CN111499575B

CN111499575B - Method for preparing lorcaserin

Info

Publication number: CN111499575B
Application number: CN202010369638.8A
Authority: CN
Inventors: 孙京国; 刘家伟; 孙辰; 龙瑶; 冯玉玲; 王玥; 蔡乐; 王涛; 王广威; 侯家宁; 王琳; 卢锡萌
Original assignee: Hebei Normal University
Current assignee: Hebei Normal University
Priority date: 2020-05-05
Filing date: 2020-05-05
Publication date: 2022-03-25
Anticipated expiration: 2040-05-05
Also published as: CN111499575A

Abstract

The invention discloses a method for preparing lorcaserin. The preparation method specifically comprises the steps of using p-chlorobenzonitrile as a starting material, preparing p-chlorobenzenethylamine through reduction, reacting the p-chlorobenzenethylamine with p-toluenesulfonyl chloride to form an amino space occupying intermediate, reacting the intermediate with monochloroacetone under an alkaline condition to form N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-propionyl) benzenesulfonamide, synthesizing 8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine through reduction, chlorination, p-toluenesulfonyl removal and intramolecular Friedel-crafts alkylation, resolving the azepine through L- (+) -tartaric acid, alkalizing to remove tartaric acid, and reacting with hydrogen chloride diethyl ether to form salt to obtain the lorcaserin. The method has the characteristics of simple synthesis method, good reaction selectivity, high product purity, environmental protection and low preparation cost.

Description

Method for preparing lorcaserin

Technical Field

The invention relates to a method for preparing lorcaserin, and belongs to the technical field of medicines and preparation thereof.

Background

The chemical name (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride of Lorcaserin (English name: Lorcaerin) is a novel weight-reducing drug developed by Arena pharmaceutical company, and is approved by FDA to be marketed in 2012. Its target of action is 5-HT_2CBy means of specific stingsLaser 5-HT_2CThe receptor increases appetite and satiety and reduces caloric intake, while on 5-HT_2AAnd 5-HT_2BThere is no effect on the receptors, which are associated with cardiovascular disease and hallucinations, respectively. Phase iii clinical results show that lorcaserin has no effect on heart valves and pulmonary arteries and also improves heart rate, blood pressure and ldl cholesterol levels. The advantage of the lorcaserin is not limited to curative effect, and the safety of the lorcaserin is better than that of other weight-reducing medicines.

In the prior art, patent WO2005003096 reports that p-chlorobenzene ethylamine is used as a starting material to react with 2-chloropropionyl chloride, and then the raw material is subjected to Friedel-crafts alkylation, reduction, resolution and salt formation to obtain lorcaserin, the total yield of the route is good, but in the process of forming alpha-chloroamide, multi-substituted impurities are generated, and the separation and purification are difficult. Patent US20090143576 uses p-chlorophenyl ethanol as starting material, and the chlorocarbaryl is obtained through bromination, amination, chlorination, friedel-crafts alkylation, resolution, and finally salification. Patent WO2008070111 uses p-chlorophenylacetic acid as a starting material, and first condenses with isopropanolamine, then reduces, chloro friedel-crafts alkylates, splits, and finally forms hydrochloride to obtain lorcaserin, in the route, the reaction of carboxylic acid and amine is difficult to be carried out, boric acid is needed, phenylboronic acid is used as a condensation reagent, the reaction temperature is high, the reaction time is long, if 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) is added at room temperature for catalytic condensation reaction, the reaction time is long, the yield is low, and the condensation product is unstable and can easily remove one molecule of water to form a byproduct. Patent CN103333111A takes p-chlorophenylacetic acid as a starting material, and the p-chlorophenylacetic acid and isopropanolamine are subjected to amidation reaction, and then chlorinated, reduced, Friedel-crafts alkylation and resolution are carried out, and finally salification is carried out to obtain lorcaserin. Patent CN104119236 andthe method is characterized in that chlorobenzene ethylamine and propylene oxide are used as initial raw materials for condensation, and the chlorocarbonserin is obtained through chlorination, Friedel-crafts alkylation, resolution and final salt formation. Patent WO2003086306 takes p-chlorophenylethylamine as a starting material, and obtains lorcaserin by aminolysis, iodination, allylation, Heck reaction, hydrogen reduction and alkaline hydrolysis deprotection and resolution salt formation₂The catalyst is expensive and the production cost is high.

