WO2018055642A1 - Procédé de préparation de bromure de tiotropium et de ses intermédiaires - Google Patents

Procédé de préparation de bromure de tiotropium et de ses intermédiaires Download PDF

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Publication number
WO2018055642A1
WO2018055642A1 PCT/IN2017/050417 IN2017050417W WO2018055642A1 WO 2018055642 A1 WO2018055642 A1 WO 2018055642A1 IN 2017050417 W IN2017050417 W IN 2017050417W WO 2018055642 A1 WO2018055642 A1 WO 2018055642A1
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WIPO (PCT)
Prior art keywords
formula
compound
carried out
protecting group
reducing
Prior art date
Application number
PCT/IN2017/050417
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English (en)
Inventor
G. Nithun REDDY
G. Samhitha REDDY
G. Madaalasa REDDY
M Ramani
G. Pratap REDDY
Original Assignee
Gbr Laboratories Pvt. Ltd.
Rachana Pharma Tech
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 Gbr Laboratories Pvt. Ltd., Rachana Pharma Tech filed Critical Gbr Laboratories Pvt. Ltd.
Publication of WO2018055642A1 publication Critical patent/WO2018055642A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Definitions

  • the present invention relates to a process for preparing tiotropium bromide and more particularly, to an improved process for preparing tiotropium bromide and intermediates thereof.
  • Tiotropium bromide chemically described as (1 ,2 ⁇ f,4 ⁇ f,7 ⁇ f)-7-[(hydroxidi-2- thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0 2,4 ] nonane bromide is an anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease. Tiotropium bromide is a very potent agent and therefore even very small amounts show therapeutic effect. Many known processes of synthesis of tiotropium bromide involve the use of Datura seeds as a natural source for natural route of synthesis.
  • D escri bed herei n i s a process for synthesi s of ti otropi um bromi de starti ng from opti cal ly pure dimethyl tartarate.
  • a lso described is synthesis of scopine starting from optically pure dimethyl tartarate.
  • tiotropium bromide of Formula 1 comprising
  • the protecting group is benzyl, para- methoxy benzyl, p-nitrophenyl, or trityl. In some embodiments of the process described above, the protecting group is benzyl.
  • step (ii) is carried out in the presence of sodium borohydride. In some of such embodiments, the reduction is carried out at a temperature of about 50 °C to about 70 °C .
  • the oxidation in step (iii) is a carried out in the presence of dimethyl sulfoxide, oxalyl chloride and tri ethyl amine. In other embodiments of the process described above, the oxidation in step (iii) is carried out in the presence of bis(acetoxy)iodobenzene (BAIB) and 2,2,6, 6-tetramethyl-1 -pi peri dinyloxy (T E MPO).
  • BAIB bis(acetoxy)iodobenzene
  • T E MPO 2,2,6, 6-tetramethyl-1 -pi peri dinyloxy
  • the condensing in step (iv) is carried out in refluxing alcohol.
  • the alcohol is methanol, ethanol, propanol, isopropanol or butanol, or a combination thereof.
  • the reduction in step (v) is carried out in the presence of sodium borohydride. In some of such embodiments, the reduction is carried out at a temperature of about 50 °C to about 70 °C .
  • the deprotection is carried out by hydrogenation.
  • the epoxide formation is carried out in the presence of di i sopropyl azodi carboxyl ate ( D IA D and tri phenyl phosphi ne.
  • Bn is a protecting group
  • Bn is a protecting group
  • R is methyl, vinyl, phenyl and di (thiophen-2-yl) methanol
  • the present invention provides a process for preparing tiotropium bromide and intermediates thereof.
  • the process of the present invention is a synthetic, eco-friendly, non- hazardous and cost effective process.
  • the process described herein utilizes dialkyl tartarate as a starting material for the synthesis of scopine and tiotropium bromide via a double Mannich reaction (Robinson-Schopf reaction).
  • the use of 2,3-Bis(benzyloxy)succinaldehyde in a Robinson-Schopf reaction, as for the process described herein, has not been disclosed previously.
  • An embodiment of the present invention relates to a process for preparing tiotropium bromide of Formula 1.
  • the process comprises benzylating (+)-di methyl tartrate of Formula 2 with benzyl bromide to form dimethyl di benzyl tartarate of Formula 3. Further, dimethyl di benzyl tartarate of Formula 3 is reduced using sodium borohydride in the presence of a solvent to form diol compound of Formula 4.
  • the solvent is selected from alcohols such as ethanol, methanol, propanol, isopropanol and butanol.
  • Other reducing agents such as L ithium aluminium hydride are contemplated within the scope of embodiments presented herein.
  • the diol compound of Formula 4 is oxidised to form a di aldehyde compound of Formula 5.
  • the reaction is carried out under Swern conditions using dimethyl sulfoxide and oxalyl chloride in the presence of dry dichloromethane.
  • diol compound of Formula 4 is oxidised using bis(acetoxy)iodobenzene (BAIB) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TE M PO) to form dialdehyde compound of Formula 5.
  • BAIB bis(acetoxy)iodobenzene
  • TE M PO 2,2,6,6-tetramethyl-1-piperidinyloxy
  • Other methods of oxidation such as o-iodoxybenzoic acid (IBX ) mediated oxidation are also contemplated within the scope of embodiments presented herein.
  • the dialdehyde compound of Formula 5 is condensed by Mannich reaction using methylamine hydrochloride and acetone- 1,3-dicarboxylic acid to form tropinone compound of Formula 6.
  • tropinone compound of Formula 6 is reduced using sodium borohydride in the presence of a solvent to form secondary alcohol compound of Formula 7.
  • the solvent is selected from alcohols such as ethanol, methanol, propanol, i sopropanol and butanol .
  • the compound of Formula 7 is esterified by Steglich esterifi cation using 2- hydroxy-2,2-di(thiophen-2-yl)acetic acid, dicyclohexylcarbodiimide and p- di methyl ami nopyri dine to form ester compound of Formula 8.
  • Other suitable methods of esterifi cation are also contemplated with the scope of embodiments presented herein.
  • the ester compound of Formula 8 is reacted with methyl bromide in the presence of a solvent to form a quaternary ammonium salt of Formula 9.
  • the solvent is selected from alcohols such as ethanol, methanol, propanol and butanol.
  • the quaternary ammonium salt of Formula 9 is debenzylated using palladium on carbon (Pd/C) in the presence of ethyl acetate to form a diol compound of Formula 10.
  • the diol compound of Formula 10 is reacted with diisopropyl azodicarboxylate (DIA D) and and tri phenyl phosphine to form compound of Formula 1.
  • DIA D diisopropyl azodicarboxylate
  • the synthetic scheme provided above may be suitably modified for the synthesis of scopine.
  • the hydroxy moiety in the compound of Formula 7 may be esterified with a suitable protection group, followed by removal of the Bn protecting group, optionally quarterni zati on of the amine, and epoxide formation. Ester hydrolysis deprotection then furnishes scopine as free base or, optionally as a quarternary salt.

