Synthesis method of novel alpha, alpha-dichloropropiophenone compound

Abstract

The invention discloses a synthesis method of a novel alpha, alpha-dichloropropiophenone compound, and particularly relates to a method for obtaining the alpha, alpha-dichloropropiophenone compound as shown in a formula II by introducing two chlorine atoms on the alpha position of carbonyl of a compound as shown in a formula I under the action of a chlorination reagent NCS. The synthesis method disclosed by the invention has the advantages of mild reaction conditions, simple reaction operation, small dosage of a chlorination reagent, cheap and small dosage of a catalyst, high selectivity, high yield, less pollution, suitability for industrial production and the like. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a novel α,α-dichloropropiophenone compound. Background Art

[0002] α,α-dichloro derivatives of various carbonyl compounds are important organic synthesis intermediates and are widely used in the synthesis of functional chemicals such as medicines and pesticides. They have always attracted the attention of synthesizers.

[0003] US3933472A discloses substituted alkyl aryl ketones, which are used as herbicides and can be used to control weeds and the germination and seedling of broadleaf weeds. Among them, the compound 2,2,3',5'-tetrachloro-4'-hydroxypropiophenone (as shown in formula a) and the compound 2,2-dichloro-4'-hydroxy-3',5'-dinitropropiophenone (as shown in formula b) show excellent anti-weed and herbicidal activity and can be used as economically feasible agricultural herbicides.

[0004] , Hiroshi Yanagita disclosed an anti-influenza virus drug, among which the compound 4-(2,2-dichloro-2-phenylacetyl)benzamide (as shown in formula c) showed good anti-influenza virus activity (Hiroshi Yanagita, NorioYamamoto, Hideyoshi Fuji, Xinli Liu, Masakazu Ogata, Mizuho Yokota, HiroshiTakaku, Hideki Hasegawa, Takato Odagiri, Masato Tashiro, and Tyuji Hoshino; ACS Chem. Biol. 2012, 7, 552−562).

[0005]

[0006] The synthesis of α,α-dichloro compounds is mainly based on carbonyl compounds as raw materials, which are prepared by chlorination with different chlorination reagents under certain conditions. The chlorination reagents mainly include Cl 2 Gas, SO 2 Cl 2 , SOCl 2 、PhICl 2 , copper chloride, lithium chloride, 1,3-dichloro-5,5-dimethylhydantoin (dichlorohydantoin or DCDMH), etc. There are some reports on the dichloro substitution reaction of α-position of phenylacetone compounds.

[0007] Norbert De Kimpe published the reaction of alkyl aryl ketones with Cl 2 A method for obtaining α,α-dichloroalkyl aryl ketone under the conditions of , DMF, 80-100°C (Norbert De Kimpe, Laurent De Buyck, Roland Verhé, Freddy Wychuyse and Niceas Schamp; Synthetic Communications (1979), 9(7), 575-582), the technical route of which is as follows:

[0008] Tu, Dewei disclosed that alkyl aryl ketones in SO 2 Cl 2 A method for obtaining α,α-dichloroalkyl aryl ketone under the conditions of , solvent-free and 80°C (Tu, Dewei; Luo, Juan; Jiang, Wengao; Tang, Qiang; Tetrahedron Letters (2021), 81, 153335), the technical route of which is as follows:

[0009] José Arimateia Nobrega disclosed a method for obtaining α,α-dichloroalkyl aryl ketone from alkyl aryl ketone in the presence of copper chloride, lithium chloride and DMF (José Arimateia Nobrega, Simone Maria C. Goncalves, and Clovis Peppe; Synthetic Communications (2002), 32(24), 3711-3717). The technical route is as follows:

[0010] Although there are several related reports of the reaction of dichloro substitution of α-position of phenylacetone compounds, the chlorination reagents used have the following shortcomings: chlorine gas is highly toxic, has low selectivity, and has a strong corrosive effect on equipment; sulfonyl chloride has a strong irritating odor, which is easy to irritate and burn organs such as human eyes or skin when used, and is inconvenient to use; some chlorine-containing inorganic salts are highly toxic, inconvenient to use, expensive, and difficult to promote industrial applications. It can be seen that the disclosed methods are neither economical nor environmentally safe. In addition, the selectivity problem of chlorination reaction is a challenge in synthetic reactions. In most cases, the product obtained is a mixture of monochloro and dichloro. It is difficult for general reaction conditions to meet complete conversion and obtain dichloro, and by-products are easily generated under severe reaction conditions. Therefore, it is urgent to develop a method that is both economical and environmentally safe, and has high selectivity.

