WO2005121066A1 - The preparation method of (1 r,2s)-(-)-ephedrine or its hydrochloride - Google Patents

The preparation method of (1 r,2s)-(-)-ephedrine or its hydrochloride Download PDF

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WO2005121066A1
WO2005121066A1 PCT/CN2005/000743 CN2005000743W WO2005121066A1 WO 2005121066 A1 WO2005121066 A1 WO 2005121066A1 CN 2005000743 W CN2005000743 W CN 2005000743W WO 2005121066 A1 WO2005121066 A1 WO 2005121066A1
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methylaminophenylacetone
acid
ephedrine
metal borohydride
hydrochloride
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PCT/CN2005/000743
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French (fr)
Chinese (zh)
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Chengjun Huang
Houyuan Zhou
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Shanghai Institute Of Pharmaceutical Industry
Zhejiang Kangyu Pharmaceutical Co., Ltd.
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Publication of WO2005121066A1 publication Critical patent/WO2005121066A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton

Definitions

  • the present invention relates to a method for producing (lR, 2S)-(-> ephedrine or its hydrochloride).
  • (lR, 2S (-) _ ephedrine is an important medicinal product. It is mainly used in the prevention and treatment of certain low blood pressure conditions, especially to prevent blood pressure drop during spinal or epidural anesthesia; treatment of nasal mucosal congestion and swelling Nasal congestion caused; prevention or relief of bronchial asthma attacks; relief of skin and mucosal symptoms of urticaria and angioedema. Its chemical structural formula is as follows:
  • the traditional ephedrine production method is the extraction method, that is, extracting ephedrine from natural ephedra, but ephedra is a sand-fixing plant.
  • ephedra is a sand-fixing plant.
  • Another method of producing ephedrine is the biological semisynthesis method. Using benzaldehyde as a starting material, (R) -phenylacetyl methanol is synthesized by yeast or yeast immobilized cells, and then prepared by chemical transformation
  • Ephedrine is usually prepared by catalytic hydrogenation or metal borohydride reduction of a-methylaminophenylacetone or its hydrochloride. JFHyde Pt0 2 or the like to catalytic reduction in acetone-benzene methanamine ⁇ - (J.RHyde, E.Browning, J.Chem.Soc 3 2287 (1928).);
  • the above literature uses catalytic hydrogenation or metal borohydride to reduce ⁇ -methylaminophenylacetone or chiral ⁇ -methylaminophenylacetone.
  • the product contains more pseudoephedrine, which can reach 25.9%, which needs to be separated; and Alpha-methylaminophenylacetone is easier to enolize, especially under alkaline conditions, which leads to racemization of chiral alpha-methylaminophenylacetone during reduction.
  • Raney Ni catalyzes the reduction of chiral ⁇ -methylaminophenylacetone hydrochloride
  • Raney Ni is easily inactivated, while Pd / C catalyzes the reduction of chiral ⁇ -methylaminophenylacetone hydrochloride, which is too costly; metal
  • the borohydride reduces chiral ⁇ -methylaminophenylacetone hydrochloride, while reducing the carbonyl, the metal borohydride will also react with the hydrogen chloride in the hydrochloride, increasing the consumption of the metal borohydride. Summary of the invention
  • the technical problem to be solved by the present invention is to disclose a method for preparing (lR, 2S)-(-)-ephedrine or its hydrochloride salt, in order to overcome the above-mentioned shortcomings existing in the prior art, and meet the development needs in the field of medicine.
  • the reducing agent is added to a solvent containing a reaction raw material, and the reduction reaction is performed at a temperature of 20 to 35 ° C.
  • (1R, 2S)-(-)-ephedrine can be collected from the reaction product by conventional methods.
  • the reaction solvent can be recovered first, and then the unreacted metal borohydride can be decomposed by adding acid, and the organic acid can be recovered. Then, add alkali to the acidic water layer to free the reduced product; or add alkali to adjust the pH value of the system to strong alkalinity after recovering the solvent.
  • the organic acid forms a salt with the base, dissolves in water, and the reduced product is released.
  • the reduced product is then extracted with an organic solvent, salted with hydrochloric acid, concentrated, and recrystallized to obtain (1R, 2S)-(-)-ephedrine hydrochloride with high purity.
