GB2451629A - 1-(Azolylcarbonyl)-2-(hydroxymethyl)pyrrolidine derivatives for use as catalysts for asymmetric reduction of imines & reductive amination of ketones - Google Patents

1-(Azolylcarbonyl)-2-(hydroxymethyl)pyrrolidine derivatives for use as catalysts for asymmetric reduction of imines & reductive amination of ketones Download PDF

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GB2451629A
GB2451629A GB0715206A GB0715206A GB2451629A GB 2451629 A GB2451629 A GB 2451629A GB 0715206 A GB0715206 A GB 0715206A GB 0715206 A GB0715206 A GB 0715206A GB 2451629 A GB2451629 A GB 2451629A
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reducing agent
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Simon Jones
Francois-Moana Gautier
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University of Sheffield
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/45—Monoamines
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/45—Monoamines
    • C07C211/48—N-alkylated amines
    • 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
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
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    • C07C2602/00—Systems containing two condensed rings
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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Abstract

Compounds of formula (I) <EMI ID=1.1 HE=49 WI=39 LX=867 LY=752 TI=CF> <PC>wherein: <DL TSIZE=22> <DT>R1, R2, R3, R4 and R5<DD>are each separately selected from the group consisting of hydrogen, alkyl and aryl; <DT>X<DD>is oxygen or sulphur; and Z has the formula (II) or (III) </DL> <EMI ID=1.2 HE=33 WI=91 LX=593 LY=1551 TI=CF> <PC>wherein: <DL TSIZE=18> <DT>R6, R7, R8 and R9<DD>are each separately selected from the group consisting of hydrogen, alkoxy, nitro, halogen, alkyl and aryl; or R6 and R7 are linked to form a cyclic group; <DT>Y<DD>is oxygen, sulfur or NR10; and R10 is selected from the group consisting of hydrogen, alkyl and aryl; </DL> are useful as catalysts. e.g. for the reduction of imine compounds or for the asymmetric reductive amination of ketone compounds.

Description

I
1 2451629
CATALYST COMPOUNDS
The present invention relates to compounds for use as catalysts, methods for producing said compounds and the use of said compounds as catalysts in catalytic processes including, but not limited to, the asymmetric reduction of imine compounds and/or the reductive amination of aldehyde or ketone compounds.
Many commercially important chemical compounds incorporate amine, particularly chiral amine, groups. Moreover, compounds incorporating amine and chiral amine functionality are valuable chemical intermediates in, for example, the pharmaceutical and fine chemicals industries. A significant amount of work has therefore been undertaken by many different groups to develop new, more efficient methods for preparing compounds incorporating amine groups and, in particular, chiral amine groups.
Different methods have been developed by which chiral amines can be produced from corresponding aldehydes and ketones by stoichiometric or catalytic asymmetric reduction. Unfortunately, each of these methods is a multi-step process, which limits the overall product yield and enantiomeric excess that can be obtained.
Rather than using a carbonyl compound as the starting material, compounds containing imine groups can also be used, whereby the imine group is reduced to the corresponding chiral amine group. The three most widely adopted methods developed to date are transition metal catalysed high pressure hydrogenation, hydrosilylation (typically using trichiorosilane) and transfer hydrogenation. Methods employing metal catalysts, however, suffer from disadvantages associated with metal leaching and catalyst regeneration and so the development of improved catalysts for the generation of chiral amines is of significant commercial interest.
In spite of the clear commercial motivation to explore new methods for producing amine, particularly chiral amine, containing compounds it is widely appreciated that the development of new catalytic protocols, particularly those which must control the chirality of the final product, is complicated and involves a great deal of optimisation of many different factors which affect the outcome of the catalytic process, such as the catalyst structure, catalyst loading, solvent, temperature and time. Relatively minor changes in any one of these factors can have a significant and often detrimental effect on the stereochemical outcome of the reaction.
The object of the present invention is to obviate or mitigate one or more of the above problems.
According to a first aspect of the present invention there is provided a compound having the formula (I)
OH Z-R2 X R1 (I)
wherein: R1, R2, R3, R4 and R5 are each separately selected from the group consisting of hydrogen, alkyl and aryl; X is oxygen or sulfur; and Z has the formula (II) or (Ill) (R> (II) (III) wherein: R6, R7, R8 and R9 are each separately selected from the group consisting of hydrogen, alkoxy, nitro, halogen, alkyl and aryl, or R6 and R7 are linked to form a cyclic group; and Y is oxygen, sulfur or NR'° in which R'° is selected from the group consisting of hydrogen, alkyl and aryl.
The results presented below in Examples 3 to 6 clearly demonstrate that compounds according to the first aspect of the present invention, in particular but not limited to compound (Villa), are eminently suitable for use as catalysts in the asymmetric reduction of imine compounds to corresponding chiral amine compounds. Moreover, Examples 7 and 8 demonstrate the applicability of compounds according to the first aspect of the present invention to the direct asymmetric reductive amination of aldehydes and ketones to corresponding chiral amine compounds.
A second aspect of the present invention provides a process for the production of a compound according the first aspect of the present invention, the process comprising reacting a compound of formula (IX) with a compound of formula (X) or formula (XI) in the presence of a base R3 HN-OH RiXY>ORll RNX (IX) (X) (XI) wherein R" is a substituted or unsubstituted alkyl group.
Examples 1 and 2 below describe preferred methods for the production of compounds (Villa) and (XVIa), which represent preferred embodiments of the first aspect of the present invention.
According to a third aspect of the present invention there is provided a process for effecting catalytic reduction of an imine compound to provide a corresponding amine compound, the process comprising reacting said imine compound with a reducing agent in the presence of a catalyst compound having a formula according to the first aspect of the present invention.