Disclosure of Invention

The invention aims to provide a method for preparing lorcaserin, aiming at the defects of the prior art, and the method is simple and convenient to operate, low in cost and capable of improving the product purity.

The preparation method provided by the invention comprises the following steps:

(1) reducing p-chlorobenzonitrile under the conditions that Raney Ni is used as a catalyst and potassium borohydride or sodium borohydride is used as a reducing agent, wherein a reaction solvent is methanol or ethanol, the reaction temperature is room temperature, preferably 25 ℃, the pH value is adjusted to 1-2, preferably the pH value is 1, salifying the product into a water phase, extracting and removing impurities, then adjusting the pH value to 12-13, preferably the pH value is 13, and extracting to obtain p-chlorobenzyl ethylamine, namely IM 1;

(2) performing sulfamoylation reaction on the IM1 and p-toluenesulfonyl chloride under an alkaline condition, and recrystallizing a crude product to obtain N- (2- (4-chlorophenyl) ethyl)) -4-methylbenzenesulfonamide, namely IM 2;

wherein, the sulfamidation reaction solvent is one or more of acetone, tetrahydrofuran, N-dimethylformamide, dichloromethane and chloroform, and the acid-binding agent is one of triethylamine, pyridine, potassium carbonate and sodium carbonate, preferably triethylamine; the recrystallization solvent is one of methanol, ethanol, isopropanol and tert-butanol, preferably ethanol; the temperature of the sulfamidation reaction is 0-80 ℃, and the optimal temperature is 25 ℃; the recrystallization reaction temperature is preferably 78 ℃;

(3) performing an N-alkylation reaction on IM2 and monochloroacetone under an alkaline condition to synthesize a compound N- (2- (4-chlorphenyl) ethyl)) -4-methyl-N- (2-propionyl) benzenesulfonamide, namely IM 3;

wherein, the reaction solvent is acetone, and the acid-binding agent is one of triethylamine, potassium carbonate, sodium carbonate and sodium hydride, preferably potassium carbonate; the reaction temperature is 20-60 ℃, and preferably 30 ℃;

(4) IM3 reduces carbonyl under the action of sodium borohydride or potassium borohydride as a reducing agent to synthesize N- (2- (4-chlorphenyl) ethyl)) -4-methyl-N- (2-hydroxypropyl) benzenesulfonamide, namely IM 4;

wherein the reaction solvent is methanol or ethanol, the reaction temperature is 0-60 ℃, and 25 ℃ is preferred; regulating the pH value to 3 for the first time and regulating the pH value to 9 for the second time, and extracting and rotatably removing the extractant to obtain IM 4;

(5) IM4 synthesizes N- (2- (4-chlorphenyl) ethyl)) -4-methyl-N- (2-chloropropyl) benzene sulfonamide by chlorination under the action of thionyl chloride or phenylphosphonyl dichloride, namely IM 5;

in the reaction, the solvent is chloroform or dichloromethane or the mixture thereof, and the reaction temperature is 25-reflux temperature; the post-treatment extractant is dichloromethane;

(6) removing the tosyl from the IM5 under the action of concentrated sulfuric acid, hydrobromic acid or glacial acetic acid, and reacting with hydrogen chloride diethyl ether to synthesize 1- (2- (4-chlorphenyl) ethyl) amino) -2-chloropropane hydrochloride, namely IM 6;

the reaction is carried out at the reaction temperature of 100-150 ℃, preferably 120 ℃;

(7) IM6 is catalyzed by aluminum trichloride or ferric trichloride to carry out intramolecular Friedel-crafts alkylation to synthesize 8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine, which is called as IM 7;

in the reaction, the reaction solvent is o-dichlorobenzene, and the reaction temperature is 130-150 ℃, preferably 150 ℃; adjusting the pH value to 13-14;

(8) IM7 is resolved by L- (+) -tartaric acid to obtain (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine hemitartrate, then potassium carbonate aqueous solution is used to dissociate tartaric acid to obtain (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine, and the obtained product is further reacted with hydrogen chloride diethyl ether to form salt to prepare lorcaserin;

the reaction, the resolution solvent is acetone or a mixed solvent of acetone and water, and the reaction temperature is 50 ℃; the alkalinizing (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine hemitartrate reagent is potassium carbonate or sodium carbonate, and the extracting agent is dichloromethane or ethyl acetate; the salifying reaction solvent is dichloromethane, the salifying reagent is hydrogen chloride ether solution, and the temperature is-10 ℃ to 5 ℃.

