Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1999-08-06
2000-11-14
Richter, Johann
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
562401, 560115, 560121, C07B 5700
Patent
active
061472549
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to processes for the preparation of compounds of formula (I) or of formula (I'), substantially free of the corresponding enantiomer, involving resolving an enantiomeric mixture of a compound of formula (IIA') and a compound of formula (IIB') by formation of a salt with an optically pure base and fractional crystallisation.
Enantiomerically pure compounds of formula (I) and (I') ##STR1## (I) wherein P is H, (I') wherein P is a protecting group; 6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (1592U89), a compound currently undergoing clinical investigation as an anti-Human Immunodeficiency Virus (HIV) drug.
The compound 1592U89 is described in EP 0434450 and has the following structure: ##STR2##
There exists, at the present time, the need to synthesise large quantities of 1592U89 for clinical trials. In the future, once 1592U89 has been approved by the national medicines regulatory agencies, for example the Food and Drug Administration in the U.S., large quantities of 1592U89 will be required for sale as a prescription medicine for the treatment of HIV infections.
Such processes for the manufacture of 1592U89 using enantiomerically pure compounds of formula (I) are described generally in GB patent application No. 9607052.9 and PCT Application No. WO91/15490.
An alternative to such synthetic routes would be to synthesise 1592U89 using enantiomerically mixed intermediates and then resolve the final product, such as described in Example 7 of EP 0434450. However, such a route is not economically viable since purification techniques are not sufficiently efficient to resolve the mixture on such a large scale and would lead to wastage of the final product not in the desired enantiomeric form.
At present there exist two commercially viable routes for the synthesis of enantiomerically pure compounds of formula (I). ##STR3##
Route A) is an enantioselective hydrolysis of the racemic lactam (VA and VB) using selective enzymes (lactamases) to produce the desired enantiomerically pure/enriched aminocyclopentene carboxylic acid (IIA), such processes are described in European Patent No. 0424064.
Route B) is a non-selective hydrolysis of enantiomerically pure/enriched lactam to produce the desired enantiomerically pure/enriched aminocyclopentene carboxylic acid (IIA). Processes for producing enantiomerically pure/enriched lactam are described in European Patent No. 0424064 and Taylor et al, J. Chem. Soc. Chem. Comm. (1990) 112b.
The compound of formula (IIA) may be converted to the compound of formula (I) by reduction with reagents capable of converting carboxylic acids to alcohols, for example lithium aluminium hydride or borane.
Routes A) and B) are unsatisfactory, producing the amino cyclopentene carboxylic acid (IIA) at a relatively high cost since routes A) and B) involve the use of expensive enzyme technology.
We have found a fast, efficient and cost effective resolution process for enantiomeric mixtures of the compound of formula (IIA') and the compound of formula (IIB'), defined below, thus producing the required enantiomer of formula (IIA') at low cost and high yield and, therefore, avoiding the expense of route A) or B).
The process involves the reaction of a chiral base in solution with an enantiomeric mixture of N-protected-cis-4-amino-2-cyclopentene-1-carboxylic acid, the compound of formula (IIA') and the compound of formula (IIB'); ##STR4## wherein P is a protecting group; to produce, in a diastereoselective manner by fractional crystallisation the salt of the compound of formula (IIA') as a substantially pure diastereomer.
Thus presented as the first feature of the present invention is a process for the manufacture of an enantiomerically pure compound of formula (IIA') ##STR5## wherein P is a protecting group; comprising the fractional crystallisation from a suitable solvent of a mixture of the diastereomeric salts of the compound of formula (IIA') and the compound of formula (IIB') ##STR6## wherein P is a protecting group; formed with a base of formula (IV) ##STR7
REFERENCES:
Allan, R.D. et al., Synthesis of Analogues of GABA. XV Preparation and Resolution of Some Potent Cyclopentene and Cyclopentane Derivatives, Aust. J. Chem., 1986, 39: 855-864.
Kam, B.L. et al., Carbocyclic Sugar Amines: Synthesis and Stereochemistry of Racemic .alpha.- and .beta.-Carbocyclic Ribofuranosylamine, Carbocyclic Lyxofuranosylamine, and Related Compounds, J. Org. Chem., 1981, 46, 3268-3272.
Csuk, Rene et, "Biocatalytical transformations, IV. Enantioselective enzymic hydrolyses of building blocks for the synthesis of carbocyclic nucleosides", Tetrahedron: Asmmetry, 1994, 5(2), 269-76, 1994.
Daluge, Susan et al: "Synthesis of Carbocylic Aminonucleosides" J. Org. Chem. (1978), 43(12), 2311-20, 1978.
Taylor S J C et al: "Development of the Biocatalytic Resolution of 2-Azabicyclo 2.2.1Hept-5-En-3-One as an Entry to Single-Enantiomercarbocyclic Nucleosides" Tetrahedron: Asymmetry, vol. 4, No. 6, pp. 1117-1128, 1993.
Allan R D et al: Synthesis of Analogues of Gaba. XV. Preparation and Resolution of Some Potent Cyclopentene and Cyclopentane Derivatives Australian Journal of Chemistry, vol. 39, No. 6, pp. 855-864, 1986.
Taylor S J C et al.: "Chemoenzymatic Synthesis of (-)-carbovir using a whole cell catalyse resolution of 2 azabicyclo [2.2.1] hept-5-en-3-one" Journal of the Chemical Society, Chemical Communications., Letchworth GB, pp. 1120-1121, 1990.
M Konishi et al.: "Cispentacin, a new antifungal antibiotic" Journal of Antibiotics., vol. XLII, No. 12, Tokyo JP, pp. 1749-1755, 1989.
Toyota, Akemi et al: "Synthesis of nucleotides and related compounds. Addition of molecular fluorine to bicyclo[2.2.1]hept-2-ene derivatives and conversion to fluorine-containing carbocylic nucleotides" Tetrahedron Lett. (1994), 35(31), 5665-8 1994.
Grenn and Wuts, Protective Groups in Organic Chemistry, 2nd ed., John Wiley & Sons, Inc., NY 1991.
Ingold Kenneth James
Sickles Barry Riddle
Wallis Christopher John
Davis Brian J.
Glaxo Wellcome Inc.
Prus Karen L.
Richter Johann
LandOfFree
Process for resolving mixtures of carbocyclic stereoisomers does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for resolving mixtures of carbocyclic stereoisomers, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for resolving mixtures of carbocyclic stereoisomers will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2066870