FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR THE MANUFACTURE OF SUBSTITUTED PROPIONIC
ACIDS"
2. APPLICANT
(a) NAME: PHOENIX CHEMICALS LIMITED
(b) NATIONALITY: GB company incorporated under GB Act
(c) ADDRESS: 34 Thursby Road, Croft Business Park, Bromborough,
Wirral, Merseyside CH62 3PW, Great Britain
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it has to be performed.

WO 2006/075177 PCT/GB 2006/000129
PROCESS FOR THE MANUFACTURE OF SUBSTITUTED PROPIONIC
ACIDS
This invention relates to an enantioselective process for synthesising certain
5 substituted propionic acids.
WO-A-2005/068477 discloses certain classes of ligand useful in chiral catalysis, and WO-A-2005/068478 discloses processes for making these and other ligands.
10
WO-A-2002/02500 discloses a stereoselective synthesis of (R)-2-alkyl-3-phenylpropionic acids comprising the addition of suitably substituted propionic acid esters to suitably substituted benzaldehydes to form corresponding substituted hydroxy propionic acid esters, followed by the conversion of the
15 hydroxyl group to a leaving group, elimination of the leaving group, hydrolysis and then hydrogenation of the resulting intermediates.
Sturm et al disclose in Adv. Synth. Catal. 2003, 345, 160-164 a series of diphosphines of the Walphos ligand family and the use thereof in
20 enantioselective hydrogenation.
WO-A-2005/030764 and Organic Letters 2005, vol 7, pp1947 disclose processes for the preparation of chiral propionic acid derivatives.
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According to the present invention, there is provided a process for the manufacture of substituted propionic acids comprising providing a substrate of formula (I):

5 wherein:
R is selected from hydrogen, substituted and unsubstituted branched and straight-chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocylic
10 aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocylic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen and oxygen; R5 is the same as or different from R and is selected from hydrogen,
15 substituted and unsubstituted branched and straight-chain alkyl, alkoxy, alkylamino, N-acyi, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocylic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocylic arylamino
20 and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen and oxygen; R6 is selected from:
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wherein:
Q is selected from O or N; and
R8 is selected from hydrogen, substituted and unsubstituted branched and
5 straight-chain alkyl, amino, alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocylic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is
10 independently selected from sulphur, nitrogen and oxygen;
R7 is the same as or different from R and/or R5 (except that if R and R7 are the same then R5 is not hydrogen) and is selected from hydrogen, substituted and unsubstituted branched and straight-chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted
15 cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocylic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocylic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen and oxygen; and
20 subjecting the substrate to enantioselective hydrogenation under enantioselective hydrogenation conditions in the presence of an enantioselective hydrogenation catalyst comprising a catalyst ligand having a
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metallocene group with a chiral phosphorus or arsenic substituent to provide in enantiomeric excess a product of formula (II):

R6
R7
(ID

or its enantiomer or if applicable its diastereomer.
5
In one process according to the invention the substrate may be of formula (III):


.(in)

wherein R1, R2, R3 and R4 are the same or different and are independently selected from hydrogen, alkyl, haioalkyl, alkoxy, alkoxylated alkyl and
10 alkoxylated alkoxy; the product of the process being of formula (IV):


•(IV)

One particularly preferred process of the invention is for the manufacture of substituted arylpropionic acids, for example 2-substituted-3-arylpropionic acids, for example 2-alkyl-3-arylpropionic acids, such as 2-alkyl-3
15 phenylpropionic acids, particularly (R)-2-alkyl-3-phenylpropionic acids.
4

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A preferred substrate for use in the process of the invention is a substrate of formula (V):

Wherein R'O is any suitable alkoxy or alkoxylated alkoxy group, and wherein
5 each R'O may be the same or different.
Enantioselective hydrogenation if the formula (V) substrate in accordance with the invention yields a product of formula (VI):

..(VI)
10 The process of the invention has been found suitable for enantioselectively hydrogenating the formula (I) substrates, and the other substrates referred to herein with good yields and reactions rates and, importantly, with high enantiomeric excesses of the desired enantiomer. Certain characteristics of the catalyst are considered to be important in achieving good ee's. Thus, in
15 some cases it is preferable that the metallocene group of the catalyst ligand comprise ortho to the chiral phosphorus or arsenic substituent a second chiral substituent group. It may also be desirable in some cases that the chiral phosphorus or arsenic substituent on the metallocene group be further connected via a linking moiety to a second chiral phosphorus or arsenic
20 substituent on a second metallocene group in the catalyst ligand. In this case

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it is also preferred that the chiral configuration of the chiral phosphorus or arsenic substituent is the same as the chiral configuration of the second chiral phosphorus or arsenic substituent. Still other catalyst characteristics may also be important and in some cases it has been found desirable that the catalyst
5 ligand exhibit C2 symmetry. Yet a further desirable characteristic of the catalyst ligand in some cases is that it be basic, for example as a result of the ability to donate one or more loan pairs from one or more nitrogen-containing substituents.
10 One preferred enantioselective hydrogenation catalyst ligand has the formula (VII):

wherein: M is a metal;
15 Z is P or As;
L is a suitable linker;
R9 is selected from substituted and unsubstituted, branched- and straight-chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted
20 cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocyclic aryloxy, substituted and unsubstituted
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heteroaryl, substituted and unsubstituted heteroaryloxy, substituted and unsubstituted carbocyclic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen;
5 X* is selected from:

wherein Ra, Rb and Rc are independently selected from and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and
10 substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen.
In the first of the structures defining X*, Rb and Rc may form, together with the nitrogen to which they are attached, an optionally substituted hetero-ring, such
15 as morpholine, pyrollidine, piperidine, and derivatives thereof.
L preferably comprises a difunctional moiety having the capability at each functionality to bind to phosphorus or arsenic, as the case may be. Generally the linker (L) will be derived from a difunctional compound, in particular a
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compound having at least two functional groups capable of binding to phosphorus or arsenic, as the case may be. The difunctional compound may conveniently comprise a compound which can be di-lithiated or reacted to form a di-Grignard reagent, or otherwise treated, to form a dianionic reactive
5 species which can then be combined directly with phosphorus or arsenic, in a diastereoselective manner to form a chiral phosphorus or arsenic as the case may be. In this case, a first anionic component of the dianionic reactive species may combine with a phosphorus (or arsenic) substituent in a first ligand precusor of the ligand according to the invention, and a second anionic
10 component of the dianionic reactive species may combine again in a diastereoselective manner with a phosphorus (or arsenic) substituent in a second ligand precursor of the ligand again to form a chiral phosphorus (or arsenic) centre according to the invention (the first and second ligand precursors being the same as each other) to connect the first and second
15 ligand precursors together via the linker. Usually a leaving group such as a halide will be provided on the phosphorus (or arsenic) substituents of the first and second ligand precursors, which leaving group departs on combination of the anionic component with the phosphorus (or arsenic) substituent. The following scheme is illustrative of this process:
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For example, L may be selected from ferrocene and other metallocenes,
5 diphenyl ethers, xanthenes, 2,3-benzothiophene, 1,2-benzene, succinimides, cyclic anhydides and many others. Conveniently, although not necessarily such dianionic linkers may be made from a corresponding di-halo precursor,
eg:

10 where R" represents any suitable number of suitable substituent groups. Certain suitable dianionic linkers (wherein again R" is simply any suitable number of any suitable substituent(s)) may be represented as follows:

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However, ferrocene is a preferred linker in accordance with the invention.
Preferably M is Fe, although Ru may be another preferred M in some cases.
5
Preferred R9 include phenyl, methyl, cyclohexyl and t-butyl groups.
Preferred Rb and Rc include, independently, methyl, ethyl, isopropyl and t-butyl groups. Also, Rb and Rc may form, together with the nitrogen to which
10 they are attached, an optionally substituted hetero-ring such as morpholine, pyrollidine, piperidine, and derivatives thereof.
With very many known ligands for asymmetric hydrogenation of substrates of formula (V) enantoselectivities of 80% are achieved (Adv. Synth. Catal. 2003,
15 345,160). In the same paper Sturm and in WO 02/02500 A1 Herold disclose that certain ligands of the Walphos family can furnish enantioselectivites of 95% for substrates of formula (V). It has been surprisingly found that certain ligands described here of general formula (VII) are especially useful for the enantioselective hydrogenation of substrates of formula (V) and can furnish
20 with industrially useful reaction rates enantioselectivites of up to 99 % or more. This improvement can offer significant cost savings during industrial manufacture of compounds of formula (VI) or their enantiomers.
Similarly certain of the ligands described here are also suitable as catalysts in 25 combination with an appropriate metal for the enantioselective hydrogenation
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of substrates (in which R'" is any suitable substituents such as substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and -substituted and unsubstituted heteroaryl, wherein the or each heteroatom is
5 independently selected from sulphur, nitrogen, and oxygen, for example) of formula (VIII).

Thus compounds such as formula (IX) are also accessible in high enantioselectivity using the ligands and processes described here.

10
Certain ligands useful in the process of the invention are derived from Ugi's
amine and one preferred ligand for use in accordance with the process of the invention (wherein the dianionic linker is ferrocene) may be represented as:

11

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The same preferred ligand, with the Ugi amine groups fully represented may be shown as:

10

The ligand above has three chiral elements; carbon centred chirality, phosphorus centred chirality and planar chirality with two examples of each type present in the ligand. Due to its symmetry (C2 symmetric) these elements are in two identical groups 2(Sp,Rc,SFe) where the labels R or S have their usual meaning and where Sp refers to phosphorus centred, Re carbon centred and SF8 planar chirality .
The invention also relates to the use of enantiomers and diastereomers of the ligands described above in the process of the invention.

Ligands used in the process of the invention may also be represented as: 15 follows:

JS^-X*

Wherein M, L, R9 and X* are as previously defined.
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Also provided in. accordance with the invention is the use in the process of the invention of a transition metal complex comprising at least one transition metal coordinated to the aforementioned ligand. The metal is preferably a Group Vlb or a Group VIII metal, especially rhodium, ruthenium, iridium, palladium,
5 platinum and nickel.
Synthesis of ferrocene-based phosphorus chiral phosphines may be effected in accordance with the following scheme:

10 Scheme 1.0 General synthetic scheme for the preparation of ligands disclosed herein
wherein L is a linker derived from an organolithium species or Grignard reagent L(Z)2 and wherein X* and R9 are as previously defined. The
15 organodilithium or di-Grignard reagent (the linker L(Z)2 in the above scheme) adds to the chlorophosphine intermediate B to generate a phosphorus chiral centre with very good diastereoselectivity as is shown in WO2005/068478 A1. Other reactions used in the synthesis of these ligands are known or are analogous to known reactions. The same synthetic scheme is generally
20 applicable to other chiral metallocene-based ligands for use in accordance with the invention.
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The metal complexes used as catalysts can be prepared and isolated separately and then added to the reaction or they can be prepared in-situ before the reaction (not isolated) and then mixed with the material to be hydrogenated. It has been unexpectedly found that with the ligands described
5 here there is no need to pre-form (either in-situ or separately with isolation) the catalyst by mixing a solution of the ligand and metal source when carrying out enantioselective hydrogenations of the acid substrates described here. Thus conveniently, all the solid materials (ligand, metal source and substrate) required for reaction can be placed in the vessel, the solvent is transferred,
10 the vessel placed under the required temperature and pressure and the reaction commenced. In this way it is convenient to add extra ligand, other ligands and/or other additives to the reaction. Additives such as protic acids and quaternary ammonium halides can be used as co-catalysts.
15 The enantioselective hydrogenation reaction can be carried out at any suitable temperature, for example temperatures of from about 0 to about 120 °C, or from about 20 to about 80 °C for example.
The enantioselective hydrogenation reaction can be carried out at any suitable 20 pressure, for example at hydrogen pressures of 5-200 bar.
The enantioselective hydrogenation reaction can be carried out using any suitable substrate to catalyst ration, for example with catalyst present in the reaction mixture in an amount of from about 0.0001 to about 10 mol% (with
25 100 mol% being the amount of material to be hydrogenated). The range 0.001
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WO 2006/075177 PCT/GB2006/000129
to 5 mol% is preferred with the range 0.01 to 1 mol% being particularly preferred.
The enantioselective hydrogenation reaction can be carried out with or without
5 the use of a solvent. When a solvent is used it is preferably at least substantially inert with respect to the substrate and/or the catalyst. The solvent when present may comprise for example one or more of: alcohols (such as methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether),
10 aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane,
petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (dichloromethane, chloroform, diandtetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ketones (acetone, methyl isobutyl ketone), carbonic esters and lactones (ethyl
15 or methyl acetate,valerolactone), N-substituted lactams (N-methylpyrrolidone), carboxamides(dimethylamide, dimethylformamide), acyclic ureas (dimethylimidazoline), and sulfoxides and sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide, tetramethylene sulfone), water, and suitable mixtures of two or more thereof.
20
The invention will now be more particularly illustrated with reference to the following Examples. In these examples the synthesised substrates are in many cases themselves novel compounds. According to the present invention there is provided a novel compound having the structure indicated
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below in one or. more of the following examples, and derivatives and close variants thereof.
Example 1
5

