Phthalimido group, amino protecting groups

Aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-l,4-dihydropyridine (amlodipine) was prepared from 2-(phthalimidoaminoethoxy)acetoacetate, 2-chlorobenzaldehyde and methyl-3-aminocrotonate under refluxing in ethanol for 24 hours. The ketoester was prepared by the method of Troostwijk and Kellog (JCS Chem. Comm., 1977, p.932). Methyl-3-aminocrotonate can be prepared by known method. Phthalimido-amino-protecting group was removed using hydrazine hydrate in ethanol at the reflux temperature. 

This triiodinated synthon has an amino functional group (A) that is potentially reactive with the chloride functional groups of the acid (B). The amino functional group is protected in the form of a phthalimido group. 

The additions of ammonia equivalents, i.e. nitrogen nucleophiles like dibenzylamine (Scheme 27) which are essentially a protected primary amino group, are of special synthetic interest with respect to their possible subsequent chemical transformations. Poorly nucleophilic ammonia equivalents like acetamide or the classical phthalimide, did not add or originally gave low yields of 92a (Scheme 28) [9],but later phthalimide was found to add to 1-Me very well under mild conditions [53]. However, the a-chlorine in 92a could neither be substituted nor could the phthalimido group be cleaved without destroying the cyclopropane ring. The potassium bis(alkoxycarbonyl)amides (Boc)2NK and (Moc)(Boc)NK add to 1-Me in satisfactory yields, but the a-chlorine atom in... 

Cleavage of phthaloyl protective group. The phthaloyl group is not useful for protection of the amino group of penicillins and cephalosporins because hydrazinolysis (Ing-Manske procedure, 1, 442) disrupts the azetidinone ring. Eli Lilly chemists have reported a new method of dephthaloylation that overcomes this difficulty. The phthalimido compound (1) is hydrolyzed by aqueous sodium sulfide to the corresponding phthalamic acid (2), which on dehydration... 

The reactions of phosphorous acid are paralleled still further by the additions of hypophosphorus acid to azomethines in practice, mixtures of amines and carbonyl reactants may be employed ", but the drawbacks to the procedure found for the synthesis of aminoalkylphosphonic acids may well apply here also. In a valuable publication, Dingwall and coworkers described the syntheses of (aminoalkyl)phosphinic acid analogues of many of the naturally occurring aminocarboxylic acids by the simple treatment of the benzyhydrylimine derivatives of the necessary amines with hypophosphorous acid, formed in situ when diphenylmethylammonium hypophosphite is treated with an appropriate aldehyde this step is followed by removal of the A -protection with 48% aqueous HBr, with 18% aqueous HCl or with trifluoroacetic acid in boiling methoxybenzene any second amino group was protected as the phthalimido derivative. 

A variation in this approach is the reduction of conjugated nitriles such as 1.159. which gave 2-ethyl-3-aminopropanoic acid (1.160) after hydrolysis of the cyano group to COOH and removal of the phthalimido protecting group. This route was also used to prepare 3-amino-2-methylpropanoic acid, in 65% yield. 

Penicilloic acid 5, the substrate for the projected lactamization reaction, could be derived from the suitably protected intermediate 6. Retrosynthetic disassembly of 6, in the manner illustrated, provides D-penicillamine hydrochloride (7) and tert-butyl phthalimido-malonaldehydate (8) as potential building blocks. In the synthetic direction, it is conceivable that the thiol and amino groupings in 7 could be induced to converge upon the electrophilic aldehyde carbonyl in 8 to give thiazolidine 6 after loss of a molecule of water. 

Primaquine Primaquine, 8-[(4-amino-l-methylbutyryl)amino]-6-methoxyquinoline (37.1.2.4), is made from 6-methoxy-8-nitroquinoline (37.1.2.1), which is synthesized in a Skraup reaction from 4-methoxy-2-nitroaniline and glycerol in the presence of sulfuric acid. The nitro group in this compound is reduced to make 6-methoxy-8-aminoquinoline (37.1.2.2). Alkylating the amino group with 4-bromo-l-phthalimidopentane gives 8-[(4-phthalimido-l-methylbutyryl)amino]-6-methoxyquinoline (37.1.2.3), the hydrazi-nolysis of which removes the phthalimide protection, giving primaqnine [28,29]. 

Glycal 18.23, the precursor of unit E, has an amino function protected by transformation to the phthalimido derivative (abbreviated to Pht). It is condensed with glycoside 18.22 in the presence of the complex PCIO4" (syffi-collidine)2 to give iodo disaccharide 18.24, which is reduced to compound 18.25 with triphenylstan-nane. On this compound, 18.25, the free hydroxyl group is activated by conversion to trifluoromethanesulfonate 18 Thus was prepared the AE fragment... 

The monoaminomonophosphonic acids, either in the free state or, very often, as their diethyl esters, have been resolved by the usual techniques of repeated crystallization of appropriate salts those of L-(+)-tartaric acid (2,3-dihydroxybutanedioic acid) or its mono-or di-benzoyl derivativesor of D-(-)-mandelic acid, have been widely employed the use of di-O-benzoylated L-tartaric anhydride, which is based on the separation of diastereoisomeric amides (111), has also been employed to a limited extent. In selected cases, such as the monoaminomonophosphonocarboxylic acids or A -acylated (aminoalkyl)phosphonic acids, resolution following salt formation with organic bases has also been carried out ephedrine, quinine and both enantiomers of l-phenylethylamine have all been used. In many cases, only one enantiomer of the (aminoalkyl)phosphonic acid (or diester) has been isolated in optically pure form. Sometimes, the acidity of the substrate, and hence choice of base for resolution, can be modified by using a mono- (as opposed to di-) ester or (or even in addition to) protection of the amino group as, for example, the phthalimido, benzyloxycarbonyl (cbz) or r r -butyloxycarbonyl (boc) derivative. Resolved di- and mono-esters can be hydrolysed to the free acids under acidic conditions, and A -protection can also be removed through the customary procedures. 

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