CN1314658C - Process for preparing optically pure N-methyl-3-phenyl-3-hydoxypropylamine - Google Patents

Abstract

The present invention relates to a preparation method of optically pure N-methyl-3-phenyl-3-hydroxy propylamine, which comprises the steps that racemate of N-methyl-3-phenyl-3-hydroxy propylamine is converted into the diastereomer salt by optically pure dibenzoyl tartaric acid, or bromocamphoric acid or hydroxyphenyl glycine; the diastereomer salt is separation; after acidification, organic acid is dissociated out to prepare optically pure S-(-)-or R-(+)-N-methyl-3-phenyl-3-hydroxy propylamine. The present invention has the advantages of short resolution period, high efficiency, simplicity and easy operation of a technology and recovered use of a resolution agent.

Description

Preparation method of optically pure N-methyl-3-phenyl-3-hydroxypropylamine

technical field

The invention relates to a preparation method of optically pure N-methyl-3-phenyl-3-hydroxypropylamine.

Background technique

N-methyl-3-phenyl-3-hydroxypropylamine is a light yellow crystalline powder, insoluble in water, easily soluble in methanol, chloroform, or n-hexane. The melting point is 60-61°C.

N-methyl-3-phenyl-3-hydroxypropylamine is an intermediate of a bicyclic antidepressant drug fluoxetine newly listed in the United States. Fluoxetine is different from tricyclic antidepressants in terms of structure and pharmacological effects. Fluoxetine and its metabolite norfluoxetine are selective and competitive to neurotransmitters, and jointly inhibit the reabsorption of 5-hydroxytryptamine by nerve cells, and have few other pharmacological effects, so they have fewer side effects and have become Promising antidepressant drug.

Fluoxetine has two types of isomers, R and S, which can be obtained through the corresponding intermediate R-(+)-N-methyl-3-phenyl-3-hydroxypropylamine or S(-)-N-methyl -3-phenyl-3-hydroxypropylamine to synthesize. According to research, some patients have side effects such as anxiety and talking to themselves after taking fluoxetine. R (+) fluoxetine or S (-) fluoxetine alone can effectively treat migraine, chronic pain, and obsessive-compulsive confusion. Reduce the side effects caused by taking fluoxetine. Therefore, it is very important to asymmetrically synthesize optically pure fluoxetine or resolve slurred fluoxetine.

Contents of the invention

The problem to be solved by the present invention is to provide a preparation method of optically pure N-methyl-3-phenyl-3-hydroxypropylamine, which can make N-methyl-3-phenyl-3-hydroxypropylamine The racemate was resolved into S(-)-N-methyl-3-phenyl-3-hydroxypropylamine or R-(+)-N-methyl-3-phenyl-3-hydroxypropylamine.

The technical scheme provided by the invention is: the preparation method of optically pure N-methyl-3-phenyl-3-hydroxypropylamine, which method comprises the racemization of N-methyl-3-phenyl-3-hydroxypropylamine The substance is converted with optically pure dibenzoyl tartaric acid or bromocamphoric acid or hydroxyphenylglycine to become the diastereomeric salt, the salt is separated, and the organic acid is freed after acidification to obtain optically pure S- (-)- or R-(+)-N-methyl-3-phenyl-3-hydroxypropylamine.

The above resolution is carried out in a mixed solvent of polarity and nonpolarity.

The above non-polar components are aliphatic, cycloaliphatic or aromatic hydrocarbon solvents, and the polar components are lower aliphatic alcohols, aliphatic amines or alcohol amine solvents.

The content ratio of the non-polar component and the polar component in the above mixed solvent is 1:0.01-5 (volume ratio).

