SU753844A1 - Method of preparing n-acetyl-dl-valine - Google Patents

Description

The invention relates to an improved method for producing derivatives of amino acids and peptides widely used in chemistry, biology, medicine. 5

Various methods are known for producing N-acetyl-B1-valine from DL-valine.

A known method of producing N-acetyl-DL-valine by the interaction of DL-valine with acetic anhydride in the presence of sodium hydroxide in an aqueous solution at 0 ° C. The yield of the target product is not specified W ·

This method has been improved. N-anethyl-WB-valine was obtained with a yield of 80% and triple extraction with chloroform, an additional 12% of the target product was isolated from the filtrate ^ 2 ^ However, despite the high yield of cet—. left product, this method is not techno logical _Λ, a hook for release N-acetyl-DL-valine requires neutralization acid sodium ion, which is associated with the rapid evolution of heat, ie. e.

the need for strong cooling per 1 mol of the amino acid according to the procedure requires 7 mol of sodium hydroxide, thereby 7 mol of hydrochloric acid, the process takes a long time (the reaction mixture is held for about 12 hours) and three times extraction with chloroform is required for additional isolation of the target product.

There is also known a method for producing N-acetyl-1} L-valine, based on the use of acetic acid as the acetylating agent, by which DL-valine is boiled with acetic acid for 20 hours. The target product is obtained in 74% 1 "3] yield. Carrying out this reaction in the presence of a catalyst - diketene can significantly reduce the reaction time. The yield of the target product is 75.3% 14].

The most common is acetylation based method

- Acetic anhydride c. the presence of glacial acetic acid.

The method is as follows.

mol TC, α-valine and 1.9 mol of glacial acetic acid with stirring · heated to a boil. Having stopped heating, gradually add

1.5 mol of acetic anhydride, again heated to a boil and kept at this temperature (12 ° C) for 2 minutes. When the reaction mixture was cooled to 25 ° C, it was evaporated in vacuo at 40 ° C. The syrupy residue was treated several times with water and each time again evaporated in vacuo. The last time added benzene. A minimal amount of dry ethyl acetate is added to the syrupy residue and the solution is cooled. After exposure at 5 ° C for 18 h, the crystals are filtered and washed on the filter; dry diethyl ether until the yellow color of the precipitate disappears. The yield of the target product 80 ° ό ^ 5].

The disadvantages of this method are the relatively low yield of the target product due to the formation of by-products, mainly azlactone, and with losses during purification; the duration of the process due to the difficult isolation and purification of the target product; the use of toxic and flammable substances, such as benzene, ethyl acetate, diethyl ether.

The aim of the invention is to increase the yield of the target process.

Delivered in Famous

N-acetyl-Ώί. β-valine by acetylation of DL-valine with acetic anhydride in the presence of glacial acetic acid at the boiling point of the reaction mixture, acetic anhydride is introduced into the reaction mixture simultaneously with DL β-valine and glacial-acetic acid with a molar ratio of DL-valine: acetic anhydride: glacial acetic acid, equal to 1 : 1.5-1.6: 19-22.

Typically, the resulting mixture is gradually heated to boiling point. The target product is isolated by adding water in the reaction mixture and subsequent distillation of acetic acid.

The yield of the target product 99%; t. pl. 148.5-150 ° C.

Example 1. A mixture of Jurassic (0,086 mol) DL-valine, 103 ml (1,799 mol) of glacial acetic acid and 13 ml (0.137 mol) of acetic anhydride15 product and simplification, the goal is achieved by the method of obtaining readings with stirring heated to 120 C (13L— valine is completely dissolved) and maintained at this temperature for 25 minutes.

At the end of the exposure, the reaction mixture is cooled to 30-40 ° C, 8 ml of distilled water are added, and the solvent is distilled off to dryness in a vacuum created by a water-jet pump at a water bath temperature of not higher than 50 ° C. Dry in a vacuum desiccator over sodium hydroxide for 10 hours.

The yield of N-acetyl-DL-valine was 13.5 g (99.4%), mp 148.5-150.0 ° С.

