WO2013008247A1 - Procédé de préparation d'un sel d'addition d'acide de norépinéphrine (dl), intermédiaire clé de la norépinéphrine (r) - (-) - - Google Patents

Procédé de préparation d'un sel d'addition d'acide de norépinéphrine (dl), intermédiaire clé de la norépinéphrine (r) - (-) - Download PDF

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Publication number
WO2013008247A1
WO2013008247A1 PCT/IN2011/000728 IN2011000728W WO2013008247A1 WO 2013008247 A1 WO2013008247 A1 WO 2013008247A1 IN 2011000728 W IN2011000728 W IN 2011000728W WO 2013008247 A1 WO2013008247 A1 WO 2013008247A1
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WIPO (PCT)
Prior art keywords
formula
acid
norepinephrine
dihydroxy
preparation
Prior art date
Application number
PCT/IN2011/000728
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English (en)
Inventor
Mahesh Bhagoji Dalvi
Rajesh Shashikant Kenny
Ganesh Ramachandra KAWLE
Original Assignee
Neon Laboratories 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.)
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Publication date
Application filed by Neon Laboratories Ltd. filed Critical Neon Laboratories Ltd.
Publication of WO2013008247A1 publication Critical patent/WO2013008247A1/fr

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems

Definitions

  • the present invention relates to a new method for synthesis of (dl)-norepinephrine acid addition salts using hexamethylenetetramine.
  • the present invention also relates to a novel intermediate formed during the synthesis.
  • norepinephrine 4-[(lR)-2-amino-l-hydroxyethyl]benzene-l,2-diol, commonly known as (R)-(-)- norepinephrine or noradrenaline is a catecholamine with multiple roles including as a hormone and a neurotransmitter.
  • norepinephrine affects parts of the brain where attention and responding actions are controlled.
  • norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle.
  • Norepinephrine also has a neurotransmitter role when released diffusely in the brain as an antiinflammatory agent.
  • norepinephrine acts as a drug it increases blood pressure by increasing vascular tone through a-adrenergic receptor activation.
  • the resulting increase in vascular resistance triggers a compensatory reflex that overcomes its direct stimulatory effects on the heart, called the baroreceptor reflex, which results in a drop in heart rate called reflex bradycardia.
  • (R)-(-)-Norepinephrine was first time disclosed in the US patent US2774789, where it was obtained by resolution of dl-norepinephrine, with optically active acids such as d- tartaric acid, 1-malic acid or N-benzoyl-l-threonine.
  • the patent does not disclose the preparation of dl-norepinephrine.
  • the patent GB747768 describes reduction of amino ketones where 3,4-dihydroxy-a- aminoacetophenone hydrochloride was converted into its d-tartrate salt; followed by reduction of the d-tartrate salt.
  • the US patent US 1680055 discloses the preparation of monohydroxy-a-substituted- aminoacetophenones either by reacting monohydroxy-a-bromoacetophenones with a substituted amine or by reacting protected monohydroxy-a-bromoacetophenones with a substituted amine followed by deprotection.
  • the patent does not disclose the preparation of dihydroxy-a-aminoacetophenones (where amino group is unsubstituted).
  • Acta Chimica Academiae Scientiarum Hungaricae (1951), 1, 395-402 discloses preparation of 3,4-dihydroxy-a-aminoacetophenone from 3,4-dihydroxyphenyloxo acetaldehyde and benzyl amine followed by reduction of benzylamino ketone intermediate.
  • the main disadvantage of this method is that the starting acetaldehyde derivative is very expensive and not easily available.
  • Chinese patent CN101798271A describes reduction of 3,4-dihydroxy-a- aminoacetophenone hydrochloride in water as solvent followed by neutralization with aqueous ammonia. Since dl-norepinephrine has partial solubility in aqueous basic medium result in to loss of product. Also it is necessary to maintain low volume of solvent throughout the process for better yields making the process stringent.
  • European patent EP1930313 discloses preparation of a-amino ketones. The preparation is carried out by reacting an organic sulfide in a polar solvent with a compound containing a leaving group attached to a primary or secondary carbon atom to form a sulfonium salt, which is reacted with a ketone in presence of a base and a polar solvent. Oxiranes obtained are further converted into the corresponding aminoketone, by aminolysis followed by selective oxidation. The following scheme is disclosed in the patent.
  • an object of the invention is to overcome or ameliorate at least one disadvantage of the prior art or to provide a useful alternative.
  • Another object of the invention is to provide a novel, safe, efficient, concise, ecological, high yielding, industrially feasible and simpler process for preparation of (R)-(-)- norepinephrine intermediates.
  • Another object of the invention is to provide a process for synthesis of 3,4-dihydroxy-a- aminoacetophenone salt, which is feasible without protecting both the hydroxyl group on the phenyl ring of acetophenone.
  • Yet another object of the invention is to provide an improved process for hydrogenation of 3,4-dihydroxy-a-aminoacetophenone salt to prepare (dl)-norepinephrine salt.
  • the present invention provides a process for preparation of (dl)-norepinephrine intermediate of formula (III) comprising reacting 3,4- dihydroxy-a-haloacetophenone of formula (I) with hexamine to provide a quaternary ammonium salt of formula (II); followed by hydrolyzing the quaternary ammonium salt of formula (II) with an acid.
  • the present invention provides a novel quaternary ammonium salt of formula (II) and its preparation.
