WO2007025481A1

WO2007025481A1 - Process for preparing (s)-n-ethyl-n-methyl-3-[1-(dimethylamino) ethyl]-phenyl carbamate and tartrate thereof

Info

Publication number: WO2007025481A1
Application number: PCT/CN2006/002246
Authority: WO
Inventors: Dawei Ma; Qiangbiao Pan; Song Pan
Original assignee: Shanghai Aobo Bio-Pharmaceutical Technology Co., Ltd; Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences; Zhejiang Huahai Pharmaceutical Co., Ltd.
Priority date: 2005-09-02
Filing date: 2006-09-01
Publication date: 2007-03-08
Also published as: CN1923801A; CN100391938C

Abstract

The present invention relates to a process for preparing (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (i.e. (S)-rivastigmine) ( I ) and tartrate ( II ) thereof, which includes the following steps: reacting 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenol ( III ) or its salt with phosgene, diphosgene or triphosgene and obtaining compound ( IV ), followed by reacting with N-methyl-N-ethyl amine and obtaining the compound ( I ). The tartrate ( II ) can be obtained by reacting compound ( I ) with L-(+)-tartaric acid ( V ) . In said process, 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenol is prepared from (S)-1-phenethylamine.

Description

Process for preparing (S)-N-ethyl-N-methyl-3-"1-(dimethylamino)ethyl]-carbamic acid phenyl ester (I) and its tartrate (II)

The present invention relates to a novel synthesis of (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-carbamic acid phenyl ester (1) and its tartrate (Π) method. technical background

Alzheimer's disease (referred to as AD) is a neurological disease caused by the death of brain nerve cells. The symptoms are mainly caused by the loss of memory and cognitive ability of patients and the disorder of behavioral activities.

Rivastigmine (chemical name (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-carbamic acid phenyl ester) (I), and its tartrate ( Π ) has the following structural formula:

It is an effective drug for relieving the development of AD disease. Its mechanism of action is to inhibit acetylcholinesterase in the human brain and increase the content of acetylcholine in the central nervous system. It is suitable for patients with mild to moderate disease. The treatment can effectively improve the patient's memory with fewer side effects. The preparation method of rivastigmine (I) is as follows, but satisfactory results have not been obtained so far.

U.S. Patent No. 5,602,176 discloses a process for the preparation of racemic rivastigmine which is then salted with hydrazine, Ο'-di-p-toluoyl tartaric acid monohydrate, crystallized to give optically pure (S)-Kabala Ting.

World Patent WO 2004037771 discloses the use of m-methoxyacetophenone as a starting material to prepare racemic 3-(1-(indolyl-dimethylamino)ethyl)-phenol by a multi-step reaction. It is purified by resolution to obtain optically pure 3-(l-(S)-(,N-dimethylamino)ethyl)-phenol, which is then reacted with N-methyl-N-ethylcarbamoyl chloride. Get (S) - rivastigmine.

British Patent GB 2409453 discloses the use of m-hydroxyacetophenone as a starting material for the first reaction with N-methylethylcarbamoyl chloride, followed by conversion to racemic rivastigmine, which is then optically pure by dissection. S) - rivastigmine.

These splitting methods mean that at least 50% of the (R)-isomer is wasted, resulting in a low overall yield and a high cost. ' Summary of the invention

In order to overcome the deficiencies of the prior art, the present invention provides a novel preparation of (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-carbamic acid phenyl ester (I And a method for the tartrate salt thereof (II), which comprises the compound (IV) by using the compound (III) or a salt thereof and phosgene, diphosgene or triphosgene under a basic substance, and the compound (IV) is not purified. The compound (I) is prepared by directly reacting with N-methyl-N-ethylamine, and the compound (I) is reacted with L-(+)-tartaric acid (V) to prepare the tartrate (11). The specific reaction is as follows.

The basic substances used in the reaction are exemplified as follows: inorganic bases (such as sodium carbonate, potassium carbonate, sodium amide, sodium hydride, potassium hydride); alkali metal alcohol compounds (such as sodium methoxide, sodium ethoxide, potassium t-butoxide); Organic bases (such as triethylamine, pyridine, quinoline, diisopropylethylamine). The solvent used in the reaction is an inert solvent, such as: ether (such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane); aromatic hydrocarbons (such as benzene, toluene, xylene); halogenated hydrocarbons (such as Dichloromethane, trichloromethane, dichloroethane). The temperature of the reaction is controlled at a temperature from 0 ° C to the boiling point of the solvent. The compound ( I ) is prepared by using any inert solvent, lower alcohols (such as methanol, ethanol, propanol, butanol); ethers (such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxins); aromatic hydrocarbons (such as benzene, toluene, xylene); halogenated hydrocarbons (such as dichloromethane, chloroform, dichloroethane); dimethylformamide, dimethylacetamide; ketones, etc.

