These are a brace of enantiomorphs and are diasymmetric every bit good as optically active. Since they promote optical rotary motion, these enantiomorphs are besides known as optical isomers. These chiral molecules consist of a tetrahedral C atom which is attached to four different groups. The C atom is the stereogenic or the asymmetric Centre of the molecule. The enantiomorphs are similar in their physical and chemical belongingss in an achiral environment.
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A process as claimed in claim 1, wherein the radical R is phenyl, phenylethyl, chloromethyl, methoxymethyl, methoxy, phenoxy or benzyloxy. A process as claimed in claim 1, in which ethers, alcohols, aromatic hydrocarbons or halogenated hydrocarbons are used as solvents.
Houpis et al. Kim et al. Askin et al. Dorsey et al. Young et al. Thompson et al. Huff, J. Lyle et al. STR2 Various routes for synthesizing 1 have been described: racemic cisaminoindanol can be prepared by isomerizing the corresponding trans compound which can be obtained in two stages from indene C.
Suter et al. The racemate resolution was carried out by chromatography of the diastereomeric phenylalaninamides and hydrolysis thereof to 1 Lit. These methods have the disadvantage that derivatives are needed for costly chromatography or elaborate recycling of the tartaric acid is required.
DE 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. Asymmetric epoxidation of indene P. 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. Didier et al. Tetrahedron Lett. 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 aminoindanol 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. Sheldon, "Chirotechnology, industrial synthesis of optically active compounds", Dekker, , page !. Direct crystallizations of this type are used, for example, in the preparation of chloramphenicol P. Amiard, Experientia 15 38! Reinhold et al. 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. To date with the exception of the enzymatic process indicated in DE We have now found, surprisingly, that the racemate resolution can be carried out at the stage of transaminoindanol by direct crystallization. For this purpose, the racemic amino alcohol 2 is converted with acids or acid derivatives of the general formula RCOX by conventional methods Houben-Weyl, Methoden der organischen Chemie, Thieme , vol. E5, pages et seq.!
For the racemate resolution, seed crystals of the appropriate enantiomerically pure amide are added to a supersaturated solution or a melt of a racemic amide A, which induces the formation of crystals which contain a large excess of the seed crystal enantiomer. The crystals are filtered off and can easily be obtained in enantiomerically pure form by recrystallization.
An amount of racemate A equivalent to the amount of crystals which has separated out is dissolved in the filtrate, which now contains an excess of the other enantiomer, by raising the temperature. The solution or melt is again supersaturated by cooling, and subsequently seed crysals of the other enantiomer are added, now making it possible for the latter to crystallize selectively.
Repetition of these steps dissolving the racemate in the filtrate, supersaturation and alternate crystallization of the two enantiomers by adding seed crystals makes complete racemate resolution possible. Only at the start is it necessary to obtain the seed crystals in an independent way, which is possible, for example, by the enzymatic racemate resolution described in DE Another possibility for direct crystallization of a conglomerate is to pump a supersaturated solution of the racemate through two parallel crystallization vessels which contain seed crystals of in each case one of the two enantiomers on filter plates.
Thus, part of one enantiomer crystallizes in one vessel, and part of the other crystallizes in the other vessel. The filtrates are combined and passed through a storage vessel which contains the conglomerate, where they are saturated again by heating.
The saturated solution is supersaturated by cooling and passed anew into the crystallization vessels, thus completing the circulation described by way of example in Chem. Suitable solvents are ethers such as tetrahydrofuran, dioxane, dimethoxyethane and diglycol dimethyl ether; C1 -C6 -alcohols such as methanol, ethanol, propanol, isopropanol, the isomeric butanols, the isomeric pentanols and hexanol; hydrocarbons such as toluene and xylene, and halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and chlorobenzene.
It is also possible to use mixtures of solvents. The process according to the invention can, however, also be carried out without using solvents in a crystal melt. Particularly preferred examples are the benzamide 3, the methoxyacetamide 4, the phenylpropionamide 5 and the chloroacetamide 6. STR4 1S, 2R Aminoindanol 1 is obtained from the 1S, 2S -amides obtained by crystallization by reaction with thionyl chloride and acid hydrolysis of the resulting oxazolines R. Lutz et al. Thus, no additional derivatizations are necessary.
It is possible and particularly advantageous to use the phenylpropionamide 5. The enantiomerically pure amide is converted by the above method with thionyl chloride into the corresponding oxazoline which is subjected to alkaline hydrolysis to give 1S, 2R phenyl-propionylaminohydroxyindane.
This compound is the stage following 1 in the synthesis of orally available HIV protease inhibitors Lit. The concentration of the supersaturated solutions depends on the solvent, the temperature and the relative ratio of the two enantiomers.
The crystals resulting from the above process are filtered off, washed with cold solvent and dried. The precipitate was filtered off with suction and washed with a little cold isopropanol.
Chirotechnology, 2nd Edition: Industrial Synthesis of Optically Active Compounds
Advanced topics in synthetic organic chemistry with a focus on regio-, chemo- and stereo-selectivity. History and purpose of synthesis. Milestones in structure elucidations and in organic synthesis. Stereoelectronic Effects; 2. Principles of stereochemistry.
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