic acid, which comprises the following steps of: mixing a compound shown as a formula I, an organic solvent and a cuprous catalyst for reaction, and post-processing to obtain a compound shown as a formula II; according to the method disclosed by the invention, the substituted aryl propanoic acid is prepared by decarboxylating the substituted aryl malonic acid at a relatively low temperature.

Description

Technical Field

[0001] The invention belongs to the field of compound preparation, and particularly relates to a method for preparing substituted aryl propionic acid by decarboxylating substituted arylmalonic acid. Background Art

[0002] Indanone compounds are important intermediates for the synthesis of pesticides and metallocene catalyst ligands. Currently, the widely used and mature synthesis method of indanone compounds has been reported in the literature (see Organometallics 2006, 25, 1217-1229 and US2007 / 0135595A1). The method uses substituted benzyl halide as raw material, and the benzyl halide reacts with substituted malonate to generate substituted aryl malonate, which is hydrolyzed under acidic conditions to obtain substituted aryl malonate, and the substituted aryl malonate is decarboxylated at high temperature to obtain substituted aryl propionic acid, which is then chlorinated and cyclized by aluminum chloride to obtain indanone compounds. Among them, the decarboxylation of substituted aryl malonate at high temperature to obtain substituted aryl propionic acid is one of the key steps in this synthesis process. The decarboxylation step used in this method needs to be carried out at a high temperature of 160 to 190° C., the reaction energy consumption is high, the safety is low, and by-products such as anhydride are easily generated at high temperature, which affects the purity and yield of the product aryl propionic acid. Summary of the invention

[0003] In order to improve the above technical problems, the present invention provides a method for preparing substituted aryl propionic acid by decarboxylation of substituted aryl malonic acid. The substituted aryl malonic acid can be decarboxylated at a relatively low temperature to obtain substituted aryl propionic acid, thereby solving the following technical problems existing in traditional high-temperature decarboxylation: (1) high temperature is prone to produce by-products such as acid anhydride, thereby affecting the purity and yield of the product aryl propionic acid; (2) high temperature has high energy consumption and low safety.

[0004] The present invention provides a method for preparing substituted aryl propionic acid by decarboxylating substituted arylmalonic acid, the method comprising the following steps:

[0005] The compound of formula I, an organic solvent and a cuprous catalyst are mixed for reaction, and then post-treated to obtain a compound of formula II;

[0006]

[0007] X is selected from C 1～20 Alkyl, halogen substituted C 1～20 Alkyl, C 1～20 Alkoxy, halogen substituted C 1～20 alkoxy, halogen or hydrogen;

[0008] R1 and R2 are the same or different and are independently selected from hydrogen, C 1～20 Alkyl, halogen substituted C 1～20 Alkyl, C 1～20Alkoxy, halogen substituted C 1～20 Alkoxy; or, R1 and R2 are connected to form a cyclic olefin structure or an aromatic hydrocarbon structure;

[0009] R3, R4, R5 are the same or different and are independently selected from hydrogen, C 1～20 Alkyl, halogen substituted C 1～20 Alkyl, C 1～20 Alkoxy, halogen substituted C 1～20 Alkoxy;

[0010] The temperature of the reaction is below 100°C.

[0011] According to an embodiment of the present invention, X is selected from C 1～10 Alkyl, halogen substituted C 1～10 Alkyl, C 1～10 Alkoxy, halogen substituted C 1～10 Alkoxy, halogen or hydrogen; preferably, X is selected from C 1～4 Alkyl, halogen substituted C 1～4 Alkyl, C 1～4 Alkoxy, halogen substituted C 1～4 Alkoxy, halogen or hydrogen; for example, X is selected from hydrogen, chlorine or bromine.

[0012] According to some embodiments of the present invention, R1 and R2 are independently selected from hydrogen, C 1～12 Alkyl, halogen substituted C 1～12 Alkyl, C 1～12 Alkoxy, halogen substituted C 1～12 Preferably, R1 and R2 are independently selected from hydrogen, C 1～4 Alkyl, halogen substituted C 1～4 Alkyl, C 1～4 Alkoxy, halogen substituted C 1～4 Alkoxy; for example, said R1, R2 are independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl.

[0013] According to some embodiments of the present invention, R1 and R2 are connected to form C 3～12 Cyclic olefin structure or C 6～12 Aromatic hydrocarbon structures, preferably linked to form C 3～8 Cyclic olefin structure or C 6～10 Aromatic hydrocarbon structures, such as those linked to form benzene ring structures.

[0014] According to an embodiment of the present invention, R3, R4, and R5 are independently selected from hydrogen, C 1～12 Alkyl, halogen substituted C 1～12 Alkyl, C 1～12 Alkoxy, halogen substituted C 1～12Preferably, R3, R4, R5 are independently selected from hydrogen, C 1～4 Alkyl, halogen substituted C 1～4 Alkyl, C 1～4 Alkoxy, halogen substituted C 1～4 Alkoxy; for example, said R3, R4, R5 are independently selected from hydrogen, methyl, ethyl.

