Mandelate salt

Diethyl dl-1 -aminobenzylphosphonate has been prepared by a Mannich reaction of diethyl phosphite, benzaldehyde, and ammonia, resolved as its D-mandelate salt, and hydrolysed to give (+)-l-aminobenzylphosphonic acid.27 While the tetraethyl-diamide (33) reacts with benzaldehyde to give the expected phosphonic diamide (34), the corresponding tetramethyl-diamide reacts, with migration of the dimethyl-amino-group, to give (35).28... 

Gastric distress (nausea and vomiting) is one of the most frequently reported adverse reactions. Bladder irritation (e.g., dysuria, polyuria, hematuria, and urgency) may occur. The mandelic salt can crystallize in urine if there is inadequate urine flow and should not be given to patients with renal failure. Patients with preexisting hepatic insufficiency may develop acute hepatic failure due to the small quantities of ammonia formed during methenamine hydrolysis. 

Compound (6) contains 3 centers of dissymmetry, and its resolution into separated enantiomers could effected using ( )-mandelic acid [7]. The least soluble diastereomer was found to be the (-)-mandelate salt (m.p. 164.5-164.8°C). Formation of the hydrochloride salts of both enantiomers gave (-i-)-isoxsuprine HCl (m.p. 196-196°C) and (-)-isoxsuprine HCl (m.p. 195-196°C). The two asymmetric centers at C-1 and C-2 were correlated with those of the erythro (p-OH-C6H4-CH(OH)-CH(CH3)-NH-) residue. 

Enzymatic enantioselectivity in organic solvents can be markedly enhanced by temporarily enlarging the substrate via salt formation (Ke, 1999). In addition to its size, the stereochemistry of the counterion can greatly affect the enantioselectivity enhancement (Shin, 2000). In the Pseudomonas cepacia lipase-catalyzed propanolysis of phenylalanine methyl ester (Phe-OMe) in anhydrous acetonitrile, the E value of 5.8 doubled when the Phe-OMe/(S)-mandelate salt was used as a substrate instead of the free ester, and rose sevenfold with (K)-maridelic acid as a Briansted-Lewis acid. Similar effects were observed with other bulky, but not with petite, counterions. The greatest enhancement was afforded by 10-camphorsulfonic acid the E value increased to 18 2 for a salt with its K-enanliomer and jumped to 53 4 for the S. These effects, also observed in other solvents, were explained by means of structure-based molecular modeling of the lipase-bound transition states of the substrate enantiomers and their diastereomeric salts. 

It must also be remembered that different forms of the same compound will give different infra-red spectra. For example, the spectra for amphetamine base and the hydrochloride have many similarities, but the hydrochloride spectrum shows much finer detail (Figs 9A and 9B). Also the spectra for the hydrochloride and mandelate salts show differences (Figs 9B and 9C) due to the absorption of the mandelic acid. However, the spectra of the hydrochloride and sulphate (Figs. 9B and 9D) are very similar since they are both inorganic salts, the only major difference being the absorption band due to the sulphate at 1110 cm ... 

H. Lopez de Diego, Crystal structure of (S)-l-phenylethylatnmonium (K)-mandelate and a comparison of diastereomeric mandelate salts of l-phenylethylamine, Acta Chem. Scand. 48 (1994) 306-311. 

Preparative Methods the commercial glycine Wmethylamide hydrochloride is converted to the racemic imidazolidinone (2) by imine formation with Pivalaldehyde and cyclization under acidic conditions (eq 1). The mandelate salt of like configuration is less soluble and is used for highly efficient resolution subsequent treatment with Boc anhydride (Di-t-butyl Dicarbonate) gives the enantiomeric Boc-BMI (1) (eq 2). 

The free base 3a was further converted to the mandelate salt, a white crystalline product. The cyclobutyl analog 3b was similarly prepared from 8 and converted to the crystalline mandelate salt. The (S ) A-tetrahydrofurfuryl derivative 3c was prepared from (S) tetrahydrofurfuryl (1/f) camphor-10-sulfonate (10) as previously reported (Mertz et al., 1997). The 10-keto morphinans were prepared by the oxidation (Michne and Albertson, 1972) of the morphi-nan 7 with Cr03/H2S04 followed by alkylation with cyclopropyl methyl bromide and 0-demethylation to yield 4b (Scheme 1). O-Demethylation of 11 to form 13 followed by alkylation with (S) tetrahydrofurfuryl (I R) camphor-10 sulfonate (10), led to 4a. The assignment of the stereochemistry of 4a was based on the work of Merz and Stockhaus (1979). 

Heagy (1970) has developed a method by which three distinctive infrared spectra can be produced for d-, dl-, and /-amphetamine as the [Pg.413]

Since l-amino-2-cyclohexene is basic, a chiral acid is needed. When (+)-mandelic acid is the resolving agent used, a mixture of diastereomeric salts is formed as shown. These diastereomers have different physical properties and can therefore be separated (often by recrystaUization). Treatment with base neutralizes the amine and allows it to be separated from the charged mandelate salt (typically by extraction), to give the neutral amines as pure enantiomers. 

In fact, as shown in Figure 3, this approach has been employed in the synthesis of ABT-627. The coupling of ketoester 1 with nitrostyrene 2 was accomplished with a catalytic quantity of KOtAm. Product nitroketone 3 was reduced over Raney nickel to prepare cyclic imine 4, which was further reduced on addition of TFA to produce Ae cis-cis pyrrolidine 5 with good selectivity. Following epimerization with DBU, trans-trans pyrrolidine 6 was resolved with good efficiency as the mandelate salt. 

So, we were able to prepare selectively syn and anti trifluoromethyl amino alcohols. The next step was a search for a chiral approach to these compounds. Two approaches have been investigated to obtain chiral anti amino alcohols first we performed the reaction of epoxy ethers 3 with the chiral dimethylaluminum amide, prepared from the fi -phenethylamine and MeaAl (Scheme 5). From 3a, the reaction was effective leading, after reduction to the anti diastereoisomers 8a and 9a stereoselectively (Scheme 5). However, the chiral amine induced no selectivity anti amino alcohols 8a and 9a were obtained in a 50/50 mixture. Their separation was performed by crystallisation of the mandelate salts. Although this access to homochiral anti amino alcohols is somehow tedious, it is general since oxirane ring opening is efficient whatever the R substituent, and since epoxy ethers, substituted with various fluoroalkyl groups, are available. ... 

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