Jan., 1951
COMMUNICATIONS TO THE EDITOR
501
pound, m.p. 105-113'. This substituted oxazole when methanol and ether was added until the solution was turbid. recrystallized from hot dilute alcohol was obtained as a white It was placed in the ice-box; crystallization occurred overflaky compound which melted a t 120-120.5' after drying night. Recrystallization was effected by dissolving the crystals in a minimum amount of absolute methanol and a t room temperature in vacuo for 2 hours. Anal.? Calcd. for CaHlNzOFa: C, 47.53; H, 2.49; N, adding pet;oleum ether. The product (930 mg.) melted 13.86. Found: C, 47.80, 47.80; H, 2.76, 2.53; N, 13.16, at 132-134 Anal. Calcd. for Cz2H2eOeNz: C, 63.75; H, 6.32. 13.35. Found: C, 63.42; H, 6.51. DEPARTMENT OF CHEMISTRY N-Carbobenzoxy-dl-alanyl-1-tyrosineamide.-One gram UNIVERSITY OF WISCOXSIN EDWINM. LARSEN MADISON,WISCONSIN GLENNA. TERRY of the ester was dissolved in 20 ml. of absolute methanol previously saturated with dry ammonia. After standing for RECEIVED JULY 20, 1950 one week in the refrigerator, the solvent was removed under reduced pressure. The residual oil crystallized on standing in a desiccator over sulfuric acid. The amide, recrystallized Some dl-Alanyl-1 -tyrosine Derivatives from aqueous methanol, 300 mg., melted a t 208-209" with N-Carbobenzoxy-dl-alanyl-1-tyrosineEthyl Ester.-Two decomposition. grams of N-carbobenzoxy-dl-alanine was suspended in 20 Anal. Calcd. for C2oH2305Na: C, 62.32; H, 6.01; N, ml. of dry ether in a two-neck flask fitted with a mercury- 11.18. Found: C,62.42; H, 6.58; N, 10.90. seal stirrer and a calcium chloride drying tube. To the N-Carbobenzoxy-dl-alanyl-1-tyrosinehydrazide.-To 100 chilled suspension was added with stirring, 2.1 g. of phosphorus pentachloride. After one-half hour the solution mg. of the ester, dissolved in about 1.0 ml. of absolute methwas filtered into an ice-cold solution of 1.99 g. of l-tyrosine anol there was added ten drops of 100% hydrazine hydrate. ethyl ester in 15 ml. of ethyl acetate. Saturated potassium The solution, after standing for two hours, became a crysbicarbonate, 20 ml., was added. After stirring for one-half talline mass. The precipitate was filtered, washed with icehour in the cold and one hour a t room temperature, the cold methanol and dried. The yield, 60 mg., melted at On recrystallizatip from absolute ethanol the solution was transferred to a separatory funnel and was 214-215 extracted with 1 N hydrochloric acid, half-saturated potas- melting point rose to 216-217 sium bicarbonate and aqueous sodium chloride. The Anal. Calcd. for C~oH240aNl: C, 59.99; H, 6.04; N, ether layer was dried over anhydrous sodium sulfate, fil- 14.01. Found: C, 59.57; H, 6.21; N, 13.46. tered and evaporated to dryness. The residue was disOF POLYMER RESEARCH solved in ethyl acetate and petroleum ether was added to INSTITUTE H. WERBIN INSTITUTE OF BROOKLYN an incipient turbidity. On cooling to -30" a precipitate POLYTECHNIC A. D. MCLAREN NEW YORK was obtained; it was filtered and placed in a desiccator BROOKLYN, RECEIVED JULY 21, 1950 overnight. The product was dissolved in warm absolute
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COMMUNICATIONS T O T H E EDITOR DIETHYL CHLOROPHOSPHITE AS A REAGENT FOR PEPTIDE SYNTHESES
Found: P, 9.86, 9.59.) Refluxing in toluene with carbobenzoxyglycine for one-half to two hours gave Sir: yields of 58 to 65% of carbobenzoxyglycyl-mThe general methods of peptide synthesis in use phenylalanine ethyl ester2 after recrystallization The phosphite involve lengthening the chain by the reaction of from ethanol-water, m.p. 88-90'. carboxy derivatives (halides, azides, anhydrides) derivative of glycylglycine ester reacted as an with an amino group. We have found diethyl undistilled oil with carbobenzoxyglycine to give chlorophosphite t o be a unique reagent in forming carbobenzoxydiglycylglycine ethyl ester,3 34% both reactive amides and anhydrides, thus allowing yield after recrystallization, m.p. 166-167'. Carbobenzoxyglycine anilide (m.p. 147-148') addition of aminoacid units to either end of a pepand carbobenzoxy-L-phenylalanine anilide (m.p. tide chain. The amides, (CzH60)zPNHCH(R)COOR', are 170'), [ a ] " ~- 5.4' (c, 3; chl~roform)~ were made oils, a t least some of which are distillable. They in good yields by the reaction of diethyl anilinoreact with carbobenzoxyaminoacids in inert sol- phosphite' with the acids. vents to form carbobenzoxypeptide esters. The Phosphate anhydrides of carbobenzoxy- and anhydrides, (CzH~0)2POCOCH(R)NHR', prepared phthalylglycine have been used for peptide synin inert anhydrous solvents, are conveniently these^.^^^ We have found that the anhydrides of treated in situ with aminoacid esters. In both re- diethyl phosphite are more conveniently prepared. actions, the by-product is presumably diethyl- These are readily obtained by the reaction of diethyl chlorophosphite with carbobenzoxy- or phthalylphosphite. Diethyl m-a-carbethoxy-P-phenylethylamino- aminoacids or peptides and triethylamine in solphosphite was obtained by the reaction of DL- vents such as toluene or dioxane. Following phenylalanine ethyl ester hydrochloride with di- filtration of triethylamine hydrochloride, the anethyl chlorophosphitel and two equivalents of hydride is treated in solution with an equivalent of triethylamine in absolute ether, filtering the tri- an aminoacid ester a t reflux for one to two hours; ethylamine hydrochloride and distilling ; yield (2) H. Neurath, et uZ., J . Biol. Chcm., 170, 222 (1947). (a) J. S. Fruton, e@., ibid., 178, 467 (1948). 48%, b.p. 148-151' at 0.25 mm., n%D 1.4908, (4) The possibility,of partial racemization is being investigated. d" 1.071 (Anal. Calcd. for CISHZ~NO~P: P, 9.88. (5) H. Chantrenne, Biochim. el Biophys. &tu, 4, 484 (1950). (1) H. G. Cook, ct al., J . Chcm. Soc., 2921 (1949).
(6) J, C. Sheehan and V. S. Frank, THISJOURNAL, 78, 1312 (1950).