1,1' bis-[(Sp,Rc,SFe)(1-N,N-Dimethylamino)ethylferrocenyl)phenylphosphino] ferrocene L1
To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine]
10 (3.09 g, 12 mmol) in Et20 (20 ml) was added 1.5 M t-BuLi solution in pentane
(8.0 ml, 12.0 mmol) at -78 °C. After addition was completed, the mixture was
warmed to room temperature, and stirred for 1.5 h at room temperature. The
mixture was then cooled to -78 °C again, and dichlorophenylphosphine (1.63
ml, 12.0 mmol) was added in one portion. After stirring for 20 min at -78 °C,
15 the mixture was slowly warmed to room temperature, and stirred for 1.5 h at
room temperature. The mixture was then cooled to -78 °C again, and a
suspension of 1,1' dilithioferrocene [prepared from 1,1' dibromoferrocene
(1.72 g, 5.0 mmol) and 1.5 M t-BuLi solution in pentane (14.0 ml, 21.0 mmol)
in Et20 (20 ml) at -78 °C] was added slowly via a cannula. The mixture was
20 warmed to room temperature and allowed to stir for 12 h. The reaction was
quenched by the addition of saturated NaHC03 solution (20 ml). The organic
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layer was separated and dried over MgSO4 and the solvent removed under reduced pressure. The filtrate was concentrated. The residue was purified by chromatography (Si02l hexane-EtOAc-Et3N = 85:10:5) to afford an orange solid (3.88 g, 85%) as a mixture of 95% bis-(SP,Rc,SFe) title compound L1 and
5 5% (Rp,Rc,SFe-Sp,Rc,SFe) meso compound. The meso compound can be removed by further careful purification using chromatography (Si02, hexane-EtOAc-Et3N = 85:10:5). Orange/yellow crystalline solid m.p. 190-192 °C. [a]D = -427 ° (c=0.005 (g/ml), toluene); 1H NMR (CDCI3, 400.13 MHz): 5 1.14 (d, 6H,J = 6.7 Hz), 1.50 (s, 12H); 3.43 (m; 2H); 3.83 (m, 2H); 3.87 (m, 2H); 4.01
10 (s, 10H), 4.09 (t, 2H, J = 2.4 Hz); 4.11 (m, 2H); 4.20 (m, 2H); 4.28 (m, 2H); 4.61 (m, 2H); 4.42 (d, 2H, J = 5.3 Hz); 7.18 (m, 6H); 7.42(m, 4H) ppm. 13C NMR (CDCI3, 100.61 MHz): 5 38.28, 57.40 (d, J = 5.6 Hz); 67.02, 69.04 (d, J = 4.0 Hz); 69.16 (d, J = 51.6 Hz); 69.66, 71.60 (d, J = 4.8 Hz), 71.91 (d, J = 7.2 Hz), 72.18 (d, J = 5.6 Hz), 75.96 (d, J = 35.7 Hz), 79.96 (d, J = 6.4 Hz),
15 95.73 (d, J = 19.1 Hz), 127.32 (d, J = 7.9 Hz), 127.62, 133.12 (d, J = 21.4 Hz), 139.73 (d, J = 4.0 Hz). 31P NMR (CDCI3, 162 MHz): 5 -34.88 (s). Found: C, 65.53; H, 5.92; N 3.01 Calculated for C5oH54Fe3N2P2; C, 65.81; H, 5.97; N, 3.07. HRMS (10eV, ES+): Calcd for C5oH55Fe3N2P2 [M+H]+: 913.1889; Found: 913.1952.
20 The label Sp refers to S configuration at phosphorus, Re refers to R configuration at carbon (or other auxiliary) and SFO refers to S configuration at the planar chiral element.
Note: To maintain consistency in all of this work when assigning configuration at phosphorus we have given the Ugi amine (1-N.N-
25 dimethylamino)ethylferrocenyl) fragment a priority of 1, the incoming lithium or
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Grignard nucleophile (in the above example lithioferrocene) a priority of 2 and the remaining group a priority of 3. This method will not always be consistent with the rigorous approach. These assignations and the proposed phosphorus configurations have been checked using single crystal x-ray
5 crystallography.
Example 2
2,2' bis-[(Sp,Rc,SFe)(1'N,N-
Dimethylamino)ethylferrocenyl)phenylphosphino]-4-tolylether L2

10 Using a similar procedure to that described above with the exception that a suspension of 2,2' dilithio-4-tolylether [prepared by known procedures from 2,2' dibromo-4-tolylether (1.78 g, 5.0 mmol) and 1.5 M t-BuLi solution in pentane (14.0 ml, 21.0 mmol) in Et20 (20 ml) at -78 °C] was used as the linker reagent rather than 1,1' dilithioferrocene.
15 Yellow crystalline solid [a]D = -105 ° (c=0.005 (g/ml), toluene);1H NMR (CDCI3, 400.13 MHz): 6 1.23 (d, 6H), 1.72 (s, 12H); 2.28 (s, 6H); 4.11 (s, 10H); 4.12 (m, 2H overlapping); 4.28 (m, 2H); 4.31 (m, 4H); 4.35 (m, 2H, overlapping); 7.00-7.30 (m, 14H) ppm. 31P NMR (CDCI3,162 MHz): 6 -40.69 (δ s) ppm.
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Example 3
2,7 'di-tert-butyl-4,5'bis-KSpiRoSFeHI-KN-
Dimethylamino)ethylferrocenyl)phenylphosphino]-9,9-dimethyl-9H-
xanthene

5 Using a similar procedure to that described above with the exception that a suspension of 2,7-di-tert-butyl-4,5-dilithio-9,9-dimethyl-9H-xanthene [prepared . by known procedures from 2,7-di-tert-butyl-4I5-dibromo-9,9-dimethyl-9H-xanthene and 1.5 M t-BuLi solution in pentane in Et20 at -78 °C] was used as the linker reagent rather than 1,1' dilithioferrocene.
10 Orange/yellow crystalline solid; 1H NMR (CDCI3) 400.13 MHz): 5 1.12 (s, 18H); 1.13 (m, 6 H overlapping); 1.78 (s, 6H); 1.98 (s, 12H); 3.99 (m, 2H); 4.15 (s, 10H overlapping); 4.32 (m, 2H); 4.41 (m, 4H); 7.00-7.40 (m, 14H) ppm. 31P NMR (CDCI3, 162 MHz): 5 -41.78 (δ s) ppm. HRMS (10eV, ES+): Calcd for CeaHysFeaNaOPa [M+H]+: 1049.4053; Found: 1049.4222

