Beta-phosphonyl-enamine derivative and preparation method therefor

Abstract

The present invention discloses the preparation method of -phosphonyl-enamine derivative. The preparation method comprising the following steps: dissolving the enamine derivative, organic phosphine compound, manganese acetate and potassium carbonate in the solvent, reacting at room temperature to obtain the -phosphonyl-enamine derivative. The enamine derivative was as the starting material, and the raw materials are easy to obtain and a great many varieties. The various forms of the products obtained therein can be directly applied and can be used in further reactions. The reaction conditions are mild, the reaction speed is high, the reaction operation and the post-treatment process are simple, the production is convenient, and the method is suitable for large-scale production.

Claims

1. A method for preparing a -phosphonoenamine derivative which comprises the following steps: dissolving an enamine derivative, an organic phosphine compound, manganese acetate, and potassium carbonate in a solvent and reacting at room temperature to obtain the -phosphonoenamine derivative; wherein the enamine derivative has the following structure: ##STR00009## wherein R.sup.1 and R.sup.2 are one of the followings: (1) R.sup.1 is selected from the group consisting of hydrogen, methyl, methoxy, fluorine, chlorine, bromine, and trifluoromethyl, and R.sup.2 is hydrogen; or (2) R.sup.2 is selected from the group consisting of methyl, methoxy, fluorine, chlorine, and bromine, and R.sup.1 is hydrogen; wherein the organic phosphine compound has the following structure: ##STR00010## and wherein R is selected from the group consisting of methoxy, ethoxy, isopropoxy, tert-butoxy, and phenyl; wherein the -phosphonoenamine derivative has the following structure: ##STR00011## in which R1, R2 and R are as defined above.

2. The method for preparing the -phosphonoenamine derivative according to claim 1, wherein the enamine derivative is selected from the group consisting of N-(styryl)benzamide, 2-chloro-N-(styryl)benzamide, 2-fluoro-N-(styryl)benzamide, 3-bromo-N-(styryl)benzamide, 4-bromo-N-(styryl)benzamide, 4-methyl-N-(styryl)benzamide, 4-methoxy-N-(styryl)benz-amide, 4-trifluoromethyl-N-(styryl)benzamide, 3,4,5-trimethoxy-N-(styryl)benzamide, N-(styryl)-thienylamide, N-(2-methylstyryl)benzamide, N-(2-methoxystyryl)benzamide, N-(2-fluorostyryl)benzamide, N-(2-chlorostyryl)benzamide, N-(3-methylstyryl)benzamide, N-(3-chlorostyryl)benzamide, N-(4-methylstyryl)benzamide, N-(4-fluorostyryl)benzamide, N-(4-chlorostyryl)-benzamide, and N-(4-bromostyryl)-benzamide.

3. The method for preparing the -phosphonoenamine derivative according to claim 1, wherein the organic phosphine compound is selected from the group consisting of dimethyl phosphite, diethyl phosphite, diisopropyl phosphite, and diphenylphosphine oxide; the solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and acetic acid.

4. The method for preparing the -phosphonoenamine derivative according to claim 1, wherein the reaction is tracked to completion by a thin layer chromatography.

5. The method for preparing the -phosphonoenamine derivative according to claim 1, wherein a molar ratio of the enamine derivative, the organic phosphine compound, manganese acetate, and potassium carbonate is 1:2:2.5:2.

6. The -phosphonoenamine derivative prepared by the method according to claim 1, wherein the -phosphonoenamine derivative has the following structure wherein R.sup.1 and R.sup.2 are one of the followings: (1) R.sup.1 is selected from the group consisting of hydrogen, methyl, methoxy, fluorine, chlorine, bromine, and trifluoromethyl, and R.sup.2 is hydrogen; or (2) R.sup.2 is selected from the group consisting of methyl, methoxy, fluorine, chlorine, and bromine, and R.sup.1 is hydrogen; and R is selected from the group consisting of methoxy, ethoxy, isopropoxy and tert-butoxy.

Description

EMBODIMENTS OF THE INVENTION

Example 17 Synthesis of N-(2-(diphenylphosphine)-2-(2-chlorophenyl) vinyl) benzamide

(1) Taking N-(2-chlorostyryl) benzamide as the raw material, the reaction steps are as follows: (1) Mixing N-(2-chlorostyryl) benzamide (257 mg, 1 mmol), diphenylphosphine (404 mg, 2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) and 10 mL of methanol in the reaction bottle. The mixture was stirred at room temperature for reaction; (2) TLC followed the whole reaction to completion (for about 0.5 hours); (3) After the reaction the crude product was separated by column chromatography (dichloromethane:methanol=100:1) to obtain the target product (yield 82%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.20 (d, J=11.0 Hz, 1H), 8.13-8.06 (m, 2H), 7.99 (dd, J=30.7, 10.6 Hz, 1H), 7.62-7.46 (m, 9H), 7.40 (td, J=7.7, 3.0 Hz, 4H), 7.22 (d, J=7.8 Hz, 1H), 7.14 (t, J=7.7 Hz, 1H), 7.01 (t, J=7.5 Hz, 1H), 6.88 (d, J=7.7 Hz, 1H).