  • the present invention provides a novel process for hydrogenation of 3,4- dihydroxy-a-aminoacetophenone acid salt to provide (dl)-norepinephrine acid addition salt.
  • any of the words 'having', 'including', 'includes', 'comprising' and 'comprises' mean 'including without limitations' and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
  • Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose illustration rather than limitation of the invention as set forth the appended claims.
  • the present invention provides a process for preparation of (R)- norepinephrine intermediate of formula (III),
  • X' is anion selected from the group consisting of CI, Br, I, HSO 4 , alkyl sulfonate, aryl sulfonate, C10 4 or I0 4 , comprising the following steps:
  • Hexamine is an easily accessible reactant; and highly soluble in water and polar organic solvents. The reaction provides selective access to 3,4-dihydroxy-a-aminoacetophenone without side reactions, in short reaction time and relatively mild reaction conditions. Hexamine is not hygroscopic and not subject to change during storage and can be used even after several months. It has very low toxicity and diluted solution can be broken down biologically.
  • Hexamine is conveniently used in an amount relative to 3,4-dihydroxy-a- haloacetophenone, preferably in a range between 1 to 10 equivalents, preferably between 1 to 4 equivalents.
  • the step (a) is carried out in presence of at least one solvent.
  • the solvent is selected from alcohol, chlorinated solvents or mixture thereof.
  • the preferred solvent for the step a is a mixture of isopropanol and chloroform.
  • the step (a) is carried out for 1 to 7 hours.
  • the time required for the step (a) is preferably 3 to 5 hours.
  • the step (a) is carried out at 40 to 80°C.
  • the step (a) is carried out at 55 to 65°C.
  • step (a) is carried out by reacting 3,4-dihydroxy-a- chloroacetophenone with hexamine.
  • the quaternary ammonium salt of formula (II) can be isolated from the reaction mixture or directly used in the subsequent step without isolation.
  • the quaternary ammonium salt is preferably isolated from the reaction mixture.
  • the quaternary ammonium salt is not hygroscopic and not subject to change during storage and can be used even after several months.
  • the acid used for the step (b) is an aqueous acid selected from hydrochloric acid, sulfuric acid, hydrobromic acid, perchloric acid, para-toluenesulfonic acid and hydroiodic acid.
  • the acid used for hydrolysis is preferably hydrochloric acid.
  • the acid is conveniently used in an amount, relative to quaternary ammonium salt of formula (II), preferably in a range between 2 to 20 equivalents, more preferably between 4 to 12 equivalents. The most preferred quantity of the acid is 5 to 8 equivalents.
  • the step (b) is advantageously carried out in a solvent selected from alcohols.
  • the solvent used for the step (b) is preferably alcohol containing 1 to 6 carbon atoms.
  • the most preferred solvent for the step (b) is methanol.
  • the step (b) is carried out for 10 to 25 hours.
  • the time required for the step (b) is preferably 15 to 20 hours.
  • the most preferred time required for the step (b) is 16 to 18 hours.
  • the step (b) is carried out at 30 to 65°C.
  • the preferred temperature for hydrolysis is 40 to 60°C.
  • the present invention provides a novel quaternary ammonium salt of formula (II).
  • the process for preparation of a quaternary ammonium salt of formula (II) comprises reaction of 3,4-dihydroxy-a-haloacetophenone of formula (I) with hexamine.
  • Hexamine is conveniently used in an amount relative to 3,4-dihydroxy-a- haloacetophenone, preferably in a range between 1 to 10 equivalents, preferably between 1 to 4 equivalents.
  • the preparation of the quaternary ammonium salt of formula (II) is advantageously carried out in a solvent selected from alcohol, chlorinated solvents or mixture thereof.
  • the preferred solvent is a mixture of isopropanol and chloroform.
  • the reaction of hexamine and 3,4-dihydroxy-a-haloacetophenone of formula (I) is carried out for 1 to 7 hours. The time required for the reaction is preferably 3 to 5 hours.
  • the reaction of hexamine and 3,4-dihydroxy-a-haloacetophenone of formula (I) is carried out at 40 to 80°C, preferably at 55 to 65°C.
  • the present invention provides a convenient method for hydrogenation of 3,4-dihydroxy-a-aminoacetophenone acid addition salts to provide (dl)-norepinephrine of formula IV; wherein, X' is anion selected from the group consisting of CI, Br, I, HS0 4 , alkyl sulfonate, aryl sulfonate, C10 4 or IO4,
  • Formula IV (dl)-norepinephrine is sparingly soluble in many solvents other than water even in basic pH. Thus when the reaction is carried out in solvents other than water the product can be isolated in maximum yields and purity.
  • the process of hydrogenation is preferably carried out in presence of a catalyst.
  • the catalyst is selected from platinum or palladium on carbon.
  • the preferred catalyst used for hydrogenation is palladium on carbon.
  • Hydrogenation is carried out for 3 to 20 hours. The time required for hydrogenation is preferably 5 to 20 hours. Hydrogenation is carried out at 25 - 80°C. The preferred temperature for hydrogenation is 40 - 50°C.
  • Hydrogenation is carried out in presence of a solvent.
  • the solvent is selected from polar solvents. The most preferred solvent for hydrogenation is methanol.
  • the compound of formula (IV) is converted to (R)-(-)-norepinephrine bitartrate by methods known in the art.
  • the pure (R)-(-)-norepinephrine bitartrate obtained by the process of the invention may be formulated into a dosage form by combining with one or more pharmaceutically acceptable excipients using known techniques. Further the dosage form may be immediate release or extended release.

