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WO2011015884A1 - Procédé pour préparer des esters de scopine - Google Patents

Procédé pour préparer des esters de scopine Download PDF

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Publication number
WO2011015884A1
WO2011015884A1 PCT/GB2010/051312 GB2010051312W WO2011015884A1 WO 2011015884 A1 WO2011015884 A1 WO 2011015884A1 GB 2010051312 W GB2010051312 W GB 2010051312W WO 2011015884 A1 WO2011015884 A1 WO 2011015884A1
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WO
WIPO (PCT)
Prior art keywords
process according
base
tiotropium
tiotropium bromide
scopine
Prior art date
Application number
PCT/GB2010/051312
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English (en)
Inventor
Vinayak Govind Gore
Bindu Manojkumar
Dattatraya Shinde
Dattatrey Kokane
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Generics [Uk] Limited
Mylan India Private Limited
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Application filed by Generics [Uk] Limited, Mylan India Private Limited filed Critical Generics [Uk] Limited
Publication of WO2011015884A1 publication Critical patent/WO2011015884A1/fr

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    • 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 novel processes for the preparation of scopine esters and their quaternary salts.
  • the present invention relates to a process for the preparation of tiotropium bromide, pharmaceutical compositions comprising tiotropium bromide and the use of such compositions in the treatment of respiratory disorders.
  • Tiotropium bromide (1) is a highly effective anticholinergic agent with a specificity for muscarinic receptors and it is presently approved for the treatment of respiratory disorders, such as asthma or chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
  • COPD chronic obstructive pulmonary disease
  • Tiotropium bromide is used in low (microgram) therapeutic doses and it is therefore particularly necessary to develop an industrial process for the commercial preparation of tiotropium bromide which ensures that the product is prepared not only in a good, economical yield but also with exceptional purity.
  • tiotropium bromide A process for the preparation of tiotropium bromide was first reported in EP0418716.
  • This method of synthesising tiotropium bromide describes, in a first step, the transesterification reaction of scopine (2) with methyl di-(2-thienyl)glycolate (4) to form the di-(2- thienyl)glycolic acid scopine ester (3), which will be referred to herein as tiotropium base (3).
  • the tiotropium base (3) is then quaternised with methyl bromide to form tiotropium bromide.
  • hazardous reagents such as sodium metal are used for the transesterification step to form the tiotropium base (3).
  • the yields for the preparation of the tiotropium base (3) are low with an HPLC purity around 45-50% - the remaining impurity being di-(2-thienyl)glycolic acid (5).
  • the reported process is also inconvenient, since the tiotropium base (3) needs to be isolated and purified before quaternisation to afford tiotropium bromide (1).
  • an "alkyl” group is defined as a monovalent saturated hydrocarbon, which may be straight-chained or branched, or be or include cyclic groups.
  • An alkyl group may optionally be substituted, and may optionally include one or more heteroatoms N, O or S in its carbon skeleton.
  • Preferably an alkyl group is straight- chained or branched.
  • Preferably an alkyl group is not substituted.
  • an alkyl group does not include any heteroatoms in its carbon skeleton.
  • alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
  • an alkyl group is a C 1 12 alkyl group, preferably a C 1 6 alkyl group.
  • a cyclic alkyl group is a C 3 12 cyclic alkyl group, preferably a C 5 7 cyclic alkyl group.
  • alkenyl is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon double bond, which may be straight-chained or branched, or be or include cyclic groups.
  • An alkenyl group may optionally be substituted, and may optionally include - A - one or more heteroatoms N, O or S in its carbon skeleton.
  • Preferably an alkenyl group is straight-chained or branched.
  • an alkenyl group is not substituted.
  • an alkenyl group does not include any heteroatoms in its carbon skeleton.
  • alkenyl groups are vinyl, allyl, but-1-enyl, but-2-enyl, cyclohexenyl and cycloheptenyl groups.
  • an alkenyl group is a C 2 12 alkenyl group, preferably a C 2 6 alkenyl group.
