WO2017046814A1 - Procédé sûr et respectueux de l'environnement permettant de produire de la nalbuphine ou ses sels pharmaceutiquement acceptables - Google Patents

Procédé sûr et respectueux de l'environnement permettant de produire de la nalbuphine ou ses sels pharmaceutiquement acceptables Download PDF

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Publication number
WO2017046814A1
WO2017046814A1 PCT/IN2016/050305 IN2016050305W WO2017046814A1 WO 2017046814 A1 WO2017046814 A1 WO 2017046814A1 IN 2016050305 W IN2016050305 W IN 2016050305W WO 2017046814 A1 WO2017046814 A1 WO 2017046814A1
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WO
WIPO (PCT)
Prior art keywords
nalbuphine
process according
methyl
base
pharmaceutically acceptable
Prior art date
Application number
PCT/IN2016/050305
Other languages
English (en)
Inventor
Kunal Naveen SAXENA
Malcolm Prakash MASCARENHAS
Nitin Punjaji LAD
Shashikant Malagoud PATIL
Original Assignee
Rusan Pharma Limited
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 Rusan Pharma Limited filed Critical Rusan Pharma Limited
Publication of WO2017046814A1 publication Critical patent/WO2017046814A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom

Definitions

  • the present invention relates to a short, simplified and eco-friendly process for producing Nalbuphine or its pharmaceutically acceptable salts thereof.
  • the process of the present invention avoids use of any hazardous, corrosive and pyrophoric chemicals and the resultant product formed is substantially free of impurities.
  • Nalbuphine which is chemically known as (-)-17-(cyclobutylmethyl)-4,5a- epoxymorphinan-3,6a,14-triol, a semi-synthetic narcotic used commercially as partial agonist-antagonist analgesic for relief of moderate to severe pain.
  • narcotic antagonist Naloxone
  • oxymorphone the potent narcotic analgesic
  • Nalbuphine is synthesized from normorphinan compounds such as noroxycodone, noroxymorphone, noroxymorphol that lack substitution on the nitrogen atom of the heterocyclic ring and contains 14 ⁇ - ⁇ group. These normorphinan compounds are derived from naturally occurring opiates such as morphine, codeine, oripavine and thebaine. Nalbuphine is the only opioid analgesic that is not a controlled substance in the United States. Nalbuphine was first reported in GB 1119270 (which has US equivalent, US3393197). Two methods are described in example 5 of GB'270 for the preparation of nalbuphine.
  • Method (a) discloses reaction of 14- hydroxydihydronormorphinone with cyclobutyl carbonyl chloride in DCM followed by reduction using LiAlH4 in THF; whereas method (b) discloses reacting 14-hydroxydihydronormorphinone with cyclobutylmethyl bromide in DMF followed by reduction with NaBH4 to give nalbuphine.
  • the processes are given in Scheme 1 below:
  • a-noroxymorphol is reacted with cyclobutanecarbonyl chloride to form N,C"3- bis(cyclobutylcarbonyl)-a-noroxymorpholand/orN- cyclobutylcarbonyl -a-noroxymorphol followed by reducing the N,Cb- bis(cyclobutylcarbonyl)-a-noroxymorphol and/or N-cyclobutylcarbonyl-a- noroxy morphol with LiAlH 4 to produce nalbuphine.
  • Synthetic Communication 1992 discloses demethylation, from its precursor, using DL methionine /methane sulfonic acid.
  • WO2006035195 discloses the preparation of nalbuphine from noroxymorphone and cyclobutane carboxaldehyde, via reductive alkylation, as shown below in Scheme 4.
  • Step VIII relates to conversion of intermediate compound 14-hydroxy nordihydro codeine to N-cyclobutyl carbonyl -14- hydroxy nordihydrocodeine using cyclobutyl carbonyl chloride. This is followed by reduction of N-cyclobutyl carbonyl- 14-hydroxy nordihydrocodeine using LiAlH4 to yield N-cyclobutyl methyl- 14-hydroxy nordihydrocodeine and further demethylation of hydroxy protected group (at C-3) using hydrobromic acid and sodium bromide to obtain the end product.
  • Nalbuphine which contain an ortho-alkoxyphenolic moiety can undergo auto oxidative carbon-carbon coupling to yield primarily the 2, 2' dimer. Further, during synthesis difference in the orientation of the hydroxyl moiety at the 6- position lead to formation of ⁇ -epimer of nalbuphine.
  • the process comprises direct condensation of cyclobutyl methyl bromide with 14-hydroxy nordihydrocodeine to obtain methyl nalbuphine.
  • the 3-O-demethylation of methyl nalbuphine is performed using alkane thiol in presence of a strong base to yield nalbuphine in good yield and purity.
  • nalbuphine is converted into its hydrochloride salt using conventional methods.
  • the present invention discloses a short, simplified and eco-friendly process for producing nalbuphine or its pharmaceutically acceptable salts, substantially free of impurities, comprising;
  • the alkane thiol is selected from the group consisting of straight chain n-alkane thiols, branched chain alkane thiols, cyclic alkane thiols, dithiols, alkali metal salts thereof, and mixtures thereof.
  • the alkane thiol is selected from the group consisting of ethanethiol, pentanethiol, heptanethiol, and mixtures thereof.
  • the solvents for the process are selected from polar protic or aprotic solvents such as ethanol, propanol, isopropanol, DMF, THF, acetone and the like.
  • the base is selected from organic or inorganic base.
  • the organic base is selected from ethylamine, trimethylamine, pyridine, potassium tertiary butoxide and the like.
  • the inorganic bases are selected from alkali or alkaline earth metal carbonates and bicarbonates.
  • 3-O-demethylation can be performed at a much lower temperature than the prior art method using alkane thiol in presence of base.
  • the lower temperature reduces the formation of undesirable impurity which tends to form when the reaction is performed at a higher temperature for example between 210°C and 220°C. This can impact the yield and purity of the final product.
  • the 3-O-demethylation of methyl nalbuphine is carried at a temperature in the range of 120-135°C for 2-4 hrs.
  • Nalbuphine obtained by the process of the present invention is substantially free of impurities such as methyl nalbuphine, beta-nalbuphine and bisnalbuphine.
  • impurities such as methyl nalbuphine, beta-nalbuphine and bisnalbuphine.
  • 14-hydroxy nordihydrocodeine as the starting material also reduces the steps of the process and renders the synthesis economical.
  • Nalbuphine is converted into its hydrochloride salt using conventional methods.
  • the details of the invention given in the examples which are provided below are for illustration only and therefore these examples should not be construed to limit the scope of the invention.
  • Nalbuphine base obtained is further converted to its pharmaceutical salt by a method known in the art.

