CN108530361A - A kind of synthesis technology of 5- [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine - Google Patents

Abstract

The invention belongs to the field of medicine and chemical industry, and specifically relates to a new synthesis process of AZD4547 key intermediate 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-3-amine. It takes 2-(3,5-dimethoxyphenyl) ethyl propionate as the starting material, reacts with acetonitrile under the condition of presence of basic catalyst and organic solvent, and then reacts the obtained product with hydrazine hydrate under the condition of concentrated sulfuric acid Cyclization to obtain the target product 5-[2-(3,5-dimethoxyphenyl) ethyl]-1H-pyrazole-3-amine. Compared with the prior art, the synthetic method of 5-[2-(3,5-dimethoxyphenyl) ethyl]-1H-pyrazole-3-amine provided by the present invention greatly shortens the reaction time, The product yield is higher, and there is no process of purifying intermediates between the two-step reactions, which shortens the reaction cycle and reduces waste water discharge, and is suitable for large-scale industrial production.

Description

Synthesis of a 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine craft

technical field

The invention belongs to the field of medicine and chemical industry, and specifically relates to a new synthesis process of AZD4547 key intermediate 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-3-amine.

Background technique

AZD4547 is a selective FGFR inhibitor developed by AstraZeneca for the treatment of gastric cancer, esophageal cancer, breast cancer and other non-small cell lung cancers. It is currently in phase II clinical research. Its structural formula is as follows:

At present, there are few synthetic documents about the key intermediate 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine of AZD4547, and Norman et al. , 55(11), 5003-5012, 2012 reported that 2-(3,5-dimethoxyphenyl) ethyl propionate was used as a raw material to react with acetonitrile under the action of sodium hydride to generate 5-(3, 5-dimethoxyphenyl)-3-carbonyl-valeronitrile, and then cyclized with hydrazine hydrate to obtain the target compound, the two-step reaction yields were 44% and 42%, and the first step required column chromatography to obtain the intermediate 5-(3,5-dimethoxyphenyl)-3-carbonyl-valeronitrile, in addition, the reaction solution in this method tends to become colloidal, difficult to stir, and the emulsification is serious during post-treatment, resulting in difficulties in separation and purification. issues such as low yields.

Therefore, it is urgent to develop a new synthesis process of 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine with simple operation, high yield and high product purity.

Contents of the invention

In view of this, the object of the present invention is to provide a kind of synthetic new technique of 5-[2-(3,5-dimethoxyphenyl) ethyl]-1H-pyrazol-3-amine, and its reaction is time-consuming Short and easy to operate.

To achieve the above object, the technical solution of the present invention is:

A new synthesis process of 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine, which comprises the following steps:

1) Cool down the aprotic organic solvent to -50～-100℃, add basic catalyst, acetonitrile and ethyl 2-(3,5-dimethoxyphenyl) propionate, and keep it at -50～-100℃ Reaction at ℃ for 2 to 5 hours;

2) Add concentrated sulfuric acid and an aprotic organic solvent of hydrazine hydrate to the solution in step 1), heat up to 50-100°C and react for 2-5 hours to generate 5-[2-(3,5-dimethoxybenzene Base) ethyl] -1H-pyrazol-3-amine.

In step 1) of the present invention, a basic catalyst is used to replace the sodium hydride used in the prior art, and the solvent used is also different, and the reaction conditions have been explored. When the temperature is -50 ~ -100 ° C, the insulation can be completed for 2 ~ 5 hours reaction, and after the reaction, the reaction solution is directly carried out to the reaction of step 2). The background technology requires reflux heating, and the reaction time is 18 hours, and after the reaction in step 1), it is necessary to pass through the column and purify the intermediate product 5-(3,5-dimethoxyphenyl)-3-carbonyl-valeronitrile, The reaction time is long and the operation is more complicated.

Step 2) of the present invention is carried out directly on the basis of the reaction liquid of step 1). After experimentation and exploration, concentrated sulfuric acid was used and carried out under strong acidic conditions, which improved the reaction selectivity and the yield of the target product was higher.

The solvent used in step 2) is an aprotic solvent, and the reaction condition is 50-100°C for 2-5 hours, followed by column chromatography, and the product yield can reach more than 60%. However, the solvent in the background technology is ethanol, which needs to be refluxed and heated, and the reaction time is 24 hours, the reaction liquid is easy to become gelatinous, and the emulsification is serious during the post-treatment, and the yield is only 42%.

Therefore, technique of the present invention solves 5-[2-(3,5-dimethoxyphenyl) ethyl]- The synthesis of 1H-pyrazol-3-amine has the problems of long reaction time, low yield and complicated operation. In the process of the present invention, the reaction time is greatly shortened, the yield is increased, and the two-step reaction is carried out in the same container, there is no process of column passing and purification of the intermediate product, and the operation is simple.

