CN101525333A - Synthesis method of metixene hydrochloride - Google Patents

Abstract

The invention discloses a method for synthesizing Methasan hydrochloride, which relates to a synthesis process of an anti-parkinsonian drug. The present invention uses thiosalicylic acid as a raw material to obtain 2-phenylthiobenzoic acid through coupling with iodobenzene, then dehydration and ring closure to obtain 9-thioxanthone, and then carbonyl reduction to obtain thioxanthene, and finally thia Anthracene reacts with 3-chloromethyl-1-methylpiperidine to obtain the target product (5) Methasan hydrochloride of the following formula. The raw materials of the invention are easy to obtain, the cost is low, the preparation route is short, the operation is simple, and the industrialization is easy.

Description

A kind of synthetic method of Methiasan hydrochloride

technical field

A method for synthesizing mesai powder hydrochloride, relating to a synthesis process of an anti-parkinsonian drug, belonging to the technical field of pharmaceutical preparation

Background technique

Methasan hydrochloride is an anti-parkinsonian drug, also known as metixene hydrochloride, which is an M-receptor blocker, used for the treatment of Parkinson's disease, including alleviating drug-induced extrapyramidal syndrome. US Patent US2905590 reports that its synthetic method is to condense thioxanthene and 3-chloromethyl-1-methylpiperidine under the effect of alkali, and then obtain Methasan hydrochloride through hydrochloric acid acidification, but this method uses the large toxic Benzene and easily flammable sodium are not conducive to industrialization. The synthesis of 2-phenylthiobenzoic acid has been reported in many literatures, but all of them use organic solvents, which cause environmental pollution and do not meet the requirements of green chemistry. And 9-thioxanthone (3) was obtained in the process of thioxanthene (4) through carbonyl reduction, Takido, Toshio (Journal of Heterocyclic Chemistry (1995), 32 (2), 687-90.) reported the use of molybdenum trisulfide As a catalyst, it can be reduced in a hydrogen environment, but molybdenum trisulfide is expensive, and the reaction must be carried out in a hydrogen environment, which raises the requirements for the reaction equipment, which is not conducive to industrialization.

Contents of the invention

The purpose of the present invention is to disclose a kind of raw material is easy to obtain, and cost is low, and preparation route is short, and operation is simple, and the synthesis process of mesai powder hydrochloride that is easy to industrialize.

In order to achieve the above purpose, we use water as solvent to avoid the generation of organic waste liquid. The present invention uses thiosalicylic acid as a raw material to obtain 2-phenylthiobenzoic acid through coupling with iodobenzene, then dehydration and ring closure to obtain 9-thioxanthone, and then carbonyl reduction to obtain thioxanthene, and finally thia Anthracene and 3-chloromethyl-1-methylpiperidine are condensed to obtain the target product Methasan hydrochloride (5) of the following formula. The specific process is carried out in the following 4 steps

In the first step, thiosalicylic acid (1) is coupled with iodobenzene under the action of a catalyst to obtain 2-phenylthiobenzoic acid (2)

First prepare the base and the solvent _H2O to form a base solution with a molar concentration of 1.3-3.2 mol/L, cool to room temperature, add thiosalicylic acid (1) into the base solution under the protection of _N2 , and stir for 0.5-3.2 mol/L 1h, add catalyst and iodobenzene, heat up to 90℃～110℃ and react for 12-30 hours, stop heating, cool to room temperature, adjust pH value to 1 with hydrochloric acid, obtain yellow solid by suction filtration, wash and dry to obtain white solid 2 - phenylthiobenzoic acid (2);

The mol ratio of above-mentioned charging amount is thiosalicylic acid: catalyst: alkali=1: 0.01～0.2: 2～5;

Above-mentioned catalyst is cuprous bromide, cuprous iodide or cuprous chloride; Alkali is potassium hydroxide or sodium hydroxide;

In the second step, 2-phenylthiobenzoic acid (2) undergoes dehydration and ring closure to obtain 9-thioxanthone (3)

