60668-24-8

Basic information

• Product Name: (S)-ALANYL-(R)-1-AMINOETHYLPHOSPHONIC ACID
• Synonyms: (S)-ALANYL-(R)-1-AMINOETHYLPHOSPHONIC ACID;L-ALANYL-L-1-AMINOETHYLPHOSPHONIC ACID;L-ALANYL-L-ALA(P)-OH;ALAFOSFALIN;ALAPHOSPHIN;L-ALANYL-L-ALA(P)-OH, (S)-ALANYL-(R)-1-AMINOETHYLPHOSPHONIC ACID;(S)-Alanyl-(R)-1-aminoethylphosphonic acid, Alafosfalin, Alaphosphin;[(1R)-1-[[(2S)-2-Aminopropanoyl]amino]ethyl]phosphonic acid
• CAS NO: 60668-24-8
• Molecular Formula: C₅H₁₃N₂O₄P
• Molecular Weight: 196.14
• EINECS: 262-362-8
• Mol File: 60668-24-8.mol
• Article Data: 12

Chemical Properties

• Melting Point: 295-296° (dec)
• Appearance: colorless or white/
• Density: 1.395g/cm³
• Refractive Index: 1.512
• Storage Temp.: 2-8°C
• PKA: 2.60±0.10(Predicted)
• Merck: 13,202
• BRN: 4801790
• CAS DataBase Reference: (S)-ALANYL-(R)-1-AMINOETHYLPHOSPHONIC ACID(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-ALANYL-(R)-1-AMINOETHYLPHOSPHONIC ACID(60668-24-8)
• EPA Substance Registry System: (S)-ALANYL-(R)-1-AMINOETHYLPHOSPHONIC ACID(60668-24-8)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• WGK Germany: 3
• Hazardous Substances Data: 60668-24-8(Hazardous Substances Data)

Usage

Originator

Alafosfalin ,Roche Product Limited

Uses

L-Alanyl-L-1-aminoethylphosphonic acid is an antibacterial agent.

Manufacturing Process

14.1 g (0.168 mol) of solid sodium bicarbonate were added to a solution of 7 g (0.056 mol) of (1R,S)-1-aminoethylphosphonic acid in 280 ml of water and 140 ml of ethanol while stirring at 0°C. While stirring this mixture at 0°C, a solution of 17.9 g (0.056 mol) of the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine in 140 ml of warm ethanol was added dropwise over ca 15 minutes. The latter solution was washed in with 70 ml of ethanol. The heterogeneous mixture was stirred for 1 hour at 0°C and then for a further 16 hours at room temperature, the mixture becoming homogeneous. The mixture was evaporated and re-evaporated with 200 ml of water to give a gum, which was dissolved in 500 ml of water. The solution was extracted firstly with 500 ml of chloroform and then with 250 ml portions of chloroform, acidified to pH 2 with ca 80 ml of 2 N hydrochloric acid and again extracted with 500 ml of chloroform followed by two 250 ml portions of chloroform. The aqueous layer was concentrated and passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 750 g; freshly regenerated in the acid cycle). The column was eluted with water and there were collected six 250 ml fractions. The first four fractions were combined, evaporated and re-evaporated with water to remove hydrogen chloride. There was obtained a final residue of (1R,S)-1-[(N-benzyloxycarbonyl-L-alanyl)- amino]ethylphosphonic acid which was separated as follows: The latter residue was dissolved in 400 ml of water and titrated with 1 M benzylamine to pH 4.5. The resulting solution was concentrated and crystallized from water to give 5.3 g of the benzylamine salt of (1S)-1-[(Nbenzyloxycarbonyl- L-alanyl)amino]ethylphosphonic acid of melting point 210- 215°C. Concentration of the mother liquors followed by further recrystallization from water gave the benzylamine salt of (1R)-1-[(Nbenzyloxycarbonyl- L-alanyl)amino]ethylphosphonic acid in a first crop of 0.59 g [melting point 226-228°C (decomposition); [α]D 20 = -32.3° (c = 1% in acetic acid)] and a second crop of 0.825 g] melting point 225-227°C (decomposition); [α]D 20 = -33.0° (c = 1% in acetic acid)]. Recrystallization of the first crop from water gave 0.333 g of pure benzylamine salt of the Rstereoisomer; melting point 226-228°C (decomposition); [α]D 20 = -33.1° (c=1% in acetic acid). 1.1 g (2.5 mmol) of the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-Lalanyl) amino]-ethylphosphonic acid were dissolved in 4 ml of 2 N ammonium hydroxide, passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 120 g; freshly regenerated in the acid cycle) and eluted with water. There were collected 200 ml of acid eluate, which was concentrated to 100 ml. To this were added 100 ml of methanol, 0.3 g of 5% palladium-on-charcoal catalyst and 3 drops of glacial acetic acid. The mixture was hydrogenated at room temperature and atmospheric pressure. The catalyst was filtered off and the solvent evaporated. The residual gum was reevaporated with three 50 ml portions of n-propanol to give 0.6 g of a gummy solid of melting point ca 275-280°C (decomposition). After further recrystallization from water and ethanol, there was obtained 0.2 g of (1R)-1- (L-alanylamino)-ethylphosphonic acid of melting point 295-296°C (decomposition); [α]D 20 = -44.0° (c=1% in water). The different ways of synthesis of alafosfalin were described: 1). 1R-1-(L-alanylamino)-ethanephosphonous acid (0.034 M), mercuric chloride (0.068 M) and water (175 ml) were mixed and heated to reflux for 1 hour The white insoluble mercuric chloride which formed was removed by filtration and the aqueous filtrate was evaporated to dryness. The oily residue was dissolved in ethanol (20 ml) and propylene oxide was added untilprecipitation was complete. Filtration gave 1R-1-(L-alanylamino)- ethylphosphonic acid, which was recrystallised from ethanol/water. MP: 293- 295°C, [α]D 20 =-49.3° (1%, H2O). Yield was 100% of theory. 2). Papain (50 mg; 2.2 U/mg) was added to the solution of 0.5 mmol Z-L-Ala, 1.15 mmol racemic diisopropyl ester of 1-aminoethylphosphonic acid and 50 ml 2-mercaptoethanol in the mixture of 2.3 ml acetonitrile and 0.2 ml water The suspension was shaken for about 2 days until all the Z-ala was consumed (TLC-control). The enzyme was filtered off and washed with 10% KHSO4, water, saturated NaHCO3, dried with anhydrous Na2SO4 and evaporated under reduced pressure. The resulting phosphonopeptide was dissolved in 2 ml of 40% HBr in glacial acetic acid and left overnight. Anhydrous ether (10 ml) was added and the mixture was stirred for 10 min and upper phase decanted. The residue was evaporated, the remaining gum was dissolved in 2 ml of methanol and treated with excess of propylene oxide. The precipitated material was filtered off and crystallized from water water-ethanol to give pure alafosfalin, yield 60%, MP: 273-276°C (decomposition); [α]D 20 =-45° (0.2% in water). Only L-aminophosthonate is involved in the peptide bond formation because of papain presence.

