CN110950802A

CN110950802A - Synthesis process of intermediate of weight-reducing drug lorcaserin hydrochloride

Info

Publication number: CN110950802A
Application number: CN201911352624.9A
Authority: CN
Inventors: 王建; 邓斐; 冷志
Original assignee: Jiangxi Boya Seehot Pharmaceutical Co ltd
Current assignee: Jiangxi Boya Seehot Pharmaceutical Co ltd
Priority date: 2019-12-25
Filing date: 2019-12-25
Publication date: 2020-04-03

Abstract

The invention discloses a synthesis process of an antiobesity drug lorcaserin hydrochloride intermediate (compound V), which is characterized by comprising the following steps of: p-chlorophenylethylamine is used as a raw material, acetic anhydride is used for protecting amino through acylation, and then the hydrochloric acid lorcaserin racemate is obtained through allyl substitution, Friedel-crafts alkylation and hydrochloric acid deprotection. The invention has simple synthesis and preparation and high yield, and is a green-carbazochrome hydrochloride intermediate synthesis process suitable for industrial mass production.

Description

Synthesis process of intermediate of weight-reducing drug lorcaserin hydrochloride

Technical Field

The invention relates to a novel synthesis process of an intermediate of an antiobesity drug, namely lorcaserin hydrochloride, and belongs to the technical field of drug synthesis.

Background

Obesity is a multifactorial chronic metabolic disease in which a human body eats more calories than is consumed, and the excess calories are stored in the body in the form of fat, and when the fat in the body is accumulated excessively or is distributed abnormally, the weight of the fat exceeds 20% of the standard weight loss. There is a great deal of relevant evidence that when the body stores too much energy in the form of fat, i.e., beyond normal physiological needs, it can have adverse effects on longevity and health. With the age, the body fat correspondingly increases, which can increase the risk of cardiovascular diseases, influence the endocrine and digestive systems and increase the probability of cancer occurrence.

The world health organization listed obesity as a disease in 1997 and is one of four major medical societal problems in the world. From the 80 s of the last century, with the rapid development of economy and technology to improve the physical living standard of people and to make the dietary structure unreasonable, obesity spreads like epidemic diseases and has a tendency to continue to expand. The incidence of obesity in China is also increasing year by year, especially in adolescent groups. Therefore, the research on the drugs for treating obesity is receiving more and more attention.

The latest large-scale phase III clinical test result shows that the hydrochloric acid Lvcardelin has the weight-losing effect, and has no influence on heart valves and pulmonary arteries; in contrast, unlike other anti-obesity agents, lorcaserin improves heart rate, blood pressure, and low density lipoprotein cholesterol (LDL-C) levels while reducing weight. The advantageous well for losing weight of the lorcaserin hydrochloride is not in curative effect, but is obviously better than the existing medicines in safety, has clear benefits for the II-type diabetes mellitus and the people with cardiovascular risk factors, is approved by the United states Food and Drug Administration (FDA) to be on the market in 2012, and therefore has good market prospect for developing the lorcaserin hydrochloride.

Lorcaserin hydrochloride is known under the english name Lorcaserin hydrochloride, CAS number: 846589-

98-8, Chinese alias: (R) -8-chloro-1-methyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride, the English alias: (R) -8-Chloro-1-methyl-2,3,4, 5-tetrahydroxy-1H-3-

benzazepine hydrochloride, molecular formula: c₁₁H₁₄Hcl, molecular structural formula as follows:

the hydrochloric acid green Carlsbergine racemate (V) and its free base-green Carlsbergine racemate (VI) are key intermediates for synthesizing the hydrochloric acid green Carlsbergine (I), and according to the literature reports, the following routes are mainly formed:

route one: the synthesis method reported in CN101123955 takes p-chlorobenzene ethylamine as a raw material, and prepares the lorcaserin racemate through six steps of reactions such as trifluoroacetic anhydride acylation protection of amino, iodo, allylation, Heck reaction, hydrogenation reduction, sodium hydroxide hydrolysis and the like. The route is a typical laboratory or pilot plant synthesis method and has the defects of long process route, low atom utilization rate, low total yield and the like. In addition, trifluoroacetic anhydride, an iodinating reagent and a palladium metal reagent which are expensive are used in the reaction, so that the production cost is high.

