WO2012098044A1 - Procédé pour la préparation de n,n-diisopropyl-3-(2-hydroxy-5-méthylphényl)-3-phénylpropylamine et de ses sels à partir d'un nouvel intermédiaire - Google Patents

Procédé pour la préparation de n,n-diisopropyl-3-(2-hydroxy-5-méthylphényl)-3-phénylpropylamine et de ses sels à partir d'un nouvel intermédiaire Download PDF

Info

Publication number
WO2012098044A1
WO2012098044A1 PCT/EP2012/050436 EP2012050436W WO2012098044A1 WO 2012098044 A1 WO2012098044 A1 WO 2012098044A1 EP 2012050436 W EP2012050436 W EP 2012050436W WO 2012098044 A1 WO2012098044 A1 WO 2012098044A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
compound
diisopropyl
tolterodine
tartrate
Prior art date
Application number
PCT/EP2012/050436
Other languages
English (en)
Inventor
Edoardo Gianolli
Elios Giannini
Laura Bigini
Oreste Piccolo
Pär Holmberg
Tommy Lundholm
Original Assignee
Cambrex Profarmaco Milano S.R.L.
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
Priority claimed from EP11151066A external-priority patent/EP2476665A1/fr
Priority claimed from IT000410A external-priority patent/ITMI20110410A1/it
Application filed by Cambrex Profarmaco Milano S.R.L. filed Critical Cambrex Profarmaco Milano S.R.L.
Publication of WO2012098044A1 publication Critical patent/WO2012098044A1/fr

Links

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
    • C07C213/02—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 involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings

Definitions

  • the invention concerns an improved process for the preparation of tolterodine (N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3 -phenyl propyl amine) and its salts, in particular for the preparation of the tartrate salt, and more particularly for the (+)-(R) enantiomer of tolterodine L-tartrate, starting from a novel intermediate, N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3- phenyl-2-propenamide, which can be used as pure Z or E isomer or as a mixture of Z and E isomers.
  • the present invention also concerns a process for the racemisation of the undesired (S)-(-)- (N,N-diisopropyl-3-(2- hydroxy-5-methylphenyl)-3-phenyl propylamine) enantiomer and its recycle in the process for the preparation of R-tolterodine.
  • (R)-N,N-Diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propylamine known as (R)- Tolterodine, is an anti-cholinergic agent, useful in the treatment of urinary incontinence presently marketed in form of its salt with L-tartaric acid.
  • US 6,310, 103 discloses the corresponding enantiomer (S)-N,N- diisopropyl- 3-(2-hydroxy-5-methylphenyl)-3-phenyl propylamine ant its salts as drugs for use in the treatment of disorders of the urinary and gastrointestinal tracts.
  • the resolution is carried out by using L-tartaric acid in ethanol or in a mixture of methanol/acetonitrile.
  • L-(+)-tartaric acid is used in excess (near 15% molar excess) to obtain the (I)-tartrate salt but in the subsequent recrystallization steps, needed to obtain final (R)-(I) of good quality, the enriched tolterodine must be recovered as free base and further L-(+)-tartaric acid must be added.
  • this resolution procedure is extremely work demanding.
  • US 5,922,914 discloses a novel intermediate, 3,4-dihydro-6-methyl-4- phenyl-2H-benzopyran-2-ol (VII), and an improved process for the preparation of (I) which involves the following steps: a) the reaction of trans-cinnamic acid with 4-methyl-phenol in acidic medium to give the above mentioned lactone (VI); b) the reduction of (VI) with diisobutyl aluminium hydride (DIBAL) to yield the corresponding benzopyran-2-ol; c) the reductive amination of the latter compound with diisopropylamine, in the presence of Pd/C catalyst in methanol.
  • DIBAL diisobutyl aluminium hydride
  • the resolution is finally carried out using ethanol or a mixture methanol/acetone with L-(+) -tartaric acid.
  • L-(+)-tartaric acid is used in excess (near 50% molar excess) to obtain the (I)-tartrate salt without adding further tartaric acid in the recrystallization step.
  • CN 1626504 describes a process for preparing (R)-(I) and its tartrate which includes the recovery of S-(I) and the subsequent treatment of the (S) enantiomer with a reagent selected among organo-lithium, such as butyl lithium, or organo-magnesium compound, such as magnesium isopropyl halide, to obtain, after a proper quenching, the conversion of S-(I) into R-(I) which is finally transformed in L-(+)-tartrate-R-(I).
  • organo-lithium such as butyl lithium
  • organo-magnesium compound such as magnesium isopropyl halide
  • Compound (II), as pure Z or E isomer or as isomeric mixture of Z and E isomers, may be advantageously obtained by the Mizoroki-Heck reaction, contrary to what could be expected from the prior art, as better described later.
  • the Z or E form, or mixtures thereof, can be obtained by modulating appropriately the reaction conditions and the related work-up because the two isomers have different solubility characteristics and a different stability with the temperature and the use of organic solvents.
  • the invention refers also to a process for the preparation of N,N-diisopropyl-3-(2-hydroxy-5- methylphenyl)-3 -phenyl-propylamine (I) starting from said compound (II) either as pure Z or E isomer or as a mixture of Z and E isomers.
  • the invention also concerns a process for the preparation of the intermediate (II) by means of the Mizoroki-Heck reaction, (a detailed overview of this reaction is reported in "The Mizoroki-Heck Reaction", ed. M.Oestreich, Wiley 2009) which comprises:
  • step 1) it should be pointed out that the Mizoroki-Heck reaction, previously described on unsaturated compounds, such as unsaturated cinnamide esters (J. Org. Chem. 2007, 72, 6056-86059), and on 3-arylacrylamides (Bull. Korean Chem. Soc. 1999), has never been used on a ⁇ , ⁇ -dialkyl substituted amide. Furthermore, the excellent result observed in the present invention was unexpected because it has been reported that this type of reaction is not easily applicable on an unsaturated amide.
