CN1293038C - Prepn process of (1R, 2S)-(-)-ephedrine or its hydrochloride - Google Patents

Abstract

The present invention relates to a method for preparing (1R, 2S)-(-)-ephedrine by using [(S)-(-)-alpha-methylamino propiophenone]2. (2R, 3R)-tartaric derivative or salt prepared from (S)-(-)-alpha-methylamino propiophenone and other kinds of organic acid as raw materials to react with a mixture composed of metal borohydride or metal borohydride and lewis acid. The reaction raw materials are not despun in the process of reduction, the ephedrine in reduction products has a very strong effect, and the utilization rate of metal borohydride is high.

Description

(1R, 2S)-(-)-ephedrine or its hydrochloride preparation method

technical field

The invention relates to a preparation method of (1R, 2S)-(-)-ephedrine or its hydrochloride.

Background technique

(1R, 2S)-(-)-ephedrine is an important medicinal product, which is mainly used clinically to prevent and treat certain hypotensive states, especially to prevent blood pressure drop during spinal anesthesia or epidural anesthesia; to treat nasal mucosa Nasal congestion caused by congestion and swelling; prevention or relief of bronchial asthma attacks; relief of skin and mucous membrane symptoms of urticaria and angioedema. Its chemical structural formula is as follows:

The traditional production method of ephedrine is the extraction method, that is, the ephedrine in the natural ephedra is extracted, but ephedra is a sand-fixing plant, and long-term indiscriminate mining and digging lead to a decrease in the grass-producing area and yield, and the desertification of the production area is becoming more and more serious.

Another method of producing ephedrine is biosynthesis. Using benzaldehyde as a starting material, yeast or yeast immobilized cells are used to synthesize (R)-phenylacetylcarbinol, and then chemically transform to prepare (1R, 2S)-(-)-ephedrine. Germany and the Czech Republic adopt this method to produce, and the process is more complicated.

Because the chemical synthesis method is not limited by natural resources, and the output can be adjusted according to changes in market demand, the method is not too complicated. For this reason, whether chemically synthesized ephedra becomes the subject that people pay close attention to.

Ephedrine is usually prepared by catalytic hydrogenation or metal borohydride reduction of α-methylaminopropiophenone or its hydrochloride.

JF Hyde et al. Catalyzed the reduction of α-methylaminopropiophenone with _PtO2 (JF Hyde, E. Browning, J. Chem. Soc., 2287 (1928));

I.K.Fel'dman etc. use Raney Ni to catalyze the reduction of α-methylaminopropiophenone (I.K.Fel'dman, N.N.Bel'stova, Zh.Priklad.khim., 35(6), 1364(1962); CA 57:11064) ;

Ger(East)11332 catalyzed the reduction of α-methylaminopropiophenone hydrochloride with Raney Ni;

H.Takamatsu catalyzed the reduction of chiral α-methylaminopropiophenone hydrochloride with metal platinum, or reduced chiral α-methylaminopropiophenone with LiAlH ₄ , NaBH ₄ (H.Takamatsu, J.Pharm.Soc, Japan , 76, 1219 (1956)).

The above-mentioned documents reduce α-methylaminopropiophenone or chiral α-methylaminopropiophenone with catalytic hydrogenation method or metal borohydride, and contain more pseudoephedrine in its product, can reach 25.9%, need to be separated; And because α-methylaminopropiophenone is easier to enolize, especially under alkaline conditions, resulting in the racemization of chiral α-methylaminopropiophenone during the reduction process. If Raney Ni is used to catalyze the reduction of chiral α-methylaminopropiophenone hydrochloride, Raney Ni is easy to deactivate, while Pd/C catalyzes the reduction of chiral α-methylaminopropiophenone hydrochloride, the cost is too high; metal Borohydride reduction of chiral α-methylaminopropiophenone hydrochloride, while reducing carbonyl, metal borohydride will also react with hydrogen chloride in hydrochloride, increasing the consumption of metal borohydride.

Contents of the invention

The technical problem to be solved in the present invention is to disclose a preparation method of (1R, 2S)-(-)-ephedrine or its hydrochloride, so as to overcome the above-mentioned defects in the prior art and meet the needs of the development of the medical field.

The steps of the present invention are as follows:

The reducing agent is added into the solvent containing the reaction raw materials, and the reduction reaction is carried out at -20-35°C. After the reaction finishes, conventional methods can be adopted to collect (1R, 2S)-(-)-ephedrine from the reaction product, as the reaction solvent can be reclaimed first, then the unreacted metal borohydride is decomposed with acid, and the organic acid is reclaimed , and then add alkali to the acidic water layer to free the reduction product; or add alkali to adjust the pH value of the system to strong alkalinity after recovering the solvent. At this time, the organic acid and alkali form a salt, dissolve in water, and the reduced product is released. Then extract the reduced product with an organic solvent, form a salt with hydrochloric acid, concentrate, and recrystallize to obtain high-purity (1R, 2S)-(-)-ephedrine hydrochloride.