[0011] In the present invention, NCS (N-chlorosuccinimide, ) This commonly used, economical, environmentally friendly and safe chlorination reagent, the synthesis method of the present invention has the advantages of mild reaction conditions, simple reaction operation, small amount of chlorination reagent, cheap catalyst and small amount, high selectivity, high yield, low pollution and suitability for industrial production, etc., and has great practical value. Summary of the invention

[0012] In view of the problems existing in the prior art, the present invention aims to provide a novel synthesis method of α,α-dichlorophenylacetophenone compounds. The synthesis method uses NCS, a commonly used, economical, environmentally friendly and safe chlorination reagent, and has the advantages of mild reaction conditions, simple reaction operation, small amount of chlorination reagent, cheap and small amount of catalyst, high selectivity, high yield, low pollution, and suitability for industrial production, and has great practical value.

[0013] In order to achieve the above objectives and the above technical effects, the present invention adopts the following technical solutions: A method for synthesizing a novel α,α-dichlorophenylacetone compound comprises the following steps: adding a compound represented by formula I, NCS and a catalyst into a solvent, reacting at a reaction temperature of 50-100° C. to obtain an α,α-dichlorophenylacetone compound represented by formula II:

[0014] in, R 1 are independently aryl, substituted aryl, heteroaryl or substituted heteroaryl; R 2 are independently H or alkyl; The catalyst is ferric chloride, cupric chloride, zinc chloride, hydrochloric acid, sulfuric acid, formic acid or p-toluenesulfonic acid; The solvent is methanol, ethanol, ethylene glycol, chloroform, N,N-dimethylformamide or acetonitrile.

[0015] In a preferred embodiment of the present invention, R 1 Independently for C 6 -C 10 Aryl, substituted C 6 -C 10 Aryl, 5-10 membered heteroaryl or substituted 5-10 membered heteroaryl; R 2 independently H or C 1 -C 6 alkyl.

[0016] In a preferred embodiment of the present invention, R 1 Independently for C 6 -C 10 Aryl, substituted C 6 -C 10 Aryl, 5-10 membered heteroaryl or substituted 5-10 membered heteroaryl; R 2 independently H or C 1 -C 4 alkyl.

[0017] In a preferred embodiment of the present invention, R 1 Independently , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R 2 is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0018] In a preferred embodiment of the present invention, The molar ratio of the compound represented by formula I to NCS is 1:2.0-4.0; The molar ratio of the compound represented by formula I to the catalyst is 1:0.05-0.5.

[0019] In a preferred embodiment of the present invention, The molar ratio of the compound represented by formula I to NCS is 1:2.0-3.0; The molar ratio of the compound represented by formula I to the catalyst is 1:0.05-0.2.

[0020] In a preferred embodiment of the present invention, The molar ratio of the compound represented by formula I to NCS is 1:2.5; The molar ratio of the compound represented by formula I to the catalyst is 1:0.1.

[0021] In a preferred embodiment of the present invention, The reaction temperature is 60-80°C.

[0022] In a preferred embodiment of the present invention, The reaction temperature is 80°C.

[0023] In a preferred embodiment of the present invention, The reaction is carried out in the air; the reaction is tracked by thin layer chromatography until it is completely completed; after the reaction is completed, the product is extracted, washed, dried, and concentrated to obtain a crude product, and then separated and purified by column chromatography.

[0024] Compared with the prior art, the technical solution of the present invention has the following positive effects: The synthesis method of the invention has the advantages of mild reaction conditions, simple reaction operation, small amount of chlorination reagent, cheap catalyst and small amount, high selectivity, high yield, low pollution and suitability for industrial production, and has great practical value.

[0025] Definitions and general terms In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced by a specific substituent. Unless otherwise indicated, a substituent can be substituted at every reasonable position of the group. When more than one position in a given structural formula can be substituted by one or more specific substituents selected, the substituents can be substituted at every reasonable position in the structural formula in the same or different manner. The substituents described in the present invention include, but are not limited to, D, F, Cl, Br, I, N 3 , -CF 3 、-CN、-NO 2 、-NH 2 、-OH、-SH、-COOH、-CONH 2 、-C(=O)NHCH 3 、-C(=O)N(CH 3 ) 2 , alkyl, alkoxy, aryl, heteroaryl and the like.

[0026] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0027] The term "alkyl" as used herein refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ),etc.

[0028] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-propyloxy, n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (isopropyloxy, i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy(s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy(t-BuO, t-butoxy, -OC(CH 3 ) 3 ),etc.

[0029] The term "aryl" refers to a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, and wherein each ring system comprises a ring consisting of 3-7 atoms. The aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. The aryl group is optionally substituted by one or more substituents described in the present invention. Examples of aryl groups can include, but are not limited to, phenyl, indenyl, naphthyl and anthracenyl.