The reaction formula is as follows:

the method for preparing the lorcaserin has the advantages of cheap and easily obtained raw materials, simple and convenient operation, good reaction selectivity and high purity of lorcaserin products, and is an economic and simple synthetic method.

Drawings

FIG. 1 is N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-propionyl) benzenesulfonamide (IM 3)¹H NMR chart.

Detailed Description

In order to make the present invention better understood, the following detailed description of the present invention is provided in conjunction with specific embodiments to help those skilled in the art understand the method of the present invention, and it is obvious to those skilled in the art that various modifications and changes can be made to the present invention in the light of the principle and idea of the present invention.

Example 1

Preparation of p-chlorophenylethylamine (IM 1)

In a 250mL three-necked flask, 15.16g (0.10mol) of p-chlorobenzonitrile was added, 180 mL of cocatalyst ethanol was added, and 5.87g (0.10mol) of Raney Ni and 16.18g (0.30 mol) of KBH were further added₄Stirring at 25 ℃, reacting completely after 2h, stopping stirring, filtering, removing ethanol by rotary evaporation, adding 200mL of ethyl acetate, 200mL of water, adjusting the pH to 1 with 6 mol/L hydrochloric acid, separating an ethyl acetate layer, adding 200mL of ethyl acetate into a water layer, adjusting the pH to 13 with 40% NaOH, separating the ethyl acetate layer, and extracting a water layer with 200mL of ethyl acetateTaking and combining ethyl acetate layers, adding anhydrous sodium sulfate for drying, carrying out suction filtration, and carrying out rotary evaporation to remove ethyl acetate, so as to obtain 14.32g of light yellow oily liquid with the yield of 92.0%.

IM1 characterizes data:

¹H NMR (500 MHz, CDCl₃) δ 7.23 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H), 1.32 (s, 2H)。

example 2

Preparation of p-chlorophenylethylamine (IM 1)

In a 250mL three-necked flask, 15.13g (0.10mol) of p-chlorobenzonitrile, 150 mL of cocatalyst methanol, 5.88g (0.10mol) of Raney Ni, and 11.36g (0.30 mol) of NaBH were added₄And the mixture is stirred and reacted for 3 hours at the temperature of 30 ℃, the post-reaction treatment is the same as example 1, wherein the pH value of the mixture is adjusted to 2, and the pH value of the mixture is adjusted to 12 after extraction and impurity removal, so that 13.23g of light yellow oily liquid is obtained, and the yield is 85.0%.

Example 3

Preparation of N- (2- (4-chlorophenyl) ethyl)) -4-methylbenzenesulfonamide (IM 2)

In a 250mL three-neck flask, 15.56g (0.10mol) of p-chlorobenzene ethylamine is added, 175mL of dichloromethane is added to dissolve the p-chlorobenzene ethylamine, 14mL of triethylamine (0.10mol) is added under the stirring at 25 ℃, 19.07g (0.10mol) of p-toluenesulfonyl chloride is added under the ice bath, the mixture is moved to the room temperature after being stirred for 30 minutes, the reaction is completed after 4 hours, the filtration is carried out, 50mL of ethanol is added after the filtrate is dried by spinning, the temperature is heated to 78 ℃, and recrystallization is carried out, thus obtaining 26.35g of IM2 white solid, the yield is 85.1%, and the HPLC purity is 99.9%.

IM2 characterizes data:

ESI-MS: m/z = 310[M+H]⁺

¹H NMR (500 MHz, CDCl₃) δ 7.69 (d, J = 8.3 Hz, 2H), 7.28 (d, 2H), 7.21 (d, 2H), 7.02 (d, J = 8.4 Hz, 2H), 4.79 (s, 1H), 3.18 (t, J = 7.0 Hz, 2H), 2.74 (t, J = 7.0 Hz, 2H), 2.44 (s, 3H)。

example 4

In a 250mL three-necked flask, 14.16g (0.09 mol) of p-chlorobenzene ethylamine was added, 160mL of acetone/N, N-dimethylformamide (v/v =1: 1) was added, 20.75g (0.15 mol) of potassium carbonate was added, 17.41g (0.09 mol) of p-toluenesulfonyl chloride was added, and the reaction was stirred at 30 ℃ for 3 hours, followed by working up with example 3 to obtain IM2 as a white solid (18.06 g, yield 64.1%).