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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 court, simplifié et respectueux de l'environnement permettant de produire de la Nalbuphine ou ses sels pharmaceutiquement acceptables En particulier, le procédé selon la présente invention évite l'utilisation de produits chimiques dangereux, corrosifs et pyrophores, et le produit formé est sensiblement dépourvu d'impuretés.
PCT/IN2016/050305 2015-09-14 2016-09-13 Procédé sûr et respectueux de l'environnement permettant de produire de la nalbuphine ou ses sels pharmaceutiquement acceptables WO2017046814A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3517/MUM/2015 2015-09-14
IN3517MU2015 2015-09-14

Publications (1)

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WO2017046814A1 true WO2017046814A1 (fr) 2017-03-23

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Application Number Title Priority Date Filing Date
PCT/IN2016/050305 WO2017046814A1 (fr) 2015-09-14 2016-09-13 Procédé sûr et respectueux de l'environnement permettant de produire de la nalbuphine ou ses sels pharmaceutiquement acceptables

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WO (1) WO2017046814A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3393197A (en) * 1966-01-19 1968-07-16 Endo Lab Nu-substituted-14-hydroxydihydronormorphines
US8981097B2 (en) * 2013-06-11 2015-03-17 Rusan Pharma Limited Industrial process for the preparation of buprenorphine and its intermediates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3393197A (en) * 1966-01-19 1968-07-16 Endo Lab Nu-substituted-14-hydroxydihydronormorphines
US8981097B2 (en) * 2013-06-11 2015-03-17 Rusan Pharma Limited Industrial process for the preparation of buprenorphine and its intermediates

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