KR101152607B1 - Process for preparing 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine - Google Patents

Abstract

The present invention relates to a method for preparing 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine In more detail, 6- [4 represented by the following Chemical Formula 1 with a high purity of 99.0% or more through a series of five steps using a commercially readily available pyridin-4-yl-acetonitrile as a starting material. It relates to a method of more easily preparing-(2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine.

6- [4- (2-Piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine, pyridin-4-yl-aceto Nitrile

Description

6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine {Process for preparing 6 -[4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine}

The present invention relates to a method for preparing 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine In more detail, 6- [4 represented by the following Chemical Formula 1 with a high purity of 99.0% or more through a series of five steps using a commercially readily available pyridin-4-yl-acetonitrile as a starting material. It relates to a method of more easily preparing-(2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine.

[Formula 1]

6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine represented by Formula 1 is diabetes Or as an AMPK inhibitor ( J. Clin . Invest. 108 , 1167-1174 (2001), Nature Med . 10 (7) , 727-733 (2004)), which is a comparison of obesity treatments, or a KDR kinase inhibitor ( Bioorg. Med). Chem. Lett. 12 , 3537-3541 (2002), Bioorg. Med. Chem. Lett. 12 , 2767-2770 (2002)).

Conventional 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine represented by Formula 1 The preparation method is illustrated in the paper ( Bioorg. Med. Chem. Lett. 12 , 3537-3541 (2002), Bioorg. Med. Chem. Lett. 12 , 2767-2770 (2002)). In summary.

The preparation method according to Scheme 1 is Bioorg. Med. Chem. Lett. 12 , 3537-3541 (2002) and Bioorg. Med. Chem. Lett. 12 , 2767-2770 (2002), wherein in reaction a), N , N -dimethylformamide dimethylacetal (DMFDMA) is added to the reaction with the pyridin-4-yl-acetonitrile compound represented by the formula (2). While reacting under reflux conditions for a long time (3 days), reaction b) uses an alcohol solvent and a low solubility hydrazine hydrogen chloride, so that the reactant remains cloudy as a suspension and a lot of by-products are generated. Due to the physical properties of 4-pyridine-2H-pyrazol-3-ylamine represented by There is a problem such as necessary, even if the compound represented by the formula (4) is difficult to obtain in the reaction c) is not performed smoothly The yield of the compound represented by Chemical Formula 6 was very low.

In addition, the preparation method according to Scheme 2 is Bioorg. Med. Chem. Lett. 12 , 3537-3541 (2002), which is carried out by reaction e) by reacting chloroethylpyrrolidine hydrogen chloride under conditions using Cs ₂ CO ₃ and NaI together in a dimethylformamide (DMF) solvent, It was observed that the reaction proceeds very complicated on TLC, and the separation between the organic layer and the aqueous layer was not performed smoothly. Thus, 6- [4- (2-pyrrolidin-1-yl-ethoxy)- There are many problems in reaction, such as poor yield (about 5%) and low purity of phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine.

Due to the problems in the conventional manufacturing method as described above, using the pyridin-4-yl-acetonitrile represented by the formula (2) as a starting material 6- [4- represented by the formula (1) which is useful in the pharmaceutical field Obtaining (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine in high purity and yield to a commercially useful degree There are many restrictions.

Accordingly, the present invention provides 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a represented by Chemical Formula 1 above. It is an object of the present invention to provide a novel synthetic method for preparing pyrimidine in high purity and high yield.

The manufacturing method according to the invention is characterized in that it comprises the following a), b), c), d) and e) process:

a) Pyridin-4-yl-acetonitrile hydrogen chloride represented by the following formula (2) under an amine base and an aromatic hydrocarbon solvent is reacted with N , N -dimethylformamide dimethylacetal (DMFDMA) to form 3-dimethyl represented by the following formula (3): Preparing amino-2-pyridin-4-yl-acrylonitrile;

b) Reacting 3-dimethylamino-2-pyridin-4-yl-acrylonitrile represented by the following formula (3) with hydrazine monohydrate under an acetic acid catalyst and an alcohol solvent, 4-pyridyl- represented by the following formula (4) Preparing 2H-pyrazol-3-ylamine;

c) 4-pyridyl-2H-pyrazol-3-ylamine represented by the following formula (4) and 2- (4-methoxyphenyl) malondialdehyde represented by the following formula (5) under an acetic acid catalyst and an alcohol solvent To prepare 6- (4-methoxy-phenyl) -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine represented by Formula 6;

d) 4 represented by the following formula (7) by acid hydrolysis of 6- (4-methoxy-phenyl) -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine represented by formula (6) Preparing-(3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol;

e) 4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol represented by the following Chemical Formula 7 under Cs ₂ CO ₃ and an alcohol solvent: The chloroethyl piperidine hydrogen chloride represented by the reaction was stirred to give 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl represented by the following formula (1). Process for preparing pyrazolo [1,5-a] pyrimidine.