Example 5

N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-propionyl) benzenesulfonamide

Preparation of (IM 3)

In a 100mL three-necked flask, 3.10g (10.01 mmol) of N- (2- (4-chlorophenyl) ethyl)) -4-methylbenzenesulfonamide was added, 30mL of acetone was added to dissolve it, 2.76g (19.97 mmol) of potassium carbonate was further added, 1.11g (12.00 mmol) of monochloroacetone was dissolved in 5mL of acetone, and slowly added dropwise with stirring at room temperature. After the dropwise addition, the reaction solution is transferred to 30 ℃, the reaction is completed after 12 hours, the reaction solution is transferred to a 250mL single-neck bottle, rotary evaporation is carried out, 50mL distilled water and 50mL ethyl acetate are added, an ethyl acetate layer is separated and then is washed by 50mL water, the ethyl acetate is separated and is dried by anhydrous sodium sulfate, suction filtration and rotary evaporation are carried out, and the IM3 white solid is obtained by column chromatography, wherein the yield is 3.03g, and the yield is 82.8%.

IM3 characterizes data:

ESI-MS: m/z = 366.2[M+H]⁺

¹H NMR (500 MHz, CDCl₃) δ 7.66 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H), 3.92 (s, 2H), 3.36 (t, 2H), 2.80 (t, 2H), 2.42 (s, 3H), 2.12 (s, 3H)。

example 6

N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-propionyl) benzenesulfonamide

Preparation of (IM 3)

In a 100mL three-necked flask, 3.07g (9.91 mmol) of N- (2- (4-chlorophenyl) ethyl)) -4-methylbenzenesulfonamide was added, 30mL of acetone was added to dissolve it, 0.76g (19.00 mmol) of 60% sodium hydride was added thereto, 1.08g (11.67 mmol) of monochloroacetone was dissolved in 5mL of acetone, and the mixture was slowly added dropwise to the reaction flask with stirring. The reaction was completed at 60 ℃ for 8h and worked up as in example 5 to give IM3 as a white solid 2.87g with a yield of 79.2%.

Example 7

N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-hydroxypropyl) benzenesulfonamide

Preparation of (IM 4)

In a 100mL single-neck flask, 3.65g (9.98 mmol) of N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-propionyl) benzenesulfonamide was added, 40mL of methanol was added, and 1.13g (29.87 mmol) of NaBH was added under ice bath₄After 30min, the reaction solution is moved to 25 ℃ for reaction, and the reaction is completed within 3 h. Adjusting pH =3 with 3 mol/L diluted hydrochloric acid, removing methanol by rotary evaporation, adding 40mL of water, adding 40mL of ethyl acetate, adjusting pH =9 with 25% NaOH, separating ethyl acetate, extracting the water layer twice with ethyl acetate, and combining the ethyl acetate layers. Adding anhydrous sodium sulfate, drying, filtering, and rotary steaming to obtain IM4 white solid 3.38g, yield 92.1%.

IM4 characterizes data:

¹H NMR (500 MHz, CDCl₃) δ 7.68 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 4.01 – 3.96 (m, 1H), 3.42 – 3.31 (m, 2H), 3.13-3.01 (m, 2H), 2.93-2.83 (m, 2H), 2.43 (s, 3H), 1.17 (d, J = 6.3 Hz, 3H)。

example 8

Preparation of (IM 4)

In a 100mL single-neck flask, 3.72g (10.17 mmol) of N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-propionyl) benzenesulfonamide was charged, 40mL of methanol was added, and 1.62g (30.00 mmol) of KBH was added₄The reaction time is 2.5 h. Working-up as in example 5 gave 3.31g of IM4 as a white solid in 88.5% yield.

Sodium borohydride-ethanol is adopted, and the reduction yield of potassium borohydride-ethanol is 86-92%.

