One step process for the preparation of phenylethylamine derivatives

Abstract

To provide a new method for preparing a phenylethylamine derivative.SOLUTION: A process for the preparation of a compound of formula (I) comprises reacting a compound of formula (II) with (a) hydrogen cyanide under acidic conditions, followed by (b) addition of water to the reaction mixture.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel method for the preparation of phenylethylamine derivatives by reacting phenylethylhydroxy compounds with hydrogen cyanide, followed by in situ hydrolysis. [Background technology]

[0002] The preparation of phenylethylamine derivatives from phenylethylhydroxy compounds has been previously described. For example, it is known that compounds of formula (I) (see Scheme 1) can be prepared by reacting compounds of formula (II) with acetonitrile or chloroacetonitrile and then isolating the corresponding acetamide. These acetamide intermediates are then further hydrolyzed to amines of formula (I). Such hydrolysis reactions can be difficult and result in low yields due to the relative stability of the acetamide intermediates. Isolation of formyl derivatives of formula (III) has also been reported. For example, F. Rachinskii (Zhurnal Obshchei Khimii, 1954, 24, 272) reported that phenylethylamines can be prepared by reacting phenylethylhydroxy compounds of formula (II) with hydrogen cyanide under acidic conditions and then isolating the formyl derivative of formula (III), as shown in Scheme 1. This formyl derivative of formula (III) is then further reacted with a strong acid to give phenylethylamines of formula (I). A similar reaction was also reported by J. Ritter (Organic Syntheses, 1964, 44, 44), in which the isolated formyl derivative of formula (III) was then hydrolyzed with a strong base to give the phenylethylamine of formula (I).

[0003] Scheme 1: [ka] wherein R1 is independently selected from halogen, nitro, cyano, formyl, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, C3-C5 alkenyloxy, C3-C5 alkynyloxy and C1-C5 alkylthio, wherein alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and alkylthio are unsubstituted or selected from halogen, C1-C3 alkyl, C1-C 3 substituted with 1 to 5 substituents independently selected from alkoxy, cyano, and C1-C3 alkylthio; n is 0, 1, 2, 3, 4, or 5; R2 is selected from C1-C5 alkyl, C3-C5 cycloalkyl, and C2-C5 alkenyl, wherein the C1-C5 alkyl, C3-C5 cycloalkyl, and C2-C5 alkenyl are unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, cyano, C1-C3 alkyl, and C1-C3 alkoxy.

[0004] Step (a) in Scheme 1 is also known as the Ritter reaction. Step (b) in Scheme 1 is a hydrolysis reaction that converts the compound of formula (III) to the compound of formula (I). As mentioned above, the prior art teaches that to obtain the compound of formula (I), the compound of formula (III) or similar acetamides must first be isolated and then reacted under strong acidic or basic conditions in step (b). The acid and base in step (b) serve as catalysts for the hydrolysis of the amide group of the compound of formula (III). This reaction generally results in a low overall yield of the compound of formula (I) due to this two-step reaction, which includes the isolation of the compound of formula (III). For example, F. Rachinskii (Zhurnal Obshchei Khimii, 1954, 24, 272) reported an overall yield of only about 40% for the compound of formula (I), and J. Ritter (Organic Syntheses, 1964, 44, 44) reported an overall yield of only about 55% for the compound of formula (I). Furthermore, in addition to the problems of low yield for the compound of formula (I) and the amount of work involved in having two separate reaction steps, another problem is the need to use harsh reaction conditions for step (b), particularly for the acetamide intermediate. For example, F. Rachinskii (Zhurnal Obshchei Khimii, 1954, 24, 272) reported that the compound of formula (III) was vigorously boiled in concentrated hydrochloric acid for 16 hours, and J. Ritter (Organic Syntheses, 1964, 44, 44) reported that the compound of formula (III) was heated under reflux in 20% sodium hydroxide solution for at least 2.5 hours. Such conditions pose safety risks when carrying out the reaction, especially on a large scale, and make waste disposal more difficult. Therefore, there is a need for a new and improved method for providing the compound of formula (I) from the compound of formula (II). It is the subject of the present invention to provide such a new and improved method for obtaining the compound of formula (I). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2007-537188 [Patent Document 2] Japanese Patent Application Publication No. 03-204855 [Non-patent literature]

[0006] [Non-Patent Document 1] Adams. M. H, et al., "THE SYNTHESIS OF NEW BRONCHODILATOR PRODRUGS", SYNTHETIC COMMUNICATIONS, 1999, Vol. 29(14), pp. 2419-2430 Summary of the Invention [Means for solving the problem]