  • a cyclic alkenyl group is a C 3 12 cyclic alkenyl group, preferably a C 5 7 cyclic alkenyl group.
  • alkynyl is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon triple bond, which may be straight-chained or branched, or be or include cyclic groups.
  • An alkynyl group may optionally be substituted, and may optionally include one or more heteroatoms N, O or S in its carbon skeleton.
  • Preferably an alkynyl group is straight-chained or branched.
  • Preferably an alkynyl group is not substituted.
  • an alkynyl group does not include any heteroatoms in its carbon skeleton. Examples of alkynyl groups are ethynyl, propargyl, but-1-ynyl and but-2-ynyl groups.
  • an alkynyl group is a C 2 12 alkynyl group, preferably a C 2 6 alkynyl group.
  • a cyclic alkynyl group is a C 5 12 cyclic alkynyl group, preferably a C 5 7 cyclic alkynyl group.
  • aryl is defined as a monovalent aromatic hydrocarbon.
  • An aryl group may optionally be substituted, and may optionally include one or more heteroatoms N, O or S in its carbon skeleton.
  • Preferably an aryl group is not substituted.
  • Examples of aryl groups are phenyl, naphthyl, anthracenyl, phenanthrenyl, thienyl and furyl groups.
  • Preferably an aryl group is a C 4 14 aryl group, preferably a C 4 10 aryl group.
  • arylalkyl arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl
  • the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • a typical example of an arylalkyl group is benzyl.
  • an "alkoxy” group is defined as a -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-arylalkyl, -O-arylalkenyl, -O-arylalkynyl, -O-alkylaryl, -O -alkenylaryl or -O -alkynylaryl group.
  • an "alkoxy” group is a -O-alkyl or -O-aryl group. More preferably an "alkoxy" group is a -O-alkyl group.
  • a "halo" group is a fiuoro, chloro, bromo or iodo group.
  • an optionally substituted group may be substituted with one or more of -F, -Cl, -Br, -I, -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -OH, -SH, -NH 2 , -CN, -NO 2 , -COOH, -R a -O-R b , -R a -S-R b , -R a -N(R b ) 2 , -R a -N(R b ) 3 + , -R a -P(R b ) 2 , -R a -Si(R b ) 3 , -R a -CO-R b , -R a -CO-OR b , -R a O-CO-R b , -R a -CO-N(R b ) 2 ,
  • -R a - is independently a chemical bond, a C 1 -C 10 alkylene, C 2 -C 10 alkenylene or C 2 -C 10 alkynylene group.
  • -R b is independently hydrogen, unsubstituted C 1 -C 6 alkyl or unsubstituted C 6 -C 10 aryl.
  • an optionally substituted group may be substituted with one or more of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halo or haloalkyl, all unsubstituted.
  • Optional substituent(s) are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituent(s).
  • a substituted group comprises 1, 2 or 3 substituents, more preferably 1 or 2 substituents, and even more preferably 1 substituent.
  • a compound is "substantially pure", if it comprises less than 1% impurity by HPLC, preferably less than 0.5%, preferably less than 0.3%, preferably less than 0.2%, preferably less than 0.1%.
  • 1 volume or “1 vol” means that for each gram of starting material 1 ml of solvent is used.
  • 2 volumes or “2 vol” and “3 volumes” or “3 vol” etc. are used accordingly.
  • the present inventors were interested in preparing highly pure tiotropium and related compounds by the most convenient and shortest route, which avoids the use of hazardous and/or environmentally unsuitable reagents.
  • the processes reported in the prior art, as described above, are not very efficient or convenient for commercial manufacture of pure product and an alternative method is required. Therefore the present invention provides an efficient, simple and non-hazardous process for the preparation of tiotropium bromide (1), tiotropium base (3) and related compounds.