  • iii) isolating the compound (I) as a salt by adding a suitable inorganic or organic acid, preferentially tartaric acid and more preferentially enantiomerically pure L- or D- tartaric acid, using the L-enantiomer to obtain the (R)-(I) tartrate salt and the D-enantiomer to obtain the (S)-(I) tartrate salt; iv) optionally, converting the racemic or nearly racemic (R,S)-(I) L-tartrate or enantiomeric enriched (R)-(I) L-tartrate into the enantiopure (R) enantiomer as L-tartrate salt by selective crystallization.
  • step iv) is carried out on the D-tartrate salt if the enantiopure (S)-(I) enantiomer is desired.
  • the intermediate (II) may be reduced with an almost quantitative yield in mild conditions to (R,S)-(V) using H 2 or an hydrogen donor such as sodium hypophosphite in the presence of Pd/C as catalyst.
  • (R,S)-(V) can be converted into (I) by reduction with Vitride: the reaction product may be isolated as a salt by adding an inorganic or organic acid.
  • the compound (I) is preferably isolated directly as racemic L-tartrate or enantiomerically enriched L-tartrate salt so avoiding, if the preparation of (R)-(I)- L-tartrate is desired, the intermediate formation of a different salt, with a clear advantage over the prior art.
  • the quality of the isolated product (I) as tartrate is particularly suitable for the subsequent crystallization to obtain (R)-(I) in enantiomerically pure form by conventional crystallization methods.
  • This invention characterized by the formation of novel (II) intermediate, enables the preparation of (I) as base and as salts, preferentially as the tartrate salt, in a simple, efficient and flexible way.
  • a further aspect of this invention is an optimized process for the resolution of tolterodine in isopropanol /water mixture using an excess of L-tartaric acid both in the resolution step and in the following recrystallization steps.
  • the isopropanol/water ratio is preferably from 80/20 to 70/30
  • the L-tartaric acid/tolterodine ratio is preferably from 1.05 to 1.30.
  • the present invention also provides a process for the preparation of enantioenriched (R)-I as detailed below.
  • the mother liquors of a resolution step containing the (S) enantiomer are collected and, after distillation under vacuum, afford enantioenriched S enantiomer as free base or salt.
  • This by-product is converted again into an equimolecular mixture of R and S enantiomer by treatment with a strong base having a pKa > 26 (as a reference for definition and estimation of the pKa values see, as for example, Acta Chem. Scand, 1995, 49, 878-887 and J.Amer. Chem.Soc, 1973, 95, 411-418) by heating at a temperature above 80°C, as shown in the following scheme:
  • the racemic R,S mixture may be conveniently reused in the resolution step allowing an improved and more economical process.
  • the Mizoroki-Heck reaction used for the preparation of the intermediate (II) can be carried out using commercially available starting materials (III) and (IV), using a ratio (IV)/(III) which is in the range 2.5/1 to 0.9/1, preferably 1.5/1 - 1/1. It is performed in the presence of a solvent, preferentially an organic solvent with medium or low polarity such as, for example, 2-methyl-tetrahydrofuran, dioxane or toluene. Typically, the ratio between amount of solvent and (III) is 2- 10/1 w/w.
  • the reaction is performed in the presence of an organic or inorganic base and, preferentially, in the presence of sterically hindered organic bases such as ⁇ , ⁇ -dicyclohexylmethylamine.
  • the stoichiometric ratio between the base and (III) is typically in the range from about 1/1 to 1.5/1, preferentially from 1.3/1 to 1/1.
  • the Mizoroki-Heck reaction requires the presence of a catalyst, preferentially a homogeneous Pd(0) catalyst, prepared in situ or preformed in a separate vessel and added to the reaction mixture, such as for example Pd(0)L 2 + R 3 P or Pd(0)(PR 3 ) 2 .
  • a suitable Pd(0)L 2 is for example Pd 2 (dba) 3 where dba is dibenzylideneacetone.
  • Pd in a different oxidation state is added to the reaction mixture, such as for example Pd(OAc), it is necessary that it is reduced in situ to obtain the active Pd(0) catalyst.
  • the most suitable phosphines for this reaction should be the hindered electron rich phosphines such as, for example, t-butylphosphine, di-t-butyl(2,2-diphenyl-l -methyl- 1- cyclopropyl)phosphine (c-BRIDP), di(l-adamantyl)- «-butylphosphine.
  • the stoichiometric ratio between (III) and the catalyst should be in the range from about 100: 1 to 10000: 1, preferably from 500: 1 to 5000: 1 and more preferably from 1000: 1 to 3000: 1.
