KR101006737B1 - Process for the preparation of 2-sulfonyliminoindoline using Cu catalyst - Google Patents

Abstract

The present invention relates to a method for preparing 2-sulfonyliminoindolin using a copper catalyst, and more particularly, an aminoacetylene compound of formula (1) and a sulfonyl azide compound of formula (2) in a solvent with a base compound and a copper catalyst. Reaction in the presence of the present invention relates to a method for preparing the 2-sulfonyliminoindolin compound of formula (3).

The present invention can prepare 2-sulfonyliminoindolin compound under moderate reaction conditions by reacting an aminoacetylene compound and a sulfonyl azide compound in the presence of a copper catalyst (CuX _n ) and a base compound. It can be provided as an intermediate.

Aminoacetylene, sulfonylazide, copper catalyst, 2-sulfonyliminoindolin

Description

Process for the preparation of 2-sulfonyliminoindoline using Cu catalyst

The present invention relates to a method for preparing 2-sulfonyliminoindolin using a copper catalyst. More specifically, the aminoacetylene compound and sulfonylazide compound are reacted in the solvent in the presence of a base compound and a copper catalyst to form 2-sulfonyliminoin. It relates to a method for producing a compound that has been turned.

Indoline compounds are one of the most important constituents of natural, highly active compounds and are often used as major intermediates in pharmaceutical manufacturing ((a) Southon, IW; Buchingham, DJ In Dictionary). of Alkaoids , Cordell, GA, Saxton, JE, Shmma, M., Eds .; Chapman and Hall; New York, 1989. (b) Chang, J .; Heieh, H .; Chang, C .; Hsu, K .; Chiang, Y .; Chen, C .; Kuo, C .; Liou, J. J. Med . Chem . 2006, 49 , 6656-6659.

Conventional methods for preparing conventional indolin compounds include radical amination reactions ((a) Viswanathan, R .; Prabhakaran, EN; Plotkin, MA; Johnston, JN J. Am. Chem. Soc. 2003, 125 , 163-168 (b) using Johnston, JN; Plotkin, MA; Viswanathan, R .; Prabhakaran, EN Org. Lett. 2001, 3 , 1009-1011.) It has a disadvantage.

In addition, a method for synthesizing indolin using a transition metal catalyst has been known in recent years, but this also has a disadvantage in that a range of reactor quality is not wide and expensive transition metal catalysts must be used ((a) Omar-Amrani, R .; Thomas, A Brenner, E. Schneider, R. Fort, Y. Org . Lett . 2003, 5 , 2311-2314. (B) Yang, BH; Buchwald, SL Org . Lett. 1999, 1 , 35-37. (c) Shintani, R .; Yamagami, T .; Hayashi, T. Org . Lett . 2006, 8 , 4799-4801. (d) Lira, R .; Wolfe, JP J. Am . Chem . Soc . 2004, 126 , 13906-13907.).

The present invention reacts an aminoacetylene compound of formula (1) with a sulfonylazide compound of formula (2) in a solvent in the presence of a base compound and a copper catalyst to prepare 2-sulfonyliminoindolin compound of formula (3) That's how.

The present inventors had the disadvantage of using an expensive transition metal catalyst limited by the dangerous reaction conditions and the reactor quality, which has been pointed out as a problem in the preparation of the conventional 2-sulfonyliminoindolin compound. However, the present invention is to eliminate these disadvantages and to synthesize the desired indole compound in a high yield using a cheap copper catalyst for the desired indole compound even under poor conditions.

The preparation of the 2-sulfonyliminoindolin compound of the present invention provides a method for preparing 2-sulfonyliminoindolin compound even under moderate reaction conditions by reacting an aminoacetylene compound and a sulfonyl azide compound in the presence of a copper catalyst and a base compound. do.

The present invention can prepare 2-sulfonyliminoindolin compound under moderate reaction conditions by reacting an aminoacetylene compound and a sulfonyl azide compound in the presence of a copper catalyst and a base compound, which can be provided as a major intermediate in the manufacture of pharmaceuticals. Can be.

A method for preparing 2-sulfonyliminoindolin of the present invention for achieving the above-mentioned object is to prepare an aminoacetylene compound of formula (1) and a sulfonyl azide compound of formula (2) in a solvent with a base compound and copper By reacting in the presence of a catalyst, 2-sulfonyliminoindolin compound of formula (3) may be prepared.

...... 화학식(1)

Chemical formula (1)

...... 화학식(2)

Chemical formula (2)

...... 화학식(3)

Chemical formula (3)

In Formulas (1) to (3), R ₁ is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, silyl, or heteroaryl containing any one or more selected from nitrogen, oxygen, and sulfur. In the formula (1), instead of the benzene skeleton, a heteroaryl or naphthalene derivative containing any one or more selected from nitrogen, oxygen, and sulfur may be selected,

R ₂ is alkyl, aryl, alkenyl, allyl, benzyl, or derivatives thereof,

R ₃ is any one selected from alkyl, aryl, or heteroaryl including nitrogen.

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.

On the other hand, the compound of formula (1), formula (2), formula (3) can be used in the main chain or ring substituted with at least one functional group selected from alcohol, thiol, alkoxy, ester, fluoroalkyl, halogen. have.

In the present invention, the method for preparing 2-sulfonyliminoindolin can be simply represented by the following Scheme (1).

Scheme (1)

The description of R ₁ , R ₂ and R ₃ in the above Reaction Scheme (1) is the same as mentioned in the above Formulas (1), (2) and (3).

In the present invention, the sulfonyl azide compound which is a reactant in the preparation of the 2-sulfonyliminoindolin compound may be used in an amount of 100 to 150 mol% based on 100 mol% of the aminoacetylene compound.

According to the present invention, various reaction conditions were applied to the aminoacetylene compound and the sulfonylazide compound, which are reactants in the preparation of the 2-sulfonyliminoindolin compound, to prepare 2-sulfonyliminoindolin compound according to the object of the present invention. For this reason, the sulfonyl azide compound may be added to 100 mol% to 150 mol% with respect to 100 mol% of the acetylene compound.

Copper used as a catalyst in the present invention can be used both the oxidation number +1 or +2, a copper compound of the formula (4) can be used.

CuXn ...... (4)

In the formula (4), n represents 1 or 2, and X may use halogen ions, sulfates, nitrates, acetates, or derivatives thereof as anions, and copper halide salts are more preferable in terms of reaction rate and yield. In the above, the halogen ion represents any one selected from fluorine ion, chlorine ion, bromine ion, iodine ion and asstatin ion.

Sulfonate, trifluorosulfonate, sulfate pentahydrate, nitrate derivatives, nitrate hydrates, nitrate trihydrates, trifluoroacetates, and trifluoroacetates as the sulfate derivatives represented by the above formula (4) Any one or more selected from the group of acetonate and acetylacetonate can be used.

In the present invention, the copper catalyst is preferably used in an amount of 1 to 30 mol%, more preferably 10 to 20 mol%, based on 100 mol% of the acetylene compound.

In the present invention, in the preparation of the 2-sulfonyliminoindolin compound, the aminoacetylene compound, the sulfonyl azide compound, and the base compound are fixed to a constant content, and the 2-sulfonyliminoindolin compound according to the change of the copper catalyst content is fixed. As a result of measuring the yield, when the content of the copper catalyst is less than 1 mol% with respect to 100 mol% of the acetylene compound, the yield of the 2-sulfonyliminoindolin compound is very low, and the content of the copper catalyst is 20 with respect to 100 mol% of the acetylene compound. When it exceeds mol%, the yield of 2-sulfonyliminoindolin compound is almost constant. Therefore, it is preferable to use 1-20 mol% of copper catalysts with respect to 100 mol% of an acetylene compound in this invention.

In the present invention, the base compound not only activates the copper catalyst when preparing 2-sulfonyliminoindolin compound but also serves to promote the reaction between reactants. In the present invention, a tertiary amine compound may be used as the base compound. One example of a tertiary amine compound in said triethyl amine (triethylamine), trioctyl amine (trioctylamine) N, N - dimethyl isopropyl amine (N, N -dimethylisopropylamine), 2,6- lutidine (2,6-Lutidine ), N - methyl morpholine (N -methylmorpholine), 2,2,6,6- tetramethyl piperidine (2,2,6,6-tetramethylpiperidine), pyridine (pyridine) and at least one selected from the derivatives Can be used.

In preparing the 2-sulfonyliminoindolin compound of the present invention, the base compound may be added in an amount of 100 to 120 mol% based on 100 mol% of the aminoacetylene compound.

In the preparation of the 2-sulfonyliminoindolin compound of the present invention, the content of the aminoacetylene compound and the sulfonyl azide compound and the copper catalyst, which are reactants, is fixed at a constant level, and 2,6-lutidine, which is one of the tertiary amine compounds, is used as a base compound. The yield of 2-sulfonyliminoindolin compound is 0% and the yield of 2-sulfonyliminoindolin compound when 0 mol% is used for 100 mol% of the acetylene compound (without base compound), respectively. Silver represents 91%, indicating that the base compound is essential when preparing the 2-sulfonyliminoindolin compound of the present invention, and it is preferable to use a tertiary amine compound of 100 to 120 mol% with respect to 100 mol% of the aminoacetylene compound. Can be.

When preparing 2-sulfonyliminoindolin of the present invention, the aminoacetylene compound and the sulfonyl azide compound are reacted in the solvent in the presence of a copper catalyst and a base compound, wherein the solvent is a reaction of the reactant according to the preparation of the 2-sulfonyliminoindolin compound. Any organic solvent can be used that does not adversely affect it. In the present invention, any one selected from tetrahydrofuran, chloroform, acetonitrile, dimethylformamide, 1,4-dioxin, and methylene chloride may be used as an example of such a solvent.

When the amount of the solvent in the preparation of 2-sulfonyliminoindolin of the present invention is too small, it may not be stirred during the reaction, and if too much, the reaction is not completed or the yield is low. In the preparation of 2-sulfonyliminoindolin of the present invention, the content of the solvent is such that the molar concentration (M) of the aminoacetylene compound as one of the reactants is 0.01 to 1.0, more preferably the molar concentration (M) of the aminoacetylene compound. ) Can be used in an amount such that 0.1 to 0.5.

In the preparation of 2-sulfonyliminoindolin of the present invention, when a base compound is added to a heterogeneous organic solution containing an aminoacetylene compound, a sulfonyl azide compound, and a copper catalyst while stirring, a nitrogen molecule is produced and a homogeneous solution is produced. May be carried out at 0 to 50 ° C. for 6 to 12 hours. After the reaction, the organic solution may be washed with a saturated ammonium chloride solution and depressurized to remove the organic solvent, and then the remaining reactant may be purified to obtain 2-sulfonyliminoindolin compound.

Under the above reaction conditions, the reaction time is significantly increased when the reaction temperature is less than 0 ° C. or more than 50 ° C., resulting in a poor yield of the 2-sulfonyliminoindolin compound. In addition, since the pyrolysis reaction of the sulfonyl azide compound proceeds too fast at 50 ° C., there is a risk of explosion because nitrogen molecules are rapidly generated. In addition, when the reaction time is less than 6 hours, there is a problem that the reaction is not terminated. When the reaction time is more than 12 hours, there is no obvious effect on the yield of the product according to the increase of the reaction time. 12 hours is recommended.

Hereinafter, the content of the present invention will be described in detail through examples. However, these are intended to explain the present invention in more detail, and the scope of the present invention is not limited thereto.

Example 1 Synthesis of 1-phenyl-2- (p-methylbenzenesulfonylimino) indolin

Copper iodide (19.0 mg, 0.1 mmol), 2-ethynyl- N -phenylaniline (96.6 mg, 0.5 mmol), p-toluenesulfonyl azide (120 mg, 0.6 mmol) was added to a 10 mL flask, and chloroform was used as an organic solvent. After adding (1 mL), the mixture was stirred, 2,6-lutidine (70 μl, 0.6 mmol) was added thereto, and the resulting nitrogen molecules were released while stirring for 12 hours.

After 12 hours, 4 mL of saturated ammonium chloride solution and 4 mL of dichloromethane were added thereto, and then the mixture of the two layers was stirred for an additional 30 minutes. Take the organic layer, dehydrate with magnesium sulfate, remove the organic solvent with a reduced pressure drier, and purify the remaining reaction mixture by silica gel column chromatography to give the tan solid benzyl 1-phenyl-2- (p-methylbenzenesulfonylimino) indole. Lean was obtained in 84% yield.

mp 146-148 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.75 (d, J = 8.3 Hz, 2H), 7.49-7.32 (m, 6H), 7.32-7.20 (m, 3H), 7.11 (t, J = 7.3 Hz, 1H ), 6.73 (d, J = 7.9 Hz, 1H), 4.42 (s, 2H), 2.37 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 169. 6, 144.6, 142.7, 139.3, 134.4, 129.6, 129.2, 128.8, 127.9, 127.1, 126.5, 126.1, 124.6, 123.9, 110.4, 36.4, 21.5; IR (KBr) n 1599, 1555, 1500, 1373, 1301, 1145, 1087, 788 cm ⁻¹ ; HRMS (EI) m / z calcd. for C ₂₁ H ₁₈ N ₂ O ₂ S [ M ] ⁺ : 362.1089, found: 362.1092.

Example 2 Synthesis of 1-benzyl-2- (p-methylbenzenesulfonylimino) indolin

Copper iodide (19.0 mg, 0.1 mmol), N -benzyl-2-ethynylaniline (103.6 mg, 0.5 mmol), p-toluenesulfonyl azide (120 mg, 0.6 mmol) was added to a 10 mL flask, and chloroform was used as an organic solvent. After adding (1 mL), the mixture was stirred, 2,6-lutidine (70 μl, 0.6 mmol) was added thereto, and the resulting nitrogen molecules were released while stirring for 12 hours.

After 12 hours, 4 mL of saturated ammonium chloride solution and 4 mL of dichloromethane were added thereto, and then the mixture of the two layers was stirred for an additional 30 minutes. Take the organic layer, dehydrate with magnesium sulfate, remove the organic solvent with a reduced pressure drier, and purify the remaining reaction mixture by silica gel column chromatography to give benzyl 1-benzyl-2- (p-methylbenzenesulfonylimino) indole as a tan solid. Lean was obtained in a yield of 80%.

mp 119-121 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.83 (d, J = 8.2 Hz, 2H), 7.32-7.19 (m, 9H), 7.06 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 5.05 (s, 2H), 4.27 (s, 2H), 2.39 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 169.7, 143.1, 142.7, 139.3, 134.6, 129.2, 128.7, 127.9, 127.8, 127.5, 126.5, 126.2, 124.4, 123.6, 110.0, 45.6, 36.1, 21.4; IR (KBr) n 1564, 1468, 1375, 1015, 850 cm ^-1 ; HRMS (EI) m / z calcd. for C ₂₂ H ₂₀ N ₂ O ₂ S [ M ] ⁺ : 376.1245, found: 376.1250.

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. You will understand that it can be changed.

The present invention can produce a high yield of 2-sulfonyliminoindolin compound by reacting an acetylene compound and a sulfonylazide compound in a solvent under mild reaction conditions in the presence of a base compound and a copper catalyst. In addition, the 2-sulfonyliminoindolin compound of the present invention can be used as a major intermediate of the pharmaceutical manufacturing process, like the conventional indoline (indoline) compound, there is industrial applicability.

Claims (15)

delete delete delete delete delete delete delete delete delete delete delete Mixing 2-ethaninyl- N -phenylaniline (96.6 mg, 0.5 mmol), p-toluenesulfonyl azide (120 mg, 0.6 mmol), chloroform (1 mL) and copper iodide (19.0 mg, 0.1 mmol); 2,6-Lutidine (70 μl, 0.6 mmol) was added to the mixed solution, and the mixture was first stirred for 11 to 13 hours to remove nitrogen molecules. Then, 4 mL of saturated ammonium chloride solution and 4 mL of dichloromethane were added, and then 20 to 40. Second stirring for minutes; Taking an organic layer from the second stirred mixture, dehydrating with magnesium sulfate, and then removing the organic solvent with a vacuum dryer; Purifying the mixture from which the dehydration and organic solvent was removed by silica gel column chromatography. Method of synthesizing 1-phenyl-2- (p-methylbenzenesulfonylimino) indolin. The method of claim 12, wherein the synthetic yield of 1-phenyl-2- (p-methylbenzenesulfonylimino) indolin is 84%. Mixing N -benzyl-2-ethynylaniline (103.6 mg, 0.5 mmol), p-toluenesulfonyl azide (120 mg, 0.6 mmol), chloroform (1 mL) and copper iodide (19.0 mg, 0.1 mmol); 2,6-Lutidine (70 μl, 0.6 mmol) was added to the mixed solution, and the mixture was first stirred for 11 to 13 hours to remove nitrogen molecules. Then, 4 mL of saturated ammonium chloride solution and 4 mL of dichloromethane were added, and then 20 ~. Second stirring for 40 minutes; Taking an organic layer from the second stirred mixture, dehydrating with magnesium sulfate, and then removing the organic solvent with a vacuum dryer; And purifying the mixture from which the dehydration and the organic solvent have been removed by silica gel column chromatography. 1-Benzyl-2- (p-methylbenzenesulfonylimino) indoline comprising the. 15. The method for synthesizing indolin according to claim 14, wherein the synthetic yield of 1-phenyl-2- (p-methylbenzenesulfonylimino) indolin is 80%.