EP1838678A1 - Process for obtaining cizolirtine and its enantiomers - Google Patents
Process for obtaining cizolirtine and its enantiomersInfo
- Publication number
- EP1838678A1 EP1838678A1 EP05822912A EP05822912A EP1838678A1 EP 1838678 A1 EP1838678 A1 EP 1838678A1 EP 05822912 A EP05822912 A EP 05822912A EP 05822912 A EP05822912 A EP 05822912A EP 1838678 A1 EP1838678 A1 EP 1838678A1
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- EP
- European Patent Office
- Prior art keywords
- process according
- ligand
- formula
- mol
- zinc
- Prior art date
- Legal status (The legal status 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 status listed.)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Definitions
- the present invention relates to the asymmetric addition of a metalated phenyl reagent to a heteroaryl aldehyde to render chiral alcohols. More particularly, it relates to a new process for the preparation of the pure enantiomers of an intermediate alcohol which is used in the preparation of Cizolirtine, ( ⁇ )-2-[phenyl(l-methyl-lH-pyrazol-5- yl)methoxy]-N,7V-dimethylethanamine and its enantiomers, comprising the enantioselective addition reaction of a phenyl zinc reagent to a pyrazolcarbaldehyde.
- (+)-I and (-)-I have been previously obtained by optical resolution of the Cizolirtine racemate by fractional crystallization with optically active acids (WO 99/02500) such as, for instance, with (-)- and (+)-di-p-toluoyrtartaric acid (Torrens, A.; Castrillo, J. A.; Frigola,
- the ( ⁇ )-Cizolirtine has been prepared by O-alkylation of compound ( ⁇ )-II of formula II:
- the pure enantiomers of Cizolirtine (+)-I and (-)-I may be prepared by separately O-alkylating the enantiomerically pure intermediates (+)-II and (-)-II.
- (+)-II and (-)-II are obtained either by reduction of a compound of formula III, which yields ( ⁇ )-II as a racemate, followed by procedures of optical resolution of the racemate ( ⁇ )-II, like fractional recrystallization from solvents or column chromatography [JA: Hueso, J. Berrocal, B. Gutierrez, AJ. Farre y J. Frigola, Bioorg. Med. Chem. Lett. 1993, 3, 269], or by EPC synthesis starting from the prochiral ketone of formula III:
- Another strategy for the enantioselective reduction of prochiral ketones with high enantiomeric excess comprises the use of a diphosphane/Ru/chiral diamine/inorganic base catalyst system.
- this process leads to the formation of heavy metal complexes of Ru or elemental Ru and trace amounts of such metal are very hard to remove.
- Lewis-basic or coordinating functional groups often lead to drastic decreases in enantioselectivity in arylzinc addition reaction due to their ability to complex to the zinc reagent or the active catalyst.
- An extreme example of this behaviour would be the asymmetric autocatalysis in the addition of zinc reagents to aldehydes as examined by Soai et al. (T. Shibata, H. Morioka, T. Hayase, K. Choji, K. Soai J. Am. Chem. Soc. 1996, 471).
- the present invention refers to a process for the asymmetric addition to a pyrazolcarbaldehyde with a phenyl zinc reagent in the presence of a chiral ligand. Said process allows the preparation of known intermediates of formula (II), which thereafter can yield, by O-alkylation, the desired enantiomers of the pharmaceutically active compound Cizolirtine.
- the invention is thus directed to a process for the preparation of an enantiomerically enriched compound of formula (II):
- the present invention is directed to a process for the preparation of an enantiomerically enriched compound of formula (II):
- 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 zinc salts used or formed during the reaction are easily removed by aqueous work-up.
- the product of formula II is especially useful in the preparation of Cizolirtine enantiomers. The details of the process are discussed below.
- Optimal conditions for the lithiation are found in the literature (T.E. Smith, M.S. Mourad, A.J. Velander, Heterocycles 2002, 57, 1211) and can be employed to the formylation reaction.
- diethyl amine can be used to prevent the deprotonation of the TV-methyl group, normally 10 mol% is sufficient.