The use of the above-mentioned racemic dibenzoyltartaric acid leads to the formation of diastereomeric salts which differ considerably in their solubility in organic solvents. It is then possible to separate the enantiomers, for example by crystallization. Usually a non-polar solvent is used and a part of the polar solvent may be added thereto. These non-polar solvents can be aliphatic, cycloaliphatic and aromatic hydrocarbons, such as petroleum ether fractions (boiling range: 60-90 ° C), cyclohexane, etc., and the polar component is preferably a Lower aliphatic alcohols, aliphatic amines. These alcohols and amines may be methanol, ethanol, isopropanol, trimethylamine, triethylamine, tripropylamine, tri-n-butylamine, various alcohol amines, and the like. Therefore, suitable mixed solvents include, for example, cyclohexane-ethanol, petroleum ether-isopropanol, benzene-tri-n-butylamine and the like.

The resolution of fluoxetine intermediate N-methyl-3-phenyl-3-hydroxypropylamine mainly has the following advantages:

(1) The inventive method uses non-racemic body dibenzoyl tartaric acid as resolving agent, splits N-methyl-3-phenyl-3-hydroxyl propylamine and directly obtains single enantiomer salt, through a Enantiomer salts with high optical purity can be obtained by secondary crystallization. The splitting efficiency is high, and the process is simple and easy.

(2) The solvent system used in the inventive method is suitable for the formation of enantiomeric salts, the formation of crystallization speed is fast, and the yield is high (40.98%), which greatly improves the resolution rate and shortens the cycle. Generally, the resolution cycle is 5 - 7 hours to complete.

(3) The para of N-methyl-3-phenyl-3-hydroxypropylamine obtained after separating the precipitated salt of the optical enantiomer and non-racemic dibenzoyl tartaric acid in the process of the present invention The enantiomeric solution is racemized again and the solution is recycled to the process.

(4) The chiral resolving agent non-racemic dibenzoyl tartaric acid after separating the optically active enantiomer N-methyl-3-phenyl-3-hydroxypropylamine in the process of the present invention is recycled again During the splitting process, the splitting agent can be recycled.

(5) After separating the enantiomeric salt formed by the chiral resolving agent non-racemic dibenzoyl tartaric acid and the enantiomer N-methyl-3-phenyl-3-hydroxyl propylamine in the process of the inventive method Solvents (including non-polar solvents and polar solvents) are recycled to the resolution process.

(6) all raw materials (comprising racemate N-methyl-3-phenyl-3-hydroxyl propylamine, resolving agent and solvent) used of the inventive method are based on domestic completely, have reduced production cost, increased Product market competitiveness.

Detailed ways

The separation of the racemic mixture of N-methyl-3-phenyl-3-hydroxypropylamine is detailed below

Suspend racemic N-methyl-3-phenyl-3-hydroxypropylamine (166 g, 1 mole) with resolving agents dibenzoyl tartaric acid, bromocamphoric acid, hydroxyphenylglycine (0.1-1 mole) In a mixed solvent of 300-1000 ml of non-polar solvent and partial polar solvent (ratio 1-10:0.1-5), the suspension is heated to reflux for 0.5-5 hours. The solution is cooled to about 20-25°C (room temperature) with or without stirring, the precipitated crystals are filtered and dried.

The crystal of the salt is recrystallized with alcohol, then the salt is suspended in water/ethyl acetate/concentrated sulfuric acid, stirred for 2 hrs, the water phase is evaporated to dryness, and the resolving agent is recovered, and its optical purity is 95-99%. The organic phase was evaporated to dryness to afford R(+)-N-methyl-3-phenyl-3-hydroxypropylamine.

The mother liquor from the first precipitation of the diastereomeric salt is combined with the mother liquor from the recrystallization of the salt, and the solvent mixture is removed (for example, by vacuum distillation or steam distillation). The obtained oily residue was stirred with water/ethyl acetate/concentrated sulfuric acid for 2 hrs, the water phase was evaporated to dryness, and the resolving agent was recovered, and its optical purity was 95-99%. The organic phase was evaporated to dryness to give S(-)-N-methyl-3-phenyl-3-hydroxypropylamine.