  • the reaction temperature can affect the isomeric ratio between the E and Z isomer of (II) and can be modulated to obtain one of the two isomers in pure form or in larger excess. Temperatures lower than 100°C usually afford higher contents of E isomer, temperatures higher than 100°C afford higher amounts of Z isomer.
  • the purity of the E or Z isomer may be increased by simple crystallization in a suitable solvent.
  • the highly pure E isomer may be obtained by crystallization in toluene where the Z isomer is more soluble, while the highly pure Z isomer may be obtained directly from the synthesis, by fine tuning the experimental conditions.
  • the reduction of product (II) to (R,S)-(V) can be performed by means of H 2 or with hydrogen donors, such as sodium hypophosphite, in the presence of wet 3%, 5% or 10% Pd/C as catalyst, using a solvent selected from the group consisting of tetrahydrofuran (THF), methyl-THF or alcohols such as methanol and ethanol, optionally adding 0.5-10% of water, and using a pressure which ranges from atmospheric pressure to 10 bar, the ratio between amount of solvent and (II) being in the range 5/1-20/1 w/w.
  • hydrogen donors such as sodium hypophosphite
  • the ratio between the catalyst and (II) is in the range of 1/300- 1/5, preferably 1/200-1/10 w/w.
  • the temperature of the hydrogenation is in the range of 30-100°C and preferentially 40-80°C.
  • the reaction time is in the range of 0.1-5 h, typically 0.5-2h.
  • the yield of isolated (R,S)-(V) is > 90%, and usually >95%.
  • the enantiomeric excess of (V) is also a function of the isomeric purity of the unsaturated product (II), so that it will be proper to proceed through the isolation of the latter compound.
  • a few known catalysts suitable for asymmetric reduction of unsaturated olefins e.g. homogeneous chiral catalyst based on Ruthenium, Rhodium, Iridium, Cobalt, Copper, Zinc with suitable chiral ligands, can be used. The outcome of this reaction is affected either by the used catalyst or by the isomeric purity and type of compound (II).
  • enantioenriched (V) is obtained with an e.e. up to 91.6% with a nearly quantitative conversion. It was observed that the absolute configuration and the e.e. of (V) may be affected by the type of isomer if the same chiral catalyst is used.
  • the reduction of the saturated amide (V) to (I) is carried out, as described in the literature, using VITRIDETM; according to a preferred procedure, the compound (I) may be isolated directly as (L) tartrate salt.
  • This product has a ratio between (R)-(I) and (S)-(I) in the range of 50/50 or 90/10 and high chemical purity, greater than 97%, and for this reason it is suitable for further enrichments by crystallization, performed in alcoholic solvents or in mixture containing alcohols, following known procedures.
  • the resolution step may be effected using known procedures in ethanol or, preferentially, according to the present invention, in a mixture of isopropanol/water, using L-tartaric acid in suitable excess during all the precipitation and re crystallization steps, to obtain a final (R)-(I) product having the quality required by Pharmacopoeia, including the crystalline form obtainable following the procedure used by the originator.
  • the racemisation step is performed in organic solvent having preferentially a boiling point above 80°C, selected from ethers and aromatic hydrocarbons such as methylTHF, cyclopentyl methyl ether, xylenes, cumene, anisole, tetraline; more preferably the solvent is 2-methylTHF, cyclopentyl methyl ether, xylenes and anisole.
  • organic solvent having preferentially a boiling point above 80°C, selected from ethers and aromatic hydrocarbons such as methylTHF, cyclopentyl methyl ether, xylenes, cumene, anisole, tetraline; more preferably the solvent is 2-methylTHF, cyclopentyl methyl ether, xylenes and anisole.
  • the racemisation is performed at temperature varying from 80°C to 200°C, preferably from 80°C to 170°C, more preferably at 80- 150°C, depending on the used solvent.
  • the preferred base for the racemisation step is sodium amide in an amount not higher than 8 molar equivalents related to compound (I).
  • the racemisation is carried out on compound (I) using 0.5-6 molar equivalents of sodium amide; metal hydroxides or metal alkoxides may be used as ancillary bases.
  • the time required for the racemisation step is in the range of 30 minutes to 24 hours, preferably 1 to 20 hours, depending on the reaction mixture.
  • the racemic compound thus obtained is recovered after the work-up and precipitated preferentially as L-tartrate salt and then subjected again to a fractional crystallization procedure as reported above.
  • Example 1 The invention will be further illustrated by the following examples.