The reducing agent is metal borohydride or a mixture of metal borohydride and Lewis acid;

Said reaction materials include [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R,3R)-(-)-dibenzoyl tartaric acid, [(S)-(-)- α-methylaminopropiophenone] ₂ ·(2R, 3R)-(-)-di-p-toluoyl tartaric acid, [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R ,3R)-(-)-Di-m-methylbenzoyl tartaric acid, [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R,3R)-(-)-Di-o-methyl Benzoyl tartaric acid, [(S)-(-)-α-methylaminopropiophenone] ₂ · (2R,3R)-(-)-diacetyl tartaric acid, [(S)-(-)-α- Methylaminopropiophenone] ₂ phthalic acid, [(S)-(-)-α-methylaminopropiophenone] ₂ d-tartaric acid, (S)-(-)-α-methylamino One of propiophenone·benzoic acid, (S)-(-)-α-methylaminopropiophenone·malic acid and (S)-(-)-α-methylaminopropiophenone·lactic acid;

The mentioned reaction raw materials can be prepared by the methods disclosed in the literature (H.Takamatsu, J.Pharm.Soc.Japan, 76, 1219 (1956)) or commercially available products;

The solvent is selected from water, C1-C5 alcohol or a mixture of water and C1-C5 alcohol;

The metal borohydride is selected from one of KBH ₄ , NaBH ₄ , Zn(BH ₄ ) ₂ , LiBH ₄ or Ca(BH ₄ ) ₂ , and the Lewis acid is selected from AlCl ₃ , CaCl ₂ or ZnCl ₂ .

The molar ratio of the reaction raw material to the reducing agent is: reaction raw material: reducing agent=1:0.5-3.

Method of the present invention has following characteristics:

1. The (S)-(-)-α-methylaminopropiophenone in the organic acid salt of (S)-(-)-α-methylaminopropiophenone does not racemize during the reduction process. Studies have shown that the racemization rate of (S)-(-)-α-methylaminopropiophenone organic acid salt is much slower than that of its free base. After the reaction, the optical purity of the reduced crude product was analyzed and determined by capillary electrophoresis, and the enantiomeric excess of ephedrine reached 97.2%, showing that (S)-(-)-α-methylaminopropiophenone organic acid salt The (S)-(-)-α-methylaminopropiophenone in the reduction process basically has no racemization.

2. experimental result shows, this method obtains the selectivity increase of ephedrine, and ephedrine occupies an absolute advantage in the product, and its weight content is at 92-98%, see Table 1. In this way, after the reduction, only the hydrochloride of the reduced crude product needs to be recrystallized to obtain high-purity (1R, 2S)-(-)-ephedrine hydrochloride.

3. The utilization rate of metal borohydride is quite high. Since the salt of (S)-(-)-α-methylaminopropiophenone and organic acid is neutral, except for the reduction of the carbonyl group, it does not increase the consumption of metal borohydride, basically reaching the borohydride theoretical utilization;

4. The mixture of free α-methylaminopropiophenone and metal borohydride or metal borohydride and Lewis acid does not react at room temperature and needs to be heated to 50°C, but at this temperature, α-methylamino Propiophenone is unstable and the yield decreases. The mixture of (S)-(-)-α-methylaminopropiophenone organic acid and metal borohydride or metal borohydride and Lewis acid can react at room temperature, reducing side reactions and improving reduction yield.

Table 1: The ratio of ephedrine and pseudoephedrine in the reduction product raw material Ephedrine: Pseudoephedrine [(S)-(-)-α-Methylaminopropiophenone] ₂ ·(2R,3R)-(-)-Dibenzoyltartaric acid 95.3:4.7 [(S)-(-)-α-Methylaminopropiophenone] ₂ ·(2R,3R)-(-)-Di-p-methylbenzoyl tartaric acid 98.0:2.0 [(S)-(-)-α-Methylaminopropiophenone] ₂ Phthalic acid 98.6:1.4 [(S)-(-)-α-Methylaminopropiophenone] ₂ d-Tartrate 99.0:1.0 (S)-(-)-α-Methylaminopropiophenone 74.1:25.9

Detailed ways

Example 1

Put 20.0g of [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R,3R)-(-)-dibenzoyltartaric acid in 80ml of water, slowly add 0.8gKBH ₄ under stirring, React for 15 minutes. Add concentrated hydrochloric acid until the pH value is about 2, extract the aqueous layer with 20ml×3 ethyl acetate, and concentrate to obtain (2R,3R)-(-)-dibenzoyltartaric acid. Adjust the pH value of the acidic water layer to 14 with 30% sodium hydroxide aqueous solution, and an oily substance precipitates out, extracts with toluene 20ml×3, and concentrates the toluene layer to obtain (1R, 2S)-(-)-ephedrine and a little (+ )-pseudoephedrine.