Found,%: N 8.80.

c, H ₁₃ NO3.

Calculated,%; N 8.80.

PRI me R 2. A mixture of 10 g (0.086 mol) D) L-valine, 93.56 ml (1.634 mol) of glacial acetic acid and 12.19 ml (0.129 mol) of acetic anhydride are heated to 12 ° C with stirring Juice-valine is completely dissolved) and maintained at this temperature for 25 minutes. Further, as in example 1.

Yield N — acetyl — X) L-valine 13.44 g (99.0%), mp 148.5-150.5 ° C.

Found,%: N8.90.

Calculated,%: N 8.80.

Example 3. A mixture of 10 g (0.086 mol) of DL-valine, 104.18 ml (1.892 mol) of glacial acetic acid and 13 ml (0.137 mol) of acetic anhydride is heated to 120 ° C under stirring) and 25

Next, Exit

13.41 g (98.8%), mp 148.5150.5 ° C.

Found,%: N8.77.

c ₇ h ₁₃ no ₃ .

Calculated,%: N 8.80.

Chromatographic homogeneity is checked by chromatography on SitufoE UV-254 'plates in the system ethyl alcohol: ammonia (7: 3), by identifying a mixture of a 1% solution of KZ, 1% solution of KZO ^ and 1% starch solution (DL- Valine is fully solubilized at this tempemin.

as in example 1.

N-Acetyl-DL-Valine

P X / o — nui V with 0.74.

Claims (2)