  • a first aspect of the present invention provides a process for the preparation of the scopine ester I or its quaternary salt II
  • R 1 and R 2 independently represent hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, or optionally substituted arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl,
  • R 3 represents alkyl, alkenyl, alkynyl, optionally substituted aryl, or optionally substituted arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, and
  • X represents a pharmaceutically acceptable anion
  • transesterification reaction is performed in the presence of an organic base and an inorganic base, wherein the inorganic base is selected from metal carbonates, metal bicarbonates and metal hydroxides.
  • R 1 represents alkyl, alkenyl, alkynyl, optionally substituted aryl, or optionally substituted arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl.
  • R 1 is represented by formula III, wherein R 4 , R and R independently represent hydrogen, hydroxy, halo, alkoxy, alkyl, hydroxyalkyl, alkenyl, alkynyl, optionally substituted aryl, or optionally substituted arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl.
  • R 2 represents alkyl, alkenyl, alkynyl, optionally substituted aryl, or optionally substituted arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl.
  • R 2 represents alkyl, preferably C 1 -C 4 -alkyl, and most preferably R 2 represents methyl.
  • R 3 represents alkyl, preferably C 1 -C 4 -alkyl, and most preferably R 3 represents methyl.
  • R 4 and/or R 5 represent aryl, wherein the aryl group can be independently selected from phenyl, naphthyl, thienyl and furyl, each of which may optionally be mono- or disubstituted by one or two groups independently selected from C 1 -C 4 -alkyl, C 1 -C 4 - alkoxy, hydroxy, halo or haloalkyl. Most preferably, the aryl group is 2-thienyl.
  • R 6 represents hydroxy, Q-Q-alkyl, C 1 -C 4 -alkoxy, hydroxyalkyl, halo or haloalkyl. Most preferably, R 6 represents hydroxy.
  • X represents halo, methanesulfonate, toluenesulfonate or trifluoromethanesulfonate. Most preferably, X represents bromo.
  • R 1 is represented by formula III, and R 4 is 2-thienyl, R 5 is 2-thienyl and R 6 is hydroxy.
  • R 2 is methyl and X is bromo.
  • the organic base is an organic amine base, preferably selected from a trialkylamine, such as triethylamine or diisopropylethylamine, or a heterocyclic amine, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo [2.2.2] octane (Dabco), pyridine or 4- (dimethylamino) pyridine (DMAP).
  • the organic base is DBU.
  • the organic base is a metal carbonate, a metal bicarbonate, a metal hydroxide or a mixture thereof.
  • the metal is selected from sodium, potassium, lithium, calcium, magnesium or mixtures thereof.
  • the inorganic base is a metal carbonate, wherein the metal is preferably selected from sodium, potassium, lithium, calcium, magnesium or mixtures thereof.
  • the inorganic base is potassium carbonate or sodium carbonate. Most preferably, the inorganic base is potassium carbonate.
  • 0.5-3 equivalents of the inorganic base are used relative to the scopine or the salt thereof, preferably about 1 equivalent of the inorganic base is used.
  • a particularly preferred process according to the first aspect of the present invention is a process for the preparation of tiotropium base or tiotropium bromide comprising transesterification of scopine, or a salt thereof, with methyl di-(2-thienyl)glycolate in the presence of an organic base and an inorganic base, wherein the inorganic base is selected from metal carbonates, metal bicarbonates and metal hydroxides.
  • the organic base is an organic amine base, preferably selected from a trialkylamine, such as triethylamine or diisopropylethylamine, or a heterocyclic amine, such as 1,8- diazabicyclo [5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2] -octane (Dabco), pyridine or 4-(dimethylamino)pyridine (DMAP), and most preferably the organic base is DBU.
  • a trialkylamine such as triethylamine or diisopropylethylamine
  • a heterocyclic amine such as 1,8- diazabicyclo [5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]
  • the organic base is 1-5 equivalents of the organic base, preferably 2-4 equivalents of the organic base are used, preferably about 3 equivalents of the organic base are used.
  • the inorganic base is a metal carbonate, preferably sodium, potassium, lithium, calcium or magnesium carbonate or a mixture thereof, more preferably sodium carbonate or potassium carbonate, most preferably potassium carbonate.