Its hydrochloride was prepared as follows:

Neutralize the toluene layer with 4N hydrochloric acid to a pH value of 6, remove the toluene, and concentrate the water layer to obtain a white solid, which is recrystallized with water to obtain 8.2 g of (1R, 2S)-(-)-ephedrine hydrochloride, mp217. 5-218.5°C, [α] _D -34.2° (c=5.0, H ₂ O), yield: 69.5%.

Example 2

Put 19.7g of [(S)-(-)-α-methylaminopropiophenone] ₂ ·phthalic acid in 40ml of water and 40ml of ethanol, slowly add 0.7g of KBH ₄ under stirring, and react for 15min. Concentrate to recover ethanol, then add 30% sodium hydroxide aqueous solution to pH to 10, oily matter precipitates out, extract with toluene 20ml×3, concentrate to obtain (1R,2S)-(-)-ephedrine and a little pseudoephedrine.

Its hydrochloride was prepared as follows:

Neutralize the toluene layer with 4N hydrochloric acid until the pH reaches 4, remove the toluene, and concentrate the water layer to obtain a white solid, which is recrystallized with water to obtain 12.2 g of (1R, 2S)-(-)-ephedrine hydrochloride, mp217. 2-218.6°C, [α] _D -34.1° (c=5.0, H ₂ O), yield: 75.3%.

Example 3-5

Using the same method as in Example 1, with ethanol as the solvent, 20.7g [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R, 3R)-(-)-di-p-methyl Benzoyl tartaric acid (embodiment 3), 13.9g [(S)-(-)-α-methylaminopropiophenone] _2.d -tartaric acid (embodiment 4) and 13.5g [(S)-(- )-alpha-methylaminopropiophenone] _2. malic acid (embodiment 5) is raw material, respectively obtains 8.3g, 8.4g and 8.2g (1R, 2S)-(-)-ephedrine hydrochloride; mp 217.2 -218.6°C, [α] _D -34.1° (c=5.0, H2O)

The yields were 70.1%, 71.3% and 74.8%, respectively.

Example 6

Adopt the method identical with embodiment 1, take methanol as solvent, and add 0.1g AlCl3, obtain 8.3g (1R, 2S)-(-)-ephedrine hydrochloride; mp 217.2-218.6 ℃, [α]D- 34.10 (c=5.0, H2O) Yield 70.1%.

Claims (6)

1. (1R, 2S)-(-)-the preparation method of ephedrine is characterized in that comprising the steps: The reducing agent is added to the solvent containing the reaction raw materials to carry out the reduction reaction, and then post-treatment by conventional methods to obtain (1R, 2S)-(-)-ephedrine; Said reaction raw materials include: [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R, 3R)-(-)-dibenzoyl tartaric acid, [(S)-(-) -α-methylaminopropiophenone] ₂ ·(2R,3R)-(-)-di-p-methylbenzoyl tartaric acid, [(S)-(-)-α-methylaminopropiophenone] ₂ ·( 2R, 3R)-(-)-di-m-toluoyl tartaric acid, [(S)-(-)-α-methylaminopropiophenone] ₂ · (2R, 3R)-(-)-di-o-methyl benzoyl tartaric acid, [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R,3R)-(-)-diacetyltartaric acid, [(S)-(-)-α -methylaminopropiophenone] ₂ phthalic acid, [(S)-(-)-α-methylaminopropiophenone] ₂ d-tartaric acid, (S)-(-)-α-methylamino One of propiophenone·benzoic acid, (S)-(-)-α-methylaminopropiophenone·malic acid and (S)-(-)-α-methylaminopropiophenone·lactic acid; The reducing agent is metal borohydride or a mixture of metal borohydride and Lewis acid. 2. The method according to claim 1, characterized in that said solvent is selected from water, C1-C5 alcohol or a mixture of water and C1-C5 alcohol. 3. The method according to claim 1, characterized in that the reaction temperature is -20 to 35°C. 4. The method according to claim 1, wherein said metal borohydride is selected from one of KBH ₄ , NaBH ₄ , Zn(BH ₄ ) ₂ , LiBH ₄ or Ca(BH ₄ ) ₂ . 5. The method according to claim 1, characterized in that said Lewis acid is selected from AlCl ₃ , CaCl ₂ or ZnCl ₂ . 6. The method according to any one of claims 1-5, characterized in that the molar ratio of the reaction raw material to the reducing agent is: reaction raw material:reducing agent=1:0.5-3.