The reaction of the compound (IV) with N-methyl-N-ethylamine is preferably carried out by adding a basic substance to facilitate the progress of the reaction. Examples of the basic substance which can be added are as follows: Inorganic bases (e.g., sodium carbonate, potassium carbonate, amino group) Sodium, sodium hydride); alkali metal alcohol compounds (such as sodium methoxide, sodium ethoxide, potassium t-butoxide); organic bases (such as triethylamine, pyridine, quinoline, diisopropylethylamine). The reaction solvent is any inert solvent such as ether (such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane); aromatic hydrocarbons (such as benzene, toluene, xylene); halogenated hydrocarbons (such as dichloromethane, three Methyl chloride, dichloroethane); dimethylformamide, dimethylacetamide; acetone, and the like.

Compound (11) and L-(+)-tartaric acid (V) were prepared according to a conventional method.

In the present invention, the compound (III) or its salt hydrazine is obtained by the following reaction. method one:

Compound (3) A bismethyl group can be introduced onto the amino group by a well-known method, including formaldehyde/formic acid, dimethyl sulfate system.

Compound (4) selectively introduces a nitro group at the 3-position of the benzene ring, and the nitrification condition which can be used is a nitric acid/sulfuric acid system. In order to selectively introduce a nitro group at the 3 position of the benzene ring, the nitrification reagent added in the reaction is controlled. The amount used and the temperature at which the reaction is applied, the reaction temperature does not exceed 50 Torr, preferably does not exceed 40 ° C, and the maximum temperature controlled varies depending on the reaction system and the amount of different nitrating reagents.

The nitro group in the compound (5) can be subjected to a conventional reduction method including catalytic hydrogenation and chemical reduction.

The diazotization reaction of the compound (6), the hydrolysis can be carried out by a conventional method to obtain the compound (111), and the compound (III) can be converted into an alkali salt or an acid salt as needed.

Method Two-

Wherein R is acetyl, propionyl, benzoyl or phenylacetyl.

The compound (4) is selectively introduced into the acyl group at the 3-position of the benzene ring, and the acylation conditions may be acetyl chloride, propionyl chloride, benzoyl chloride, phenylacetyl chloride system in the presence of a Lewis acid or a protic acid, preferably B. Acyl chloride, benzoyl chloride, phenylacetyl chloride system; in order to control the selective introduction of an acyl group on the benzene ring, the acylation test used in the acylation reaction The amount of the agent is controlled to be 1 mole amount of the compound (4), and the amount of the acylating agent is preferably 1.1-10.0 moles, preferably 1.1 to 2.0 moles.

Compound (7) is reacted with Baeyer-Villar oxidant in a conventional Baeyer-Villager oxidation reaction system to prepare compound (8), including m-chloroperoxybenzoic acid, trifluoroperoxyacetic acid system.

The compound (8) is hydrolyzed or subjected to alcoholysis under basic conditions to give the compound (III) or a salt thereof, and the compound (III) can be converted into an alkali salt or an acid salt as needed.

In the above method 1 to method 2, the compound (3) may be subjected to a substitution reaction of a nitro group or an acyl group, and the obtained compound is further reacted with a conventional aminomethylating agent, wherein the acyl group may be an acetyl group, a propionyl group or a benzene group. Formyl or phenylacetyl, the resulting product is subjected to subsequent reactions.

Method three:

III

The compound (3) can be introduced into a bismethyl group by a well-known method, including a formaldehyde/formic acid, dimethyl sulfate system.

The compound (4) is introduced into the sulfonic acid group at the 3-position of the benzene ring, and the sulfonating reagent which can be used is a sulfuric acid system or a chlorosulfonic acid system. In order to control the selective introduction of a sulfonic acid group on the benzene ring, the amount of the sulfonating agent to be added to the reaction and the temperature of the reaction can be controlled.

The compound (11) is obtained by melting under a strong alkali to obtain a compound (111), and the strong base used in the reaction may be sodium hydroxide and/or potassium hydroxide. The compound (III) can be converted into an alkali salt or an acid salt as needed.

Method four:

III The compound (3) introduces a sulfonic acid group at the 3-position of the benzene ring, and the sulfonating reagent which can be used is a sulfuric acid system or a chlorosulfonic acid system. In order to control the selective introduction of a sulfonic acid group on the benzene ring, the amount of the sulfonating agent to be reacted and the temperature of the reaction are controlled.

Compound (11) is melted by a strong base to obtain compound (12), and the strong base used for the reaction may be sodium hydroxide and/or potassium hydroxide.