And a second route: CN105367497 and CN106496122 report that p-chlorophenylethylamine is used as a raw material, and the chlorocarbanilide racemate (VI) is prepared by four-step reactions such as Boc anhydride acylation to protect amino, allylation, deprotection, friedel-crafts reaction (ring closing) and the like. Although the route is short, the Boc anhydride used is expensive, and the removal of Boc protecting group requires the use of HCl saturated ethyl acetate solution, which generates a large amount of waste gas and waste acid, thus being unfavorable for equipment maintenance.

In the third route, US20090143576 reports that racemic lucarniline (VI) is obtained by bromination, amination, chlorination and Friedel-crafts reaction (cyclization) by taking p-chlorobenzene ethanol as a starting material. Although the route only has four-step reaction and the price of the starting raw materials is low, the used brominating reagents such as phosphorus tribromide and thionyl chloride are corrosive hazardous chemicals, and have the advantages of large molecular weight, large relative dosage, high cost, more waste gas and waste acid, and great industrial pollution; meanwhile, during substitution, secondary substitution side reaction is easy to occur, and the total yield is low.

And a fourth route: WO2008070111 reports that 4-chlorophenylacetic acid is used as a starting material, condensed with isopropanolamine under the catalysis of a condensing agent 3,4, 5-trimethoxyphenylboronic acid, and subjected to amide reduction, chlorination and Friedel-crafts cyclization to obtain racemic lorcaserin (VI). The phenylboronic acid condensing agent used in the first step of the route is expensive, the post-treatment period is long, and the workload is large; dangerous sodium borohydride or borane reducing agents are used for reducing the second step of amide, and a large amount of ether solvents such as tetrahydrofuran and the like are used, so that the reaction explosion risk is high, and the reaction solvent is expensive and is not beneficial to recycling. Thionyl chloride generates a large amount of waste gas and waste acid, which is not beneficial to environmental protection.

And a fifth route: WO2005019179 reports that racemic lorcaserin (VI) is obtained by reacting p-chlorobenzene ethylamine serving as a starting material with 2-chloropropionyl chloride and then carrying out Friedel-crafts alkylation and reduction. Although the reaction route is short, the price of the 2-chloropropionyl chloride and the borane is high, and the operation of the 2-chloropropionyl chloride and the borane is inconvenient. The ring closing reaction adopts the reaction temperature which is higher than 150 ℃ and the time is long, so that more impurities are generated, and the separation and purification difficulty is high; and a large amount of ether solvents such as tetrahydrofuran and the like are used in the third step of reaction, and the solvents are high in price, flammable and explosive and are not beneficial to recycling and reusing.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a synthesis process of an intermediate of the weight-reducing drug lorcaserin hydrochloride, which has the advantages of simple process, safety, reliability, stable quality, low cost and high yield, is suitable for industrial mass production and has great social, economic and environmental benefits.

In order to solve the technical problems, the invention adopts the following technical scheme:

the invention discloses a synthesis process of an antiobesity drug lorcaserin hydrochloride intermediate (compound V). The synthesis process comprises the steps of taking p-chlorphenethylamine as a raw material, substituting cheap acetic anhydride for Boc anhydride or trifluoroacetic anhydride adopted in the traditional route, protecting amino by acylation, and then obtaining lorcaserin hydrochloride racemate by allyl substitution, Friedel-crafts alkylation and hydrochloric acid deprotection. The invention has simple synthetic route, low production cost and high yield, and is a hydrochloric acid lorcaserin intermediate synthetic process suitable for industrial mass production.