Example 9

N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-chloropropyl) benzenesulfonamide

Preparation of (IM 5)

In a 100mL three-necked flask, 3.67g (9.98 mmol) of N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-hydroxypropyl) benzenesulfonamide was added, 30mL of chloroform was added, 1.43g (12.02 mmol) of thionyl chloride was dissolved in 5mL of chloroform and placed in a dropping funnel, the mixture was dropped into a reaction flask at 25 ℃ and the dropping was completed, the reaction was refluxed for 8 hours, and rotary evaporation was carried out, 30mL of dichloromethane was added, the dichloromethane layer was washed with saturated sodium bicarbonate, the dichloromethane layer was separated, the aqueous solution was extracted with 30mL of dichloromethane, the dichloromethane layers were combined, dried over anhydrous sodium sulfate, and rotary evaporation was carried out. The IM5 white solid obtained by column chromatography was 2.79g, 72.4% yield.

IM5 characterizes data:

ESI-MS: m/z = 386.2[M+H]⁺

¹H NMR (500 MHz, CDCl₃) δ 7.69 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 4.20-4.14 (m, 1H), 3.48 – 3.38 (m, 2H), 3.32 – 3.20 (m, 2H), 2.91 – 2.83 (m, 2H), 2.42 (s, 3H), 1.51 (d, J = 6.6 Hz, 3H)。

example 10

Preparation of (IM 5)

In a 100mL three-necked flask, 3.65g (9.92 mmol) of N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-hydroxypropyl) benzenesulfonamide was charged, 40mL of methylene chloride/chloroform (v/v =1: 1) was added, 1.94g (9.95 mmol) of phenylphosphonyl dichloride was dissolved in 5mL of methylene chloride and placed in a dropping funnel, and the mixture was dropped into a reaction flask at room temperature and refluxed for 5 hours to complete the reaction, followed by the same workup as in example 9 to obtain 2.83g of an IM5 white solid with a yield of 73.8%.

Example 11

Preparation of 1- (2- (4-chlorophenyl) ethyl) amino) -2-chloropropane hydrochloride (IM 6)

In a 100mL single-neck flask, 3.87g (10.02mmol) of N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-chloropropyl) benzenesulfonamide was added, 5mL of water and 20 mL of concentrated sulfuric acid were added, the temperature was raised to 120 ℃ and the reaction was completed after 2 hours, the flask was cooled to room temperature, 20 mL of water and 20 mL of ethyl acetate were added under ice bath conditions, liquid was separated, the aqueous layer was extracted again with 20 mL of ethyl acetate, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Suction filtration and rotary evaporation are carried out, 4mL of dichloromethane and 20 mL of hydrochloric ether are added, ice water bath stirring is carried out for 1h, and suction filtration is carried out, thus obtaining IM6 white solid 2.28g with yield of 84.7%.

IM6 characterizes data:

ESI-MS (formula C)₁₁H₁₅Cl₂N·HCl): m/z = 232.1[M+H⁺-HCl]

¹H NMR (500 MHz, CDCl₃) δ 7.28 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 4.22-4.15 (m, 1H), 2.97 – 2.80 (m, 6H), 2.05 (s, 1H), 1.52 (d, J = 6.6 Hz, 3H)。

Example 12

In a 100mL single-neck flask, 3.66g (9.47 mmol) of N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-chloropropyl) benzenesulfonamide was added, 6 mL of water and 20 mL of concentrated sulfuric acid were added, the temperature was raised to 150 ℃ and the reaction was completed after 2 hours, and the post-treatment was the same as in example 11 to obtain 2.12g of IM6 as a white solid with a yield of 83.3%.

Example 13

In a 100mL single-neck flask, 3.45g (8.93 mmol) of N- (2- (4-chlorophenyl) ethyl)) -4-methyl-N- (2-chloropropyl) benzenesulfonamide was added, 5mL of water and 24.4g (0.30 mol) of hydrobromic acid were added, and the reaction was heated to 100 ℃ until completion to post-treat the same as in example 12 to obtain IM6 as a white solid, 1.96g, in 81.7% yield.