The amino group in the compound (12) can be introduced into the amino group by a well-known method to obtain the compound (III), including a formaldehyde/formic acid system.

The compound (III) can be converted into an alkali salt or an acid salt as needed.

The synthetic process of the invention has reasonable selection, no complicated resolution and purification, convenient source of raw materials, simple operation, convenient chemical yield, high optical purity, and an economical preparation of the compound (I) and its tartrate (Π). Methods.

The invention also provides a novel compound intermediate (5) having the following structural formula:

The invention further provides a novel compound intermediate (6) having the following structural formula:

detailed description

The contents of the present invention are further clarified by the following examples, which are not intended to limit the scope or spirit of the invention.

Example 1 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenyl chloroformate

The triphosgene (15.9 g, 53.5 mmol) was dissolved in 400 mL of tetrahydrofuran, and 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenolate was added under cooling in an ice salt bath. (25 g, 133.7 mmol), stirred at 0 ° C for 20 minutes, then heated to 55-60 ° C for 4 hours, the remaining phosgene was purged with nitrogen, filtered, and filtered to give an oily liquid (30 g). Without purification, go directly to the next step.

Example 2 Preparation of rivastigmine

The oily liquid GO g obtained in Example 1 was dissolved in 200 mL of anhydrous diethyl ether under ice-cooling, and the solution was added dropwise to triethylamine (18.7 mL), methylethylamine (7.9 g, 133.7 mmol). And a mixture of 300 mL of anhydrous ether. Stirring was continued for 20 minutes while cooling under ice water, and then allowed to react at room temperature overnight. Filtration to remove triethylamine hydrochloride The salt is washed with saturated brine (2×200 mL), dried over anhydrous sodium sulfate, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. g, two-step yield 80%).

Example 3 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenyl chloroformate

Sodium hydroxide (3.18 g, 79.5 mmol) was dissolved in 100 mL of ethanol, and 3-(l-(S)-(Ν,Ν-dimethylamino)ethyl)-phenol hydrochloride was slowly added dropwise. (8 g, 39.7 mmol) in 100 mL of ethanol, stirred at room temperature for 1 hour, concentrated and evaporated to dryness ethyl alcohol and water. The resulting solid was slowly added to a solution of triphosgene (4.7 g, 15.9 mmol) in tetrahydrofuran (120 mL), stirred at 0 ° C for 20 min, then heated to 55-60 ^Q C for 4 h. The remaining phosgene was purged with nitrogen, sodium chloride was filtered off, and concentrated to give an oily liquid (9 g). Without purification, rivastigmine can be prepared by directly reacting with methyl ethylamine (refer to Example 2 for the procedure).

Example 4 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenyl chloroformate

Absolute anhydrous pyridine (8.85 g, 110 mmol) was slowly added dropwise to a double phosgene ( 14.2 mL, 200 mmol) at 0 ° C, then 3-(l-(S)-(N,N- A solution of dimethylamino)ethyl)-phenol (16.5 g, 100 mmol) in dry diethyl ether (30 mL) was evaporated, and then stirred at 0 ° C for 1 hour, then warmed to room temperature for 8 hours. Hydrogen chloride gas and excess phosgene were removed under reduced pressure, and then 200 mL of anhydrous diethyl ether was added, filtered and concentrated to give an oily liquid (23 g). Without purification, rivastigmine can be prepared by directly reacting with methyl ethylamine (refer to Example 2 for the procedure).

Example 5 Preparation of rivastigmine tartrate

The rivastigmine (2.0 g, 8.0 mmol) and L-(+)-tartaric acid (1.2 g, 8.0 mmol) were dissolved in 5 mL of methanol, heated to 60 ° C, stirred until clear, then the solution was cooled to room temperature. Acetone (about 50 mL) was added, and the crystals were crystallized at 5 ° C overnight. The crystals were filtered, washed with acetone (2×10 mL), and dried in vacuo at 40 ° C to give white crystals of rivastigmine tartrate (2.56 g, 80%) .

Example 6 Preparation of (S)-N,N-dimethyl-1-phenylethylamine

Under ice cooling, add formic acid (129 g, 2.47 mol) in (5)-1-phenylethylamine (100 g, 0.825 mol), add formaldehyde (162 g, 2.06 mol), and then heat to reflux for 12 hours. After cooling to room temperature, 5M hydrochloric acid was adjusted to pH=2, then extracted with ml ethyl acetate (3×250 mL) to remove impurities. The aqueous phase was adjusted to pH=9-10 with 5M NaOH solution and extracted with ethyl acetate (3×400 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate and evaporated.