As a preferred solution, the basic catalyst in step 1) is one or more of n-butyllithium, tert-butyllithium, potassium tert-butoxide, lithium diisopropylamide, and potassium hydroxide.

Further, n-butyllithium and tert-butyllithium are preferred.

As a preferred solution, the aprotic organic solvent in step 1) is one or more of tetrahydrofuran, dioxane, n-hexane, and cyclohexane.

Further, tetrahydrofuran is preferred.

As a preferred scheme, the heat preservation reaction time of step 1) is 3-4 hours.

As a preferred scheme, the reaction temperature in step 1) is -70 to -80°C.

As a preferred solution, the molar ratio of the basic catalyst, acetonitrile, and ethyl 2-(3,5-dimethoxyphenyl)propionate in step 1) is 1.5-2.5:0.8-1.2:1.0.

Further, it is preferably 2.0:1.0:1.0.

As a preferred solution, the reaction temperature in step 2) is 75-90°C.

As a preferred solution, the concentrated sulfuric acid in step 2) is a sulfuric acid solution with a mass fraction greater than 75%.

Further, it is preferably a sulfuric acid solution with a mass fraction of 98%.

As a preferred scheme, the molar ratio of the concentrated sulfuric acid, hydrazine hydrate described in step 2) and 2-(3,5-dimethoxyphenyl) ethyl propionate in step 1) is 0.9-1.1:1.3- 1.8:1.0.

Further, it is preferably 1.0:1.4-1.6:1.

As a preferred scheme, the reaction time in step 2) is 3-4 hours.

As a preferred solution, step 2) includes a post-treatment process, specifically: the reaction solution in step 2) is concentrated and subjected to column chromatography to obtain the product 5-[2-(3,5-dimethoxyphenyl )ethyl]-1H-pyrazol-3-amine.

The second object of the present invention is to provide 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine prepared by the process of the first object.

The preparation of 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine by the process of the present invention shortens the reaction time and improves the yield, thereby reducing the cost of the product . Moreover, the process of the invention is simple to operate and is suitable for large-scale industrial production. It is of great significance for the further preparation of AZD4547.

The beneficial effects of the present invention are:

1) The synthesis reaction time of 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine provided by the present invention is greatly shortened, the operation is simpler, and it is suitable for industrialization Big production.

2) In the process of the present invention, the two-step reaction is carried out in the same container, and the column passing and purification process are placed in the post-treatment of the reaction, which solves the problem that the original reaction solution easily becomes gelatinous and the emulsification is serious during post-treatment , and simplify the operation process.

3) The process of the present invention improves the yield of 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine to more than 60%, and the product has high purity and reduces Cost of production.

Detailed ways

Preferred embodiments of the present invention will be described in detail below. The experimental method that does not indicate specific conditions in the preferred embodiment is usually according to conventional conditions, and the examples given are to better illustrate the content of the present invention, but the content of the present invention is not limited to the examples given. Therefore, non-essential improvements and adjustments to the implementation by those skilled in the art based on the content of the invention above still fall within the protection scope of the present invention.

Example 1 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine Synthesis Scheme 1

1) Cool 10 mL of anhydrous tetrahydrofuran to -78°C, add 1.01 mL (2.52 mmol) of n-butyllithium (2.5 mol/L n-hexane solution), and dropwise add 66.5 μL of acetonitrile. After the dropwise addition, 300 mg of ethyl 2-(3,5-dimethoxyphenyl)propionate in tetrahydrofuran was added dropwise. After dropping, react at -78°C for 3h.

2) After the completion of the reaction was monitored by TLC, 68.5 μL of concentrated sulfuric acid with a mass fraction of 98% was added. Then slowly add 115 μL (1.89 mmol) of a tetrahydrofuran solution of hydrazine hydrate dropwise. After the dropwise addition is complete, transfer to 80° C. for 3 h of reaction.

3) After the reaction solution was concentrated, 156 mg of a yellow solid was directly obtained by column chromatography, and the yield was 50.1%.

Example 2 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine Synthesis Scheme 2

1) Cool 10 mL of anhydrous dioxane to -70°C, add 1.01 mL (2.52 mmol) of n-butyllithium (2.5 mol/L n-hexane solution), and dropwise add 66.5 μL of acetonitrile. After the dropwise addition, 300 mg of ethyl 2-(3,5-dimethoxyphenyl)propionate was added dropwise. After dropping, react at -60°C for 3h.

2) After the completion of the reaction was monitored by TLC, 68.5 μL of concentrated sulfuric acid with a mass fraction of 98% was added. Then, 115 μL (1.89 mmol) of hydrazine hydrate in dioxane solution was slowly added dropwise, and after the addition was completed, the reaction was carried out at 60° C. for 3 h.

3) After the reaction solution was concentrated, 147 mg of a yellow solid was directly obtained by column chromatography, with a yield of 48%.