15
Scheme 2.0 Route for the synthesis of substrates of formula (III) (R" being any suitable substituent group).
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Example 4
(E)-2~(4-methoxybenzylidine)'3-methylbutenoic acid
Step 1
Ethyl-2-hydroxy(4-methoxyphenyl)-methyl-3-methylbutanoate
5

A solution of diisopropylamine (66 ml, 467 mmol) and anhydrous THF (394 ml) was cooled to (-30 °C). To this was added drop-wise n-butyl lithium (1.6
10 M, 292 ml) using syringe over a period of (20 min) and under stream of nitrogen. After addition of the n-BuLi, the reaction mixture was stirred at -30 °C for 10 min. Ethylisovalarate (55.8 ml, 428 mmol) in THF (250 ml) was added drop-wise over a period of (10 min). The reaction mixture was stirred for a further of 15 min then a solution of 4-methoxybenzaldehyde (34g, 250
15 mmol) in THF (250 ml) was added over a period of 30 min at (maintaining temperature at -30 °C).The reaction mixture was stirred for 2h at -30 °C and then saturated ammonium chloride (325 ml) was added drop-wise over a period of 30 min. The product was then extracted with EtOAc (200 ml), washed with brine and dried over sodium sulphate. Evaporation of the solvent
20 under reduced pressure afforded a colourless oil 66.5g (93%) which gave only one spot by TLC. m/z = [(ES) 289 (M +Na)+, 555 (2M + Na)+, calculated for Ci5H2204Na 289.1428, found 289.1426]. 1H NMR (250 MHz, CDCI3) 5 7.33-7.24 (2H, m, Ar), 6.92-6.84 (2H, m, Ar), 4.93 (1H, d), 3.93 (2H, q, CH2CH3), 3.89 (3H, s, OCH3), 2.73 (1H, m), 2.44 (1H, m, CH), 2.40 (1H, m, OH) ,1.19
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(3H, t, CH2Ch3), 1.17 (3H, d, CH CH3), 1.15 (3H, d, CH3), 1.13 (3H, d, CH CH3).
Step 2
5' (E)-ethyl 2-(4-methoxybenzylidene)~3-methylbutanoate

A solution of (31.56 g, 118 mol) of ethyl-2-hydroxy(4-methoxyphenyl)-methyl-3-methylbutanoate and dimethylaminopyridine (DMAP) (0.72 g, 5.9 mmol) in
10 anhydrous THF (200 ml) were cooled to 0 °C using an ice bath. To this mixture was added acetic anhydride (12.3 ml, 12.5 mmol) drop-wise and then the reaction mixture was left stirring at 0 °C for 2h. Potassium-t-butoxide (34.5g, 350 mol) in 265 ml of THF was then added drop-wise using syringe. The reaction mixture was then stirred for two hours at 0 °C and overnight at
15 room temperature. The mixture was then cooled to 0 °C and treated with water (150 ml). The mixture was extracted with TBME (100 ml), washed with brine and dried over sodium sulphate., Evaporation of the solvent under reduced pressure afforded a colourless light oil 18.52g (63 %).
20 Step 3
21
(E)-2- (4-methoxybenzylidine)-3-methylbutanoic acid


WO 2006/075177 ,. PCT/GB2006/000129
The oil from above (2-(4-methoxybenzylidine)-3-methoxyethylbutanoate) (16 g, 64.5 mmol) was dissolved in methanol (150 ml). To this was then added anhydrous lithium hydroxide (10g, 417 mmol) at room temperature and the mixture was refluxed under a plug of nitrogen on oil bath for 12 h. The mixture
5 was then cooled to 0-10 °C and quenched with water (100 ml). The basic solution was washed with EtOAc (3 x 50 ml) and then acidified with HCI (2 molar) and the precipitated product was extracted with EtOAc (3 x 50ml), washed with brine and dried over sodium sulphate. Evaporation of solvent under reduced pressure afforded a solid residue this was then re-crystallised
10 from EtOAc/hexane to afford 6.8g (48%) of the title compound as white fine crystals, m.p. 137-138°C. H NMR (250 MHz, CDCI3) 5 ppm: 11.50 (1H, δ s, COOH), 7.71 (1H, s, CH=C), 7.34-7.38 (2H, m, Ar), 6.87-6.97 (2H, m, Ar), 3.81 (3H, s, OCH3), 3.21 (1H, m, CH(CH3)2), 1.26 (6H, d, CH(CH3)2). M/z [(CI) 221 (M+H)+ 45%, 238 (M+NH4) 100%].
15
Using a similar procedure to that described above the following compounds were prepared: Example 5
(E)-2-(4-Fluorobenzylidine)-3-methylbutanoicacid

20

White crystalline solid. 1H NMR (250 MHz, CDCI3) 5 ppm: 12.44 (1H, br s, COOH), 7.68 (1H, s, CH=C), 7.19-7.25 (2H, m, Ar), 6.99-719 (2H, m, Ar), 3.01-3.19 (1H, m, CH(CH3)2), 1.33 (6H, d, CH(CH3)2).
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Example 6
(E)-2-((thiophen~2~yl)methylene)butanoic acid

5 White crystalline solid M.p. 116-117 °C; H NMR (250 MHz, CDCI3) 5 ppm: 12.46 (1H, br s, COOH), 7.92 (1H, s, CH=C), 7.47 (1H, m, Ar), 7.24 (1H, m, Ar), 7.08 (1H, m, Ar), 2.69 (2H, q, CH2) and 1.25 (3H, s, CH3) ppm.
Example 7
10 (E)-3-methyl-2-((thiophen-2-yl)methylene)butanoic acid
o

Beige crystalline solid. M.p. 116-117 °C; H NMR (250 MHz, CDCI3) 6 ppm: 12.57 (1H, br s, COOH), 7.87 (1H, s, CH=C), 7.52 (1H, d, Ar), 7.26 (1H, d, Ar), 7.09 (1H, dd, Ar), 3.40-3.59 (1H, m, CH), 1.33 (6H, d, CH(CH3)2). M/z
15 [(CI) 196 (M)+ 10%, 197 (M+H)+ 30%, 214 (M+NH4)+ 100%].