- THF is used as a solvent; in this case no additive is necessary.
- the deprotonation reaction is preferably performed below -10 0 C (usually at -20 0 C) to prevent the formation of side products by ring-opening of THF.
- distillation or extractive workup with an organic solvent can be used to remove the byproducts. Otherwise, as previously mentioned, the aldehyde can be used directly for the addition.
- Phenyl zinc reagent to be used in the process of the invention is also known to the person skilled in the art as mentioned above.
- it can be diphenylzinc or a mixed zinc species generated from diphenylzinc and diethylzinc or can be prepared in situ by a transmetallation reaction of a phenylboron reagent with dimethyl- or diethyl-zinc.
- the active species are presumably a mixed phenyl-ethyl-zinc or phenyl- methyl-zinc.
- phenyl-boron reagents phenylboronic acid (C. BoIm, J. Rudolph J. Am. Chem. Soc.
- triphenylborane J. Rudolph, F. Schmidt, C. BoIm, Adv. Synth. Catal. 2004, 346, 867
- triphenylborane ammonia complex or 2-aminoethyl diphenylborinate can be used.
- Diphenylzinc and triphenylborane are relatively expensive reagents. Therefore, stable complexes of aryl boranes are preferred. Especially triphenylborane ammonia complex, which can readily be prepared from commercially available triphenylborane sodium hydroxide complex, has proven very suitable. Additionally, commercially available and stable 2-aminoethyl diphenylborinate can also be employed. Preferably, the phenyl-boron reagent is triphenylborane ammonia complex.
- a variable that can affect the enantioselectivity of the addition reaction is the ratio of borane reagent versus diethylzinc (when the phenyl zinc reagent is obtained from these compounds).
- N 5 O-, N 5 N-, N,S-, N,Se- or O,O- refers to ligands that have at least these two coordinating heteroatoms.
- N,O-ligands are employed. In general they are derived from ⁇ -amino alcohols and therefore have two carbon atoms between the heteroatoms. However, some of the ligands used in this reaction are those which present three carbon atoms between the heteroatoms.
- ligands react with the zinc reagent forming a zinc-alcoxide complex which is more Lewis-acidic than the other present zinc species (reagent and product). Additionally, it is a Lewis-base catalyst (usually at the oxygen atom). This zinc- alcoxide complex formed in situ is the active catalyst. When the lewis-base is oxygen, more preferably O is an alcohol.
- ligands have the advantage of being commercially available or readily synthesised from the corresponding aminoacids. In this case the preferred ligands have a structure-type (V) such as described below:
- N,S-ligands are employed, preferably , those of formula VII
- Ra is selected from hydrogen or an alkoyl group, such as the aminothioacetates.
- Ligands of formula VII are readily available through known procedures (see J. Kang, J. W. Lee, J. Kim, Chem. Commun. 1994, 17, 2009 or M. -J. Jin, S.-J. Ahn, K.-S. Lee, Tetrahedron Lett. 1996, 37, 8767.).
- the active catalyst formed in situ by said N,S-ligands are similar to those formed by N,O-ligands. However, without being bound by theory, it is believed that the catalytic mechanism followed by aminothioacetates (Ra is alkoyl) is different from the catalytic mechanism followed by aminothiols or aminoalcohols.
- Typical ligands to be used in this addition reaction are the following compounds, their enantiomers, or derivatives thereof:
- SD286 -2-piperidinyl- 1,1,2- ti ⁇ phenylethanol
- ligand (V) catalyst (VI) wherein n is 0 or 1 and R"' is phenyl, ethyl or methyl.
- This zinc alkoxide complex (VI) is the active catalyst in the addition reaction which subsequently coordinates with the pyrazolcarbaldehyde in such a way that it induces the enantioselective addition of the phenyl group to said aldehyde.
- the concentration of the ligand should be low to reduce costs but sufficient to provide good ee.