[0015] According to some embodiments of the present invention, R4 and R5 are both hydrogen.

[0016] According to an embodiment of the present invention, the halogen includes fluorine, chlorine, bromine, and iodine.

[0017] According to an embodiment of the present invention, the compound of formula I is selected from any one of the following compounds:

[0018]

[0019] According to an embodiment of the present invention, the compound of formula II is selected from any one of the following compounds:

[0020]

[0021] According to an embodiment of the present invention, the organic solvent is a nitrile compound having a structure shown in Formula III,

[0022]

[0023] The R6 is selected from C 1～20 Alkyl, C 1～20 Alkylene, C 1～20 Alkoxy, C 2～20 Alkenyl, C 6～20 Aryl, C 1～20 Alkyl substituted C 6～20 Aryl; Preferably, said R6 is selected from C 1～12 Alkyl, C 1～12 Alkylene, C 2～12 Alkenyl, C 6～12 Aryl, C 1～12 Alkyl substituted C 6～12 Aryl; Also preferably, said R6 is selected from C 1～6 Alkyl, C 1～6 Alkylene, C 2～6 Alkenyl, C6 aryl, C 1～6 Alkyl-substituted C6 aryl; exemplified by ethyl, propyl, butyl, pentyl, hexyl, propylene, hexylene, propenyl, phenyl, phenethyl;

[0024] n is selected from 1 or 2.

[0025] According to an exemplary embodiment of the present invention, the organic solvent is selected from one or more of acetonitrile, propionitrile, acrylonitrile, malononitrile, butyronitrile, valeronitrile, adiponitrile and benzyl cyanide.

[0026] According to an embodiment of the present invention, the amount of the organic solvent used is sufficient to dissolve the compound of formula I, for example, the mass volume ratio of the compound of formula I to the organic solvent is 1g:(2-10)ml, for example 1g:(2.5-7)ml, exemplified by 1g:3ml, 1g:4ml, 1g:5ml, 1g:6ml.

[0027] According to an embodiment of the present invention, the cuprous catalyst is selected from one or more of cuprous oxide, cuprous sulfide, cuprous cyanide, cuprous chloride, cuprous bromide and cuprous iodide.

[0028] According to an embodiment of the present invention, the mass ratio of the compound of formula I to the cuprous catalyst is (10-70):1, for example (15-60):1, exemplified by 18:1, 20:1, 30:1, 40:1, 50:1.

[0029] According to an embodiment of the present invention, the reaction temperature is 30-90°C, such as 30-81.6°C, exemplified by 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 85°C.

[0030] According to an embodiment of the present invention, the reaction time is 2 to 12 hours, preferably 3 to 8 hours.

[0031] According to an embodiment of the present invention, the post-treatment includes: after the reaction is completed, the solvent is removed by rotary evaporation, deionized water is added to the residue, an acid (such as hydrochloric acid) is added dropwise, ether or methyl tert-butyl ether (MTBE) is added for extraction, and an organic phase is separated; the organic phase is dried, filtered, and then the organic phase solvent is removed by rotary evaporation to obtain a compound of formula II.

[0032] According to a preferred embodiment of the present invention, the method for preparing substituted aryl propionic acid by decarboxylation of substituted arylmalonic acid comprises the following steps:

[0033] The compound of formula I, an organic solvent and a cuprous catalyst are mixed for reaction, and then post-treated to obtain a compound of formula II;

[0034]

[0035] The organic solvent is a nitrile compound having a structure shown in Formula III,

[0036]

[0037] X, R1, R2, R3, R4, R5, R6, and n are as defined above;

[0038] The reaction temperature is 30-81.6° C. and the reaction time is 3-10 hours.

[0039] Beneficial Effects

[0040] The invention provides a method for preparing substituted aryl propionic acid by decarboxylating substituted arylmalonic acid, which realizes the decarboxylation of substituted arylmalonic acid to prepare substituted aryl propionic acid at a relatively low temperature, has low reaction energy consumption, high safety, and high product purity and yield, with the yield reaching 95% to 99%.

[0041] Definitions and explanations of terms

[0042] Unless otherwise specified, the definitions of terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions of specific compounds in the examples, etc., may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of the description of this application.

[0043] Unless otherwise specified, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-12" is equivalent to describing each integer value in the numerical range "1-12", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0044] The term "C 1-20 The term "alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 20 carbon atoms. 1-12 The term “alkyl” refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0045] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy.

