February 24, 2014
Here’s an improved method for synthesizing an antipsychotic drug. trans-1-[(1R,3S)-6-Chloro-3-phenylindan-1-yl]-3,3-dimethylpiperazine (9) is an antipsychotic drug that is used to treat schizophrenia and similar mental disorders. A. C. Dahl and co-inventors describe a process for preparing 9 in which the molecule’s chirality is introduced at an earlier stage in the synthesis than in the original method. The inventors also disclose that the undesired enantiomer can be racemized to improve the overall process efficiency.
The route to 9 (see Figure 1) begins with the preparation of compound 3 by treating starting materials 1 and 2 with ClCO2Me. Spontaneous ring closure forms indene 3, which is subjected to acid hydrolysis to make carboxylic acid 4. Heating 4 decarboxylates it to give 5 as a racemic mixture.
Unfortunately, the inventors give no experimental details for synthesizing rac-5 by this method, and there are no references to published methods. The racemate is resolved by using one of two chiral chromatography techniques. The first uses a mixture of n-heptane, EtOH, and Et2NH as the mobile phase over a chiral polymer phase on silica gel. The two enantiomers are obtained as solutions; each is recovered in >98% ee after the solvent is evaporated.
The second resolution method uses supercritical fluid chromatography (SFC) with a chiral polymer supported on silica gel. The supercritical fluid is CO2 combined with a solvent modifier (MeOH, EtOH, i-PrOH, or MeCN). The modifiers can be used with or without adding an amine such as Et2NH. SFC is carried out by using commercially available equipment at room temperature and a pressure of 100–200 bar. The procedure allows both enantiomers to be recovered in >99% ee after decompression and solvent removal.
Unwanted enantiomer (R)-5 can be racemized by treating it with strong base, initially with LiN-i-Pr2 (prepared in situ) and then with KO-t-Bu. The mixture is quenched with HCl; and after workup, the product has 2% ee. It also contains 6% of an impurity that the inventors did not identify but believe to be a dimer formed from rac-5 and one of its enantiomers. Formation of the impurity can be suppressed by controlling the racemization step and recrystallizing the racemate from EtOH or i-PrOH.
The inventors screened a range of bases and the manner in which they are used in the racemization. One or two bases may be used; when two are used, they may be added sequentially or simultaneously.
The inventors reduced pure enantiomer (S)-5 to alcohol (S,S)-58a with NaBH4 by using a method developed by W. F. Huffman and co-workers (see Figure 2). After recrystallization, the product is isolated in 90% yield and >99% ee. Alcohol (S,S)-6 is treated with SOCl2 to convert it to chloro compound (S,S)-7 in a cis/trans ratio of 77:23.The mixture is used directly to synthesize 9 by the reaction with 2,2-dimethylpiperazine (8) in the presence of K2CO3. The crude product is isolated as an oil with an 18:82 cis/trans ratio.
Crude 9 is initially purified by column chromatography to give an oil with a cis/trans ratio of 10:90. Treating this oil with maleic acid forms the maleate salt; it is isolated as a solid with >99% ee and no cis isomer. The yield from the crude oil product, however, appears to be only 17.5%.
The preparation of compound 8, shown in Figure 3, begins with the condensation of bromo ester 10 and diamine 11 in the presence of K2CO3. Product 12 is isolated in 52% yield and then reduced with LiAlH4 to give 8 in 72% yield after distillation. The preparation of >5 kg of 8 is described, whereas the examples of the other steps describe bench-scale experiments.
The inventors state that undesired enantiomer alcohol (R,R)-6 can be racemized by oxidizing it to ketone (S)-5 and then racemizing this compound with base as described above. The oxidant is pyridinium chlorochromate.
This process is an improvement over the original one because it gives high optical purity of the final product and recycles the undesired enantiomer to increase the overall process efficiency. But the poor recovery of 9 from the crude product is a drawback. (H. Lundbeck A/S [Valby, Denmark]. US Patent 8,569,499, Oct. 29, 2013; Keith Turner)