Example 18 Synthesis of N-(2-(diphenylphosphine)-2-(3-methylphenyl)vinyl)benzamide

(2) Taking N-(3-methylstyryl) benzamide as the raw material, the reaction steps are as follows: (1) Mixing N-(2-chlorostyryl)benzamide (237 mg, 1 mmol), diphenylphosphine (404 mg, 2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) and 10 mL of methanol in the reaction bottle. The mixture was stirred at room temperature for reaction; (2) TLC followed the whole reaction to completion (for about 0.5 hours); (3) After the reaction the crude product was separated by column chromatography (dichloromethane:methanol=100:1) to obtain the target product (yield 90%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.12 (d, J=8.3 Hz, 1H), 7.78 (s, 4H), 7.58-7.48 (m, 6H), 7.45 (s, 4H), 7.41-7.36 (m, 2H), 7.24 (s, 1H), 7.12 (d, J=17.2 Hz, 2H), 2.28 (s, 3H).

Example 19 Synthesis of N-(2-(diphenylphosphine)-2-(3-chlorophenyl)vinyl)benzamide

(3) Taking N-(3-chlorostyryl)benzamide as the raw material, the reaction steps are as follows: (1) Mixing N-(3-chlorostyryl) benzamide (257 mg, 1 mmol), diphenylphosphine (404 mg, 2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) and 10 mL of methanol in the reaction bottle. The mixture was stirred at room temperature for reaction; (2) TLC followed the whole reaction to completion (for about 0.5 hours); (3) After the reaction the crude product was separated by column chromatography (dichloromethane:methanol=100:1) to obtain the target product (yield 88%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.03 (d, J=11.6 Hz, 1H), 7.77 (dd, J=11.6, 7.5 Hz, 4H), 7.65-7.45 (m, 6H), 7.48 (dd, J=9.7, 4.4 Hz, 4H), 7.42 (t, J=7.6 Hz, 2H), 7.37-7.29 (m, 3H), 7.24 (d, J=6.4 Hz, 1H).

Example 20 Synthesis of N-(2-(diphenylphosphine)-2-(4-methylphenyl)vinyl)benzamide

(4) Taking N-(4-methylstyryl)benzamide as the raw material, the reaction steps are as follows: (1) Mixing N-(4-methylstyryl) benzamide (237 mg, 1 mmol), diphenylphosphine (404 mg, 2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) and 10 mL of methanol in the reaction bottle. The mixture was stirred at room temperature for reaction; (2) TLC followed the whole reaction to completion (for about 0.5 hours); (3) After the reaction the crude product was separated by column chromatography (dichloromethane:methanol=100:1) to obtain the target product (yield 84%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.14 (d, J=11.3 Hz, 1H), 7.76 (dd, J=11.5, 7.7 Hz, 4H), 7.68-7.62 (m, 1H), 7.57 (d, J=7.6 Hz, 2H), 7.53-7.48 (m, 3H), 7.47-7.42 (m, 4H), 7.39 (t, J=7.6 Hz, 2H), 7.18 (dd, J=20.4, 7.8 Hz, 4H), 2.31 (s, 3H).

Example 21 Synthesis of N-(2-(diphenylphosphine)-2-(4-methoxyphenyl)vinyl)benzamide

(5) Taking N-(4-methoxystyryl) benzamide as the raw material, the reaction steps are as follows: (1) Mixing N-(4-methoxystyryl)benzamide (253 mg, 1 mmol), diphenylphosphine (404 mg, 2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) and 10 mL of methanol in the reaction bottle. The mixture was stirred at room temperature for reaction; (2) TLC followed the whole reaction to completion (for about 0.5 hours); (3) After the reaction the crude product was separated by column chromatography (dichloromethane:methanol=100:1) to obtain the target product (yield 83%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.10 (d, J=11.3 Hz, 1H), 7.76 (dd, J=11.6, 7.4 Hz, 4H), 7.66-7.60 (m, 1H), 7.58 (d, J=7.5 Hz, 2H), 7.51 (d, J=6.0 Hz, 3H), 7.46 (dd, J=9.8, 4.5 Hz, 4H), 7.40 (t, J=7.6 Hz, 2H), 7.25 (d, J=8.3 Hz, 1H), 6.89 (d, J=8.5 Hz, 2H), 3.78 (s, 3H).