Example 14

Preparation of 8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine (IM 7)

In a 100mL single-neck flask, 2.69g (10.01 mmol) of 1- (2- (4-chlorophenyl) ethyl) amino) -2-chloropropane hydrochloride, 35mL of o-dichlorobenzene, 4.03g (30.22 mmol) of anhydrous aluminum trichloride were added, and the reaction was completed after heating and stirring to 150 ℃ for 1 hour. Cooling to room temperature, slowly adding 40mL of water, standing for layering, separating liquid, washing an organic layer twice with water, and combining aqueous phases. Adding 50mL of ethyl acetate for extraction, adjusting the pH value to 13-14 by using 40% NaOH, separating liquid, washing a water layer for 2 times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, performing suction filtration, and performing rotary evaporation to obtain a crude product, namely a brown yellow oily substance, of 1.65g, wherein the yield is 84.3%.

IM7 characterizes data:

IM7 molecular formula C₁₁H₁₄ClN, molecular weight 195.6, ESI-MS: m/z = 196.1[ M + H%]⁺。

IR（KBr）：3430.84，2982.24，2685.05，1580.37，1471.03，1389.72，935.51，879.44，817.76cm^-1。

¹H NMR (500 MHz, CDCl₃) δ 7.12 (s, J = 5.3 Hz, 1H), 7.06 (d, J = 8.0, 2.1 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 3.06 – 2.83 (m, 6H), 2.73-2.67 (m, 1H), 2.08 (s, 1H), 1.31 (d, J = 7.2 Hz, 3H)。

¹³C NMR (101 MHz, CDCl₃) δ 144.35（s）, 136.86（s）, 133.38（s）, 131.12（s）, 127.22（s）, 126.25（s）, 51.48（s）, 45.60（s）, 34.62（s）, 31.99（s）, 17.97（s）。

Example 15

Preparation of 8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine (IM 7)

In a 100mL single-neck flask, 2.65g (9.87 mmol) of 1- (2- (4-chlorophenyl) ethyl) amino) -2-chloropropane hydrochloride, 30mL of o-dichlorobenzene, 4.8g (29.59 mmol) of anhydrous ferric chloride were added, and the mixture was heated to 130 ℃ with stirring until the reaction was completed. Working-up as in example 14 gave 1.41g of a crude tan oil in 73.0% yield.

Example 16

Preparation of (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (TM)

(1) 1.96g (10.02mmol) of 8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine (IM 7) is added into a 100mL single-neck flask, 8 mL of acetone is added, the temperature is raised to 50 ℃, 1 mL of aqueous solution containing 0.38g (2.53mmol) of L- (+) tartaric acid is dropped into the flask, the mixture reacts for 3H at 50 ℃, the mixture is cooled to room temperature, 2.5 mL of acetone is added, the mixture is stirred for 1H in an ice water bath and is filtered by suction, and a large amount of (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine hemitartrate white solid is obtained.

¹H NMR (500 MHz, DMSO) δ 7.23 – 7.08 (m, 3H), 3.99 (s, 1H), 3.25 (s, 2H), 3.18 (d, 1H), 3.09 – 2.94 (m, 2H), 2.86 (d, J = 34.5 Hz, 2H), 1.26 (s, J=7.2Hz, 3H)。

(2) Adding the white solid into a 250mL single-neck flask, adding 50mL of dichloromethane, 30mL of water and 2.76g of potassium carbonate, stirring and reacting at room temperature for 1h, standing and demixing, washing an organic phase by 2X 15mL of water, drying the organic phase by anhydrous sodium sulfate, filtering, and performing rotary evaporation to obtain a yellow oily substance.

(3) And adding 10mL of dichloromethane into the yellow oily matter, transferring the yellow oily matter into a 100mL single-neck flask, dripping 50mL of hydrogen chloride ether solution, crystallizing for 4 hours in ice bath, performing suction filtration, and drying to obtain 0.82g of white solid lorcaserin. The yield thereof was found to be 35.3%. HPLC purity greater than 99.5%, e.e value greater than 99.0%.

TM characterization data:

ESI-MS (formula C)₁₁H₁₄ClN·HCl）: m/z = 196.1[M+H⁺-HCl]

¹H NMR (500 MHz, CDCl₃) δ 10.19 (s, 1H), 9.91 (s, 1H), 7.20 (s, 1H), 7.18 (d, J = 8.1, 1.7 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 3.63 (d, J = 7.4 Hz, 2H), 3.55 – 3.41 (m, 2H), 3.05 (d, J = 11.5 Hz, 1H), 2.94 (d, J = 47.9 Hz, 2H), 1.50 (d, J = 7.2 Hz, 3H)。

(TM i.e. lorcaserin).

