阅读说明：本技术 一种芳基环丁烷化合物的合成方法 (Synthetic method of aryl cyclobutane compound ) 是由 马力 郭记松 周勇 于 2021-09-30 设计创作，主要内容包括：本发明公开了一种芳基环丁烷化合物的合成方法以1eq苯乙腈类和1.1eq的1-溴-3-氯丙烷为原料,以N,N-二甲基乙酰胺为溶剂,加2.5eq氢化钠,在惰性气体保护下,加料时温度在-15±5℃,室温下反应5到16小时,即可。本发明可以方便地得到目标化合物,且该反应的投料操作简便,适用范围较传统的合成方法更广,反应条件温和,为后续衍生物的合成也提供了比较方便的路线。(The invention discloses a synthesis method of an aryl cyclobutane compound, which comprises the steps of taking 1eq of phenylacetonitrile and 1.1eq of 1-bromo-3-chloropropane as raw materials, taking N, N-dimethylacetamide as a solvent, adding 2.5eq of sodium hydride, and reacting at the temperature of minus 15 +/-5 ℃ for 5 to 16 hours at room temperature under the protection of inert gas. The invention can conveniently obtain the target compound, has simple and convenient feeding operation of the reaction, wider application range than the traditional synthetic method and mild reaction conditions, and provides a more convenient route for the synthesis of the subsequent derivatives.)

1. A synthetic method of an aryl cyclobutane compound is characterized in that 1eq of phenylacetonitrile and 1.1eq of 1-bromo-3-chloropropane are used as raw materials, N-dimethylacetamide is used as a solvent, 2.5eq of sodium hydride is added, and the raw materials are reacted at the temperature of minus 15 +/-5 ℃ for 5 to 16 hours at room temperature under the protection of inert gas.

2. The method for synthesizing an arylcyclobutane compound according to claim 1 wherein the obtained product is purified by column separation.

3. The method of synthesizing an arylcyclobutane compound according to claim 1 wherein the amount of said N, N-dimethylacetamide is 15V.

4. The method of synthesizing an arylcyclobutane compound of claim 1 wherein said inert gas is nitrogen.

5. The method of synthesizing an arylcyclobutane compound according to claim 1 wherein the temperature at the time of feeding is-15 ℃.

6. The method of synthesizing arylcyclobutane compounds of claim 1 wherein said sodium hydride concentration is 60%.

7. The method of synthesizing an arylcyclobutane compound of claim 1 wherein said arylcyclobutane compound comprises:

Technical Field

The invention belongs to the field of organic synthesis intermediates, and particularly relates to a synthesis method of an aryl cyclobutane compound.

Background

Aryl cyclobutane and derivatives thereof are not only basic structures of some natural products, but also important organic synthesis intermediates. As an active small molecule compound (building block compound), the compound is widely applied to the fields of medicines, pesticides, materials and the like. The aryl cyclobutane derivatives have very wide application in the fields of bioactive compounds, gas adsorption compounds, electrochemistry and the like. In recent years, the following synthetic methods have been reported in the literature:

in addition, there are many cases concerning the synthesis of arylcyclobutane compounds, such as [2+2] thermal cyclization reaction and [2+2] photocyclization reaction, which have the following characteristics: firstly, a cyclobutane carbon skeleton system can be constructed in one step with high selectivity; second, the reaction conditions are substantially room temperature; third, group protection is not required for organic compounds with more complex structures.

However, olefins with more substituents also slow down the reaction due to greater steric hindrance, and there are also some cases where the substrate reaction is incomplete during synthesis of the molecule. Therefore, it is necessary to develop a synthetic method with simple operation and wider applicability.

Disclosure of Invention

The invention aims to solve the problems, and provides a synthesis method of an aryl cyclobutane compound, which can conveniently obtain a target compound, has simple and convenient feeding operation of the reaction, wider application range than the traditional synthesis method and mild reaction conditions, and provides a more convenient route for the synthesis of subsequent derivatives.

The purpose of the invention is realized as follows:

the synthesis method of the aryl cyclobutane compound comprises the steps of taking 1eq of phenylacetonitrile and 1.1eq of 1-bromo-3-chloropropane as raw materials, taking N, N-dimethylacetamide as a solvent, adding 2.5eq of sodium hydride, and reacting at the temperature of minus 15 +/-5 ℃ for 5 to 16 hours at room temperature under the protection of inert gas.

The product obtained in the synthesis method of the aryl cyclobutane compound is separated and purified by a column.

In the synthesis method of the aryl cyclobutane compound, the dosage of N, N-dimethylacetamide is 15V.

The inert gas in the synthesis method of the aryl cyclobutane compound is nitrogen.

In the synthesis method of the aryl cyclobutane compound, the temperature is-15 ℃ when materials are added.

In the above synthesis method of the arylcyclobutane compound, the concentration of sodium hydride is 60%.

The arylcyclobutane compound in the above synthesis method of arylcyclobutane compound comprises:

the invention can conveniently obtain the target compound, has simple and convenient feeding operation of the reaction, wider application range than the traditional synthetic method and mild reaction conditions, and provides a more convenient route for the synthesis of the subsequent derivatives.

Detailed Description

The present invention will be further described with reference to the following examples.

The invention discloses a synthesis method of an aryl cyclobutane compound, which takes 1eq of phenylacetonitrile and 1.1eq of 1-bromo-3-chloropropane as raw materials, takes 15V of N, N-dimethylacetamide as a solvent, adds 2.5eq of sodium hydride (the concentration is 60 percent), and reacts for 5 to 16 hours at room temperature at the temperature of minus 15 +/-5 ℃ under the protection of inert gas during feeding.

The obtained crude product is separated and purified by a column to obtain a pure product.

Using the process of the present invention, the following arylcyclobutane compounds can be prepared:

examples 1-1 to 1-24

Examples 2-1 to 2-20

Examples 3-1 to 3-16

Examples 4-1 to 4-21

Examples 1 to 1

DMF (135ml) was added to a 250ml three-necked flask, cooled to-10 ℃ to 0 ℃ under nitrogen protection, and 60% NaH (10g, 2.5eq.) was added. After the addition, the temperature is kept and the stirring is carried out for 5 to 10 minutes. Phenylacetonitrile (1.0eq.) was slowly added dropwise. After the addition, the reaction was continued for 1 hour with stirring while maintaining the temperature. Slowly dropwise adding 1-bromo-3-chloropropane (15.7g,1.0eq.) and keeping the temperature at-10-10 ℃ for continuously stirring and reacting for 1-3 hours after the addition. LC-MS monitored the completion of the reaction of the starting materials, quenched by addition of water (675ml), extracted twice with ethyl acetate/petroleum ether (1: 10) (135mlx2), the combined extracts washed 5 times with saturated brine (135mlx 5). Dried over anhydrous sodium sulfate, filtered, and concentrated. And (5) purifying the crude product by a column.

In this example, the phenylacetonitrile was 4-fluorophenylacetonitrile (13.5g,1.0eq.), and the obtained crude product was purified by column chromatography to obtain 1- (4-fluorophenyl) cyclobutane-1-carbonitrile (9.0g) as a colorless liquid, yield: 51.4 percent.

LC-MS(ESI)m/z 149 176.2[M+H]⁺

¹H NMR(400MHz,cdcl₃)δ7.38(dd,J＝7.5,6.0Hz,2H),7.08(t,J＝8.5Hz,2H),2.83(t,J＝8.4Hz,2H),2.59(dd,J＝19.9,9.6Hz,2H),2.43(dq,J＝17.7,8.9Hz,1H),2.20–1.91(m,1H).