Example 22 Synthesis of N-(2-(diphenylphosphine)-2-(4-fluorophenyl)vinyl)benzamide

(6) Taking N-(4-fluorostyryl) benzamide as the raw material, the reaction steps are as follows: (1) Mixing N-(4-fluorostyryl) benzamide (241 mg, 1 mmol), diphenylphosphine (404 mg, 2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) and 10 mL of methanol in the reaction bottle. The mixture was stirred at room temperature for reaction; (2) TLC followed the whole reaction to completion (for about 0.5 hours); (3) After the reaction the crude product was separated by column chromatography (dichloromethane:methanol=100:1) to obtain the target product (yield 84%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.01 (d, J=11.3 Hz, 1H), 7.76 (dd, J=11.9, 7.2 Hz, 4H), 7.67-7.60 (m, 1H), 7.55 (dd, J=12.1, 4.4 Hz, 4H), 7.53 (d, J=2.3 Hz, 1H), 7.47 (td, J=7.4, 2.7 Hz, 4H), 7.41 (t, J=7.7 Hz, 2H), 7.32 (dd, J=7.3, 5.5 Hz, 2H), 7.07 (t, J=8.6 Hz, 2H).

Example 23 Synthesis of N-(2-(diphenylphosphine)-2-(4-chlorophenyl)vinyl)benzamide

(7) Taking N-(4-chlorostyryl)benzamide as the raw material, the reaction steps are as follows: (1) Mixing N-(4-chlorostyryl)benzamide (257 mg, 1 mmol), diphenylphosphine (404 mg, 2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) and 10 mL of methanol in the reaction bottle. The mixture was stirred at room temperature for reaction; (2) TLC followed the whole reaction to completion (for about 0.5 hours); (3) After the reaction the crude product was separated by column chromatography (dichloromethane:methanol=100:1) to obtain the target product (yield 81%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.02 (d, J=11.5 Hz, 1H), 7.82-7.70 (m, 4H), 7.66-7.51 (m, 6H), 7.51-7.45 (m, 4H), 7.42 (t, J=7.7 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.32-7.29 (m, 2H).

Example 24 Synthesis of N-(2-(diphenylphosphine)-2-(4-bromophenyl)vinyl)benzamide

(8) Taking N-(4-bromostyryl)benzamide as the raw material, the reaction steps are as follows: (1) Mixing N-(4-bromostyryl)benzamide (301 mg, 1 mmol), diphenylphosphine (404 mg, 2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) and 10 mL of methanol in the reaction bottle. The mixture was stirred at room temperature for reaction; (2) TLC followed the whole reaction to completion (for about 0.5 hours); (3) After the reaction the crude product was separated by column chromatography (dichloromethane:methanol=100:1) to obtain the target product (yield 85%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.05 (d, J=11.0 Hz, 1H), 7.76 (dd, J=11.5, 7.7 Hz, 4H), 7.60 (t, J=11.6 Hz, 3H), 7.54-7.44 (m, 9H), 7.41 (t, J=7.6 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H).

Example 25 Synthesis of A53868A (A)