- the ligands are preferably used in amounts of 0.1 to 100 mol%. According to one embodiment, ligands may be used in amounts of 1 to 20 mol%, 3- 25%, 3-10% or 5 to 10 mol%. The enantiomeric excesses obtained using these amounts are excellent (>95 ee). However, in industrial synthesis it may be convenient to lower the amount of chiral ligand even though enantiomeric excesses are slightly reduced.
- the ligands are used in amounts of 0.1 to 2.5 mol%, preferably between 0.1 and 2 mol%, more preferably between 0.1 and 1 mol% and even more preferably between 0.1 and 0.5 mol%.
- the use of more than the optimal amount of ligand is uneconomical and in some cases can lead to lower selectivity. On the contrary, using less than optimal amount of ligand diminishes the selectivity due to a stronger influence of the non-catalysed and non- enantioselective background reaction.
- Suitable solvents for the process of the invention are known from similar reactions and can be found in the above-mentioned references.
- they are non- coordinating hydrocarbons like e.g. pentane, hexane, heptane; aromatic solvents like benzene, toluene; chlorinated solvents like dichloromethane and 1,2-dichloroethane and weakly coordinating solvents like diethyl ether and methyl-fert-butyl ether (MTBE).
- the most preferred solvents are toluene and hexane. These solvents allow the optional O-alkylation to be carried out in the same reaction mixture.
- a mixture of ligand and the compounds that form the zinc reagent can be prepared and stirred before the addition of the aldehyde.
- a pre-stirring is presumed to be beneficial for the selectivity because the deprotonation of the ligand by the zinc reagent giving the active catalyst requires a certain amount of time.
- the concentration of the aldehyde in the reaction is preferably low, such as between 0.01 molar and 2 molar, more preferably between 0.1 and 1 molar and most preferably at about 0.1 molar. Although in some cases it has been seen that enantioselectivity increases at lower concentrations, this is not suitable for a technical process. In these cases a proper balance between enantioselectivity and adequate concentrations has to be found.
- the process of the invention can be carried out at temperatures between -40 and
- reaction 100 0 C.
- temperatures between 0 and 20 0 C are used.
- the reactions are carried out at 10 0 C.
- the person skilled in the art will readily find out the optimal temperature for each combination of reagents.
- the enantioselectivity of the reaction can also be dependent on the reaction temperature.
- the process of the invention can also comprise the presence of additives, for example in order to improve the enantioselectivity by scavenging or complexing Lewis- acidic zinc salts present in the reaction or formed as products.
- Suitable additives are for example alcohols, amines and derivatives of polyethylenglycol. More preferably the additive is selected from polyethylenglycols such as DiMPEG 1000, DiMPEG 2000, PEG 750, PEG 1000, PEG 2000, monoMPEG
- the obtained alcohol can be purified through chromatography or crystallization; the zinc salts used or formed during the reaction are easily removed by aqueous workup.
- the R enantiomer is the preferred enantiomer due to its higher biological activity.
- the ee of the product alcohol can be enriched by storing a concentrated solution of the chiral alcohol in toluene at +8 0 C for several hours or days, because the racemic alcohol crystallises out.
- the alcohol was enriched from 82% ee to >96% ee.
- 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 the pharmaceutically active Cizolirtine (I).
- 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; Cj -4 alkyl sulphonyloxy, for example methanesulphonyloxy; arylphosphoryloxy, for example diphenylphosphoryloxy, dibenzylphosphoryloxy or a Ci -4 alkyl phosphoryloxy, for example dimethylphosphoryloxy.
- arylphosphoryloxy for example diphenylphosphoryloxy, dibenzylphosphoryloxy or a Ci -4 alkyl phosphoryloxy, for example dimethylphosphoryloxy.
- O-alkylation is carried out in conditions of phase transfer, using for example 2-chloro- N, ⁇ -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. Accordingly, the same solvent as the one used in the process of the invention is used, such as toluene. In these conditions we have the further advantage that the impurities like any remaining zinc salts are also eliminated through the aqueous phase.
- the resulting product of formula I enantiomerically enriched can be further purified using polar organic solvents.
- a pharmaceutically acceptable salt of the compound of formula I 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, such as the oxalate salt, will be readily apparent to the person skilled in the art.