Scheme 1.0 Route for the synthesis of substrates of formula (VI)
Example 8
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(Z)-2-Ethoxy-3~(thiophen-3-yl) acrylic acid

Ethyl chloroacetate (44.8 ml, 421 mmol) and anhydrous ethanol (30 ml) were cooled to 10-12 °C. A solution of sodium ethoxide in ethanol (21% w/w, 165
5 ml) was added over 25 min at 12-16 °C under N2. After addition was
complete the reaction mixture was warmed to 25°C and stirred for 1h. The mixture was then cooled to 10 °C and solid NaOEt (33.3 g, 488 mmol) was then added portion-wise over 0.5 h at 10-14 °C. Ethanol (20 ml) was then added followed by the addition of diethyl carbonate (31 ml, 256 mmol). The
10 slurry was then cooled to 0-5 °C and then 3-thiophene carboxaldehyde (20.2 g, 179.5 mmol) was added over a period of 1 h. After addition was complete the mixture was stirred at 40 °C in an oil bath for 15 h. The slurry was then cooled to 10-15 °C and then water (40 ml) was added followed by the addition of aqueous NaOH (55 ml of a 10 M solution). The resulting slurry was then
15 stirred at pH 14 for 3 h at 20 °C. The mixture was then diluted with water (60 ml) and then placed under reduced pressure at 45 °C to remove most of the ethanol and some water. The resulting thick slurry was then cooled to 4 °C in an ice-bath and then treated with cone. HCI (115 ml) drop-wise. The resulting slurry was then stirred at room temperature for 1.5 h and then extracted with
20 EtOAc (2 x 200 ml) and the organic layer washed with water, brine and then dried (sodium sulphate). Evaporation of the solvent under reduced pressure afforded a deep-brown residue. This was dissolved in 5 M NaOH (250 ml)
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and this solution. was washed with EtOAc (100 ml). The basic aqueous was then cooled to 4 °C and acidified with cone. HCI (11 M) to pH 4-6. The product was extracted with diethyl ether (3 x 200 ml), washed with brine, dried (sodium sulphate) and the solvent removed under reduced pressure. The
5 residue was then filtered through a pad of silica (eluent hexane:EtOAc 90:10). The solvent was removed under reduced pressure and then the residue recrystallised from EtaO/hexane to afford the title compound as yellow crystals . (79%). M.p. 88-89 °C. 1H NMR (CDCI3, 250MHz) 5 11.16 (1H, br s, COOH), 7.73-7.75(1 H, dd, j= 0.5 Hz, Ar), 7.44-7.47 (1H, dd, J= 1Hz, Ar), 7.25-7.28
10 (1H, m, Ar), 7.18 (1H, s, CH=C), 3.96-4.05 (2H, q, J= 7Hz, CH2CHs), 1.35 (3H, t, J = 7 Hz, CH2CHa),). Found: C, 54.64; H, 5.08; Calculated for C9H10SO3 C, 54.54; H, 5.08. M/z [(CI) 222 (M)+ 30%, 223 (M+H)+ 50%, 240 (M+NH4)+ 100%; Found: 223.09705; required for Ci2H1504 223.09155]. M/z [(CI) 198 (M)+ 22%, 199 (M+H)+ 50%, 216 (M+NH4)+ 100%].
15
Using a similar procedure to that described above the following compounds were prepared:
Example 9
(Z)-2-ethoxy-3-(thiophen-2-yl)acrylic acid
20 Pink crystalline solid (77%). M.p. 103-104°C. 1H NMR (CDCI3 250MHz) δ
12.15 (1H, brs, COOH), 7.48(1 H, s CH=C), 7.40 (1H, m, Ar), 7.29 ((1H, m,
25

WO 2006/075177 PCT/GB2006/000129
Ar), 7.08 (1H, mr Ar), 4.11 (2H, q, J= 7Hz, CHpCH*), 1.48 (3H, t, J = 7 Hz, CHsCHa). Found: C, 54.82; H, 5.11, S, 16.00 Calculated for C9H10SO3 C, 54.54; H, 5.08; S, 16.16]. M/z [(CI) 222 (M)+ 30%, 223 (M+H)+ 50%, 240 (M+NH4)+ 100%; Found: 223.09705; required for Ci2H1504 223.09155. M/z
5 [(CI) 198 (M)+ 22%, 199 (M+H)+ 50%, 216 (M+NH4)+ 100%].
Example 10
(Z)~3-(4-Cyanophenyl)'2-ethoxy acrylic acid

Following the procedure of (Vol. 8, No. 6, 2004, Organic Research &
10 Development) with modification, this compound was synthesised as follows:
Ethyl chloroacetate (44.5 ml, 421 mmol) and anhydrous ethanol (30 ml) were
mixed and the solution cooled to 10-12 °C and treated slowly with NaOEt
(21% w/w in EtOH, 165 ml, 421 mmol) over a period of 30 minutes. After the
addition was complete, the reaction mixture was warmed to 25°C and stirred
15 for 1h then cooled to 10°C. To this mixture was then added portion wise solid
sodium ethoxide (33.5g, 488 mmol) over a period of 0.5 h at 10-12°C followed
by addition ethanol (10 ml) and diethyl carbonate (31 ml, 256 mmol). The
mixture was then cooled to 5-8°C and then treated very slowly with 4-
cyanobenzaldehyde (16.75 ml, 175 mmol) over a period of 1h. After the
20 addition of the reagent was complete, the reaction mixture was stirred on oil
bath at 350C for 15 h. The slurry was then cooled to 15 °C and water (38 ml)
was then added followed by the addition of sodium hydroxide (10 M, 55 ml, 55
26

WO 2006/075177 PCT/GB2006/000129
mmol).The basic slurry at (pH 14) was stirred at 20 °C for 2.5 h. The mixture was diluted with water (120 ml) and most of the alcohol and some water was removed on rotary evaporator at 45 °C. The resulting thick slurry was then diluted with water (105 ml) and cooled to 10-12 °C on ice bath. The slurry was
5 then treated portion wise with dilute HCI (0.5 M, until pH 7) for a period of 1h. The slightly acidic solution was then extracted with EtOAc (2 x 200 ml) washed with water, and then dried over sodium sulphate. After evaporation of the solvent the title compound was afforded as a solid and was re-crystallised from EtOAc-hexane to afford 21 g (54%) as fine white crystals M.p. 171-172
10 °C. 1H NMR (CDCI3, 250MHz) 5 10.75 (1H, br s, COOH), 7.87 (2H, m, Ar), 7.67 (2H, m, Ar), 7.07 (1H, s, CH=C), 4.09-4.12 (2H, q, CH2CH3), 1.38 (3H, t, J= 5 and 7.5Hz, CHgCH-0. Found: C, 66.28: H, 5.12; N, 6.42. Calculated for C12HHNO3 C, 66.36; H, 5.09; NS, 6.45]. M/z [(CI) 217 (M)+ 250%, 218 (M+H)+ 200%, 235 (M+NH4)+ 100%.
15
Example 11
(Z)-3-(3-(bQnzyloxy)-4-methoxyphenyl)'2-ethoxyacrytic acid

