KR101011775B1 - Method for the preparation of 2-H-1,2,4-Benzothiadiazine 1,1-Dioxide via Cu and 1,10-phenanthroline catalyzed intramolecular C-N cross coupling - Google Patents

Abstract

The present invention relates to a method for synthesizing 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide via an intramolecular carbon-nitrogen cross-pairing reaction using a copper catalyst. More specifically, the 2-bromobenzenesulfonylamidine derivative of formula (1) was reacted at 50 to 100 ° C. by a carbon-nitrogen cross-coupling reaction under a copper catalyst and 1,10-phenanthrosine of formula (2). It is characterized by making the 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound represented by General formula (3).

......화학식(1)

Formula (1)

......화학식(2)

Formula (2)

......화학식(3)

Formula (3)

In formulas (1) and (3), R ¹ represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, silyl or heteroaryl containing one or more nitrogen, oxygen or sulfur atoms.

Alkyl, alkenyl, or alkynyl in the above substituent definition preferably contains 1 to 10 carbon atoms in the main chain, and cycloalkenyl preferably contains 3 to 7 carbon atoms and 1 cyclic double bond. Contains more than two. In addition, aryl preferably represents phenyl or naphthyl, and heteroaryl containing one or more nitrogen, oxygen or sulfur atoms preferably represents pyridyl, furanyl or thienyl. It may also include one or more additional functional groups selected from the group of acetyl, thiol, alkoxy, ester, fluoroalkyl and halogen in the main chain or ring of the formula (1).

Carbon-nitrogen cross-coupling reaction, 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide, 2-bromobenzenesulfonylamidine derivative, copper catalyst

Description

Method for preparing 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound through intramolecular carbon-nitrogen cross-coupling reaction using copper catalyst and 1,10-phenanthrosine ligand the preparation of 2-H-1,2,4-Benzothiadiazine 1,1-Dioxide via Cu and 1,10-phenanthroline catalyzed intramolecular CN cross coupling}

The present invention relates to a method for preparing a 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound through an intramolecular carbon-nitrogen cross-coupling reaction using a copper catalyst. 2-Bromobenzenesulfonylamidine derivative of 1) was reacted under a copper catalyst with 1,10-phenanthrosine of formula (2) and cesium carbonate to form 2-hydrogen-1,2,4 represented by formula (3). Provided is a method for preparing a benzothiadiazine 1,1-dioxide compound.

......화학식(1)

Formula (1)

......화학식(2)

Formula (2)

......화학식(3)

Formula (3)

In formulas (1) and (3), R ¹ represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, silyl or heteroaryl containing one or more nitrogen, oxygen or sulfur atoms.

Alkyl, alkenyl, or alkynyl in the above substituent definition preferably contains 1 to 10 carbon atoms in the main chain, and cycloalkenyl preferably contains 3 to 7 carbon atoms and 1 cyclic double bond. Contains more than two. In addition, aryl preferably represents phenyl or naphthyl, and heteroaryl containing one or more nitrogen, oxygen or sulfur atoms preferably represents pyridyl, furanyl or thienyl. It may also include one or more additional functional groups selected from the group of acetyl, thiol, alkoxy, ester, fluoroalkyl and halogen in the main chain or ring of the formula (1).

The 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound is an important and useful heterocyclic compound that is used as an antihypertensive and antimicrobial agent. ((A) Topliss, JG; Yudis, MD J. Med. Chem. 1972, 15 , 394-400. (B) Tait, A .; Luppi, A. Franchini, S .; Preziosi, E .; Parenti, C. Buccioni, M .; Marucci, G .; Leonardi, A .; Poggesi, E .; Brasili, L. Bioorg. Med. Chem. Lett. 2005, 15 , 1185-1188.) In addition, 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide 1-Butyl-3- (1,1-dioxido-2-hydrogen-1,2,4-benzothiadiazin-3yl) -4-hydroxy-2 (1-hydrogen) with substrate Quinolinone is known to be a potent inhibitor of RNA dependent RNA polymerase of hepatitis C virus. ((2) (a) Zhou, Y .; Webber, SE; Murphy, DE; Li, L.-S .; Dragovich, PS; Tran, CV; Sun, Z .; Ruebsam, F .; Shah, AM; Tsan, M .; Showalter, RE; Patel, R .; Li, B .; Zhao, Q .; Han, Q .; Hermann, T .; Kissinger, CR; LeBrun, L .; Sergeeva, MV; Kirkovsky, L Bioorg.Med.Chem.Lett . 2008, 18 , 1413-1418. (B) Tedesco, R .; Shaw, AN; Bambal, R .; Chai, D .; Concha, NO; Darcy, MG; Dhanak, D. ;; Fitch, DM; Gates, A .; Gerhardt, WG; Halegoua, DL; Han, chao .; Hofmann, GA; Johnston, VK; Kaura, AC; Liu, N .; Keenan, RM; Lin-Goerke, J Sarisky, RT; Wiggall, KJ; Zimmerman, MN; Duffy, KJ J. Med. Chem. 2006, 49 , 971-983.