Example 3 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine Synthesis Scheme 3

1) Cool 10 mL of anhydrous n-hexane to -80°C, add 1.01 mL (2.52 mmol) of n-butyllithium (2.5 mol/L n-hexane solution), and dropwise add 66.5 μL of acetonitrile. After the dropwise addition, 300 mg of ethyl 2-(3,5-dimethoxyphenyl)propionate was added dropwise. After dropping, react at -95°C for 3h.

2) After the completion of the reaction was monitored by TLC, 68.5 μL of concentrated sulfuric acid with a mass fraction of 98% was added. Then, 115 μL (1.89 mmol) of hydrazine hydrate in n-hexane was slowly added dropwise. After the dropwise addition was completed, the reaction was carried out at 90° C. for 3 h.

3) After the reaction solution was concentrated, 143.8 mg of a yellow solid was directly obtained by column chromatography, and the yield was 46%.

Example 4 5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine Synthesis Scheme 4

1) Cool 10mL of tetrahydrofuran to -70°C, add 200mg (0.840mmol) of ethyl 2-(3,5-dimethoxyphenyl) propionate, dissolve in tetrahydrofuran, add 188.35mg of potassium tert-butoxide, Then 44.3 μL of acetonitrile was added, and the reaction was stirred at -70°C for 3 h.

2) Add 45.7 μL of concentrated sulfuric acid with a mass fraction of 98%, slowly add 76.3 μL (1.26 mmol) of hydrazine hydrate in tetrahydrofuran solution dropwise, after the dropwise addition is complete, transfer to 80° C. for 3 h.

3) After the reaction solution was concentrated, 128 mg of a yellow-white solid was directly obtained by column chromatography, and the yield was 61%.

The product is carried out proton nuclear magnetic resonance spectrum analysis, and the results are as follows:

mp110～112℃. ¹ H-NMR (DMSO-d6, 400MHz), δ: 6.62(br s, 2H), 6.38(d, J=2.0Hz, 2H), 6.32(t, J=2.0Hz, 1H), 5.45(s, 1H), 3.78(s,6H), 2.86(s,4H).

Thus, the present invention has developed a 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H- A new process for the synthesis of pyrazol-3-amine.

Finally, it is noted that the above embodiments are only used to illustrate the technical solutions of the present invention without limitation. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be carried out Modifications or equivalent replacements without departing from the spirit and scope of the technical solution of the present invention shall be covered by the claims of the present invention.

Claims (10)

1. a synthesis technique of 5-[2-(3,5-dimethoxyphenyl) ethyl]-1H-pyrazol-3-amine, is characterized in that, comprises the following steps: 1) Cool down the aprotic organic solvent to -50～-100℃, add basic catalyst, acetonitrile and ethyl 2-(3,5-dimethoxyphenyl) propionate, and keep it at -50～-100℃ Reaction at ℃ for 2 to 5 hours; 2) Add concentrated sulfuric acid and an aprotic organic solvent dissolved in hydrazine hydrate to the reaction solution in step 1), heat up to 50-100°C for reaction, and 5-[2-(3,5-dimethoxy phenyl)ethyl]-1H-pyrazol-3-amine. 2. technology according to claim 1, is characterized in that, step 1) described basic catalyst is n-butyl lithium, tert-butyl lithium, potassium tert-butoxide, lithium diisopropylamide, potassium hydroxide one or more. 3. The process according to claim 1, characterized in that, the aprotic organic solvent described in steps 1) and 2) is one or more of tetrahydrofuran, dioxane, normal hexane, and cyclohexane. 4. The process according to claim 1, characterized in that the reaction temperature in step 1) is -70 to -80°C. 5. technique according to claim 1, is characterized in that, the mol ratio of basic catalyst, acetonitrile, 2-(3,5-dimethoxyphenyl) ethyl propionate feeding intake of step 1) is 1.5 -2.5:0.8-1.2:1.0. 6. The process according to claim 1, characterized in that the reaction temperature in step 2) is 75-90°C. 7. The process according to claim 1, characterized in that, the concentrated sulfuric acid in step 2) is a sulfuric acid solution with a mass fraction greater than 75%. 8. technique according to claim 1, is characterized in that, step 2) described concentrated sulfuric acid, hydrazine hydrate and step 1) described 2-(3,5-dimethoxyphenyl) ethyl propionate feed intake The molar ratio is 0.9-1.1:1.3-1.8:1.0. 9. The process according to claim 1, characterized in that, after step 2), the reaction solution is concentrated and subjected to column chromatography to obtain the product 5-[2-(3,5-dimethoxyphenyl) ethyl Base]-1H-pyrazol-3-amine. 10. 5-[2-(3,5-dimethoxyphenyl) ethyl]-1H-pyrazol-3-amine prepared by the process described in claim 1.