RU2527454C1 - Method of producing l-proline ethylamide hydrochloride - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method includes suspending L-proline in pyridine, adding at 0-10°C and mixing dichlorodimethylsilane in molar ratio to L-proline of 1.1-1.2:1, subsequent mixing of the reaction mixture at room temperature, adding ethylamine to the reaction mixture while cooling to 0-7°C and mixing the mixture at room temperature, evaporating the reaction mixture in a vacuum, adding to the formed oil-like precipitate aqueous sodium carbonate solution to pH 7.8-8.0 and a mixture of diethyl ether with petroleum ether in ratio of 1:1, separating the aqueous layer, evaporating the residue in a vacuum, converting the formed L-proline ethylamide into a hydrochloride by treating with hydrochloric acid.

EFFECT: method enables to obtain the end product in a single step.

2 ex

Description

The invention relates to the production of chemical compounds, to the preparation of amino acid derivatives, and specifically relates to the production of proline derivatives, namely to the production of L-proline ethylamide hydrochloride, which is the starting material for the synthesis of biologically active peptides, and can be used in the pharmaceutical industry (pharmaceutical chemistry).

It is well known that proline (pyrrolidine-α-carboxylic acid) -heterocyclic amino acid exists in two optically isomeric forms - L and D, as well as in the form of a racemate; L-proline is one of the 20 proteinogenic amino acids. It is known that L-proline ethylamide is an important intermediate compound (intermediate) in the synthesis of some biologically active peptides, which are pharmaceutical substances, in particular, for the preparation of buserelin (CN 101735308, 2010 [1]; RU 2442791, 02.20.2012), leuprorelin ( WO 2007059921, 2007 [2]; RU 2043362, 09/10/1995) - synthetic analogues of gonadotropin releasing hormone (GnRH), as well as other peptide synthesis products.

It is known that the traditional synthesis of L-proline ethylamide is based on the formation of a protective group at the nitrogen atom of L-proline, subsequent amidation of the protected L-proline and deprotection. Thus, the process of obtaining the target compound includes 3 stages. As a protective group, benzyloxycarbonyl (Z) is usually used (SU 1028663, 07.15.1983; RU 2442791, 02.20.2012; Collect. Czech. Chem. Commun. V. 52, No. 12, p. 3034, 1987 (3) or tert - butyloxycarbonyl (Boc) (US 20080108632, 2008 (4); RU 2084458, 07.20.1997).

When using Z-protection [3], Z-L-proline is first prepared by the reaction of L-proline and benzyl chloroformate, which is then converted into ethyl Z-L-proline using ethyl chloroformate and ethylamine and finally released with a solution of hydrogen bromide in acetic acid to the target compound. In another embodiment, the release can be performed by hydrogenation of Z-L-proline ethylamide on a palladium catalyst (Pd-C) [5].

In the case of using Boc protection from L-proline and tert-butyl pyrocarbonate, Boc-L-proline is obtained [6], condensation of which with ethylamine leads to Boc-L-proline ethylide and further deprotection with a solution of hydrogen chloride in dioxane gives the target compound [4].

Thus, based on the known methods for the synthesis of L-proline ethylamide, a significant role in its preparation is played not only by the labor costs of a 3-stage synthesis, but also by the cost of reagents for setting up and removing protective groups.

The technical task of the present invention is to simplify the process of producing a proline derivative, L-proline ethylamide, by eliminating reagents for setting and removing protective groups, and also to develop an easily scalable method for producing L-proline ethylamide hydrochloride.

The stated technical problem and the technical result achieved are provided by a method for producing L-proline ethylamide hydrochloride, including suspending L-proline in pyridine, adding dichlorodimethylsilane at 0-10 ° C (1.1-1.2 in molar ratio to L-proline: 1) followed by stirring the reaction mixture at room temperature, introducing ethylamine into the reaction mixture while cooling to 0-7 ° C and stirring the mixture at room temperature, evaporating the reaction mixture in vacuo, adding oil to the resulting a precipitate of an aqueous solution of sodium carbonate to a pH of 7.8-8.0 and a mixture of diethyl ether and petroleum ether in the ratio of 1: 1, subsequent separation of the aqueous layer, evaporation of the residue in vacuo, conversion of the resulting L-proline ethylamide to the hydrochloride salt by adding to the obtained residue (when cooled to 5-10 ° C) of hydrochloric acid to a pH of 2.0-2.3, separation of inorganic salts with isopropyl alcohol, crystallization of it, filtration and drying in vacuo to isolate (obtain) the crystalline target product.

