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WO2009004593A2 - Procédés de préparation d'épinéphrine - Google Patents

Procédés de préparation d'épinéphrine Download PDF

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Publication number
WO2009004593A2
WO2009004593A2 PCT/IB2008/052677 IB2008052677W WO2009004593A2 WO 2009004593 A2 WO2009004593 A2 WO 2009004593A2 IB 2008052677 W IB2008052677 W IB 2008052677W WO 2009004593 A2 WO2009004593 A2 WO 2009004593A2
Authority
WO
WIPO (PCT)
Prior art keywords
epinephrine
acid
chloride
formula
reaction mixture
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2008/052677
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English (en)
Other versions
WO2009004593A3 (fr
Inventor
Ramprasad Yadav
Zakir Gafoor Shaikh
Shafakat Ali Nasir Ali
Arvind Merwade
Jaweed Mukarram Siddiqui Mohammad
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wockhardt Research Centre
Original Assignee
Wockhardt Research Centre
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 Wockhardt Research Centre filed Critical Wockhardt Research Centre
Publication of WO2009004593A2 publication Critical patent/WO2009004593A2/fr
Publication of WO2009004593A3 publication Critical patent/WO2009004593A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • 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
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives

Definitions

  • the invention relates to efficient and cost effective processes for the preparation of pure (-)-epinephrine. More particularly, it relates to processes for the resolution of racemic epinephrine. [3] Background of the Invention
  • (-)-Epinephrine also referred as adrenaline, is an endogenous catcholamine with combined a- and b- agonist activity. It is chemically known as
  • (-) -Epinephrine is available as injection and orally inhaled dosage forms. It is used to relieve temporary shortness of breath, chest tightness, and wheezing due to bronchial asthma.
  • (-) -Epinephrine is also available as a prescription drug as injection in emergencies, including acute asthma attacks and severe allergic reactions.
  • the synthesis of (-)-epinephrine is disclosed in U.S. Patent No. 6,218,575 and Tetrahedron Letters 5 (1979), 425-428.
  • pure (-)-epinephrine having a purity of greater than about 99.0% when measured by HPLC and enantiomeric excess of more than about 95.0% .
  • pure (-)-epinephrine having a purity more than 99.8% when measured by HPLC.
  • the process may produce (-) -epinephrine having a purity of greater than about 99.0% when measured by HPLC having enantiomeric excess of more than 95.0%.
  • the process may produce (-) -epinephrine having enantiomeric excess of more than 95.0 % and 3% or less (+)-epinephrine.
  • composition that includes a therapeutically effective amount of pure (-)-epinephrine prepared by the process of the invention having purity more than 99.0% by HPLC and enantiomeric excess of more than 95.0%; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a first aspect of the invention provides a process for the preparation of pure
  • (-)-epinephrine of Formula I having a purity of greater than about 99.0% when measured by HPLC and enantiomeric excess of more than 95.0%.
  • the process includes the steps of:
  • a second aspect of the invention provides a process for the preparation of
  • Suitable Lewis acids for the reaction may include one or more of aluminium chloride, zinc chloride, ferric chloride, stannous chloride, boron triflouride, aluminium bromide, and the like.
  • Suitable organic solvents may include one or more of carbon disulphide, nitrobenzene, halogenated solvent such as 1,2-dichloroethane, methylene chloride, chloroform, carbon tetrachloride, and mixtures thereof.
  • the reaction may be carried out at a temperature in the range from about -2O 0 C to about 5O 0 C.
  • the product may be isolated by breaking the Lewis acid complex formed.
  • the Lewis acid complex may be treated with one or more acids to get 3,4-dihydroxyphenacyl chloride in 85% or more yield.
  • the acid used for breaking the complex may be diluted with water.
  • Suitable acids which can be used include one or more of hydrochloride acid, sulphuric acid, acetic acid, formic acid, and the like.
  • a third aspect of the invention provides a process for the preparation of racemic epinephrine.
  • the process includes the steps of:
  • the 3,4-dihydroxyphenacyl chloride of Formula II may be treated with N- methyl benzyl amine in a suitable aprotic solvent at a temperature from about O 0 C to about 30 0 C.
  • Suitable aprotic solvents may include one or more of N,N-dimethylacetamide;
  • N,N-dimethylformamide N,N-dimethylformamide; dimethylsulphoxide; hexa methyl phosphorotriamide, acet- onitrile, dioxane, tetrahydrofuran, or mixtures thereof.
  • the product may be isolated by acid base treatment.
  • the term 'acid base treatment' refers to acidifying the reaction mixture to a pH 5 or less with acids and then basifying with a base to pH 7.2 or above.
  • acids and bases which may be used are known to a person of ordinary skill and include hydrochloric acid, acetic acid, sulphuric acid, ammonia, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, and the like. Acids or bases can be used in the form of their solutions in water.
  • the 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone may be isolated from the solution by a technique which includes, for example, filtration, filtration under vacuum, decantation, and centrifugation.
  • the steps of debenzylation and hydrogenation may be carried out simultaneously in a single step.
  • the ketone functionality may be reduced to hydroxyl and the amino functionality may be debenzylated using a catalytic hydrogenation.
  • the intermediate 3',4'-dihydroxy-2-N-benzyl-N-methylaminoacetophenone may be treated with a catalyst such as 5% to 10% Palladium on charcoal, platinum on charcoal, and ruthenium on carbon in the presence of a hydrogen source such as hydrogen gas in a suitable organic solvent.
  • the hydrogenation reaction may be performed under acidic conditions at pH from about 1.0 to about 3.0.