(9) ##STR00008##

(10) With enamine (A1) and dimethyl phosphite as raw materials, the reaction steps are as follows: (1) Mixing enamine A1 (213 mg, 1 mmol), dimethyl phosphite (220 mg, 2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) and 10 mL of methanol in in the reaction flask. The mixture was stirred at room temperature for reaction; (2) TLC followed the whole reaction to completion (for about 0.5 hours); (3) After the reaction, the crude product was separated by silica gel column chromatography to obtain the target product A2 (yield 76%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 9.66 (s, 1H), 7.40 (s, 1H), 7.33 (dd, J=16.9, 10.1 Hz, 1H), 5.38 (dd, J=16.8, 2.1 Hz, 1H), 5.07 (s, 2H), 4.60 (t, J=7.3 Hz, 1H), 4.41 (dd, J=10.0, 2.1 Hz, 1H), 3.54 (s, 2H), 1.86 (t, J=7.3 Hz, 1H), 1.68-1.55 (m, 2H), 0.98 (d, J=6.2 Hz, 6H); (4) Mixing A2 (321 mg, 1 mmol) and tetrahydrofuran (12 mL) in the reaction flask, and then add catalyst Pd/C (32.1 mg, 10 mol %). The mixture was reacted at room temperature under the hydrogen (1 atmosphere) atmosphere for 6 hours. After the reaction, the crude product was separated by silica gel column chromatography to obtain the target product A3 (yield 91%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.00 (s, 1H), 7.39 (s, 1H), 5.07 (s, 2H), 4.52 (t, J=3.4 Hz, 1H), 3.67 (d, J=11.0 Hz, 6H), 3.55-3.51 (m, 3H), 3.43 (t, J=6.1 Hz, 1H), 2.09-2.00 (m, 3H), 1.74 (t, J=3.6 Hz, 2H), 1.73-1.67 (m, 1H), 0.84 (d, J=6.3 Hz, 6H); (5) Mixing A3 (323 mg, 1 mmol), paraformaldehyde (150 mg, 5 mmol) diethylamine (80 mg, 1 mmol) and anhydrous methanol (1 mL) in the reaction flask. The mixture was refluxed for 24 h under the protection of argon. After the reaction, the solvent was removed in vacuo, and then toluene was added for distillation to remove methanol. P-toluenesulfonic acid (1.5 mg, 0.01 mmol), anhydrous toluene (5 mL) and 4 molecular sieves were added, and the mixture was refluxed under argon for 24 h. After the reaction, the crude product was separated by silica gel column chromatography to obtain the target product A4 (yield 83%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.77 (s, 1H), 7.16 (s, 1H), 5.11 (s, 2H), 5.07 (s, 2H), 4.59 (t, J=3.4 Hz, 1H), 3.93 (s, 2H), 3.78 (d, J=10.8 Hz, 6H), 3.54 (s, 2H), 1.88-1.83 (m, 1H), 1.67 (dd, J=4.6, 3.4 Hz, 1H), 1.57 (dd, J=4.6, 3.4 Hz, 1H), 1.00 (d, J=6.3 Hz, 6H); (6) Mixing A4 (335 mg, 1 mmol) and concentrated hydrochloric acid (20 mL) in the reaction flask. Heating it and refluxing until to the end of the reaction. Adding 50 ml of water, extracting with dichloromethane, concentrating, and drying. The crude product was recrystallization of ethanol/water to obtain the target, product A (yield 89%). The analytical data of the products are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 8.49 (s, 1H), 7.99 (s, 1H), 5.12 (s, 2H), 5.07 (s, 2H), 4.57 (t, J=3.4 Hz, 1H), 4.16 (s, 1H), 4.05 (s, 1H), 3.54 (s, 2H), 1.93 (s, 3H), 1.89 (dd, J=7.3, 3.3 Hz, 1H), 1.61 (dd, J=7.3, 3.5 Hz, 1H), 1.45-1.32 (m, 1H), 0.87 (d, J=6.4 Hz).

Example 26 Synthesis of (2-benzamido-1-phenethyl)dimethylphosphonate

(11) (1) Taking (2-benzamido-1-styryl)dimethylphosphonate as the raw material, the reaction steps are as follows:

(12) (2) Adding (2-benzamido-1-styryl)dimethylphosphonate (3.3 g, 10 mmol), Raney-Ni (660 mg, 20 mol %) and methanol (200 mL) into the reaction kettle. At 40 C. with hydrogen (10 atm), the reaction taken for 24 hours. The reaction product was filtered and concentrated to obtain the product (2-benzamido-1-phenethyl)dimethylphosphonate (yield 95%). The analytical data of the product are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3): 7.72 (t, J=5.6 Hz, 1H), 7.70-7.65 (m, 2H), 7.40-7.31 (m, 3H), 7.27 (t, J=7.4 Hz, 4H), 7.24-7.20 (m, 1H), 4.10-3.98 (m, 1H), 3.97-3.83 (m, 1H), 3.74-3.63 (m, 4H), 3.46 (d, J=10.6 Hz, 3H).

Example 27 Synthesis of 2-amino-1-phenethylphosphonic Acid

(13) (1) Taking (2-benzamido-1-phenethyl)dimethylphosphonate as the raw material, the reaction steps are as follows: Adding (2-benzamido-1-phenethyl)dimethylphosphonate (1.33 g, 4 mmol) and 8 M hydrochloric acid (50 mL) into the reaction flask, and the mixture was refluxed; (2) TLC followed the reaction to completion; (3) The reaction solution was cooled to room temperature, washed with dichloromethane, concentrated, and recrystallized to obtain 2-amino-1-phenethylphosphonic acid (yield 81%). The analytical data of the product are as follows: .sup.1H NMR (400 MHz, D.sub.2O): 7.40-7.24 (m, 5H), 3.62-3.36 (m, 2H), 3.30-3.11 (m, 1H).