Examples 1 to 2

In this example, the phenylacetonitrile was 3-fluorophenylacetonitrile, and the product was 1- (3-fluorophenyl) cyclobutane-1-carbonitrile (11.2g) as a colorless liquid by the method of example 1-1, yield: 64.1 percent.

LC-MS(ESI)m/z 149 176.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.37(dd,J＝14.1,7.9Hz,1H),7.20(d,J＝7.8Hz,1H),7.12(d,J＝9.8Hz,1H),7.02(td,J＝8.3,1.9Hz,1H),2.91–2.74(m,2H),2.69–2.53(m,2H),2.53–2.34(m,1H),2.17–2.00(m,1H).

Examples 1 to 3

In this example, the phenylacetonitrile was 2-fluorophenylacetonitrile, and the product was 1- (2-fluorophenyl) cyclobutane-1-carbonitrile (9.7g) as a colorless liquid by the method of example 1-1, yield: 55.5 percent.

LC-MS(ESI)m/z 176.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.32(dd,J＝13.3,6.6Hz,1H),7.25(dd,J＝8.9,5.5Hz,1H),7.16(t,J＝7.5Hz,1H),7.13–7.04(m,1H),2.85(t,J＝9.3Hz,2H),2.68(dd,J＝20.1,10.5Hz,2H),2.59–2.40(m,1H),2.04(tdd,J＝12.3,8.8,3.3Hz,1H).

Examples 1 to 4

In this example, the phenylacetonitrile was 2, 6-difluorophenylacetonitrile, and the product was 1- (2, 6-difluorophenyl) cyclobutane-1-carbonitrile (10g) as a pale yellow solid by the method of example 1-1, with the yield: 52 percent.

LC-MS(ESI)m/z 194.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.36–7.19(m,1H),6.89(t,J＝8.3Hz,2H),2.90(t,J＝9.2Hz,2H),2.73(dd,J＝20.2,10.4Hz,2H),2.55(dq,J＝11.2,8.4Hz,1H),2.01(dd,J＝19.7,8.9Hz,1H).

Examples 1 to 5

In this example, the phenylacetonitrile was 2, 4-difluorophenylacetonitrile, and the product was 1- (2, 4-difluorophenyl) cyclobutane-1-carbonitrile (19.7g) as a colorless liquid by the method of example 1-1, yield: 50 percent.

LC-MS(ESI)m/z 194.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.21(dd,J＝14.9,8.4Hz,1H),6.87(dd,J＝21.2,8.9Hz,2H),2.83(t,J＝9.3Hz,2H),2.64(dd,J＝20.2,9.7Hz,2H),2.55–2.38(m,1H),2.12–1.91(m,1H).

Examples 1 to 6

In this example, the phenylacetonitrile was 3, 4-difluorophenylacetonitrile, and the product was 1- (3, 4-difluorophenyl) cyclobutane-1-carbonitrile (18.7g) as a colorless liquid by the method of example 1-1, yield: 59.1 percent.

LC-MS(ESI)m/z 194.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.33–7.05(m,3H),2.90–2.75(m,2H),2.56(dd,J＝20.3,9.4Hz,2H),2.43(tt,J＝17.6,8.7Hz,1H),2.15–1.98(m,1H).

Examples 1 to 7

In this example, the phenylacetonitrile compound was 4-bromophenylacetonitrile, and the product was 1- (4-bromophenyl) cyclobutane-1-carbonitrile (17g) as a colorless liquid by the method of example 1-1, yield: 57.8 percent.

LC-MS(ESI)m/z 236.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.52(d,J＝8.3Hz,1H),7.29(d,J＝8.3Hz,1H),2.83(t,J＝8.3Hz,1H),2.58(dd,J＝19.8,9.5Hz,1H),2.43(dq,J＝17.6,9.0Hz,1H),2.15–1.97(m,1H).

Examples 1 to 8

In this example, the phenylacetonitrile compound was 3-bromophenylacetonitrile, and the product was 1- (3-bromophenyl) cyclobutane-1-carbonitrile (11.9g) as a colorless liquid by the method of example 1-1, yield: 50.7 percent.

LC-MS(ESI)m/z 236.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.55(t,J＝1.9Hz,1H),7.49–7.42(m,1H),7.38–7.32(m,1H),7.28–7.24(m,1H),2.91–2.77(m,2H),2.68–2.54(m,2H),2.53–2.36(m,1H),2.09(dtt,J＝11.6,9.1,4.4Hz,1H).

Examples 1 to 9

In this example, the phenylacetonitrile was 3-chlorophenylacetonitrile, and the product was 1- (3-chlorophenyl) cyclobutane-1-carbonitrile (15.7g) as a colorless liquid by the method of example 1-1, yield: 60.5 percent.

LC-MS(ESI)m/z 192.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.40(s,1H),7.33(dd,J＝12.4,7.1Hz,3H),2.82(d,J＝8.3Hz,2H),2.61(dd,J＝19.8,9.5Hz,2H),2.44(dq,J＝17.8,8.9Hz,1H),2.09(dt,J＝17.1,7.1Hz,1H).

Examples 1 to 10

In this example, the phenylacetonitrile compound was 2-chlorophenylacetonitrile, and the product was 1- (2-chlorophenyl) cyclobutane-1-carbonitrile (16g) as a colorless liquid by the method of example 1-1, with the following yields: 53.4 percent.

LC-MS(ESI)m/z 191.9[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.39(d,J＝7.3Hz,1H),7.23(t,J＝16.5Hz,3H),2.92(t,J＝9.1Hz,2H),2.64(dd,J＝20.6,9.7Hz,2H),2.56–2.33(m,1H),2.06–1.85(m,1H).

Examples 1 to 11

In this example, the phenylacetonitrile was 2, 3-dichlorophenylacetonitrile, and the product was 1- (2, 3-dichlorophenyl) cyclobutane-1-carbonitrile (13.7g) as a colorless liquid by the method of example 1-1, with the yield: 58.1 percent.

LC-MS(ESI)m/z 226.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.45(d,J＝7.9Hz,1H),7.24(t,J＝8.0Hz,1H),7.17(d,J＝7.7Hz,1H),2.95(t,J＝9.0Hz,2H),2.64(dd,J＝20.7,9.6Hz,2H),2.57–2.40(m,1H),1.97(dd,J＝19.9,9.0Hz,1H).

Examples 1 to 12

In this example, the phenylacetonitrile was 2, 4-dichlorophenylacetonitrile, and the product was 1- (2, 4-dichlorophenyl) cyclobutane-1-carbonitrile (14.6g) as a colorless liquid by the method of example 1-1, with the yield: 52.5 percent.

LC-MS(ESI)m/z 226.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.42(s,1H),7.28(d,J＝8.8Hz,1H),7.18(d,J＝8.4Hz,1H),2.92(t,J＝8.9Hz,2H),2.74–2.39(m,3H),1.98(dd,J＝19.7,8.9Hz,1H).

Examples 1 to 13

In this example, the phenylacetonitrile was p-tolylacetonitrile, and the product was 1- (p-tolyl) cyclobutane-1-carbonitrile (12.5g) as a colorless liquid by the method of example 1-1, yield: 59.1 percent.

LC-MS(ESI)m/z 172.2[M+Na]⁺

¹H NMR(400MHz,CDCl₃)δ7.33(d,J＝7.5Hz,2H),7.23(d,J＝7.7Hz,2H),2.83(dd,J＝14.1,6.5Hz,2H),2.62(dd,J＝19.5,9.5Hz,2H),2.51–2.33(m,4H),2.15–2.01(m,1H).