Hereinafter, the present invention will be described in detail.

The present invention comprises a 5-step reaction process using pyridin-4-yl-acetonitrile hydrogen chloride represented by Chemical Formula 2 as a starting material, 6- [4- (2-piperidine-1) represented by Chemical Formula 1 It is characterized by a process for preparing -yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine. The present invention is to obtain the effect of maximizing the yield and purity of the final target by specifically configuring the conditions of each reaction consisting of the above five steps.

 Each manufacturing process according to the present invention in more detail step by step as follows.

a) The reaction step is represented by the reaction of pyridin-4-yl-acetonitrile hydrogen chloride represented by the formula (2) in the presence of N , N- dimethylformamide dimethylacetal (DMFDMA) and an amine base and an aromatic hydrocarbon solvent, represented by the formula (3) To prepare 3-dimethylamino-2-pyridin-4-yl-acrylonitrile. In the present invention, by selectively adding the amine base as the reaction catalyst, the conventional manufacturing method was able to obtain the effect of greatly reducing the reaction time of about 3 days at reflux temperature conditions to about 24 hours, through the post-treatment process and purification process By removing impurities and inorganic salts, 3-dimethylamino-2-pyridin-4-yl-acrylonitrile represented by Chemical Formula 3 having high purity was obtained. N , N -dimethylformamide dimethylacetal (DMFDMA) may be used in the range of 1 equivalent to 3 equivalents based on the compound represented by Formula 2. As the amine base, a catalytic amount is used, and aromatic amines such as aliphatic amines such as triethylamine, pyridine, and piperidine can be used, and more preferably, aromatic amines are used. As a reaction solvent, it can select from normal aromatic hydrocarbon solvents, such as toluene. The reaction temperature is in the range of 60 ℃ to reflux temperature of the solvent, preferably to maintain the range of 80 ℃ to 100 ℃. After the reaction is completed, the impurities and inorganic salts are removed through appropriate post-treatment and purification to obtain a compound represented by Chemical Formula 3, which is then used in the following b) reaction.

In addition, in the present invention, when the reaction is completed, a method of performing the following b) reaction by a one-pot reation without separately performing an appropriate post-treatment process and purification process for separation of the target compound. Include. That is, even if the a) reaction proceeds smoothly, even if the purification process is not performed, it does not greatly affect the following b) reaction, and even if impurities are included, the purification process performed after the reaction b) is sufficient. This is because separation and removal are possible.

b) the reaction step is the reaction of 3-dimethylamino-2-pyridin-4-yl-acrylonitrile represented by the formula (3) under conditions using a hydrazine monohydrate, an acetic acid catalyst and an alcohol solvent, represented by the formula (4) To prepare 4-pyridyl-2H-pyrazol-3-ylamine. By the conventional method is used for the low solubility of hydrazine hydrogen chloride salt (H ₂ NNH _2? HCl) with a reactant being the reaction solution is maintained as a suspension whereas were the reaction is not not proceed thoroughly, in the present invention, hydrazine monohydrate (H ₂ NNH ₂ By using? H ₂ O) as a reactant while maintaining the conditions of using a catalytic amount of acetic acid together, the reactants form a homogeneous solution phase to complete the reaction in a short time (about 2 hours). The hydrazine monohydrate may be used in the range of 1 equivalent to 3 equivalents based on the compound represented by Chemical Formula 3. The reaction solvent can be selected from among lower aliphatic alcohol solvents selected from methanol, ethanol, propanol and butanol. The reaction temperature is maintained at 40 ℃ to reflux temperature of the solvent.

c) The reaction step is a 4-pyridyl-2H-pyrazol-3-ylamine represented by the formula (4) and 2- (4-methoxyphenyl) malondialdehyde represented by the formula (5) and acetic acid catalyst and alcohol The reaction is carried out under a solvent to prepare 6- (4-methoxy-phenyl) -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine represented by Chemical Formula 6. The compound represented by Formula 5 may be used in the range of 1 equivalent to 2 equivalents based on the compound represented by Formula 4, preferably 1 equivalent. At this time, the acetic acid catalyst and the alcohol solvent used in the reaction can be selected and used among those described in the step b), the reaction temperature is to maintain the reflux temperature range of 40 ℃ to the solvent.

d) the reaction step is carried out by acid hydrolysis of 6- (4-methoxy-phenyl) -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine represented by Chemical Formula 6 to Chemical Formula 7. This is a process for preparing 4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol. Acid hydrolysis can be carried out in a conventional manner, preferably under conditions using a hydrogen halide catalyst selected from HF, HCl, and HBr and an acetic acid solvent. The hydrolysis reaction is to maintain the reflux temperature range of 90 ℃ to the solvent, preferably to maintain the reflux temperature conditions.