  • Example 1 The invention will be further illustrated by the following examples.
  • Example 1
  • N,N-diisopropylcinnamamide (278 g, 1.2 mol), 2-bromo-4-methylphenol (150 g, 0.8 mol), N,N-dicyclohexylmethylamine (204 g, 1.0 mol) and 2-methyltetrahydrofuran (1.5 L) are loaded and the temperature is adjusted to 80°C.
  • the catalyst, bis(tri-tert-butylphosphine)Pd, (0.82 g, 2mmol) is added to the vessel and the reaction mixture is stirred until complete conversion is reached (time about 4 h).
  • the solution is then concentrated under vacuum at ⁇ 50°C to remove water by azeotropic distillation of water and 2-methyltetrahydrofuran mixture and finally treated with celite and charcoal at 50°C under stirring for 30' and filtered.
  • the filter cake is washed with 2-methyltetrahydrofuran.
  • the solvent is then removed under vacuum at ⁇ 50°C and the residue is charged with toluene (0.75 L) and temperature adjusted to about 80°C to obtain a homogeneous solution. Finally the mixture is slowly cooled to 0 - 5°C and the product (II) isolated by filtration and dried under vacuum (23 1 g, 85%, E/Z isomeric ratio 75/25, purity >98%).
  • hypophosphite An aqueous solution of hypophosphite is prepared by mixing water (1.0 L), sodium hypophosphite (85 g) and sodium carbonate (85 g) and stirred until dissolution.
  • a 3 L round bottomed flask, fitted with a mechanical stirrer, is loaded with compound (II) (168 g, 0.499 mol), 2-Me-THF (2.0 L) and 1 ⁇ 4 of the prepared hypophosphite solution.
  • the flask is washed three times with nitrogen, 5%Pd/C (18 g, 50% wet) is added and the reaction is warmed, under vigorously stirring, at 50-55°C. After 20' at this temperature, the rest of the hypophosphite solution is dropped over 1.5 hrs at 55°C.
  • the mixture is filtered, at 55°C, trough a pad of celite and the filter is washed with wet, warm 2-Me-THF (180 mL).
  • the aqueous phase is separated and the organic phase is washed two times with warm water (2 x 200 mL) maintaining the temperature at 50-55°C.
  • the organic phase is treated as in previous example to afford 163 g of pure (R,S)-(V).
  • the suspension is cooled with an ice bath and a first portion of VitrideTM (27 g, >65% w/w in toluene) is added, dropwise, over 30 min., at 5-10°C (exothermic reaction and H 2 evolution occur). Then the second portion of VitrideTM (157 g, >65% w/w in toluene) is added, over 30 min, warming gently to 20-25°C. Then, the temperature is allowed to rise up to 30°C.
  • tolterodine Hydrochloride as racemate (0.124 mol)
  • 400 ml of methylene chloride, 220 ml of water, 8.7 ml of NaOH 30% and 4.5 g of Na 2 CO 3 are mixed and stirred.
  • the residue is dissolved in 112 ml of ethanol 95% and the solution is heated to 60-70°C and added with 27.9 g of L-tartaric acid dissolved in 280 ml of ethanol 95%.
  • the mixture is heated at 60-70°C for 1 hour, cooled to 0-5°C, and stirred for 10 hours before filtration.
  • the isolated product is washed with cold ethanol 95% and dried under vacuum to obtain 46.9 g of (R)/(S)-tolterodine tartrate ratio 60/40.
  • the product was characterized by means of IR, DSC and XRDP, showing that the crystalline form is equivalent to the originator one [main XRDP °2Th peaks: 11.9, 14.2, 15.9 16.9, 18.4, 18.8, 20.3, 21.0, 22.0, 23.9, 24.8, 25.4, 26.3, 29.8].
  • the product was characterized by means of IR, DSC and XRDP showing that the crystalline form is equivalent to the originator one [main XRDP °2Th peaks: 1 1.9, 14.2, 15.9 16.9, 18.4, 18.8, 20.3, 21.0, 22.0, 23.9, 24.8, 25.4, 26.3, 29.8].
  • the suspension is maintained at 70-65°C for about 15-30 minutes, finally it is slowly cooled to 0-5°C and kept under stirring at this temperature till the product (I)-L-tartrate is isolated by filtration and dried under vacuum (79 g, 79%, (R)/(S) ratio 50/50).
  • the organic phase is heated to reflux, to remove water by azeotropic distillation.
  • the obtained solution is then cooled to 60°C and 4.8 g of Sodium amide (124 mmol) are charged portionwise before heating the mixture to reflux for about 20 hours, till the racemisation process is completed.
  • the reaction is cooled under 60°C and charged with 100 ml of water; the aqueous phase is discarded and the organic phase is washed, with 7% NaHCO 3(aq) (50 ml) and water (2x50 ml). Finally, the xylene solution is concentrated to a thick residue under reduced pressure. The residue is dissolved in 200 ml of isopropanol, added with 15.1 g of L-tartaric acid (100 mmol) and heated to reflux. The obtained suspension is cooled to 60-65 °C, stirred for 15 min at this temperature and then cooled to room temperature, in about 1 hr.

Landscapes

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

Abstract

L'invention porte sur un procédé perfectionné pour a préparation de toltérodine (N,N-diisopropyl-3-(2-hydroxy-5-méthylphényl)-3-phénylpropylamine) et de ses sels, en particulier pour la préparation du sel de type tartrate, et plus particulièrement pour l'énantiomère (+)-(R) du L-tartrate de toltérodine, à partir d'un nouvel intermédiaire, le N,N-diisopropyl-3-(2-hydroxy-5-méthylphenyl)-3-phényl-2-propénamide, qui peut être utilisé sous forme de l'isomère Z ou E pur ou sous forme d'un mélange des isomères Z et E. Lorsque l'objectif est la préparation de l'énantiomère (R)-(+)-(N,N-diisopropyl-3-(2-hydroxy-5-méthylphényl)-3-phénylpropylamine) et lorsqu'une cristallisation des diastéréoisomères du composé approprié est appliquée, la présente invention porte également sur l'utilisation de la racémisation de l'énantiomère (S)-(-N,N-diisopropyl-3-(2-hydroxy-5-méthylphényl)-3-phénylpropylamine) non voulu et son recyclage dans le procédé.
PCT/EP2012/050436 2011-01-17 2012-01-12 Procédé pour la préparation de n,n-diisopropyl-3-(2-hydroxy-5-méthylphényl)-3-phénylpropylamine et de ses sels à partir d'un nouvel intermédiaire WO2012098044A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP11151066A EP2476665A1 (fr) 2011-01-17 2011-01-17 Procédé pour la préparation de N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenyl propylamine et ses sels démarrant à partir d'un nouvel intermédiaire
EP11151066.5 2011-01-17
ITMI2011A000410 2011-03-15
IT000410A ITMI20110410A1 (it) 2011-03-15 2011-03-15 Procedimento per la preparazione di (r)-tolterodina l-tartrato di forma cristallina definita

Publications (1)

Publication Number Publication Date
WO2012098044A1 true WO2012098044A1 (fr) 2012-07-26

Family

ID=45562969

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/050436 WO2012098044A1 (fr) 2011-01-17 2012-01-12 Procédé pour la préparation de n,n-diisopropyl-3-(2-hydroxy-5-méthylphényl)-3-phénylpropylamine et de ses sels à partir d'un nouvel intermédiaire

Country Status (1)

Country Link
WO (1) WO2012098044A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11351115B2 (en) 2014-02-13 2022-06-07 Crystec Ltd Inhalable particles

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5382600A (en) 1988-01-22 1995-01-17 Pharmacia Aktiebolag 3,3-diphenylpropylamines and pharmaceutical compositions thereof
US5922914A (en) 1996-12-31 1999-07-13 Pharmacia & Upjohn Company Process to prepare tolterodine
US6310103B1 (en) 1996-07-19 2001-10-30 Bridge Pharma, Inc. S(−)-tolterodine in the treatment of urinary and gastrointestinal disorders
US6310248B2 (en) 1999-12-30 2001-10-30 Pharmacia Ab Process and intermediates
US6822119B1 (en) 2001-08-03 2004-11-23 Ranbaxy Laboratories Limited Process for the preparation of tolterodine
CN1626504A (zh) 2004-08-16 2005-06-15 鲁南制药股份有限公司 托特罗定及其酒石酸盐的制备方法
EP1693361A1 (fr) * 2005-02-18 2006-08-23 Dipharma S.p.A. Un procédé pour la préparation de toltérodine
US7119212B2 (en) 2004-03-30 2006-10-10 Dipharma S.P.A. Process for the preparation of tolterodine and intermediates thereof
WO2008020332A2 (fr) 2006-07-04 2008-02-21 Uquifa México, S.A. De C.V. Procédé de préparation de tartrate de (r)-tolterodine
US7355077B2 (en) 2004-10-28 2008-04-08 Dr. Reddy's Laboratories Limited Process for preparing tolterodine
US7538249B2 (en) 2003-12-24 2009-05-26 Cipla Limited Tolterodine, compositions and uses thereof, and preparation of the same
CN101445462A (zh) 2008-12-29 2009-06-03 药源药物化学（上海）有限公司 托特罗定及其酒石酸盐的制备方法

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5382600A (en) 1988-01-22 1995-01-17 Pharmacia Aktiebolag 3,3-diphenylpropylamines and pharmaceutical compositions thereof
US6310103B1 (en) 1996-07-19 2001-10-30 Bridge Pharma, Inc. S(−)-tolterodine in the treatment of urinary and gastrointestinal disorders
US5922914A (en) 1996-12-31 1999-07-13 Pharmacia & Upjohn Company Process to prepare tolterodine
US6310248B2 (en) 1999-12-30 2001-10-30 Pharmacia Ab Process and intermediates
US6822119B1 (en) 2001-08-03 2004-11-23 Ranbaxy Laboratories Limited Process for the preparation of tolterodine
US7538249B2 (en) 2003-12-24 2009-05-26 Cipla Limited Tolterodine, compositions and uses thereof, and preparation of the same
US7119212B2 (en) 2004-03-30 2006-10-10 Dipharma S.P.A. Process for the preparation of tolterodine and intermediates thereof
CN1626504A (zh) 2004-08-16 2005-06-15 鲁南制药股份有限公司 托特罗定及其酒石酸盐的制备方法
US7355077B2 (en) 2004-10-28 2008-04-08 Dr. Reddy's Laboratories Limited Process for preparing tolterodine
EP1693361A1 (fr) * 2005-02-18 2006-08-23 Dipharma S.p.A. Un procédé pour la préparation de toltérodine
US7335793B2 (en) 2005-02-18 2008-02-26 Dipharma S.P.A. Process for the preparation of tolterodine
WO2008020332A2 (fr) 2006-07-04 2008-02-21 Uquifa México, S.A. De C.V. Procédé de préparation de tartrate de (r)-tolterodine
CN101445462A (zh) 2008-12-29 2009-06-03 药源药物化学（上海）有限公司 托特罗定及其酒石酸盐的制备方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ACTA CHEM. SCAND, vol. 49, 1995, pages 878 - 887
BULL. KOREAN CHEM. SOC., 1999
J. ORG. CHEM., vol. 72, 2007, pages 86056 - 86059
J.AMER.CHEM.SOC., vol. 95, 1973, pages 411 - 418
OESTREICH M.: "The Mizoroki-Heck Reaction", 2009, WILEY

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11351115B2 (en) 2014-02-13 2022-06-07 Crystec Ltd Inhalable particles

Similar Documents

Publication Publication Date Title
JP5202519B2 (ja) （ｒ）−（−）−３−（カルバモイルメチル）−５−メチルヘキサン酸及びプレガバリン及び合成中間体の製法
US20070149813A1 (en) Process for preparation of phenethylamine derivatives
CA2603145A1 (fr) Procede de preparation de chlorhydrate de cinacalcet
JP5503670B2 (ja) シナカルセト塩酸塩の製造方法
CN1216033C (zh) 亚环己基胺的顺式选择性催化氢化方法
EP2349976B1 (fr) Procédé de production de (s)-3-[(1-diméthylamino)éthyl]phényl-n-éthyl-n-méthyl-carbamate par le biais de nouveaux intermédiaires
JP3533179B2 (ja) ケチミンの新規な製造方法
AU2017200463B2 (en) The process for the preparation of metaraminol
WO2012098044A1 (fr) Procédé pour la préparation de n,n-diisopropyl-3-(2-hydroxy-5-méthylphényl)-3-phénylpropylamine et de ses sels à partir d'un nouvel intermédiaire
WO2009086283A1 (fr) Synthèse de 2-hydroxy-2-aryl-éthylamines énantiomériquement pures
EP2476665A1 (fr) Procédé pour la préparation de N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenyl propylamine et ses sels démarrant à partir d'un nouvel intermédiaire
EP2036881B1 (fr) Procédé de production d'un dérivé optiquement actif de 1-(phényle à substitution fluoro, trifluorométhyle ou trifluorométhoxy)alkylamine n-monoalkyle
WO2013090161A1 (fr) Synthèse stéréosélective du tapendatol et de ses sels
EP1503978A1 (fr) Procede de fabrication de sertraline
US20120253074A1 (en) Process for the preparation of o-desmethyl-venlafaxine and salts thereof
WO2013105109A1 (fr) Procédé de préparation de tapentadol
JP4049548B2 (ja) 光学活性１−（フルオロフェニル）エチルアミンの精製方法
US20120022292A1 (en) Method for preparing eplivanserin hemifumarate
MXPA00006986A (en) Novel process for preparing a ketimine
WO2014012832A1 (fr) Procédé pour la préparation de 2-(3-n,n-diisopropylamino-1-phénylpropyl)-4-hydroxyméthylphénol et de ses dérivés

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12702444

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12702444

Country of ref document: EP

Kind code of ref document: A1