Example 7 Preparation of Nitro-substituted 0S)-N,N-Dimethyl-1-phenylethylamine

(5 N,N-Dimethylacetophenethylamine (30 g, 201 mmol) was dissolved in 150 mL of chloroform, added dropwise to concentrated sulfuric acid (52 mL) under ice-cooling, and the temperature of the solution was controlled at 25 ^Q C. After that, it was stirred at room temperature for 20 minutes. A mixed acid solution of concentrated nitric acid (15 mL, 221 mmol) and concentrated sulfuric acid (15 mL) was added dropwise, and the temperature was controlled at 30 to 35 ^Q C when added dropwise. about. After the completion of the dropwise addition, the reaction solution was cooled to room temperature, stirring was continued for half an hour, and then the pH was adjusted to 9-10 with a 5 N NaOH solution, followed by extraction with chloroform (3 x 200 mL), and the organic phase was combined with saturated brine. (2 x 200 mL) EtOAc (EtOAc m.)

EXAMPLES Preparation of octanitro substituted (5)-N,N-dimethyl-1-phenylethylamine

Dissolve S)-N,N-dimethyl-1-phenylethylamine (20 g, 134 mmol) in 50 mL of CHC1 ₃ and add dropwise to concentrated sulfuric acid (40 mL) with ice-water bath to keep the solution. The temperature was below room temperature and then stirred at room temperature for 20 minutes. Concentrated nitric acid (11 mL) was added dropwise, and the temperature of the solution was maintained at about 30-35^ during the dropwise addition. After the completion of the dropwise addition, the reaction system was stirred to room temperature, and the pH was adjusted to 9-10 with a 5 N NaOH solution, then extracted with chloroform (3×250 mL), and the organic phase was combined and washed with saturated brine (2 150 mL). Dry over anhydrous sodium sulfate and concentrate to give a yellow oil (23.5 g, 90%, HPLC).

Example 9 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-aniline

The yellow oil (20 g, 103 minol) obtained in Example 8 was dissolved in 100 mL of ethanol, heated to 50 ° C, and SnCl ₂ .2H ₂ 0 (76.5 g, 339 mmol) of hydrochloric acid was added dropwise (5 N, 240 mL) was added dropwise maintaining the reaction temperature during 50~60 ^Q C, after the addition was complete the reaction at 50 ^Q C for two hours. Part of the ethanol in the system was distilled off under reduced pressure, and the pH was adjusted to 9-10 with 5 N NaOH solution, then extracted with chloroform (3 200 mL). The organic phases were combined and washed with brine (2×200 mL). Drying over anhydrous sodium sulfate, EtOAc (EtOAc m.)

Example 10 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol

17 mL of concentrated H ₂ S0 _{4 was} dissolved in 50 mL of water, and 3-(l-(S)-(N,N-dimethylamino)ethyl)-aniline (8.1 g, 49.39 mmol) was added under ice-cooling. ), keep the temperature below 25 ^Q C during the dropwise addition, and continue to stir at room temperature for 30 minutes after the addition. Then, the reaction system was cooled with an ice salt bath, and a 20 mL aqueous solution of sodium nitrite (3.9 g, 56.5 mmol) was added dropwise. The temperature of the reaction system was kept below 5 ^Q C when added dropwise, and after cooling, it was cooled in an ice salt bath. Stirring was continued for 1 hour to obtain a pale yellow diazonium salt solution. Next, the pale yellow diazonium salt solution is added dropwise to a mixed solution of 120 mL of concentrated sulfuric acid and 15 mL of water at a temperature of 120-125 ^G C. After the dropwise addition is completed, the mixture is cooled to room temperature, and 5 N is used. The NaOH solution was neutralized to a pH of 9-10, extracted with ethyl acetate (2 100 mL), washed with saturated brine (2×50 mL), evaporated and evaporated. 3-(l-(S)-(N,N-Dimethylamino)ethyl)-phenol (6.53 g, 80%).

Example 11 Preparation of 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenol hydrochloride

The ethyl acetate extract obtained in Example 10 was added to 1 N hydrochloric acid (100 mL), and stirred at room temperature for half an hour. The aqueous layer was separated and the organic layer was washed with EtOAc EtOAc (EtOAc) Phenol hydrochloride (8.0 g, 80%).

Example 12 Preparation of 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenol sodium

Sodium (0.92 g, 40 mmol) was weighed and dissolved in 100 mL of absolute absolute ethanol, followed by the addition of 3-(l-(S)-(N,N-dimethylamino)ethyl group obtained in Example 10. -Phenol (6.58 g, 39.9 mmol), stirred at room temperature for half an hour, and concentrated to give 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol sodium (7.45 g, 100) %).