  • the reducing agent is a metal borohydride or a mixture of a metal borohydride and a Lewis acid.
  • the reaction raw materials include [(SM-)-ct-methylaminophenylacetone] 2 ⁇ (2R, 3R)-(-)-dibenzoyltartaric acid, [(S)-(-)- ⁇ -methyl Aminophenylacetone] 2 ⁇ (2R, 3R)-(-)-Di-p-methylbenzoyltartaric acid, [(S)-(-)- «-methylaminophenylacetone] 2 ⁇ (2R, 3R) -(-)-Di-m-benzoyl tartaric acid, [(S)-(-)- ⁇ -methylaminophenylacetone] 2 * (21,31)-(-)-di-o-methylbenzoyl Tartaric acid, [(S)-(-)- ⁇ -methylaminophenylacetone] 2 ⁇ (2R, 3R)-(-)-diacetyltartaric acid, [(S)-(-)-methylaminobenzen
  • reaction raw materials mentioned can be used in the literature (; H. Takamatsu J. Pharm. Soc. Japan,
  • the solvent is selected from water, C1 C5 alcohol or a mixture of water and C1 ⁇ C5 alcohol;
  • the metal borohydride is selected from KBH 4 , NaBH 4 , Zn (BH 4 ) 2 > LiBH 4 or Ca of a medium 2 (4 BH)
  • the method of the invention has the following characteristics: 1. (SM)-(d) -methylaminophenylacetone in (S)-(-)- ⁇ -methylaminophenylacetone organic acid salt is not racemic during reduction. Studies have shown that the racemization rate of (s)-(-)- a -methylaminophenylacetone organic acid salt is much slower than its free base. After the reaction, the optical purity of the reduced crude product was analyzed by capillary electrophoresis.
  • a mixture of free ⁇ -methylaminophenylacetone and metal borohydride or metal borohydride and Lewis acid does not react at room temperature. It needs to be heated to 50 ° C, but at this temperature, ⁇ -methylamine Phenylacetone is unstable and yield is reduced.
  • the mixture of (S)-(-)-a-methylaminophenylacetone organic acid and metal borohydride or metal borohydride and Lewis acid can react near room temperature, reducing side reactions and improving reduction. Yield.
  • hydrochloride is prepared as follows:
  • hydrochloride is prepared as follows:
  • the yield was 70.1%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

IN this invention, (1 R,2S)-(-)-ephedrine is obtained by reacting, [(S)-(-)-α-methylaminophenylacetone]2 . (2R,3R)-tartaric acid derivatives or the salts of (S)-(-)-α-methylaminophenylacetone and other organic acids with metal borohydride or the mixture consisting of metal borohydride and lewis acid. Since the staring materials don't racemize during the reductive reaction, the ephedrine should be predominant in the product. In addition, the utilization of the metal borohydride is high.

Description

aR,2SW- 麻黄碱或其盐酸盐的制备方法 技术领域 本发明涉及 (lR，2S)-(->麻黄碱或其盐酸盐的制备方法。  TECHNICAL FIELD The present invention relates to a method for producing (lR, 2S)-(-> ephedrine or its hydrochloride).