  • 0.5-3 equivalents of the metal carbonate are used relative to the scopine or the salt thereof, preferably about 1 equivalent of the metal carbonate is used.
  • the organic and inorganic bases may be used in any order, i.e. one base may be added to the reaction mixture before, after and/or simultaneous with another base.
  • the inorganic base is added before the organic base.
  • the bases are believed to deprotonate the scopine hydroxyl group and/or a protonated reaction intermediate.
  • the bases in particular the inorganic base, are believed to liberate scopine free base in situ.
  • the reaction temperature used in the trans esterification step is preferably in the range of 30 to 90 0 C, more preferably in the range of 40 to 70 0 C, and more preferably in the range of 50 to 70 0 C. Most preferably, the reaction is carried out at about 60 0 C.
  • the process according to the first aspect of the invention is carried out such that the quaternary salt II, preferably tiotropium bromide, is obtained without isolation and/ or purification of ester I, preferably tiotropium base.
  • the transesterification reaction is carried out in a polar aprotic solvent, such as a solvent selected from dimethylformamide, dimethylsulfoxide, acetonitrile or N- methylpyrrolidine.
  • a polar aprotic solvent such as a solvent selected from dimethylformamide, dimethylsulfoxide, acetonitrile or N- methylpyrrolidine.
  • the solvent is dimethylformamide.
  • the scopine is used in the form of a salt, preferably an acid addition salt, and most preferably in the form of its hydrochloride salt.
  • the scopine ester I or its quaternary salt II obtained is substantially pure, preferably having a purity of at least 99%, preferably at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9% (as measured by HPLC).
  • the scopine ester I or its quaternary salt II are obtained from scopine or a salt thereof in a yield of greater than 50%, preferably greater than 55%, more preferably greater than 60%.
  • a second aspect of the present invention provides scopine ester I or its quaternary salt II prepared by a process according to the first aspect of the present invention.
  • the second aspect provides tiotropium base or tiotropium bromide prepared by a process according to the first aspect of the present invention.
  • the scopine ester I or its quaternary salt II, such as tiotropium base or tiotropium bromide according to the second aspect of the present invention is substantially pure, preferably having a purity of at least 99%, preferably at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9% (as measured by HPLC).
  • the tiotropium bromide according to the second aspect of the present invention is suitable for use in medicine, preferably for the treatment of respiratory disorders, such as asthma or COPD, wherein the COPD can include chronic bronchitis and emphysema.
  • a third aspect of the present invention provides substantially pure scopine ester I or substantially pure quaternary salt II, preferably having a purity of at least 99%, preferably at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9% (as measured by HPLC).
  • the third aspect provides substantially pure tiotropium base or substantially pure tiotropium bromide, preferably having a purity of at least 99%, preferably at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9% (as measured by HPLC).
  • the tiotropium bromide according to the third aspect of the present invention is suitable for use in medicine, preferably for the treatment of respiratory disorders, such as asthma or COPD, wherein the COPD can include chronic bronchitis and emphysema.
  • a fourth aspect of the present invention provides a pharmaceutical composition comprising tiotropium bromide according to the second or third aspect of the present invention.
  • the pharmaceutical composition is suitable for use in a dry powder inhaler (DPI), an aqueous nebulizer or a pressurized metered dosage inhaler (pMDI).
  • DPI dry powder inhaler
  • pMDI pressurized metered dosage inhaler
  • the pharmaceutical composition is suitable for the treatment of respiratory disorders, such as asthma or COPD, wherein the COPD can include chronic bronchitis and emphysema.
  • a fifth aspect of the invention provides for the use of tiotropium bromide according to the second or third aspect of the present invention, or the use of the pharmaceutical composition according to the fourth aspect of the invention, in the manufacture of a medicament for the treatment of respiratory disorders, such as asthma or COPD, wherein the COPD can include chronic bronchitis and emphysema.