Examples 1 to 14

In this example, the phenylacetonitrile compound was 3, 5-dimethylbenzylacetonitrile, and the product was 1- (3, 5-dimethylphenyl) cyclobutane-1-carbonitrile (13.9g) as a colorless liquid by the method of example 1-1, with the yield: 55.1 percent.

LC-MS(ESI)m/z 186.3[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.01(s,2H),6.94(s,1H),2.86–2.72(m,2H),2.67–2.54(m,2H),2.50–2.35(m,1H),2.33(s,3H),2.12–1.98(m,1H).

Examples 1 to 15

In this example, the phenylacetonitrile was 3- (trifluoromethyl) phenylacetonitrile, and the product was 1- (3- (trifluoromethyl) phenyl) cyclobutane-1-carbonitrile (14.7g) as a colorless liquid by the method of example 1-1, with the following yields: 56.3 percent.

LC-MS(ESI)m/z 226.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.75–7.45(m,4H),2.88(t,J＝8.5Hz,2H),2.64(dd,J＝20.0,9.5Hz,2H),2.48(dq,J＝17.7,9.0Hz,1H),2.11(m,J＝16.3,9.1,4.9Hz,1H).

Examples 1 to 16

In this example, the phenylacetonitrile was 2- (trifluoromethyl) phenylacetonitrile, and the product was 1- (2- (trifluoromethyl) phenyl) cyclobutane-1-carbonitrile (17.5g) as a colorless liquid by the method of example 1-1, yield: 75 percent.

LC-MS(ESI)m/z 226.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.70(d,J＝7.8Hz,1H),7.57(t,J＝7.5Hz,1H),7.44(t,J＝7.5Hz,1H),7.33(d,J＝7.7Hz,1H),2.92(t,J＝8.7Hz,2H),2.71(dd,J＝19.8,9.6Hz,2H),2.62–2.43(m,1H),1.95(dd,J＝18.7,9.4Hz,1H).

Examples 1 to 17

In this example, the phenylacetonitrile was 4- (trifluoromethoxy) phenylacetonitrile, and the product was 1- (4- (trifluoromethoxy) phenyl) cyclobutane-1-carbonitrile (16.8g) as a colorless liquid by the method of example 1-1, yield: 61.0 percent.

LC-MS(ESI)m/z 242.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.45(d,J＝8.4Hz,2H),7.25(d,J＝8.7Hz,2H),2.84(dd,J＝14.6,6.4Hz,2H),2.61(dd,J＝20.1,9.5Hz,2H),2.45(dq,J＝17.7,8.9Hz,1H),2.18–2.01(m,1H).

Examples 1 to 18

In this example, the phenylacetonitrile compound was 4-methoxybenzylacetonitrile, and the product was 1- (4-methoxyphenyl) cyclobutane-1-carbonitrile (11.5g) as a colorless liquid by the method of example 1-1, with the yield: 50.5 percent.

LC-MS(ESI)m/z 188.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.32(d,J＝8.4Hz,2H),6.91(d,J＝8.4Hz,2H),3.81(s,3H),2.79(dd,J＝14.4,6.5Hz,2H),2.58(dd,J＝19.8,9.6Hz,2H),2.40(dd,J＝18.8,9.6Hz,1H),2.06(dd,J＝12.2,7.9Hz,1H).

Examples 1 to 19

In this example, the phenylacetonitrile compound was 3-methoxybenzylacetonitrile, and the product was 1- (3-methoxyphenyl) cyclobutane-1-carbonitrile (16.7g) as a colorless liquid by the method of example 1-1, with the yield: 54.8 percent.

LC-MS(ESI)m/z 188.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.30(t,J＝8.0Hz,1H),6.99(d,J＝7.7Hz,1H),6.93(s,1H),6.84(d,J＝8.2Hz,1H),3.82(s,3H),2.87–2.74(m,2H),2.61(dd,J＝20.4,9.4Hz,2H),2.41(dd,J＝20.0,8.8Hz,1H),2.14–1.98(m,1H).

Examples 1 to 20

In this example, the phenylacetonitrile compound was 3, 4-dimethoxyphenylacetonitrile, and the product was 1- (3, 4-dimethoxyphenyl) cyclobutane-1-carbonitrile (17.4g) as a colorless liquid by the method of example 1-1, yield: 58.9 percent.

LC-MS(ESI)m/z 218.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.00–6.81(m,3H),3.89(d,J＝10.4Hz,6H),2.79(dd,J＝14.7,6.3Hz,2H),2.59(dd,J＝20.2,9.4Hz,2H),2.49–2.31(m,1H),2.14–1.94(m,1H).

Examples 1 to 21

In this example, the phenylacetonitrile compound was 3, 5-dimethoxyphenylacetonitrile, and the product was 1- (3, 5-dimethoxyphenyl) cyclobutane-1-carbonitrile (13.9g) as a colorless liquid by the method of example 1-1, yield: 51.5 percent.

LC-MS(ESI)m/z 218.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ6.52(s,2H),6.39(s,1H),3.80(s,6H),2.78(dd,J＝14.5,6.3Hz,2H),2.60(dd,J＝20.3,9.4Hz,2H),2.41(dt,J＝18.2,8.9Hz,1H),2.12–1.97(m,1H).

Examples 1 to 22

In this example, the phenylacetonitrile compound was 3,4, 5-trimethoxyphenylacetonitrile, and the product was 1- (3,4, 5-trimethoxyphenyl) cyclobutane-1-carbonitrile (16.2g) as a colorless liquid by the method of example 1-1, with the following yields: 55.7 percent.

LC-MS(ESI)m/z 248.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ6.56(d,J＝19.0Hz,2H),3.88(s,6H),3.84(s,3H),2.79(dd,J＝14.4,6.2Hz,2H),2.61(dd,J＝20.0,9.6Hz,2H),2.42(dq,J＝17.9,9.0Hz,1H),2.06(m,J＝13.7,9.0,5.2Hz,1H).

Examples 1 to 23

In this example, the phenylacetonitrile compound was 3-fluoro-4-methoxybenzonitrile, and the product was 1- (3-fluoro-4-methoxyphenyl) cyclobutane-1-carbonitrile (16.7g) as a colorless liquid by the method of example 1-1, with the yield: 58.1 percent.

LC-MS(ESI)m/z 228.2[M+Na]⁺

¹H NMR(400MHz,CDCl₃)δ7.19–7.08(m,2H),6.97(t,J＝8.7Hz,1H),3.90(s,3H),2.89–2.67(m,2H),2.56(dd,J＝20.7,9.2Hz,2H),2.41(dd,J＝20.0,8.6Hz,1H),2.06(m,J＝16.3,9.0,4.6Hz,1H).

Examples 1 to 24

In this example, the phenylacetonitrile was phenylacetonitrile, and the product was 1-phenylcyclobutane-1-carbonitrile (15.7g) as a colorless liquid by the method of example 1-1, with the yield: 53.2 percent.

LC-MS(ESI)m/z 158.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.46–7.35(m,3H),7.31(t,J＝6.4Hz,2H),2.91–2.75(m,2H),2.63(dd,J＝20.8,9.3Hz,2H),2.50–2.34(m,1H),2.07(ddq,J＝17.9,9.1,4.4Hz,1H).