Under the protection of _N2 , mix 2-phenylthiobenzoic acid (2) with a dehydrating agent, heat to 100°C-160°C, stir and react for 5-12 hours, cool to room temperature, pour into water and filter with suction to obtain a gray-green solid. The solid was washed with water, dried, extracted twice with acetone, and the solvent was spin-dried to obtain a yellow solid 9-thioxanthone (3);

Above-mentioned dehydrating agent is concentrated sulfuric acid or polyphosphoric acid;

The mass ratio of above-mentioned charging amount is 2-phenylthiobenzoic acid: dehydrating agent=1: 5～10;

In the third step, 9-thioxanthone (3) undergoes carbonyl reduction to obtain thioxanthene (4)

First measure 9-thioxanthone: sodium borohydride or lithium aluminum hydride: aluminum chloride = 1: 1 ~ 5: 1 ~ 5 molar ratio, then under the protection of _N2 , cool the solvent to 0 ° C ~ 5 ° C Add sodium borohydride or lithium aluminum tetrahydride, keep at 0°C~5°C, then add 9-thioxanthone (3) and stir for 1 hour, then dissolve aluminum chloride in a solvent and add it slowly, until the dropwise addition is complete Afterwards, heat to 20°C to 80°C, stir for 8 hours, cool to 2°C to 5°C, slowly add 2N HCl or water dropwise to quench the reaction, filter with suction, and dry to obtain a white precipitate as thioxanthene (4);

Above-mentioned solvent is acetonitrile or ether;

The fourth step, thioxanthene (4) and 3-chloromethyl-1-methylpiperidine condensation reaction to obtain Methasan hydrochloride (5)

Dissolve thioxanthene (4) in anhydrous organic solvent under anhydrous and oxygen-free conditions, cool down to -78°C to 0°C, add organic base dropwise, keep stirring in ice-salt bath for 1 hour, add 3-chloromethyl-1 dropwise -Methylpiperidine, return to room temperature after the dropwise addition, react for 8-12h, cool in an ice bath to 0°C-5°C, slowly add saturated NH ₄ Cl solution dropwise to quench the reaction, filter with suction, wash the precipitate with an organic solvent, and the filtrate Spin dry to obtain a yellow solid-liquid mixture, dissolve the solid-liquid mixture with ethanol, add concentrated hydrochloric acid dropwise, stir for 15 minutes, add methyl tert-butyl ether, and cool in an ice bath to precipitate a large amount of white solid, which is Methasan hydrochloride (5);

Above-mentioned organic solvent is THF;

The above-mentioned organic base is n-butyllithium or lithium diisopropylamide;

The molar ratio of the above-mentioned feeding amount is thioxanthene: 3-chloromethyl-1-methylpiperidine: organic base=1:1～6:1～6.

The advantages of the present invention are as follows:

1. raw material thiosalicylic acid of the present invention and iodobenzene are purchased in the market, and source is extensive, and price is cheap, especially selects water as solvent in the process of synthesizing 2-phenylthiobenzoic acid in the first step, accords with green chemistry requirements, low cost and no pollution.

2. The synthesis route of the present invention is relatively short, the method is simple, the operation is convenient, and it has higher practical value in industrialized production

3. The catalyst used in the present invention and reductant are cheap and easy to obtain, so the production cost has been greatly reduced

Detailed ways

Example 1

Synthesis of 2-phenylthiobenzoic acid (2)

KOH (54.5 g, 972.7 mmol) and 600 ml H ₂ O were made into a solution, and cooled to room temperature. Under the protection of N ₂ , the raw material thiosalicylic acid (30 g, 389.1 mmol) was added into a 1000 ml three-necked flask, dissolved in the KOH solution prepared above and heated to 60° C. and stirred for 30 minutes, and then added with nitrous bromide under the protection of N ₂ Copper (1.675g, 11.6mmol), add iodobenzene, heat up to reflux, react for 20h, stop heating, cool the reaction solution to room temperature, add 100ml of concentrated hydrochloric acid dropwise for 30min, pH value is 1, a large amount of yellow solids are formed , obtained a yellow solid by suction filtration, washed the precipitate with 2×500ml water to obtain a white solid, and dried to obtain the target product 2-phenylthiobenzoic acid (2) 85.5g yield 95.5%