Finally, e) the reaction step is represented by the formula (8) and 4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol represented by the formula (7) Chloroethylpiperidine hydrogen chloride was stirred under the conditions of using Cs ₂ CO ₃ and an alcohol solvent, and 6- [4- (2-piperidin-1-yl-) represented by the general formula (1) of the present invention. Ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine. In this reaction, the reaction conditions using Cs ₂ CO ₃ and an alcohol solvent are maintained. That is, the present reaction is characterized in that the efficiency of the reaction is increased by using an alcohol solvent while using Cs ₂ CO ₃ alone without using an alkali metal iodide such as NaI and KI. The chloro compound represented by the formula (8) is used in the range of 1 equivalent to 4 equivalents, and preferably in the range of 2 equivalents to 3 equivalents based on the phenolic compound represented by the formula (7). Cs ₂ CO ₃ is used in the range of 2 to 10 equivalents, preferably 3 to 7 equivalents, based on the phenolic compound represented by Formula 7. The alcohol solvent can be selected and used among those described in the step b). The reaction temperature is maintained at 50 ℃ to reflux temperature of the solvent.

In addition, the present invention is also characterized by the post-treatment process proceeds after the reaction e), e) MPLC (Medium Pressure Liquid) using a 3 to 15% MeOH / CHCl ₃ solution as a developing solution after the reaction is complete Chromatography), washing with dichloromethane (CH ₂ Cl ₂ ), and filtration under reduced pressure, followed by recrystallization with ethanol can give the desired compound represented by Chemical Formula 1 with higher purity.

As a prior art similar to the above e) reaction, as shown in Scheme 2, 4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl represented by Chemical Formula 7 ) -Phenol and chloroethylpyrrolidine hydrogen chloride represented by Chemical Formula 9 are known to have been combined under Cs ₂ CO ₃ / NaI / dimethylformamide (DMF) solvent conditions, but the yield is very low. It has been pointed out that there is a limit to use. On the other hand, the inventors of the conventional method according to Scheme 2 above 4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol represented by Formula 7 and the It was applied to the coupling reaction of chloroethylpiperidine hydrogen chloride represented by the formula (8). (Comparative Examples 1 to 3 of the present application) According to the experimental results of the present inventors, when reacted under Cs ₂ CO ₃ / NaI / DMF solvent conditions The yield was about 5% (Comparative Example 1), the yield was about 11% when reacted under Cs ₂ CO ₃ / NaI / DMSO solvent conditions (Comparative Example 2), K ₂ CO ₃ / KI / DMF solvent conditions When reacted at, the yield was found to be very low, about 5% (Comparative Example 3). However, as shown in Example 5 the reaction solvent was changed to ethanol according to the invention and 4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol (1 eq) was combined with chloroethylpiperidine hydrogen chloride (3 eq) and Cs ₂ CO ₃ (5 eq). The reaction was carried out for a short time of 1 to 2 hours at < RTI ID = 0.0 > C, < / RTI > resulting in desired 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3- in a relatively high yield of 41%. Pyridin-4-yl-pyrazolo [1,5-a] pyrimidine could be obtained.

The present invention will be described in more detail with reference to Examples, but the following Examples are merely to illustrate the content of the present invention, but the scope of the present invention is not limited by the following Examples.

Example 1. Preparation of 3-dimethylamino-2-pyridin-4-yl-acrylonitrile

To a suspension of toluene (120 mL) of pyridin-4-yl-acetonitrile hydrogen chloride (4.2 g) was added N , N -dimethylformamide dimethylacetal (7.7 mL, 2.0 eq) and the temperature was 97. After raising to ℃, the mixture was stirred for 7 hours. Add N , N -dimethylformamide dimethylacetal (3.9 mL, 1.0 eq) to the reaction. It was raised to ℃ and stirred for 15 hours. After cooling to room temperature the reaction was concentrated under reduced pressure. The residue was diluted with 10% MeOH / CHCl ₃ solution (250 mL) and washed with saturated NaHCO ₃ aqueous solution (250 mL). The aqueous layer was extracted with 10% MeOH / CHCl ₃ solution (150 mL), and the organic layers were collected and dried over MgSO ₄ . The organic layer was filtered under reduced pressure and concentrated. The residue was MPLC (10% MeOH / CHCl ₃ ) to give 4-pyridyl-2H-pyrazol-3-ylamine (3.75 g) which was used directly in Example 2 below.