Example 2-1

The compound 1- (2-fluorophenyl) cyclobutane-1-carbonitrile (11.5g,40mmol) was dissolved in 58ml ethanol, an aqueous solution (58ml) of potassium hydroxide (11g,197mmol) was added thereto, the reaction was heated to reflux for 12 hours, after completion of the reaction, ethanol was concentrated off, the residue was dissolved in 25ml water, and pH was adjusted to 3-4 with hydrochloric acid solution, a white solid was precipitated, the filtrate was washed with water, and the cake was dried to give the compound 1- (2-fluorophenyl) cyclobutane-1-carboxylic acid (8.6g) in 67.6% yield.

LC-MS(ESI)m/z 195.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ9.75(s,1H),7.27(dd,J＝8.7,5.2Hz,2H),7.11–6.88(m,2H),2.85(m,J＝12.9,6.9,3.6Hz,2H),2.59–2.36(m,2H),2.18–1.98(m,1H),1.95–1.78(m,1H).

Examples 2 to 2

The phenylacetonitrile compound in this example was 1- (4-fluorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 2-1 was adopted to give 1- (4-fluorophenyl) cyclobutane-1-carboxylic acid (7.5g) as a white solid in yield: 96.6 percent.

LC-MS(ESI)m/z 195.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ10.75(s,1H),7.25(q,J＝8.3Hz,2H),7.13(t,J＝7.4Hz,1H),7.01(t,J＝9.3Hz,1H),2.94–2.73(m,2H),2.57(q,J＝9.7Hz,2H),2.38–2.13(m,1H),1.93(dd,J＝11.9,7.2Hz,1H).

Examples 2 to 3

The phenylacetonitrile compound in this example was 1- (3-fluorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 2-1 was adopted to give 1- (3-fluorophenyl) cyclobutane-1-carboxylic acid (12.8g) as a white solid in yield: 85.1 percent.

LC-MS(ESI)m/z 195.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ11.13(s,1H),7.41–7.15(m,1H),7.17–6.81(m,3H),2.86(d,J＝12.5Hz,2H),2.51(dd,J＝19.4,9.4Hz,2H),2.22–1.99(m,1H),1.89(dd,J＝9.1,4.5Hz,1H).

Examples 2 to 4

The procedure of example 2-1 was adopted, using the compound of phenylacetonitrile type in this example which was 1- (3-bromophenyl) cyclobutane-1-carbonitrile, to give 1- (3-bromophenyl) cyclobutane-1-carboxylic acid (7.2g) as a white solid in yield: 87.06 percent.

LC-MS(ESI)m/z 255.00[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ9.98(s,1H),7.50–7.30(m,2H),7.30–7.11(m,2H),2.84(dd,J＝15.5,8.4Hz,2H),2.50(dd,J＝19.5,9.0Hz,2H),2.21–1.97(m,1H),1.88(m,J＝14.1,9.5,4.8Hz,1H).

Examples 2 to 5

The procedure of example 2-1 was adopted, using the compound of phenylacetonitrile type in this example which was 1- (4-bromophenyl) cyclobutane-1-carbonitrile, to give 1- (4-bromophenyl) cyclobutane-1-carboxylic acid (9.08g) as a white solid in yield: 88.75 percent.

LC-MS(ESI)m/z 255.10[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.44(t,J＝12.2Hz,2H),7.17(d,J＝7.4Hz,2H),2.84(t,J＝12.0Hz,2H),2.48(dd,J＝19.3,9.1Hz,2H),2.19–1.98(m,1H),1.88(dt,J＝14.2,4.7Hz,1H).

Examples 2 to 6

The procedure of example 2-1 was used to obtain 1- (4-chloro-2-fluorophenyl) cyclobutane-1-carboxylic acid (13.3g) as a white solid in the present example, in which the phenylacetonitrile was 1- (4-chloro-2-fluorophenyl) cyclobutane-1-carbonitrile (yield: 93.6 percent.

LC-MS(ESI)m/z 229.10[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ11.09(s,1H),7.23–7.09(m,2H),7.05(d,J＝10.3Hz,1H),2.94–2.71(m,2H),2.65–2.40(m,2H),2.39–2.13(m,1H),2.07–1.79(m,1H).

Examples 2 to 7

The phenylacetonitrile compound in this example was 1- (2, 6-difluorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 2-1 was employed to give 1- (2, 6-difluorophenyl) cyclobutane-1-carboxylic acid (7.84g) as a white solid in yield: 77.31 percent.

LC-MS(ESI)m/z 213.10[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ10.46(s,1H),7.23–7.10(m,1H),6.92–6.69(m,2H),2.88(t,J＝9.8Hz,2H),2.81–2.61(m,2H),2.50–2.23(m,1H),2.00–1.81(m,1H).

Examples 2 to 8

The phenylacetonitrile compound in this example was 1- (3-methoxyphenyl) cyclobutane-1-carbonitrile, and the procedure of example 2-1 was used to give 1- (3-methoxyphenyl) cyclobutane-1-carboxylic acid (3.0g) as a white solid in yield: 82.1 percent.

LC-MS(ESI)m/z 207.20[M+H]⁺

¹H NMR(400MHz,DMSO-d6)δ7.30–7.10(m,1H),6.89–6.70(m,3H),3.80–3.67(m,3H),2.66(t,J＝12.2Hz,2H),2.42–2.23(m,2H),1.88(dq,J＝16.8,8.4Hz,1H),1.79–1.65(m,1H).

Examples 2 to 9

The procedure of example 2-1 was followed, using the procedure of example 2-1, to give 1- (3,4, 5-trimethoxyphenyl) cyclobutane-1-carboxylic acid (3.2g) as a white solid in the yield: 82.9 percent.

LC-MS(ESI)m/z 267.30[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ6.49(d,J＝13.7Hz,2H),3.84(d,J＝9.4Hz,9H),2.91–2.74(m,2H),2.53(dd,J＝19.9,9.3Hz,2H),2.07(dq,J＝17.2,8.7Hz,1H),1.88(dq,J＝14.5,4.7Hz,1H).

Examples 2 to 10

The phenylacetonitrile compound in this example was 1- (4- (trifluoromethyl) phenyl) cyclobutane-1-carbonitrile, and the procedure of example 2-1 was used to give 1- (4- (trifluoromethyl) phenyl) cyclobutane-1-carboxylic acid (4.1g) as a white solid in yield: 80.3 percent.

¹H NMR(400MHz,CDCl₃)δ9.38(s,1H),7.59(d,J＝8.0Hz,2H),7.43(t,J＝11.7Hz,2H),3.00–2.80(m,2H),2.53(dd,J＝19.9,9.3Hz,2H),2.13(dq,J＝17.4,8.7Hz,1H),1.89(qt,J＝25.1,12.5Hz,1H).

Examples 2 to 11

The procedure of example 2-1 was followed, using the phenylacetonitrile compound of this example which was 1- (3, 5-bis (trifluoromethyl) phenyl) cyclobutane-1-carbonitrile, to give 1- (3, 5-bis (trifluoromethyl) phenyl) cyclobutane-1-carboxylic acid (4.9g) as a white solid in yield: 90.23 percent.

¹H NMR(400MHz,CDCl₃)δ7.77(s,1H),7.72(s,2H),2.94(t,J＝8.4Hz,2H),2.56(dd,J＝19.9,9.5Hz,2H),2.30–2.12(m,1H),2.02–1.84(m,1H).

Examples 2 to 12

The phenylacetonitrile compound in this example was 1- (3, 5-dimethylphenyl) cyclobutane-1-carbonitrile, and the method of example 2-1 was employed to give 1- (3, 5-dimethylphenyl) cyclobutane-1-carboxylic acid (6.7g) as a white solid in yield: 85.5 percent.