[0007] Therefore, formula (I) [ka] wherein R1 is independently selected from halogen, nitro, cyano, formyl, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, C3-C5 alkenyloxy, C3-C5 alkynyloxy, and C1-C5 alkylthio, wherein alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, and alkylthio are unsubstituted or selected from halogen, C1-C3 alkyl, C1-C6 alkynyl, C1-C6 cycloalkyl ...oxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, and C1-C6 alkylthio; substituted with 1 to 5 substituents independently selected from C3 alkoxy, cyano, and C1-C3 alkylthio; n is 0, 1, 2, 3, 4, or 5; R2 is selected from C1-C5 alkyl, C3-C5 cycloalkyl, and C2-C5 alkenyl, wherein the C1-C5 alkyl, C3-C5 cycloalkyl, and C2-C5 alkenyl are unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, cyano, C1-C3 alkyl, and C1-C3 alkoxy. A method for preparing a compound of the formula: The method comprises reacting a compound of formula (II) [ka] wherein R1, n, and R2 are as defined for compounds of formula (I). (a) reacting a compound of formula (I) with hydrogen cyanide under acidic conditions, followed by (b) the subsequent addition of water to the reaction mixture to obtain a compound of formula (I).

[0008] It has been unexpectedly found that after reacting a compound of formula (II) with hydrogen cyanide under acidic conditions, the addition of water to the reaction mixture results in the formation of a compound of formula (I) in high yield. This means that instead of using two reaction steps, only one reaction step is used, and the reaction is carried out under much milder conditions than those reported in the prior art. Therefore, the so-called "one-pot" reaction for obtaining a compound of formula (I) has been unexpectedly found to have numerous advantages over prior art teachings. For example, the processing conditions are less severe, which leads to improvements in terms of safety. Furthermore, fewer operations need to be performed to obtain a compound of formula (I), which results in a commercially more attractive process with less waste. DETAILED DESCRIPTION OF THE INVENTION

[0009] Those skilled in the art will understand how the reaction conditions for a Ritter-type reaction, i.e., the reaction of a compound of formula (II) to a compound of formula (III), can be adjusted to obtain the conversion of a compound of formula (II) to a compound of formula (III). However, this conversion is typically carried out by adding a cyanide salt, such as potassium or sodium cyanide, to a suitable solvent, such as acetic acid, and then mixing it with a strong acid, such as sulfuric acid. The compound of formula (II) is then added to this reaction mixture, and the temperature is raised to a suitable temperature. The reaction temperature of the hydrogen cyanide reaction mixture before the addition of the compound of formula (II) is typically 20°C to 80°C, preferably 50°C to 70°C.

[0010] A compound of formula (II) is then added to the reaction mixture. A strong acid, such as sulfuric acid, can be added to the reaction mixture either simultaneously with the compound of formula (II), or before or after the addition of the compound of formula (II). After the addition of the compound of formula (II), the temperature of the acidic reaction mixture is adjusted to 50°C to 100°C, preferably 60°C to 90°C, and even more preferably 70°C to 90°C. This temperature range is preferably maintained for a time suitable for the Ritter-type transformation.

[0011] After conversion to the compound of formula (III) in the reaction mixture, a suitable amount of water is added to the reaction mixture. This results in the conversion of the compound of formula (III) to the compound of formula (I). Preferably, the reaction mixture is charged with 1 to 50 molar equivalents of water relative to the compound of formula (II), more preferably 5 to 20 molar equivalents of water. The reaction is preferably carried out at an elevated temperature, for example, 75°C to 100°C, more preferably 90°C to 100°C.

[0012] Those skilled in the art will know how to monitor the progress of the reaction and adjust the duration of the reaction accordingly. The obtained compound of formula (I) is worked up by a typical method well known to those skilled in the art. For example, the compound of formula (I) can be extracted with a suitable organic solvent such as methyl tert-butyl ether (MTBE).

[0013] Those skilled in the art will understand that various phenylethylamine derivatives can be prepared according to the method of the present invention.The compound of formula (II) is either commercially available or can be prepared according to the method in the literature.For example, the compound of formula (II) can be prepared as shown in Scheme 2.

[0014] Scheme 2 [ka] wherein R1, R2 and n are as defined in Scheme 1. Compounds of formula (II) can be prepared from carbonyl compounds of formula (IV) or (VII) by treatment with organometallic species of formula (V) or (VI), respectively, where X is a lithium, aluminum or magnesium salt, in an inert solvent such as diethyl ether at temperatures between -90°C and 60°C.