Therapeutic Function

Antibacterial

InChI:InChI=1/C5H13N2O4P/c1-3(6)5(8)7-4(2)12(9,10)11/h3-4H,6H2,1-2H3,(H,7,8)(H2,9,10,11)/t3-,4+/m0/s1

Upstream product

• 60668-26-0 1-R-1-[(N-benzyloxycarbonyl-L-alanyl)amino]ethanephosphonic acid 
• 7446-09-5 sulfur dioxide 
• 153413-60-6 tert-butyl ((S)-1-(((R)-1-(diethoxyphosphoryl)ethyl)amino)-1-oxopropan-2-yl)carbamate 
• 56-41-7 L-alanin 
• 60687-36-7 (R)-(1-aminoethyl)phosphonic acid 
• 73336-76-2 (R)-[1-N-(S-alanyl)aminoethylphosphinic acid] 
• 7487-94-7 mercury (II) chloride 
• 50-00-0 formaldehyd 
• 289658-75-9 Diethyl-N-(benzyloxycarbonyl)-L-alanyl-(2-decarboxy-DL-alanin-2-yl)phosphonat 
• 67739-69-9 [(R)-1-((S)-2-Benzyloxycarbonylamino-propionylamino)-ethyl]-phosphonic acid dimethyl ester 
• 423124-71-4 <1-(alanylamino)ethyl>phosphonic acid 
• 126306-90-9 [1-((S)-2-Benzyloxycarbonylamino-propionylamino)-ethyl]-phosphonic acid diisopropyl ester 
• 54788-36-2 diethyl N-benzyloxycarbonyl-D-alanyl-1-aminoethylphosphonate 

Relevant articles and documents

Use of the dehydrophos biosynthetic enzymes to prepare antimicrobial analogs of alaphosphin

The C-terminal domain of the dehydrophos biosynthetic enzyme DhpH (DhpH-C) catalyzes the condensation of Leu-tRNALeu with (R)-1-aminoethylphosphonate, the aminophosphonate analog of alanine called Ala(P). The product of this reaction, Leu-Ala(P), is a phosphonodipeptide, a class of compounds that have previously been investigated for use as clinical antibiotics. In this study, we show that DhpH-C is highly substrate tolerant and can condense various aminophosphonates (Gly(P), Ser(P), Val(P), 1-amino-propylphosphonate, and phenylglycine(P)) to Leu. Moreover, the enzyme is also tolerant with respect to the amino acid attached to tRNALeu. Using a mutant of leucyl tRNA synthetase that is deficient in its proofreading ability allowed the preparation of a series of aminoacyl-tRNALeu derivatives (Ile, Ala, Val, Met, norvaline, and norleucine). DhpH-C accepted these aminoacyl-tRNA derivatives and condensed the amino acid with l-Ala(P) to form the corresponding phosphonodipeptides. A subset of these peptides displayed antimicrobial activities demonstrating that the enzyme is a versatile biocatalyst for the preparation of antimicrobial peptides. We also investigated another enzyme from the dehydrophos biosynthetic pathway, the 2-oxoglutarate dependent enzyme DhpA. This enzyme oxidizes 2-hydroxyethylphosphonate to 1,2-dihydroxyethylphosphonate en route to l-Ala(P), but longer incubation results in overoxidation to 1-oxo-2-hydroxyethylphosphonate. This α-ketophosphonate was converted by the pyridoxal phosphate dependent enzyme DhpD into l-Ser(P). Thus, the dehydrophos biosynthetic enzymes can generate not only l-Ala(P) but also l-Ser(P).

Preparation and transmetallation of enantioenriched α- aminoorganostannanes derived from N-boc phenylglycinol: Application to the synthesis of alafosfalin

Enantioenriched tributylstannylated α-amino alcohols were synthesised by an improved procedure based on ring opening of 2- tributylstannyloxazolidines. Corresponding α-amino organolithiums were generated from O-silylated tributylstannylated α-amino alcoho

STEREOSELECTIVE PAPAIN-CATALYZED SYNTHESIS OF ALAFOSFALIN

Papain in powdered form efficiently catalyzes alafosfalin synthesis in miscible aqueous-organic solvent involving L-aminophosphonate in peptide bond formation.