LC-MS(ESI)m/z 205.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ6.89(d,J＝11.5Hz,3H),2.88–2.72(m,2H),2.50(dt,J＝15.7,7.7Hz,2H),2.32(d,J＝20.6Hz,6H),2.11–1.94(m,1H),1.85(qd,J＝9.3,4.6Hz,1H).

Examples 2 to 13

The phenylacetonitrile compound in this example was 1-phenylcyclobutane-1-carbonitrile, and the procedure of example 2-1 was used to give 1-phenylcyclobutane-1-carboxylic acid (7.1g) as a white solid in yield: 90.1 percent.

¹H NMR(400MHz,CDCl₃)δ7.43–7.14(m,5H),2.85(dd,J＝16.0,8.5Hz,2H),2.64–2.43(m,2H),2.18–1.98(m,1H),1.96–1.75(m,1H).

Examples 2 to 14

The phenylacetonitrile compound in this example was 1- (2, 4-difluorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 2-1 was employed to give 1- (2, 4-difluorophenyl) cyclobutane-1-carboxylic acid (9.2g) as a white solid in yield: 89.5 percent.

LC-MS(ESI)m/z 213.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ8.77(s,1H),7.35–7.07(m,1H),6.81(dt,J＝19.4,9.3Hz,2H),2.94–2.65(m,2H),2.52(dd,J＝20.3,9.6Hz,2H),2.39–2.14(m,1H),2.06–1.77(m,1H).

Examples 2 to 15

The phenylacetonitrile compound in this example was 1- (3-chlorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 2-1 was adopted to give 1- (3-chlorophenyl) cyclobutane-1-carboxylic acid (8.1g) as a white solid in yield: 81.9 percent.

LC-MS(ESI)m/z 211.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.62–7.34(m,4H),2.76(dd,J＝16.4,11.2Hz,2H),2.61(dd,J＝17.8,10.8Hz,2H),2.37–2.16(m,1H),2.05–1.81(m,1H).

Examples 2 to 16

The procedure of example 2-1 was followed, using the compound of phenylacetonitrile type in this example which was 1- (3-fluoro-4-methoxyphenyl) cyclobutane-1-carbonitrile, to give 1- (3-fluoro-4-methoxyphenyl) cyclobutane-1-carboxylic acid (8.7g) as a white solid in yield: 75.9 percent.

LC-MS(ESI)m/z 225.2[M+H]⁺

¹H NMR(400MHz,cdcl₃)δ7.01(dd,J＝17.1,10.6Hz,2H),6.89(t,J＝8.4Hz,1H),2.77(s,2H),2.43(dd,J＝18.2,8.9Hz,2H),2.01(dd,J＝17.1,8.6Hz,1H),1.85(d,J＝3.9Hz,1H).

Examples 2 to 17

The phenylacetonitrile compound in this example was 1- (3- (trifluoromethyl) phenyl) cyclobutane-1-carbonitrile, and the procedure of example 2-1 was used to give 1- (3- (trifluoromethyl) phenyl) cyclobutane-1-carboxylic acid (8.3g) as a white solid in yield: 83.9 percent.

¹H NMR(400MHz,cdcl₃)δ7.59–7.36(m,4H),2.97–2.78(m,2H),2.54(dd,J＝20.6,9.2Hz,2H),2.22–2.04(m,1H),1.96–1.80(m,1H).

Examples 2 to 18

The phenylacetonitrile compound in this example was 1- (4- (trifluoromethoxy) phenyl) cyclobutane-1-carbonitrile, and the procedure of example 2-1 was used to give 1- (4- (trifluoromethoxy) phenyl) cyclobutane-1-carboxylic acid (8.5g) as a white solid in yield: 86.5 percent.

LC-MS(ESI)m/z 261.1[M+H]⁺

¹H NMR(400MHz,cdcl₃)δ7.32(d,J＝8.6Hz,2H),7.17(d,J＝8.1Hz,2H),2.95–2.72(m,2H),2.51(dd,J＝20.1,9.2Hz,2H),2.20–2.00(m,1H),1.89(ddt,J＝14.3,9.3,4.7Hz,1H).

Examples 2 to 19

The procedure of example 2-1 was adopted in this example, in which phenylacetonitrile was 1- (3, 4-dimethoxyphenyl) cyclobutane-1-carbonitrile to give 1- (3, 4-dimethoxyphenyl) cyclobutane-1-carboxylic acid (10.7g) as a white solid in yield: 93.4 percent.

LC-MS(ESI)m/z 237.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ6.85(dd,J＝16.7,9.0Hz,3H),2.90–2.73(m,2H),2.59–2.40(m,2H),2.12–1.96(m,1H),1.94–1.77(m,1H).

Examples 2 to 20

The phenylacetonitrile compound in this example was 1- (m-tolyl) cyclobutane-1-carbonitrile, and the procedure of example 2-1 was used to give 1- (m-tolyl) cyclobutane-1-carboxylic acid (7.8g) as a white solid in yield: 86.1 percent.

LC-MS(ESI)m/z 237.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.21(d,J＝7.8Hz,1H),7.16–6.98(m,3H),2.81(d,J＝12.4Hz,2H),2.52(dd,J＝19.7,9.2Hz,2H),2.34(s,3H),2.15–1.96(m,1H),1.86(qd,J＝9.5,4.8Hz,1H).

Example 3-1

The compound 1- (4-fluorophenyl) cyclobutane-1-carboxylic acid (6g,30.89mmol) and triethylamine (15.6g,154.47mmol) were dissolved in t-butanol (60ml), and diphenyl azide phosphate (21.2g,77.23mmol) was added thereto, followed by stirring at room temperature for 1 hour, heating to 80 ℃ and stirring for 12 hours. Cool, quench the reaction with water and extract with a solvent of ethyl acetate to 1:10 petroleum ether, combine the organic phases, concentrate and dissolve the concentrate in 6M hydrochloric acid (30 ml). Heating to 80 ℃ was continued and stirring was continued for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and diluted with water, extracted with a solvent of ethyl acetate-petroleum ether (1: 10), the PH of the aqueous phase was adjusted to 8 to 9, and then extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the resulting crude product was dissolved in ethyl acetate, added with a 4M hydrochloric acid/1, 4-dioxane solution, and filtered to obtain the compound 1- (4-fluorophenyl) cyclobutane-1-amine hydrochloride (1.48g) as a white solid in 23.75% yield. LC-MS (ESI) M/z 149.10 (M-NH)₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.63–7.46(m,2H),7.21(t,J＝8.3Hz,2H),2.76(dd,J＝16.4,10.8Hz,2H),2.62(dd,J＝18.1,10.2Hz,2H),2.25(t,J＝12.9Hz,1H),2.03–1.83(m,1H).

Examples 3 to 2

In this example, phenylacetonitrile was 1- (2-fluorophenyl) cyclobutane-1-carboxylic acid, and the procedure of example 3-1 was used to give 1- (2-fluorophenyl) cyclobutane-1-amine hydrochloride (1.3g) as a white solid in yield: 25.5 percent.

LC-MS(ESI)m/z:149.10(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.49(t,J＝7.4Hz,2H),7.26(dt,J＝19.8,8.5Hz,2H),2.85(dd,J＝20.8,9.1Hz,2H),2.63(dd,J＝15.8,11.1Hz,2H),2.33(dq,J＝17.2,8.5Hz,1H),2.09–1.91(m,1H).

Examples 3 to 3

In this example, phenylacetonitrile was 1- (3-fluorophenyl) cyclobutane-1-carboxylic acid, and the procedure of example 3-1 was used to give 1- (3-fluorophenyl) cyclobutane-1-amine hydrochloride (2.7g) as a white solid in yield: 27.5 percent.

