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CA-3154266-C - METHOD FOR PREPARING ARYL 2-TETRAZOL-2-YL KETONE WITH IMPROVED SELECTIVITY

CA3154266CCA 3154266 CCA3154266 CCA 3154266CCA-3154266-C

Abstract

The present disclosure relates to a method for preparing aryl 2-tetrazol-2-yl ketone of Formula la with improved selectivity: (see formula 1a).

Inventors

  • Kyu Woong Lee
  • KYUNG MI CHA
  • SU YEON YEOM
  • JI SEON WOO

Assignees

  • SK BIOPHARMACEUTICALS CO., LTD.

Dates

Publication Date
20260505
Application Date
20201023
Priority Date
20191024

Claims (20)

  1. 23 CLAIMS I. A method for preparing a compound of Formula la, comprising: [Formula la] 0 N::::=\ l~L~/ R1 ~ R2 reacting a compound of Formula 2 with a salt of a compound of Formula 3: [Formula2] [Formula 3] H N (' N ,,N -N wherein R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, pertluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; and X is a leaving group.
  2. 2. A method for preparing a compound of Formula la, comprising: [Formula la] 0 N::::=\ -dt,~~''t/N R1 ~ R2 reacting a compound of Formula 2 with a salt of a compound of Formula 3; and purifying the reaction product of the salt of the compound of Formula 3 and the compound of Formula 2, wherein the purifying step comprises a crystallizing process or a heat Date Re9ue/Date Received 2024-03-19 treatment process; [Formula2] [Formula 3] H rr N, N ,,N -N wherein 24 R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; and X is a leaving group.
  3. 3. The method according to claim 1 or 2, wherein the salt of the compound of Formula 3 is obtained by reacting the compound of Formula 3 with a base.
  4. 4. The method according to claim 3, wherein the salt is one or more selected from the group consisting of a lithium salt, a sodium salt, a potassium salt and a cesium salt.
  5. 5. The method according to claim 3, wherein the base is an inorganic base or an organic base.
  6. 6. The method according to claim 5, wherein the inorganic base is a metal hydroxide or a metal carbonate, and the organic base is an amine compound.
  7. 7. The method according to claim 6, wherein the metal hydroxide is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide; the metal carbonate is selected from lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; and the amine compound is selected from triethylamine and diisopropylethylamine. Date Re9ue/Date Received 2024-03-19
  8. 8. The method according to claim 3, wherein the compound of Formula 3 is reacted with a base in a reaction solvent, and then the salt of the compound of Formula 3 is separated from the reaction product of the compound of Formula 3 and the base.
  9. 9. The method according to claim 8, wherein the separated salt of the compound of Formula 3 is reacted with the compound of Formula 2.
  10. 10. The method according to claim 3, wherein after reacting the compound of Formula 3 with a base, the compound of Formula 2 is added to the reaction product to react with the salt of the compound of Formula 3.
  11. 11. The method according to claim 2, wherein the crystallizing process comprises a first crystallizing process and a second crystallizing process.
  12. 12. The method according to claim 11, wherein a solvent of the first crystallizing process is selected from the group consisting of water, C1-C4 lower alcohol, diethyl ether, tert-butyl methyl ether, isopropyl ether, pentane, hexane, cyclohexane, heptane and a mixture thereof.
  13. 13. The method according to claim 11, wherein a solvent of the second crystallizing process is selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C1-C4 lower alcohol and a mixture thereof.
  14. 14. The method according to claim 1 or 2, wherein the leaving group is selected from the group consisting of chloride, bromide, mesylate, tosylate and 4-nitrophenyl sulfonate.
  15. 15. The method according to claim 2, wherein the purifying step is a heat treatment process of the mixture comprising the compound of Formula la and the compound of Formula lb: [Formula la] 0 N:::::'\ d ~t~/ R1 ~ R2 Date Re9ue/Date Received 2024-03-19 26 [Formula lb] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalk:yl having I to 8 carbon atoms, alkyl having I to 8 carbon atoms, thioalkoxy having I to 8 carbon atoms, and alkoxy having I to 8 carbon atoms.
  16. 16. The method according to claim 2 or 15, wherein the heat treatment process is a step of transforming the compound of Formula lb to a compound of Formula 5: [Formula 5] wherein R1 and R2 are the same as defined in claim 15.
  17. 17. The method according to claim 2 or 15, wherein the heat treatment process is carried out in the presence of a solvent.
  18. 18. The method according to claim 17, wherein the solvent is acetone, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C1-C4 lower alcohol or a mixture thereof.
  19. 19. The method according to claim 2 or 15, wherein the heat treatment process is carried out at a pressure of I atmosphere to 50 atmosphere.
  20. 20. The method according to claim 2 or 15, wherein the heat treatment process is carried out at a reaction temperature of 100°c to 250°C. Date Re9ue/Date Received 2024-03-19 27