A fourth aspect of the present invention provides use of a compound having a formula according to the first aspect of the present invention to catalyse the reduction of an imine compound to provide a corresponding amine compound.
According to a fifth aspect of the present invention there is provided a process for effecting the direct asymmetric reductive amination of a first compound including an aldehyde or ketone group with a second compound including a first amine group to provide a third compound including a second amine group, the process comprising reacting said first compound with said second compound and a reducing agent in the presence of a catalyst compound having a formula according to the first aspect of the present invention.
A sixth aspect of the present invention provides use of a compound having a formula according to the first aspect of the present invention to catalyse the direct asymmetric reductive animation of an aldehyde or ketone compound to provide an amine compound.
Where the term "alkyl" or "alkyl group" is used herein without any further qualification it is to be interpreted as encompassing both substituted and unsubstituted alkyl groups. Moreover, where the term "alkyl" or "alkyl group" is used herein without any further qualification it will be understood to encompass linear, branched and cyclic alkyl groups.
Where the term "aryl" or "aryl group" is used herein without any further qualification it is to be interpreted as encompassing both substituted and unsubstituted aryl groups. Any substitution may be provided as an appendage to the carbocyclic ring structure and/or within the carbocyclic ring structure wherein at least one carbon atom forming part of the aryl ring structure is replaced with a non-carbon atom so as to provide a heteroaryl ring structure, e.g. a pyridinyl group.
It will be understood that where formulae are used herein to depict chemical structures which include one or more chiral atoms, formulae which depict a particular stereochemistry should be interpreted as relating to a particular enantiomer having the stereochemistry shown, but in formulae where no particular stereochemistry is depicted (e.g. a single solid line is used to represent an interatomic bond, rather than a bold wedge or a hashed wedge) those formulae should be interpreted as encompassing both enantiomers. To aid understanding, where non-stereospecific formulae are used to refer generically to both enantiomers a Roman reference numeral will be used and where a formula is used to depict a specific enantiomer of that compound the Roman reference numeral will be suffixed by a letter a' or b'. By way of example, a preferred compound according to the first aspect of the present invention has a generic formula denoted (VIII)' and the (S)-enantiomer of this preferred compound is denoted (Villa)'.
0 Ph N 0 Ph (VIII) (Villa) With regard to the compound of formula (I) defined above in the first aspect of the present invention, while X may be oxygen or sulfur, it is preferred that X is oxygen such that compound (I) incorporates a central carbonyl moiety. By virtue of the carbon atom of the carbonyl group being bonded to a nitrogen atom, the preferred embodiment of compound (I), wherein X is oxygen, incorporates an amide functional group. Since the nitrogen atom bonded to the carbonyl carbon atom forms part of a 5-membered heterocyclic ring, the amide functional group is a cyclic amide.
In the group Z which forms part of compound (I), substituent Y may be oxygen, sulfur or NR'° in which R'° is hydrogen, alkyl or aryl. It is preferred that Z is NR'° such that group Z is an imidazole of formula (XXVII) or (XXVIII).
(XXVII) (XXVIII) It is preferred that R° is an alkyl group, more preferably a C1-C6 linear or branched alkyl group, such as a methyl, ethyl or propyl group. Most preferably, R'° is a methyl group.
When group Z has the formula (II) including substituents R6 and R7, each of these substituents may be individually selected from the group consisting of hydrogen, alkoxy (e.g. methoxy, ethoxy), nitro (-NO2), halogen (e.g. F, Cl, Br, I), alkyl (e.g. C1-C6 linear or branched alkyl group, such as methyl, ethyl or propyl) and aryl (e.g. phenyl). It is preferred that at least one of R6 and R7 is hydrogen, more preferably, both of R6 and R7 are hydrogen.
In a preferred embodiment of the compound of the first aspect of the present invention, group Z has a formula (V). (V)
Alternatively, R6 and R7 may be linked to form a cyclic group, which may be substituted with one or more substituent selected from the group consisting of hydrogen, alkoxy (e.g. methoxy, ethoxy), nitro (-NO2), halogen (e.g. F, Cl, Br, I), alkyl (e.g. C1-C6 linear or branched alkyl group, such as methyl, ethyl or propyl) and aryl (e.g. phenyl). It is particularly preferred that the cyclic group, which may be substituted or unsubstituted, is a cycloalkyl group or an aromatic group.
A preferred embodiment of the compound having formula (I) incorporates group Z having the formula (VI) (VI) in which, with reference to formula (II) above, Y is nitrogen substituted with a methyl group, and R6 and R7 are linked to form an unsubstituted phenyl group.
In the compound of formula (I), wherein Z has the formula (III), R8 and R9 are individually selected from the group consisting of hydrogen, alkoxy (e.g. methoxy, ethoxy), nitro (-NO2), halogen (e.g. F, CI, Br, I), alkyl (e.g. C1-C6 linear or branched alkyl group, such as methyl, ethyl or propyl) and aryl (e.g. phenyl).
At least one of R8 and R9 may be hydrogen and it is preferred that both R8 and R9 are hydrogen.
A preferred embodiment of the compound having formula (I) incorporates group Z having the formula (VII) (VII) in which, with reference to formula (III) above, Y is nitrogen substituted with a methyl group, and R8 and R9 are hydrogen.
With regard to the compound of formula (I), R' and R2 are each separately selected from the group consisting of hydrogen, alkyl (e.g. C1-C6 linear or branched alkyl group, such as methyl, ethyl or propyl) and aryl (e.g. phenyl).