When implementing the inventive method using a 4.5-5.5% solution of sodium carbonate, added to achieve a pH of ~ 7.8-8.0; hydrochloric acid is used with a concentration of about 17% (16.5-17.5%), added to achieve a pH of 2.0-2.3.

So, the task is achieved by the claimed method, which consists in the fact that the cyclic unstable silicon-containing intermediate obtained from L-proline and dichlorodimethylsilane in pyridine is treated with ethylamine without isolation from the reaction mass, followed by the conversion of the resulting L-proline ethylide to the hydrochloride salt by treatment with hydrochloric acid:

Thus, the process of obtaining the target compound is reduced to one stage, while not using blocking and releasing reagents. In addition, it was shown that this method is easily scalable - the yield of L-proline ethylamide hydrochloride does not significantly change with increasing load of the starting reagents.

The purity of the obtained L-proline ethylamide hydrochloride was confirmed by HPLC and PMR spectroscopy. Analytical HPLC was performed on a Shimadzu chromatograph. Column: Grom-Sil 12J ODS-4HE, 5 μm, 250 · 4.6 mm. Conditions: gradient 20% B (0 min), 60% B (10 min), 70% B (15 min), 70% B (30 min). A — phosphate buffer pH 3 (20.4 g of KH ₂ PO _{4 was} dissolved in 3 L of distilled water and adjusted to pH 3 with concentrated phosphoric acid), B — acetonitrile. PMR spectra were obtained on a Bruker AM-360 instrument (operating frequency 360.13 MHz). The solvent used was DMSO-d ₆ , D ₂ O.

The described method is illustrated by the following examples.

experimental part

Example 1

8.2 g (0.071 mol) of L-proline are suspended in 32 ml of pyridine, cooled to -10 ° C and 10.6 g (0.081 mol) of dichlorodimethylsilane are added with stirring. Warm up to room temperature and stir the reaction mass for 1 h. Cool to 0 ° C and add at this temperature 12.9 g (0.286 mol) of ethylamine. The reaction mixture is allowed to warm to room temperature and stirred for another 1 hour. The reaction mixture is evaporated in vacuo (45 ° C, 2 mm Hg), a 5% aqueous solution of sodium carbonate is added to the oily residue to pH 8 and 50 ml of diethyl ether - petroleum ether (1: 1). The aqueous layer was separated and evaporated in vacuo (45 ° C, 2 mm Hg), 17% hydrochloric acid was added to the residue to pH 2 while cooling to 5-10 ° C and evaporated to dryness again in vacuo. The residue was dissolved in 20 ml of isopropyl alcohol, inorganic salts were filtered off and the solvent was removed in vacuo (45 ° C, 2 mmHg). The resulting oil is triturated until crystallization with diethyl ether (3 times 25 ml), filtered and dried in vacuo to constant weight (45 ° C, 2 mm Hg). 10.3 g (81%) of white crystalline L-proline ethylamide hydrochloride are obtained. The content of the main substance of 98.6% (HPLC). Mp 96-98 ° C. [Α] _D ²⁵ = -52.15 (5% solution, water). ¹ H NMR spectrum (d ₆ -DMSO, δ, ppm): 1.04 (t, 3Н, С Н ₃ ), 1.72-1.89 (m, 3Н, γ-С Н ₂ + 1H-β-С Н ₂ ) 2.23-2.35 (m, 1H, 1H-β-C H ₂ ), 3.08-3.24 (m, 4H, NC H ₂ + δ-C H ₂ ), 4.12 (t, 1H, α-C H ), 8.81 (s, 1H, CON H ).

