Synthesis of optically active aminoindanol

Details Synthesis of optically active aminoindanol Synthesis of optically active aminoindanol

1997-10-28

1999-02-16

Burn, Brian M.

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

Organic compounds

Amino nitrogen containing

564182, 564211, 564428, 560 28, C07C21302

Patent

active

058722963

DESCRIPTION:

BRIEF SUMMARY
(1S, 2R)-1-Aminoindan-2-ol (1) is an important intermediate for HIV 9355; 2) B. Kim et al., Tetrahedron Lett. 35 (1994) 5153; 3) D. Askin et al., Tetrahedron Lett. 35 (1994) 673; 4) B. Dorsey et al., J. Med. Chem. 37 (1994) 3443; 5) EP 617968; 6) S. Young et al., J. Med. Chem. 35 (1992) 1702; 7) W. Thompson et al., J. Med. Chem. 35 (1992) 1685; 8) D. Askin et al., J. Org. Chem. 57 (1992) 2771; 9) J. Huff, J. Med. Chem. 34 (1991) 2305; 10) T. Lyle et al., J. Med. Chem. 34 (1991) 1228!. ##STR2##
Various routes for synthesizing 1 have been described: racemic cis-1-aminoindan-2-ol can be prepared by isomerizing the corresponding et al., J. Am. Chem. Soc. 62 (1940) 3473; Lit. Ref. 7)!. The racemate resolution was carried out by chromatography of the diastereomeric Inc) at the "Chiral '94" Congress (Reston/Virginia, USA)!. These methods have the disadvantage that derivatives are needed for costly chromatography or elaborate recycling of the tartaric acid is required.
DE 4332738.9 describes a process for resolving the racemates of cis- and trans-1-aminoindan-2-ol by enzymatic acylation, with only trans-1-aminoindan-2-ol being acylated with sufficient enantioselectivity. The resulting amide can be used directly for isomerization. The disadvantages of this method are the lack of chemical and thermal stability and the high cost of the enzymes. "Chiral '94" Congress (Reston/Virginia, USA)! results in optically active indene epoxide (ee=86%), from which 1 can be obtained in a few stages. However, because the enantiomeric excess is insufficient, it is necessary in this case to enrich to ee>99.5%, which can be achieved by crystallizing the benzamide of trans-1-aminoindan-2-ol or of cis-1-aminoindan-2-ol tartrate. However, this process requires additional derivatization steps and recycling of the tartaric acid, and relatively large amounts of the epoxidation catalyst are needed.
Another possibility for preparing optically pure 1 was described by E. diastereo- and enantioselective reduction of 1-methoxycarbonylindan-2-one with baker's yeast. However, this synthesis has many stages and gives low yields.
It is an object of the present invention to find a novel, low-cost method for preparing enantiomerically pure (1S, 2R)-1-aminoindan-2-ol (1).
Racemate resolution by crystallization is still the most widely used method for preparing pure enantiomers. If suitable functional groups are present, the resolution is usually effected by crystallizing diastereomeric salts. However, in certain cases, direct crystallization of one enantiomer is possible. The prerequisite for this is that a compound is, in the solid state, in the form of a conglomerate, i.e. a 1:1 mixture of the two of optically active compounds", Dekker, 1993, page 173!. Direct crystallizations of this type are used, for example, in the preparation of
It is advantageous to resolve a racemate into the antipodes at the earliest possible stage of the synthesis in order to minimize the amount of superfluous ballast carried through the reaction sequence. With the exception of the multistage synthesis of Didier et al. (see above), all the other routes to 1 start from indene, which can easily be converted into trans-1-aminoindan-2-ol by epoxidation and opening of the epoxide with ammonia. To date (with the exception of the enzymatic process indicated in DE 4332738.9) no resolutions of racemates of trans-1-aminoindan-2-ol or derivatives thereof have been described.
We have now found, surprisingly, that the racemate resolution can be carried out at the stage of trans-1-aminoindan-2-ol by direct crystallization. For this purpose, the racemic amino alcohol 2 is converted with acids or acid derivatives of the general formula RCOX by 1985, vol. E5, pages 934 et seq.! into amides of type A. ##STR3##
The substituent R has the following meanings: hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl and phenyl, it being possible for these groups to carry one to three halogen atoms and/or one to three of the following radicals: cyano, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.

REFERENCES:
Jr. of Med. Chem. Bd. 35, N4. 10, (1992).
Jr. of American Chem. Soc., Bd. 73, (1951).
Tetrahedron, Bd. 47, N4. 27, (1991).

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