It is preferred that at least one of R' and R2 is a relatively bulky group, i.e. possessing an atomic radius greater than hydrogen. It is thus preferred that at least one of R' and R2 is an alkyl group or an aryl group. Suitable alkyl groups incorporate at least one to six carbon atoms and possibly more, and include linear or branched alkyl groups, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
At least one of R' and R2 is preferably an aryl group, preferably both of R' and R2 are the same or different aryl groups, such as phenyl, benzyl, tolyl or xylyl groups. It is particularly preferred that both R' and R2 are phenyi groups, such formula (XXIX) below represents a preferred structure for the compound according to the first aspect of the present invention. R4 R3
N-OH Z-Ph X Ph
(XXIX) In the compound of formula (I), R3, R4 and R5 are each separately selected from the group consisting of hydrogen, atkyl (e.g. C1-C6 linear or branched alkyl group, such as methyl, ethyl or propyl) and aryl (e.g. phenyl). It is preferred that at least one of R3, R4 and R5 is hydrogen, more preferably at least two of R3, R4 and R5 is hydrogen, and most preferably R3, R4 and R5 are all hydrogen.
In a preferred embodiment of the compound of formula (I) according to the first aspect of the present invention said compound has a formula (IV) 0 Ph (IV) in which, with reference to formula (I), R' and R2 are phenyl, R3, R4 and R5 are hydrogen and X is oxygen.
A particularly preferred embodiment of the first aspect of the present invention has the formula (VIII)
CNNH F 0 p
(VIII) which encompasses both the (S)-and (R)-enantiomers which are depicted below in formulae (Villa) and (VIlil,) respectively. 0 0
Ph I>-Ph N 0 Ph N 0 Ph (Villa) (Vilib) Another preferred embodiment of the first aspect of the present invention has the formula (XIXa) (XIXa) which is similar to formula (VIII) but lacks the gem-diphenyl groups bonded to the carbon atom cariying the hydroxyl group.
The second aspect of the present invention provides a process for the production of a compound according to the first aspect of the present invention, that is, a compound of formula (I), the process comprising reacting a compound of formula (lix) with a compound of formula (X) or formula (XI) in the presence of a base R7YHOR11 R8NX (IX) (X) (Xl) wherein R" is a substituted or unsubstituted alkyl group.
It will be appreciated that the selection of compound (X) or (XI) will determine whether a compound incorporating a Z group (see formula (I)) of formula (11) or (III) is obtained. Thus, if it is desired to produce a compound of formula (I) according to the first aspect of the present invention wherein Z corresponds to formula (II) then compound (LX) above should be reacted with compound (X). Alternatively, if it is desired to produce a compound of formula (I) in which Z corresponds to formula
II
(III), then compound (1X) should be reacted with compound (XI). This is represented below. R4 R4
R6 N X R-,'(R R-"NR RlXYORll + HOH (X) (IX) (I), Z=(II) R4 R8 N X R R-)NR3 + R(R R8N< (XI) (IX) (I),Z=(III) Where it is desired to produce the (S)-enantiomer of compound (I) the (S)-enantiomer of compound (IX) should be used and when the (R)-enantiomer of compound (I) is desired, the (R)-enantiomer of compound (IX) should be used.
Preferred embodiments of the compound of formula (I) incorporate a central carbonyl moiety, i.e. where X is oxygen, and so preferred processes for producing these preferred embodiments of compound (I) utilise an ester derivative of compounds (X) and (XI).
A preferred method for producing preferred compound (VIlla) is set out below in Example I, wherein a preferred embodiment of compound (X), ester compound (XII), is reacted with a preferred embodiment of compound (IX), compound (XllIa), to produce compound (Villa). +
(XII) (XiIla) (Villa) A further preferred method for producing a different preferred compound (XVIa) is set out below in Example 2, wherein a preferred embodiment of compound (X), ester compound (XIV), is reacted with a preferred embodiment of compound (LX), compound (XVa), to produce compound (XVIa).
CN>OEt + _____ (XIV) (XVa) (XVIa) In the above two reaction schemes, the (S)-enantiomers of preferred compounds (Villa) and (XVIa) have been produced using the (S)-enantiomers of starting materials (XIIIa) and (XVa) respectively. It will be appreciated that the (R)- enantiomers of compounds (VIHb) and (XVIb) may be produced by using the (R)- enantiomer of compounds (XIIIb) and (XVb) respectively.
While any appropriate base may be used, it is preferred that the base is sodium hydride.
The reaction of compound (IX) with compound (X) or (Xl) may be effected at any suitable temperature. It is preferred that the reaction is carried out at an elevated temperature, that is, a temperature above room temperature. Preferably, the reaction is effected at a temperature of at least around 40 °C, more preferably at least around °C, more preferably at least around 60 °C, and most preferably at a temperature of around 70 °C.
Compound (IX) may be reacted with compound (X) or (XI) over any appropriate time period. It is desirable that the reaction time should be sufficiently long to ensure that as much of starting material as possible has been converted to product.
Preferably the reaction is effected over a time period of at least around 10 hours, more preferably at least around 20 hours and still more preferably at least around 30 hours. Most preferably the reaction is effected over a time period of around 40 hours.
The third aspect of the present invention relates to a process for effecting catalytic reduction of an imine compound to provide a corresponding amine compound, the process compnsing reacting said imine compound with a reducing agent in the presence of a catalyst compound having a formula according to the first aspect of the present invention, that is, a compound of formula (I). This aspect of the present invention is depicted in general terms below with reference to the conversion of imine compound (XXX) to the corresponding chiral amine compound (XXXI).
N.R Reducing agent HN_R ii R12NR13 ataiysi R12"R13 (XXX) (XXXI) wherein each of R'2, R'3 and R'4 is a chemical group, for example but not limited to, hydrogen, alkyl or aryl, moreover, R'2 arid R'3 may be linked to form a carbocyclic or heterocyclic ring structure.
The third aspect of the present invention therefore provides a means by which an imine, preferably a ketimine, functional group present in a compound can be selectively converted, via asymmetric reduction, to a chiral amine group. Moreover, by appropriate selection of the stereochemistry of the catalyst compound of formula (I), the achiral imine functionality can be converted to a chiral amine possessing the desired stereochemistry in high enantiomeric excess.