背景技术 Background technique
(lR,2S (-)_麻黄碱是一种重要的医药产品， 临床上主要用于防治某些低 血压状态， 特别是椎管麻醉或硬膜外麻醉时预防血压下降； 治疗鼻粘膜充 血肿胀引起的鼻塞； 预防或缓解支气管哮喘发作； 缓解荨麻疹和血管神经 性水肿的皮肤粘膜症状。 其化学结构式如下： (lR, 2S (-) _ ephedrine is an important medicinal product. It is mainly used in the prevention and treatment of certain low blood pressure conditions, especially to prevent blood pressure drop during spinal or epidural anesthesia; treatment of nasal mucosal congestion and swelling Nasal congestion caused; prevention or relief of bronchial asthma attacks; relief of skin and mucosal symptoms of urticaria and angioedema. Its chemical structural formula is as follows:
Figure imgf000002_0001
传统的麻黄碱的生产方法是萃取法， 即提取天然麻黄草中的麻黄碱， 但麻黄草是固沙植物， 长期的滥采滥挖导致产草面积和产草量下降， 产地 沙化日益严重。 另一种生产麻黄碱的方法是生物半合成法。 以苯甲醛为起始原料， 通 过酵母或酵母固定化细胞来合成 (R)-苯基乙酰基甲醇， 再经化学转化制备
Figure imgf000002_0001
The traditional ephedrine production method is the extraction method, that is, extracting ephedrine from natural ephedra, but ephedra is a sand-fixing plant. Long-term excessive mining and excavation have led to a decline in the area and yield of grass, and the desertification of the growing area has become increasingly serious. Another method of producing ephedrine is the biological semisynthesis method. Using benzaldehyde as a starting material, (R) -phenylacetyl methanol is synthesized by yeast or yeast immobilized cells, and then prepared by chemical transformation
(lR,2SM-)_麻黄碱。 德国和捷克采用该方法生产， 工艺较复杂。 (lR, 2SM-) _ ephedrine. Germany and the Czech Republic use this method to produce, and the process is more complicated.
由于化学合成法不受自然资源的限制， 且可据市场需求变化调整产量， 方法也不太复杂。 为此， 化学合成麻黄成为人们是否关注的课题。 通常以催化氢化或金属硼氢化物还原 a —甲胺基苯丙酮或其盐酸盐制 备麻黄碱。 J.F.Hyde等以 Pt02催化还原 α—甲胺基苯丙酮 （J.RHyde, E.Browning, J.Chem.Soc.32287 (1928)); Since the chemical synthesis method is not restricted by natural resources, and the output can be adjusted according to changes in market demand, the method is not too complicated. For this reason, chemical synthesis of ephedra has become a topic of concern. Ephedrine is usually prepared by catalytic hydrogenation or metal borohydride reduction of a-methylaminophenylacetone or its hydrochloride. JFHyde Pt0 2 or the like to catalytic reduction in acetone-benzene methanamine α- (J.RHyde, E.Browning, J.Chem.Soc 3 2287 (1928).);
I.K.Feldman等以 Raney Ni催化还原 α—甲胺基苯丙酮 （LK.Fel'dman, N.N.Bel'stova,Zh.Priklad.khim.,35(6), 1364(1962)； CA 57:11064) ；  IKFeldman et al. Used Raney Ni to catalyze the reduction of α-methylaminophenylacetone (LK. Fel'dman, NNBel'stova, Zh. Priklad.khim., 35 (6), 1364 (1962); CA 57: 11064);
Ger(East)11332以 Raney M催化还原 α—甲胺基苯丙酮盐酸盐；  Ger (East) 11332 catalytic reduction of α-methylaminophenylacetone hydrochloride with Raney M;
H.Takamatsu 以金属铂催化还原手性 α—甲胺基苯丙酮盐酸盐， 或以 LiAlH4、 NaBH4还原手性 α —甲胺基苯丙酮 (ELTakamatsu, J.Pharm.Soc, Japan,76,1219(1956))。 H. Takamatsu uses metal platinum to reduce chiral α-methylaminophenylacetone hydrochloride or LiAlH 4 or NaBH 4 to reduce chiral α-methylaminophenylacetone (ELTakamatsu, J. Pharm.Soc, Japan, 76 , 1219 (1956)).