¹ H NMR (300MHz, CDCl ₃ ) δ 3.31 (s, 6H), 7.17-7.20 (m, 3H), 8.40-8.43 (m, 2H)

 Example 2. Preparation of 4-pyridyl-2H-pyrazol-3-ylamine

To the ethanol (90 mL) solution of 4-pyridyl-2H-pyrazol-3-ylamine obtained in Example 1, hydrazine monohydrate (2.1 mL, 2 eq) and glacial acetic acid (0.5 mL) were added sequentially. It was refluxed for 2 hours with stirring. The reaction was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by MPLC (10% MeOH / CHCl ₃ ) to afford 4-pyridyl-2H-pyrazol-3-ylamine (1.48 g, 35% (2-step)).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.13 (br s, 2H), 7.47-7.50 (m, 2H), 7.87 (s, 1H), 8.39-8.41 (m, 2H), 11.50 (br s, 1H)

Example 3. Preparation of 6- (4-methoxy-phenyl) -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine

In an ethanol (50 mL) solution of 4-pyridyl-2H-pyrazol-3-ylamine (1.48 g), 2- (4-methoxyphenyl) malondialdehyde (1.73 g, 1 eq) and glacial acetic acid (0.15 mL ) Was added in sequence and refluxed for 1 hour 30 with stirring. Reactants 0 After the temperature was lowered to 30 ° C., the mixture was stirred for 30 minutes, and the precipitated solid was filtered under reduced pressure, washed with cold ethanol, and dried under reduced pressure to obtain pure 6- (4-methoxy-phenyl) -3-pyridin-4-yl-pyrazolo [ 1,5-a] pyrimidine (2.38 g, 85%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.83 (s, 3H), 7.10 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H), 8.15 (d, J = 6.0 Hz, 2H), 8.59 (d, J = 5.7 Hz, 2H), 8.95 (s, 1H), 9.11 (d, J = 2.0 Hz, 1H), 9.51 (d, J = 2.0 Hz, 1H)

Example 4. Preparation of 4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol

6- (4-methoxy-phenyl) -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine (2.38 g) was added to a solution of 48% HBr (15 mL) and glacial acetic acid (15 mL). Mix, 120 It was refluxed for 20 hours at ℃. The reaction was cooled to rt, diluted with H ₂ O (90 mL) and stirred at rt for 30 min. The precipitated solid was filtered under reduced pressure, washed with H ₂ O and dried under reduced pressure (55). C.) to give quantitatively 4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.95 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 8.71 (d, J = 6.6 Hz, 2H), 8.84 ( d, J = 6.3 Hz, 2H), 9.25 (d, J = 2.4 Hz, 2H), 9.62 (d, J = 1.8 Hz, 1H), 9.84 (br s, 1H)

Example 5. Preparation of 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine

4- (3-Pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol (2.1 g), 1- (2-chloroethyl) piperidine hydrogen chloride (4.1 g, 3 eq), Cs ₂ CO ₃ (11.8 g, 5 eq) and ethanol (150 mL) It was refluxed for 1 hour and 30 minutes while stirring at ℃. The reaction was cooled to room temperature, diluted with saturated aqueous NaHCO ₃ (300 mL) and extracted twice with 10% MeOH / CHCl ₃ solution (250 mL). The organic layer was dried over Na ₂ SO ₄ , filtered under reduced pressure and concentrated under reduced pressure. The residue was purified by MPLC (5% MeOH / CHCl ₃ ) to give 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5- a] pyrimidine (1.13 g, yield 41%) was obtained.

And the obtained 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine is CH ₂ Cl ₂ (150 mL) and then filtered under reduced pressure. The filtrate was recrystallized from ethanol to obtain high purity 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyridine Midine (0.83 g, 41%, purity 99.9%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.44-1.50 (m, 2H), 1.61-1.67 (m, 4H), 2.53 (br t, J = 1.8 Hz, 4H), 2.82 ((t, J = 6.0 Hz) , 2H), 4.18 (t, J = 6.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 6.0 Hz, 2H ), 8.53 (s, 1H), 8.81 (d, J = 2.1 Hz, 2H), 8.87 (d, J = 2.1 Hz, 2H)

Comparative Example 1. Preparation of 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine

4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol (200 mg), 1- (2-chloroethyl) piperidine hydrogen chloride (156 mg, 1.2 eq), Cs ₂ CO ₃ (452 mg, 2 eq), NaI (208 mg, 2 eq) and dimethylformamide (DMF, 15 mL) It was refluxed for 20 hours with stirring at ℃. The reaction was cooled to rt, diluted with saturated aqueous NaHCO ₃ (300 mL) and extracted twice with 10% MeOH / CHCl ₃ solution (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered under reduced pressure and concentrated under reduced pressure. The residue was purified by MPLC (5% MeOH / CHCl ₃ ) to give 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5- a] pyrimidine (15 mg, yield 5%) was obtained.

Comparative Example 2. Preparation of 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine

4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol (200 mg), 1- (2-chloroethyl) piperidine hydrogen chloride (156 mg, 1.2 eq), Cs ₂ CO ₃ (452 mg, 2.0 eq), NaI (125 mg, 1.2 eq) and dimethylsulfoxide (DMSO, 15 mL) It was refluxed for 6 hours with stirring at ℃. The reaction was cooled to rt, diluted with saturated aqueous NaHCO ₃ (300 mL) and extracted twice with 10% MeOH / CHCl ₃ solution (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered under reduced pressure and concentrated under reduced pressure. The residue was purified by MPLC (5% MeOH / CHCl ₃ ) to give 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5- a] pyrimidine (31 mg, yield 11%) was obtained.

Comparative Example 3. Preparation of 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine

4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol (200 mg), 1- (2-chloroethyl) piperidine hydrogen chloride (156 mg, 1.2 eq), K ₂ CO ₃ (288 mg, 3 eq), KI (210 mg, 2 eq) and dimethylformamide (DMF, 15 mL) It was refluxed for 8 hours with stirring at ℃. The reaction was cooled to room temperature, diluted with saturated aqueous NaHCO ₃ (300 mL) and extracted twice with 10% MeOH / CHCl ₃ solution (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered under reduced pressure and concentrated under reduced pressure. The residue was purified by MPLC (5% MeOH / CHCl ₃ ) to give 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5- a] pyrimidine (15 mg, yield 5%) was obtained.

As described above, the manufacturing method according to the present invention uses commercially available starting materials and reactants, and finds and applies the optimum reaction conditions for each manufacturing process, thereby providing high purity 6- [4- (2-P It has become possible to synthesize perridin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine more effectively.

Thus, the present invention provides 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine commercially. Very useful for production

Claims (5)

Method for producing a process comprising the following a), b), c), d) and e) process: a) Pyridin-4-yl-acetonitrile hydrogen chloride represented by the following formula (2) under an amine base and an aromatic hydrocarbon solvent is reacted with N , N -dimethylformamide dimethylacetal (DMFDMA) to form 3-dimethyl represented by the following formula (3): Preparing amino-2-pyridin-4-yl-acrylonitrile;

b) Reacting 3-dimethylamino-2-pyridin-4-yl-acrylonitrile represented by the following formula (3) with hydrazine monohydrate under an acetic acid catalyst and an alcohol solvent, 4-pyridyl- represented by the following formula (4) Preparing 2H-pyrazol-3-ylamine;

c) under reaction with an acetic acid catalyst and an alcohol solvent, 4-pyridyl-2H-pyrazol-3-ylamine represented by the following formula (4) and 2- (4-methoxyphenyl) malondialdehyde represented by the following formula (5) Preparing 6- (4-methoxy-phenyl) -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine represented by Formula 6;

d) 4 represented by the following formula (7) by acid hydrolysis of 6- (4-methoxy-phenyl) -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine represented by formula (6) Preparing-(3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol;

e) 4- (3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-6-yl) -phenol represented by the following Chemical Formula 7 under Cs ₂ CO ₃ and an alcohol solvent: The chloroethyl piperidine hydrogen chloride represented by the reaction was stirred to give 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl represented by the following formula (1). Process for preparing pyrazolo [1,5-a] pyrimidine.

The process according to claim 1, wherein the amine base used in the reaction a) is an aliphatic or aromatic amine selected from triethylamine, pyridine and piperidine. The method according to claim 1, wherein the alcohol solvent used in the b), c), and e) reactions is a lower aliphatic alcohol selected from methanol, ethanol, propanol and butanol. The method according to claim 1, wherein the d) acid hydrolysis reaction is performed under conditions using a hydrogen halide catalyst selected from HF, HCl, and HBr and an acetic acid solvent. The method of claim 1, wherein after e) the reaction is completed, Medium Pressure Liquid Chromatography (MPLC) is performed, washed with dichloromethane (CH ₂ Cl ₂ ), filtered under reduced pressure, and recrystallized with ethanol to Chemical Formula 1. To obtain the indicated 6- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine Manufacturing method.