Asymmetric hydrogenation

Details Asymmetric hydrogenation Asymmetric hydrogenation

2000-12-05

2002-07-02

Geist, Gary (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S512000

Reexamination Certificate

active

06414187

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to processes suitable for the large scale preparation of enantiomerically enriched chiral carboxylic acid derivatives. In particular, it relates to asymmetric hydrogenation of prochiral substrates, using a transition metal catalyst complex.
BACKGROUND OF THE INVENTION
Asymmetric hydrogenation has been used to convert prochiral substrates having the partial formula C═C—C—COOX to chiral compounds of the formula C—C—C—COOX. See, for example, Yamamoto et al,
J. Organometallic Chem.,
1989, 370, 319, where the substrate is 3-phenyl-3-butenoic acid, and the catalyst is Rh—DIOP. X depends on the additive, including tertiary amines.
Examples of other substrates in such a reaction have generally had a carboxylate function at at least one chiral centre. For example, itaconic acid derivatives have been used.
Enantiomerically enriched 2-substituted succinic acids (see formulae 2a and 2b, below) have recently attracted interest as useful chiral building blocks and pepidomimetics in the design of pharmaceuticals, flavours and fragrances, and agrochemicals with improved properties. For example, the utility of 2-substituted acid derivatives has been amply demonstrated through the synthesis of a range of new potent orally bioavailable drugs [J. T. Talley et al., in
Catalysis of Organic Reactions,
J. R. Kosak, T. A. Johnson (eds.) Marcel Dekker, Inc. (1994) Chapter 6; and H. Jendralla,
Synthesis
(1994) 494].
Chiral succinates can be prepared simply (e.g., via Stobbe condensation) from unsubstituted succinic esters and aldehydes or ketones, followed by asymmetric hydrogenation of the intermediate &bgr;-substituted itaconate derivatives. For example, itaconic acid or its sodium salt, can be enantioselectively hydrogenated to 2-methylsuccinic acid with rhodium catalysts bearing the chiral ligand N-acyl-3,3′-bis(diphenylphosphino)pyrrolidine (BPPM) in up to 92% enantiomeric excess (ee) [I. Ojima et al.,
Chem. Lett.,
1978, 567; I. Ojima et al.,
Chem. Lett.,
1978, 1145; K. Achiwa,
Tetrahedron Lett.,
1978, 1475]. A rhodium catalyst bearing the chiral diphosphine DIPAMP affords 2-methylsuccinate in up to 88% ee [W. C. Christofel, B. D. Vineyard,
J. Am. Chem. Soc.
1979, 101, 4406; and U.S. Pat. No. 4,939,288]. Similar results have been obtained with a ruthenium catalyst containing the chiral diphosphine ligand BINAP [H. Kawano et al.,
Tetrahedron Lett.,
1987, 28, 1905]. Rhodium catalysts bearing modified DIOP ligands provide 2-methylsuccinic acid derivatives with variable enantioselectivities, between 7 and 91% ee. In these latter reactions, the ee value is very dependent on the rhodium catalyst precursor and whether the free acid or the ester is used [T. Morimoto et al.,
Tetrahedron Lett.,
1989, 30, 735]. Better results have been reported with a neutral rhodium catalyst of the chiral diphosphine 2,2′-bis(dicyclohexylphosphino)-6,6′-dimethyl-1,1′-biphenyl (BICHEP), whereby dimethylitaconate was hydrogenated in 99% ee [T. Chiba et al.,
Tetrahedron Lett.,
1991, 32, 4745].
In contrast to the success achieved with unsubstituted itaconate derivatives, asymmetric hydrogenation of &bgr;-substituted itaconic acid derivatives has been more challenging; relatively few reports of high enantioselectivity (over 90% ee) have appeared. No enantioselectivities above 90% ee have been reported for &bgr;-alkyl-substituted itaconates.
Itaconate derivatives that possess two substituents in the &bgr;-position (&bgr;,&bgr;-disubstituted itaconates of formula 1 where R
3
,R
4
≠H) have thus far proven impossible to hydrogenate with high enantioselectivities and high rates. The only reported example of this type revealed that dimethyl &bgr;,&bgr;-dimethylitaconate may be hydrogenated with a Rh-TRAP catalyst system with the highest enantioselectivities being 78% ee [R. Kuwano et al,
Tetrahedron: Asymmetry,
1995, 6, 2521].