Example 13 Preparation of Nitro-Substituted Phenylethylamine

Weigh 0S)-1-phenylethylamine 20 g (165 mmol) dissolved in 50 mL of CHC1 ₃ , cooled in an ice water bath, added dropwise to 35 mL of concentrated sulfuric acid, and kept at a temperature below 25 ^Q C when dropped. After stirring at room temperature for 20 minutes. The mixed acid prepared by adding 13.5 mL of concentrated HN0 ₃ (d = 1.4) and 13.5 mL of concentrated sulfuric acid was added, and the temperature was controlled to be about 30 to 35 ^Q C during the dropwise addition. After the completion of the dropwise addition, the reaction solution was cooled to room temperature, stirring was continued for half an hour, and then the pH was adjusted to 9-10 with a 5 N NaOH solution, followed by extraction with chloroform (3 x 200 niL), and the organic phase was combined with saturated brine. (2 x 200 mL), EtOAc (EtOAc m.)

Example Fourteen Preparation of Nitro-substituted (S)-N,N-Dimethyl-1-phenylethylamine

The yellow oil obtained in Example 13 (13.3 g, 80 mmol) was weighed, and then cooled with ice-water bath, and then, formic acid (12.6 g, 240 mmol) and formaldehyde 15.7 g (200 mmol) were added, and the mixture was heated under reflux for 12 hours and cooled to At room temperature, adjust to pH 2-3 with 5N hydrochloric acid, extract with ethyl acetate (3 100 mL) to remove impurities, and adjust the aqueous phase to pH 9-10 with 5 N NaOH solution. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

Preparation of the acetylation product of the fifteenth (<S)-N,N-dimethyl-1-phenylethylamine

A 250 mL round bottom flask equipped with a condenser and a nitrogen inlet was charged with aluminum trichloride (30.7 g, 230 mmol), carbon disulfide (150 mL) and acetyl chloride (3.8 mL, 48 mmol). -N,N-Dimethyl-1-phenylethylamine (5.5 g, 37 mmol) was added portionwise to this mixture (about 15 min), then the mixture was stirred for 10 min then refluxed for two hours. The reaction was cooled, added to ice and stirred well. The system was neutralized with a 5 N aqueous NaOH solution to pH 12, extracted with chloroform (3 x 200 mL), and the organic phase was combined with saturated brine (2×100 mL) Washed, dried over anhydrous sodium sulfate to give acetylated product (5.66 g, 80%)

Example 16 Preparation of benzoylated product of 0S)-N,N-dimethyl-1-phenylethylamine

In a 250 mL round bottom flask equipped with a condenser and a nitrogen inlet, add aluminum trichloride (15.4 g, 115 mmol), carbon disulfide (75 mL) and benzoyl chloride (2.1 mL, 24 mmol) in 15 min. Will (-N,N-dimethyl-1- Phenylethylamine (2.7 g, 18 mmol) was added portionwise to the stirred mixture and the mixture was stirred for 10 min then refluxed for two hours. The reaction was cooled, added to ice and stirred well. The system was neutralized with a 5 N aqueous solution of NaOH to pH 12, extracted with chloroform (3 x 200 mL), and the organic phase was combined with saturated brine (2×100 mL) The mixture was washed with anhydrous sodium sulfate and dried to give the product of the product (3.4 g, 75%).

Example 17 Baeyer-Villager oxidation of the acetylated product of 0S)-N,N-dimethyl-1-phenylethylamine

The acetylation product of (S)-N,N-dimethyl-1-phenylethylamine obtained in Example 16 (6 g, 31.4 mmol) was dissolved in dichloromethane (400 mL), and phosphoric acid was added. Sodium dihydrogen (4.46 g, 31.4 mmol) was added to m-chloroperoxybenzoic acid (29.5 g, 55%, 94.2 mmol), and the mixture was stirred at 0 ° C for 12 hours. Then a saturated Na ₂ SO ₃ solution (100 mL) was added and stirred at room temperature for 5 hours. The pH was adjusted to 9 with saturated sodium bicarbonate, and extracted with chloroform (3×200 mL). The organic phase was combined, washed with saturated brine (2×200 mL), dried over anhydrous sodium sulfate, and concentrated. A mixture of 1,2 and 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenylacetate (5.2 g, 80%) was obtained.