[0030] The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring consisting of 5-7 atoms. The heteroaryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the heteroaryl group. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl consisting of 5-10 atoms contains 1,2,3 or 4 heteroatoms independently selected from O, S and N. Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), and the like.

[0031] The term "jk-membered", where j and k are integers greater than 0, and k is greater than j, typically describes the number of ring atoms in the molecule. For example, 5-10 membered heteroaryl means a heteroaryl consisting of 5, 6, 7, 8, 9 or 10 ring atoms. For another example, pyridyl is a 6-membered heteroaryl.

[0032] "Ph-" means ; "BnO-" means . DETAILED DESCRIPTION

[0033] The above technical scheme of the present invention is specifically described below by way of examples. It is necessary to point out that the present examples are only used to further illustrate the present invention, but do not constitute any limitation to the present invention. Those skilled in the art may make some non-essential improvements and adjustments based on the content of the present invention.

[0034] Further, specifically, the synthesis method of the novel α,α-dichlorophenylacetophenone compounds involved in the present invention is specifically described as follows: Example 1 Synthesis of 2,2-dichloro-1-(3-(trifluoromethyl)phenyl)propyl-1-one (Compound II-c):

[0035] 1-(3-(trifluoromethyl)phenyl)propyl-1-one Ic (0.5 mmol, 94 mg), p-toluenesulfonic acid (0.05 mmol, 9 mg), acetonitrile (5 mL) and N-chlorosuccinimide (1.25 mmol, 167 mg) were added to the reaction flask, heated to reflux for 16 h, cooled to room temperature, the solvent was dried, water was added to dissolve the residue, extracted with ethyl acetate (20 mL×3), and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was subsequently separated and purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 10 / 1) to obtain the title compound II-c (white solid 128 mg, yield 95%).

[0036] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.55-8.53 (m, 2H), 7.85 (d, J = 7.8Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 2.37 (s, 3H). Example 2 Synthesis of 2,2-dichloro-1-(3-chlorophenyl)propyl-1-one (Compound II-f):

[0037] 1-(3-chlorophenyl)propyl-1-one If (0.5 mmol, 77 mg), p-toluenesulfonic acid (0.05 mmol, 9 mg), acetonitrile (5 mL) and N-chlorosuccinimide (1.25 mmol, 167 mg) were added to the reaction flask, heated to reflux for 16 h, cooled to room temperature, the solvent was dried, water was added to dissolve the residue, extracted with ethyl acetate (20 mL×3), and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was subsequently separated and purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 10 / 1) to obtain the title compound II-f (white solid 108 mg, yield 93%).

[0038] 1 H NMR (400 MHz, CDCl 3): δ (ppm) 8.26 (t, J = 1.8 Hz, 1H), 8.23-8.21(m, 1H), 7.58-7.55 (m, 1H), 7.42 (t, J = 7.9 Hz, 1H), 2.34 (s, 3H). Example 3 Synthesis of 2,2-dichloro-1-(4-fluorophenyl)propyl-1-one (Compound II-g):

[0039] 1-(4-fluorophenyl)propyl-1-one Ig (0.5 mmol, 77 mg), p-toluenesulfonic acid (0.05 mmol, 9 mg), acetonitrile (5 mL) and N-chlorosuccinimide (1.25 mmol, 167 mg) were added to the reaction flask, heated to reflux for 16 h, cooled to room temperature, the solvent was dried, water was added to dissolve the residue, extracted with ethyl acetate (20 mL×3), and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was subsequently separated and purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 10 / 1) to obtain the title compound II-g (white solid 107 mg, yield 97%).

[0040] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.39-8.35 (m, 2H), 7.17-7.12 (m, 2H), 2.34 (s, 3H). Example 4 Synthesis of 2,2-dichloro-1-(4-methylphenyl)propyl-1-one (Compound II-i):

[0041] 1-(4-methylphenyl)propyl-1-one Ii (0.5 mmol, 67 mg), p-toluenesulfonic acid (0.05 mmol, 9 mg), acetonitrile (5 mL) and N-chlorosuccinimide (1.25 mmol, 167 mg) were added to the reaction flask and heated to reflux for 16 h, cooled to room temperature, the solvent was dried, water was added to dissolve the residue, and the organic phase was collected by extraction with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was subsequently separated and purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 10 / 1) to obtain the title compound II-i (white solid 106 mg, yield 98%).