[0046] The term "C 1～20 "Alkylene" is understood to mean straight-chain and branched alkylene groups having 1 to 20 carbon atoms. 1-12The term "alkylene" refers to straight-chain and branched alkylene groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The alkylene group is, for example, methylene, ethylene, propylene, butylene, pentylene, hexylene, etc. or isomers thereof.

[0047] The term "C 2～20 "Alkenyl" is understood to mean straight-chain and branched alkenyl groups having 1 to 20 carbon atoms. 1-12 The term "alkenyl" refers to straight-chain and branched alkenyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The alkenyl group is, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc. or isomers thereof.

[0048] The term "C 6～20 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-～12 "Aryl", particularly a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; when the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position. DETAILED DESCRIPTION

[0049] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0050] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0051] Example 1

[0052]

[0053] Add 69g of the raw material compound of formula I-1 to a flask, then add 300mL of butyronitrile, stir to dissolve, add 1.72g of cuprous oxide, heat to 80°C, and react for 6 hours. Remove the solvent by rotary evaporation, add 150mL of deionized water to the residue, and drop 15mL of concentrated hydrochloric acid. Then add ether to extract, separate the organic phase, add anhydrous sodium sulfate to the organic phase to dry, filter, and rotary evaporation to remove the organic phase solvent to obtain 68g of an oily product, i.e., the compound of formula II-1, with a yield of 95%. There is no impurity in the product after nuclear magnetic resonance detection.

[0054] The NMR characterization results of the product are as follows:

[0055] 1 H NMR (DMSO, 500MHz), δ: 12.23 (s, 1H), 7.52-7.65 (d, 1H), 7.29-7.35 (t, 2H), 7.13-7.21(m,1H),2.95-3.12(m,1H),2.65-2.78(m,2H),1.02-1.11(d,3H).

[0056] Example 2

[0057]

[0058] Add 3.5g of the raw material formula I-2 compound to a flask, add 10mL of acetonitrile, stir to dissolve, add 70mg of cuprous oxide, heat to 60°C, and react for 6 hours. Remove the solvent by rotary evaporation, add 30mL of deionized water to the residue, and drop 3mL of concentrated hydrochloric acid. Then add methyl tert-butyl ether (MTBE) to extract, separate the organic phase, add anhydrous sodium sulfate to the organic phase, dry it, filter, and remove the organic phase solvent by rotary evaporation to obtain 3g of yellow oily product, i.e., the compound of formula II-2, with a yield of 98%. There is no impurity in the product after nuclear magnetic resonance detection.

[0059] The NMR characterization results of the product are as follows:

[0060] 1 H NMR (DMSO, 500MHz), δ: 12.21 (s, 1H), 7.52 (s, 1H), 7.28-7.35 (d, 1H), 7.18-7.2 5(d,1H),2.94-3.03(m,1H),2.60-2.74(m,2H),1.25(s,9H),1.04-1.09(d,3H).

[0061] Example 3

[0062]

[0063] Add 2.6 g of the raw material formula I-3 compound to a flask, add 15 mL of acetonitrile, stir to dissolve, add 140 mg of cuprous oxide, heat to 40 ° C, and react for 8 hours. Remove the solvent by rotary evaporation, add 5 mL of deionized water to the residue, and drop 1.4 mL of concentrated hydrochloric acid. Then add ether to extract, separate the organic phase, add anhydrous sodium sulfate to the organic phase, dry it, filter, and remove the organic phase solvent by rotary evaporation to obtain 2.1 g of a yellow-brown solid, i.e., the compound of formula II-3, with a yield of 96%. There is no impurity in the product after nuclear magnetic resonance detection.

[0064] The NMR characterization results of the product are as follows:

[0065] 1 H NMR (DMSO, 500MHz), δ: 12.14 (s, 1H), 7.75-7.90 (m, 3H), 7.69 (s, 1H), 7.41-7.52 (m ,2H),7.33-7.40(d,1H),3.00-3.12(m,1H),2.66-2.84(m,2H),1.04-1.10(d,3H).

[0066] Example 4

[0067]

[0068] Add 27.5g of the raw material formula I-3 compound to a flask, then add 150mL of acetonitrile, stir to dissolve, add 1.5g of cuprous oxide, heat to 30°C, and react for 10 hours. Remove the solvent by rotary evaporation, add 50mL of deionized water to the residue, and drop 15mL of concentrated hydrochloric acid. Then add methyl tert-butyl ether (MTBE) to extract, separate the organic phase, add anhydrous sodium sulfate to the organic phase, dry it, filter, and rotary evaporation to remove the organic phase solvent to obtain 22.5g of a yellow-brown solid, i.e., the compound of formula II-3, with a yield of 99%. There is no impurity in the product after nuclear magnetic resonance detection.

[0069] The NMR characterization results of the product are as follows:

[0070] 1 H NMR (DMSO, 500MHz), δ: 12.14 (s, 1H), 7.75-7.90 (m, 3H), 7.69 (s, 1H), 7.41-7.52 (m ,2H),7.33-7.40(d,1H),3.00-3.12(m,1H),2.66-2.84(m,2H),1.04-1.10(d,3H).