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

Abstract

La présente invention concerne un procédé de préparation de sel de norépinéphrine (dl) par réaction de 3,4-dihydroxy-a-haloacétophénone avec de l'hexaméthylènetétramine pour donner un sel d'hexamine ; puis par hydrolyse et hydrogénation. L'invention concerne également un nouvel intermédiaire formé dans le procédé et sa synthèse.
PCT/IN2011/000728 2011-07-13 2011-10-20 Procédé de préparation d'un sel d'addition d'acide de norépinéphrine (dl), intermédiaire clé de la norépinéphrine (r) - (-) - WO2013008247A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2017/MUM/2011 2011-07-13
IN2017MU2011 2011-07-13

Publications (1)

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WO2013008247A1 true WO2013008247A1 (fr) 2013-01-17

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013111605A1 (fr) 2012-01-25 2013-08-01 Sharp Kabushiki Kaisha Procédés de décodage vidéo et procédés de codage vidéo
CN107298646A (zh) * 2017-06-15 2017-10-27 江西永通科技股份有限公司 一种去甲基肾上腺素的制备方法
CN108069863A (zh) * 2016-11-17 2018-05-25 武汉武药制药有限公司 一种合成去甲肾上腺素的方法
EP3725765A1 (fr) 2019-04-18 2020-10-21 Edmond Pharma S.R.L. Procédé de préparation de noradrénaline énantiomériquement pure
CN112079733A (zh) * 2020-09-25 2020-12-15 南京仁为医药科技有限公司 一种不对称合成重酒石酸去甲肾上腺素的方法
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
CN114394907A (zh) * 2022-03-03 2022-04-26 福安药业集团宁波天衡制药有限公司 一种重酒石酸去甲肾上腺素的制备方法
US11413259B2 (en) 2017-01-30 2022-08-16 Nevakar Injectables Inc. Norepinephrine compositions and methods therefor
CN115850096A (zh) * 2022-12-27 2023-03-28 武汉嘉诺康医药技术有限公司 一种高纯度外消旋去甲肾上腺素的制备方法
CN116041194A (zh) * 2021-10-28 2023-05-02 武汉武药制药有限公司 去甲肾上腺酮盐酸盐的合成方法
CN116675612A (zh) * 2023-08-03 2023-09-01 北京元延医药科技股份有限公司 动态动力学拆分消旋去甲肾上腺素的方法