Example 1:

Weigh 3g of N-methyl-3-phenyl-3-hydroxypropylamine and 3.27g of dibenzoyl-L-tartaric acid into a 100ml round bottom flask, add 10ml of methanol and stir at room temperature. The crystals gradually dissolved and the solution became transparent. Acetone was added until the solution just became cloudy, and a small amount of methanol was added until the solution became clear again. Stir for two days, filter, and dry under an infrared lamp to obtain 3.07 g of white powdery crystals-2,3-dibenzoyl-L-tartaric acid-bis[methyl(1R-1-phenyl-1-hydroxy)propyl ] Ammonium salt. The resolution yield is 48.99%. Optical rotation: -46.0 (C=1, CH ₃ OH).

Weigh 3g of 2,3-dibenzoyl-L-tartaric acid-bis[methyl(1R-1-phenyl-1-hydroxy)propyl]ammonium salt into a 100ml round bottom flask, add 3ml of water , 6ml of ethyl acetate, 0.5ml of concentrated sulfuric acid, stirred for 2hr. Then transfer to a separatory funnel. The upper organic phase was evaporated to dryness to obtain dibenzoyl-L-tartaric acid. 0.28 g of calcium oxide and 0.1 g of calcium carbonate were added to the lower aqueous phase, and stirred for 4 hr until pH = 7-8. The calcium sulfate precipitate was removed by filtration, and the mother liquor was evaporated to dryness to obtain optically pure R-(+)-N-methyl-3-phenyl-3-hydroxypropylamine, a colorless viscous liquid. Optical rotation: +37.64 (C=1, chloroform)

The remaining mother liquor of the primary crystallization was evaporated to dryness to obtain a colorless viscous liquid. Put into a 100ml round bottom flask, add 3ml of water, 6ml of ethyl acetate, and 0.5ml of concentrated sulfuric acid in sequence, and stir for 2hr. Then transfer to a separatory funnel. The upper organic phase was evaporated to dryness to obtain dibenzoyl-S,S-tartaric acid. 0.28 g of calcium oxide and 0.1 g of calcium carbonate were added to the lower aqueous phase, and stirred for 4 hr until pH = 6-7. The calcium sulfate precipitate was removed by filtration, and the filtrate was evaporated to dryness to obtain 1.02 g of optically pure S-(-)-N-methyl-3-phenyl-3-hydroxypropylamine, a colorless viscous liquid. Optical rotation: -37.64 (C=1, chloroform).

Example 2:

Weigh 3g of N-methyl-3-phenyl-3-hydroxypropylamine and 3.27g of bromocamphoric acid into a 100ml round bottom flask, add 10ml of methanol and stir at room temperature. The crystals gradually dissolved and the solution became transparent. Add acetone until the solution just becomes cloudy, then add a small amount of methanol until the solution becomes clear again. Stir for two days, filter, and dry with an infrared lamp to obtain 2.57 g of white powdery crystals. The resolution yield is 40.98%. Optical rotation: -44.6 (C=1, CH ₃ OH).

Recrystallize the above-mentioned salt crystals with alcohol, then weigh 3g of the salt and put it into a 100ml round bottom flask, add 3ml of water, 6ml of ethyl acetate, and 0.5ml of concentrated sulfuric acid, and stir for 2hr. Then transfer to a separatory funnel. The upper organic phase was evaporated to dryness to obtain bromocamphoric acid. 0.28 g of calcium oxide and 0.1 g of calcium carbonate were added to the lower aqueous phase, and stirred for 4 hr until pH = 7-8. The calcium sulfate precipitate was removed by filtration, and the mother liquor was evaporated to dryness to obtain optically pure R-(+)-N-methyl-3-phenyl-3-hydroxypropylamine as a colorless viscous liquid. Optical rotation: +37.37 (C=1, chloroform)

The remaining mother liquor from the primary crystallization was combined with the mother liquor obtained from the recrystallization of the salt, and the solvent was evaporated to obtain a colorless viscous liquid. Put into a 100ml round bottom flask, add 3ml of water, 6ml of ethyl acetate, and 0.5ml of concentrated sulfuric acid in sequence, and stir for 2hr. Then transfer to a separatory funnel. The upper organic phase was evaporated to dryness to obtain bromocamphoric acid. 0.28 g of calcium oxide and 0.1 g of calcium carbonate were added to the lower aqueous phase, and stirred for 4 hr until pH = 6-7. The calcium sulfate precipitate was removed by filtration, and the filtrate was evaporated to dryness to obtain 1.10 g of optically pure S-(-)-N-methyl-3-phenyl-3-hydroxypropylamine, a colorless viscous liquid. Optical rotation: -37.37 (C=1, chloroform).