上述文献以催化氢化法或金属硼氢化物还原 α —甲胺基苯丙酮或手性 α—甲胺基苯丙酮， 其产物中含有较多的伪麻黄碱， 可达 25.9% , 需加以 分离； 而且由于 α—甲胺基苯丙酮较易烯醇化， 特别在碱性条件下， 导致 手性 α―甲胺基苯丙酮在还原的过程中消旋。 如以 Raney Ni催化还原手性 α—甲胺基苯丙酮盐酸盐， Raney Ni易失活， 而 Pd/C催化还原手性 α— 甲胺基苯丙酮盐酸盐， 则成本太高； 金属硼氢化物还原手性 α—甲胺基苯 丙酮盐酸盐， 则在还原羰基的同时， ·金属硼氢化物也会与盐酸盐中的氯化 氢反应， 增加了金属硼氢化物的消耗。 发明内容  The above literature uses catalytic hydrogenation or metal borohydride to reduce α-methylaminophenylacetone or chiral α-methylaminophenylacetone. The product contains more pseudoephedrine, which can reach 25.9%, which needs to be separated; and Alpha-methylaminophenylacetone is easier to enolize, especially under alkaline conditions, which leads to racemization of chiral alpha-methylaminophenylacetone during reduction. If Raney Ni catalyzes the reduction of chiral α-methylaminophenylacetone hydrochloride, Raney Ni is easily inactivated, while Pd / C catalyzes the reduction of chiral α-methylaminophenylacetone hydrochloride, which is too costly; metal The borohydride reduces chiral α-methylaminophenylacetone hydrochloride, while reducing the carbonyl, the metal borohydride will also react with the hydrogen chloride in the hydrochloride, increasing the consumption of the metal borohydride. Summary of the invention
本发明需要解决的技术问题是公开一种 (lR,2S)-(-)-麻黄碱或其盐酸盐 的制备方法， 以克服现有技术存在的上述缺陷， 满足医药领域发展的需要。  The technical problem to be solved by the present invention is to disclose a method for preparing (lR, 2S)-(-)-ephedrine or its hydrochloride salt, in order to overcome the above-mentioned shortcomings existing in the prior art, and meet the development needs in the field of medicine.
本发明的步骤如下：  The steps of the invention are as follows:
将还原剂加入含有反应原料的溶剂中， 在一 20〜35 °C下进行还原反应。 反应结束后， 可采用常规的方法从反应产物中收集 (1R，2S)- (-) -麻黄碱， 如 可先回收反应溶剂， 然后加酸分解未反应的金属硼氢化物， 并回收有机酸， 然后向酸水层加碱以游离还原产物； 或在回收溶剂后先加碱调体系的 pH 值至强碱性， 此时有机酸与碱成盐， 溶于水中， 还原产物则游离出。 然后 以有机溶剂萃取还原产物， 与盐酸成盐， 浓缩， 重结晶后可得高纯度的 (lR，2S)-(-)-麻黄碱盐酸盐。 所说的还原剂为金属硼氢化物或金属硼氢化物与路易斯酸组成的混合 The reducing agent is added to a solvent containing a reaction raw material, and the reduction reaction is performed at a temperature of 20 to 35 ° C. After the reaction, (1R, 2S)-(-)-ephedrine can be collected from the reaction product by conventional methods. For example, the reaction solvent can be recovered first, and then the unreacted metal borohydride can be decomposed by adding acid, and the organic acid can be recovered. Then, add alkali to the acidic water layer to free the reduced 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 forms a salt with the base, dissolves in water, and the reduced product is released. The reduced product is then extracted with an organic solvent, salted with hydrochloric acid, concentrated, and recrystallized to obtain (1R, 2S)-(-)-ephedrine hydrochloride with high purity. The reducing agent is a metal borohydride or a mixture of a metal borohydride and a Lewis acid.