Conventional methods for preparing 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compounds include reacting a suitable 2-aminobenzenesulfonamide with a highly reactive carboxylic acid derivative (( a) Imai, Y .; Mochizuki, A .; Kakimoto, M. Synthesis , 1983, 851. (b) Imai, Y .; Sato, S. Takasawa, R. Ueda, M. Synthesis , 1981, 35-36. N , N -dimethyl-2-nitrobenzenesulfonamide is reacted with a suitable nitrile. (Su, W. Cai, H. Yang, B. J. Chem. Res. 2004, 87-88) However, these methods require the use of a high temperature of 150 ° C. or the use of 6 equivalents of samarium. There is this.

The present invention relates to a method for preparing 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound through an intramolecular carbon-nitrogen cross-coupling reaction using a copper catalyst, which will be described later in more detail. The 2-bromobenzenesulfonylamidine derivative of formula (1) was reacted at 50 to 100 DEG C by a carbon-nitrogen cross-coupling reaction under a copper catalyst and 1,10-phenanthrosine of formula (2). Provided is a method for producing a 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound.

The present invention provides a method for synthesizing medically very useful 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide at a relatively mild temperature with the use of catalytic amounts of metal and exploring the possibility of various changes in its structure. It is to maximize the ability through.

The present invention relates to a 2-bromobenzenesulfonylamidine derivative of formula (1) described below by a carbon-nitrogen cross-coupling reaction under a copper catalyst and 1,10-phenanthrosine of formula (2). Provided is a method for producing the 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound represented by the formula (3).

The present invention provides a 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound represented by the following formula (3) through intramolecular carbon-nitrogen cross-coupling reaction under relatively mild reaction conditions. Obtained in yield.

The present invention provides a 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound through an intramolecular carbon-nitrogen cross-coupling reaction using a copper catalyst. A bromobenzenesulfonylamidine derivative is reacted under a copper catalyst with 1,10-phenanthrosine of formula (2) and cesium carbonate to form 2-hydrogen-1,2,4-benzothiadiazine represented by formula (3). 1,1-dioxide compounds can be prepared.

......화학식(1)

Formula (1)

......화학식(2)

Formula (2)

......화학식(3)

Formula (3)

In formulas (1) and (3), R ¹ represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, silyl or heteroaryl containing one or more nitrogen, oxygen or sulfur atoms.

Alkyl, alkenyl, or alkynyl in the above substituent definition preferably contains 1 to 10 carbon atoms in the main chain, and cycloalkenyl preferably contains 3 to 7 carbon atoms and 1 cyclic double bond. Contains more than two. In addition, aryl preferably represents phenyl or naphthyl, and heteroaryl containing one or more nitrogen, oxygen or sulfur atoms preferably represents pyridyl, furanyl or thienyl. It may also include one or more additional functional groups selected from the group of acetyl, thiol, alkoxy, ester, fluoroalkyl and halogen in the main chain or ring of the formula (1).

The preparation method of 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide through the intramolecular carbon-nitrogen cross-coupling reaction of the present invention can be simply represented by the following scheme (1).

Scheme (1)

10 to 30 moles of 1,10-phenanthroline (1,10-phenanthroline) of formula (2) relative to 100 mol% of 2-bromobenzenesulfonylamidine derivative of formula (1) in Scheme (1) %, Cesium carbonate (Cs ₂ CO ₃ ) 150 to 250 mol% can be used.

To 100 mol% of 2-bromobenzenesulfonylamidine derivatives of the formula (1) in the above scheme (1), 20 mol% of 1,10-phenanthrosine of the formula (2) and 200 mol% of cesium carbonate Can be used.

The copper catalyst in the present invention is a copper metal having an oxidation number of +1, preferably a salt with an anion, and can be represented by the formula (5).

CuY ...... (5)

In the formula (5), Y may be a halogen ion, a sulfate, a nitrate, a acetate, or a derivative thereof as an anion. The use of a copper halogen salt is more preferable in terms of reaction rate and yield, and copper iodide may be It is most effective to use.

