Di-P-toluoyl- -tartaric acid

To prepare aprepitant in optically active form, this group reported a resolution-based scheme using di-p-toluoyl-tartaric acid (D-(+)-DPTTA) to afford the key morpholinone intermediate 36.24... 

Resolving Agent for Certain lypes of Amines. TAPA has also been used as resolving agent for some amines that formed either unstable, insoluble, or noncrystalline salts with common resolving acids. Compounds (3) and (4) were among those resolved with TAPA, whereas camphor-10-sulfonic acid, 3-bromo-8-camphorsulfonic acid, 0,0-di-p-toluoyl-(+)-tartaric acid, (+)-tartaric acid, and (+)-camphoric acid could not be used. ... 

Resolution with tartaric acid 3 required up to seven recrystallisations to get pure material and by that time the yield was only 8%. Di-p-toluoyl tartaric acid 49 (cf 9 used earlier) was spectacularly better when used in the right proportions (4 1 48 49). The solubility of the required diastereoisomer as the salt of one molecule of (+)-49 with two molecules of (+)-48 was very much less than that of (+)-49 with two molecules of (—)-48 so that merely mixing 48 and (+)-49 in the right proportions in ethanol at 60 °C for twenty minutes, cooling, and filtering off the crystals gave a 45% yield in >99% ee. Neutralisation with NaOH and extraction with f-BuOMe gave pure (+)-48. 

R,5,S)-l-Allyl-2,5-dimethylpiperazine has been prepared by direct enantiospecific synthesis [29,39] and via classical resolution of the racemic piperazine [23,29]. Kilo-scale batches of (-)-(2R,55)-l-allyl-2,5-dimethylpi-perazine have been prepared from tra s-2,5-dimethylpiperazine by the three-step monoallylation shown in Scheme 5, followed by a resolution using di-p-toluoyl-D-tartaric acid. This resolution has also been achieved in a two-stage process using (—)-camphoric acid followed by di-p-toluoyl-D-tartaric acid, giving (—)-(22 ,5S)-l-allyl-2,5-dimethylpiperazine in >99% optical purity. 

To a stirred solution of the Step 4 product (0.072 mol) in 150 ml EtOAc was added a solution of di-p-toluoyl-D-tartaric acid (0.041 mol) dissolved in 120 ml EtOAc and within 15 minutes, a colorless solid began precipitating out. The suspension was stirred 4 hours at ambient temperature and the solid isolated by filtration. It was washed with EtOAc, then dried in vacuo, and the product isolated in 37.6% yield as a colorless solid. 

Resolution of 6-(N-di-ii-propyl)aniiiiomethy 1-4,5,6,7-tetrahydrobenzo /i thiophene (36).To a solution of 4 g (15.9 mmol) free amine 36 in 60 mL of isopropyl acetate was added dropwise a solution of 6.4 g (15.9 mmol) of (+)-di-p-toluoyl-D-tartaric acid in isopropyl acetate (60 mL). The precipitate was collected and three times recrystallised from ethanol/diethyl ether to give 3.8 g (36.5 %) of the diastereomeric salt (mp 173-174 °C) [a] = + 114.5°. 

The filtrate of the salt formation and the filtrate of the first recrystallization were combined. After evaporation under vacuo and treatment of the residue with NaOH solution gave impure (-)-amine. This amine (2.0 g), 3.2 g (-)-di-p-toluoyl-L-tartaric acid and 400 mL of methanol was heated to solution. According to the procedure as described above, 1.3 g (28.4 %) of (-)-13.HCl was obtained with (mp 113-114 °C) [a] = - 62.5°. 

Dithiocyclohexane-2-thione, 441 Di-p-toluoyl-L-tartaric acid, 213 Di-(2,2,2-trichloroethyl)phosphoro-... 