Baeyer-Villager oxidation of the benzoylation product of the eighteen (S)-N,N-dimethyl-1-phenylethylamine

(S)-N,N-Dimethyl-1-phenylethylamine benzoylation product (10.6 g, 41.8 mmol) was dissolved in dichloromethane (500 mL) and sodium dihydrogen phosphate (5.94 g, 41.8 Methanol), with ice-water bath cooling, add m-chloroperoxybenzoic acid (39.3 g, 55%, 125.4 mmol), stir at 0 ° C overnight, then add saturated Na ₂ SO ₃ solution (120 mL) and stir at room temperature for 5 hours . The pH was adjusted to 9 with saturated sodium bicarbonate, and extracted with chloroform (3×300 mL). The organic phase was combined, washed with saturated brine (2×200 mL), dried over anhydrous sodium sulfate 2 and 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenylbenzoate mixture (5.51 g, 49%)

Example 19 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol

The mixture of 1,2 and 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenylacetate obtained in Example 17 (5 g, 24.7 mmol) was weighed. Dissolved in tetrahydrofuran (100 mL), then a solution of NaOH (1.48 g, 37 mmol) in water (10 mL). Was stirred at room temperature for 3 hours and then treated with saturated NaHC0 ₃ solution was adjusted to pH 9, extracted with ethyl acetate (3x150 mL), the organic phases were combined, saturated brine (2x150 mL), dried over anhydrous sodium sulfate, concentrated and column chromatography Isolated to give 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol (2.03 g, 51%).

Example Twenty-three (1-(S)-(N,N-dimethylamino)ethyl)-phenol preparation

The mixture of 1,2 and 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenylbenzoate obtained in Example 18 (7 g, 26 mmol) was weighed. ), dissolved in tetrahydrofuran (100 mL), then a solution of NaOH (1.48 g, 37 mmol) in water (10 mL). Was stirred at room temperature for 3 hours and then treated with saturated NaHC0 ₃ solution was adjusted to pH 9, extracted with ethyl acetate (3x150 mL), the organic phases were combined, saturated brine (2x150 mL), dried over anhydrous sodium sulfate, concentrated and column chromatography Separation gave 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol (2.10 g, 49%). Example sulfonation of twenty-one (5)-N,N-dimethyl-1-phenylethylamine

Weigh out (5 N,N-dimethyl phenethylamine (23 g, 154 mmol) in 150 mL of chloroform, and add chlorosulfonic acid (30.8 mL, 462 mmol) at room temperature. The reaction is exothermic and the temperature is very high. Rise to 60 ° C, add in 20 minutes, and naturally cool to room temperature. Pour the reaction into ice (300 g), gradually warm to 100 ° C for 1 hour, cool to room temperature, use 5 N NaOH The solution was adjusted to pH 12, the water in the system was spun off, and then extracted with ethanol (500 mL). After hot filtration, the obtained mother liquid was concentrated to give an off-white solid 1, 2 and 3-(S)-N, N- Mixture of sodium dimethyl-1-phenylethyl sulfonate (30.9 g, 80%).

Example 22 Sulfonation of (S)-N,N-Dimethyl-1-phenylethylamine

Weigh (5}-N,N-dimethylacetophenethylamine (20 g, 134 mmol) in 150 mL of chloroform, pass HC1 gas to all salt, evaporate the solvent, and dry in the infrared to obtain a white solid. (S)-N,N-Dimethyl-1-phenylethylamine hydrochloride (24.9 _g , 134 mmol).

The chlorosulfonic acid (13.4 mL, 201 mmol) was heated to 140 ° C, and the above-obtained (S-N,W-dimethyl-1-phenylethylamine hydrochloride was added thereto at 140 ° C after the addition was completed. After one hour of reaction, naturally cool to room temperature, pour the reaction solution into ice (300 g), then gradually heat up to 100 ° C for 1 hour, adjust the pH to 12 with 5 N NaOH solution, and reduce the water in the system. Concentrated by pressure, then dissolved in hot ethanol (500 mL), and concentrated to give a white solid. 1,2 and 3-(S)-N,N-dimethyl-1-phenylethylamine Mixture of sodium (30.30 g, 90%)

Example Twenty-three (5)-sulfonation of N,N-dimethyl-phenethylamine

Concentrated sulfuric acid (50 g, 500 mmol) was heated to 180 ^D C, (5)-N,N-dimethyl-1-phenylethylamine (14.9 g, 100 mmol) was added, and the reaction mixture was reacted at 180 ° C. Hour, naturally cool to room temperature. The reaction solution was poured into ice (200 g), and the pH was adjusted to 12 with a 5 N NaOH solution. The water in the system was concentrated under reduced pressure and then dissolved in hot ethanol (350 mL). Concentration gave a mixture of 1,2 and 3-(<S)-N,N-dimethyl-1-phenylethylamine sulfonate (21.6 g, 86%).