In a preferred embodiment of the third aspect of the present invention the catalyst is provided in an amount of around 0.01 mol % to around 10 mol % of the amount of the reducing agent. The catalyst loading may be lowered further, such that the catalyst may be provided in an amount of around 0.01 mol % to around 5 mol % of the amount of the reducing agent, or an amount of around 0.01 mol % to around 2 mol % of the amount of the reducing agent. More preferably still lower catalyst loadings may be employed, such as around I mol % of the amount of the reducing agent. Most preferably the catalyst is provided in an amount of around 0.01 mol % to around I mol % of the amount of the reducing agent.
Any suitable reducing agent may be used provided it shows the potential to reduce a carbon-nitrogen double bond to a carbon-nitrogen single bond, that is, reduce an imine to a corresponding amine. Preferred reducing agents are silanes and a particularly preferred reducing agent is trichiorosilane, not least because it is known to be a cheap, versatile reducing agent.
Preferably the initial molar amount of the reducing agent is in excess of the initial molar amount of the imine that is to undergo asymmetric reduction to a corresponding amine. The initial molar ratio of the reducing agent compared to the imine may lie in the range around 1: 1 (reducing agent: imine) to around 5: 1. That is, the reducing agent and imine may be provided initially in approximately equal molar amounts or up to an amount whereby the reducing agent is provided in a five-fold excess compared to the amount of the imine starting material.
The initial molar ratio of the reducing agent compared to the imine may be in the range around 1.5: I (reducing agent: imine) to around 4: 1, and may lie in the range around 1.5: I to around 2: 1. Most preferably, the reducing agent is provided in about two-fold excess compared to the initial amount of imine, i.e. a molar ratio of around 2: 1 (reducing agent: imine).
As is demonstrated below in Example 5, the asymmetric reduction reaction may be effected over a wide range of reaction temperatures without detriment to the enantiomeric excess obtained. The process may be effected at a reaction temperature in the range around -20 °C to around 30 °C, more preferably at a reaction temperature in the range around 0 °C to around 25 °C. Still more preferably, the process is effected at a reaction temperature in the range around 0 °C to around 15 oc.
Any appropriate reaction solvent or mixture of solvents may be employed in the asymmetric reduction reaction. Preferred solvents are selected from the group consisting of trichioromethane, dichioromethane and toluene.
Any suitable reaction time may be adopted in order to obtain the optimum yield. The process may effected over a time period of up to around 15 hours, more preferably a time period in the range around 1 hour to around 13 hours, or most preferably a time period of around 4 hours.
The fifth aspect of the present invention provides a process for effecting the direct, i.e. single-step or one-pot', asymmetric reductive amination of a first compound including an aldehyde or ketone group with a second compound including a first amine group to provide a third compound including a second amine group, the process comprising reacting said first compound with said second compound and a reducing agent in the presence of a catalyst compound having a formula according to the first aspect of the present invention.
This aspect of the present invention is depicted in general terms below, with reference to the asymmetric reductive amination of an aldehyde or ketone (XXXII) to an amine (XXXIV) by reaction with an amine (XXXIII) in the presence of a reducing agent (e.g. trichlorosilane) and a catalyst (e.g. compound (Vifia)). As can be seen, the basis of the reductive amination process is to couple compound (XXXII) to compound (XXXIII) by linking the carbonyl carbon atom of compound (XXII) to the amine nitrogen atom of compound (XXXIII). In this way, the new amine compound (XXXIV) is generated in which groups R15, R'6 and R'7 are linked via a new carbon-nitrogen bond and resulting in that carbon atom being a chiral centre when R'6 and R'7 are different chemical groups.
0 Reducing agent A + H2N-R17 HN H R15 R'6 Catalyst R152cR16 OO(lI) O(XlIl) (XXXIV) wherein each of R'5, R'6 and R'7 is any chemical group, for example but not limited to, hydrogen, alkyl or aryl. R'5 and R16 can also be linked to form a carbocyclic or heterocyclic ring.
Any appropriate reducing agent may be employed in the direct asymmetric reductive amination process, for example, the reducing agent may be a silane, and is preferably trichlorosj lane.
In a preferred embodiment of the fifth aspect of the present invention the catalyst is provided in an amount of around 0.01 mol % to around 10 mol % of the amount of the reducing agent. The catalyst loading may be lower, for example 0.01 mol % to around 5 mol %, or around 0.01 mol % to around 2 mol % of the amount of the reducing agent. Yet more preferably even lower catalyst loadings may be employed, such as around 1 mol % of the amount of the reducing agent. Most preferably the catalyst is provided in an amount of around 0.01 mol % to around 1 mol % of the amount of the reducing agent.
While the first compound (i.e. the aldehyde or ketone starting material) and the second compound (i.e. the amine starting material) are preferably provided in approximately equal amounts, i.e. a molar ratio of around 1: I (first compound second compound), the initial molar amount of the reducing agent is preferably in excess of the initial molar amount of the aldehyde or ketone that is to undergo reductive amination to the third compound (i.e. the product incorporating the second amine group). The initial molar ratio of the reducing agent compared to the aldehyde or ketone may lie in the range around I: I to around 5: 1. That is, the reducing agent and aldehyde/ketone may be provided initially in approximately equal molar amounts or up to an amount whereby the reducing agent is provided in a five-fold excess compared to the amount of the aldehyde/ketone starting material.
The initial molar ratio of the reducing agent compared to the aldehyde/ketone may be in the range around 1.5: I (first compound: second compound) to around 4: I, and may lie in the range around 1.5: I to around 2: 1. Most preferably, the reducing agent is provided in about two-fold excess compared to the initial amount of aldehyde/ketone, i.e. a molar ratio of around 2: 1.