LC-MS(ESI)m/z:149.10(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.52(dd,J＝14.3,7.4Hz,1H),7.32(dd,J＝24.8,8.9Hz,2H),7.17(t,J＝8.2Hz,1H),2.76(dd,J＝16.7,10.9Hz,2H),2.63(dd,J＝18.1,10.5Hz,2H),2.35–2.13(m,1H),2.05–1.85(m,1H).

Examples 3 to 4

In this example, when phenylacetonitrile was 1- (3-bromophenyl) cyclobutane-1-carboxylic acid, the procedure of example 3-1 was employed to give 1- (3-bromophenyl) cyclobutane-1-amine hydrochloride (1.4g) as a white solid in yield: 22.5 percent.

LC-MS(ESI)m/z:209.10(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.69(s,1H),7.60(d,J＝7.9Hz,1H),7.50(d,J＝7.8Hz,1H),7.42(t,J＝7.9Hz,1H),2.87–2.69(m,2H),2.61(dt,J＝12.9,9.4Hz,2H),2.34–2.16(m,1H),2.04–1.87(m,1H).

Examples 3 to 5

In this example, when phenylacetonitrile was 1- (4-bromophenyl) cyclobutane-1-carboxylic acid, the procedure of example 3-1 was employed to give 1- (4-bromophenyl) cyclobutane-1-amine hydrochloride (1.1g) as a white solid in yield: 21.9 percent.

LC-MS(ESI)m/z:209.10(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.65(d,J＝8.3Hz,2H),7.44(d,J＝8.3Hz,2H),2.85–2.68(m,2H),2.68–2.53(m,2H),2.35–2.15(m,1H),2.05–1.85(m,1H).

Examples 3 to 6

In this example, when phenylacetonitrile was 1- (4-chloro-2-fluorophenyl) cyclobutane-1-carboxylic acid, 1- (4-chloro-2-fluorophenyl) cyclobutane-1-amine hydrochloride (1.5g) was obtained as a white solid in the same yield as in example 3-1: 25.6 percent.

LC-MS(ESI)m/z:183.10(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.48(t,J＝8.5Hz,1H),7.34(d,J＝7.9Hz,2H),2.84(dt,J＝18.0,9.1Hz,2H),2.62(dt,J＝18.6,9.5Hz,2H),2.42–2.22(m,1H),2.09–1.90(m,1H).

Examples 3 to 7

The procedure of example 3-1 was adopted, using the compound of phenylacetonitrile type in this example which was 1- (2, 6-difluorophenyl) cyclobutane-1-carboxylic acid, to give 1- (2, 6-difluorophenyl) cyclobutane-1-amine hydrochloride (1.9g) as a white solid in yield: 29.1 percent.

LC-MS(ESI)m/z:167.20(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.62–7.42(m,1H),7.16–6.99(m,2H),2.98(dd,J＝22.0,10.5Hz,2H),2.63(t,J＝10.4Hz,2H),2.56–2.38(m,1H),2.10(dd,J＝20.8,10.0Hz,1H).

Examples 3 to 8

Phenylacetonitrile in this example was 1- (3, 5-dimethylphenyl) cyclobutane-1-carboxylic acid, and the method of example 3-1 was used to give 1- (3, 5-dimethylphenyl) cyclobutane-1-amine hydrochloride (1.6g) as a white solid in yield: 24.8 percent.

LC-MS(ESI)m/z:159.20(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.07(d,J＝14.3Hz,3H),2.82–2.67(m,2H),2.64–2.48(m,2H),2.35(s,6H),2.28–2.12(m,1H),2.00–1.86(m,1H).

Examples 3 to 9

Phenylacetonitrile in this example was 1-phenylcyclobutane-1-carboxylic acid, and the procedure of example 3-1 was employed to give 1-phenylcyclobutane-1-amine hydrochloride (2.2g) as a white solid in yield: 26.3 percent.

LC-MS(ESI)m/z:131.10(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.49(dt,J＝15.2,7.7Hz,5H),2.87–2.71(m,2H),2.70–2.53(m,2H),2.33–2.14(m,1H),2.04–1.82(m,1H).

Examples 3 to 10

The phenylacetonitrile compound in this example was 1- (3-chlorophenyl) cyclobutane-1-carboxylic acid, and the procedure of example 3-1 was employed to give 1- (3-chlorophenyl) cyclobutane-1-amine hydrochloride (2.4g) as a white solid in yield: 27.1 percent.

LC-MS(ESI)m/z:165.00(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.59–7.35(m,4H),2.87–2.69(m,2H),2.61(dt,J＝13.1,9.4Hz,2H),2.25(dd,J＝7.5,4.2Hz,1H),1.97(dd,J＝9.3,2.5Hz,1H).

Examples 3 to 11

In this example, phenylacetonitrile was 1- (3-fluoro-4-methoxyphenyl) cyclobutane-1-carboxylic acid, and the procedure of example 3-1 was used to obtain 1- (3-fluoro-4-methoxyphenyl) cyclobutane-1-amine hydrochloride (2.0g) as a white solid in yield: 20.5 percent.

LC-MS(ESI)m/z:179.20(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.33–7.03(m,3H),3.90(s,3H),2.72(dd,J＝15.6,11.2Hz,2H),2.57(dd,J＝19.1,9.7Hz,2H),2.28–2.10(m,1H),1.92(dd,J＝18.2,8.6Hz,1H).

Examples 3 to 12

In this example, phenylacetonitrile was 1- (4- (trifluoromethoxy) phenyl) cyclobutane-1-carboxylic acid, and the procedure of example 3-1 was used to obtain 1- (4- (trifluoromethoxy) phenyl) cyclobutane-1-amine hydrochloride (2.0g) as a white solid in yield: 24.6 percent.

LC-MS(ESI)m/z:215.10(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.63(d,J＝8.5Hz,2H),7.38(t,J＝13.6Hz,2H),2.78(dd,J＝16.5,11.5Hz,2H),2.64(dd,J＝18.1,10.9Hz,2H),2.37–2.13(m,1H),2.06–1.85(m,1H).

Examples 3 to 13

In this example, phenylacetonitrile was 1- (3, 4-dimethoxyphenyl) cyclobutane-1-carboxylic acid, and the procedure of example 3-1 was used to give 1- (3, 4-dimethoxyphenyl) cyclobutane-1-amine hydrochloride (1.0g) as a white solid in yield: 22.3 percent.

LC-MS(ESI)m/z:191.20(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.15–6.92(m,3H),3.98–3.73(m,6H),2.76(dd,J＝16.0,11.5Hz,2H),2.66–2.47(m,2H),2.29–2.11(m,1H),1.93(dd,J＝19.1,8.3Hz,1H).

Examples 3 to 14

The phenylacetonitrile in this example was 1- (m-tolyl) cyclobutane-1-carboxylic acid, and the method of example 3-1 was used to give 1- (m-tolyl) cyclobutane-1-amine hydrochloride (1.2g) as a white solid in yield: 55.5 percent.

LC-MS(ESI)m/z:145.10(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.31(m,J＝27.1,17.3,7.5Hz,4H),2.87–2.65(m,2H),2.67–2.50(m,2H),2.40(s,3H),2.31–2.14(m,1H),2.03–1.83(m,1H).

Examples 3 to 15

The procedure of example 3-1 was adopted in the present example in which phenylacetonitrile was 1- (2, 4-difluorophenyl) cyclobutane-1-carboxylic acid to give 1- (2, 4-difluorophenyl) cyclobutane-1-amine hydrochloride (1.1g) as a white solid in yield: 21.8 percent.