Example 24 (sulfonation of 5-1-phenethylamine)

(S) Small phenethylamine (12.1 g, 100 mmol) was dissolved in 150 mL of chloroform, and chlorosulfonic acid (20.0 mL, 300 mmol) was added dropwise at room temperature. The reaction was exothermic and the temperature rose rapidly to 60 °C. After 20 minutes, the mixture was cooled and allowed to cool to room temperature. The reaction solution was poured into ice (150 g), gradually heated to 100 ° C for 1 hour, cooled to room temperature, adjusted to pH 12 with 5 N NaOH solution, the water in the system was concentrated under reduced pressure, and then It was extracted with hot ethanol GOO mL), and the resulting mother liquid was concentrated by hot filtration to give a mixture (20.5 g, 92%) of an off-white solid 1,2 and sodium 3-(5)-1-phenylethylamine.

Example Twenty-five (S)-l-Phenylethylamine Sulfonation

Weigh (S)-l-phenethylamine (24.2 g, 200 mmol) in 150 mL of chloroform, and pass HC1 gas to all The salt was evaporated in vacuo to give a white solid ("S)-1-phenylethylamine hydrochloride (31.5 g, 200 mmol). The chlorosulfonic acid (40.0 mL, 600 mmol) was heated to 140 ° C, and the above-obtained (5)-1-phenylethylamine hydrochloride was added. After the addition was completed, the mixture was reacted at 140 ° C for one hour, and then naturally cooled to room temperature. The reaction solution was poured into ice (350 g), then gradually heated to 100 ° C for 1 hour, adjusted to pH 12 with 5 N NaOH solution, and the water in the system was concentrated under reduced pressure, then hot ethanol ( After extraction with 500 mL), the obtained mother liquid was concentrated to give a white solid (1,2) and a mixture of sodium acetophenone sulfonate (41.1 g, 92%).

Example Twenty-six Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol

a mixture of 1,2 and 3-0S)-N,N-dimethyl-1-phenylethylamine sulfonate obtained in Examples 21, 22 and 23 (25.1 g, 100 mmol) Dissolve with NaOH (40 g, 1 mol) in a small amount of water (70 mL), heat to 120 °C, evaporate the water, continue to warm to 280 °C, the system enters a molten state, continue the reaction for 5 minutes, stop heating, and naturally cool To the room temperature, add water (200 mL), adjust the pH to 9 with 6 N hydrochloric acid solution, then extract with ethyl acetate (3 χ 200 mL), and then wash the organic phase and wash with saturated brine (2×200 mL). The aqueous sodium sulfate was dried (MgSO4), evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Example 27 Preparation of 3-(l-(S)-aminoethyl)-phenol

The sodium 1,2 and 3-0SH-phenylethyl sulfonate (22.3 g, 100 mmol) and NaOH (40 g, 1 mol) obtained in Examples 24 and 25 were dissolved in a small amount of water (70 mL). ), heated to 120 ° C, evaporated to dryness, and then continued to warm to 280 ° C, the system into a molten state, continue to react for 5 minutes, stop heating, naturally cooled to room temperature, add water (200 mL), adjust with 6 N hydrochloric acid solution The mixture was extracted with ethyl acetate (3×200 mL). The organic phase was combined, washed with saturated brine (2200 mL), dried over anhydrous sodium sulfate, and concentrated. -(S)-Aminoethyl)-phenol (7.54 g, 55%).

Example 28 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol

The 3-(l-(S)-aminoethyl)-phenol (11.0 g, 80 mmol) obtained in Example 27 was weighed, and the formic acid ( 12.6 g, 240 mmol) and formaldehyde were added under ice-cooling. 15.7 g (200 mmol), heated under reflux for 12 hours, cooled to room temperature, adjusted to pH 2-3 with 5N hydrochloric acid, extracted with ethyl acetate G x 100 mL), and the aqueous phase was adjusted with 5 N NaOH solution. The mixture was extracted with ethyl acetate (3×200 mL). The organic layer was combined and washed with brine (2×500 mL). 1-(S)-(N,N-Dimethylamino)ethyl)-phenol (10.4 g, 79%).

Example 29 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol hydrochloride

25.5 mL of concentrated H ₂ S0 _{4 was} dissolved in 75 mL of water, and 3-(l-(S)-(N,N-dimethylamino)ethyl)-aniline (12.15 g, 74 mmol) was added under ice-cooling. ), keep the temperature at 25 when dropping. Below C, continue to stir at room temperature after the addition 30 minutes. Then, the reaction system was cooled with an ice salt bath, and a 30 mL aqueous solution of sodium nitrite (5.85 g, 84.75 mmol) was added dropwise, and the temperature of the reaction system was kept below 5 ^Q C when added dropwise, and after cooling, it was cooled in an ice salt bath. Stirring was continued for 1 hour to obtain a pale yellow diazonium salt solution. Subsequently, the pale yellow diazonium salt solution was added dropwise to 120 ^Q C in 30 mL of concentrated sulfuric acid and a mixed solution of 15 mL of water, controlling the temperature at 120-125 ^Q C, after the addition was complete, cooled to room temperature, 5 N NaOH solution was neutralized to a pH of 9-10, extracted with chloroform (3 x 200 mL), and the organic phases were combined, washed with saturated brine (2×200 mL), dried over anhydrous sodium sulfate Concentrate to about 200 mL in vacuo and pass HC1 gas for 30 minutes. Concentration gave 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol hydrochloride (12.7 g, 85%).