  • the acidic pH may be obtained with any acid, for example, dilute hydrochloride acid, dilute sulphuric acid, acetic acid, and formic acid.
  • Suitable organic solvents may include one or more of methanol, ethanol, ethyl acetate, acetic acid, tetrahydrofuran, dioxane, halogenated solvents such as chloroform, methylene chloride, ethylene dichloride, and the like.
  • a fourth aspect of the invention provides a process for the resolution of racemic epinephrine.
  • the process includes the steps of:
  • chiral auxiliaries may be used for resolution of the racemic epinephrine to (-)-epinephrine.
  • the term 'chiral auxiliary' refers to enantio- merically pure organic acids having at least one chiral centre.
  • Examples of chiral auxiliaries for optically resolving epinephrine may include D- tartaric acid, L-tartaric acid, D-camphor-10-sulfonic acid, L-camphor-10-sulfonic acid, D-dibenzoyltartaric acid, L-dibenzoyltartaric acid, D-mandelic acid, L-mandelic acid, and the like.
  • the reaction of epinephrine free base with a chiral auxiliary may be carried out in an organic solvent.
  • the organic solvent may include one or more solvents for example, methanol, ethanol, isopropanol, butanol, acetonitrile, dioxane, di- methylformamide, dimethylsulphoxide, halogenated solvents such as dichloromethane, chloroform and mixtures thereof.
  • the solvent mixture also includes aqueous organic solvent mixtures.
  • the reaction of epinephrine free base with a chiral auxiliary in an organic solvent may result in the formation of two diastereomeric salts of epinephrine.
  • the separation of the diastereomeric salt from the reaction mixture may be carried out by filtration. Desired isomer may be c onverted into a free base by treating the separated diastereomeric salt with a basifying agent. T he steps of formation of the diastereomeric salt, separation of the desired salt and subsequent conversion of the salt to the free base can be repeated t o enrich the optical purity of (-)-epinephrine free base.
  • the basifying agent may include bases such as ammonia, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide and similar bases to liberate the diastereomer.
  • a fifth aspect of the invention provides a process for the preparation of pure (-)
  • a solution or suspension of (-) -epinephrine may be obtained in water or may be obtained directly from the reaction mixture in which (-)-epinephrine is formed.
  • the solution or suspension of (-)-epinephrine in water may be acidified.
  • Suitable acids which may be used for acidification include acids such as hydrochloric acid, sulphuric acid, acetic acid, formic acid, and the like.
  • the solution or suspension of (-)-epinephrine may be acidified up to pH about 4 with an acid.
  • the reaction mixture may be basified with one or more bases.
  • bases may include one or more of ammonia, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, and the like.
  • the product may be isolated by a technique which includes, for example, filtration, filtration under vacuum, decantation, and centrifugation.
  • the pure (-)-epinephrine may have a chemical purity more than 99% and enantiomeric excess of more than 95%. It may have 3% or less (- ⁇ -)-epinephrine.
  • the solid so obtained was filtered and the wet solid was washed with water (4 L).
  • the w et solid was suspended in dilute acetic acid (mixture of acetic acid 600 mL and water 4 L) and heated to about 85-90 0 C tO get a clear solution.
  • carbon (15 g) was added and stirred for 30 minutes.
  • the reaction mixture was filtered hot.
  • the filtrate was cooled and the solid so obtained was filtered and washed with water (4 L). It was dried to obtain 3,4-dihydroxyphenacyl chloride.
  • pH of the reaction mixture was adjusted to 8.5 with dilute ammonia (240 mL). Solid so obtained was filtered and wet solid was washed with water (4 L). The wet solid was suspended in water (10 L) and pH was adjusted to 5.5. The suspension was stirred for 1 hour and the solid obtained was filtered and dried.
  • N-Benzyl epinephrine (950 g) was dissolved in methanol (9.5 L) and pH was adjusted with dilute HCl (345 mL) to about 1.0-2.4 and stirred.
  • 10% Pd/C 250 g was added and hydrogen gas was bubbled through the reaction mixture. It was heated to about 4O 0 C and stirred for about 30-35 hours at 40 0C .
  • the r eaction mass was filtered and washed with methanol (1 L). The filtrate was cooled to 10-15 0 C and pH was adjusted by ammonia solution (275 ml) to 8.5.
  • the reaction mixture was filtered, washed with methanol (1 L) and dried to get epinephrine.
  • Step A To a solution of racemic epinephrine (crude) (500 g) in methanol (1.0 L) was added L-tartaric acid (820 g). The reaction was stirred and after 1-3 hours, a thick precipitation was observed. Methanol (1.5 lit) was added and stirred for 24-30 hours at room temperature. The reaction mixture filtered and washed.
  • Step B Epinephrine tartrate (wet wt.) (464 g) was dissolved in purified water (4.5 L) and sodium meta bisulphite (4 g) was added and the reaction mixture was cooled to 5-10 0 C. The pH of the reaction mixture was adjusted with ammonia sol (270 mL) to about 8.5. The reaction stirred for 15 min and filtered. The solid obtained was washed with water (500 mL) followed by methanol (500 mL) and dried to obtain (-)-epinephrine base 232 g as solid. The reaction sequence of Step A and Step B is repeated twice to enrich the optical purity. The crude (-) -epinephrine is used in the next step.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur des procédés efficaces et rentables pour la préparation d'(-)-épinéphrine pure. Plus particulièrement, l'invention porte sur des procédés pour la résolution de l'épinéphrine racémique.
PCT/IB2008/052677 2007-07-03 2008-07-03 Procédés de préparation d'épinéphrine Ceased WO2009004593A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN1265/MUM/2007 2007-07-03
IN1272/MUM/2007 2007-07-03
IN1265MU2007 2007-07-03
IN1268MU2007 2007-07-03
IN1272MU2007 2007-07-03
IN1268/MUM/2007 2007-07-03