LC-MS(ESI)m/z:167.10(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.50(dd,J＝15.2,8.2Hz,1H),7.10(t,J＝8.6Hz,2H),2.84(dd,J＝20.4,9.3Hz,2H),2.60(m,2H),2.31(dd,J＝18.9,9.1Hz,1H),2.01(d,J＝5.4Hz,1H).

Examples 3 to 16

The phenylacetonitrile compound in this example was 1- (3-chlorophenyl) cyclobutane-1-carboxylic acid, and the procedure of example 3-1 was employed to give 1- (3-chlorophenyl) cyclobutane-1-amine hydrochloride (1.7g) as a white solid in yield: 19.6 percent.

LC-MS(ESI)m/z:165.00(M-NH₂)⁺

¹H NMR(400MHz,CD₃OD)δ7.57–7.35(m,4H),2.86–2.69(m,2H),2.68–2.52(m,2H),2.25(m,J＝15.3,9.5,4.4Hz,1H),1.96(dt,J＝9.1,6.9Hz,1H).

Example 4-1

Under the protection of nitrogen at 0 ℃. Lithium aluminum hydride (1.14g,30mmol) was dissolved in tetrahydrofuran (11.4ml), 1- (4-fluorophenyl) cyclobutane-1-carbonitrile (1.75g,10mmol) was dissolved in tetrahydrofuran (17.5ml), and the solution was slowly added dropwise to the above system while controlling the temperature at 0-5 ℃ and after completion of the dropwise addition, the temperature was naturally raised to room temperature, and stirring was carried out for 1-2 hours. After completion of the reaction, the reaction mixture was quenched with water (1.14ml), 10% sodium hydroxide solution (2.28ml) and water (3.42ml), and the mixture was filtered, washed with tetrahydrofuran, dried over anhydrous sodium sulfate and concentrated. The concentrate was dissolved in ethyl acetate, and 4M hydrochloric acid/1, 4-dioxane was added to form a salt, which was stirred at room temperature for 1 hour, followed by filtration to give the compound (1- (3-fluorophenyl) cyclobutyl) methylamine hydrochloride (1.768g) as a white solid in 81.96% yield.

LC-MS(ESI)m/z 180.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.38–7.19(m,2H),7.12(t,J＝8.6Hz,2H),3.33(s,2H),2.45(dd,J＝20.2,9.8Hz,2H),2.31(t,J＝9.0Hz,2H),2.22–2.06(m,1H),2.02–1.81(m,1H).

Example 4 to 2

In this example, the phenylacetonitrile compound was 1- (2-fluorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (2-fluorophenyl) cyclobutyl) methylamine hydrochloride (1.6g) as a white solid in yield: 75.5 percent.

LC-MS(ESI)m/z:180.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.34(d,J＝6.3Hz,1H),7.23(p,J＝7.5Hz,2H),7.16–7.03(m,1H),3.41(s,2H),2.62–2.43(m,2H),2.35(t,J＝9.8Hz,2H),2.21(dq,J＝18.3,9.3Hz,1H),1.97(dd,J＝20.2,10.1Hz,1H).

Examples 4 to 3

In this example, the phenylacetonitrile compound was 1- (3-fluorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (3-fluorophenyl) cyclobutyl) methylamine hydrochloride (2.2g) as a white solid in yield: 81.5 percent.

LC-MS(ESI)m/z:180.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.42(dd,J＝14.3,7.3Hz,1H),7.12–6.94(m,3H),3.35(s,2H),2.55–2.38(m,2H),2.32(t,J＝9.3Hz,2H),2.16(dq,J＝17.6,8.8Hz,1H),1.94(dd,J＝20.1,9.8Hz,1H).

Examples 4 to 4

The phenylacetonitrile compound in this example was 1- (4-chloro-2-fluorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was employed to give (1- (4-chloro-2-fluorophenyl) cyclobutyl) methylamine hydrochloride (2.4g) as a white solid in yield: 76.6 percent.

LC-MS(ESI)m/z:214.10(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.31–7.13(m,3H),3.40(s,2H),2.59–2.42(m,2H),2.34(t,J＝9.9Hz,2H),2.22(dt,J＝18.8,9.2Hz,1H),1.97(q,J＝9.6Hz,1H).

Examples 4 to 5

The phenylacetonitrile in this example was 1- (2, 6-difluorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was employed to give (1- (2, 6-difluorophenyl) cyclobutyl) methylamine hydrochloride (2.1g) as a white solid in yield: 87.7 percent.

LC-MS(ESI)m/z:198.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.46–7.27(m,1H),6.98(t,J＝8.4Hz,2H),3.43(s,2H),2.63(q,J＝10.7Hz,2H),2.43(t,J＝9.7Hz,2H),2.21(dd,J＝19.7,9.5Hz,1H),1.98(q,J＝9.6Hz,1H).

Examples 4 to 6

The procedure of example 4-1 was adopted to obtain (1-phenylcyclobutyl) methylamine hydrochloride (1.1g) as a white solid in the yield: 85.6 percent.

LC-MS(ESI)m/z:162.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.40(t,J＝7.4Hz,2H),7.34–7.21(m,2H),3.33(s,2H),2.47(dd,J＝19.9,9.7Hz,2H),2.32(t,J＝9.2Hz,2H),2.16(dq,J＝17.7,8.9Hz,1H),1.93(dd,J＝20.2,9.7Hz,1H).

Examples 4 to 7

The phenylacetonitrile compound in this example was 1- (2-fluorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (2-chlorophenyl) cyclobutyl) methylamine hydrochloride (1.75g) as a white solid in yield: 79.9 percent.

LC-MS(ESI)m/z:196.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.32(ddt,J＝27.5,20.1,10.1Hz,3H),3.55(s,2H),2.58(dd,J＝21.3,10.8Hz,2H),2.43(dd,J＝24.7,14.3Hz,2H),2.19(dq,J＝19.0,9.7Hz,1H),1.91(dd,J＝20.9,9.7Hz,1H).

Examples 4 to 8

In this example, the phenylacetonitrile compound was 1- (2, 4-dichlorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was employed to give (1- (2, 4-dichlorophenyl) cyclobutyl) methylamine hydrochloride (1.3g) as a white solid in yield: 87.1 percent.

LC-MS(ESI)m/z:230.10(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.46(s,1H),7.37(d,J＝8.4Hz,1H),7.25(d,J＝8.3Hz,1H),3.54(s,2H),2.55(dd,J＝20.7,10.3Hz,2H),2.43(t,J＝9.9Hz,2H),2.19(dq,J＝19.0,9.6Hz,1H),1.92(dd,J＝20.0,9.9Hz,1H).

Examples 4 to 9

The phenylacetonitrile compound in this example was 1- (3-fluorophenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (3-chlorophenyl) cyclobutyl) methylamine hydrochloride (1.5g) as a white solid in yield: 84.6 percent.

LC-MS(ESI)m/z:196.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.39(t,J＝7.7Hz,1H),7.29(d,J＝9.1Hz,2H),7.18(d,J＝7.6Hz,1H),3.34(s,2H),2.45(dd,J＝20.3,9.9Hz,2H),2.32(dd,J＝15.5,6.4Hz,2H),2.17(dt,J＝20.0,8.8Hz,1H),1.95(qd,J＝9.4,4.6Hz,1H).

Examples 4 to 10

The phenylacetonitrile compound in this example was 1- (3- (trifluoromethyl) phenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (3- (trifluoromethyl) phenyl) cyclobutyl) methylamine hydrochloride (1.65g) as a white solid in yield: 82.5 percent.