所说的反应原料包括 [(SM-)- ct -甲胺基苯丙酮] 2 · (2R,3R)-(-)-二苯甲酰 基酒石酸、 [(S)-(-)- α -甲胺基苯丙酮] 2 · (2R,3R)- (-) -二对甲基苯甲酰基酒 石酸、 [(S)-(-)- « -甲胺基苯丙酮] 2 · (2R,3R)-(-)-二间甲基苯甲酰基酒石酸、 [(S)-(-)- α -甲胺基苯丙酮] 2 *(21，31 )-(-)-二邻甲基苯甲酰基酒石酸、 [(S)- (-) - α -甲胺基苯丙酮] 2 · (2R,3R)-(-)-二乙酰基酒石酸、 [(S)-(-)- -甲胺基苯丙 酮] 2 ·邻苯二甲酸、 [(S)-(-)- α -甲胺基苯丙酮] 2 · d-酒石酸、、 (S)-(-)- α -甲胺 基苯丙酮 ·苯甲酸、 （S)-(-)- α -甲胺基苯丙酮 ·苹果酸及 (SM-)- α -甲胺基 苯丙酮 *乳酸中的一种； The reaction raw materials include [(SM-)-ct-methylaminophenylacetone] 2 · (2R, 3R)-(-)-dibenzoyltartaric acid, [(S)-(-)-α -methyl Aminophenylacetone] 2 · (2R, 3R)-(-)-Di-p-methylbenzoyltartaric acid, [(S)-(-)-«-methylaminophenylacetone] 2 · (2R, 3R) -(-)-Di-m-benzoyl tartaric acid, [(S)-(-)-α-methylaminophenylacetone] 2 * (21,31)-(-)-di-o-methylbenzoyl Tartaric acid, [(S)-(-)-α-methylaminophenylacetone] 2 · (2R, 3R)-(-)-diacetyltartaric acid, [(S)-(-)--methylaminobenzene Acetone] 2 · phthalic acid, [(S)-(-)-α-methylaminophenylacetone] 2 · d-tartaric acid, (S)-(-)-α-methylaminophenylacetone · benzene One of formic acid, (S)-(-)-α-methylaminophenylacetone · malic acid, and (SM-)-α-methylaminophenylacetone * lactic acid;
所述及的反应原料可采用文献 (； H.Takamatsu J.Pharm.Soc. Japan, The reaction raw materials mentioned can be used in the literature (; H. Takamatsu J. Pharm. Soc. Japan,
76，1219(1956))公开的方法进行制备或采用市售产品； 76, 1219 (1956)) to prepare or use commercially available products;
所说的溶剂选自水、 C1 C5的醇或水与 C1〜C5的醇组成的混合物； 所说的金属硼氢化物选自 KBH4、 NaBH4、 Zn(BH4)2> LiBH4或 Ca(BH4)2 中的一种， 所说的路易斯酸选自 A1C13、 &( 12或211 2。 反应原料与还原剂的摩尔比为： 反应原料：还原剂 = 1： 0.5〜3。 The solvent is selected from water, C1 C5 alcohol or a mixture of water and C1 ~ C5 alcohol; the metal borohydride is selected from KBH 4 , NaBH 4 , Zn (BH 4 ) 2 > LiBH 4 or Ca of a medium 2 (4 BH), said Lewis acid is selected from A1C1 3, & (1 2 2112 or molar ratio of the raw material and the reducing agent is: starting material: reducing agent = 1: 0.5~3.
本发明的方法有如下特点： 1. (S)- (-) - α—甲胺基苯丙酮的有机酸盐中的 （SM-)- d -甲胺基苯丙酮 在还原的过程中不消旋。 研究表明： （s)-(-)- a -甲胺基苯丙酮有机酸盐的消 旋速度比其游离碱要慢得多。 反应结束后， 以毛细管电泳法对还原粗产物 的光学纯度进行了分析测定， 麻黄碱的对映体过量达 97.2%， 表明 (S)-(-)- α —甲胺基苯丙酮有机酸盐中的 (S)-(-)- a—甲胺基苯丙酮在还原的过程中 基本没有消旋。 The method of the invention has the following characteristics: 1. (SM)-(d) -methylaminophenylacetone in (S)-(-)-α-methylaminophenylacetone organic acid salt is not racemic during reduction. Studies have shown that the racemization rate of (s)-(-)- a -methylaminophenylacetone organic acid salt is much slower than its free base. After the reaction, the optical purity of the reduced crude product was analyzed by capillary electrophoresis. The enantiomeric excess of ephedrine reached 97.2%, indicating that (S)-(-)-α-methylaminophenylacetone organic acid salt The (S)-(-)-a-methylaminophenylacetone in the reduction process is basically not racemic.
2.实验结果表明， 本法获得麻黄碱的选择性增加， 产物中麻黄碱占绝 对优势， 其重量含量在 92— 98%， 见表 1。 如此， 在还原结束后， 只需对 还原粗产物的盐酸盐重结晶， 便可得到高纯度的 (lR，2S)-(->麻黄碱盐酸盐。  2. The experimental results show that the selectivity of ephedrine obtained by this method is increased, and the ephedrine in the product has an absolute advantage, and its weight content is 92-98%, as shown in Table 1. In this way, after the reduction is completed, only the hydrochloride of the reduced crude product is recrystallized to obtain (lR, 2S)-(-> ephedrine hydrochloride with high purity.