Example 2

In a 10 L reactor with a mechanical stirrer, 1150 g (10 mol) of L-Proline was suspended in 4.4 L of pyridine, while maintaining a temperature of 0-10 ° C, 1484 g (11.4 mol) of dichlorodimethylsilane were added with stirring. Heated to 20-22 ° C and stirred the reaction mass for 1 h at this temperature. Again cooled to 0 ° C and at a temperature of 0-7 ° C) 1800 g (40 mol) of ethylamine are added. Stir the reaction mass for 30 minutes at 10 ° C and 1 hour at 20-22 ° C. The precipitate of ethylamine hydrochloride is filtered off, washed with 3 L of ethyl acetate on a filter. The combined liquid phases are evaporated in vacuo (45 ° C, 2 mm Hg), 3 L of a 5% aqueous solution of sodium carbonate (up to pH 8) and 4 L of a mixture of diethyl ether - petroleum ether (1: 1) are added to the oily residue. . The aqueous layer was separated, and the organic was further extracted with 0.7 L of water. The combined aqueous layers were evaporated in vacuo (45 ° C, 2 mm Hg), 2 L of 17% hydrochloric acid was added to the residue to pH 2 while cooling to 5-10 ° C and evaporated to dryness again in vacuo. The residue was dissolved in 3.5 L of isopropyl alcohol, inorganic salts were filtered off and the solvent was removed in vacuo (45 ° C, 2 mm Hg). The resulting oil is stirred until crystallization with diethyl ether (2 times 3 l), filtered and dried in vacuum to constant weight (45 ° C, 2 mm Hg). 1394 g (78.3%) of white crystalline L-proline ethylamide hydrochloride are obtained. The content of the main substance of 99.2% (HPLC). Mp 98-100 ° C. [Α] _D ²⁷ = -52.44 (5% solution, water). ¹ H NMR spectrum (d ₆ -DMSO, δ, ppm): 1.04 (t, 3Н, С Н ₃ ), 1.72-1.89 (m, 3Н, γ-С Н ₂ + 1H-β-С Н ₂ ), 2.23-2.35 (m, 1H, 1H-β-C H ₂ ), 3.08-3.24 (m, 4H, NC H ₂ + β-C H ₂ ), 4.12 (t, 1H, α-C H ), 8.81 (s, 1H, CON H ).

As can be seen from the above examples, the described method is simple, the absence of blocking and unlocking reagents and is suitable for obtaining the target product with high yield on a semi-industrial scale.

Literature

1. Chinese patent CN 101735308, Method for liquid-phase synthesis of buserelin, 2010.

2. International application WO 2007059921, Solution-phase synthesis of leuprolide and its intermediates, 2007.

3. Collect.Czech.Chem.Commun. V. 52, N12, p. 3034 (1987).

4. US patent US 20080108632, Preparation of peptides as HCV protease inhibitors, 2008.

5. Polish J. Chem. V.69, N5, p. 674 (1995).

6. Organic Lett. V.13, N2, p. 216 (2011).

Claims (1)

A method for producing L-proline ethylamide hydrochloride, including suspending L-proline in pyridine, adding dichlorodimethylsilane at a temperature of 0-10 ° C (1.1-1.2: 1 in molar ratio to L-proline), followed by stirring the reaction mixture at at room temperature, introducing ethylamine into the reaction mixture while cooling to 0-7 ° C and stirring the mixture at room temperature, evaporating the reaction mixture in vacuo, adding an aqueous solution of sodium carbonate to pH 7.8-8.0 and a diethyl mixture ether with ethereal ether in a ratio of 1: 1, subsequent separation of the aqueous layer, evaporation of the residue in vacuo, conversion of the resulting L-proline ethylamide to the hydrochloride salt by adding hydrochloric acid to a obtained residue (when cooled to 5-10 ° C) to a pH of 2.0- 2,3, the separation of inorganic salts with isopropyl alcohol, crystallization, filtration and drying in vacuum with the selection (receipt) of the crystalline target product.