WO2006063860A2

WO2006063860A2 - Process for obtaining enantiomers of thienylazolylalcoxyethanamines

Info

Publication number: WO2006063860A2
Application number: PCT/EP2005/013826
Authority: WO
Inventors: Antoni Torrens Jover; Helmut H. Buschmann; Stefan Dahmen; Matthias Lormann
Original assignee: Laboratorios Del Dr. Esteve, S.A.
Priority date: 2004-12-17
Filing date: 2005-12-16
Publication date: 2006-06-22
Also published as: WO2006063860A3; EP1828175A2

Abstract

A process is described for the preparation of a precursor alcohol of (±)-2-[thienyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethyletanamine and in general for thyenylazolylalcoxyethanamines and their enantiomers. It comprises the asymmetric addition of a metalated thienyl reagent to a pyrazolcarbaldehyde in the presence of a chiral ligand to render chiral alcohols. The chiral alcohols are further O-alkylated to render the corresponding pharmaceutically active thyenylazolylalcoxyethanamines.

Description

PROCESS FOR OBTAINING ENANTIOMERS OF THIENYLAZOLYLALCOXYETHANAMINES

FIELD OF THE INVENTION 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 addition reaction of a thienyl zinc reagent to a pyrazolcarbaldehyde. The carbinols are useful intermediates for the preparation of pharmaceutically active thyenylazolylalcoxyethanamines.

BACKGROUND OF THE INVENTION

The compound (±)-2-[phenyl(l -methyl-lH-pyrazol-5-yl)methoxy]-N,N- dimethylethanamine, also referred to as (±)-5-[α-(2-dimethylaminoethoxy)benzyl]-l- methyl-lH-pyrazole, or Cizolirtine of formula

was described in the European patent EP 289 380. This compound is a potent analgesic which is currently in phase II clinical trials. Optical resolution by fractional crystallization with optically active acids has been applied to the Cizolirtine racemate (WO 99/02500). The study of their analgesic activities has shown that the dextrorotatory enantiomer, (+)-Cizolirtine, is more potent than the (-)-Cizolirtine.

A further family of active compounds wherein a thiophene ring is present instead of the phenyl ring has been described in WO 99/52525. Among them, the compound (±)-2-[thienyl(l-methyl-lH-pyrazol-5-yl)methoxy]-jV,iV-dimethylethanamine of formula (I)

(D is currently in clinical trials for the treatment of depression. It can be prepared by O- alkylation of the compound of formula II:

(H)

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 (+)-I and (-)-I may be prepared by separately O-alkylating the enantiomerically pure intermediates (+)-II and (-)-II. Thus, a synthetic process to the enantiomerically pure/enriched intermediates (+)-

II and (-)-II is needed.

The enantioselective reduction of prochiral ketones has been proposed in organic synthesis to obtain secondary alcohols with high enantiomeric purity. Accordingly, a number of strategies for the asymmetric reduction of prochiral ketones to single enantiomer alcohols have been developed [R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed., 2001, 40, 40-73, Wiley- VCH Verlag]. However, no procedure has been described yet for methanols substituted with two heterocycles.

A phenyl transfer reaction to aryl aldehydes as an approach towards enantio-pure diarylalcohols has also been proposed, as alternative to the enantioselective reduction of prochiral ketones [P.I. Dosa, J.C. Ruble, G.C. Fu, J. Org. Chem. 1997, 62 444; W.S. Huang, L. Pu, Tetrahedron Lett. 2000, 41, 145; M. Fontes, X.Verdaguer, L. Sola, M. A. Pericas, A. Riera, J. Org. Chem. 2004, 69, 2532]. For this transformation, the group of BoIm et al. developed a protocol which utilized a ferrocene-based ligand (or catalyst) and diphenylzinc in combination with diethylzinc as aryl source [C. BoIm, N. Hermanns, M. Kesselgruber, J.P. Hildebrand, J. Organomet. Chem. 2001, 624, 157; C. BoIm, N. Hermanns, A. Claβen, K. Muniz, Bioorg. Med. Chem. Lett. 2002, 12,1795]. Enantiomerically enriched diarylmethanols with excellent enantiomeric excess (up to 99% ee) were thus obtained in a straightforward manner. Subsequently, the applicability of air-stable arylboronic acids as aryl source was also demonstrated [C. BoIm, J. Rudolph, J. Am. Chem. Soc. 2002, 124, 14850]. However, these systems require a high catalyst loading (of commonly 10% mol.) to achieve that high enantioselectivity. With the aim of reducing this problem, recently, it has been proposed the use of triphenylborane as an alternative phenyl source in a reaction where the ferrocene-based catalyst is also used (J. Rudolph, F. Schmidt, C. BoIm, Adv. Synth. Catal. 2004, 346, 867). It has been applied with difficulties to heteroaromatic aldehydes, for example to 2- thiophenecarbaldehyde.