3.金属硼氢化物的利用率相当高。 由于 (SM-)- α -甲胺基苯丙酮与有机 酸所成的盐呈中性， 所以除羰基被还原外， 不另外增加金属硼氢化物的消 耗， 基本上达到硼氢化物的理论利用率；  3. The utilization rate of metal borohydride is quite high. Since the salt formed by (SM-)-α-methylaminophenylacetone and organic acid is neutral, it does not increase the consumption of metal borohydride except for the reduction of carbonyl group, which basically achieves the theoretical use of borohydride. Rate
4.游离的 α —甲胺基苯丙酮与金属硼氢化物或金属硼氢化物与路易斯 酸组成的混合物于室温下不反应， 需加热至 50°C， 但在此温度下， α—甲 胺基苯丙酮不稳定， 收率降低。 而 (S)-(-)- a —甲胺基苯丙酮有机酸与金属 硼氢化物或金属硼氢化物与路易斯酸组成的混合物在室温附近就可发生反 应， 减少了副反应， 提高了还原收率。  4. A mixture of free α-methylaminophenylacetone and metal borohydride or metal borohydride and Lewis acid does not react at room temperature. It needs to be heated to 50 ° C, but at this temperature, α-methylamine Phenylacetone is unstable and yield is reduced. The mixture of (S)-(-)-a-methylaminophenylacetone organic acid and metal borohydride or metal borohydride and Lewis acid can react near room temperature, reducing side reactions and improving reduction. Yield.
表 1 : 还原产物中， 麻黄碱与伪麻黄碱的比例  Table 1: Ratio of ephedrine to pseudoephedrine in the reduction products
Figure imgf000005_0001
具体实施方式 实施例 1
Figure imgf000005_0001
detailed description Example 1
将 20.0g[(S)- (-) - α -甲胺基苯丙酮] 2 · (2R，3R)- (-) -二苯甲酰基酒石酸置 于 80ml水中， 搅拌下缓慢加入 0.8gKBH4，反应 15min。 加入浓盐酸至 pH 值为 2左右， 以 20mlX 3乙酸乙酯萃取水层， 浓縮， 得 (2R,3R)-(-)-二苯甲 酰基酒石酸。 以 30%氢氧化钠水溶液调节酸水层的 pH值至 14, 有油状物 析出， 以甲苯 20mlx3 萃取， 浓缩甲苯层， 得 (lR,2S)-(-)-麻黄碱和少许 (+) 一伪麻黄碱。 20.0g of [(S)-(-)-α-methylaminophenylacetone] 2 · (2R, 3R)-(-)-dibenzoyltartaric acid was placed in 80ml of water, and 0.8g KBH 4 was slowly added under stirring, Reaction for 15min. Concentrated hydrochloric acid was added to a pH of about 2, and the aqueous layer was extracted with 20 ml × 3 ethyl acetate and concentrated to obtain (2R, 3R)-(-)-dibenzoyltartaric acid. The pH value of the acidic water layer was adjusted to 14 with a 30% sodium hydroxide aqueous solution. An oily substance precipitated, and extracted with toluene 20 ml × 3. The toluene layer was concentrated to obtain (lR, 2S)-(-)-ephedrine and a little (+). Pseudoephedrine.
其盐酸盐制备如下：  Its hydrochloride is prepared as follows:
以 4N盐酸中和甲苯层至 pH值 6， 分去甲苯， 水层浓缩， 得白色固体， 以水重结晶， 得 8.2g(lR，2S)-(- 麻黄碱盐酸盐， mp217.5-218.5 °C ,[ a ]D- 34.2°(c=5.0,H2O)， 收率： 69.5%。 The toluene layer was neutralized with 4N hydrochloric acid to pH 6, the toluene was separated, and the aqueous layer was concentrated to obtain a white solid, which was recrystallized from water to obtain 8.2 g of (lR, 2S)-(-ephedrine hydrochloride, mp217.5- 218.5 ° C, [a] D -34.2 ° (c = 5.0, H 2 O), yield: 69.5%.