Further, the method sequentially comprises the following steps:

first step acetylation

；

① adding p-chlorobenzene ethylamine dropwise into acetic anhydride, and reacting at a certain temperature;

② post-treatment, namely distilling off excessive acetic anhydride and byproduct acetic acid after the reaction is finished, adding an aromatic organic solvent, washing with water, and directly putting the organic phase of the compound II into the next reaction without concentration;

the second step is that: substitution

；

① adding a certain amount of alkali into the organic phase obtained in the previous step,

② adding a certain amount of phase transfer catalyst into the organic phase obtained in the previous step

③ dropping a certain amount of allyl halogenated hydrocarbon, and reacting for a period of time while keeping the temperature after dropping;

④ post-treatment, filtering to remove residual alkali after the reaction is finished, washing with water, and concentrating under reduced pressure to obtain compound III.

The third step: closing ring

；

① putting the compound III and Lewis acid catalyst into halohydrocarbon solvent, and carrying out Friedel-crafts reaction at a certain temperature;

② post-treatment, namely washing with 1% dilute hydrochloric acid and water after the reaction is finished, standing for layering, and concentrating the organic phase under reduced pressure to obtain a compound IV;

the fourth step: deprotection of the amino acid

；

① adding hydrochloric acid into a reaction kettle containing compound IV, deprotecting at a certain temperature and simultaneously reacting to form a salt;

② post-treatment, adding alkali metal hydroxide or alkali metal carbonate for neutralization after the reaction is finished, extracting by organic solvent, introducing HCl gas for crystallization, filtering and drying to obtain the hydrochloric acid lorcaserin racemate.

Further, in the first step, the feeding molar ratio of the p-chlorobenzene ethylamine to the acetic anhydride is 1: 1-5;

further, in the first step, the aromatic hydrocarbon solvent is toluene or xylene, etc.;

further, in the first step, the reaction temperature is 30-130 ℃;

further, in the first step, the reaction time is kept at 0.5-4 hours.

Further, in the second step, the alkali is one or a mixture of any two of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride, calcium hydride, potassium tert-butoxide, sodium methoxide or sodium ethoxide;

further, in the second step, the feeding molar ratio of the compound II to the alkali is 1: 1-5;

further, in the second step, the phase transfer catalyst is quaternary ammonium salt, quaternary phosphonium salt or polyether catalyst;

further, in the second step, the feeding molar ratio of the compound II to the phase transfer catalyst is 1: 0.01-0.2;

further, in the second step, the allyl chlorohydrocarbon is one of allyl chloride and allyl bromide;

further, in the second step, the feeding molar ratio of the compound II to the allyl chlorohydrocarbon is 1: 1-5;

further, in the second step, the reaction temperature is 20-100 ℃;

further, in the second step, the reaction time is 2-20 hours.

Further, in the third step, the halogenated hydrocarbon solvent for the ring closure reaction is any one or a mixture of any two of dichloromethane, dichloroethane, chlorobenzene, o-dichlorobenzene and the like;

further, in the third step, the lewis acid catalyst for the ring closing reaction is ferric trichloride, aluminum trichloride, boron trifluoride, titanium tetrachloride, stannic chloride or zinc chloride;

further, in the third step, the feeding molar ratio of the compound III to the Lewis acid catalyst is 1: 1-5;

further, in the third step, the ring closing reaction time is 1-8 hours;

further, in the third step, the ring closing reaction temperature is 50-150 ℃;

further, in the fourth step, the feeding molar ratio of the compound IV to the HCl is 1: 2-8;

further, in the fourth step, the deprotection reaction temperature is 50-150 ℃;

further, in the fourth step, the deprotection reaction time is 1-12 hours;

further, in the fourth step, the alkali metal hydroxide or alkali metal carbonate used for neutralization is lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, or the like;

in the fourth step, the organic solvent used for extraction is an organic solvent commonly used in laboratories and industry, such as dichloromethane, trichloromethane, cyclohexane, toluene, xylene, methyl tert-butyl ether, ethyl acetate, butyl acetate and the like.

Further: the racemate (V) of the hydrochloric acid green Carlsbergine prepared by the synthesis process of the intermediate of the hydrochloric acid green Carlsbergine is subjected to manual resolution to obtain the weight-reducing medicine green Carlsbergine hydrochloride;

further: a novel oral weight-reducing medicine is prepared by manually splitting the obtained hydrochloric acid lorcaserin racemate (V) to obtain weight-reducing medicine hydrochloric acid lorcaserin, and preparing the weight-reducing medicine suitable for oral administration by using the conventional technology and auxiliary materials.