However, there are still some difficulties to obtain chiral alcohols with a high yield and enantioselectivity without a high amount of catalyst. For their large-scale preparation, the application of highly efficient catalytic system and enantioselective methods employing inexpensive starting materials and simple purification steps would be most desirable.

On the other hand, the application of these processes to heteroaryl systems is challenging. There is at the present time no example of an enantioselective addition of thienyl- or phenylzinc reagents to heteroaryl aldehydes which comprise one or two nitrogen atoms, such as methyl-pyrazol aldehyde. Understandably, because substrates containing a nitrogen heteroatom can be expected to form catalytically active complexes

(or product complexes) which would usually drastically diminish the selectivity by favouring competing catalytic pathways. Indeed, it is well known in zinc chemistry that various functional groups like esters or nitriles are tolerated on the aldehyde substrates.

However, 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). Thus, to attain satisfactory ee values by an enantioselective addition reaction, an appropriate coordination of the catalyst system and the aldehyde is required. The results with unusual substrates cannot be predicted and each addition has to be investigated separately with regard to the substrate.

SUMMARY OF THE INVENTION

We have now surprisingly found that pyrazolcarbaldehydes can be successfully used as substrates for a thienyl transfer reaction. Indeed, the reaction works remarkably well even in the presence of two N on the heteroaromatic part of the aldehyde providing the desired diheteroarylmethanols with high conversion and high enantiomeric purity. We have therefore applied this process to the synthesis of the enantiomerically pure intermediates (+)-II and (-)-II and to a process to obtain 2-[thienyl(l -methyl- IH- pyrazol-5-yl)methoxy]-N,iV-imethylethanamine, and in general thienylazolylalcoxyethanamines and their enantioniers. This process should operate particularly well on an industrial scale and be satisfactory as regards enantiomeric excess, less quantity of catalyst and in general raw material costs. Further, heavy metals are not used, avoiding the presence of potentially toxic impurities. Another advantage is that impurities are easily eliminated.

Accordingly, in one aspect the present invention refers to a process for the asymmetric addition to a pyrazolcarb aldehyde with a thienyl 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 pharmaceutically active thienylazolylalcoxyethanamines, particularly the pharmaceutically active compound 2-[thienyl(l-methyl-lH-pyrazol-5-yl)methoxy]-N,iV- dimethylefhanamine.

The invention is directed to a process for the preparation of an enantiomerically enriched compound of formula (II):

(H) wherein: Ri and R₂ are independently selected from hydrogen, halogen, lower alkyl or aryl; which comprises an enantioselective addition reaction to a methylpyrazolcarbaldehyde compound of formula (IV):

(IV) with a thienyl zinc reagent optionally susbtituted on the thienyl ring, in the presence of a chiral ligand.

In a preferred embodiment R] is H.

In another preferred embodiment R₂ is H.

In a most preferred embodiment both Ri and R₂ are H.

According to another aspect, the present invention is directed to a process for the preparation of an enantiomerically enriched compound of formula (II):

(H) wherein:

Ri and R₂ are independently selected from hydrogen, halogen, lower alkyl or aryl; which comprises an enantioselective addition reaction to a methylpyrazolcarbaldehyde compound of formula (IV):

(IV) with dialkyl zinc reagent and 2-aminoethyl dithienylborinate in the presence of a chiral ligand of formula SD-623:

SD-623 or the enantiomer of the same.

