2- Amino-2-propylphosphonic acid

The rather low yields of the aminophosphonic acids can be fairly substantially improved over those reported by Kabachnik and Medved if anhydrons ammonia and the aldehyde are premixed in alcohol solution. Using this procedure, a few amino-substituted phosphonic acids are prepared a-aminobenzylphosphonic acid (benzaldehyde, dibutyl H-phosphonate, solution of dry ammonia in absolute ethyl alcohol) a-amino-propylphosphonic acid propionaldehyde, diethyl H-phosphonate, and a solntion of dry ammonia in absolute ethyl alcohol) p-methoxybenzyl-a-aminophosphonic acid (p-hydroxybenzaldehyde, diethyl H-phosphonate, and solution of dry ammonia in absolute ethyl alcohol). 

A series of addition reactions use the more nucleophilic cerium(III)5 " - or zinc(II) derivatives prepared in situ. Thus, ihe organozinc reagent derived from diethyl l-bromo-1,1-difluoromethylphosphonate reacts smoothly with cx-bromoacrylic acid in THF at room temperature in the presence of catalytic quantities of Cul to give the 1,4-addition product in 33% yield. After several transformations, this is converted into diethyl 3-(hydroxycarbonyl)-3-amino-l,l-difluoro-propylphosphonate, an analogue of phosphoserine (Scheme 3.84). °" ... 

An asymmetric synthesis of 2-amino-4-phosphonobutanoic acid has been developed from diethyl 3-oxo-4-(ethoxycarbonyl)propylphosphonate and L-( -nf/fro-(lS,27 )-l,2-diphenyl-2-hydrox-ylamine as chiral source. Formation of Schiff s base and acid-catalyzed transesterification are successfully performed in boiling n-BuOH. After reduction of the imino linkage with Al-Hg in moist DME, debenzylation [H2, PdiUll) 7( and hydrolysis with 4 M HCl, (7 )-(-)-2-amino-4-phosphonobutanoic acid is isolated in 66% yield and 67% ee. ... 

Chung and coworkers reported an efficient stereoselective synthesis of dual orexin receptor anatagonist MK-6096 (61) (Scheme 41) (14OL5890). The pyrimidine moiety was introduced via a Negishi coupling reaction of 2-chloropyrimidine with (2-cyano-4-methylphenyl)zinc(II) chloride. Subsequent hydrolysis with 12N HCl in acetonitrile furnished the required carboxylic acid, which was coupled with the hydrochloric acid salt of amino ether 62 via a 1-propylphosphonic-anhydride-catalyzed amidation. The overall yield of this synthesis was 37%. 

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