[0042] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.24 (d, J = 8.4 Hz, 2H), 7.28 (d, J =8.4 Hz, 2H), 2.43 (s, 3H), 2.35 (s, 3H). Example 5 Synthesis of 2,2-dichloro-1-(4-ethylphenyl)propyl-1-one (Compound II-k):

[0043] Add p-1-(4-ethylphenyl)propyl-1-one Ik (0.5 mmol, 74 mg), p-toluenesulfonic acid (0.05 mmol, 9 mg), acetonitrile (5 mL) and N-chlorosuccinimide (1.25 mmol, 167 mg) to the reaction flask and heat to reflux for 16 h, cool to room temperature, spin dry the solvent, add water to dissolve the residue, extract with ethyl acetate (20 mL×3), and collect the organic phase. The organic phase is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, which is subsequently separated and purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 10 / 1) to obtain the title compound II-k (white solid 111 mg, yield 97%).

[0044] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.27-8.26 (m, 2H), 7.31-7.29 (m, 2H), 2.73 (q, J = 7.6 Hz, 2H), 2.35 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H). Example 6 Synthesis of 2,2-dichloro-1-(4-chlorophenyl)pentyl-1-one (Compound II-r):

[0045] 1-(4-chlorophenyl)pentyl-1-one Ir (0.5 mmol, 98 mg), p-toluenesulfonic acid (0.05 mmol, 9 mg), acetonitrile (5 mL) and N-chlorosuccinimide (1.25 mmol, 167 mg) were added to the reaction flask and heated to reflux for 16 h, cooled to room temperature, the solvent was dried, water was added to dissolve the residue, and the organic phase was collected by extraction with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was subsequently separated and purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 10 / 1) to obtain the title compound II-r (white solid 129 mg, yield 98%).

[0046] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.24-8.22 (m, 2H), 7.45-7.43 (m, 2H), 2.47-2.44 (m, 2H), 1.77-1.69 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H). The above description is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept, which all belong to the protection scope of the present invention.

Claims

1. A method for synthesizing a novel α,α-dichloropropiophenone compound, characterized in that: The following steps are involved: The compound represented by formula I, NCS and a catalyst are added to a solvent and reacted at a reaction temperature of 50-100° C. to obtain an α,α-dichlorophenylacetophenone compound represented by formula II: in, R 1 are independently aryl, substituted aryl, heteroaryl or substituted heteroaryl; R 2 are independently H or alkyl; The catalyst is ferric chloride, cupric chloride, zinc chloride, hydrochloric acid, sulfuric acid, formic acid or p-toluenesulfonic acid; The solvent is methanol, ethanol, ethylene glycol, chloroform, N,N-dimethylformamide or acetonitrile.

2. The method for synthesizing the novel α,α-dichloropropiophenone compound according to claim 1, characterized in that: R 1 Independently C6-C 10 Aryl, substituted C6-C 10 Aryl, 5-10 membered heteroaryl or substituted 5-10 membered heteroaryl; R 2 are independently H or C1-C6 alkyl.

3. The method for synthesizing the novel α,α-dichloropropiophenone compound according to claim 2, characterized in that: R 1 Independently C6-C 10 Aryl, substituted C6-C 10 Aryl, 5-10 membered heteroaryl or substituted 5-10 membered heteroaryl; R 2 are independently H or C1-C4 alkyl.

4. The method for synthesizing the novel α,α-dichlorophenylpropiophenone compound according to claim 3, characterized in that: R 1 Independently , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R 2 is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

5. The method for synthesizing the novel α,α-dichloropropiophenone compound according to claim 1, characterized in that: The molar ratio of the compound represented by formula I to NCS is 1:2.0-4.0; The molar ratio of the compound represented by formula I to the catalyst is 1:0.05-0.

5.

6. The method for synthesizing the novel α,α-dichloropropiophenone compound according to claim 5, characterized in that: The molar ratio of the compound represented by formula I to NCS is 1:2.0-3.0; The molar ratio of the compound represented by formula I to the catalyst is 1:0.05-0.

2.

7. The method for synthesizing the novel α,α-dichloropropiophenone compound according to claim 6, characterized in that: The molar ratio of the compound represented by formula I to NCS is 1:2.5; The molar ratio of the compound represented by formula I to the catalyst is 1:0.

1.

8. The method for synthesizing the novel α,α-dichloropropiophenone compound according to claim 1, characterized in that: The reaction temperature is 60-80°C.

9. The method for synthesizing the novel α,α-dichloropropiophenone compound according to claim 8, characterized in that: The reaction temperature is 80°C.

10. The method for synthesizing the novel α,α-dichloropropiophenone compound according to claim 1, characterized in that: The reaction is carried out in the air; the reaction is tracked by thin layer chromatography until it is completely completed; after the reaction is completed, the product is extracted, washed, dried, and concentrated to obtain a crude product, and then separated and purified by column chromatography.

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