¹ HNMR (500MHz, CDCl ₃ ) 8.2～8.4(d, 1H), 7.7～7.8(t, 2H), 7.5～7.6(t, 3H), 7.3～7.4(t, 1H), 7.2～7.3(t, 1H) ), 6.7～6.8(d, 1H)

Synthesis of 9-thioxanthone (3)

Under the protection of _N2, compound 2 (65.3g, 283.5mmol) and 300ml of polyphosphoric acid were added to a 1000ml three-necked flask, heated to 150°C, stirred for 8h, and the reaction solution was cooled to room temperature, and slowly poured into a 2000ml Suction filter in water to obtain a gray-green solid, wash the solid with 1000ml, dry the solid, extract the dried solid with 2×1000ml acetone twice, spin the solvent to obtain a yellow solid, and dry to obtain 9-thioxanthone (3) 55.5g, yield 92.8%

¹ HNMR (500MHz, CDCl ₃ ) 7.4～7.5(m, 2H), 7.6～7.7(m, 4H), 8.6～8.7(m, 2H)

Synthesis of Thioxanthene (4)

Under the protection of _N2 , add 135ml of anhydrous acetonitrile into a 1000ml three-necked flask, cool in an ice bath to 0-5°C, add sodium borohydride (7.22, 190.8mmol) into the three-necked flask, keep it in an ice bath, and protect it under _N2 Next, add 9-thioxanthone (3) (27.0g, 127.2mmol) into the three-necked flask, keep stirring in an ice bath for 1h after the addition, and weigh aluminum trichloride (17.0g, 127.2mmol) in the Erlenmeyer flask Dissolve in 90ml of anhydrous acetonitrile, keep the ice bath, slowly add the acetonitrile solution of aluminum trichloride into the three-necked bottle, after the dropwise addition, remove the ice bath, heat to 40°C, stir for 8h, and cool in the ice bath When the system was brought to 0-5°C, 150ml 2N HCl was slowly added dropwise, and suction filtered to obtain a white precipitate. The precipitate was washed with 100ml 2N HCl, and dried to obtain 20.2g of the product Thioxanthene (4). The yield was 80.0%. ¹ HNMR (500MHz , CDCl ₃ ) 7.5～7.6(t, 2H) 7.3～7.4(d, 2H), 7.1～7.2(m, 4H) 3.8(s, 2H)

Synthesis of Methasan Hydrochloride (5)

Anhydrous and oxygen-free operation, compound 4 (11.3g, 56.9mol) was dissolved in 100ml of anhydrous tetrahydrofuran, and added to a 250ml three-necked flask. Cool the ice-salt bath to -10°C to 0°C, add n-butyllithium (27.5ml, 2.5M) dropwise, keep stirring in the ice-salt bath for 1h, and add 3-chloromethyl-1-methylpiperone dropwise in the ice-salt bath Pyridine (8.0 g, 54.2 mmol). Remove the ice-salt bath after the dropwise addition, return to room temperature, react for 12 hours, cool the system in an ice bath to 0-5°C, slowly add 2ml of saturated NH ₄ Cl solution dropwise to quench the reaction, filter with suction, wash the precipitate with 15ml of tetrahydrofuran, and spin the filtrate to dry A yellow solid-liquid mixture was obtained. The mixture was dissolved in 200ml of ethanol, then 10ml of concentrated hydrochloric acid was added, stirred for 15min, 500ml of methyl tert-butyl ether was added, and a large amount of white solid was precipitated by ice-bath cooling to obtain 14.4g of the compound Methiasan hydrochloride (5), with a yield of 76.8%

¹ HNMR (500MHz, CDCl ₃ ) 7.1～7.5(m, 8H), 4.1(t, 3H), 3.4(d, 1H), 3.0(d, 1h), 2.6(m, 3H), 2.4(m, 1H) ), 2.3(m, 2H), 2.1(m, 1H), 1.8(m, 2H), 1.7(m, 2H), 1.0(m, 1H)