实施例 2  Example 2
将 19.7g[(-)- a—甲胺基苯丙酮] 2 ·邻苯二甲酸置于 40ml水和 40ml 乙 醇中， 搅拌下缓慢加入 0.7gKBH4，反应 15min。 浓縮以回收乙醇， 然后加 入 30%氢氧化钠水溶液至 pH至 10, 有油状物析出， 以甲苯 20mlx3萃取， 浓缩， 得 (1R,2S (-)-麻黄碱和少许伪麻黄碱。 19.7 g of [(-)-a-methylaminophenylacetone] 2 · phthalic acid was placed in 40 ml of water and 40 ml of ethanol, 0.7 g of KBH 4 was slowly added under stirring, and the reaction was allowed to proceed for 15 min. Concentrate to recover ethanol, then add 30% sodium hydroxide aqueous solution to pH to 10, an oily substance precipitates, extract with toluene 20ml × 3, and concentrate to obtain (1R, 2S (-)-ephedrine and a little pseudoephedrine.
其盐酸盐制备如下：  Its hydrochloride is prepared as follows:
以 4N盐酸中和甲苯层至 pH至 4， 分去甲苯， 水层浓缩， 得白色固体， 以水重结晶，得 12.2g(lR,2S)-(+)-麻黄碱盐酸盐， mp217.2-218.6°C,[ a ]D-34.1Q (c=5.0,H2O), 收率： 75.3%。 实施例 3~5 The toluene layer was neutralized with 4N hydrochloric acid to pH to 4, the toluene was separated, and the aqueous layer was concentrated to obtain a white solid, which was recrystallized from water to obtain 12.2 g (lR, 2S)-(+)-ephedrine hydrochloride, mp217. 2-218.6 ° C, [a] D -34.1 Q (c = 5.0, H 2 O), Yield: 75.3%. Examples 3 to 5
采用与实施例 1相同的方法， 以乙醇为溶剂， 分别以 20.7g[(S)- (-) - - 甲胺基苯丙酮] 2 · (2R,3RM-)_二对甲基苯甲酰基酒石酸（实施例 3)、 13.9g[(S)-(-)- α -甲胺基苯丙酮] 2 · d-酒石酸 (实施例 4)和 13.5g[(S)-(-)- a -甲 胺基苯丙酮] 2 ·苹果酸（实施例 5)为原料， 分别获得 8.3g、 8.4g 和 8.2g(lR，2S)-(+)-麻黄碱盐酸盐； mp 217.2-218.6°C， [ a ]D-34.1° (c=5.0,H2O) 收率分别为 70.1%， 71.3%和 74.8%。 Using the same method as in Example 1, using ethanol as the solvent, 20.7 g [(S)-(-)--methylaminophenylacetone] 2 · (2R, 3RM-) _ di-p-methylbenzoyl Tartaric acid (Example 3), 13.9 g [(S)-(-)-α-methylaminophenylacetone] 2 · d-tartaric acid (Example 4) and 13.5 g [(S)-(-)-a- Methylaminophenylacetone] 2 malic acid (Example 5) as raw material, 8.3g, 8.4g and 8.2g (lR, 2S)-(+)-ephedrine hydrochloride were obtained respectively; mp 217.2-218.6 ° C , [A] D -34.1 ° (c = 5.0, H2O) The yields are 70.1%, 71.3% and 74.8%, respectively.
实施例 6  Example 6
采用与实施例 1 相同的方法， 以甲醇为溶剂， 并加入 O.lg A1C13, 获 得 8.3g (lR,2S)-(+)-麻黄碱盐酸盐； mp 217.2-218.6 °C , [ a ]D-34.10 (c=5.0，H2O)  Using the same method as in Example 1, methanol was used as the solvent, and 0.1 g of A1C13 was added to obtain 8.3 g of (lR, 2S)-(+)-ephedrine hydrochloride; mp 217.2-218.6 ° C, [a] D-34.10 (c = 5.0, H2O)
收率为 70.1%。 The yield was 70.1%.

