Stereospecific hydrolysis of optically active esters

Details Stereospecific hydrolysis of optically active esters Stereospecific hydrolysis of optically active esters

2002-06-24

2003-07-15

Solola, Taofiq (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S475000

Reexamination Certificate

active

06593478

ABSTRACT:

The invention described herein relates to a stereospecific process for the preparation of compounds of general formula (R)-(I) and of absolute configuration (R)
where:
Q and Q
1
are hydrogen atoms; or,
Q and Q
1
taken together form the ═O group;
M is the trimethylammonium group or an -OZ group;
W is a group selected from —OH, -OL, or -OZ, or
M and W, taken together, form the group —O—, so that the compound of formula (R)-(I) is the compound of formula (R)-(A)
L is a C
1
-C
6
linear or branched alkyl or a benzyl group;
-OZ group is the residue of an ester of a sulphuric, phosphonic or phosphoric acid selected from:
where:
T is C
1
-C
10
linear or branched alkyl, optionally substituted with one or more halogen groups, such as, for example, trihalomethyl; or T is an aryl group, such as, for example, phenyl, tolyl, halophenyl or nitrophenyl.
The compounds of formula (R)-(I) can be prepared starting from (S)-(II) derivatives
where:
Q, Q
1
, M, W and -OZ have the above defined meanings.
Derivatives of formula (S)-(II) can be prepared starting from (S)-(I) compounds according to the following reaction scheme 1:
where Q, Q
1
, M, W and -OZ have the above defined meanings, which comprises an esterification reaction of the hydroxyl group of the (S)-(I) compound to yield derivative (S)-(II), according to known methods.
The compound of formula (S)-(I) where Q and Q
1
taken together form the ═O group, M is the trimethylammonium group, W is —OH and the —OH group is in position &bgr; with respect to the -CQQ
1
group, is (S)-carnitine, which is a discard product of the process for the preparation of (R)-carnitine. The compound of formula (S)-(I), wherein Q and Q
1
, taken together, form the group ═O, M and W, taken together, are the group —O— and the —OH group is in position &bgr; with respect to the group -CQQ
1
, is obtained easily and at low cost, using the process described in Italian patent IT 1276207, starting from (S)-carnitine, whereas the compound of formula (S)-(I), where Q and Q
1
are hydrogen atoms, M and W, taken together, are the group —O— and the —OH is in position &bgr; with respect to the group -CQQ
1
, is obtained, for example, following the process described in Organic Synthesis (38) 1958, 37-38.
Compounds of formula (R)-(I) are versatile chiral intermediates used in various industrial synthesis processes. For example, the compound of formula (R)-(I), in which Q and Q
1
, taken together, form the ═O group, M and W, taken together, are the group —O— and the group —OH is in position &bgr; with respect to the group -CQQ
1
, can be used in the synthesis of beta-lactam antibiotics, in the well-known anticonvulsant GABOB ((R)-4-amino-3-hydroxy-butyric acid), and in the synthesis of (R)-carnitine. (R)-carnitine can be even prepared from the discard product (S)-carnitine.
Despite the acknowledged usefulness of compounds of formula [R]-[I] as versatile intermediates, to date no satisfactory processes have been developed to enable them to be synthesised on an industrial scale.
In fact, the synthesis of (R)-(I) compounds, where Q and Q
1
, taken together, form the ═O group, M and W, taken together, are the group —O— and the —OH group is in the &bgr; position with respect to the group -CQQ
1
, starting from L-ascorbic acid, requires as many as seven steps with low yields (29%) (Tanaka, A.; Yamashita, K.,
Synthesis,
1987, 570-572).
The synthesis of (R)-(I) compounds where Q and Q
1
are hydrogen atoms, M and W, taken together, are the group —O— and the —OH group is in the &bgr; position with respect to the group -CQQ
1
, starting from dimethyl-(R)-malate, entails a cumbersome reduction (practically impossible to implement on an industrial scale) with borane-dimethylsulphide complex, which is fraught with problems of safety and pollution (Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu, S.; Moriwake, T.,
Chem. Lett.,
1984, 1389-1392).
Italian patent application RM95A000652 describes the synthesis of (S)-beta-hydroxy-gamma-butyrolactone starting from (S)-carnitine. With the method described in RM95A000652 it is also possible to prepare (R)-(I) compounds starting from (R)-carnitine. This process is clearly not economically advantageous since (R)-carnitine is a particularly valuable and expensive compound.
Italian patent application RM97A000780 describes the synthesis of (R)-(I) compounds using as the starting product (S)-(I) compounds where Q and Q
1
taken together form the ═O group, M and W, taken together are the group —O— and the —OH group is in the &bgr; position with respect to the group -CQQ
1
. This process is not advantageous in that involves a large number of steps and gives low yields.
It would therefore be advantageous to have a process for the preparation of (R)-(I) compounds which can be implemented on an industrial scale and which does not present the numerous serious drawbacks of the known methods: large number of steps, low yields, use of expensive, hazardous and/or polluting reactants.
A new process has now been found, and constitutes the subject matter of the invention described herein, for the preparation of compounds of formula (R)-(I) starting from derivatives of formula (S)-(II) that overcomes the technical problems encountered with the above-mentioned known processes.
The process according to the invention described herein can be represented schematically by means of scheme 2 here below:
where:
the groups M, W, Z, Q and Q
1
are as above defined.
comprising reacting derivatives of formula (S)-(II) with an aqueous solution of a strong organic or inorganic acid at a temperature ranging from about 60 to about 100° C. and preferably from about 75 to about 85° C.
What is meant by strong organic or inorganic acid is any acid that has a negative pKa in relation to water (March Advanced Organic Chemistry fourth edition pp. 248-252).
Examples of such acids, though not exclusively these, are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, methanesulphonic acid, sulphuric acid, trifluoromethanesulphonic acid, or benzenesulphonic acid. A convenient molar ratio of acid to substrate is ≧1, and preferably ≧2.
The amount of water utilised in the process according to the invention is the minimum amount possible. The optimal ratio of ester to water, in the presence of strong acid, is easily calculated on the basis of hot solubility tests.
The reaction is conducted at a temperature ranging from about 60 to about 100° C., and preferably from about 75 to about 85° C. The person skilled in this field will understand that the term about, relating to the above mentioned temperature range means that the temperature can be kept around the indicated term within a range which does not substantially change the reaction conditions given at the indicated temperature level, such as, for instance, the reaction conveniently proceeds, there is no unwanted degradation of products or reactants, the limit can also be given by the boiling point of the solvent.
A further object of the invention described herein is a process for the preparation of compounds of formula (R)-(I) starting from (S)-(I) compounds according to scheme 3 here below:
where:
the groups M, W, Z, Q and Q
1
are as defined above comprising:
b) esterification of the hydroxyl group of compound (S)-(I) to give the formula (S)-(II) derivative;
c) reacting the derivative of formula (S)-(II) obtained in a) with an aqueous solution of a strong organic or inorganic acid at a temperature ranging from about 60 to about 100° C.
All meanings, conditions and explanations for the process above disclosed in scheme 3 are essentially the same as the ones explained for the process disclosed in the scheme 2 above.
Thanks to the process according to the invention, in its various embodiments, it is now possible to accomplish inversion of the configuration of the asymmetrical carbon atom with a high degree of stereospecificity and high yields, and in a much more practicable manner than when using any of the known techniques adopte

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