Example 2

Synthesis of 2-phenylthiobenzoic acid (2)

KOH (54.5 g, 972.7 mmol) and 600 ml H ₂ O were made into a solution, and cooled to room temperature. Under the protection of _N2 , add the raw material thiosalicylic acid (1) (30g, 389.1mmol) into a 1000ml three-neck flask, dissolve it with the KOH solution prepared above, heat it to 60°C and stir for 30 minutes, then add it under the protection of _N2 Cuprous iodide (2.2g, 11.6mmol), add iodobenzene, heat up to reflux, react for 20h, stop heating, cool the reaction solution to room temperature, add 100ml of concentrated hydrochloric acid dropwise for 30min, the pH value is 1, and there is a large amount of A yellow solid was formed, and the yellow solid was obtained by suction filtration, and the precipitate was washed with 2×500ml of water to obtain a white solid, which was dried to obtain 85.5 g of the target product 2-phenylthiobenzoic acid (2) with a yield of 95.5%

Synthesis of 9-thioxanthone (3)

Add compound 2 (65.3g, 283.5mmol) and concentrated sulfuric acid 300ml into a 1000ml three-neck flask in turn under _N2 protection, heat to 100°C, stir for 8h, cool the reaction solution to room temperature, and slowly pour it into a 2000ml ice Suction filter the yellow solid in water, wash the solid with 1000ml, and dry the solid to obtain 50.0g of 9-thioxanthone (3), with a yield of 83.6%

Synthesis of Thioxanthene (4)

Under the protection of _N2 , add 20ml of anhydrous diethyl ether into a 50ml three-necked flask, cool in an ice bath to 0-5°C, add lithium aluminum hydride (0.6g, 17.6mmol) into a three-necked flask, keep in an ice bath, N Add compound 3 (2.5g, 11.75mmol) into a three-necked flask under the protection _{of 2} , keep stirring in an ice bath for 1h after the addition, weigh aluminum trichloride (1.6g, 11.75mmol) and dissolve it with 9ml of anhydrous ether, keep In an ice bath, slowly add the ether solution of AlCl ₃ into the three-neck flask dropwise. After the dropwise addition, remove the ice bath, heat to 40°C, stir for 8 hours, cool the system to 0-5°C in an ice bath, and slowly add dropwise 15ml of water, 15ml of 15% NaOH solution, suction filtration, the filtrate was concentrated to give a white precipitate, dried to obtain 21.5g of product thioxanthene (4), yield 85.0%

Synthesis of Methasan Hydrochloride (5)

For anhydrous and oxygen-free operation, dissolve 10.6ml of diisopropylamine in 100ml of anhydrous tetrahydrofuran and add it to a 250ml three-necked bottle. Cool down to -78°C, add n-butyllithium (68.3mmol, 27.5ml, 2.5M) dropwise, keep stirring at -78°C for 1h after dropping, and add compound Thioxanthene 4 (11.3g, 56.9mmol) into In the reaction flask, stirred for 30 minutes, and 3-chloromethyl-1-methylpiperidine (8.0 g, 54.2 mmol) was added dropwise. Return to room temperature after the dropwise addition, react for 12 hours, cool the system in an ice bath to 0-5°C, slowly add 2ml of saturated NH ₄ Cl solution dropwise to quench the reaction, filter with suction, wash the precipitate with 15ml of tetrahydrofuran, and spin the filtrate to obtain a yellow solid-liquid mixture . The mixture was dissolved in 200ml of ethanol, then 10ml of concentrated hydrochloric acid was added, stirred for 15min, 500ml of methyl tert-butyl ether was added, and a large amount of white solid was precipitated by cooling in an ice bath to obtain 15.0g of the compound Mesaisan hydrochloride (5), with a yield of 80%

¹ HNMR (500MHz, CDCl ₃ ) 7.1～7.5(m, 8H), 4.1(t, 3H), 3.4(d, 1H), 3.0(d, 1h), 2.6(m, 3H), 2.4(m, 1H) ), 2.3(m, 2H), 2.1(m, 1H), 1.8(m, 2H), 1.7(m, 2H), 1.0(m, 1H).