[0015] In a preferred embodiment of the present invention, there is provided a method for preparing a compound of formula (I), wherein R1 is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, methoxy, allyloxy, propargyloxy, and C1-C2 alkylthio, where alkyl, cyclopropyl, alkenyl, alkynyl, methoxy, allyloxy, propargyloxy, and alkylthio are unsubstituted or substituted with 1 to 3 substituents independently selected from fluoro, chloro, methyl, and cyano; and n is 0, 1, 2, or 3. More preferably, R1 is independently selected from fluoro, bromo, chloro, cyano, methyl, and methoxy, where methyl and methoxy are unsubstituted or substituted with 1 to 3 substituents independently selected from fluoro, bromo, and chloro; and n is 0, 1, or 2. Even more preferably, R1 is independently selected from fluoro, bromo, and chloro; and n is 0 or 1. Most preferably, n is 0 or 1, and when n is 1, R1 is fluoro, bromo, or chloro and is attached to the ortho (1st) or meta (2nd) position of the phenyl ring, preferably the ortho position.

[0016] In a further preferred embodiment of the present invention, there is provided a method for preparing a compound of formula (I), wherein R2 is selected from C1-C5 alkyl and C3-C5 cycloalkyl, where C1-C5 alkyl and C3-C5 cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from halogen. More preferably, R2 is C1-C5 alkyl, where C1-C5 alkyl is unsubstituted or substituted with 1 or 3 fluoro substituents. Even more preferably, R2 is selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, -CH2CF3, -CH2-C(CH3)3, -CH2-C(CH3)2F, and -CH2-C(CH3)F2. Most preferably, R2 is selected from methyl, ethyl, n-propyl, isopropyl, and isobutyl.

[0017] The present invention includes any combination of preferred R1, n, and R2.

[0018] Definition: The term "alkyl" as used herein - either separately or as part of a chemical group - refers to a straight or branched chain hydrocarbon, preferably of 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylpropyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, and 2-ethylbutyl. Alkyl groups of 1 to 4 carbon atoms are preferred, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl.

[0019] The term "alkenyl" - either separately or as part of a chemical group - refers to a straight or branched chain hydrocarbon, preferably having 2 to 6 carbon atoms and at least one double bond, such as vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl- 2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2 -pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl It represents methyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, and 1-ethyl-2-methyl-2-propenyl. Alkenyl groups having 2 to 4 carbon atoms, such as 2-propenyl, 2-butenyl, or 1-methyl-2-propenyl, are preferred.

[0020] The term "alkynyl" - either separately or as part of a chemical group - preferably refers to a straight or branched chain hydrocarbon having 2 to 6 carbon atoms and at least one triple bond, such as 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hex ... -hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl, and 2,5-hexadiynyl. Alkynyl groups of 2 to 4 carbon atoms, such as ethynyl, 2-propynyl, or 2-butynyl-2-propenyl, are preferred.

[0021] The term "cycloalkyl" - either separately or as part of a chemical group - denotes a saturated or partially unsaturated monocyclic, bicyclic or tricyclic hydrocarbon, preferably of 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl or adamantyl.

[0022] The term "halogen" or "halo" refers to fluoro, chloro, bromo, or iodo, especially fluoro, chloro, or bromo. A chemical group substituted with a halogen, such as haloalkyl, halocycloalkyl, haloalkyloxy, haloalkylsulfanyl, haloalkylsulfinyl, or haloalkylsulfonyl, is substituted with one or up to the maximum number of halogen substituents. When an "alkyl," "alkenyl," or "alkynyl" is substituted with a halogen, the halogen atoms can be the same or different and can be bonded to the same or different carbon atoms.

[0023] As used herein, the term "in situ" refers to carrying out a reaction directly in the reaction mixture without isolating intermediate compounds, meaning that "in situ" refers to a so-called "one-pot reaction" as opposed to a two-step reaction. [Example]

[0024] Example The following examples are intended to illustrate the invention but should not be construed as limitations thereon.

[0025] Compound synthesis and characterization The following abbreviations are used throughout this section: s = singlet; bs = broad singlet; d = doublet; dd = double doublet; dt = double triplet; bd = broad doublet; t = triplet; td = triplet doublet; bt = broad triplet; tt = triplet triplet; q = quartet; m = multiplet; Me = methyl; Et = ethyl; Pr = propyl; Bu = butyl; DME = 1,2-dimethoxyethane; THF = tetrahydrofuran.