Pink crystalline solid. M.p. 147-148°C. 1H NMR (CDCI3l 250MHz) 5 11.82 (1H, brs, COOH), 7.66 (1H, s CH=C), 7.24-7.57 (8H, m, Ar), 5.17 (2H, s,
20 CH20), 3.83-3.99 (2H, q, CH3CH3), 3.94 (3H, s, OCH3), 1.22-1.29 (3H, t, CH2CH3.). Found: C, 69.40; H, 6.18, Calculated for C19H2o05; C, 69.51; H, 6.15. M/z [(CI) 328 (M)+ 20%, 329 (M+H)+ 45%, 346 (M+NH4)+ 100%.
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Example 12
(Z)-3-(4-(benzyloxy)-3-methoxyphenyl)-2-ethoxyacrylic acid

Pink crystalline solid. M.p. 148-149qC. 1H NMR (CDCI3, 250MHz) 5 9.62 (1H,
5 brs, COOH), 7.66 (1H, s, Ar), 7.11 (1H, s, (CH=C)), 7.10-7.45 (5H, m, Ar), 6.88 (2H, d, Ar), 4.17 (2H, q, CH3CH2), 3.94 (3H, s, OCH3), 1.40 (3H, t, J = 7 Hz,& J= 5 Hz CH2CH3.). Found: C, 69.27; H, 6.11: Calculated C19H2o05; C, 69.51; H, 6.15. M/z [(CI), 328 (M)+ 25%, 329 (M+H)+ 35%, 346 (M+NH4)+ 100%.

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Example 13
(Z)-2-ethoxy-3-(3~methoxyphenyl)acrylicacid

White crystalline solid. M.p. 99-100°C. 1H NMR (CDCI3, 250MHz) δ 12.07
5(1H, brs, COOH), 7.56 (1H, brs, Ar), 7.29 (2H, m, Ar), 7.15 (1H, s, CH=C), 6.92 (1H, m, Ar), 4.07 (2H, q, J= 7.5Hz, CH2), 3.83 (3H, s, OCH3), and 1.37 (3H, t, J= 7 Hz). Found: C, 65.13; H, 6.37, Calculated for C12H1404; C, 64.86; H, 6.35. M/z [(CI) 222 (M)+ 30%, 223 (M+H)+ 50%, 240 (M+NH4)+ 100%; [Found: 223.09705; required for C12H1504; 223.09155].
Example 14
General hydrogenation screening method:
Into a 45 ml autoclave was placed ligand (3.25 x 10"3 mM) and the vessel placed under vacuum/Ar cycles. The vessel was then flushed with Argon. A
15 degassed solution of [(COD)2Rh]BF4 in MeOH (5 ml of a 0.64 mM solution) was then added by syringe/needle and a rubber bung placed over the vessel to maintain an inert atmosphere. This mixture was stirred for 10 min to give a clear yellow solution. A degassed solution of starting material in MeOH was then added by syringe/needle while carefully attempting to maintain an inert
15 atmosphere. The autoclave was then connected to a Parr 3000 multi-vessel reactor system and then placed under Ar (5 bar) and vented while stirring, this process was repeated 3 times. After the final vent the mixture was placed
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under H2 (50 bar) and again vented carefully. The mixture was then placed under H2 (50 bar), sealed and heated to the desired temperature for the required time. After this time the reaction mixture was cooled and the vessel vented. An aliquot of 0.5-1.0 ml was then taken for analysis.
5
Example 15
(S)-2~(3-(3-methoxypropoxy)-4-methoxybenzyt)-3-methylbutanoicacid

Into a 45 ml autoclave was placed 1,1' bis-[(RP,Sc,RFe) L1 (0.0063 g,0.0069
10 mmol), [(COD)2Rh]BF4 (0.0025 g, 0.0061 mmol) and (E)-2-(3-(3-
methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanoic acid (2 g, 6.49
mmol). The vessel was then placed under vacuum/Ar cycles. The vessel was
then flushed with Argon and a rubber bung placed over the vessel to maintain
an inert atmosphere. Degassed MeOH (10 ml) was then added by cannula
15 taking care to maintain an inert atmosphere in the vessel. The vessel was
then sealed and stirring commenced. The vessel was then placed under Ar (5
bar) and vented, this process was repeated three times. The autoclave was
then placed under hfe (50 bar) and again vented carefully. The mixture was
then placed under H2 (50 bar), sealed and heated to 40 °C for 12 h. After this
20 time the reaction mixture was cooled and the vessel vented. An aliquot of 0.5-
1.0 ml was then taken for analysis. Conversion >98%, e.e >98.5 % (major
enantiomer second running peak).
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1H NMR (CDCI3, 250.13 MHz): 5 1.01 (m, 6H), 1.95 (m, 1H); 2.05 (m, 2H); 2.45 (m, 1H); 2.78 (m, 2H); 3.35 (s, 3H), 3.55 (m, 2H); 3.83 (s, 3H); 4.10 (m, 2H); 6.65-6.80 (m, 3H).
5 HPLC method for e.e. determination of 2~(3-(3-methoxypropoxy)-4-methoxybenzyI)-3-methylbutanoic acid
Chiralpak-AD column (250 mm x 4.6 mm), 94 % Hexane, 3 % 2-methyl-2~ propanol and 3 % t-amyl alcohol, flow: 1 ml/min, 230 nm. S-acid 13.15 min (largest peak with bis-[(/?P,Sc,ftFe)] 1), R-acid 14.01 min, starting material
10 42.73 min.
HPLC method for e.e. determination of 2-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3~methylbutanoic acid (methyl ester) - diazomethane derivatization
15 Into a 10 ml vial was placed a stirring bar and a 1ml aliquot of the crude hydrogenation reaction mixture. With vigorous stirring trimethylsilyl diazomethane in hexane (2 M) was added drop-wise into the reaction mixture and the good yellow colour of the diazomethane solution disappeared along with good gas evolution. This drop-wise process was continued until the
20 reaction mixture became a yellow colour and gas evolution ceased. Neat acetic acid (15-30 μI, - Caution too much acetic acid and excessive gas evolution occurs) was then added upon which the mixture became very pale yellow. Approximately 1/3 of this mixture was then filtered through a small pad of wetted silica in a Pasteur pipette washing with a little hexane/lPA
25 (80:20). The resulting solution was then analysed using HPLC: Chiralpak-AD
31