Publications (2)

Publication Number Publication Date
WO2009004593A2 true WO2009004593A2 (fr) 2009-01-08
WO2009004593A3 WO2009004593A3 (fr) 2009-06-04

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104711299A (zh) * 2015-03-31 2015-06-17 苏州汉酶生物技术有限公司 一种肾上腺素的制备方法
WO2016038422A1 (fr) * 2014-09-11 2016-03-17 Rouver Investment S.À.R.L Procédé de préparation d'adrénaline enrichie optiquement
CN106748835A (zh) * 2017-01-16 2017-05-31 蚌埠丰原医药科技发展有限公司 一种盐酸肾上腺酮的制备方法
CN108329218A (zh) * 2018-02-08 2018-07-27 河南普瑞制药有限公司 一种（r）-肾上腺素的制备方法
WO2020028215A1 (fr) * 2018-07-30 2020-02-06 Biothea Pharma, Inc. Sel de malonate d'épinéphrine cristallin
US10865180B2 (en) 2018-08-10 2020-12-15 Harman Finochem Limited Process for the preparation of l-Norepinephrine bitartrate monohydrate having high enantiomeric purity
CN112225665A (zh) * 2020-10-28 2021-01-15 合肥亿帆生物制药有限公司 一种重酒石酸去甲肾上腺素制备方法
CN112409193A (zh) * 2019-08-23 2021-02-26 武汉武药科技有限公司 高纯度（-）-肾上腺素及其制备方法
CN113735720A (zh) * 2021-10-26 2021-12-03 成都倍特药业股份有限公司 一种(±)-肾上腺素的制备方法
CN114085137A (zh) * 2021-11-29 2022-02-25 杭州发元生物科技有限公司 α-氯代-3,4-二羟基苯乙酮和肾上腺素类药物的制备方法
CN117658833A (zh) * 2023-11-13 2024-03-08 河北广祥制药有限公司 一种用于l-肾上腺素及其盐提纯的混合溶剂、及l-肾上腺素及其盐的提纯方法
WO2025058704A1 (fr) * 2023-09-15 2025-03-20 Virginia Commonwealth University Procédé de préparation d'épinéphrine et de norépinéphrine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD36003A (fr) *
US5047592A (en) * 1989-08-21 1991-09-10 Ethyl Corporation Selective hydrogenolysis process
DE19938709C1 (de) * 1999-08-14 2001-01-18 Boehringer Ingelheim Pharma Verfahren zur Herstellung von Adrenalin

