Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
1999-07-23
2001-07-10
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S197000, C435S280000
Reexamination Certificate
active
06258574
ABSTRACT:
This invention relates to a Process for the Production of Optically Active 2-Substituted tetrahydropyran-4-ones.
Certain tetrahydropyran-4-ones are of interest as chemical intermediates in the production of biologically active materials, for example those of European Patents 465,812; 462,813; 409,413; 420,511; 410,661; 385,662 and 375,404. In at least some cases compounds of enhanced activity are produced if the tetrahydropyran-4-one is 2-substituted and is in the (S) configuration. Compounds of the (R) configuration are also of possible research interest.
This invention comprises a process of producing an optically active 2-substituted tetrahydropyran-4-ol or ester thereof which comprises stereospecifically esterifying a 2-substituted tetrahydropyran-4-ol using a stereospecific esterase or stereospecifically hydrolysing an ester thereof with a stereospecific hydrolase.
We have found that the invention may be carried out with surprisingly high stereo specificity.
If desired the hydrolysis of the ester product may be carried out using a stereospecific hydrolase in order to increase the optical purity further.
The cis 2-substituted tetrahydropyran-4-ols or esters react more readily in the invention than the trans compounds and the (R) compounds can be reacted stereospecifically both in esterification and hydrolysis thereby leaving the (S) compounds unconverted.
The racemic mixture of the 2-substituted tetra-hydropyran-4-ol in substantially the cis form may be produced by reacting but-3-ene-1 ol with an aldehyde of formula X CHO in which X is the desired 2-substituent of the pyranol in the presence of an acid which is preferably sulphuric acid. X is suitably an alkyl for example, an ethyl or methyl group or a substituted alkyl for example mono or di fluoro-substituted alkyl for example methyl or ethyl group. A method for this process using H
2
SO
4
as catalyst is described by Hanschke (Chem Ber (1955) vol 88 p 1053). Cis and trans orientations are lost on oxidation to the corresponding ketone but we have found the cis product to be very suitable for this invention.
The invention also comprises a process of producing an optically active 2-substituted tetrahydropyran-4-ol or ester thereof which comprises producing a cis-racemic 2-substituted tetrahydopyran-4 or by reacting but -3-ene-1-ol with an aldehyde of formula XCHO in which X is the desired 2-substituent of the pyranol in the presence of an acid, esterifying the racemic mixture using a stereospecific esterase or esterifying the racemic mixture optionally non stereospecifically and hydrolysing it with a stereospecific hydrolase.
The esters may be made by normal methods, preferably using the free acids, acyl halides and/or anhydrides, in non stereospecific esterification. In stereospecific esterification it is preferred to transesterify with another ester, which is suitably a vinyl ester, as the by-product, acetaldehyde, is not involved in a back-reaction. It is preferred that the stereospecific esterification reaction and/or hydrolysis be carried out at a pH of 5 to 10, at least if excess water for example water of reaction, is present, more preferably 6 to 9, and a temperature of preferably 20 to 65° C., more preferably 25 to 50° C. The esters are preferably esters of lower alkanoic acids having 2 to 8 carbon atoms, benzoic acid or substituted derivatives thereof.
The enzymes may be provided as such or as whole cells comprising them. It is preferred that they be immobilised so as to facilitate their separation from the product and, if desired, re-use.
The stereospecific esterification and/or hydrolysis step(s) may be carried out by mixing the reactant(s) with the enzyme, normally in the presence of at least an amount of water sufficient to allow enzyme activity and, in the case of hydrolysis to supply the water of reaction and optionally an inert solvent.
Preferred enzymes include those from Humicola lanuginosa for example that sold under the Trade Mark Lipolase and Pseudomonas for example that sold under the Trade Mark SAM II and more preferably those from Candida antarctica, for example that sold under the Trade Mark NOVOZYM.
Oxidation of the alcohol to the ketone is suitably carried out with a strong oxidising agent, for example chromic acid suitably in the presence of a strong acid for example sulphuric acid and an inert organic solvent for example a ketone. The temperature is preferably in the range 0 to 40° C. for example 0 to 30° C.
If desired, the alcohol may be further reacted, for example by oxidation of the corresponding ketone in the presence of the ester. Any separation of the ester which is required may be carried out after such further reaction. The invention may be used as a route to either the product of the stereospecific reaction or to the unconverted isosmer.
REFERENCES:
patent: 5395766 (1995-03-01), Koizumi et al.
patent: 5443970 (1995-08-01), Blacker et al.
patent: 5443971 (1995-08-01), Blacker et al.
patent: 5527916 (1996-06-01), Blacker et al.
patent: 5670662 (1997-09-01), Cosby et al.
patent: 93 06236 (1993-04-01), None
patent: 93 06235 (1993-04-01), None
Computer Abstract CEABA 97:6771890, Auartey et al, “Selectivity enhancement of PPL-catalyzed resolution by enzyme fractionation and medium engineering: syntheses of both enantiomers of tetrahydropyran-2-methanol”, Enzyme Micro. Technol. (1996) 19(5), pp. 361-366.
Holt Robert Antony
Rigby Stuart Richard
Waterson David
Lilling Herbert J.
Pillsbury & Winthrop LLP
Zeneca Limited
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