The solvent in which the reductive amination process is carried out may be any appropriate solvent. It is preferred that the process in carried out in a non-polar solvent. A preferred reaction solvent is dichioromethane.
The reductive amination can be conducted at any suitable temperature, for example, a temperature in the range around 0 °C to around 50 °C. The reaction is more preferably carried out at a temperature in the range around 10 °C to around 40 °C, still more preferably around 20 °C to around 30 °C The reaction is most preferably carried out at around room temperature.
Any appropriate reaction time period may be adopted to provide optimum generation of the chiral amine product, that is, a satisfactory yield over, a realistic and economically viable time period. It is preferred that the reaction is carried out over a time period of up to around 30 hours, more preferably around 1 hour to around 20 hours, and still more preferably around 5 hours to around 20 hours. It is most preferred that the process is carried out over a time period of around 15 hours.
A further related aspect of the present invention relates to a compound for use as a catalyst, said compound comprising a catalytic moiety linked to a polymer support, wherein said compound has the formula (XXXV) H R18
O-A
(XXXV) wherein R'8 is alkyl or alkoxy; A is alkyl, aryl or -(CH2O)m-CH2-in which m is an !nteger that may be zero or higher; p is a non-zero integer; and n is a non-zero integer representing the number of repeating units of the structure shown comprised in the backbone of the polymer support.
It will be appreciated that the catalytic moiety is the oxazaborolidine functional group and the polymer support is the bracketed portion of formula (XXXV) incorporating the cyclopentane ring. The polyether containing chain incorporating the group A may be considered as a linking group which connects the catalytic moiety to the polymer support.
The compound of general formula (XXXV) may be used to catalyse the reduction of an imine or oxime functional group within a molecule to an amine, typically chiral amine, functional group, as depicted generically below.
R21,R21 Reducingagent,e.g BH3 HNH R19"R20 R19"'R20 catalyst (XXXV) (X)(XVI) (XXXVIII) OR NHR22 Redung agent, e.g. BH3 R'9 R2° catalyst (XXXV) R19 R2° (XXXVII) (XXXIX) wherein R'9, R2° and R2' may be any chemical group, such as but not limited to, hydrogen, alkyl or aryl. R22 may be an alkyl group. Moreover, R'9 and R2° may be linked to form a carbocyclic or heterocyclic ring.
A further related aspect of the present invention relates to a process for the reduction of an imine or oxime functional group present in a molecule to provide an amine functional group, wherein the process comprises reacting the molecule containing the imine or oxime functional group with a reducing agent in the presence of a compound of formula (XXXV).
Another aspect of the present invention relates to use of a compound of formula (XXXV) to catalyse the reduction of an imine or oxime functional group present in a molecule to provide an amine functional group in said molecule.
The compound of general formula (XXXV) may be used to catalyse the reduction of a k etone functional group within a molecule to an alcohol, typically chiral alcohol, functional group, as depicted generically below.
Reduang agent, e.g. 8H3 l9'' 20 R19 R2° R R catalyst (XXXV) (X)O(X) (X)O(XI) wherein R'9 and R2° may be alkyl or aryl. Moreover, R19 and R2° may be linked to form a carbocyclic or heterocyclic ring.
A still further related aspect of the present invention relates to a process for the reduction of a ketone functional group present in a molecule to provide an alcohol functional group, wherein the process comprises reacting the molecule containing the ketone functional group with a reducing agent in the presence of a compound of formula (XXXV). Another aspect of the present invention relates to use of a compound of formula (XXXV) to catalyse the reduction of a ketone functional group present in a molecule to provide an alcohol functional group in said molecule.
Any appropriate reducing agent may be used, such as a borane, e.g. BH3. The reducing agent may be provided in any suitable amount to provide the desired yield of the amine or alcohol. The reaction time and temperature may each be selected to suit a particular application. While the reduction reaction may be carried out in any suitable solvent, it is preferred that the reaction is carried out in tetrahydrofuran.
The catalyst compound (XXXV) may be provided in any desirable amount. For example, a catalyst loading of around 10 % compared to the molar amount of the imine/oxime/ketone starting material may be used. More preferably a catalyst loading of around 0.1 % to around 10 % is used, more preferably from around 0.1 % to around 5 %. Most preferably a lower catalyst loading of around 0.1 % to around 2 % is used. Most preferably a catalyst loading of around 1 % compared to the molar amount of the imine/oxime/ketone starting material is used.
With regard to catalyst compound (XXXV), R'8 may be an alkyl group or an alkoxy group. It is preferred that R'8 is a C1-C6 linear or branched alkyl group. More preferably R'8 is a C1-C3 linear alkyl group, most preferably a methyl group.
Group A which forms part of the linker connecting the catalytic moiety to the polymer support may be an alkyl, aryl or (CH2O)m-CH2-group. The alkyl group is preferably a C1-C6 linear or branched alkyl group, such as methyl, ethyl or propyl group. Alternatively, group A may be an aryl group, such as a phenyl, benzyl, tolyl or xylyl group. With regard to the option of A being a (CH2O)mCH2-group, it is preferred that m is an integer from I to 6, more preferably I to 4 and most preferably I to 2. It will be appreciated that when integer m is zero, the -(CH2O)-repeating unit is not present such that a methylene group connects the oxygen atom bonded to the benzene ring of the catalytic moiety to the oxygen atom linked via a methylene group to the cyclopentane ring forming part of the backbone of the polymer support.
The polymer support may incorporate any appropriate number of cyclopentane-containing repeating units, in other words, n may take any appropriate value. The provision of the polymer support significantly eases separation of the catalytic moiety from the reaction mixture once the reaction has run to completion or reached the desired end point.
