1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline preparation method

Abstract

The invention provides a 1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline preparation method. The 1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline preparation method comprises the following steps of: mixing benzoyl chloride or benzoic acid, phenethylamine and alkali metal hydroxide with water, and reacting to obtain N-(2-phenethyl) benzamide; then mixing the N-(2-phenethyl) benzamide with phosphorus pentoxide, chloride phosphorus and a benzene solvent, heating and reacting to obtain 1-phenyl-3, 4-dihydro-isoquinoline; and further mixing the 1-phenyl-3, 4-dihydro-isoquinoline with a first alcohol solvent and hydroboron, and reacting to obtain the product. Compared with the prior art, the 1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline preparation method has the advantages that firstly, no organic solvents are added, the product N-(2-phenethyl) benzamide is insoluble in an aqueous solution, and therefore, the steps of skimming and the like are avoided in the after-treatment process, and the after-treatment operation is simplified; secondarily, as the organic solvents are not added, the cost is reduced, and the pollution to environments is avoided; and thirdly, as the phosphorus pentoxide and the chloride phosphorus are subjected to oxidization cyclization reaction, polyphosphoric acids are prevented from being heated and decomposed to generate hypertoxic phosphorus oxide exhaust gas.

Description

technical field

[0001] The invention belongs to the technical field of synthesis and preparation of organic compounds, in particular to a preparation method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline. Background technique

[0002] Solifenacin, the chemical name is 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylic acid (1R,3R′)-quinuclidinyl ester. It has been reported that a series of quinucidine derivatives including solifenacin or its salts have no effect on muscarine M 3 The receptor has excellent selective antagonism and is useful in urological disorders such as neurogenic urinary frequency, neurogenic bladder, nocturia, unstable bladder, bladder contractures, and chronic cystitis, as well as in respiratory disorders such as chronic obstructive pulmonary disease , chronic bronchitis, asthma and rhinitis) preventive or therapeutic agents. Among them, solifenacin is a urinary system antispasmodic drug, is M 3 Selective antagonists of receptors, usually used to treat ...

Examples

preparation example Construction

[0030] The invention provides a preparation method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline, comprising the following steps: a) oxidizing benzoyl chloride or benzoic acid, phenethylamine, and alkali metal hydroxide The compound is mixed with water, and after the reaction, N-(2-phenylethyl)benzamide is obtained; b) the N-(2-phenylethyl)benzamide, phosphorus pentoxide, phosphorus chloride and benzene 1-phenyl-3,4-dihydroisoquinoline; c) the 1-phenyl-3,4-dihydroisoquinoline, the first alcohol solvent and boron The hydrides are mixed and reacted to give 1-phenyl-1,2,3,4-dihydroisoquinoline.

[0031] Wherein, the benzoyl chloride or benzoic acid, phenethylamine and phosphorus pentoxide are benzoyl chloride or benzoic acid, phenethylamine and phosphorus pentoxide well known to those skilled in the art, and there is no special source limits.

[0032] The alkali metal hydroxide can be any alkali metal hydroxide well known to those skilled in the art, and there is no special limita...

Embodiment 1

[0066] 1.1 Mix and stir 60.6g (1.5mol) sodium hydroxide and 405ml water to dissolve it completely, then cool down to 18°C, add 96ml (0.76mol) phenethylamine, cool down in an ice bath, and slowly Add 132ml (1.13mol) of benzoyl chloride dropwise. During the dropwise addition, keep the temperature of the reaction system not higher than 10°C. The filter cake was washed with water until neutral, and the white solid obtained was vacuum-dried at 70°C for 9 hours to obtain 168.6 g of N-(2-phenylethyl)benzamide with a yield of 98.5%.

[0067] 1.2 Dissolve 119.4g (0.53mol) of N-(2-phenylethyl)benzamide obtained in 1.1 in 800ml of toluene, stir until completely dissolved, then add 76.8g (0.53mol) of phosphorus pentoxide and 185.6ml of (1.98mol) phosphorus oxychloride, heated to reflux reaction for 4 hours, the detection of raw materials completely disappeared, stop heating, naturally cool to room temperature, slowly add water, keep the temperature of the system not exceeding 50°C during ...

Embodiment 2

[0074] 2.1 Mix and stir 84g (1.5mol) potassium hydroxide and 405ml water to dissolve it completely, then cool down to 18°C, add 96ml (0.76mol) phenethylamine, cool down in an ice bath, and slowly drop under vigorous stirring Add 132ml (1.13mol) of benzoyl chloride, keep the temperature of the reaction system not higher than 10°C during the dropwise addition, remove the ice bath after the dropwise addition, and react at room temperature for 3 hours, detect the disappearance of the raw materials by TLC, filter with suction, and wash with a large amount of water The filter cake was neutralized, and the obtained white solid was vacuum-dried at 70°C for 9 hours to obtain 168.8 g of N-(2-phenylethyl)benzamide with a yield of 98.6%.