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US1680055A (en) 1926-03-22 1928-08-07 Legerlotz Helmut Monooxy-omega-aminoacetophenone derivatives
GB747768A (en) 1953-07-01 1956-04-11 Carnegies Of Welwyn Ltd Reduction of aminoketones
US2774789A (en) 1947-10-24 1956-12-18 Sterling Drug Inc 1-arterenol and its acid-addition salts and preparation thereof
US2786871A (en) 1954-03-26 1957-03-26 Winterhalder Ludwig Process for the preparation of aminomethyl-(monohydroxyphenyl)-ketones
EP1930313A2 (fr) 2004-07-08 2008-06-11 Ciba Holding Inc. Préparation d'alpha-aminocétones
CN101798271A (zh) 2010-03-15 2010-08-11 杭州亚培克生物科技有限公司 一种(±)-去甲肾上腺素的制备方法

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US1680055A (en) 1926-03-22 1928-08-07 Legerlotz Helmut Monooxy-omega-aminoacetophenone derivatives
US2774789A (en) 1947-10-24 1956-12-18 Sterling Drug Inc 1-arterenol and its acid-addition salts and preparation thereof
GB747768A (en) 1953-07-01 1956-04-11 Carnegies Of Welwyn Ltd Reduction of aminoketones
US2786871A (en) 1954-03-26 1957-03-26 Winterhalder Ludwig Process for the preparation of aminomethyl-(monohydroxyphenyl)-ketones
EP1930313A2 (fr) 2004-07-08 2008-06-11 Ciba Holding Inc. Préparation d'alpha-aminocétones
CN101798271A (zh) 2010-03-15 2010-08-11 杭州亚培克生物科技有限公司 一种(±)-去甲肾上腺素的制备方法

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013111605A1 (fr) 2012-01-25 2013-08-01 Sharp Kabushiki Kaisha Procédés de décodage vidéo et procédés de codage vidéo
CN108069863A (zh) * 2016-11-17 2018-05-25 武汉武药制药有限公司 一种合成去甲肾上腺素的方法
CN108069863B (zh) * 2016-11-17 2020-08-11 武汉武药制药有限公司 一种合成去甲肾上腺素的方法
US11602508B2 (en) 2017-01-30 2023-03-14 Nevakar Injectables Inc. Norepinephrine compositions and methods therefor
US11413259B2 (en) 2017-01-30 2022-08-16 Nevakar Injectables Inc. Norepinephrine compositions and methods therefor
CN107298646A (zh) * 2017-06-15 2017-10-27 江西永通科技股份有限公司 一种去甲基肾上腺素的制备方法
US10865180B2 (en) 2018-08-10 2020-12-15 Harman Finochem Limited Process for the preparation of l-Norepinephrine bitartrate monohydrate having high enantiomeric purity
EP3725765A1 (fr) 2019-04-18 2020-10-21 Edmond Pharma S.R.L. Procédé de préparation de noradrénaline énantiomériquement pure
WO2020212157A1 (fr) 2019-04-18 2020-10-22 Edmond Pharma S.R.L. Procédé de préparation de norépinéphrine énantiomériquement pure
CN112079733A (zh) * 2020-09-25 2020-12-15 南京仁为医药科技有限公司 一种不对称合成重酒石酸去甲肾上腺素的方法
CN112079733B (zh) * 2020-09-25 2022-09-06 南京仁为医药科技有限公司 一种不对称合成重酒石酸去甲肾上腺素的方法
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
CN116041194A (zh) * 2021-10-28 2023-05-02 武汉武药制药有限公司 去甲肾上腺酮盐酸盐的合成方法
CN114394907A (zh) * 2022-03-03 2022-04-26 福安药业集团宁波天衡制药有限公司 一种重酒石酸去甲肾上腺素的制备方法
CN115850096A (zh) * 2022-12-27 2023-03-28 武汉嘉诺康医药技术有限公司 一种高纯度外消旋去甲肾上腺素的制备方法
CN116675612A (zh) * 2023-08-03 2023-09-01 北京元延医药科技股份有限公司 动态动力学拆分消旋去甲肾上腺素的方法
CN116675612B (zh) * 2023-08-03 2023-10-10 北京元延医药科技股份有限公司 动态动力学拆分消旋去甲肾上腺素的方法

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