[0071] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing substituted aryl propionic acid by decarboxylation of substituted arylmalonic acid, characterized in that: The method comprises the following steps: The compound of formula I, an organic solvent and a cuprous catalyst are mixed for reaction, and then post-treated to obtain a compound of formula II; X is selected from C 1～20 Alkyl, halogen substituted C 1～20 Alkyl, C 1～20 Alkoxy, halogen substituted C 1～20 alkoxy, halogen or hydrogen; R1 and R2 are the same or different and are independently selected from hydrogen, C 1～20 Alkyl, halogen substituted C 1～20 Alkyl, C 1～20 Alkoxy, halogen substituted C 1～20 Alkoxy; or, R1 and R2 are connected to form a cyclic olefin structure or an aromatic hydrocarbon structure; R3, R4, R5 are the same or different and are independently selected from hydrogen, C 1～20 Alkyl, halogen substituted C 1～20 Alkyl, C 1～20 Alkoxy, halogen substituted C 1～20 Alkoxy; The temperature of the reaction is below 100°C.

2. The method according to claim 1, characterized in that The X is selected from C 1～10 Alkyl, halogen substituted C 1～10 Alkyl, C 1～10 Alkoxy, halogen substituted C 1～10 Alkoxy, halogen or hydrogen; preferably, X is selected from C 1～4 Alkyl, halogen substituted C 1～4 Alkyl, C 1～4 Alkoxy, halogen substituted C 1～4 Alkoxy, halogen or hydrogen.

3. The method according to claim 1, characterized in that The R1 and R2 are independently selected from hydrogen, C 1～12 Alkyl, halogen substituted C 1～12 Alkyl, C 1～12 Alkoxy, halogen substituted C 1～12 Preferably, R1 and R2 are independently selected from hydrogen, C 1～4 Alkyl, halogen substituted C 1～4 Alkyl, C 1～4 Alkoxy, halogen substituted C 1～4 Alkoxy; Alternatively, R1 and R2 are connected to form C 3～12 Cyclic olefin structure or C 6～12 Aromatic hydrocarbon structures, preferably linked to form C 3～8 Cyclic olefin structure or C 6～10 Aromatic hydrocarbon structure.

4. The method according to claim 1, characterized in that The R3, R4, and R5 are independently selected from hydrogen, C 1～12 Alkyl, halogen substituted C 1～12 Alkyl, C 1～12 Alkoxy, halogen substituted C 1～12 Preferably, R3, R4, R5 are independently selected from hydrogen, C 1～4 Alkyl, halogen substituted C 1～4 Alkyl, C 1～4 Alkoxy, halogen substituted C 1～4 Alkoxy.

5. The method according to claim 1, characterized in that The compound of formula I is selected from any of the following compounds:

6. The method according to claim 1, characterized in that The compound of formula II is selected from any of the following compounds:

7. The method according to claim 1, characterized in that The organic solvent is a nitrile compound having a structure shown in Formula III, The R6 is selected from C 1～20 Alkyl, C 1～20 Alkylene, C 1～20 Alkoxy, C 2～20 Alkenyl, C 6～20 Aryl, C 1～20 Alkyl substituted C 6～20 Aryl; Preferably, said R6 is selected from C 1～12 Alkyl, C 1～12 Alkylene, C 2～12 Alkenyl, C 6～12 Aryl, C 1～12 Alkyl substituted C 6～12 Aryl; Also preferably, said R6 is selected from C 1～6 Alkyl, C 1～6 Alkylene, C 2～6 Alkenyl, C6 aryl, C 1～6 Alkyl substituted C6 aryl; n is selected from 1 or 2.

8. The method according to claim 1, characterized in that The organic solvent is selected from one or more of acetonitrile, propionitrile, acrylonitrile, malononitrile, butyronitrile, valeronitrile, adiponitrile and benzyl cyanide; And / or, the cuprous catalyst is selected from one or more of cuprous oxide, cuprous sulfide, cuprous cyanide, cuprous chloride, cuprous bromide and cuprous iodide; And / or, the mass ratio of the compound of formula I to the cuprous catalyst is (10-70):

1.

9. The method according to claim 1, characterized in that: The reaction temperature is 30 to 90° C., and / or the reaction time is 2 to 10 hours.

10. The method according to claim 1, characterized in that The post-treatment comprises: after the reaction is completed, the solvent is removed by rotary evaporation, deionized water is added to the residue, acid is added dropwise, ether or methyl tert-butyl ether is added for extraction, and an organic phase is separated; the organic phase is dried, filtered, and the organic phase solvent is removed by rotary evaporation to obtain a compound of formula II.

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