Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfonate esters
Reexamination Certificate
2000-10-27
2002-05-28
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfonate esters
Reexamination Certificate
active
06395918
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of organic chemistry. More particularly, the present invention provides a new method of converting a hydroxy group in certain alcohols into a good leaving group and that with inversion of configuration where the hydroxyl-bearing carbon is chiral. Such a method is particularly useful for preparing chiral compounds for pharmaceutical and agrochemical use.
BACKGROUND OF THE INVENTION
Government regulations in various countries, especially in the U.S., have raised the necessity of finding an economical way for the production of the more active enantiomer of a drug whose molecule is chiral, other than by resolution of the racemic final (or intermediate) product, by the use of expensive chiral catalysts or auxiliaries—usually of the non-recoverable or partially recoverable kind, or by the discovery of an enzymatic process. To satisfy this necessity three requirements must be met [see A. N. Collins, G. M. Sheldrake, and J. Crosby (Eds.), Chirality in Industry (1992), and Chirality in Industry II (1997), John Wiley & Sons, Chichester]. The first one is to select an inexpensive, preferably naturally occurring starting material, from a renewable source, which can be elaborated to the desired product enantiomer. The second requirement is to ensure that during this elaboration chirality of the intermediates is maintained, and that relative stereochemistry, during possible introduction of further chiral centers, is predictable. The third requirement is that yields as high as possible are achieved during this elaboration, with minimal expense of auxiliary reagents, so as to make the whole process economically feasible.
Preferred such naturally occurring chiral compounds are esters derived from lactic acid (in particular the ethyl and methyl esters), because such esters are inexpensive and available in large amounts. This invention refers mainly to these esters, but is equally applicable to other alkyl lactates, as well as to esters of other naturally occurring chiral &agr;-hydroxy acids such as malic acid or mandelic acid and in general to compounds having a hydroxyl group attached to a chiral carbon atom.
&agr;-Hydroxycarboxylic acids are important starting materials for pharmaceutically and agrochemically important compounds, particularly when they contain a chiral carbon atom in the molecule. In the more abundant form of all these &agr;-hydroxycarboxylic acids the carbon atom attached to the hydroxyl group has the S-absolute configuration. However, they also occur or are commercially available with this carbon atom having the R-configuration (see G. M. Coppola and H. F. Schuster, &agr;-Hydroxy Acids in Enantioselective Synthesis, VCH-Wiley, Weinheim, 1997; A. N. Collins, G. M. Sheldrake, and J. Crosby, Eds., Chirality in Industry II, Wiley, 1997, Chapter 10).
It is well known that SN
2
substitution reactions at an asymmetric carbon proceed with inversion of configuration. When such substitution takes place at the chiral carbon next to the hydroxyl group in a chiral alcohol, a clean inversion of configuration occurs (as schematically shown in FIG.
1
), with retention of chirality. In SN
2
reactions the hydroxyl group has to be converted into the best possible leaving group L. However, both L and the incoming nucleophile group Nu are negatively charged (or electron-rich) and if there is little difference between the two in this respect, they can exchange roles and the reaction can go in the opposite direction. In that case chirality may be lost because at the intermediate stage the carbon is connected neither to Nu nor to L, thus being trihedral and planar. Each group can enter and leave from either direction leading to racemisation (as schematically shown in
FIG. 2
) and elimination. The difference between the nucleophility of the two groups is a function of the relative acid strengths of the two corresponding acids Nu-H and L-H.
In order to avoid racemisation and elimination, the hydroxyl group has to be converted into a good leaving group, such as, for example, an ester of a sulfonic acid. The most common sulfonic acids are methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. However, trifluoromethylsulfonic acid and fluorosulfonic acid are among the strongest known sulfonic acids and are of the order of 10
4
stronger than toluene- and benzenesulfonic acids (see P. J. Stang, M. Hanack and L. R. Subramanian, Synthesis 1982, 85).
Hence, in order to fulfill the above requirements, i.e. maximum retention of chirality in a predictable manner and highest possible yields resulting from absence of side reactions such as elimination, organic chemists have for many years tended to use in particular trifluoromethylsulfonate (hereinafter “triflate”) esters of hydroxyl groups as leaving groups in such substitution reactions. The main problem is the high cost of trifluoromethylsulfonic acid, in particular when considering the fact that to make esters of trifluoromethylsulfonic acid, one has to use its anhydride which is made from two molecules of the acid, only one of which ends up in the ester. On the basis of current prices, the process of triflation of an hydroxyl group is more than 56 times the cost of toluenesulfonation (“tosylation”) and 35 times the cost of benzenesulfonation (ignoring the cost of solvents, amine bases which have to be of the more expensive hindered type in case of triflation, and not counting the possible recovery of the other molecule of triflic acid which is a rather involved process). If only one equivalent of trifluoromethylsulfonic acid itself could be used, the cost difference would drop to ca. 28 times that of tosylation. However, no method is known in the prior art for carrying out such a reaction.
The situation with fluorosulfonate esters is more complex and intriguing. The acid itself is used in other industrial applications, and is presently available in tank loads at a very low price. If it were possible to use it, rather than its anhydride, the cost of fluorosulfonation could be practically identical to that of tosylation or mesylation, and perhaps even cheaper. However, no method is known in the prior art for carrying out such a reaction. The anhydride itself is very difficult to prepare, is very volatile and is poisonous (of the same order as phosgene). It has recently been offered for sale at a price which would make fluorosulfonation over 200 times more expensive than tosylation, apart from the additional hazards involved.
Can. J. Chem. 59(2), 1981, 362-372 describes the reaction of N,N-dimethylsulfamates with methyl fluoro(trifluoromethane) sulfates.
It is an object of this invention to provide an efficient and economical method for the preparation of fluorosulfonic and perfluoroalkanesulfonic esters of hydroxy compounds.
It is another object of this invention to provide such a method by which such esters of chiral starting materials can be prepared in good yield, with inversion of configuration and maximal retention of chirality in the resulting product.
It is a further object of this invention to provide such a method that is particularly useful in the case of carboxylic esters of lactic acid.
Other objects and advantages of the invention will become apparent from the description of the invention.
SUMMARY OF THE INVENTION
The present invention provides a method of substituting a hydroxyl group attached to a chiral carbon atom bearing an electron withdrawing group such as carboxylic ester, carbonyl or cyano in a hydroxy compound with a leaving group selected from fluorosulfonate and perfluoroalkylsulfonate, which comprises the steps of:
(a) converting said hydroxyl group to an O—N,N-dialkylsulfamate ester thereof, and
(b) reacting said O—N,N-dialkylsulfamate ester, optionally in a suitable inert solvent, with 1±0.2 equivalent of either perfluoroalkylsulfonic acid or fluorosulfonic acid.
The substitution occurs with inversion of configuration and substantial retention of chirality.
As used herein the term “alkyl” refers to a linear, branched or cyclic alkyl
Loewenthal Hans Jacob Edgar
Loewenthal Ron Benjamin
Browdy and Neimark , P.L.L.C.
Geist Gary
Zucker Paul A.
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