- the reaction mixture is then poured into 100 ml of a 1 M acetic acid / sodium acetate buffer (pH: 4.5), 50 ml MTBE is added and the organic layer is separated, washed with 50 ml sat. Na 2 CO 3 -solution to remove excess acetic acid (extraction with ethyl acetate leads to DMF in the final product).
- the organic layer is separated, dried with MgSO 4 and the solvent is removed by a rotary evaporator.
- the crude product is purified by vacuum distillation (bp: 67 0 C, 21 mbar). 3 preparations which were distilled together yielded 5.969g (54 mmol, 90%) of the title compound.
- Example 2 Synthesis of (2 ⁇ Methyl-2i/-pyrazol-3-yl)-phenyl-methanol using triphenylborane ammonia complex
- a 20 ml vial is placed 8.91 mg (10 mol%) of (5)-2- ⁇ i ⁇ eridinyl-l,l,2-triphenyl-ethanol and 43 mg (0.17 mmol) of triphenylborane ammonia complex.
- the vial is closed and flushed with argon. Dry toluene (2 mL) is added and the vial is placed in a cooling bath of 10 0 C.
- the product can be further purified by column chromatography on silica using ethyl acetate / hexane (1 :1) as eluent to afford [R)-Il (37 mg, 79%) in 93% ee.
- 1 mol% may provide excellent ee in the case ligand SD623 and ligand SD634. Also acceptable enantiomeric excesses where obtained when reducing catalyst loads to 0.5 mol% or even 0.1 mol%.
- reaction is quenched by addition of 1 M HCl with vigorous stirring.
- the reaction mixture is placed in a separation funnel, further IM HCl and MTBE is added.
- the organic layer is washed with sat. Na 2 CO 3 -solution, dried with MgSO 4 and the solvent is removed by a rotary evaporator to yield >95% (95% ee) of virtually pure product.
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05822912A EP1838678A1 (en) | 2004-12-17 | 2005-12-16 | Process for obtaining cizolirtine and its enantiomers |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04380266A EP1671953A1 (en) | 2004-12-17 | 2004-12-17 | Process for obtaining cizolirtine and its enantiomers |
US11/041,637 US7109349B2 (en) | 2004-12-17 | 2005-01-24 | Process for obtaining Cizolirtine and its enantiomers |
EP05077140 | 2005-09-20 | ||
PCT/EP2005/013827 WO2006063861A1 (en) | 2004-12-17 | 2005-12-16 | Process for obtaining cizolirtine and its enantiomers |
EP05822912A EP1838678A1 (en) | 2004-12-17 | 2005-12-16 | Process for obtaining cizolirtine and its enantiomers |
Publications (1)
Publication Number | Publication Date |
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EP1838678A1 true EP1838678A1 (en) | 2007-10-03 |
Family
ID=36001075
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP05822912A Withdrawn EP1838678A1 (en) | 2004-12-17 | 2005-12-16 | Process for obtaining cizolirtine and its enantiomers |
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EP (1) | EP1838678A1 (en) |
WO (1) | WO2006063861A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US20100291151A1 (en) * | 2009-04-21 | 2010-11-18 | Auspex Pharmaceuticals, Inc. | 1-methylpyrazole modulators of substance p, calcitonin gene-related peptide, adrenergic receptor, and/or 5-ht receptor |
Family Cites Families (1)
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ES2130083B1 (en) * | 1997-08-04 | 2000-01-16 | Esteve Labor Dr | PROCEDURE FOR THE OBTAINING OF CIZOLIRTINE ENANTIOMERS. |
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2005
- 2005-12-16 EP EP05822912A patent/EP1838678A1/en not_active Withdrawn
- 2005-12-16 WO PCT/EP2005/013827 patent/WO2006063861A1/en active Application Filing
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WO2006063861A1 (en) | 2006-06-22 |
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Inventor name: RIDDER, MATTHIAS Inventor name: TORRENS JOVER, ANTONI Inventor name: BUSCHMANN, HELMUT H. Inventor name: DAHMEN, STEFAN |
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