It should be noted that enantiomerically pure compounds are required for many applications in, for example, the pharmaceutical industry. Consequently, providing enantiomeric purity is the ultimate objective of an asymmetric process, and achieving high enantioselectivity in a transformation of the type described herein is crucial from a process standpoint. 90% ee is often selected as a lower acceptable limit because compounds often may be purified to enantiomeric purity through recrystallisation when the initial value is above 90% ee. Enantiomeric excesses lower than 90% ee become increasingly more difficult to purify.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that an efficient and high-yielding preparation of an enantiomerically enriched chiral carboxylic acid by asymmetric hydrogenation, e.g. in the presence of a transition metal complex of a chiral phosphine, is facilitated by use of particular salt forms of the hydrogenation substrate. Examples of such substrates are itaconates, which are referred to herein by way of example only. More generally, the products of the invention have the partial formula C—C—C—COOX, X being a cation. The corresponding acid will usually be obtained, on work-up.
The use of salt forms can have a number of advantages. Firstly, formation and isolation of a salt form, using a substantially stoichiometric amount of base, may provide a convenient means of effecting substrate purification prior to hydrogenation, should this be required. Secondly, at a given molar ratio of substrate to catalyst (S/C ratio) and reaction time, a higher substrate conversion and/or higher enantioselectivity can be achieved. Thirdly, high reaction rates allow reactions to be performed at low temperatures, e.g. 0° C., whereby higher product enantiopurity is observed.
DESCRIPTION OF THE INVENTION
The substrate for hydrogenation is prochiral, i.e. it is asymmetrically substituted about the C═C bond. One substituent is —C—COOX, and the combination of chain length and carboxylate anion provides the ability of the substrate to coordinate a metal catalyst. There may be none or any substituents on the same C atom of the C═C bond as —C—COOX, provided that they do not interfere with the reaction. For example, in the hydrogenation of a substrate of the formula R
3
R
4
C═CR
1
—CH
2
— COOR
2
, R
1
, R
3
and R
4
are each essentially spectators, although R
3
and R
4
are not both hydrogen. A characteristic of this invention is that no carboxylate function other than COOX is necessary.
Such substrates are known or may be prepared by methods known to those skilled in the art. In the particular case when R
1
is COOR
2
, COOalkyl or COOaryl, both &bgr;-substituted and &bgr;,&bgr;-disubstituted derivatives may be prepared. Itaconates for use as substrates are also described in PCT/GB98/03784 and U.S. patent application Ser. No. 09/213,745, filed Dec. 17, 1998, the contents of which are incorporated herein by reference.
Suitable substrates for the hydrogenation process outlined above are of the general structure 7 or 8 (for the preparation of products 2)
or a mixture thereof, wherein R
1
, R
3
and R
4
can be independently H or an organic group of up to 30 C atoms or R
3
and R
4
are joined to form a ring, provided that at least one of R
3
and R
4
is not H. In one embodiment, the invention provides an improved procedure in the case where one of R
3
and R
4
is H; typically, the other is C
1-20
alkyl or aralkyl. By way of example, the fact that &bgr;,&bgr;-disubstituted itaconates can be effectively hydrogenated in this process means also that R
3
and R
4
may each be an organic group of up to 30 C atoms, e.g. C
1-20
alkyl or aralkyl, and preferably the same, or may be linked to form a ring, e.g. a saturated carbocyclic ring. In this case, R
1
may be COOC
1-10
alkyl, COO aryl or COO aralkyl.
X may represent a metal, e.g. alkali metal, or other cation. The metal salt may be preformed or formed in situ, by introducing a strong base such as a metal alkoxide, e.g. NaOMe.
Alternatively, the salt may be formed w

Affiliated with

Also associated with

Rating

Asymmetric hydrogenation does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Asymmetric hydrogenation, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Asymmetric hydrogenation will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2842344