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column (250 mm x 4.6 mm), 95 % Hexane, 5 % i-Propyl alcohol, flow: 1 ml/min, 230 nm. Product enantiomers; 9-10 min, Starting material; 14-16 min. Note: the order of elution of the enantiomers is reversed relative to analysis on the non-derivatized acids.
5
1,1' bis-ftSnRoSFs)] L1 yields (R)-2-(3-(3-methoxypropoxy)-4-
methoxybenzyl)-3-methylbutanoicacid
1,1' bis-[(Rp,Sc,RFe)] L1 yields (S)-2-(3-(3-methoxypropoxy)-4-
methoxybenzyl)-3-methylbutanoic acid
10
Example 16
Table 1.0 Results of enantioselective hydrogenations on (E)-2-(3-(3-
methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanoic acid with bis-[(SP,Rc,SFe)] L1 at 50 bar H2 pressure.

entry s/c ratio T(°C) Substrate [M] Conversion (%) e.e. (%)
1 500:1 40 0.16 >95 99.6^
2 500:1 50 0.16 >95 99.62
3 500:1 65 0.16 >95 99.32
4 1000:1 40 0.55 72 98.53
5 2000:1 40 0.55 72 98.33
15 1 Reactions carried out in MeOH for 20 h
2 Reactions carried out in MeOH for 5 h
3 Reactions carried out in MeOH for 14 h
Example 17
20 Table 2.0 Results of enantioselective hydrogenations on (E)-2-(3-(3-
methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanoic acid with bis-[(Sp,Rc,SR>)] L1 at 50 bar H2 pressure.

entry s/c ratio T(°C) Substrate [M] Solvent MeOH:1-BuOH e.e. (%)
1 2 3 1000:1 1000:1 1000:1 40 50 65 0.65 0.65 0.65 8.75:1 8.75:1 8.75:1 98.7 98.2 96.6
Example 18
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Table 3.0 Results of enantloselective hydrogenations on (E)-2-(3-(3-
methoxypropoxy)-4-methoxybenzylidene)-3-rnethylbutanoic acid with b\s-[(Sp,Rc,SFe)] L1 at 50 bar H2 pressure (using solid addition method*)
entry Time T(°C) Substrate s/c ratio ee
(h) [M] (%)
1 4 50 0.55 1000:1 98.6
2 4 60 0.55 2000:1 98.4
3 4 60 for 1 h then 50 0.55 1000:1 98.2
5 Note: in all cases >98 % conversion was observed
* All solids (substrate, ligand and metal source) placed in vessel then solvent
added
Example 19
10 It has been found to be preferable for very high enantioselectivity that the
meso impurity (Rp,Rc,SFe-SP)Rc,SFe)- L1 present in the ligand should be
minimised .
Table 4.0 Results of enantioselective hydrogenations on (E)-2-(3-(3-
methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanoic acid with bis-|(Sp,Rc,SFe)] L1 contaminated with meso impurity at 50 bar H2 pressure.
entry meso T Time Solvent Conversion e.e.
present (°C) (h) MeOH:1-BuOH (%) (%)
53 98.5
92 98.2
25 96.4
74 95.1
>99 94.5
40 90.2
(%)
1 ~2 45 5 8.75:1
2 ~2 55 5 8.75:1
3 ~2 45 5 1:1.7
4 6-8 45 5 8.75:1
5 6-8 55 5 8.75:1
6 6-8 45 5 1:1.7 All reactions carried out at s/c ratio of 1000:1
Example 20
Ligands containing flexible linker units have been found to be most preferable, for the enantioselective hydrogenation of the acid substrates described, eg
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Table 5.0 Results of enantioselective hydrogenations on (E)-2-(3-(3-
methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanoic acid . with ligands L1-L3 at 50 bar H2 pressure in MeOH.

entry Ligand T (°C) Time (h) S/C ratio Conversion (%) e.e. (%) -
1 2 L1 L2 40 40 12 12 1000:1 1000:1 83 52 >99 90.8

Example 21
HPLC method for e.e. determination for (S)-2-ethoxy-3-(thiophen-2-
yl)propanoic acid (as methyl ester)
p
"OH

After derivatization:
10 Chiralpak-AD column (250 mm x 4.6 mm), 95 % Hexane, 2.5 % 2-methyl-2-propanol and 2.5 % t-amyl alcohol, flow: 1 ml/min, 236 nm. Enantiomers 5.44 and 5.81 min (largest peak with bis-[(SP,Rc,SFe)] 1)
Example 22

WO 2006/075177 PCT/GB2006/000129
HPLC method for e.e. determination for (S)-3-(3-(benzyloxy)-4-methoxyphenyl)-2-ethoxypropanoicacid

Chiralpak-AD column (250 mm x 4.6 mm), 93 % Hexane, 7 % i-Propyl alcohol,
5 flow: 1.2 ml/min, 235 nm. Enantiomers 11.71 min, 13.33 min (largest peak with b\s-[(Rp,Sc,RFe)] 1), starting material 36.68 min.
Example 23
Table 6.0 Results of enantioselective hydrogenations on (Z)-[-(3-
10 BenzyIoxy-4-methoxyphenyl)]-2-ethoxyacrylic acid with bis-
[(SP,Rc,SFe)] 1 at 48 bar H2 pressure for 12 h.

entry s/c ratio T(°C) Substrate [M] e.e. (%)
1 2000:1 50 0.40 96.2
2 2000:1 50 0.83 93.4
3 250:1 55 0.25 97.1
4 500:1 55 0.5 97.6
5 1000:1 55 1.0 94.9
6 1500:1 55 1.5 90.9
7 1000:1 80 1 81.2
All reactions carried out in MeOH
All reactions achieved >98% conversion
15
Example 24
HPLC method for e.e. determination for (S)-2-ethoxy-3-(thiophen-3-
yl)propanoic acid
o

35

WO 2006/075177 PCT/GB2006/000129
Chiralpak-AD column (250 mm x 4.6 mm), 99 % Hexane, 1 % i-Propyl alcohol, flow: 0.7 ml/min, Integrated 235-239 nm. Enantiomers 9.71 min, 10.88 min (largest peak with b\s-[(Rp,Sc,RFe)] 1), starting material16.35 min.
5 Example 25
HPLC method for e.e. determination for (S)-2-ethoxy-3-(3-methoxyphenyl)propanoic acid (as methyl ester)
'
After derivatization:
10 Chiralpak-AD column (250 mm x 4.6 mm), 95 % Hexane, 2.5 % 2-methyl-2-propanol and 2.5 % t-amyl alcohol, flow: 1 ml/min, Integrated 280-290 nm. Enantiomers 7.49 and 10.00 min (largest peak with bis-[(SP,Rc,SFe)] 1).
Example 26
15 Table 7.0 Screening results of enantioselective hydrogenations on various (Z)-substituted 3-aryl-2-ethoxyacrylic acid substrates with bis-[(SP,Rc,SFe)] 1 at 50 bar H2 pressure.