LC-MS(ESI)m/z:230.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.71–7.38(m,4H),3.39(s,2H),2.49(dd,J＝20.4,10.1Hz,2H),2.37(t,J＝9.2Hz,2H),2.20(dd,J＝19.9,8.7Hz,1H),2.04–1.89(m,1H).

Examples 4 to 11

The phenylacetonitrile compound in this example was 1- (3, 5-dimethylphenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (3, 5-dimethylphenyl) cyclobutyl) methylamine hydrochloride (1.55g) as a white solid in yield: 84.1 percent.

LC-MS(ESI)m/z:190.30(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ6.92(s,1H),6.84(s,2H),3.30(s,2H),2.44(dd,J＝20.1,9.7Hz,2H),2.36–2.20(m,8H),2.13(dq,J＝17.5,8.7Hz,1H),1.92(dt,J＝15.6,7.5Hz,1H).

Examples 4 to 12

The procedure of example 4-1 was used to obtain 1- (3-fluoro-4-methoxy-phenyl) -cyclobutyl-methylamine hydrochloride (1.8g) as a white solid in the present example as 1- (3-fluoro-4-methoxy-phenyl) cyclobutane-1-carbonitrile in yield: 75.0 percent.

LC-MS(ESI)m/z:210.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.11(t,J＝8.6Hz,1H),7.06–6.93(m,2H),3.87(s,3H),3.65(s,2H),2.41(dd,J＝19.6,9.5Hz,2H),2.27(t,J＝8.3Hz,2H),2.13(dq,J＝17.1,8.6Hz,1H),2.01–1.86(m,1H).

Examples 4 to 13

The phenylacetonitrile compound in this example was 1- (2- (trifluoromethyl) phenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (2- (trifluoromethyl) phenyl) cyclobutyl) methylamine hydrochloride (1.33g) as a white solid in yield: 71.5 percent.

LC-MS(ESI)m/z:230.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.75(d,J＝7.9Hz,1H),7.65(t,J＝7.6Hz,1H),7.49(t,J＝7.6Hz,1H),7.32(d,J＝7.9Hz,1H),3.47(s,2H),2.63(dd,J＝21.6,10.5Hz,2H),2.45(t,J＝9.0Hz,2H),2.16(dd,J＝19.9,9.6Hz,1H),1.90(q,J＝9.7Hz,1H).

Examples 4 to 14

In this example, phenylacetonitrile was 1- (3, 4-dimethoxyphenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (3, 4-dimethoxyphenyl) cyclobutyl) methylamine hydrochloride (1.45g) as a white solid in yield: 77.1 percent.

LC-MS(ESI)m/z:222.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ6.97(d,J＝8.8Hz,1H),6.79(d,J＝5.0Hz,2H),3.83(d,J＝8.1Hz,6H),2.45(dd,J＝20.0,9.5Hz,2H),2.27(t,J＝10.4Hz,2H),2.13(dd,J＝18.8,9.6Hz,1H),1.94(dd,J＝12.8,7.5Hz,1H).

Examples 4 to 15

The phenylacetonitrile compound in this example was 1- (4- (trifluoromethoxy) phenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (4- (trifluoromethoxy) phenyl) cyclobutyl) methylamine hydrochloride (1.66g) as a white solid in yield: 79.0 percent.

LC-MS(ESI)m/z:246.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.33(dd,J＝22.3,8.6Hz,4H),3.36(s,2H),2.47(dd,J＝20.5,9.6Hz,2H),2.33(t,J＝10.5Hz,2H),2.16(dq,J＝17.4,8.6Hz,1H),1.94(dt,J＝16.2,7.3Hz,1H).

Examples 4 to 16

In this example, when the phenylacetonitrile compound was 1- (4-bromophenyl) cyclobutane-1-carbonitrile, the procedure of example 4-1 was employed to give (1- (4-bromophenyl) cyclobutyl) methylamine hydrochloride (1.58g) as a white solid in yield: 88.1 percent.

LC-MS(ESI)m/z:240.10(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.56(d,J＝8.3Hz,2H),7.18(d,J＝8.3Hz,2H),3.33(s,2H),2.45(dd,J＝20.5,9.6Hz,2H),2.30(t,J＝8.9Hz,2H),2.16(dd,J＝20.0,8.7Hz,1H),1.94(d,J＝10.8Hz,1H).

Examples 4 to 17

In this example, when the phenylacetonitrile compound was 1- (3-bromophenyl) cyclobutane-1-carbonitrile, the procedure of example 4-1 was employed to give (1- (3-bromophenyl) cyclobutyl) methylamine hydrochloride (1.46g) as a white solid in yield: 87.2 percent.

LC-MS(ESI)m/z:240.10(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.49–7.38(m,2H),7.33(t,J＝7.8Hz,1H),7.23(d,J＝7.7Hz,1H),3.35(s,2H),2.46(dd,J＝20.3,10.1Hz,2H),2.32(dd,J＝15.7,6.4Hz,2H),2.16(dd,J＝20.0,8.7Hz,1H),

Examples 4 to 18

The phenylacetonitrile in this example was 1- (p-tolyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (p-tolyl) cyclobutyl) methylamine hydrochloride (2.2g) as a white solid in yield: 80.8 percent.

LC-MS(ESI)m/z:159.10(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.22(d,J＝7.8Hz,2H),7.13(d,J＝7.9Hz,2H),2.45(dd,J＝20.1,9.7Hz,2H),2.36–2.21(m,5H),2.14(dd,J＝19.6,8.8Hz,1H),2.01–1.84(m,1H).

Examples 4 to 19

The phenylacetonitrile compound in this example was 1- (3,4, 5-trimethoxyphenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (3,4, 5-trimethoxyphenyl) cyclobutyl) methylamine hydrochloride (2.5g) as a white solid in yield: 81.3 percent.

LC-MS(ESI)m/z:252.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ6.49(s,2H),3.85(s,6H),3.75(s,3H),3.33(s,2H),2.54–2.41(m,2H),2.27(d,J＝9.8Hz,2H),2.13(dd,J＝18.4,9.0Hz,1H),1.93(d,J＝10.0Hz,1H).

Examples 4 to 20

The phenylacetonitrile in this example was 1- (m-tolyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (m-tolyl) cyclobutyl) methylamine hydrochloride (1.7g) as a white solid in yield: 83.8 percent.

LC-MS(ESI)m/z:176.20(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.28(t,J＝7.5Hz,1H),7.16–6.93(m,3H),2.46(dd,J＝19.8,9.5Hz,2H),2.39–2.23(m,5H),2.14(dq,J＝17.6,8.9Hz,1H),1.92(dd,J＝20.5,9.7Hz,1H).

Examples 4 to 21

The phenylacetonitrile compound in this example was 1- (4- (tert-butyl) phenyl) cyclobutane-1-carbonitrile, and the procedure of example 4-1 was used to give (1- (4- (tert-butyl) phenyl) cyclobutyl) methylamine hydrochloride (1.8g) as a white solid in yield: 80.5 percent.

LC-MS(ESI)m/z:218.30(M+H)⁺

¹H NMR(400MHz,CD₃OD)δ7.45(d,J＝8.2Hz,2H),7.18(d,J＝8.2Hz,2H),2.57–2.35(m,2H),2.28(t,J＝8.7Hz,2H),2.13(dd,J＝18.7,9.7Hz,1H),1.93(dd,J＝10.6,4.7Hz,1H),1.31(s,9H).

The above embodiments are provided only for illustrating the present invention and not for limiting the present invention, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention, and therefore all equivalent technical solutions should also fall within the scope of the present invention, and should be defined by the claims.