In the present invention, the copper metal catalyst may be used in an amount of 1 to 20 mol% based on the 2-bromobenzenesulfonyl amidine derivative of Formula (1), more preferably 5 to 10 mol%. to be. Yield according to the catalyst usage confirmed by the experiment was shown to decrease for less than 1 mol% catalyst usage, and showed no improvement for more than 20 mol% catalyst usage. Therefore, the amount of copper catalyst used for effectively obtaining 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide as an object of the present invention is 2-bromobenzenesulfonylamidine derivative of Formula (1). 1-20 mol% is most preferable with respect to.

In the present invention, as the inorganic base, any one or more selected from the group consisting of potassium carbonate, potassium phosphate, and cesium carbonate may be used, but more preferably cesium carbonate is used to obtain a good yield of the final target.

In the present invention, the solvent may be used any organic solvent that does not adversely affect the reaction, more preferably dimethylformamide. The amount of the solvent may be used at a concentration of 0.01 to 1.0 M, preferably at a concentration of 0.1 to 0.5 M, based on the 2-bromobenzenesulfonylamidine derivative of Formula (1). If the reaction may not be stirred, and if too much at 1.0M concentration, the reaction is not completed or the yield is low, so the amount of solvent is 0.01 based on 2-bromobenzenesulfonylamidine derivative of formula (1). A concentration of ˜1.0 M is preferred. The reaction time is 12 to 24 hours, preferably 16 hours in order to prevent the problem of low yield, and since the improvement of the yield was not seen for the reaction time of 24 hours or more, 12 to 24 to obtain a more economically effective yield Time Preferably, the reaction time of 16 hours is good.

In the present invention, the reaction temperature is 50 to 100 ℃, more preferably about 80 ℃ is suitable when the temperature is lower than 50 ℃ is a slow reaction rate, when the temperature is higher than 100 ℃ is accompanied with various unnecessary reactions Reaction temperature is 50-100 degreeC, More preferably, about 80 degreeC is suitable.

The present invention is prepared by the above-mentioned method and includes the 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound represented by the formula (3).

Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are provided to help the understanding of the present invention, and the scope of the present invention is not limited thereto.

Example 1 3-benzyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide

Copper iodide (5.7 mg, 0.03 mmol), 1,10-phenanthrosine (10.8 mg, 0.06 mmol), cesium carbonate (195.5 mg, 0.6 mmol), N- (2-bromobenzenesulfonyl) in a 10 mL flask 2-phenylacetamidine (106.0 mg, 0.3 mmol) was added thereto, 4 mL of dimethylformamide was added as an organic solvent, and the reaction was stirred at 80 ° C. for 16 hours. After 16 hours, 4 mL of saturated sodium chloride solution and 4 mL of ethyl acetate were added thereto, and the organic layer was separated. The aqueous layer was washed twice with 4 mL of ethyl acetate and the organic layer was extracted. After dehydration with magnesium sulfate, the organic solvent was removed with a vacuum dryer, and the remaining reaction mixture was purified by recrystallization to give 3-benzyl-2-hydrogen-1,2,4-benzothiadiazine 1,1- as a pale yellow solid. Dioxide was obtained in 75% yield.

Yellowish solid; mp 213-214 ° C; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.2 (s, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.45-7.28 (m, 7H), 3.87 (s, 2 H); ^{13 C NMR (100 MHz, DMSO-} d 6) δ 158.5, 135.1, 135.0, 133.1, 129.0, 128.6, 127.1, 126.4, 123.4, 121.1, 117.5, 41.5; IR (KBr) v 3436, 3255, 1613, 1578, 1531, 1492, 1274, 1162, 767 cm ^-1 HRMS (FAB) m / z calcd. for C ₁₄ H ₁₃ O ₂ N ₂ S [ M + H ] ⁺ : 273.0698, found: 273.0695.

Example 2 3-pentyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide

Proceed in the same manner as in Example 1, but using N- (2-bromobenzenesulfonyl) hexaneamidine instead of N- (2-bromobenzenesulfonyl) -2-phenylacetamidine 3- Pentyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide was obtained in a yield of 86%.

white solid; mp 158-159 ° C .; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.9 (s, 1H), 7.77 (d, J = 7.3 Hz, 1H), 7.65 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 2.52 (t, J = 7.4 Hz, 2H), 1.70-1.63 (m, 2H), 1.32-1.30 (m, 4H), 0.87 ( d, J = 6.9 Hz, 3H); ^{13 C NMR (100 MHz, DMSO-} d 6) δ160.3, 135.1, 133.0, 126.1, 123.4, 121.2, 117.3, 35.2, 30.4, 25.7, 21.7, 13.8 IR (NaCl) ν 3274, 3184, 3126, 1611, 1582, 1534, 1288, 1154, 1134, 759 cm ^-1 HRMS (EI) m / z calcd. for C ₁₂ H ₁₆ O ₂ N ₂ S [ M ] ⁺ : 252.0932, found: 252.0936