Claims

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1, S)-N-

Preparation method,

a compound of (III) or a salt thereof and a phosgene, a diphosgene or a triphosgene acting on a basic substance

(IV), Compound (IV) is directly reacted with N-methyl-N-ethylamine without purification to prepare Compound (I).

2. The method according to claim 1, wherein the compound of the formula (III) or a salt thereof is obtained by the following reaction _: a. starting material compound (3)

Reaction with an aminomethylation reagent to obtain a compound (4) b. The compound (4) is reacted with a nitrating reagent to obtain a compound (5) c compound (5) which is reacted with a reducing reagent to obtain a compound (6)

d. Compound (6) is subjected to diazotization reaction under acidic conditions with nitrite, followed by hydrolysis to give compound (III); e. Compound (III) is converted to the corresponding base salt or acid salt as needed.

The method according to claim 1, wherein the compound of the formula (III) or a salt thereof is obtained by the following reaction: a. the compound (3) is reacted under aminomethylation conditions to prepare a compound (4);

b. Compound (4) is reacted with an acylating reagent in the presence of a Lewis acid or a protic acid to prepare a compound (7)

Wherein R is acetyl, propionyl, benzoyl or phenylacetyl; c. Compound (7) is oxidized by Baeyer-Villager to prepare compound (8)

Wherein R is acetyl, propionyl, benzoyl or phenylacetyl;

d. Compound (8) is hydrolyzed to give a compound (ΠΙ);

e. Conversion of compound (III) to the corresponding base salt or acid salt, as needed.

4. The method according to claim 1, wherein the compound (III) or a salt thereof is subjected to the following reaction, a compound (3) is reacted under ammonia methylation conditions to obtain a compound (4);

b. Compound (4) is reacted with a sulfonating reagent to obtain a compound (9) c compound (9) which is alkalized by sodium hydroxide and/or potassium hydroxide.

Melting compound (III)

d. Conversion of compound (III) to the corresponding base salt or acid salt, as needed.

The method according to claim 1, wherein the compound (III) or a salt thereof is subjected to the following reaction: a. the compound (3) is reacted with a sulfonating reagent to obtain a compound (11) b. the compound (11) is hydrogen. Alkali in the presence of sodium oxide and/or potassium hydroxide

Melting compound (12) c. Compound (12) is reacted under aminomethylation conditions to obtain compound (III)

The method according to claim 2 or 3, wherein the compound (3) is first introduced into a nitro group by introducing a nitrating reagent into a nitro group or an acylating reagent, and the resulting product is further reacted with an aminomethylating reagent, wherein the acyl group is acetyl. Base, propionyl, benzoyl or phenylacetyl.

7. The method of claim 1 wherein said basic material is selected from the group consisting of sodium carbonate, potassium carbonate, sodium amide, sodium hydride, potassium hydride; and sodium methoxide, sodium ethoxide, potassium t-butoxide An alkali metal alcohol compound; and an organic base comprising triethylamine, pyridine, quinoline, diisopropylethylamine.

8. The method according to claim 1, wherein the reaction for preparing the compound (I) from the compound (IV) is carried out in a basic substance selected from the group consisting of sodium carbonate, potassium carbonate, sodium amide, sodium hydride Inorganic bases; alkali metal alcohol compounds including sodium methoxide, sodium ethoxide, potassium t-butoxide; and organic bases including triethylamine, pyridine, quinoline, diisopropylethylamine.

The method according to claim 1, wherein the reaction for preparing the compound (IV) from the compound (III) is carried out in an inert solvent selected from the group consisting of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and dioxane. Ethers, including benzenes of benzene, toluene, xylene; and acetone; the reaction for preparing compound (I) from compound (IV) is carried out in an inert solvent selected from the group consisting of methanol, ethanol, propanol, Lower alcohol of butanol; ethers including tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxins; benzenes including benzene, toluene, ethylbenzene; halogens of dichloromethane, chloroform, dichloroethane Hydrocarbons; dimethylformamide; dimethylacetamide; and acetone.

A process for producing a tartrate (II) of the compound (I), which is prepared by reacting the compound (I) with L-(+)-tartaric acid (V).

11. A compound of the following formula (5)

12. A compound of the following formula (6)