Example 3:

Weigh 3g of N-methyl-3-phenyl-3-hydroxypropylamine and 3.27g of hydroxyphenylglycine into a 100ml round bottom flask, add 10ml of methanol and stir at room temperature. The crystals gradually dissolved and the solution became transparent. Add acetone until the solution just becomes cloudy, then add a small amount of methanol until the solution becomes clear again. Stir for two days, filter, and dry with an infrared lamp to obtain 2.29 g of white powdery crystals. The resolution yield is 36.5%. Optical rotation: -42.1 (C=1, CH ₃ OH).

Weigh 3g of salt into a 100ml round bottom flask, add 3ml of water, 6ml of ethyl acetate, 0.5ml of concentrated sulfuric acid, and stir for 2hr. Then transfer to a separatory funnel. The upper organic phase was evaporated to dryness to obtain hydroxyphenylglycine. 0.28 g of calcium oxide and 0.1 g of calcium carbonate were added to the lower aqueous phase, and stirred for 4 hr until pH = 7-8. The calcium sulfate precipitate was removed by filtration, and the mother liquor was evaporated to dryness to obtain R-(+)-N-methyl-3-phenyl-3-hydroxypropylamine as a colorless viscous liquid. Optical rotation: +36.68 (C=1, chloroform).

The remaining mother liquor of the primary crystallization was evaporated to dryness to obtain a colorless viscous liquid. Put into a 100ml round bottom flask, add 3ml of water, 6ml of ethyl acetate, and 0.5ml of concentrated sulfuric acid in sequence, and stir for 2hr. Then transfer to a separatory funnel. The upper organic phase was evaporated to dryness to obtain hydroxyphenylglycine. 0.28 g of calcium oxide and 0.1 g of calcium carbonate were added to the lower aqueous phase, and stirred for 4 hr until pH = 6-7. The calcium sulfate precipitate was removed by filtration, and the filtrate was evaporated to dryness to obtain 1.18 g of optically pure S-(-)-N-methyl-3-phenyl-3-hydroxypropylamine, a colorless viscous liquid. Optical rotation: -36,68 (C=1, chloroform).

The polar solvent methyl alcohol in the foregoing embodiment can be replaced with ethanol, Virahol, trimethylamine, triethylamine, tripropylamine, tri-n-butylamine, and various alcohol amines etc.; Nonpolar solvent acetone can be replaced with aliphatic, cycloaliphatic and aromatic hydrocarbons etc. instead.

Claims (4)

1. the preparation method of optically pure N-methyl-3-phenyl-3-hydroxyl propylamine, the method comprises the racemate of N-methyl-3-phenyl-3-hydroxyl propylamine with optically pure di Benzoyl tartaric acid is transformed into the diastereomeric salt, the salt is separated, and the organic acid is freed after acidification to obtain optically pure S-(-)- or R-(+)-N-methyl -3-phenyl-3-hydroxypropylamine; the above resolution was carried out in a mixed solvent of methanol and acetone. 2. The method according to claim 1, characterized in that: the N-methyl-3-benzene obtained after separating the precipitated salt of the optical enantiomer and the non-racemic dibenzoyl tartaric acid The enantiomeric solution of yl-3-hydroxypropylamine is again racemized and this solution is recycled to the process. 3. The method according to claim 1, characterized in that: the chiral resolving agent non-racemate after separating the optically active enantiomer N-methyl-3-phenyl-3-hydroxypropylamine Dibenzoyltartaric acid is recycled to the resolution process. 4. method according to claim 1 is characterized in that: will separate chiral resolving agent unracemic dibenzoyl tartaric acid and enantiomer N-methyl-3-phenyl-3-hydroxyl propylamine The solvent after the enantiomeric salts are formed is recycled again to the resolution process.