Example 3 3-methyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide

Proceed in the same manner as in Example 1, but using N- (2-bromobenzenesulfonyl) -2-trimethylsilylacetamidine instead of N- (2-bromobenzenesulfonyl) -2-phenylacetamidine A pale yellow solid, 3-methyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide, was obtained in 72% yield.

yellowish solid; mp 254-255 ° C .; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.0 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 2.29 (s, 3H); ^{13 C NMR (100 MHz, DMSO-} d 6) δ 157.1, 135.1, 133.0, 126.1, 123.4, 121.0, 117.2, 22.6 IR (KBr) ν 3446, 3265, 3184, 3124, 1614, 1585, 1534, 1479, 1277 , 1159, 813, 763 cm ^-1 HRMS (EI) m / z calcd. for C ₈ H ₈ O ₂ N ₂ S [ M ] ⁺ : 196.0306, found: 196.0304.

As described above, although described with reference to a preferred embodiment of the present invention, those skilled in the art will be variously modified and modified within the scope of the present invention without departing from the spirit and scope of the invention described in the claims below. It will be appreciated that it can be changed.

The present invention provides a high yield of the 2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide compound represented by the formula (3) through intramolecular carbon-nitrogen cross-coupling reaction under relatively mild reaction conditions. As it can be obtained, there is industrial applicability.

Claims (15)

delete delete delete delete delete delete delete delete delete Copper iodide (5.7 mg, 0.03 mmol), 1,10-phenanthrosine (10.8 mg, 0.06 mmol), cesium carbonate (195.5 mg, 0.6 mmol), N- (2-bromobenzenesulfonyl) -2-phenyl Adding acetamidine (106.0 mg, 0.3 mmol), 4 mL of dimethylformamide as an organic solvent, and then stirring the reaction at 80 ° C. for 16 hours; After 16 hours, 4 mL of saturated sodium chloride solution and 4 mL of ethyl acetate were added, and then the organic layer was separated. The organic layer was washed twice with 4 mL of ethyl acetate. The organic layer was extracted. Is a second step of purifying through recrystallization; 3-benzyl-2-hydrogen-1,2,4-benzothiadiazine 1,1- via intramolecular carbon-nitrogen cross-pairing reaction, comprising Method for preparing the dioxide. The intramolecular carbon-nitrogen cross-coupling reaction according to claim 10, wherein the yield of 3-benzyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide is 75%. Method of preparing 3-benzyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide through. Copper iodide (5.7 mg, 0.03 mmol), 1,10-phenanthrosine (10.8 mg, 0.06 mmol), cesium carbonate (195.5 mg, 0.6 mmol), N- (2-bromobenzenesulfonyl) hexaneamidine ( 106.0 mg, 0.3 mmol), 4 mL of dimethylformamide is added to the organic solvent, and the first step of stirring the reaction at 80 ° C. for 16 hours; After 16 hours, 4 mL of saturated sodium chloride solution and 4 mL of ethyl acetate were added, and then the organic layer was separated. The organic layer was washed twice with 4 mL of ethyl acetate. The organic layer was extracted. Is a second step of purifying through recrystallization; 3-pentyl-2-hydrogen-1,2,4-benzothiadiazine 1,1- via intramolecular carbon-nitrogen cross-pairing reaction, comprising Method for preparing the dioxide. 13. The intramolecular carbon-nitrogen cross-coupling reaction according to claim 12, wherein the yield of 3-pentyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide is 86%. Method of preparing 3-pentyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide through. Copper iodide (5.7 mg, 0.03 mmol), 1,10-phenanthrosine (10.8 mg, 0.06 mmol), cesium carbonate (195.5 mg, 0.6 mmol), N- (2-bromobenzenesulfonyl) -2-trimethyl Adding silyl acetamidine (106.0 mg, 0.3 mmol) and adding 4 mL of dimethylformamide as an organic solvent, and then stirring the reaction at 80 ° C. for 16 hours; After 16 hours, 4 mL of saturated sodium chloride solution and 4 mL of ethyl acetate were added, and then the organic layer was separated. The organic layer was washed twice with 4 mL of ethyl acetate. The organic layer was extracted. Is a second step of purifying through recrystallization; 3-methyl-2-hydrogen-1,2,4-benzothiadiazine 1,1- via intramolecular carbon-nitrogen cross-pairing reaction, comprising Method for preparing the dioxide. 15. The intramolecular carbon-nitrogen cross-coupling reaction according to claim 14, wherein the yield of 3-methyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide is 72%. To prepare 3-methyl-2-hydrogen-1,2,4-benzothiadiazine 1,1-dioxide through.