Aminomethylation acetic acid

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

An important extension of these reactions is the Mannich reaction, in which aminomethyl-ation is achieved by the combination of formaldehyde, a secondary amine and acetic acid (Scheme 24). The intermediate immonium ion generated from formaldehyde, dimethyl-amine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethylthiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The use of A,iV-dimethyf (methylene) ammonium chloride (Me2N=CH2 CF) has been recommended for the iV,iV-dimethylaminomethylation of thiophenes (83S73). 

A solution of 60 g of chromic anhydride in 40 ml of water was added dropwise to a suspension of 60 g of 2-aminomethyl-1 -methyl-5-chloro-3-(o-fluorophenyl)-indole hydrochloride in 600 ml of acetic acid. The mixture was stirred at room temperature overnight. To the reaction mixture was added 1.1 liters of ether and 1 liter of water and then 800 ml of 28% ammonium hydroxide, in small portions. The ethereal layer separated, washed with water, dried, and concentrated under reduced pressure. The residue (51.8 g) was dissolved in 100 ml of ethanol, and 100 ml of 20% ethanollc hydrogen chloride was added to the solution and the mixture was cooled. The precipitate was collected by filtration to yield 46.5 g of 1 -methyl-7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one hydrochloride, melt-... 

Acid-catalyzed aminomethylations of 5W-dibenz[/>,/]azepine (5) in ethanolic solution with formaldehyde and a secondary amine yield the 2-(aminoalkyl) derivatives, e.g. 6.186 If acetic acid is used as the solvent, however, then 2,8-bis(aminoaIkylatiou), e.g. formation of 7, results. 

The tetramerization of suitable monopyrroles is one of the simplest and most effective approaches to prepare porphyrins (see Section 1.1.1.1.). This approach, which is best carried out with a-(hydroxymethyl)- or ot-(aminomethyl)pyrroles, can be designated as a biomimetic synthesis because nature also uses the x-(aminomethyl)pyrrole porphobilinogen to produce uroporphyrinogen III. the key intermediate in the biosynthesis of all kinds of naturally occurring porphyrins, hydroporphyrins and corrins. The only restriction of this tetramerization method is the fact that tnonopyrroles with different -substituents form a mixture of four constitutionally isomeric porphyrins named as porphyrins I, II, III, and IV. In the porphyrin biosynthesis starting from porphobilinogen, which has an acetic acid and a propionic acid side chain in the y6-positions, this tetramerization is enzymatically controlled so that only the type III constitutional isomer is formed. 

Khalfan, H., Abuknesha, R., Rand-Weaver, M., Price, R.G., and Robinson, D. (1986) Aminomethyl cou-marin acetic acid A new fluorescent labeling reagent for proteins. Histochem. /. 18, 497-499. 

Tolmetin Tohnetin, l-methyl-5-n-tolylpyrrol-2-acetic acid (3.2.61) is synthesized from 1-methylindole, which is aminomethylated using formaldehyde and dimethylamine, forming 2-dimethylaminomethyl-l-methylindol (3.2.57). The product is methylated by methyl iodide, giving the corresponding quaternary salt (3.2.58). Reaction of the product with sodium cyanide gives l-methylpyrrole-2-acetonitrile (3.2.59), which is acylated at the free... 

Molindone Molindone, 3-ethyl-6,7-dihydro-2-methyl-5-(morpholinomethyl)indol-4(5F0-one (6.4.3), is synthesized by the nitrozation of diethylketone using nitric acid or methyl-nitrite into nitrozodiethylketone (6.4.1). Reduction of this product with zinc in acetic acid into 2-aminodiethylketone in the presence of cyclohexandion-1,3 gives 3-ethyl-2-methyl-4,5,6,7-tetrahydroindol-4-one (6.4.2). Aminomethylation of this product using morpholine and formaldehyde gives molindone (6.4.3) [51-52]. 

