ORGANIC AMINE SALT OF KEY INTERMEDIATE OF ELAGOLIX SODIUM AND PREPARATION METHOD THEREOF

Abstract

The present disclosure discloses a compound 1,1,3,3-tetramethylguanidine (R)-(tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dicarbonyl-3,6-dihydropyrimidine-1(2H)-yl)-1-phenylethyl) sulfamate (of structural formula I) and a preparation method thereof.

##STR00001##

Claims

1. A compound 1,1,3,3-tetramethylguanidine(R)-(tert-butoxycarbonyl) (2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dicarbonyl-3,6-dihydropyrimidine-1(2H)-yl)-1-phenylethyl) sulfamate with a structure of formula I: ##STR00010##

2. A method for preparing the compound 1,1,3,3-tetramethylguanidine(R)-(tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dicarbonyl-3,6-dihydropyrimidine-1(2H)-yl)-1-phenylethyl) sulfamate of claim 1, comprising the following steps: reacting 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione of formula II with tert-butyl (R)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide of formula III in an organic solvent in the presence of an alkali, wherein the alkali is 1,1,3,3-tetramethylguanidine, ##STR00011##

3. The method of claim 2, wherein the organic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide.

4. The method of claim 2, wherein the reacting is carried out at a temperature of 60° C. for 16 hours.

5. The method of claim 2, wherein the method further comprises: after the reaction, concentrating the resulting reaction solution to dryness, adding 2-methyltetrahydrofuran, and conducting a recrystallization, to obtain 1,1,3,3-tetramethylguanidine(R)-(tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dicarbonyl-3,6-dihydropyrimidine-1(2H)-yl)-1-phenylethyl) sulfamate.

6. A method for preparing Elagolix sodium, comprising the following steps: sequentially mixing 70 g of 1,1,3,3-tetramethylguanidine(R)-(tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dicarbonyl-3,6-dihydropyrimidine-1(2H)-yl)-1-phenylethyl) sulfamate of claim 1 with 385 mL of ethanol, 300 mL of water and 97 mL of concentrated hydrochloric acid, to obtain a mixture; stirring the mixture at 50° C. for 4 hours, adjusting the mixture to a pH value of 7-8 with sodium carbonate, and extracting and concentrating with isopropyl acetate, to obtain an oily matter; mixing the oily matter with 16 g of ethyl bromobutyrate, 20 g of potassium carbonate and 300 ml of DMF, heating the resulting mixture to 70° C. for 48 hours, and cooling to ambient temperature; adding 300 mL of NaOH at a concentration of 1N and stirring at ambient temperature for 3 hours, and extracting with isopropyl acetate to collect an aqueous phase; extracting the aqueous phase with methyl isobutyl ketone, to collect a methyl isobutyl ketone phase; and concentrating the methyl isobutyl ketone phase, to obtain the Elagolix sodium.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0014] The following examples and preparation examples are described to illustrate the present disclosure, but the present disclosure is not limited thereto.

[0015] The raw materials and devices used in the examples of the present disclosure are all known products, which were obtained by purchasing commercially available products.

Example 1

[0016] ##STR00008##

[0017] 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl pyrimidine-2,4(1H,3H)-dione (of structural formula II, 70.06 g, 1.0 equivalent), tert-butyl(R)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (of structural formula III, 54.06 g, 1.1 equivalents) and acetonitrile (350 mL) were added sequentially into a 2 L three-necked reaction flask, and were stirred at ambient temperature, and then 1,1,3,3-tetramethylguanidine (28.36 g, 1.5 equivalents) was added, and the resulting reaction system was heated to 60° C. for 16 hours. After TLC showed that the raw materials were completely converted, the reaction solution was concentrated to dryness, and 2-methyltetrahydrofuran (200 mL) was then added thereto, and the resulting mixture was subjected to a recrystallization, to obtain a product 1,1,3,3-tetramethylguanidine(R)-(tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dicarbonyl-3,6-dihydropyrimidine-1(2H)-yl)-1-phenylethyl) sulfamate (of structural formula I, 122.8 g, yield of 89%, off-white solid).

[0018] 1H-NMR (300 MHz, d.sub.6-DMSO) δ 7.77-7.14 (m, 11H), 7.00-6.93 (d, 1H), 5.76 (s, 1H), 5.51-5.39 (m, 1H), 5.27-5.14 (m, 1H), 5.08-4.87 (m, 1H), 4.39-4.24 (m, 1H), 3.85 (s, 3H), 2.88 (s, 12H), 2.06 (s, 3H), 1.10 (s, 9H).

[0019] LCMS (ESI) m/z, 645.6 (M+1).sup.+.

Example 2

[0020] ##STR00009##

[0021] 1,1,3,3-tetramethylguanidine(R)-(tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dicarbonyl-3,6-dihydropyrimidine-1(2H)-yl)-1-phenylethyl)sulfamate (of structural formula I, 70 g), ethanol (385 mL), water (300 mL) and concentrated hydrochloric acid (97 mL) were added sequentially into a 2 L reaction flask and stirred at 50° C. for 4 hours, and the resulting reactant was adjusted to a pH value of 7-8 with sodium carbonate, and extracted and concentrated with isopropyl acetate to obtain an oily matter. The oily matter was mixed with ethyl bromobutyrate (16 g) and potassium carbonate (20 g) and DMF (300 mL). Then the resulting mixture was heated to 70° C. for 48 hours. The reactant was cooled to ambient temperature, added with NaOH (1N, 300 mL) and stirred at ambient temperature for 3 hours, and then extracted with isopropyl acetate, and the resulting aqueous phase was extracted with methyl isobutyl ketone. The methyl isobutyl ketone phase was collected and concentrated to obtain the product Elagolix sodium (44.6 g, off-white solid, yield of 82.0%).

[0022] The above description is only preferred embodiments of the present disclosure. It should be pointed out that, for those of ordinary skill in the art, several improvements and modifications could be made without departing from the principle of the present disclosure. These improvements and modifications should also be considered as falling into the protection scope of the present disclosure.