Enzymatic resolution of aminotetralins

Details Enzymatic resolution of aminotetralins Enzymatic resolution of aminotetralins

2000-05-10

2001-08-07

Barts, Samuel (Department: 1621)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing nitrogen-containing organic compound

C564S202000

Reexamination Certificate

active

06271005

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to preparation of organic chemical compounds, in particular to preparation of carbocyclic amine compounds. More specifically, it relates to processes for separation of stereoisomers of carbocyclic amine compounds from a mixture containing the different isomers.
BACKGROUND OF THE INVENTION
Carbocyclic amines, in which a primary or secondary amine group is bonded to a carbon of the carbocyclic structure, commonly exhibit chirality, with one of the stereoisomers having a different utility, or a different degree of utility, from the other. Accordingly there is a need for efficient processes for separation of streoisomers of carbocyclic amines.
One class of carbocyclic amines which can exhibit chirality is the aminotetralins. Various 2-aminotetralin compounds are known to exert pharmacological effects on the nervous system of the mammalian body, by binding selectively to 5-HT receptors. One specific such compound, showing promise as an agent for treatment of Parkinson's disease, is N-0923, a chiral 2-aminotetralin-ethylthiophene compound of formula:
The chirality at C-2 is important in the activity of this and similarly useful 2-aminotetralins, and synthetic methods for its production need to be capable of producing the specific stereoisomer in substantially pure form. A key intermediate in the chemical synthesis of compounds such as N-0923 is (S)-5-alkoxy-2-aminotetralin hydrochloride of formula I:
where R represents lower alkoxy (in the specific case of N-0923 preparation, R is methoxy). Producing the substantially pure (S) enantiomer of this intermediate compound is necessary, in the preparation of N-0923 from it.
BRIEF REFERENCE TO THE PRIOR ART
Ames et al., J. Chem. Soc. (1965) 2636 describe the preparation of racemic mixtures of 5-methoxy-2-aminotetralin, by, firstly, reaction of 5-methoxy-2-tetralone with hydroxylamine hydrochloride and sodium hydroxide to convert the 2-oxo group to a 2-hydroxylamine ═N—OH) group and secondly, hydrogenation of this product with hydrogen over Raney nickel in the presence of ammonia. No consideration is given to the preparation of specific stereoisomers, or to the separation of the stereoisomers, since these compounds are prepared as part of a synthetic scheme where stereo specificity is unimportant.
U.S. Pat. No. 5,300,437 Sterling et al., describes a process for stereos elective synthesis of chiral amines, such as 2-amino-5-methoxytetralin, in which a corresponding ketone is contacted with an omega-amino acid transaminase in the presence of an amino donor. However, these enzymes are not widely available.
Tschaen et al. J. Org. Chem. 1995, 60, 4324-4330, disclose, as part of a synthetic scheme for preparing stereospecific tetralin compounds substituted with N-heterocycles (MK-0499), a chiral reduction of 5-bromo-2-tetralone to the corresponding chiral 2-alcohol using a yeast (trichosporon capitatum), followed by conversion to the 2-azide and reduction to the 2-amine. This approach is not attractive for scale-up, since the yeast is not commercially available.
The prior art contains other disclosures of preparation of racemic mixtures of aminotetralins, followed by chemical resolution thereof, for example U.S. Pat. No. 4,968,837 Thanikavelu et al., issued Nov. 6, 1990, which shows resolution of substituted aminotetralins with diaroyltartaric acid; Sonesson et al. “Synthesis and Evaluation of Pharamacological and Pharmacokinetic Properties of Monopropyl Analogs of 5-, 7-, and 8-[[(Trifluoromethyl)sulfonyl]oxy]-2-Aminotetralins: Central Dopamine and Serotonin Receptor Activity”, J. Med. Chem. 1995, Vol. 38, page 1319-1329, which shows resolution of substituted aminotetralins with 2-chlocyphos (a chiral cyclic phosphoric acid); and Hillver et al. “(S)-5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin: A Putative 5-HT
1A
-Receptor Antagonist”, J. Med. Chem., 1990, Vol. 33, pages 1541-1544, which discloses resolution of substituted aminotetralins with tartaric acid. Such process are relatively inefficient, and relatively expensive to operate.
McDermed et.al., “Synthesis and Dopaminergic Activity of (±)-, (+)-, and (−)-2 Dipropylamino-5-hydroxy-1,2,3,4-tetrahydronaphthalene”, J.Med.Chem (1976), 19, 547, describe the resolution of aminotetralin derivatives, namely (±)-2-(N)-benzylamino-5-methoxytetralin, by reaction with (−)-mandelic acid. Bakthavachalan et.al., “Fluorescent Probes for Dopamine Receptors: Synthesis and Characterization of Fluorescein and 7-Nitrobenz-2-oxa-1,3-diazol-4-yl Conjugates of D-1 and D-2 Receptor Ligands”, J.Med.Chem. (1991), 34, 3235 disclose the resolution of 2-(N-benzylamino)-5-methoxytetralin by reaction with D- and L-ditoluoyltartaric acids. These chemical methods of resolution require repeated recrystallization of the product, which lowers the eventual yield.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel and effective process for the separation of (R)-isomers and (S)-isomers of carbocyclic amines, from a mixture thereof.
The present invention provides a process of selective enzymatic acylation of carbocyclic amines. A mixture of (S) and (R) carbocyclic amines is subjected to reaction with an acylating agent in the presence of the enzyme Chiro CLEC-PC (
Pseudomonas cepacia
lipase). The (R) isomer is selectively acylated, while the (S)-isomer remains substantially unaffected. Accordingly, after the reaction has proceeded to a sufficient extent towards completion, the two isomers can be separated from one another and from the reaction medium by standard physico-chemical methods such as chromatography or acid extraction. Then further chemical reactions can be conducted on the desired isomer (in most cases, the (S)-isomer), to the exclusion of the undesired isomer, to obtain stereospecific final products.
Thus according to the present invention, there is provided a process of extracting a stereoisomer of a carbocyclic amine compound from a mixture containing two or more such stereoisomers, which comprises subjecting the mixture to reaction with an acylating agent in the presence of the enzyme
Pseudomonas cepacia
lipase to effect selective acylation of one said stereoisomer, whilst leaving other said stereoisomers substantially unchanged, and separating the selectively acylated carbocyclic amine stereoisomer from the reaction mixture.