In summary, the invention has the following advantages:

(1) the invention provides a synthesis process of a new antiobesity drug lorcaserin hydrochloride intermediate (compound V). Acylation with acetic anhydride to give intermediate 1 (compound II); the synthetic routes adopted by the intermediate 2 (compound III) and the intermediate 3 (compound IV) are not reported in the literature, and the synthetic process of the invention is simple to operate.

(2) The compound can be used for synthesizing lorcaserin hydrochloride, and then is prepared into a weight-reducing medicine suitable for oral administration by using the traditional technology and auxiliary materials.

(3) The invention achieves the aim of the invention, overcomes the defects in the prior art, and provides the intermediate synthesis process of the weight-reducing medicine lorcaserin hydrochloride, which has the advantages of simple process, safety, reliability, high yield, stable intermediate and finished product quality, suitability for industrial mass production and great social, economic and environmental benefits.

Drawings

FIG. 1 is the H-NMR spectrum of the racemic modification of lorcaserin hydrochloride (V).

Detailed Description

The technical solution of the present invention will be described in detail with reference to the following embodiments.

The first step is as follows: acetylation

Adding 7.4kg of acetic anhydride into a 50L reaction kettle in sequence, then dropwise adding 7.5kg of p-chlorobenzene ethylamine, starting stirring and heating, heating to 50-60 ℃ for reaction for 2 hours, and sampling and sending to HPLC (high performance liquid chromatography) for central control; after the reaction is finished, evaporating excessive acetic anhydride and byproduct acetic acid under reduced pressure; 20kg of toluene and water are added for washing, and after standing and layering, the organic phase directly enters the next allyl substitution reaction.

The second step is that: substitution

Adding 3.0kg of tetrabutylammonium bromide, 11.4kg of allyl bromide, 19.6kg of potassium carbonate and 26.5kg of potassium hydroxide into a 100L reaction kettle, starting stirring, and heating to 50-60 ℃ for reaction for 10-12 hours; filtering, and washing a filter cake with a small amount of toluene; and washing the filtrate with water, and concentrating to obtain a compound III.

The third step: closing ring

Adding 57.5 kg of o-dichlorobenzene into a dry 200L reaction kettle, starting stirring, adding 9.7kg of anhydrous aluminum trichloride, uniformly mixing 11.5 kg of compound III and 11.5 kg of o-dichlorobenzene, pumping into an overhead tank for dropwise adding, after dropwise adding, keeping the temperature at 120-130 ℃ for reaction for 3.0-4.0 hours; after the reaction is finished, washing the reaction product by using 1% hydrochloric acid and water in sequence; the organic phase is decompressed and concentrated to obtain the compound IV.

The fourth step: deprotection of the amino acid

Adding 38.7kg of industrial concentrated hydrochloric acid into the 200L reaction kettle filled with the compound IV, starting stirring and heating, and heating for reflux reaction for 8-10 hours; after the reaction is finished, adjusting the pH value with sodium carbonate, extracting with 62kg of toluene, introducing hydrogen chloride gas into the organic phase for crystallization, filtering and drying to obtain 9.1kg of hydrochloric acid lorcaserin racemate. HPLC purity 99.49%.

The above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and do not limit the concept and the protection scope of the present invention, and the ordinary skilled person of the present invention can modify the technical solutions of the present invention or substitute the equivalent without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.

Claims

1. A synthesis process of an antiobesity drug lorcaserin hydrochloride intermediate comprises the following steps: using p-chlorophenylethylamine as a raw material, acylating acetic anhydride to protect amino, namely acetylating, then performing allyl substitution, Friedel-crafts alkylation, namely ring closing, and hydrochloric acid deprotection to obtain a hydrochloric acid lorcaserin intermediate, namely hydrochloric acid lorcaserin racemate; the reaction formula is as follows:

。

2. the process for synthesizing a lorcaserin hydrochloride intermediate according to claim 1,

first step acetylation

；

Dropwise adding p-chlorophenylethylamine into acetic anhydride, wherein the reaction temperature is 30-130 ℃; the reaction time is kept at 0.5-4 hours;

② post-treatment, namely distilling off excessive acetic anhydride and byproduct acetic acid after the reaction is finished, adding an aromatic organic solvent, washing with water, and directly putting the organic phase containing the compound II into the next reaction without concentration.

