A method for preparing 2,3,4,9-tetrahydro-β-carbolin-1-one

Abstract

A preparation method of 2, 3, 4, 9-tetrahydro-beta-carboline-1-one comprises: chloridizing indole-3-propionic acid (III) with a chloridizing agent in an aprotic solvent to prepare indole-3- propionyl chloride (IV), or carrying out condensation reaction between indole-3-propionic acid (III) and chloro-formate in an aprotic solvent under catalysis of an acid binding agent to prepare an active mixed acid anhydride (V); then carrying out an azidation reaction with an azidation reagent to prepare indolepropionyl azide (VI); carrying out a Curtius rearrangement reaction to prepare indoleethyl isocyanate(VII); and finally preparing 2, 3, 4, 9-tetrahydro-beta-carbolin-1-one through a cyclization reaction under catalysis of an acid catalyst. The method is mild in reaction conditions, simple to operate, less in pollution, cheap and accessible in raw materials, simple in technology, high in yield, and ingenious in technology design; and the azidation reaction, Curtius rearrangement and the cyclization are carried out by one-pot synthesis; and in the reaction process, there are not complex operations such as column chromatography, repeated recrystallization and the like, and the technology scaling-up is easy to operate.

Description

technical field

[0001] The invention belongs to the field of chemistry or medicinal chemistry, and specifically relates to a preparation method of 2,3,4,9-tetrahydro-β-carbolin-1-one. Background technique

[0002] 2,3,4,9-tetrahydro-β-carbolin-1-one (I) (hereinafter referred to as "carboline") is a key intermediate for the preparation of quinazolinone carboline alkaloid (II), carboline (1) chemical structural formula is as follows:

[0003]

[0004] Quinazolinone carboline alkaloids contain biological activities such as mGluR1 antagonists and MAPKAP-K2 inhibitors, and have good cardiotonic, antihypertensive, vasodilation, diuretic, analgesic, anti-inflammation, reduction of platelet aggregation, and relaxation of vascular smooth muscle , anal sphincter and anti-cancer effects. The chemical structural formula of quinazolinone carboline alkaloids (II) is as follows:

[0005]

[0006] Among them, R 1 =CH 3 , R 2 =OMe,R 3 =H,2-methoxy-13-methylrutea caprine [0007...

Examples

Embodiment 1

[0039] Add 20g of indolepropionic acid (0.106mol), 65g of toluene and 22g of thionyl chloride (0.185mol) into a 500ml four-neck flask, and start stirring. React at 70-75°C for 4 hours, distill the excess thionyl chloride under reduced pressure, evaporate to dryness, and add 100ml of fresh toluene. Add 10g of sodium azide (0.153mol), react at 10-15°C for 30 minutes, add 30ml of water, let stand to separate layers, and remove the lower water layer. The organic layer was heated to 85°C and stirred for 2.0 hours. Cool to room temperature, add 10g of zinc chloride, and stir overnight. After suction filtration, the filter cake was washed with water until neutral, and dried to obtain 15.7 g of a yellow solid with a yield of 80.1%. Melting point: 180.7-183.0°C;

[0040] 1 HNMR(400MHZ,Acetone-d6):δ3.01(2H,m),3.04(1H,m),3.66(2H,m),7.08(1H,m),7.21(1H,m),7.51(1H, d),7.61(1H,d),10.84(1H,s);

[0041] IR(KBr):3210(NH),2990,2870(CH),1665(C=O),1548,1512,1490,1455,1416(Ph and CH),1328,129...

Embodiment 2

[0044]Add 20 g of indole propionic acid (0.106 mol), 35 g of tetrahydrofuran and 25 g of oxalyl chloride (0.197 mol) into a 500 ml four-neck flask, and start stirring. React at 50-60°C for 4 hours, distill the excess oxalyl chloride under reduced pressure, evaporate to dryness, and add 25 g of fresh tetrahydrofuran. Add 8g of sodium azide (0.123mol) and react at 0-5°C for 1 hour. Add 100ml of toluene and 30ml of water, stir to dissolve, and separate the lower aqueous layer. The organic layer was heated to 80°C and stirred for 2.5 hours. Cool to room temperature, add 40g hydrochloric acid / 20g water, and stir overnight. After suction filtration, the filter cake was washed with water until neutral, and dried to obtain 14.9 g of a yellow solid with a yield of 75.8%. Melting point: 180.1-182.5°C.