Another aspect of the present invention provides a process for the production of compound (XXXV). It is preferred that the process comprises ring opening metathesis polymerisation (ROMP) of appropriate starting materials. A generalised scheme for the production of the compound (XXXV) is set out below. NH2
+ by SN2 CH2Br -/ iii) hydrogen and OA deprotection
HO-A
BH2R18
O-A
Aspects of the present invention will be further described, by way of example only, with reference to the following non-limiting Examples.
EXAMPLES
EXAMPLE 1
Compound (Villa), which represents a preferred embodiment of the first aspect of the present invention, was prepared by reacting compound XII with compound XIIIa in the presence of a base as follows: + H1(h (XII) (XIIIa) (Villa)
EXAMPLE 2
Compound (XVIa), which represents a further preferred embodiment of the first aspect of the present invention, was prepared by reacting compound XIV with compound XVa in the presence of a base as follows: CN>(OEt + _____ (XIV) XVa' (XVIa)
EXAMPLE 3
A compound having the formula (VIlla) in accordance with a preferred embodiment of the present invention was tested as a catalyst in the asymmetric reduction of the ketimine, N-phenyl acetophenone (XVII), to the corresponding chiral amine (XVIIIa).
N c?OH Ph r 0 Ph (Villa) HN' (XVII) (XVIIIa) The asymmetric reduction reaction was carried out by addition of trichlorosilane to a stirred solution of the ketimine (XVII) and catalyst (Villa) in dry dichioromethane under an atmosphere of nitrogen at 0 °C. After 4 hours, the reaction was quenched with I M hydrochloric acid and subjected to standard work-up procedures.
The reaction produced a product yield of 55 % (based on isolated product) with an enantiomeric excess of 86 % of the (S)-enantiomer of the chiral amine, compound (XVIIIa). The enantiomeric excess was determined by integration of the appropriate signals in the HPLC chromatogram of the crude reaction mixture. The configuration of the final product was confirmed by comparison of HPLC retention times arid specific rotations which those in the literature.
EXAMPLE 4
A compound having the formula (XIXa) in accordance with a preferred embodiment of the present invention was tested as a catalyst in the asymmetric reduction of the ketimine, N-phenyl acetophenone (XVII), to the corresponding chiral amine (XVIIIa).
N
(XIXa) N HN" cH2a2,0°c,4h (XVII) (XV!IIa) The asymmetric reduction reaction was carried out by addition of trichiorosilane to a stirred solution of the ketimine (XVII) and catalyst (XIXa) in dry dichioromethane under an atmosphere of nitrogen at 0 °C. After 4 hours, the reaction was quenched with 1 M hydrochloric acid and subjected to standard work-up procedures.
The reaction produced a product yield of 67 % (based on isolated product) with an enantiomeric excess of 42 % of the (S)-enantiomer of the chiral amine, compound (XVIIIa). The enantiomeric excess was determined by integration of the appropriate signals in the HPLC chromatogram of the crude reaction mixture. The configuration of the final product was confirmed by comparison of HPLC retention times and specific rotations which those in the literature.
EXAMPLE 5
A series of reactions were carried out to investigate the optimum conditions for the asymmetric reduction of ketimine (XVII) to chiral amine (XVIIIa) using the catalyst compound (VIlla).
N 0 Ph (Villa)
HN
(Villa), CI3SiH (XVII) (XVIIIa) Each asymmetric reduction reaction was carried oul by addition of trichiorosilane to a stirred solution of the ketimine (XVII) and catalyst (Villa) in a dry solvent under an atmosphere of nitrogen at a predefined temperature. After a predetermined amount of time (indicated in Table 1 below) each reaction was quenched with 1 M hydrochloric acid and subjected to standard work-up procedures.
The results of this series of reactions are set out below in Table 1. Product yields were based on isolated product. The enantiomeric excess was determined by integration of the appropriate signals in the HPLC chromatogram of the crude reaction mixture. In all cases the (S)-enantiomer of the chiral amine, compound (XVIIIa) was formed as the major product.
Entry Temp. Time Solvent CI3S1H (Villa) I(XVII)1o Yield e.e.
(°C) (hrs) (equiv.) (equiv.) (mol L') (%) (%) 1 0 13 CFI2CI2 1.5 0.1 0.4 59 87 2 0 13 CH2CI2 1.5 0.05 0.4 65 86 3 0 13 CH2CI2 1.5 0.01 0.4 45 85 4 25 13 CH2CJ2 1.5 0.01 0.4 39 83 -20 13 CH2CI2 1.5 0.01 0.4 42 88 6 15 13 CH2CJ2 1.5 0.01 2.0 56 83 7 15 13 CH2CI2 1.5 0.01 0.2 32 84 8 15 13 CH2CI2 4 0.01 0.4 76 84 9 0 4 CH2CI2 2 0.01 2.0 82 85 0 4 CHCI3 2 0.01 2. 0 81 86 11 0 4 PhCH3 2 0.01 2.0 87 86
Table I
It can be appreciated from the results presented in Table I that compound (Villa) exhibited good enantioselectivity over a wide range of different reaction conditions when catalysing the conversion of imine (XVII) to the (S)-enantiomer of the chiral amine, compound (XVIIIa).
The most unexpected result, which is of great commercial significance, was that the enantioselectivity of the reaction was essentially unaffected by reducing the catalyst loading from 10 % to 1 % (see entries I to 3). At a catalyst loading of I %, varying the reaction temperature from -20 °C to 0 °C to 25 °C was not detrimental to the product yield or e.e. (see entries 3 to 5), while increasing the amount of trichlorosilane above 1.5 eq. significantly increased the product yield without affecting the e.e. (see entries 6 to 9). Switching the solvent from dichioromethane to trichioromethajie marginally increased the e.e. and using toluene as solvent increased the product yield obtained (see entries 9 to 11).