3. The process for the synthesis of the lorcaserin hydrochloride intermediate according to claim 1, characterized in that in the second step: substitution

；

①, adding a certain amount of alkali into the organic phase obtained in the previous step, wherein the feeding molar ratio of the compound II to the alkali is 1: 1-5;

② adding a certain amount of phase transfer catalyst into the organic phase obtained in the previous step, wherein the feeding molar ratio of the compound II to the phase transfer catalyst is 1: 0.01-0.2;

③, dropwise adding a certain amount of allyl halogenated hydrocarbon, wherein the feeding molar ratio of the compound II to the allyl chlorinated hydrocarbon is 1: 1-5, and after dropwise adding, the reaction temperature is 20-100 ℃;

the reaction time is 2-20 hours;

4. The process for synthesizing a lorcaserin hydrochloride intermediate according to claim 1, wherein the third step comprises: closing ring

；

①, putting a compound III and a Lewis acid catalyst into a halogenated hydrocarbon solvent, wherein the feeding molar ratio of the compound III to the Lewis acid catalyst is 1: 1-5, the ring closing reaction temperature is 50-150 ℃, and the ring closing reaction time is 1-8 hours;

② post-treatment, washing with 1% dilute hydrochloric acid and water, standing for layering, and concentrating under reduced pressure to obtain compound IV.

5. The process for synthesizing a lorcaserin hydrochloride intermediate according to claim 1, wherein the fourth step comprises: deprotection of the amino acid

；

① adding hydrochloric acid into a reaction kettle filled with a compound IV, wherein the feeding molar ratio of the compound IV to the HCl is 1: 2-8, deprotecting at 50-150 ℃, and reacting for 1-12 hours;

6. The synthesis process of the intermediate of lorcaserin hydrochloride as claimed in claim 2, wherein in the first step, the feeding molar ratio of p-chlorophenylethylamine to acetic anhydride is 1: 1-5; the aromatic hydrocarbon solvent includes toluene or xylene.

7. The process for synthesizing the lorcaserin hydrochloride intermediate according to claim 3, wherein: in the second step, the alkali is one or the mixture of any two of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride, calcium hydride, potassium tert-butoxide, sodium methoxide or sodium ethoxide;

the phase transfer catalyst is quaternary ammonium salt, quaternary phosphonium salt or polyether catalyst;

the allyl chlorohydrocarbon is one of allyl chloride and allyl bromide.

8. The process for synthesizing the lorcaserin hydrochloride intermediate according to claim 4, wherein: in the third step, the halogenated hydrocarbon solvent for the ring closing reaction comprises any one or a mixture of any two of dichloromethane, dichloroethane or chlorobenzene and o-dichlorobenzene;

the Lewis acid catalyst for the ring closing reaction is ferric trichloride, aluminum trichloride, boron trifluoride, titanium tetrachloride, stannic chloride or zinc chloride.

9. The process for synthesizing the lorcaserin hydrochloride intermediate according to claim 5, wherein: in the fourth step, the alkali metal hydroxide or alkali metal carbonate used for neutralization comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate;

the organic solvent used for extraction comprises dichloromethane, chloroform, cyclohexane, toluene, xylene, methyl tert-butyl ether, ethyl acetate and butyl acetate.

10. The lorcaserin hydrochloride racemate (V) prepared by the lorcaserin hydrochloride intermediate synthesis process according to claim 1 is manually split to obtain the weight-reducing drug lorcaserin hydrochloride;

and/or the obtained hydrochloric acid lorcaserin racemate (V) is manually split to obtain the weight-reducing medicine hydrochloric acid lorcaserin, and the weight-reducing medicine suitable for oral administration is prepared by using the traditional technology and auxiliary materials.