The direct addition of nitromethane, in a mixture of anhydrous methanol and sodium methoxide, to 9-(3,5-0-isopropylidene-/ -D-fhreo-hexo-furanosyl-2-ulose)adenine (22) gave 9-(2-C-nitromethyl-/ -D-h/xo-hexo-furanosyl)adenine (94) in 75% yield.38 Reduction of 94 in 5 5 1 methanol-water-acetic acid in the presence of 10% palladium-on-charcoal, followed by N-acetylation of the resulting aminomethyl group, afforded, in 62% yield, 9-(2-C-acetamidomethyl-3,5-0-isopropyIidene-/ -D-h/xo-hexofuranosyl)adenine (95). 

Oxidation of 8-hydroxymethyl-2-isopropyl-l 1 //-pyrido[2,l-b]quinazolin-11-one with pyridinium chlorochromate in methylene chloride gave the 8-carboxaldehyde, which was converted into its 8-aminomethyl derivatives by reacting with amines followed by reduction of the Schiff bases with sodium cyanoborohydride in acetic acid (87JOC2469). 

The benzene ring has been proposed as an isosteric replacement in a dipeptide to enforce either the tram l1 1 or the cis conformation 312>31 (Scheme 1). Similarly, 2-(amino-methyl)pyrrole-l-acetic acid (8, R = H) has been proposed as a cis peptide bond mimic,141 having the same number of atoms between the amino and carboxylic acid functions as in a dipeptide. Several other amino- and carboxy-substituted aromatic structures have been used as spacers in peptides 2-, 3-, and 4-aminobenzoic acids (Abz, e.g., 7), 2-, 3-, and 4-(amino-methyl)benzoic acids (Amb, e.g., 2), 2-, 3-, and 4-(aminophenyl)acetic acids (APha, e.g., 5), 2- (4), 3-, and 4-(aminomethylphenyl)acetic acid (Ampa), (aminomethyl)pyrrole-, -thiophene-, and -furancarboxylic acids 6, (aminomethyl)pyrrole- 8 and -thienylacetic acids, and aminobiphenylcarboxylic acids. 

Scheme 20 Synthesis of 2 -(Aminomethyl)biphenyl-2-carboxylic Acid and -acetic Acid...

Aminomethyl)biphenyl-2-carboxylic acid (70) and -acetic acid (69) have been prepared from dibenzo-substituted oxepin-2-one 66 by potassium phthalimide ring opening. Further Arndt-Eistert homologation of 67 provided 68.[104]... 

The 5-(aminomethyl)thiophene-2-acetic acid isomer 76 was prepared by chloromethylation in position 2 of thiophene followed by nucleophilic displacement with phthalimide to afford 81, and a second chloromethylation in position 5 to give 82 (Scheme 23). Subsequent reaction with cyanide gave 83, the hydolysis of which afforded the phthalide-protected amino acid 84 which was coupled to H-Ala-Ile-Gly-OMe using propanephosphoric anhydride, followed by hydrazine N-deprotection)110 ... 

Scheme 23 Synthesis of 5-(Aminomethyl)thiophene-2-acetic Acid...

Scheme 25 Preparation of 2-(Aminomethyl)pyrrole-l-acetic Acid Derivatives1"2-1141...

Aminomethyl)phenyI]acetic Acid Bridged Peptides Single or Overlapping... 

Cundy, K. C., Annamalai, T., Bu, L., et al. XP13512 [( )-l-([(a-isobutanoyloxyethoxy) carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J. Pharmacol. Exp. Ther. 311 324-333, 2004. 

N-jS-Aminoethylethylenimine, 30, 39 d-Aminoethylsulfuric acid, 30, 38 l-(Aminomethyl)cyclohexanol, acetic acid salt, 34, 22... 

Debenzylation with hydrogen in the presence of Pd/C as a catalyst in acetic acid or alcohol/water produces N-hydroxycarbonylmethyl-aminomethyl)alkyl- and -arylphosphinic acids (3)... 

---