Embodiment 3

[0046] Add 20g of indole propionic acid (0.106mol), 90g of acetone and 20g of triethylamine into a 500ml four-necked flask, and start stirring. 20 g of methyl chloroformate (0.211 mol) were added dropwise at 0-8°C. After dropping, add 10.5g of potassium azide (0.129mol) and react at 5-10°C for 2 hours. Add 100ml of toluene and 30ml of water, stir to dissolve, and separate the lower aqueous layer. The organic layer was heated to 85°C and stirred for 1.5 hours. Cool to room temperature, pass through 0.5mol hydrogen chloride gas, and stir overnight. After suction filtration, the filter cake was washed with water until neutral, and dried to obtain 15.4 g of a yellow solid with a yield of 78.1%. Melting point: 178.4-181.6°C.

technical field

[0001] The invention belongs to the field of chemistry or medicinal chemistry, and specifically relates to a preparation method of 2,3,4,9-tetrahydro-β-carbolin-1-one. Background technique

[0002] 2,3,4,9-tetrahydro-β-carbolin-1-one (I) (hereinafter referred to as "carboline") is a key intermediate for the preparation of quinazolinone carboline alkaloid (II), carboline (1) chemical structural formula is as follows:

[0003]

[0004] Quinazolinone carboline alkaloids contain biological activities such as mGluR1 antagonists and MAPKAP-K2 inhibitors, and have good cardiotonic, antihypertensive, vasodilation, diuretic, analgesic, anti-inflammation, reduction of platelet aggregation, and relaxation of vascular smooth muscle , anal sphincter and anti-cancer effects. The chemical structural formula of quinazolinone carboline alkaloids (II) is as follows:

[0005]

[0006] Among them, R 1 =CH 3 , R 2 =OMe,R 3 =H,2-methoxy-13-methylrutea caprine [0007...

Examples

Embodiment 1

[0039] Add 20g of indolepropionic acid (0.106mol), 65g of toluene and 22g of thionyl chloride (0.185mol) into a 500ml four-neck flask, and start stirring. React at 70-75°C for 4 hours, distill the excess thionyl chloride under reduced pressure, evaporate to dryness, and add 100ml of fresh toluene. Add 10g of sodium azide (0.153mol), react at 10-15°C for 30 minutes, add 30ml of water, let stand to separate layers, and remove the lower water layer. The organic layer was heated to 85°C and stirred for 2.0 hours. Cool to room temperature, add 10g of zinc chloride, and stir overnight. After suction filtration, the filter cake was washed with water until neutral, and dried to obtain 15.7 g of a yellow solid with a yield of 80.1%. Melting point: 180.7-183.0°C;

[0040] 1 HNMR(400MHZ,Acetone-d6):δ3.01(2H,m),3.04(1H,m),3.66(2H,m),7.08(1H,m),7.21(1H,m),7.51(1H, d),7.61(1H,d),10.84(1H,s);

[0041] IR(KBr):3210(NH),2990,2870(CH),1665(C=O),1548,1512,1490,1455,1416(Ph and CH),1328,129...

Embodiment 2

[0044]Add 20 g of indole propionic acid (0.106 mol), 35 g of tetrahydrofuran and 25 g of oxalyl chloride (0.197 mol) into a 500 ml four-neck flask, and start stirring. React at 50-60°C for 4 hours, distill the excess oxalyl chloride under reduced pressure, evaporate to dryness, and add 25 g of fresh tetrahydrofuran. Add 8g of sodium azide (0.123mol) and react at 0-5°C for 1 hour. Add 100ml of toluene and 30ml of water, stir to dissolve, and separate the lower aqueous layer. The organic layer was heated to 80°C and stirred for 2.5 hours. Cool to room temperature, add 40g hydrochloric acid / 20g water, and stir overnight. After suction filtration, the filter cake was washed with water until neutral, and dried to obtain 14.9 g of a yellow solid with a yield of 75.8%. Melting point: 180.1-182.5°C.

Embodiment 3

[0046] Add 20g of indole propionic acid (0.106mol), 90g of acetone and 20g of triethylamine into a 500ml four-necked flask, and start stirring. 20 g of methyl chloroformate (0.211 mol) were added dropwise at 0-8°C. After dropping, add 10.5g of potassium azide (0.129mol) and react at 5-10°C for 2 hours. Add 100ml of toluene and 30ml of water, stir to dissolve, and separate the lower aqueous layer. The organic layer was heated to 85°C and stirred for 1.5 hours. Cool to room temperature, pass through 0.5mol hydrogen chloride gas, and stir overnight. After suction filtration, the filter cake was washed with water until neutral, and dried to obtain 15.4 g of a yellow solid with a yield of 78.1%. Melting point: 178.4-181.6°C.

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