[0075] 2.2 Dissolve 119.4g (0.53mol) of N-(2-phenylethyl)benzamide obtained in 2.1 in 800ml of toluene, stir until completely dissolved, then add 76.8g (0.53mol) of phosphorus pentoxide and 185.6ml of (1.98mol) phosphorus oxychloride, heated to reflux f...

technical field

[0001] The invention belongs to the technical field of synthesis and preparation of organic compounds, in particular to a preparation method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline. Background technique

[0002] Solifenacin, the chemical name is 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylic acid (1R,3R′)-quinuclidinyl ester. It has been reported that a series of quinucidine derivatives including solifenacin or its salts have no effect on muscarine M 3 The receptor has excellent selective antagonism and is useful in urological disorders such as neurogenic urinary frequency, neurogenic bladder, nocturia, unstable bladder, bladder contractures, and chronic cystitis, as well as in respiratory disorders such as chronic obstructive pulmonary disease , chronic bronchitis, asthma and rhinitis) preventive or therapeutic agents. Among them, solifenacin is a urinary system antispasmodic drug, is M 3 Selective antagonists of receptors, usually used to treat ...

Examples

preparation example Construction

[0030] The invention provides a preparation method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline, comprising the following steps: a) oxidizing benzoyl chloride or benzoic acid, phenethylamine, and alkali metal hydroxide The compound is mixed with water, and after the reaction, N-(2-phenylethyl)benzamide is obtained; b) the N-(2-phenylethyl)benzamide, phosphorus pentoxide, phosphorus chloride and benzene 1-phenyl-3,4-dihydroisoquinoline; c) the 1-phenyl-3,4-dihydroisoquinoline, the first alcohol solvent and boron The hydrides are mixed and reacted to give 1-phenyl-1,2,3,4-dihydroisoquinoline.

[0031] Wherein, the benzoyl chloride or benzoic acid, phenethylamine and phosphorus pentoxide are benzoyl chloride or benzoic acid, phenethylamine and phosphorus pentoxide well known to those skilled in the art, and there is no special source limits.

[0032] The alkali metal hydroxide can be any alkali metal hydroxide well known to those skilled in the art, and there is no special limita...

Embodiment 1

[0066] 1.1 Mix and stir 60.6g (1.5mol) sodium hydroxide and 405ml water to dissolve it completely, then cool down to 18°C, add 96ml (0.76mol) phenethylamine, cool down in an ice bath, and slowly Add 132ml (1.13mol) of benzoyl chloride dropwise. During the dropwise addition, keep the temperature of the reaction system not higher than 10°C. The filter cake was washed with water until neutral, and the white solid obtained was vacuum-dried at 70°C for 9 hours to obtain 168.6 g of N-(2-phenylethyl)benzamide with a yield of 98.5%.

[0067] 1.2 Dissolve 119.4g (0.53mol) of N-(2-phenylethyl)benzamide obtained in 1.1 in 800ml of toluene, stir until completely dissolved, then add 76.8g (0.53mol) of phosphorus pentoxide and 185.6ml of (1.98mol) phosphorus oxychloride, heated to reflux reaction for 4 hours, the detection of raw materials completely disappeared, stop heating, naturally cool to room temperature, slowly add water, keep the temperature of the system not exceeding 50°C during ...

Embodiment 2

[0074] 2.1 Mix and stir 84g (1.5mol) potassium hydroxide and 405ml water to dissolve it completely, then cool down to 18°C, add 96ml (0.76mol) phenethylamine, cool down in an ice bath, and slowly drop under vigorous stirring Add 132ml (1.13mol) of benzoyl chloride, keep the temperature of the reaction system not higher than 10°C during the dropwise addition, remove the ice bath after the dropwise addition, and react at room temperature for 3 hours, detect the disappearance of the raw materials by TLC, filter with suction, and wash with a large amount of water The filter cake was neutralized, and the obtained white solid was vacuum-dried at 70°C for 9 hours to obtain 168.8 g of N-(2-phenylethyl)benzamide with a yield of 98.6%.

[0075] 2.2 Dissolve 119.4g (0.53mol) of N-(2-phenylethyl)benzamide obtained in 2.1 in 800ml of toluene, stir until completely dissolved, then add 76.8g (0.53mol) of phosphorus pentoxide and 185.6ml of (1.98mol) phosphorus oxychloride, heated to reflux f...

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