Example 17

Preparation of (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (lorcaserin)

(1) In a 100mL single-neck flask, 0.36g (2.40mmol) of L- (+) tartaric acid is added, 6.5mL of 90% acetone/water solution is added, 1.95g (9.96mmol) of 8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine is added, the temperature is raised to 50 ℃ for reaction for 3H, the mixture is cooled to room temperature, 2.5 mL of acetone is added, and a large amount of white solid (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine hemitartrate is obtained by stirring in ice water bath.

(2) Adding the white solid into a 250mL single-neck flask, adding 100mL of ethyl acetate, 30mL of water and 2.35g of sodium carbonate, stirring and reacting at room temperature for 1h, standing and demixing, washing an organic phase by 2X 15mL of water, drying the organic phase by anhydrous sodium sulfate, filtering, and performing rotary evaporation to obtain a yellow oily substance.

(3) Adding 10mL of dichloromethane into the yellow oily matter, transferring the yellow oily matter into a 100mL single-neck flask, dripping 50mL of hydrogen chloride ether solution, crystallizing for 3 hours at the temperature of minus 10 ℃, filtering, and drying to obtain 0.76g of white solid lorcaserin. The yield thereof was found to be 32.9%.

Claims

1. A method for preparing lorcaserin, characterized by comprising the steps of:

(1) reducing p-chlorobenzonitrile under the conditions that Raney Ni is used as a catalyst and potassium borohydride or sodium borohydride is used as a reducing agent, and then adjusting the pH value to obtain p-chlorobenzenethylamine which is called as IM 1;

(8) IM7 is resolved by L- (+) -tartaric acid to obtain (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine hemitartrate, then the free tartaric acid is alkalized to obtain (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine, and the obtained product is further reacted with hydrogen chloride diethyl ether to form salt to prepare the lorcaserin.

2. The preparation method according to claim 1, wherein in the step (1), the reaction solvent is methanol or ethanol, the reaction temperature is room temperature, the pH value is adjusted to 1-2 for the first time, the product is salified into an aqueous phase, and after extraction and impurity removal, the pH value is adjusted to 12-13.

3. The preparation method according to claim 1, wherein in the step (2), the reaction solvent of the reaction is one or more of acetone, tetrahydrofuran, N-dimethylformamide, dichloroethane and chloroform, and the acid-binding agent is one of triethylamine, pyridine, potassium carbonate and sodium carbonate; the recrystallization solvent is one of methanol, ethanol, isopropanol and tert-butanol; the sulfonylation reaction temperature is 25 ℃, and the recrystallization reaction temperature is 78 ℃.

4. The preparation method according to claim 1, wherein in the step (3), the reaction solvent is acetone, the acid-binding agent is one of triethylamine, potassium carbonate, sodium carbonate and sodium hydride, and the reaction temperature is 20-60 ℃.

5. The process according to claim 1, wherein in the step (4), the reaction solvent is methanol or ethanol, the reaction temperature is 25 ℃, the pH is adjusted to 3 for the first time, and the pH is adjusted to 9 for the second time.

6. The process according to claim 1, wherein in the step (5), the reaction solvent is chloroform or dichloromethane or a mixture thereof, and the reaction temperature is from 25 ℃ to reflux temperature; the post-treatment extractant was dichloromethane.

7. The production method according to claim 1, wherein in the step (6), the reaction temperature is 120 ℃.

8. The method according to claim 1, wherein in the step (7), the reaction solvent is o-dichlorobenzene, and the reaction temperature is 130-150 ℃; the pH value is adjusted to 13-14.

9. The preparation method according to claim 1, wherein in the step (8), the resolution solvent is acetone or a mixed solvent of acetone and water, and the reaction temperature is 50 ℃; the alkalinizing (R) -8-chloro-1-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine hemitartrate reagent is potassium carbonate or sodium carbonate, and the extracting agent is dichloromethane or ethyl acetate; the salifying reaction solvent is dichloromethane, the salifying reagent is hydrogen chloride ether solution, and the temperature is-10 ℃ to 5 ℃.