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Chem Abstract Online 1995:182487, 1995.*
Ames, et al. J. Chem. Soc. (1965) 2636 The Synthesis of Alkoxy-1,2,3,4-tetrahydronaphthalene Derivatives.
Tschaen, et al. J. Org. Chem. (1995) 60, 4324-4330 Asymmetric Synthesis of MK-0499.
Sonesson, et al. J. Med. Chem. (1995) 38, 1319-1329.
Hilver, et al. J. Med. Chem. (1990) 33, 1541-1544.
McDermed, et al. J. Med. Chem. (1976) 19, 547 Synthesis and Dopaminergic Activity of (=)-, (+)-, and (−)-2-Dipropylamino-5-hydroxy-1,2,3,4-tetrahydronaphthalene1.
Bakthavachalam, et al. J. Med. Chem.(1991) 34, 3235 Florescent Probes for Dopamine Receptors.
Ye, et al. J. Med. Chem. (1989) 32, 478-486 Conformationally Restricted and Conformationally Defined Tyramine Analogues Inhibitors of Phenylethanolamine N-Methyltransferasela.
Devocelle, et al. Tetrahedron Letters (1999) 40, 4551-4554 Alternative synthesis of the chiral atypical &bgr;-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation.
Tillyer, et al. Tetrahedron Letters (1995) 36, No. 25, 4337-4340 Asymmetrric Reduction of Keto Oxime Ethers Using Oxazaborolidine Reagents. The Enantioselective Synthesis of Cyclic Amino Alcohols.
Gmeiner, et al. Tetrahedron Letters (1994) 50, No. 37, 10909-10922 Asymmetric Synthesis of &bgr;-Aminotetralins by Electrophilic Amination.
Charlton, et al. Can. J. Chem. (1990) 68, 2028-2032 An asymmetric synthesis of 2-amino-6, 7-dihydroxy-1,2,3,4-tetrahydronaphtalene (AD

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