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016038422A1 (fr) * 2014-09-11 2016-03-17 Rouver Investment S.À.R.L Procédé de préparation d'adrénaline enrichie optiquement
CN104711299B (zh) * 2015-03-31 2018-02-09 苏州汉酶生物技术有限公司 一种肾上腺素的制备方法
CN104711299A (zh) * 2015-03-31 2015-06-17 苏州汉酶生物技术有限公司 一种肾上腺素的制备方法
CN106748835B (zh) * 2017-01-16 2018-12-14 蚌埠丰原医药科技发展有限公司 一种盐酸肾上腺酮的制备方法
CN106748835A (zh) * 2017-01-16 2017-05-31 蚌埠丰原医药科技发展有限公司 一种盐酸肾上腺酮的制备方法
CN108329218B (zh) * 2018-02-08 2021-02-02 河南普瑞制药有限公司 一种（r）-肾上腺素的制备方法
CN108329218A (zh) * 2018-02-08 2018-07-27 河南普瑞制药有限公司 一种（r）-肾上腺素的制备方法
WO2020028215A1 (fr) * 2018-07-30 2020-02-06 Biothea Pharma, Inc. Sel de malonate d'épinéphrine cristallin
US12134588B2 (en) 2018-07-30 2024-11-05 Biothea Pharma, Inc. Crystalline epinephrine malonate salt
US11505521B2 (en) 2018-07-30 2022-11-22 Biothea Pharma, Inc. Crystalline epinephrine malonate salt
CN112739334A (zh) * 2018-07-30 2021-04-30 拜欧西亚制药公司 结晶丙二酸肾上腺素盐
US10995059B2 (en) 2018-07-30 2021-05-04 Biothea Pharma, Inc. Crystalline epinephrine malonate salt
IL280448B1 (en) * 2018-07-30 2024-08-01 Biothea Pharma Inc Crystalline epinephrine malonate salt
US10865180B2 (en) 2018-08-10 2020-12-15 Harman Finochem Limited Process for the preparation of l-Norepinephrine bitartrate monohydrate having high enantiomeric purity
CN112409193A (zh) * 2019-08-23 2021-02-26 武汉武药科技有限公司 高纯度（-）-肾上腺素及其制备方法
CN112409193B (zh) * 2019-08-23 2022-07-26 武汉武药科技有限公司 高纯度(-)-肾上腺素及其制备方法
CN112225665A (zh) * 2020-10-28 2021-01-15 合肥亿帆生物制药有限公司 一种重酒石酸去甲肾上腺素制备方法
CN113735720A (zh) * 2021-10-26 2021-12-03 成都倍特药业股份有限公司 一种(±)-肾上腺素的制备方法
CN114085137A (zh) * 2021-11-29 2022-02-25 杭州发元生物科技有限公司 α-氯代-3,4-二羟基苯乙酮和肾上腺素类药物的制备方法
WO2025058704A1 (fr) * 2023-09-15 2025-03-20 Virginia Commonwealth University Procédé de préparation d'épinéphrine et de norépinéphrine
CN117658833A (zh) * 2023-11-13 2024-03-08 河北广祥制药有限公司 一种用于l-肾上腺素及其盐提纯的混合溶剂、及l-肾上腺素及其盐的提纯方法

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