  • a sixth aspect of the invention provides a method of treating a respiratory disorder, comprising administering to a patient in need thereof a therapeutically effective amount of tiotropium bromide according to the second or third aspect of the present invention or a therapeutically effective amount of the pharmaceutical composition according to the fourth aspect of the invention.
  • the respiratory disorder is asthma or COPD, wherein the COPD can include chronic bronchitis and emphysema.
  • the patient is a mammal, preferably a human.
  • tiotropium base (3) and tiotropium bromide (1) can be obtained in substantially pure form when synthesised by the efficient and more advantageous process of the first aspect of the present invention.
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • potassium or sodium carbonate gives a very economical and facile process for commercial scale manufacture and a very pure product (>99.6% by HPLC).
  • the solvent used in the transesterification step is dimethylformamide, but alternatively the solvent used can be dimethylsulfoxide, acetonitrile or N-methylpyrrolidine.
  • the reaction temperature used in the transesterification step is preferably in the range of 30 to 90 0 C, more preferably in the range of 40 to 70 0 C, and more preferably in the range of 50 to 70 0 C. Most preferably, the reaction is carried out at about 60 0 C. Most preferably, in the transesterification step, the solvent used is preferably dimethylformamide and the reaction is preferably carried out at about 60 0 C.
  • the tiotropium base (3) formed by the process of the present invention is so pure that it can surprisingly be quaternised, for example with methyl bromide, without isolation and purification to afford a highly pure quaternary salt product. This is a huge benefit in a commercial operation, since it saves very significantly on time and cost, if an isolation and/or purification step can be avoided.
  • the organic bases used in the present invention are preferably organic amines, most preferably trialkylamines, such as diisopropylethylamine or triethylamine, or heterocyclic amines, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5- ene (DBN), l,4-diazabicyclo[2.2.2]octane (Dabco), pyridine or 4- (dimethylamino) pyridine (DMAP).
  • the organic base used is most preferably DBU.
  • the inorganic base is a metal carbonate, a metal bicarbonate or a metal hydroxide, preferably selected from sodium, potassium, lithium, calcium, magnesium or mixtures thereof.
  • the inorganic base is a metal carbonate, preferably potassium carbonate or sodium carbonate, and most preferably potassium carbonate.
  • addition of NaH is done slowly and portionwise maintaining the reaction temperature below 5°C, since the reaction is exothermic. This is time consuming on scale-up, since the addition of 8g of NaH takes around 3 hours.
  • the addition of a metal carbonate, bicarbonate or hydroxide is done at 20-25 0 C in a single lot, thus reducing the reaction time of the process.
  • the metal carbonate, bicarbonate or hydroxide preferably the metal carbonate, preferably potassium carbonate, is preferably added at 25-30 0 C in a single lot. If the tiotropium base (3) is purified, preferably the process for purifying the tiotropium base (3) uses acetonitrile as solvent, preferably involving heating tiotropium base (3) in acetonitrile, cooling and filtering.
  • the scopine is used in the form of its hydrochloride salt, but alternatively it can be used in the form of the free base or any other suitable salt, such as other mineral acid addition salts (e.g. HBr, HI or H 2 SO 4 ) or organic acid addition salts (e.g. acetate, benzoate, propionate, maleate, fumarate, oxalate, besylate, mesylate, tosylate, citrate or salicylate).
  • mineral acid addition salts e.g. HBr, HI or H 2 SO 4
  • organic acid addition salts e.g. acetate, benzoate, propionate, maleate, fumarate, oxalate, besylate, mesylate, tosylate, citrate or salicylate.
  • scopolamine represented by ester I wherein R 1 is represented by formula III and R 4 is hydrogen, R 5 is phenyl and R 6 is hydroxymethyl (CH 2 OH)]; scopolamine hydrogen bromide [represented by salt II wherein R 1 is represented by formula III and R 4 is hydrogen, R is phenyl and R is hydroxymethyl; R 2 is hydrogen and X is bromo]; oxitropium bromide [represented by salt II wherein R 1 is represented by formula III and R 4 is hydrogen, R 5 is phenyl and R 6 is hydroxymethyl; R 2 is ethyl and X is bromo] and cimetropium bromide [represented by salt II wherein R 1 is represented by formula III and R 4 is hydrogen, R 5 is phenyl and R 6 is hydroxymethyl; R 2 is -CH 2 -cyclopropyl and X is bromo] .