Claims

权利要求 Rights request
1. (lR,2S)-(->麻黄碱的制备方法， 其特征在于包括如下步骤： 1. A method for preparing (lR, 2S)-(-> ephedrine, comprising the following steps:
将还原剂加入含有反应原料的溶剂中进行还原反应， 然后采用常规的 方法后处理即可得 ( 1 R,2S)-(-)-麻黄碱；  Adding a reducing agent to a solvent containing a reaction raw material to perform a reduction reaction, and then using a conventional method for post-treatment to obtain (1 R, 2S)-(-)-ephedrine;
所说的反应原料包括： [(S)-(-)- α -甲胺基苯丙酮] 2 · (2R,3R)- (-) -二苯 甲酰基酒石酸、 [(S)- (-) - α -甲胺基苯丙酮] 2 * (2 3 -(-)-二对甲基苯甲酰 基酒石酸、 [(S)- (-) - α -甲胺基苯丙酮] 2 · (2R,3R)- (-) -二间甲基苯甲酰基酒 石酸、 [(SM-)- t -甲胺基苯丙酮 ] 2 ' (2 31 -(-)-二邻甲基苯甲酰基酒石酸、 [(S)- (-) - -甲胺基苯丙酮] 2 · (2R,3R)-(-)-二乙酰基酒石酸、 [(S)- (-) - α -甲胺 基苯丙酮] 2 ·邻苯二甲酸、 [(S)- (-) - α -甲胺基苯丙酮] 2 · d-酒石酸、 （S)- (-) - α -甲胺基苯丙酮 *苯甲酸、 （S)-(-)- -甲胺基苯丙酮 ·苹果酸及 (S)-(-)- α - 甲胺基苯丙酮 ·乳酸中的一种； The reaction raw materials include: [(S)-(-)-α-methylaminophenylacetone] 2 · (2R, 3R)-(-)-dibenzoyltartaric acid, [(S)-(-) -α-methylaminophenylacetone] 2 * (2 3-(-)-di-p-methylbenzoyltartaric acid, [(S)-(-)-α-methylaminophenylacetone]] 2 · (2R, 3R)-(-)-di-m-benzoyl tartaric acid, [(SM-)-t-methylaminophenylacetone] 2 '(2 31-(-)-di-o-methylbenzoyl tartaric acid, [ (S)-(-)--methylaminophenylacetone] 2 (2R, 3R)-(-)-diacetyltartaric acid, [(S)-(-)-α-methylaminophenylacetone] 2 · Phthalic acid, [(S)-(-)-α-methylaminophenylacetone] 2 · d-tartaric acid, (S)-(-)-α-methylaminophenylacetone * benzoic acid, (S )-(-)--Methylaminophenylacetone · malic acid and (S)-(-)-α -methylaminophenylacetone · lactic acid;
还原剂为金属硼氢化物或金属硼氢化物与路易斯酸组成的混合物。  The reducing agent is a metal borohydride or a mixture of a metal borohydride and a Lewis acid.
2. 根据权利要求 1 所述的方法， 其特征在于， 所说的溶剂选自水、 C1-C5的醇或水与 C1~C5的醇组成的混合物。  2. The method according to claim 1, wherein the solvent is selected from the group consisting of water, a C1-C5 alcohol, or a mixture of water and a C1-C5 alcohol.
3. 根据权利要求 1所述的方法， 其特征在于， 反应温度为一 20〜35° (：。  3. The method according to claim 1, wherein the reaction temperature is between 20 ° and 35 ° (:.
4.根据权利要求 1所述的方法， 其特征在于， 所说的金属硼氢化物选 自 KBH4、 NaBH4、 Zn(BH4)2、 8114或 Ca(BH4)2中的一种。 4. The method according to claim 1, wherein the metal borohydride is selected from one of KBH 4 , NaBH 4 , Zn (BH 4 ) 2 , 811 4 or Ca (BH 4 ) 2 .
5. 根据权利要求 1 所述的方法， 其特征在于， 所说的路易斯酸选自 A ¾、 CaC¾或 ZnCl2。 5. The method according to claim 1, wherein the Lewis acid is selected from A ¾, CaC ¾ or ZnCl 2 .
6. 根据权利要求 1〜5任一项所述的方法， 其特征在于， 反应原料与还 原剂的摩尔比为： 反应原料：还原剂- 1： 0.5〜3。  The method according to any one of claims 1 to 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.
PCT/CN2005/000743 2004-06-07 2005-05-27 The preparation method of (1 r,2s)-(-)-ephedrine or its hydrochloride WO2005121066A1 (en)

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