The invention relates to an improved method for the preparation of derivatives: amino acids and peptides, widely used in chemistry, biology, medicine. Various methods are known for the preparation of N-acetyl-1) 1, -valine from DL -valine. A known method for the preparation of N-acetyl-b-valine by the interaction of TiL-uanine with acetic anhydride in the presence of sodium hydroxide in aqueous solution at. The yield of the target product is not specified 1. This method has been improved. N - acetyl-Bb-valine was obtained with a yield of 8O% and extraction with chloroform three times, an additional 12% of the desired product was isolated from the filtrate 2 However, despite the high yield of the desired product, this method is not technologically advanced, since for the isolation of N-acetyl -DL-valine requires neutralization of the sodium ion with acid, which is associated with rapid heat generation, i.e., the need for strong cooling of 1 mol of the amino acid by the method requires 7 mol of sodium hydroxide, and the process requires a long at Yemeni (; "a promotional mixture was incubated about 12 h) and to further isolate the desired product requires a threefold extraction with chloroform. There is also known a method for producing N-acetyl-DL-valine, based on the use of acetic acid as the targeting agent, which is boiled with acetic acid for 2 hours. The desired product is obtained in 74% yield. Carrying out this reaction in the presence of a catalyst, diketene, significantly reduces the reaction time. The yield of the target product is 75.3%. 4. The most common method is based on acetylation of 3 tsb-valine with acetic anhydride c. the presence of glacial acetic acid. The method is as follows. 1 -saline and 1.9 mol of glacial acetic acid are heated to boiling while stirring. After stopping the heating, Ij5 mol of acetic anhydride is constantly added to the foam, heated to boiling again and held at this temperature (12 ° C) for 2 minutes. When the reaction mixture is cooled to 2, it is evaporated in vacuo at 40 ° C. With a syrup, the residue is treated with water several times and each time it is again evaporated in vacuo. The last time benzene is added. A minimal amount of dry ethyl acetate is added to the syrupy residue, and the solution is cooled. After soaking for 18 hours, the crystals are filtered and washed on the filter with cyxifM with diethyl ether until the yellow color of the precipitate disappears. The yield of the target product 80% b. The disadvantages of this method are the relatively low yield of the target product in connection with the formation of by-products, mainly azlactone, and with the loss during cleaning; the duration of the process is due to the complex isolation and purification of the target product; the use of toxic and flammable substances, such as benzene, ethyl acetate, diethyl ether. The aim of the invention is to increase the yield of the target product and simplify the process. The goal is achieved by the fact that in a known method of producing N-acetyl-T) B-valine by acetylating DL-valine with acetic anhydride in the presence of glacial acetic acid at the boiling point of the reaction mixture, acetic anhydride is introduced into the reaction mixture simultaneously with DL -valine and ice with acetic acid at a molar ratio of DL-roller: acetic anhydride ID: ice on acetic acid, equal to 1: 1.5-1.6: 19-22. As a rule, the resulting mixture is gradually heated to boiling point. The desired product is isolated by adding water to the reaction mixture and then distilling off acetic acid. The yield of the target product is 99%; m.p. 148.5-15 ° C. : Example 1. A mixture of Ure (0.086 mol) DL-roller, 103 ml (1.799 mol) of glacial acetic acid and 13 ml (0.137 mol) of acetic anhydride, was heated to 12 ° C with stirring (TEN-valine completely dissolved) and incubated at this temperature 25 min. At the end of the exposure, the reaction mixture is cooled to ZO-4O C, 8 ml of distilled water is added and the solvent is distilled off to dryness in a vacuum created by a water-jet pump at a water bath temperature no higher than 5 ° C. Dry in a vacuum desiccator over sodium hydroxide for 10 hours. Output of N-acetyl-DL-valine 13.5 g (99.4%), mp, 148.5-15 O. Found,%: N 8.80. C, H ,, N03. Calculated,%: N8,80. PRI mme R 2. A mixture of 10 g (0.086 mol) Pb-valine, 93.56 ml (1.634 mol) of glacial acetic acid and 12.19 ml (0.129 mol) of acetic anhydride is heated to 12 ° C (t i-valine is completely dissolved) and is kept at this temperature for 25 minutes. Next, as in example 1. Output N-acetyl-Val-13.44 g (99.0%), so pl. 148.5-150 ,. Found,%: N8.90. , Calculated,%: N 8.80. EXAMPLE 3 A mixture of 10 g (0.086 mol) of DL-valine, 104.18 ml (1.892 mol) of glacial acetic acid and 13 ml (0.137 mol) of acetic anhydride is heated to 12 ° C with stirring (DL-valine completely dissolved) and kept at this temperature for 25 minutes. Further, as in example 1. Output of N-acetyl-TEN-valine 13.41 g (98.8%), mp., 148.5-: 150.5 ° C. Found,%: N8.77. . Calculated,%: N8,80. Chromatographic homogeneity. check, chromatography on the Situfpt UV-254 plates in the system ethyl alcohol: ammonia (7: 3), identifying a mixture of 1% KD solution, 1% KLO solution, and 1% starch solution with Rg 0, 74. DETAILED DESCRIPTION OF THE INVENTION The method of producing N-acetyl- 1) L-Ia by acetylating DL-valine with aceticus angiaride in the presence of glacial acetic acid at the boiling point of the reaction mixture, characterized in that, in order to increase the yield of the target product and simplify the process, acetic anhydride t in the reaction mixture simultaneously with DL-valine and glacial acetic acid at a molar ratio of DL-valine: acetic anhydride: ice to acetic acid, equal to 1: 1.5-1.6: 19-22, and the target product is isolated adding water to the reaction mixture and then guide distilling acetic acid. Sources of information taken into account in the examination  R-U.IA-, Amino acids.l.Ttie port-itioti of Qcetaminosacids taetween imtnisc4b .e soEvents, Bioc1ieni.3., I2, -i9i, 1939. 2. Over L R-, 3ngersote A.W.Tlie resolution about ominoQCids. I. PVien jEatanine and vaLine.O..C1iem-, Soc, l3j5363 195-13 .Be.6 f.A Reactions olqwinodcids. SN-iiVi aceiic acndi, a.Ctieni.Soc., P.2 .. 4. Luknitsky F. I. Synthesis and. Reaction of β-lactones, XU1. About kispotko-catapic function of 7b-lactones. Organic Chemistry, 1971, 7, №.-6, p. 1247. 5-Greevi5tein cl., (, C-herflistrv about om-inoocAd9,1962., T 4, v, 3, p. (Prototype).