DETAILED DESCRIPTION OF THE INVENTION In one aspect, the present invention relates to a process for the preparation of an enantiomerically enriched compound of formula (II):

(H) wherein: Ri and R₂ are independently selected from hydrogen, halogen, lower alkyl or aryl; which comprises an enantioselective addition reaction to a methyl pyrazolcarbaldehyde compound of formula (IV):

(IV) with a thienyl zinc reagent optionally substituted on the thienyl ring, in the presence of a chiral ligand.

It will be readily apparent to the person skilled in the art that the process is also applicable for the thienyl addition to other aldehydes having a different nitrogen- containing heterocycle instead of the methyl pyrazole ring, such as methyl pyrrole, methyl imidazole and methyl triazole.

The term "lower alkyP refers to a linear or branched hydrocarbon chain which contains 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. By "thienyl zinc reagent optionally substituted on the thienyl ring", we refer to a thienyl zinc reagent which can be substituted at 2, 3, 4 or 5 position of the thienyl ring by an halogen, a lower alkyl or an aryl group.

Such a process gives the desired products of formula II with a 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 the enantiomers of the above mentioned thienylazolylalcoxyeihanamines. Different compounds can be obtained depending on the substituents present on the thienyl or N-containing heterocyclic rings.

We will discuss below the different reagents and conditions for the process of the invention.

Pyrazolcarbaldehvde fAzolylcarbaldehvde^')

The synthesis of methylpyrazolcarbaldehyde (IV) which is the essential starting material for the addition route, is known to the person skilled in the art. For example, (IV) can be easily prepared through the lithiation of 1 -methyl pyrazole (V):

(V) and concomitant quenching with dimethyl formamide (DMF). Then the reaction product is hydrolyzed, for example with water or sodium acetate buffer (pH 4.5), and either employed directly or after distillation (scheme I). Residual amounts of DMF apparently do not influence the selectivity of the subsequent addition process.

Scheme I

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 of the appropriate substrate. If necessary diethyl amine can be used to prevent the deprotonation of the N-methyl group, normally 10 mol% is sufficient. Preferably, THF is used as solvent, in this case no additive is necessary. The deprotonation reaction is preferably performed below -10⁰C (usually at -20⁰C) to prevent the formation of side products by ring-opening of THF. To purify the obtained 1-methylpyrazolcarbaldehyde, distillation or extractive workup with an organic solvent can be used to remove the by-products. Otherwise, as previously mentioned, the aldehyde can be used directly for the addition.

A person skilled in the art would readily know how to prepare other aldehydes having different nitrogenated heterocycles such as pyrrole, imidazole and triazole, or different patterns of substitution.

Thienyl zinc reagent

The thienylzinc reagent can be prepared in situ by a transmetallation reaction of a thienylboron reagent with dimethyl- or diethyl-zinc. Diethyl-zinc gives good results, although dimethyl-zinc is less prone to give alkylation reaction by-products in the reaction mixture with the aldehyde. The active species are presumably a mixed thienyl- ethyl-zinc or thienyl-methyl-zinc.

Among the suitable thienyl-boron reagents, thienylboronic acid, trithienylborane or 2-aminoethyl dithienylborinate depicted below:

are preferably selected. More preferably, the thienyl-boron reagent is 2-aminoethyl dithienylborinate, because it can be made in higher purity and can be recrystallised from ethanol. Stable complexes of thienyl boranes are also preferred such as the NH₃ complex. The thienyl zinc can optionally have a Rj substituent as defined above.

Chiral Ligand

With the aim of enantioselectively synthesizing a compound of formula (II) by an enantioselective addition reaction, the addition reaction must be carried out in the presence of a chiral catalyst or ligand, which forms the active catalyst in situ by reaction with the zinc reagent. That means that the ligand (or catalyst) must have at least one element of chirality like one or more stereocentres or elements of planar chirality.