  • step (d) heating the mixture from step (c) at 60 0 C;
  • the tiotropium base can be converted directly, without isolation, to tiotropium bromide by reaction with methyl bromide.
  • the tiotropium base can be converted directly, after isolation, to tiotropium bromide by reaction with methyl bromide. The preferred process is very mild and results in a very pure tiotropium bromide, importantly with improved yield.
  • a fourth aspect of the present invention provides a pharmaceutical composition comprising tiotropium bromide prepared by the process according to the first aspect of the present invention.
  • the pharmaceutical composition is suitable for use in a dry powder inhaler (DPI), an aqueous nebulizer or a pressurized metered dosage inhaler
  • DPI dry powder inhaler
  • aqueous nebulizer or a pressurized metered dosage inhaler
  • the DPI compositions of the present invention preferably contain, in addition to the active substance, the following physiologically acceptable excipients: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another.
  • monosaccharides e.g. glucose or arabinose
  • disaccharides e.g. lactose, sucrose, maltose
  • oligo- and polysaccharides e.g. dextrane
  • polyalcohols e.g. sorbitol, mannitol, xylitol
  • salts e.g. sodium chloride, calcium carbonate
  • lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
  • the pMDI of the present invention uses HFA 134a, HFA 227 or mixtures thereof as propellant gas.
  • compositions of the present invention preferably contain about 0.001 to 20% tiotropium bromide in admixture with one or more physiologically acceptable excipients.
  • Preferred compositions contain 0.01 to 10% of tiotropium bromide, more preferred are compositions which contain 0.01 to 2% of tiotropium bromide, and most preferred are compositions which contain 0.04 to 0.8% of tiotropium bromide.
  • the following examples are provided to illustrate the present invention and should not be construed as limiting thereof.
  • Scopine HCl (1 eq with respect to methyl di-(2-thienyl)glycolate) was dissolved in dimethylformamide (2 vol with respect to methyl di-(2-thienyl)glycolate) at 20-25 0 C and stirred for 5 minutes.
  • Potassium carbonate (1 eq) was added under nitrogen at 20-25 0 C and stirred at 20-25 0 C for 1 hour.
  • DBU (1 eq) and methyl di-(2-thienyl)glycolate (1 eq) were added and the reaction mixture was heated to 60 0 C and maintained at 60 0 C for 1 hour. A further amount of DBU (2 eq) was added at 60 0 C and heating continued for 12 hours.
  • reaction mixture was cooled to 0-5 0 C and a solution of cone.
  • HCl (2.5 vol) in water (5 vol) was added slowly through an addition funnel maintaining the temperature at 0-5 0 C.
  • Water (10 vol) was added and the mixture stirred for 1 hour at 0-5 0 C.
  • the reaction mass was basified with 20% aqueous sodium carbonate solution (3 vol) and the sticky mass formed was removed by filtration.
  • the filtrate was again cooled to 0-5 0 C and 20% aqueous sodium carbonate solution (11 vol) was added.
  • the precipitated solid was filtered and washed with water (5 vol) to afford the product, tiotropium base (3), as a white solid.
  • the purified tiotropium base (3) (1 eq) was dissolved in DCM (10 vol) and acetonitrile (3 vol) and purged with methyl bromide gas for 20 minutes. The solution was kept at 25-30 0 C for 30 hours. The precipitated solid was filtered and washed with DCM (20 vol). Drying of the solid at 25-30 0 C under vacuum gave the product, tiotropium bromide (1), as a white solid.