It therefore appears that a very low catalyst loading can be employed at an economically viable reaction temperature (e.g. 15 °C) without concern that either of these factors will harm the enantioselectivity of the reaction. Moreover, the product yield can be improved by increasing the amount of trichiorosilane reducing agent, increasing the initial concentration of the imine starting material and/or using toluene as solvent.
EXAMPLE 6
The applicability of compound (Villa) to the asymmetric reduction of different imine substrates ((XX) to (XXVI)) was investigated using a series of reactions. The results were compared to the results obtained in respect of imine (XVII) in Example 5.
N QOH
r[>-Ph N 0 Ph (Villa)
N N N
(XVII) R=Ph (XXI) R=Ph (XXIII) R=Ph (XX) RpOMePh (XXII) RpOMePh (XXIV) R=pOMePh NPhpOMe (XXV) (XXVI) Each asymmetric reduction reaction was carried out by addition of trichlorosilane (2 eq.) to a stirred solution of the ketimine under investigation and catalyst (Villa) in dry CH2CI2 under an atmosphere of nitrogen at 0 °C. After 4 hours each reaction was quenched with I M hydrochloric acid and subjected to standard work-up procedures.
The results of this series of reactions are set out below in Table 2. E/Z ratio was determined by comparison to literature precedent and nOe studies. Product yields were based on isolated product. The enantiomeric excess was determined by integration of the appropriate signals in the HPLC chromatogram of the crude reaction mixture. In all cases the (S)-enantiomer was formed as the major product.
Entry Imine E/Z ratio Yield e.e.
(%) (%) I (XVII) 100/0 82 85 2 (XX) 100/0 96 87 3 (XXI) 91/9 59 79 4 (XXII) 88/12 95 83 (XXIII) 100/0 42 19 6 (XXIV) 100/0 41 22 7 (XXV) 100/0 85 73 8 (XXVI) 80/20 71 74
*From Example 5
Table 2
From the results presented in Table 2 it can be seen that a significant improvement in product yield was obtained when imine (XVII) was replaced with imine (XX) (see entries 1 and 2). While the inventors do not wish to be bound by any particular theory, this observation may be due to imine (XX) being more electron rich than imine (XVII) which could enable imine (XX) to undergo more efficient binding to the trichlorosilane reducing agent. A similar trend was observed in respect of imines (XXI) and (XXII) (see entries 3 and 4). Good yields and e.e.s were also observed for substrate imines (XXV) and (XXVI) (see entries 7 and 8).
EXAMPLE 7
The use of compounds according to the first aspect of the present invention to catalyse reductive processes, other than those described in Examples 3 to 6, was investigated.
Specifically, the ability of a preferred embodiment of the first aspect of the present invention, compound (Villa), to catalyse the asymmetric reductive amination of a ketone to the corresponding chiral amine was studied. The starting materials were the ketone, acetophenone (1 -phenylethanone) and the amine, p-methoxyaniline. The reducing agent was trichiorosilane, as in Examples 3 to 6. The reaction was carried out in dichioromethane, at room temperature over a period of 15 hours. A catalyst loading of 10 % was used.
NH2 IO%(VIIIa) HN) C1,siH + MeO CH2CI2,RT, 15h Eighty-four percent of the starting material was converted to product with an enantiomeric excess ((S)-enantiomer) of 80 %.
EXAMPLE 8
Following Example 7, the use of compound (Villa) to catalyse the asymmetric reductive amination of a different ketone was investigated.
In this Example, the starting ketone was 1-phenyipropanone. The amine starting material and the reducing agent were the same as in Example 7, that is, p-methoxyaniline and trichlorosilane respectively. The reaction was again carried out in dichioromethane, at room temperature over a period of 15 hours. A catalyst loading of 10 % was used, as in Example 7.
j IO%(VItIa) HN) -* C1,SiH + MeO CH?CI.. RI ISh Twenty percent of the starting material was converted to product with an enantiomeric excess ((S)-enantiomer) of 80 %.
Significantly, the asymmetric reductive amination reactions described in Examples 7 and 8 were carried out as direct, single-step, one-pot' procedures, requiring no isolation of intermediate compounds. This has not previously been possible. Given the extent to which asymmetric reductive animation processes are employed in synthetic chemistry to generate chiral amine fi.inctionalities, it will be appreciated that the above methodology represents an important breakthrough, which has been made possible by the development of the new class of compounds according to the first aspect of the present invention.

Claims (51)

  1. I. A compound having the formula (1) R4 R3 z--< (I) wherein: R', R2, R3, R4 and R5 are each separately selected from the group consisting of hydrogen, alkyl and aryl; X is oxygen or sulfur; and Z has the formula (H) or (III) (R8 (II) (III) wherein: R6, R7, R8 and R9 are each separately selected from the group consisting of hydrogen, alkoxy, nitro, halogen, alkyl and aryl, or R6 and R7 are linked to form a cyclic group; and Y is oxygen, sulfur or NR'° in which R'° is selected from the group consisting of hydrogen, alkyl and aryl.
  2. 2. A compound according to claim 1, wherein X is oxygen.
  3. 3. A compound according to claim 1 or 2, wherein Y is NR'°.
  4. 4. A compound according to claim 3, wherein R'° is an alkyl group.
  5. 5. A compound according to claim 3, wherein R'° is a C1-C6 linear or branched alkyl group.
  6. 6. A compound according to claim 3, wherein R'° is selected from the group consisting of methyl, ethyl and propyl.
  7. 7. A compound according to any preceding claim, wherein at least one of R' and R2 is an alkyl group or an aryl group.
  8. 8. A compound according to claim 7, wherein said aryl group is a phenyl group.
  9. 9. A compound according to any preceding claim, wherein at least one of R3, R4 and R5 is hydrogen.
  10. 10. A compound according to any preceding claim, wherein said compound has a formula (IV) 0 Ph (N)
  11. 11. A compound according to any preceding claim, wherein at least one of R6 and R7 is hydrogen.