In principle, there is a great variety of N,O-, N₅N-, N₅S-, N₅Se- or O,O-ligands that can be used in the process of the invention and all of them have to be in enantiomerically pure form. There are in the art about 600 known ligands for this type of reaction. Most of them can be found, for example in a recent review on catalytic asymmetric organozinc additions to carbonyl compounds [L. Pu, H. -B. Yu, Chem. Rev. 2001, 101, 757]. The nomenclature N,O-, N₅N-, N₅S-, N₅Se- or O₅O- refers to ligands that have at least these two coordinating heteroatoms. It is obvious to the skilled person that in order obtain a compound of formula II with the opposite configuration it is only necessary to use the enantiomer of the chiral ligands used in the present invention. Therefore, when a structure of a ligand is given throughout the present patent application, said structure is also meant to encompass the enantiomer of said ligand. In a preferred embodiment of the present invention N,O-ligands and N,S-ligands are employed. N,O-ligands are derived from β-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. More preferably, the O is an alcohol.

In one embodiment a N,O-ligand having a structure-type (V) such as described below:

(V) wherein n is 0 or 1 is used. These 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 or sulfur atom). This zinc-alcoxide complex in situ formed is the active catalyst.

Typical ligands to be used in this addition reaction are the following compounds, their enantiomers, or derivatives thereof:

(S,S)-499 (S_p,S)-TD10a (R_p,S)-311a

(S)-2-piperidinyl-l ,1 ,2-

SD-31 1b

SD-498a triphenylethanol (SD-286)

SD504 SD591

SD522

(IR, 2S)-(-)-2-dibuthylamine-l-phenyl-propanol

These ligands are available in both enantiomeric forms, allowing the selective synthesis of both enantiomers of the desired alcohol.

Good results are obtained for example with SD311a together with dimethylzinc and specially with (ιS)-2-piperidinyl-l,l,2-triphenylethanol (SD-286), which is commercially available, together with diethylzinc.

Due to the fact that good results were obtained using SD-286 as ligand, different derivatives of this compound were synthesised in order to prove their utility in the enantioselective synthesis of the desired alcohol. These derivatives have a general formula (Va):

(Va) wherein R₂, taking together with N atom, is selected from the group consisting of pyrrolidine (TD99b), pyperazine (SD 286), N-methyl pyperazine (TD99c), 4-methyl pyperidine (TD99i), 3 -methyl pyperidine (TD99q), morpholine (TD99a) and perhydroazepine (TD99o).

These derivatives were synthesised according to scheme I:

The first step is a Jacobsen epoxidation of the compound 1,1,2-trifenilethene followed by the introduction of the amine group NR₂ by opening the epoxide ring in the presence Of LiClO₄.

Additionally, two ligands with an ephedrine core structure, which is related to the backbone of ligand SD-286, were prepared and used. These ligands have the following structure:

TDlOIa SD-623

While the ligand TDlOIa behaves like other typical amino alcohol ligands, which lead to an enantiomeric excess ranged between 50-68%, the thioacetate ligand SD-623 brought a breakthrough, providing in an example a 93% of enantiomeric excess and a yield of 75%. Although this ligand was described in literature for the addition of diethylzinc to benzaldehydes, there has been no evidence on its special behaviour. SD- 623 therefore gave the desired product with high enantiomeric excess and small amounts of alkylation by-products, which is the major by-product when using N,O- ligands.

Therefore, in an embodiment of the invention a N,S-ligand is used. N,S-ligands provided the desired product in good yield and remarkable enantiomeric excess. Among the N,S-ligands, those of formula VII

Formula VII wherein Ra is selected from hydrogen or an alkoyl group, such as the aminothioacetates, are preferred. 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. Aim, K.-S. Lee, Tetrahedron Lett. 1996, 37, 8767.) According to another embodiment, the ligand of the present invention is a compound having the following formula:

SD-633

SD-639 ML-176

or the enantiomer thereof.

In a preferred embodiment of this invention the ligand has a thioacetate-amino structure, more preferably it is SD-623.

The reaction that takes place between the zinc reagent and the ligand leads to a complex of formula (VI):

zinc reagent

ligand (V) catalyst (VI) wherein n is 0 or 1 and R"¹ is thienyl, ethyl or methyl. A sulphur atom can be used instead of the oxygen atom, for example when using SD-623. 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 thionyl group to said aldehyde. Without being bound by theory, it is believed that aminothiols and aminothioesters form similar complexes. However, the mechanism followed by aminothioesters complexes seems to be different from the mechanism followed by the intermediates of formula VI.

The concentration of the ligand should be low to reduce costs but sufficient to provide good enantiomeric excess (ee). The ligands are preferably used in amounts of 0.1 to 100 mol%, more preferably 1 to 20 mol % and most preferably 5 to 10 mol%. However, good enantiomeric excesses have been achieved even with catalyst loads as low as 0.5 or 0.2 mol%. According to a further embodiment, the ligands are preferably used in amounts of 0.1 to 20 mol%, preferably between 0.1 and 5 mol%, more preferably between 0.1 and 2 mol%, even 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 a 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.

Solvent Suitable solvents for the process of the invention are known from similar reactions and can be found in the above-mentioned references. Preferably 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, methyl-fer?-butyl ether (MTBE) and even polar coordinating solvents such as tiophene or dioxane. The most preferred solvents are toluene, hexane and heptane. These solvents allow the subsequent optional O-alkylation to be carried out in the same reaction mixture. In another variant of the process of the invention tiophene is used as the solvent, drastically improving yield and enantioselectivity and suppressing by-reactions such as the ethylation.

To perform the process, a mixture of ligand and the compounds that form the zinc reagent can be prepared and stirred before the addition of the aldehyde. Usually, 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.

Unexpectedly, it has been found that higher enantiomeric excess is achieved if short pre-stirring times are used. The highest selectivities were obtained upon simultaneous addition of aldehyde and dialkylzinc. Thus, in a preferred embodiment these reagents are simultaneously added. Once the aldehyde is added to the mixture of ligand and zinc reagent, the reaction time ranges between 1 h and 24 h.

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 less 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

100⁰C. Preferably, temperatures between -20 and 2O⁰C are used. Most preferably, the reactions are earned out at about -1O⁰C to 1O⁰C. 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

2000 and PE-block-PEG, or from compounds such as 1,4-dioxane, z-propanol, triethylamine, tretramethylethylenediamine (TMEDA), imidazol, anisole, furane and thiophene. As mentioned above, the tiophene has the advantage of improving yield and enantioselectivity of the reaction, and can be used in quantities such that it acts also as a solvent. In one case using thiophene as a solvent and SD286 as a ligand an ee of 81% was obtained.

In a preferred embodiment the process is directed to the synthesis of each of the following alcohols of formula II with the highest possible enantiomeric purity:

(Ha) (lib)

wherein Rj and R₂ are as defined above.

It will be readily apparent to the person skilled in the art that the process is also applicable for the thienyl addition to other aldehyde having a different nitrogen- containing heterocycle instead of the pyrazole ring, such as pyrrole, imidazole and triazole.

The obtained alcohol can be purified through chromatography or crystallization, the zinc salts used are easily removed by aqueous work-up. Alternatively, the alcohol can advantageously be used without further purification in the next step, which can be carried out in the same reaction medium.

Thus, in another aspect, 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. To this end the compound of formula (II) is treated with an amine of formula

wherein

X is a suitable leaving group such as halogen, more preferably chlorine, bromine or iodine; a reactive esterifϊed 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 R₃, R₄ and R_4B are independently selected from H and a lower alkyl.

Preferably R₃ is hydrogen.

Preferably R₄ and R_4B are independently selected from H and methyl. In one embodiment both R₄ and R₄B are methyl.

A particularly preferred amine for the step of O-alkylation is X-CH₂-CH₂N(Me)₂. More preferably X is chlorine.

The O-alkylation has been described in WO 99/52525, the content of this patent application is incorporated herein in its entirety. 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. Besides being more economical, this direct alkylation avoids racemisation of the compound of formula (II) during workup of the addition reaction according to the present invention. In general, the O-alkylation is carried out in conditions of phase transfer, using for example 2-chloro-N,iV,-dimethylethylamme (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 is enantiomerically enriched, it can be further purified using polar organic solvents. Further, a pharmaceutically acceptable salt of the obtained compound can be formed. For example, 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, will be readily apparent to the person skilled in the art.

The following examples will further illustrate the invention, they should not be interpreted as limiting the scope of the invention.

EXAMPLES

Example 1. Synthesis of 2-methyI-2H-pyrazole-3-carbaldehyde

In a dry 50 ml vial is placed a solution of 1.642 g (20 mmol) jV-Methylpyrazole in 30 ml dry THF. The mixture is cooled to -20 °C and while stirring 8 ml (20 mmol,

2.5M in hexane) n-BuLi-solution is slowly added. The reaction mixture is stirred for 2.5 h at -20 ⁰C. With vigorous stirring 4.7 ml (4.39g, 60 mmol) dry DMF is slowly added at

-20 ⁰C and the mixture kept at this temperature for 1 h. 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. Na₂CO₃-solution to remove excess acetic acid (extraction with ethyl acetate leads to DMF in the final product). The organic layer is separated, dried with MgSO₄ and the solvent is removed by om a rotary evaporator. The crude product is purified by vacuum distillation (bp: 67

°C, 21 mbar). 3 preparations which were distilled together yielded 5.969g (54 mmol, 90%) of the title compound.

¹H-NMR (300 MHz, CDCl₃): 4.18 (s, 3H, CH₃-N), 6.91 (d, IH, ³J=2.0 Hz, CH=C-N), 7.53 (d, 1Η, ³J=2.0 Hz, CH=N), 9.87 (s, 1Η, CH=O) ppm.

¹³C-NMR (100 MHz, CDCl₃): 39.31 (CH₃-N), 114.78 (CH=C-N), 138.54 (CH=N), 138.98 (CH=C-N), 179.83 (CH=O) ppm. Example 2. Synthesis of (2-methyl-2H-pyrazole-3-yI)-thiophene-2-yl-methanol

A) With ligand SD31 Ia and dimethylzinc at 10 ⁰C

In a 20 ml vial 50 mg (0.21 mmol) 2-aminoethyl-dithienyl-borinate and 3.7 mg (O.OlOmmol) of ligand SD311a (4 mol%) is placed. 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 °C. Dimethylzinc (0.35 mL, 0.7 mmol, 2M solution in toluene) and 25 μl (0.25 mmol) 2-methyl-2H-pyrazole-3-carbaldehyde is added and the reaction mixture is stirred for at least 12 h at 10 ⁰C. The reaction is quenched by addition of 2 mL of 1 M HCl with vigorous stirring. The reaction mixture is placed in a separation funnel, 10 ml 1 M HCl and approx. 25 ml MTBE is added. The organic layer is washed with 15 ml of sat. Na₂CO₃ -solution, dried with MgSO₄ and the solvent is removed by a rotary evaporator. The product is further purified by chromatography on silica affording the title compound (25 mg, 52% yield) in 67% ee.

Evaluation of enantiomeric excess: ΗPLC Column: Diacel Chiralpak AD 250x4 mm heptane / propane-2-ol 93/7 Flow: 0.5 ml/min; Temp.: 15 ⁰C; det: 230 nm Ret-Times: 32.5 min / 34.5 min

¹H-NMR (400 MHz, CDCl₃): 3.64 (s, 3H, CH₃-N), 5.73 (s, IH, OH), 6.03 (s, 1Η, CH- OH), 6.13 (d, IH, ³J=I .92 Hz, CH-CH=C-N), 6.82 (dt, 1Η, ³J=3.57, ⁴J=LlO Hz, CH=C- S-CΗ), 6.92 (dd, 1Η, ³J=4.94, ³J=3.57 Hz, CH=CH-S-C), 7.19 (d, IH, ³J=I .92 Hz, CH- CH=C-N), 7.24 (dd, 1Η, ³J=4.94, ⁴J=LlO Hz, S-CH=CH) ppm.

¹³C-NMR (100 MHz, CDCl₃): 36.78 (CH₃-N), 64.15 (CH-OH), 105.15 (CH=C-N), 124.62 (CH=C-S), 125.28 (CH=CH-S), 126.53 (CH=CH-S), 137.41 (CH-CH=N), 143.94 (CH=C-S), 145.16 (CH=C-N) ppm.

B) With ligand (>S>2-piperidinyl-l,l,2-triphenylethanol and diethylzinc at -10 ⁰C In a 20 ml vial 50 mg (0.21 mmol) 2-aminoethyl-dithienyl-borinate and 9.3 mg (0.025mmol) of ligand (5)-2-piperidinyl-l,l,2-tripheaiylethanol (10 mol%) (SD-286) is placed. 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 ⁰C. Diethylzinc (0.7 mL, 0.7 mmol, 2M solution in toluene) and 25 μl (0.25 mmol) 2-methyl-2H-pyrazole-3-carbaldehyde is added and the reaction mixture is stirred for at least 12 h at -10 ⁰C. Work-up is conducted as described in Example 2^a affording the title compound (24 mg, 51 % yield) in 70% ee.

Example 3. Synthesis of (2-methyl-2H-pyrazole-3-yl)-thiophene-2~yl-methanol in the presence of derivatives of ligand SD-286.

Using the conditions of example 2B) which leads to 70% ee with ligand SD-286 but changing the temperature to 10⁰C, a ligand screening with a variety of derivatives of the cited ligand was carried out. The results are given in the following table:

entry ligand (10 mol%), zinc reagent ee (%)

1 TD99o, ZnEt₂ 51

2 TD99a, ZnEt₂ 46

3 TD99c, ZnEt₂ 55

4 TD99i, ZnEt₂ 66

5 TD99q, ZnEt₂ 66

Example 4. Synthesis of (2-methyl-2H-pyrazole-3-yl)-thiophene-2-yl-methanol in the presence of ligand SD-623.

Using the same conditions as example 3 (toluene, diethylzinc, 2-aminoethyl dithienylborinate, 10⁰C) but in the presence of SD-623 (10 mol%) as ligand, the addition reaction affords an alcohol in 93% ee and 75% yield and complete conversion of the aldehyde. Example 5. Reaction conditions in the synthesis of (2-methyl-2H-pyrazole-3-yl)- thiophene-2-yl-methanol using ligand SD-623

In order optimize the reaction, different reactions where carried out under different conditions using SD-623.

The above data shows a large variety of ethylation by-products depending on the conditions. When using dimethylzinc as transmetallation reagent, no alkylation byproduct is obtained, but enantiomeric excess decreases to 83% (entry 3). Example 6. Synthesis of (2-methyl-2H-pyrazole-3-yl)-thiophene-2-yl-methanol using different N,S-ligands and different catalyst loads

As shown above, the best results where obtained with free aminothiol SD634 and aminothioacetate SD-623 (entries 2 and 5) using a 10 mol% catalyst load. In the case of SD-623, even good enantiomeric excesses are obtained with catalyst loads of 2-5 mol% (entries 6 and 7).

Example 7. Gram-scale synthesis of (2-methyl-2H^r-pyrazole-3-yl)-thiophene-2-yl- methanol

In view of the excellent results obtained with SD-623, a gram-scale synthesis was carried out. In a flask is placed 138 mg (10 mol%) of ligand SD-623 and 1.06 g (4.5 mmol) of 2- aminoehtyl-dithionyl-borinate. The flask is closed and flushed with argon. Dry toluene (45 mL) is added and the flask is placed in a cooling bath of 10 °C. Diethylzinc (20.0 mL, 1 M in hexane) and then 561 mg (5 mmol) 2-methyl-2H-pyrazole-3-carbaldehyde in 10 ml of dry toluene is added slowly (over 2h) and the reaction mixture is stirred for 16 h at 10 ⁰C. The 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. Na₂CO₃ -solution, dried with MgSO₄ and the solvent is removed by a rotary evaporator to yield >80% (93% ee) of product. About 15% of ethylation product was obtained.

Claims

1. A process for the preparation of an enantiomerically enriched compound of formula (II):

(II) wherein: Ri and R₂ are independently selected from hydrogen, halogen, lower alkyl or aryl; which comprises an enantioselective addition reaction to a methylpyrazolcarbaldehyde compound of formula (IV):

2. A process according to claim 1 wherein the methyl pyrazolcarbaldehyde is replaced by a methyl pyrrolecarbaldehyde, a methyl imidazolecarb aldehyde or a methyl triazolecarbaldehyde.

3. A process according to claim 1 wherein the thienyl zinc reagent is prepared in situ by a transmetallation reaction of a thienylboron reagent with dimethyl-zinc or diethyl-zinc.

4. A process according to claim 3 wherein the thienylboron reagent is selected from thienylboronic acid, trithienylborane or 2-aminoethyl dithienylborinate depicted below:

5. A process according to claim 1 wherein the chiral ligand is a N₇O-, N₅N-, N, S-, N, Se- or O,O-ligand in its enantiomerically pure form.

6. A process according to claim 5 wherein the chiral ligand is a N,O-ligand, most preferably the O is an alcohol.

7. A process according to claims 6 wherein the N,O-ligands are selected from the following compounds:

(S,S)-499

SD-311b

SD-498a

SD504 SD591

SD522

(IR, 2S)-(-)-2-dibuthylamine-l- TDlOIa phenyl-propanol

TD99c TD99i TD99q

or an enatiomer thereof.

8. A process according to anyone of claims 1-5 wherein the ligand is a N,S-ligand.

9. A process according to claim 8 wherein the ligand is an amino-thioacetate ligand.

10. A process according to any of claims 8 or 9, wherein the ligand is SD-623

SD-623 or the enantiomer of the same.

11. A process according to any of claims 8 or 9, wherein the ligand is selected from the compounds having the following formulas

SD-633

SD-639 ML- 176

ML-188 or the enantiomers of the same.

12. A process according to claim 8 wherein the ligand is an aminothiol ligand, preferably an aminothiol of formula SD-634

SD-634 or the enantiomer of the same.

13. A process according to anyone of claims 1-12 wherein the ligands are used in amounts ranged between 0.1 and 20 mol%.

14. A process according to claim 13 wherein the ligands are used in amounts ranged between 1 and 20 mol%, preferably between 5 and 10 mol%.

15. A process according claim 13 wherein the ligands are used in amounts ranged between 0.1 and 5 mol%.

16. A process according to claim 15 wherein the ligands are used in amounts ranged between 0.1 and 1 mol%, preferably between 0.1 and 0.5 mol%.

17. A process according to anyone of claims 1-16 wherein the temperature is comprised between -2O⁰C and 20⁰C, preferably -1O⁰C to 1O⁰C.

18. A process according to anyone of claims 1-17 wherein the aldehyde concentration ranges between 0.01 molar and 2 molar.

19. A process according anyone of claims 1-18 wherein the solvent is non-coordinating, chlorinated or weakly coordinating.

20. A process according to claim 19 wherein the solvent is toluene or hexane.

21. A process according to claim 1 which further comprises an O-alkylation of the enantiomerically enriched compound of formula II, with an amine of formula

wherein X is a leaving group selected from halogen or a reactive esterified hydroxyl, and R₃, R₄ and R_4B are each independently selected from H and lower alkyl.

22. A process according to claim 21 wherein the O-alkylation is carried out on the product of the process as defined in anyone of claims 1-20, without an intermediate separation or purification step.

23. A process for the preparation of an enantiomerically enriched compound of formula (II):

(H) wherein:

Ri and R₂ are independently selected from hydrogen, halogen, lower alkyl or aryl; which comprises an enantioselective addition reaction to a mefhylpyrazolcarbaldehyde compound of formula (IV) :

(IV) with dialkyl zinc reagent and 2-aminoethyl dithienylborinate in the presence of a chiral ligand of formula SD-623

SD-623 or the enantiomer of the same.