[0026] Example 1: 2-methyl-1-phenyl-propan-2-amine: [ka] A suspension of potassium cyanide (0.135 g, 1.997 mmol) in acetic acid (0.22 mL, 3.861 mmol) was prepared and cooled to 0-10 °C in an ice / water bath. Meanwhile, a mixture of sulfuric acid (0.255 mL, 4.527 mmol) and acetic acid (0.22 mL, 3.861 mmol) was prepared. A strong exothermic effect was observed. The acidic solution was then added dropwise to the suspension over 5 min. The reaction mixture turned into a milky suspension. 2-Methyl-1-phenyl-propan-2-ol (0.2 g, 1.331 mmol) was added dropwise to the suspension over 5 min, and the reaction mixture was heated to 80 °C. After stirring at this temperature for 3 h, water (0.240 mL, 13.314 mmol) was added in one portion, and it was stirred at 80 °C overnight.

[0027] The cooled reaction mixture was slowly poured into cold saturated Na2CO3 solution. As expected, gas formation could be observed during the addition. It was extracted three times with tert-butyl methyl ether. The organic layers were combined, washed once with brine, and dried over Na2SO4. It was filtered and evaporated to give 2-methyl-1-phenyl-propan-2-amine in 93.0% purity and 89.2% chemical yield. 1 H NMR(400MHz,CDCl3)δ ppm 1.15(s,6H)1.49(br s,2H)2.69(s,2H)7.19-7.36(m,5H)

[0028] Example 2: 1-(2-fluorophenyl)-2-methyl-propan-2-amine: [ka] Procedure as above for Example 1. 1-(2-fluorophenyl)-2-methyl-propan-2-amine was obtained in 72% purity and 61.6% chemical yield. 1 H NMR(400MHz,CDCl3)δ ppm 1.17(d,6H)1.64(br s,2H)2.75(d,2H)7.00-7.18(m,2H)7.19-7.26(m,2H)

[0029] Example 3: 1-(2-chlorophenyl)-2-methyl-propan-2-amine: [ka] Procedure as above for Example 1. 1-(2-chlorophenyl)-2-methyl-propan-2-amine was obtained in 86% purity and 87.6% chemical yield. 1 H NMR(400MHz,CDCl3)δ ppm 1.20(s,6H)1.61(br s,2H)2.91(s,2H)7.16-7.33(m,3H)7.35-7.45(m,1H)

[0030] Example 4: 1-(3-fluorophenyl)-2-methyl-propan-2-amine: [ka] Procedure as above for Example 1. 1-(3-fluorophenyl)-2-methyl-propan-2-amine was obtained in 39% purity and 24.3% chemical yield. 1 H NMR(400MHz,CDCl3)δ ppm 1.26(s,6H)2.78-2.87(m,2H)3.71-3.99(br s,2H)6.90-7.05(m,3H)7.23-7.33(m,1H)

[0031] Example 5: 2-methyl-1-(o-tolyl)propan-2-amine: [ka] Procedure as above for Example 1. 2-Methyl-1-(o-tolyl)propan-2-amine was obtained in 64.4% purity and 58.9% chemical yield. 1 H NMR(400MHz,CDCl3)δ ppm 1.18(s,6H)1.66(br s,2H)2.39(s,3H)2.77(s,2H)7.13-7.22(m,4H)

[0032] Example 6: 1-(2-bromophenyl)-2-methyl-propan-2-amine: [ka] Procedure as above for Example 1. 1-(2-Bromophenyl)-2-methyl-propan-2-amine was obtained in 72.9% purity and 73.2% chemical yield. 1 H NMR(400MHz,CDCl3)δ ppm 1.22(s,6H)1.73(br s,2H)2.95(s,2H)7.08-7.15(m,1H)7.23-7.35(m,2H)7.59(d,1H)

[0033] Example 7: 2-methyl-1-phenyl-butan-2-amine: [ka] Procedure as above for Example 1. 2-Methyl-1-phenyl-butan-2-amine was obtained in 83% purity and 78.1% chemical yield. 1 H NMR(400MHz,CDCl3)δ ppm 0.96-1.02(m,3H)1.05(s,3H)1.34-1.51(m,4H)2.68(s,2H)7.17-7.36(m,5H)