  12. 12. A compound according to any preceding claim, wherein group Z has a formula (V) (V)
  13. 13. A compound according to any one of claims I to 10, wherein R6 and R7 are linked to form a cyclic group and said cyclic group is substituted with one or more substituent selected from the group consisting of hydrogen, alkoxy, nitro, halogen, alkyl and aryl.
  14. 14. A compound according to claim 13, wherein the cyclic group is a cycloalkyl group or an aromatic group.
  15. 15. A compound according to any one of claims 1 to 10, wherein group Z has the formula (VI) (c (VI)
  16. 16. A compound according to any one of claims 1 to 10, wherein at least one of R8 and R9 is hydrogen.
  17. 17. A compound according to any one of claims I to 10, wherein group Z has a formula (VII) (VII)
  18. 18. A compound according to claim 1, wherein the compound has the formula (VIII) (VIII)
  19. 19. A process for the production of a compound according to any one of claims I to 18, the process comprising reacting a compound of formula (LX) with a compound of formula (X) or formula (XI) in the presence of a base R7YOR11 R8NX (IX) (X) (XI) wherein R" is a substituted or unsubstituted alkyl group.
  20. 20. A process according to claim 19, wherein the base is sodium hydride.
  21. 21. A process according to claim 19 or 20, wherein the reaction is effected at a temperature of around 70 °C.
  22. 22. A process according to claim 19, 20 or 21, wherein the reaction is effected over a time period of around 40 hours.
  23. 23. A process for effecting catalytic reduction of an imine compound to provide a corresponding amine compound, the process comprising reacting said imine compound with a reducing agent in the presence of a catalyst compound having a formula according to any one of claims I to 18.
  24. 24. A process according to claim 23, wherein the catalyst is provided in an amount of around 0.01 mol % to around 10 mol % of the amount of the reducing agent.
  25. 25. A process according to claim 23, wherein the catalyst is provided in an amount of around 0.01 mol % to around 5 mol % of the amount of the reducing agent.
  26. 26. A process according to claim 23, wherein the catalyst is provided in an amount of around 0.01 mol % to around 2 mol % of the amount of the reducing agent.
  27. 27. A process according to claim 23, wherein the catalyst is provided in an amount of around 1 mol % of the amount of the reducing agent.
  28. 28. A process according to any one of claims 23 to 27, wherein the reducing agent is a silane.
  29. 29. A process according to any one of claims 23 to 27, wherein the reducing agent is trichiorosilane.
  30. 30. A process according to any one of claims 23 to 29, wherein the initial molar amount of the reducing agent is in excess of the initial molar amount of the imine.
  31. 31. A process according to any one of claims 23 to 29, wherein the initial molar ratio of the reducing agent compared to the imine is in the range around I: 1 toaround5:1.
  32. 32. A process according to any one of claims 23 to 29, wherein the initial molar ratio of the reducing agent compared to the imine is in the range around 1.5 Ito around 4: 1.
  33. 33. A process according to any one of claims 23 to 29, wherein the initial molar ratio of the reducing agent compared to the imine is in the range around I.5 ito around 2: 1.
  34. 34. A process according to any one of claims 23 to 33, wherein the process is effected at a reaction temperature in the range around -20 °C to around 30 oc.
  35. 35. A process according to any one of claims 23 to 33, wherein the process is effected at a reaction temperature in the range around 0 °C to around 25 °C.
  36. 36. A process according to any one of claims 23 to 33, wherein the process is effected at a reaction temperature in the range around 0 °C to around 15 °C.
  37. 37. A process according to any one of claims 23 to 36, wherein the process is effected in a solvent selected from the group consisting of trichioromethane, dichloromethane and toluene.
  38. 38. A process according to any one of claims 23 to 37, wherein the process is effected over a time period of up to around 15 hours.
  39. 39. A process according to any one of claims 23 to 37, wherein the process is effected over a time period of around 4 hours.
  40. 40. Use of a compound having a formula according to any one of claims 1 to 18 to catalyse the reduction of an imine compound to provide a corresponding amine compound.
  41. 41. A process for effecting the direct asymmetric reductive amination of a first compound including an aldehyde or ketone group with a second compound including a first amine group to provide a third compound including a second amine group, the process comprising reacting said first compound with said second compound and a reducing agent in the presence of a catalyst compound having a formula according to any one of claims I to 18.
  42. 42. A process according to claim 41, wherein the catalyst is provided in an amount of around 0.01 mol % to around 10 mol % of the amount of the reducing agent.
  43. 43. A process according to claim 41 or 42, wherein the reducing agent is a silane.
  44. 44. A process according to claim 41 or 42, wherein the reducing agent is trichlorosilane.
  45. 45. A process according to any one of claims 41 to 44, wherein the initial molar amount of the reducing agent is in excess of the initial molar amount of the first compound.
  46. 46. A process according to any one of claims 41 to 44, wherein the initial molar ratio of the reducing agent compared to the first compound is in the range around 1: Ito around 5: 1.
  47. 47. A process according to any one of claims 41 to 46, wherein the process in carried out in a non-polar solvent.
  48. 48. A process according to any one of claims 41 to 46, wherein the process is carried out in dichioromethane.
  49. 49. A process according to any one of claims 41 to 48, wherein the process is carried out at around room temperature.
  50. 50. A process according to any one of claims 41 to 48, wherein the process is carried out over a time period of around 15 hours.
  51. 51. Use of a compound having a formula according to any one of claims I to 18 to catalyse the direct asymmetric reductive aanination of an aldehyde or ketone compound to provide an amine compound.
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WO2003090680A2 (en) * 2002-04-23 2003-11-06 Axys Pharmaceuticals, Inc. Novel phenyl derivatives as inducers of apoptosis
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