WO2005121066A1 - Procede de preparation de (1r, 2s)-(x)-ephedrine ou d'un hydrochlorure de cette derniere - Google Patents

Procede de preparation de (1r, 2s)-(x)-ephedrine ou d'un hydrochlorure de cette derniere Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
methylaminophenylacetone
acid
ephedrine
metal borohydride
hydrochloride
Prior art date
Application number
PCT/CN2005/000743
Other languages
English (en)
Chinese (zh)
Inventor
Chengjun Huang
Houyuan Zhou
Original Assignee
Shanghai Institute Of Pharmaceutical Industry
Zhejiang Kangyu Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute Of Pharmaceutical Industry, Zhejiang Kangyu Pharmaceutical Co., Ltd. filed Critical Shanghai Institute Of Pharmaceutical Industry
Publication of WO2005121066A1 publication Critical patent/WO2005121066A1/fr

Links

Classifications

    • 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%.

Abstract

L'invention permet d'obtenir de la (1R, 2S)-(-)-éphédrine en faisant réagir des dérivés de l'acide [(S)-(-)-α-méthylaminophénylacétone]2 ? (2R, 3R)-tartrique ou les sels de la (S)-(-)-α-méthylaminophénylacétone et d'autres acides organiques avec un borohydrure métallique ou un mélange composé d'un borohydrure métallique et d'un acide de Lewis. Etant donné que les matières de départ ne se racémisent pas durant la période de réduction, l'éphédrine est prédominante dans le produit. En outre, il est fait une utilisation importante du borohydrure métallique.
PCT/CN2005/000743 2004-06-07 2005-05-27 Procede de preparation de (1r, 2s)-(x)-ephedrine ou d'un hydrochlorure de cette derniere WO2005121066A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200410024953.8 2004-06-07
CNB2004100249538A CN1293038C (zh) 2004-06-07 2004-06-07 （1r，2s）－（－）－麻黄碱或其盐酸盐的制备方法

Publications (1)

Publication Number Publication Date
WO2005121066A1 true WO2005121066A1 (fr) 2005-12-22

Family

ID=35502989

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2005/000743 WO2005121066A1 (fr) 2004-06-07 2005-05-27 Procede de preparation de (1r, 2s)-(x)-ephedrine ou d'un hydrochlorure de cette derniere

Country Status (2)

Country Link
CN (1) CN1293038C (fr)
WO (1) WO2005121066A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101870660A (zh) * 2010-05-10 2010-10-27 青海省青海湖药业有限公司 一种L-(-)-盐酸麻黄碱和d-(+)-盐酸伪麻黄碱制备方法
CN102399158B (zh) * 2010-09-16 2014-04-02 哈尔滨工业大学 一种化学制备麻黄碱的工艺
CN106008183B (zh) * 2016-06-07 2019-05-07 浙江普洛康裕制药有限公司 麻黄碱或伪麻黄碱及麻黄碱或伪麻黄碱中间体的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD94396A (fr) *

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD94396A (fr) *

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TONGQING S ET AL: "Synthesis of dl-Ephedrine and dl-Pseudoephedrine.", CHINESE JOURNAL OF PHARMACEUTICALS., vol. 31, no. 12, 2000, pages 534 - 535 *

Also Published As

Publication number Publication date
CN1706812A (zh) 2005-12-14
CN1293038C (zh) 2007-01-03

Similar Documents

Publication Publication Date Title
CN100418964C (zh) (s,s)-顺式-2-二苯甲基-3-苄基氨基奎宁环的制备方法
CN109503462B (zh) 托法替布中间体(3r，4r)-n，4-二甲基-1-苄基-3-哌啶胺的合成方法
WO2019154436A1 (fr) Procédé de préparation d'adrénaline racémique de haute pureté
CA2381246C (fr) Procede de fabrication d'adrenaline
WO2005121066A1 (fr) Procede de preparation de (1r, 2s)-(x)-ephedrine ou d'un hydrochlorure de cette derniere
US8569492B2 (en) Method for preparing halofuginone derivative
CN102229538B (zh) 一种达泊西汀的合成方法
CN102140084A (zh) 一种曲美他嗪及其盐酸盐的生产方法
ZA200303214B (en) O-substituated 6-methyl-tramadol derivatives.
CN107903147A (zh) 一种克里唑替尼中间体的合成工艺
CN104326927B (zh) 一种1-[2-氨基-1-(4-甲氧基苯基)乙基]环己醇硫酸盐的制备方法
MXPA06007686A (es) Proceso para la obtencion del tartrato de tolterodina.
CN103864627B (zh) 福莫特罗手性中间体的拆分方法
CN106632038B (zh) 一种八氢异喹啉的拆分方法
CN105418489A (zh) 一种布比卡因的合成方法
CN107325039B (zh) 一种盐酸右哌甲酯的制备方法
CN114380703B (zh) 一种肾上腺素的精制方法
US20100312010A1 (en) Process for the Preparation of (S)-Pregabalin
CN113264839B (zh) 一种使用手性辅基制备左旋特布他林的方法
CN104402798B (zh) 一种3-氨基-1，2，3，4-四氢咔唑的拆分方法
CN112094241B (zh) 一种1,4-二氮杂螺[5,5]十一烷-3-酮的制备方法
EP4332085A1 (fr) Procédé de préparation de l-terbutaline par utilisation d'un groupe auxiliaire chiral
KR100829894B1 (ko) 디메크로트산 및 그의 마그네슘염의 제조방법
CN111196759B (zh) 盐酸西那卡塞及其中间体的制备方法
CN114292198A (zh) 一种文拉法辛杂质的制备方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase