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WO2006069767A1 - Procede pour obtenir des enantiomeres de thienylazolylalcoxyethanamines - Google Patents

Procede pour obtenir des enantiomeres de thienylazolylalcoxyethanamines Download PDF

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Publication number
WO2006069767A1
WO2006069767A1 PCT/EP2005/014024 EP2005014024W WO2006069767A1 WO 2006069767 A1 WO2006069767 A1 WO 2006069767A1 EP 2005014024 W EP2005014024 W EP 2005014024W WO 2006069767 A1 WO2006069767 A1 WO 2006069767A1
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Prior art keywords
process according
mmol
diamine
formula
base
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PCT/EP2005/014024
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English (en)
Inventor
Antoni Torrens Jover
Helmut H. Buschmann
Detleff Heller
Hans Joachim Drexler
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Esteve Pharmaceuticals SA
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Laboratorios del Dr Esteve SA
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Priority claimed from EP04380275A external-priority patent/EP1674465A1/fr
Application filed by Laboratorios del Dr Esteve SA filed Critical Laboratorios del Dr Esteve SA
Publication of WO2006069767A1 publication Critical patent/WO2006069767A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a new process for the preparation of enantiomerically enriched carbinols substituted simultaneously with pyrazolyl and thienyl heterocycles.
  • the process comprises the enantioselective asymmetric hydrogenation of ketones using chiral catalytic systems to render nonracemic chiral alcohols. More particularly, it relates to a new process for the preparation of the pure enantiomers of intermediate alcohols that are useful intermediates for the preparation of pharmaceutically active thyenylazolylalcoxyethanamines.
  • the carbinols such as the one of formula II are key intermediates to reach the compounds described in WO 99/52525.
  • the pure enantiomers of (+)-! and (-)-I may be prepared by separately O-alkylating the enantiomerically pure intermediates (+)-II and (-)-II.
  • a strategy for the enantioselective reduction of aromatic and heteroaromatic prochiral ketones with high ee values comprises the use of an optically active diphosphane/Ru/diamine/inorganic base catalyst system.
  • Examples of asymmetric reduction of heteroaromatic ketones are disclosed in WO 2004/01 1452 and in P. Cao, X. Zhang, J. Org. Chem. 1999, 64, 2127.
  • Enantioselective hydrogenation of ketonic structures to nonracemic secondary alcohols has been achieved with also a wide range of chiral ruthenium catalyst systems which can be prepared by different combinations of Ru (II) chiral phosphanes and diamine ligands.
  • the object of the present invention was to provide a process for the enantioselective hydrogenation of a thienyl pyrazoyl ketone.
  • This process should operate particularly well on industrial scale and be satisfactory as regards yield, conversion and enantiomer excess.
  • the process should be suitable for providing in an advantageous manner specific enantiomer-enriched alcohols as intermediates for the preparation of (+)- and (-)-thienylazolylalcoxyethanamines.
  • R ⁇ and R 2 are independently selected from hydrogen, halogen, lower alkyl or aryl; which comprises the asymmetric hydrogenation of a prochiral ketone of formula (III)
  • Ri or R 2 is H, preferably both are H.
  • the present invention is directed to a process for the preparation of an enantiomerically enriched compound of formula (II):
  • R ⁇ and R 2 are independently selected from hydrogen, halogen, lower alkyl or aryl; which comprises the asymmetric hydrogenation of a prochiral ketone of formula (III)
  • the process of the invention gives the desired product of formula II with high conversion and enantiomeric excess.
  • This process has the further advantage that the starting materials are not expensive and that it works under low or normal pressures.
  • the product of formula II is especially useful in the preparation of the enantiomers of ( ⁇ )-2-[thienyl(l-methyl-lH-pyrazol-5-yl)methoxy]-7V,N-dimethyl- ethanamine, among others. It will be readily apparent to the person skilled in the art that the process is also applicable to the hydrogenation of other ketones comprising a thienyl substituent and having a different nitrogen-containing heterocycle instead of the methyl pyrazole ring, such as methyl pyrrole, methyl imidazole and methyl triazole. Different compounds can be obtained depending on the substituents present on the thienyl or N- containing heterocyclic rings.
  • the chiral ruthenium (II) catalyst system used in the process of the present invention is known to the person skilled in the art and is composed of Ruthenium (II) complexes with two different ligands, a bidentate phosphorous-containing ligand and a diamine, in the presence of a base.
  • Said catalyst system components can be provided to the reaction mixture individually to form the reactive catalyst system in situ or they can be provided as preformed complexes.
  • the bidentate phosphorous-containing ligand is in general of the biphosphines or biphosphites types, more preferably it is of the biphosphine type.
  • Illustrative examples of nonracemic chiral diphosphines are 2,2'-bis(diphenyl-phosphino)-l,l '-binaphtyl (BINAP), ToIBINAP and XyIBlNAP [R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed., 2001, 40, 40-73], 2,2'-bis(diphenylphosphino)-l,l '-dicyclopentane (BICP) [P. Cao, X.
  • the diphosphine ligand comprises a binaphthyl group. They are more preferably selected from the group consisting of the enantiomers of 2,2'-bis(diphenyl-phosphino)-l ,l '-binaphtyl (BINAP), ToIBINAP and XyIBINAP [see R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed., 2001, 40, 40-73].
  • Suitable diamines are 1,2-diamine species that exhibit a sufficient activity or selectivity in the catalyst under consideration. They can be chiral or non-chiral. Illustrative examples are any stereoisomers of l,l-bis(4-methoxyphenyl)-3 -methyl- 1,2- butanediamine (DAIPEN), 1 ,2-diphenylethylendiamine (DPEN), 1,2- diaminocyclohexane (DACH) or achiral diamines such as ethylenediamine. Achiral amines are further discussed in US 6,743,921 which is incorporated herein by reference in its entirety.
  • the use of enantiomeriacally enriched diamines such as DAIPEN and DPEN has proved particularly advantageous, DPEN regards costs and DAIPEN regards higher activity and selectivity.
  • the bidentate phosphorous-containing ligand together with the diamine and the ruthenium (II) form a complex referred to hereinafter as the ruthenium (II) component of the catalyst system.
  • Examples of preformed complexes of the ruthenium with the diphosphine ligand and the diamine include complexes represented by the formula RuX 2 LA wherein X represents a halogen atom or pseudo-halide group, preferably chloride or bromide, L represents the diphosphine ligand and A is the diamine.
  • Specially good conditions have been achieved with the use of RuCl 2
  • Said component is present in catalytic amounts, meaning less than stoichiometric relative to the ketone reactants and as low as possible while ensuring the optimum possible conversion rate.
  • the minimum amount of the ruthenium (II) component of the catalyst system may depend on the activity of the specific catalyst system composition, the reaction temperature, the concentration of the reactants and catalyst system components in the solution, and the maximum time allowed for completion of the reaction.
  • the molar ratio of the ruthenium (II) component of the catalyst to the ketone reactant (s/c) is in the range from about 50 to 20,000, preferably from about 200 to about 20,000, more preferably from about 10,000 to about 20,000.
  • Suitable bases include organic bases and inorganic bases which should not have a negative influence on, for example, the enantiomer purity of the products that are formed.
  • the base is selected from the group consisting of a hydroxide, Ci- C 5 -alkoxide, bicarbonate, carbonate, di- and tribasic phosphate, borate, fluoride, amine optionally substituted with Ci-Gj-alkyl or aryl, silane optionally substituted with Ci-C 3 - alkyl.
  • alkali metal alcoholates are advantageous, such as for example /-BuOK, as well as inorganic bases such as for example KOH or K 2 CO 3 .
  • organic nitrogen bases such as NEt 3 and salts as for example AgCF 3 SO 3 are used.
  • /-BuOK is used.
  • the base used is /-BuOK it is preferably added to the reaction vessel in form of a solution of /-BuOK in /-BuOH. It has been found that a molar excess of base referred to the ruthenium (II) component of the catalyst system is advantageous.
  • the typical mole ratio base: ruthenium (II) component of the catalyst system is comprised between 10: 1 and 1 , more preferably between about 6: 1 and about 4: 1. It has been found that both the activity and the selectivity of the hydrogenation vary with the amount of the base. In this connection the activity of the hydrogenation increases with rising concentration of the base. However, if the concentration of base is too high there is a possibility of racemization of the end product, which is not desirable. A ratio of about 6:1 is particularly preferred.
  • the hydrogenation reaction is conducted in a solvent system that is capable of dissolving the catalyst system and is reaction-inert.
  • solvent system is used to indicate that a single solvent or a mixture of two or more solvents can be used.
  • reaction-inert is used to mean that the solvent system does not react unfavourably with the reactants, products, or the catalyst system.
  • the solvent system need not bring about complete solution of the ketone reactant or the chiral alcohol product.
  • the ketone reactant may be incompletely dissolved at the beginning of the reaction or the chiral alcohol product may be incompletely dissolved at the end of the reaction, or both.
  • Representative solvents are alcohol solvents such as methanol, ethanol, n-propanol, 2- propanol, n-butanol, sec-butanol or ?-butanol and their mixtures, organic solvents containing heteroatoms such as DMF and ethers like THF.
  • the solvent system comprises an alcohol solvent, more preferably methanol, isopropanol, /-butanol and their mixtures. 7er/-butanol is particularly preferred.
  • the hydrogenation takes place in a suitable reactor known to the person skilled in the art, such as an autoclave. It is advisable to carry out the hydrogenation under an inert gas atmosphere. Suitable media are nitrogen gas or a noble gas such as argon.
  • Suitable media are nitrogen gas or a noble gas such as argon.
  • the temperature during the reaction may in principle be chosen arbitrarily by the person skilled in the art as long as a sufficient quick and selective reaction is guaranteed. However, it has to be taken into account that the temperature depends strongly on solvent and that some catalyst systems are instable above 40 0 C. In typical embodiments the reaction is suitably conducted at a temperature comprised between 10- 45 0 C, preferably between 20-35 0 C.
  • the hydrogenation refers to reacting the ketone with a source of hydrogen atoms under appropriate conditions so that two hydrogen atoms are added to the carbonyl group of the ketone to produce the hydroxyl group of the chiral alcohol.
  • the source of hydrogen atoms includes molecular hydrogen (H 2 ).
  • H 2 molecular hydrogen
  • the hydrogen pressure in the reaction is preferably low, typically at least about a 1.3 bar. Normally it is in the range from 0.8 to 100 bar. More typically the hydrogen pressure is in the range from 1.3 to 8 bar.
  • the ketone of formula (III) is known and can be prepared as described for example in WO99/52525 or any other method readily apparent to the person skilled in the art. Normally the ketone substrate (III), the catalyst system and the base (if it is a solid) are weighted and introduced in the reactor. Then the solvent is added and stirred to complete dissolution of the catalyst. Thereafter the base, if not a solid, is added. The reactor is brought to the adequate temperature and pressure to complete the reaction. Alternatively, the ketone of formula (III) is dissolved in an appropriate solvent, then the constituents of the catalyst system or the catalyst in preformed form are added, and then the hydrogenation is performed at an appropriate temperature and suitable hydrogen pressure.
  • the ketone concentration ranges from about 0.025 to 0.125 mol/1, preferably from about 0.05 to 0.1 mol/1.
  • the reaction is allowed to continue until complete conversion of the ketone. Times comprised between 1 to 1 10 hours are sufficient, although shorter times are preferred in terms of economy of the process.
  • the advantages associated with the invention are numerous:
  • the process according to the invention provides a simple means of access to isomers which were previously relatively difficult to obtain, and also allows this to be done on a large industrial scale with excellent productivity.
  • the process according to the invention makes it possible to prepare the desired product not only in high yields but also with very high enantioselectivity. No additional purification steps are needed, the products may be further processed directly just as they occur.
  • the invention relates to a process as defined above which further comprises the step of O-alkylation of an enantiomerically enriched compound of formula (II) to yield the desired enantiomer of a pharmaceutically active compound as described in WO 99/52525.
  • the compound of formula (II) is treated with an amine of formula
  • X is a suitable leaving group such as halogen, more preferably chlorine, bromine or iodine; a reactive esterified hydroxyl, for example arylsulphonyloxy such as phenylsulphonyloxy; tosyloxy; mesyloxy; C 1 . 4 alkyl sulphonyloxy, for example methanesulphonyloxy; arylphosphoryloxy, for example diphenylphosphoryloxy, dibenzylphosphoryloxy or a Ci -4 alkyl phosphoryloxy, for example dimethylphosphoryloxy, and R 3 , R 4 and R 4B are independently selected from H and a lower alkyl.
  • R 3 is hydrogen.
  • R 4 and R 4B are independently selected from H and methyl. In one embodiment both R 4 and R 4B are methyl.
  • a particularly preferred amine for the step of O-alkylation is X-CH 2 - CH 2 N(Me) 2 . More preferably X is chlorine.
  • the alkylation is preferably carried out directly in the same reaction medium resulting from the process of the invention, without further purification of the carbinol.
  • the O-alkylation is carried out in conditions of phase transfer, using for example 2-chloro-/V,./V,-dimethylethylamine (other leaving groups instead of chloro are possible), an alkaline aqueous solution such as NaOH or KOH, in the presence of a catalyst such as a quaternary ammonium salt.
  • a catalyst such as a quaternary ammonium salt.
  • the resulting product of formula I is enantiomerically enriched; it can be further purified using polar organic solvents. Further, a pharmaceutically acceptable salt of the obtained compound can be formed.
  • the citrate salt can be prepared by dissolving the amine of formula I in ethanol and treating the solution with citric acid monohydrate. The preparation of other salts will be readily apparent to the person skilled in the art.
  • the substrate, and the components of the chiral ruthenium (II) catalyst system used in the process of the present invention bidentate phosphorous-containing ligand, amine and base (if the base is a solid) are weighed (not necessarily anaerobic) in a schlenk flask.
  • the substrate With larger quantities of substrate (more than 1.5 mmol) the substrate is filled directly into the autoclave
  • the schlenk flask is securated and the solvent (stock solution) is added under anaerobic conditions
  • the formed suspension is sti ⁇ ed up to the dissolution of the chiral ruthenium (II) catalyst system (ca 5 min)
  • the base solution is added with a secuiated Hamilton glass syringe and stirred again 5 min if it was not already added as a solid at the beginning Afterwards the solution is transferred into the securated autoclave standing under vacuum (via capillary and argon pressure)
  • the reaction solution is then heated up to the desired temperature
  • the desired hydrogen pressure is adjusted
  • the compound was prepared from 0 5 mmol thienyl 1-methylpyrazoyl ketone 0 01 mmol .R-Ru(BlNAP), 0 01 mmol ⁇ -DA1PEN, ⁇ ,i?-DPEN or R 1 R-OACK, 0 06 mmol /-BuOK (60 ⁇ l, /-BuOK 1 0 M solution in /-BuOH), 20 ml isopropanol, at 25°C and 8 bar H 2
  • the compound was prepared from 1 mmol thienyl 1 -methylpyrazoyl ketone 0.01 mmol ⁇ -Ru(BINAP); 0.01 mmol R,R-O?EN;
  • the compound was prepared from 2 mmol thienyl 1 -methylpyrazoyl ketone 0.01 mmol ⁇ , ⁇ -Ru(BINAP); 0.01 mmol ⁇ . ⁇ -DPEN; 0.06 mmol ?-BuOK (120 ⁇ l, /-BuOK 0.5 M solution in /-BuOH); 19 ml r-butanol and 1 ml isopropanol; at 30 0 C and 1 bar H 2 . Conversion: 100 % after 4.5 h with 86 %ee Entries 16, 17, 18, 19 and 20 according to method a)
  • the compound was prepared from 2 mmol thienyl 1 -methylpyrazoyl ketone 0.01 mmol ⁇ , ⁇ -Ru(BINAP); 0.01 mmol R 1 R-OFEN;
  • the compound was prepared from 2 mmol thienyl 1 -methylpyrazoyl ketone 0.01 mmol ⁇ , ⁇ -Ru(BINAP); 0.01 mmol R,R-O?EN; 0.06 mmol /-BuOK (120 ⁇ l, /-BuOK 0.5 M solution in /-BuOH); 19 ml /-butanol and 1 ml isopropanol; at 30 0 C and 20 bar or 50 bar H 2 .
  • the compound was prepared from 50 or 100 mmol thienyl 1 -methylpyrazoyl ketone

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé pour la préparation d'un alcool précurseur de la (±)-2-[thiényl(1-méthyl-1H-pyrazol-5-yl)méthoxy]-N,N-diméthyléthanamine et des thyénylazolylalcoxyéthanamines et leurs énantiomères en général. Il comprend la réduction asymétrique d'une cétone prochirale en présence d'un système catalyseur de ruthénium (II) chiral comprenant au moins un ligand bidentate contenant du phosphore et un ligand diamine pour produire des alcools chiraux. Les alcools chiraux sont ensuite O-alkylés pour produire les éthanamines pharmaceutiquement actives correspondantes.
PCT/EP2005/014024 2004-12-27 2005-12-26 Procede pour obtenir des enantiomeres de thienylazolylalcoxyethanamines Ceased WO2006069767A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP04380275.0 2004-12-27
EP04380275A EP1674465A1 (fr) 2004-12-27 2004-12-27 Procédé pour l'obtention des enanntiomères des thienylazolylalkoxyethanamines.
US11/041,639 2004-12-27
US11/041,639 US6979742B1 (en) 2004-12-27 2005-01-24 Process for obtaining enantiomers of thienylazolylalcoxyethanamines

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007017127A3 (fr) * 2005-07-29 2007-04-19 Esteve Labor Dr Forme dosifiee a liberation controlee de composes pyrazole

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1072266A1 (fr) * 1998-04-15 2001-01-31 Laboratorios Del Dr. Esteve, S.A. Thienylazolylalcoxyethanamines, leur preparation et leur application en tant que medicaments

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1072266A1 (fr) * 1998-04-15 2001-01-31 Laboratorios Del Dr. Esteve, S.A. Thienylazolylalcoxyethanamines, leur preparation et leur application en tant que medicaments

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
A. TORRENS ET. AL.: "Enantioselective Synthesis of (R) and (S)-Cizolirtine ; Application of Oxazaborolidine Catalyzed Asymmetric Borane Reduction to Azolyl Phenyl Ketones.", SYNLETT, vol. 1999, no. 6, 1999, pages 765 - 767, XP002331338 *
CHENG-YI CHEN ET. AL.: "Highly Enantioselective Hydrogenation of Aromatic-Heteroaromatic Ketones.", ORGANIC LETTERS, vol. 5, no. 26, 2003, pages 5039 - 42, XP002331352 *
R. NOYORI ET. AL.: "Asymmetric Catalysis by Architectural and Functional Molecular Engineering. Practical Chemo- and Stereoselective Hydrogenation of Ketones.", ANGEWANDTE CHEMIE, INTERNATIONAL EDITION, vol. 40, 2001, pages 40 - 73, XP002331339 *
T. OHKUMA ET. AL.: "Selective Hydrogenation of Benzophenones to Benzhydrols. Asymmetric Synthesis of Unsymmetrical Diarylmethanols.", ORGANIC LETTERS, vol. 2, no. 5, 2000, pages 659 - 662, XP002331337 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007017127A3 (fr) * 2005-07-29 2007-04-19 Esteve Labor Dr Forme dosifiee a liberation controlee de composes pyrazole
ES2334548A1 (es) * 2005-07-29 2010-03-11 Laboratorios Del Dr. Esteve, S.A Forma de dosificacion de liberacion controlada de compuestos de pirazol para el tratamiento de la incontinencia urinaria.
ES2334548B1 (es) * 2005-07-29 2010-10-27 Laboratorios Del Dr. Esteve, S.A Forma de dosificacion de liberacion controlada de compuestos de pirazol para el tratamiento de la incontinencia urinaria.

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