entry s/c ratio T(°C) Substrate [M] Substituted aryl e.e. (°/
1 500:1 40 0.41 3-OMe 95.2
2 1000:1 40 0.82 3-OMe 94.6
3 500:1 35 0.50 4-CN 98.0
4 500:1 55 0.50 4-CN 96.5
5 500:1 50 0.41 2-thienyl 95.0
6 1000:1 55 0.41 3-thienyl 96.5
All reactions carried out in MeOH
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CLAIMS
1. A process for the manufacture of substituted propionic acids comprising providing a substrate of formula (I):5

wherein:
R is selected from hydrogen, substituted and unsubstituted branched and straight-chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkylamino, substituted and
10 unsubstituted carbocyclic aryl, substituted and unsubstituted carbocylic
aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocylic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen and oxygen;
15 R5 is the same as or different from R and is selected from hydrogen,
substituted and unsubstituted branched and straight-chain alkyl, alkoxy, alkylamino, N-acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocylic aryloxy,
20 substituted and unsubstituted heteroaryl, substituted and unsubstituted
carbocylic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen and oxygen;
37

WO 2006/075177 PCT/GB2006/000129
R6 is selected from:

wherein:
Q is selected from O or N; and
5 R8 is selected from hydrogen, substituted and unsubstituted branched and
straight-chain alkyl, amino, alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocylic
10 arylamino and substituted and unsubstituted heteroarylamino, wherein the
or each heteroatom is independently selected from sulphur, nitrogen and oxygen;
R7 is the same as or different from R and/or R5 (except that if R and R7 are the same then R5 is not hydrogen) and is selected from hydrogen",
15 substituted and unsubstituted branched and straight-chain alkyl, alkoxy,
alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocylic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocylic
20 arylamino and substituted and unsubstituted heteroarylamino, wherein the
or each heteroatom is independently selected from sulphur, nitrogen and oxygen; and
38

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subjecting the substrate to enantioselective hydrogenation under
enantioselective hydrogenation conditions in the presence of an
enantioselective hydrogenation catalyst comprising a catalyst ligand
having a metallocene group with a chiral phosphorus or arsenic substituent
5 to provide in enantiomeric excess a product of formula (II):

R7

R5

..(II)

or its enantiomer or if applicable its diastereomer.
2. A process according to claim 1 wherein the substrate is of formula (111):

(III)
JU
10
wherein R1, R2, R3 and R4 are the same or different and are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, alkoxylated alkyl and alkoxylated alkoxy; the product of the process being of formula (IV):


-{IV)

15 3. A process according to claim 2 wherein the substrate is a substrate of formula (V):
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WO 2006/075177

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Wherein R'O is any suitable alkoxy or alkoxylated alkoxy group, and wherein each R'O may be the same or different.
5 4. A process according to claim 3 wherein the product is a product of formula (VI):

5. A process according to any one of claims 1 to 4 wherein the metallocene
group comprises ortho to the chiral phosphorus or arsenic substituent a
10 second chiral substituent group.
6. A process according to any one of claims 1 to 5 wherein the chiral
phosphorus or arsenic substituent on the metallocene group is further
connected via a linking moiety to a second chiral phosphorus or arsenic
15 substituent on a second metallocene group.
7. A process according to claim 6 wherein the configuration of the chiral
phosphorus or arsenic substituent is the same as the configuration of the
second chiral phosphorus or arsenic substituent.
20
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8. A process according to any one of claims 1 to 7 wherein the catalyst ligand
exhibits C2 symmetry.
9. A process according to any one of claims 1 to 8 wherein the catalyst ligand
5 is basic.
10. A process according to any one of claims 1 to 9 wherein the catalyst ligand
has the formula (VII):

10 wherein:
M is a metal;
Z is P or As;
L is a suitable linker;
R9 is selected from substituted and unsubstituted, branched- and straight-
15 chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl,
substituted and unsubstituted cycloalkoxy, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocyclic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted heteroaryloxy, substituted and
20 unsubstituted carbocyclic arylamino and substituted and unsubstituted
41

WO 2006/075177 PCT/GB2006/000129
heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen;
X* is selected from:

10

wherein Ra, Rb and Rc are independently selected from substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen.
11. A process according to claim 10 wherein Rb and Rc form, together with the nitrogen to which they are attached, an optionally substituted hetero-ring.

12. A process according to claim 10 or claim 11 wherein L the linker is derived
15 from a dianionic reactive species.
13. A process according to any one of claims 10 to 12 wherein L is selected
from metallocenes, diphenyl ethers, xanthenes, 2,3-benzothiophenes, 1,2-
benzenes, cyclic anhydrides and succinimides.
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14. A process according to claim 13 wherein the linker comprises ferrocene.
15. A process according to any one of claims 10 to 14 wherein the 5 enantioselective hydrogenation catalyst comprises the enantiomer or
diastereomer of a ligand having the formula (VII).
16. A process for the preparation of substituted propionic alcohols comprising
preparing a substituted propionic acid by the process of any one of claims
10 1 to 15, and then hydrogenating the acid.
17. A process for the preparation of substituted propionic halides comprising
preparing a substituted propionic alcohol by the process of claim 16 and
halogenating the alcohol.
15
18. A process for the preparation of substituted lactic acid comprising
preparing by a process of any one of claims 1 to 15 a substituted propionic
acid of formula (II) wherein R5 is alkoxy and converting the alkoxy group to
a hydroxy group.
20
19. A process according to any one of claims 1 to 18 wherein the
enantioselective hydrogenation catalyst comprises a transition metal
coordinated to the catalyst ligand.
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WO 2006/075177 PCT/GB2006/000129
20. A process according to claim 19 wherein coordination between the
transition metal and the catalyst ligand takes place in situ in the presence of the substrate.
5 21. A process according to claim 19 wherein the transition metal and the catalyst ligand are pre-coordinated before contact with the substrate;
22. A process according to any one of claims 19 to 21 wherein the transition
metal is a Group Vlb or a Group VIII metal.
10
23. A process according to claim 22 wherein the transition metal is selected
from rhodium, ruthenium, iridium, palladium, platinum or nickel.

44

Abstract:
The invention concerns a process for the manufacture of substituted propionic acids comprising providing a substrate of formula (I): And subjecting the substrate to enantioselective hydrogenation under enantioselective hydrogenation conditions in the presence of an enantioselective hydrogenation catalyst comprising a catalyst ligand having a metallocene group with a chiral phosphorus or arsenic substituent to provide in enantiomeric excess a product of formula (II): or its enantiomer or if applicable its diastereomer.