Claims (1)

1. a kind of synthetic method of Methiasan hydrochloride is characterized in that: carry out by following four reaction steps, The first step is to prepare 2-phenylthiobenzoic acid (2) with thiosalicylic acid (1) as raw material

First prepare the alkali solution with the solvent H ₂ O to a molar concentration of 1.3-3.2 mol/L, cool to room temperature, add thiosalicylic acid (1) into the alkali solution under the protection of N ₂ , and stir for 0.5-3.2 mol/L. 1h, add catalyst and iodobenzene, heat up to 90℃～110℃ and react for 12-30 hours, stop heating, cool to room temperature, adjust pH value to 1 with hydrochloric acid, obtain yellow solid by suction filtration, wash and dry to obtain white solid 2 -Phenylthiobenzoic acid (2); The mol ratio of above-mentioned charging amount is thiosalicylic acid: catalyst: alkali=1: 0.01～0.2: 2～5; Above-mentioned catalyst is cuprous bromide, cuprous iodide or cuprous chloride; Alkali is potassium hydroxide or sodium hydroxide; In the second step, 2-phenylthiobenzoic acid (2) undergoes dehydration and ring closure to obtain 9-thioxanthone (3)

Under the protection of _N2 , mix 2-phenylthiobenzoic acid (2) with a dehydrating agent and heat to 100°C-160°C, stir for 5-12 hours, cool to room temperature, pour into water and filter with suction to obtain a gray-green solid. The solid is washed with water, dried, extracted twice with acetone, and spin-dried to obtain a yellow solid 9-thioxanthone (3); the dehydrating agent is concentrated sulfuric acid or polyphosphoric acid; the mass ratio of the above-mentioned feeding amount is 2-phenylthiobenzoic acid : Dehydrating agent=1:5～10; In the third step, 9-thioxanthone (3) undergoes carbonyl reduction to obtain thioxanthene (4)

First measure 9-thioxanthone: sodium borohydride or lithium aluminum hydride: aluminum chloride = 1: 1 ~ 5: 1 ~ 5 molar ratio, then under the protection of _N2 , cool the solvent to 0 ° C ~ 5 ° C Add sodium borohydride or lithium aluminum tetrahydride, keep 0°C to 5°C, then add 9-thioxanthone (3), then stir for 1 hour, dissolve aluminum chloride in a solvent and slowly drop into the reaction system, After the dropwise addition, heat to 20°C to 80°C, stir for 8h, cool to 0°C to 5°C, slowly add 2N HCl or water dropwise to quench the reaction, filter with suction, and dry to obtain a white precipitate as Thioxanthene (4 ); Above-mentioned solvent is acetonitrile or ether; The fourth step, thioxanthene (4) and 3-chloromethyl-1-methylpiperidine condensation reaction to obtain Methasan hydrochloride (5) Dissolve thioxanthene (4) in anhydrous organic solvent under anhydrous and oxygen-free conditions, cool down to -78°C to 0°C, add organic base dropwise, keep stirring in ice-salt bath for 1 hour, add 3-chloromethyl-1 dropwise -Methylpiperidine, after the dropwise addition, return to room temperature, react for 8-12h, cool in an ice bath to 0°C-5°C, slowly add saturated NH ₄ Cl solution dropwise to quench the reaction, filter with suction, wash the precipitate with an organic solvent, The filtrate was spin-dried to obtain a yellow solid-liquid mixture. The solid-liquid mixture was dissolved in absolute ethanol, then concentrated hydrochloric acid was added, stirred for 15 minutes, methyl tert-butyl ether was added, and a large amount of white solid was precipitated by cooling in an ice bath, which was Methasan hydrochloride (5) ; The above-mentioned organic base is n-butyllithium or lithium diisopropylamide; The organic solvent is tetrahydrofuran The molar ratio of the above-mentioned feeding amount is thioxanthene: 3-chloromethyl-1-methylpiperidine: organic base=1:1～6:1～6.