Description

Description Title of Invention: METHOD FOR PREPARING ARYL 2-TETRAZOL-2-YLKETONE WITH IMPROVED SELECTIVITY Technical Field The present disclosure relates to a method for preparing aryl 2-tetrazol-2-yl ketone of Formula la with improved selectivity: [Formula la] wherein R, and R2 are as defined herein. Background Art [6] Carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester (hereinafter also referred to as "carbamate compound") is useful in the treatment of CNS disorders, particularly anxiety. depression, convulsions, epilepsy, migraine, manic depression, drug abuse, smoking, attention deficit hyperactivity disorder (ADHD), obesity, sleep disorders, neuropathic pain, stroke, cognitive impairment, neurodegeneration, muscle spasm due to stroke and the like, according to its anticonvulsant effects. [7] The carbamate compound is prepared from a compound of Formula la, which is [8] [9] [10] CA 03154266 2022-4-8 obtained from a substitution reaction of a compound of Formula 2 and a compound of Formula 3, as an intermediate. Conventionally, a base is added to the compound of Formula 2, and a tetrazole solution is then added thereto to carry out a substitution reaction. However, in this case, the compound of Formula I b, which is a positional isomer thereof, in addition to the desired compound of Formula 1 a, is obtained together as a mixture by the substitution reaction (WO 2011/046380). [Formula 2] [Formula 3] 2 [11] [12] [13] [14] [15] [16] H rf N\ N .,.,N .... N [Formula I a] 0 N~ ¢ J--..1N R1 ::::::-.. R2 [Formula I b] (In the Formulas, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having I to 8 crubon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms and alkoxy having 1 to 8 carbon atomss; and X is a leaving group) [ 17] Furthermore, when the compound of Formula 2 and the compound of Formula 3 are subjected to the substitution reaction. the reaction selectivity of number 1 nitrogen of the compound of Formula 3 is better than the reaction selectivity of number 2 nitrogen, and thus the compound of Formula 1 b is produced with superior selectivity with respect to the compound of Formula la (Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999). (7). 1157-63; 1986). Therefore, according to the conventional method, the compound of Formula la used for preparing the carbamate compound is less produced than the compound of Formula lb, and thus the yield is low when preparing the carbamate compound by using the compound of Formula 2 and the compound of Formula 3 as starting materials. [18] In this regard, there is an alternative method for selectively preparing only a compound of the same form as substituted with number 2 nitrogen by synthesizing a tetrazole ring shape (Chem. Phann. Bull 30(9) 3450-3452; 1982). However, there may be problems in that it is difficult to be commercially used since a diazomethane-based material-which has a risk of explosion during the reaction-is used, and 2 equivalents or more of lithium diisopropylamide is used as a raw material. [ 19] As such, there is a need for developing a method that the ary 1 2-tetrazol-2-yl ketone CA 03154266 2022-4-8 of Formula la may be prepared from the compound of Formula 2 and the compound of Formula 3 with better selectivity than the aryl 2-tetrazol-1-yl ketone of Formula lb, 3 [20] and as a result, can be commercialized while obtaining the aryl 2-tetrazol-2-yl ketone of Formula la and the carbamate compound in high yield. Disclosure of Invention Technical Problem [21] The purpose of the present disclosure is to provide a commercially available method [22] [23] [24] [25] [26] [27] [28] [29] capable of improving the productivity of a carbamate compound by more selectively synthesizing aryl 2-tetrazol-2-yl ketone. which is useful as an intermediate of carbamate compound, in large scale. Solution to Problem One aspect of the present disclosure provides a method for preparing a compound of Formula la, which comprises a step of reacting a compound of Formula 2 with a salt of a compound of Formula 3: [Formula la] 0 N~ ¢ ~---..J'N R1 :::::::-... Rz [Formula 2] [Formula 3] wherein R1 and R2 are each independently selected from the group consisting of hydrogen. halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having I to 8 carbon atoms, and alkoxy having I to 8 carbon atoms; and Xis a leaving group. [30] Another aspect of the present disclosure provides a method for increasing the se- CA 03154266 2022-4-8 lectivity of a compound of Formula la by using a salt of a compound of Formula 3 in the synthesis of a compound of Formula la and a compound of Formula lb from a compound of Formula 2 and a compound of Formula 3: 4 [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] CA 03154266 2022-4-8 [Formula I b] [Formula 2] [Formula 3] wherein R1, R2 and X are the same as defined abov