Abstract

L'invention concerne un procédé de synthèse de bromure de tiotropium et un procédé de synthèse de scopine à partir d'un composé de tartrate de diméthyle. La séquence synthétique comprend une double réaction de Mannich (réaction de Robinson-Schopf).
PCT/IN2017/050417 2016-09-23 2017-09-21 Procédé de préparation de bromure de tiotropium et de ses intermédiaires WO2018055642A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201641032567 2016-09-23
IN201641032567 2016-09-23

Publications (1)

Publication Number Publication Date
WO2018055642A1 true WO2018055642A1 (fr) 2018-03-29

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418716A1 (fr) * 1989-09-16 1991-03-27 Boehringer Ingelheim Kg Esters aminoalcohol d'acide thienylcarboxyliques leurs produits quaternaires, leur préparation et l'utilisation de ces composés
US6486321B2 (en) * 2000-12-22 2002-11-26 Boehringer Ingelheim Pharma Kg Process for preparing an anticholinergic
US20130030182A1 (en) * 2010-04-01 2013-01-31 Mahmut Bilgic Methods for the synthesis of tiotropium bromide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418716A1 (fr) * 1989-09-16 1991-03-27 Boehringer Ingelheim Kg Esters aminoalcohol d'acide thienylcarboxyliques leurs produits quaternaires, leur préparation et l'utilisation de ces composés
US6486321B2 (en) * 2000-12-22 2002-11-26 Boehringer Ingelheim Pharma Kg Process for preparing an anticholinergic
US20130030182A1 (en) * 2010-04-01 2013-01-31 Mahmut Bilgic Methods for the synthesis of tiotropium bromide

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BROWN, MELANCTHON S. ET AL.: "THE REDUCTION OF ESTERS WITH SODIUM BOROHYDRIDE", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 28, no. 11, 1963, pages 3261 - 3263, XP002638930 *
CHAIKIN, SAUL W. ET AL.: "REDUCTION OF ALDEHYDES, KETONES AND ACID CHLORIDES BY SODIUM BOROHYDRIDE", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 71, no. 1, 1949, pages 122 - 125, XP055498034 *
DE MICO, ANTONELLA ET AL.: "A VERSATILE AND HIGHLY SELECTIVE HYPERVALENT IODINE (III)/2, 2, 6, 6-TETRAMETHYL-1-PIPERIDINYLOXYL-MEDIATED OXIDATION OF ALCOHOLS TO CARBONYL COMPOUNDS", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 62, no. 20, 3 October 1997 (1997-10-03), pages 6974 - 6977, XP000740746 *
OMURA, KANJI ET AL.: "OXIDATION OF ALCOHOLS BY ''ACTIVATED'' DIMETHYL SULFOXIDE. A PREPARATIVE, STERIC AND MECHANISTIC STUDY", TETRAHEDRON, vol. 34, no. 11, 1978, pages 1651 - 1660, XP003030809 *
POLLINI, GIAN P. ET AL.: "SYNTHETIC APPROACHES TO ENANTIOMERICALLY PURE 8-AZABICYCLO [3.2. 1] OCTANE DERIVATIVES", CHEMICAL REVIEWS, vol. 106, no. 6, 2006, pages 2434 - 2454, XP055498029 *
ROBINSON, PHILIP L. ET AL.: "REGIOSELECTIVE CYCLODEHYDRATION OF CHIRAL DIOLS WITH DIETHOXYTRIPHENYLPHOSPHORANE, TRIPHENYLPHOSPHINE-TETRACHLOROMETHANE-POTASSIUM CARBONATE, AND TRIPHENYLPHOSPHINE-DIETHYL AZODICARBOXYLATE REAGENTS. A COMPARATIVE STUDY", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 48, no. 26, 1983, pages 5396 - 5398, XP055498026 *
SARTORI, GIOVANNI ET AL.: "PROTECTION (AND DEPROTECTION) OF FUNCTIONAL GROUPS IN ORGANIC SYNTHESIS BY HETEROGENEOUS CATALYSIS", CHEMICAL REVIEWS, vol. 104, no. 1, 2004, pages 199 - 250, XP055129088 *

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