  • Scopine HCl (1 eq with respect to methyl di-(2-thienyl)glycolate) was dissolved in dimethylformamide (2 vol with respect to methyl di-(2-thienyl)glycolate) at 20-25 0 C and stirred for 5 minutes.
  • Potassium carbonate (1 eq) was added under nitrogen at 20-25 0 C and stirred at 20-25 0 C for 1 hour.
  • DBU (1 eq) and methyl di-(2-thienyl)glycolate (1 eq) were added and the reaction mixture was heated to 60 0 C and maintained at 60 0 C for 1 hour. A further amount of DBU (2 eq) was added at 60 0 C and heating continued for 12 hours.
  • reaction mixture was cooled to 0-5 0 C and a solution of cone.
  • HCl (2.5 vol) in water (5 vol) was added slowly through an addition funnel maintaining the temperature at 0-5 0 C.
  • Water (10 vol) was added and the mixture stirred for 1 hour at 0-5 0 C.
  • the mixture was washed with toluene (1 vol) and the aqueous layer was basified with saturated sodium carbonate (7.5 eq) solution to pH 10 and extracted with DCM (3 x 10 vol). The combined DCM layers were washed with water (3 x 10 vol) and dried over anhydrous sodium sulfate.

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Abstract

La présente invention porte de nouveaux procédés pour la préparation d'esters de scopine et de leurs sels quaternaires. En particulier, la présente invention porte sur un procédé pour la préparation de bromure de tiotropium, sur des compositions pharmaceutiques comprenant du bromure de tiotropium et sur l'utilisation de telles compositions dans le traitement de troubles respiratoires.
PCT/GB2010/051312 2009-08-07 2010-08-06 Procédé pour préparer des esters de scopine WO2011015884A1 (fr)

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IN1047/KOL/2009 2009-08-07

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ITRM20110508A1 (it) * 2011-09-27 2013-03-28 Lusochimica Spa Processo per la preparazione degli esteri della scopina.
WO2013117886A1 (fr) 2012-02-10 2013-08-15 Hovione International Ltd Procédé pour la préparation de bromure de tiotropium
WO2013135219A1 (fr) * 2012-03-16 2013-09-19 Zentiva, K.S. Procédé de préparation de l'ester de scopine de l'acide di-(2- thiényl)glycolique, un intermédiaire dans la synthèse du bromure de tiotropium, et sa nouvelle forme
US8697719B2 (en) 2009-08-07 2014-04-15 Generics [Uk] Limited Anhydrate of tiotropium bromide
US12264192B2 (en) 2015-04-13 2025-04-01 Jellagen Pty Ltd Modified collagen, methods of manufacture thereof

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697719B2 (en) 2009-08-07 2014-04-15 Generics [Uk] Limited Anhydrate of tiotropium bromide
US9181268B2 (en) 2009-08-07 2015-11-10 Generics [Uk] Limited Anhydrate of tiotropium bromide
ITRM20110508A1 (it) * 2011-09-27 2013-03-28 Lusochimica Spa Processo per la preparazione degli esteri della scopina.
WO2013046138A1 (fr) * 2011-09-27 2013-04-04 Lusochimica S.P.A. Procédé de préparation d'esters de scopine
WO2013117886A1 (fr) 2012-02-10 2013-08-15 Hovione International Ltd Procédé pour la préparation de bromure de tiotropium
JP2015506970A (ja) * 2012-02-10 2015-03-05 ホビオネ インターナショナル リミテッド 臭化チオトロピウムの調製方法
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RU2634715C2 (ru) * 2012-02-10 2017-11-03 Ховион Интернэшнл Лтд Способ получения тиотропия бромида
WO2013135219A1 (fr) * 2012-03-16 2013-09-19 Zentiva, K.S. Procédé de préparation de l'ester de scopine de l'acide di-(2- thiényl)glycolique, un intermédiaire dans la synthèse du bromure de tiotropium, et sa nouvelle forme
US12264192B2 (en) 2015-04-13 2025-04-01 Jellagen Pty Ltd Modified collagen, methods of manufacture thereof

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