[0034] Example 8: 2-Methyl-1-phenyl-pentan-2-amine: [ka] Procedure as above for Example 1. 2-Methyl-1-phenyl-pentan-2-amine was obtained in 86% purity and 31.7% chemical yield. 1 H NMR(400MHz,CDCl3)δ ppm 0.96(t,3H)1.12(s,3H)1.36-1.53(m,4H)2.71(br s,2H)2.74(s,2H)7.19-7.35(m,5H)

[0035] Example 9: 2,4-dimethyl-1-phenyl-pentan-2-amine: [ka] Procedure as above for Example 1. 2,4-Dimethyl-1-phenyl-pentan-2-amine was obtained in 93% purity and 85.0% chemical yield. 1 H NMR(400MHz,CDCl3)δ ppm 1.01(dd,6H)1.08(s,3H)1.2(brs,2H)1.37((qd)m,2H)1.83-1.93(m,1H)2.65-2.72(m,2H)7.19-7.35(m,5H)

[0036] Example 10: 1-(3-fluorophenyl)-2,4-dimethyl-pentan-2-amine: [ka] Procedure as above for Example 1. 1-(3-fluorophenyl)-2,4-dimethyl-pentan-2-amine was obtained in 57% purity and 43.9% chemical yield. 1 H NMR(400MHz,CDCl3)δ ppm 1.01(dd,6H)1.09(s,3H)1.28 1.44(m,4H)1.84-1.90(m,1H)2.68(s,2H)6.92-7.00(m,3H)7.27(m,1H)

Claims

1. Formula (I) 【Chemistry 1】 wherein R1 is independently selected from halogen, nitro, cyano, formyl, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, C3-C5 alkenyloxy, C3-C5 alkynyloxy, and C1-C5 alkylthio, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, and alkylthio are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, cyano, and C1-C3 alkylthio; n is 0, 1, 2, 3, 4, or 5; and R2 is C 1 ~C 5 Alkyl, C 3 ~C 5 Cycloalkyl and C 2 ~C 5 alkenyl, wherein C 1 ~C 5 Alkyl, C 3 ~C 5 Cycloalkyl and C 2 ~C 5 Alkenyl is unsubstituted or substituted with halogen, cyano, C 1 ~C 3 Alkyl and C 1 ~C 3 substituted with 1 to 4 substituents independently selected from alkoxy; A method for preparing a compound of the formula The method comprises reacting a compound of formula (II) 【Chemistry 2】 wherein R1, n, and R2 are as defined for compounds of formula (I). (a) reacting a compound of formula (I) with hydrogen cyanide under acidic conditions, followed by (b) the subsequent addition of water to the reaction mixture to obtain a compound of formula (I).

2. R1 is independently selected from fluoro, bromo, chloro, cyano, methyl, and methoxy, wherein said methyl and methoxy are unsubstituted or substituted with 1 to 3 substituents independently selected from fluoro and chloro; n is 0, 1, or 2; R2 is C 1 ~C 5 Alkyl and C 3 ~C 5 cycloalkyl, wherein said C 1 ~C 5 Alkyl and C 3 ~C 5 The method of claim 1, wherein the cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen.

3. R1 is independently selected from fluoro, bromo, and chloro; n is 0 or 1; R2 is methyl, ethyl, n-propyl, isopropyl, isobutyl, —CH 2 CF 3 , -CH 2 -C(CH 3 ) 3 , -CH 2 -C(CH 3 ) 2 F and -CH 2 -C(CH 3 ) F 2 The method according to claim 1 or 2, wherein the compound is selected from the group consisting of:

4. 4. The method of any one of claims 1 to 3, wherein n is 0 or 1, and when n is 1, R1 is fluoro, bromo, or chloro and is attached at the ortho (1st position) or meta (2nd position) position of the phenyl ring; and R2 is selected from methyl, ethyl, n-propyl, isopropyl, and isobutyl.

5. 5. The process of any one of claims 1 to 4, wherein the reaction mixture is charged with 1 to 50 molar equivalents of water relative to the compound of formula (II).

6. 6. The process according to any one of claims 1 to 5, wherein the reaction (a) of the compound of formula (II) with hydrogen cyanide under acidic conditions is carried out at a temperature of from 50°C to 100°C.

7. 7. The method of any one of claims 1 to 6, wherein the reaction (a) is carried out by adding a cyanide salt to a suitable solvent, followed by adding a strong acid and a compound of formula (II).

8. 8. The method of claim 7, wherein the cyanide salt is potassium cyanide and the strong acid is sulfuric acid.

9. 9. The method of claim 8, wherein the reaction (b) is carried out at a temperature of from 75°C to 100°C.

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