The initial asymmetric synthesis (see Scheme 5.2) of pyrrolidine acid 3 suffered from a chiral HPLC bottleneck. As a result, chiral salt resolution was investigated. The rapid discovery of a crystalline di-p-toluoyl-D-tartaric acid salt provided the necessary means to resolve and purify the desired diastereomer. Using 0.65 equivalent of the acid in methyl (cr(-butyl ether (MTBE), the crystallized salt was shown to be a 92 8 ratio of (3S,4R) (3R,4S) diastereomers. The resolved tartaric acid salts were then recrystalhzed from n-butanol to ratios of >99 1 in a 42% overall yield on a 2-kg scale. Further improvements were made in the preparation of the azomethine ylide precursor 38. In step 1, using dimethyl sulfoxide (DMSO) as the solvent, the reaction temperature of trimethylsilylmethylation of tert-butylamine was lowered from 200°C used in the original synthesis to 80°C. In step 2, substituting n-butanol in place of methanol reduced the amount of oligomerization observed and increased the yield to 69%. Overall, these improvements allowed for the preparation of pyrrolidine acid 3 in 22% overall yield in 99% ee from cinnamate 39 (Scheme... 

Fractional distillation after synthesis of volatile amides or esters met with little success, due to low differences in boiling points (4-5 K or < 1 K) and laborious transformations. [7] An early distillation approach using different volatilities of diastereomeric salts of various amines with tartaric acid or its diben-zoyl- (also di-p-toluoyl-) derivatives yielded optical purities of the distillates from 5 to 47 % with a better performance in the case of methamphetamine (56.5-66.5 %). [8] However, probably due to the ban or restrictions with this drug (and most further drugs that might be misused) for use in scientific research by many countries, that publication did not find its due recognition. A further rea-... 

The diastereomers can be separated by crystallisation. While the marketed products contain the racemic mixture of (RJi)-and (S,S)-enantiomers, their separation may be possible using tartaric acid, its 0,0 -dibenzoyl or 0,0 -di-p-toluoyl derivatives, or mandelic acid. [114,115]... 

Bagi P, Kdllay M, Hessz D, Kubinyic M, Holczbauer T, Czugler M, Fogassy E, Keglevich G (2014) Resolution of l-n-propoxy-3-methyl-3-phospholene 1-oxide by diastereomeric complex formation using TADDOL derivatives and calcium salts of O, 0 -dibenzoyl-(2R,3R)-or O, 0 -di-P-toluoyl-(2R,3R)-tartaric acid. Tetrahedron Asymmetry 25 318-326... 

Treatment of 20 with dimethyl carbonate led to carbamate 21, which was reduced by hydrogenation over 5% Rh/C to afford the corresponding piperidine 22 as a 17 1 mixture of cis trans diastereomers. A reductive amination using benzaldehyde provided 23 as the hydrochloride salt. The carbamate was reduced with LAH and resolved with di-p-toluoyl-L-tartaric acid to provide the DPTTA salt of 14. 

The absolute configuration of natural l-( -f- )-laudanosine was determined by chemical correlation with l-( — )-iV-norlaudanosine (LXXVI) whose configuration was established by oxidative degradation. Resolution of racemic LXXVI with V-acetyl-L-Ieucine gave the levorotatory base [oil, bp 210° [a]j> —13.3° in EtOH —21° in CHCI3 B HCl, mp 167° [a]i) -f 38° in H2O]. From the mother liquors the enantiomer was obtained by using di-p-toluoyl-L-tartaric acid -1-13° —21°). 

Resolution of l- -propo5y-3-methyl-3-phospholene 1-oxide (754) using TADDOL derivatives (755) or Ca salts of 0,0 -dibenzoyl-(2R,3R)- (756a) or 0,0 -di-p-toluoyl-(2R,3)-tartaric acid (756b) has been developed (Scheme 212). Both antipodes of l-n-propo qr-3-phos-pholene 1-oxide (754) have been obtained with ee >96% by exploiting the different antipode preference of the TADDOL derivatives (755). The absolute configuration of the 3-phospholene oxide (754) enantiomers has been determined by CD spectroscopy, assisted by TD-DFT quantum chemical calculations. Moreover, it has been found that the solvent used for resolution had a significant effect on the efficiency of the resolutions. ... 

DTT 0,0 -di-p-toluoyl-D-tartaric acid FDA U.S. Food and Drug Administration... 

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