A preparation method of amlodipine intermediate

Abstract

The invention discloses a preparation method of 4-(2-chlorophenyl)-2-({[2-(phthaloyl)ethyl]oxy}methyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester, wherein phthalic anhydride and ethanolamine are reacted to obtain N-hydroxyethylphthalimide, which is then condensed with ethyl 4-chloroacetoacetate under sodium alcoholate conditions, and finally condensed with o-chlorobenzaldehyde and 3-aminocrotonic acid methyl ester to obtain a product. This scheme adopts a one-pot preparation method for the whole four steps, avoids the use of sodium hydrogen, greatly improves the economy and safety compared with the preparation method of the prior art, and is more in line with the requirements of industrial production.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for preparing an amlodipine intermediate. Background Art

[0002] Amlodipine is a dihydropyridine calcium channel inhibitor used to treat hypertension and various types of angina pectoris. Compared with the same type of dihydropyridine drugs, it has the advantages of lower effects on the sympathetic nervous system. It is often widely used in clinical treatment in the form of benzenesulfonate. 4-(2-chlorophenyl)-2-({[2-(phthalyl)ethyl]oxy}methyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester (also known as phthalyl amlodipine) is an important intermediate for the synthesis of amlodipine. There are many reports on its synthesis method. The common synthesis route is to use phthalic anhydride as a starting material to react with ethanolamine to obtain N-hydroxyethylphthalimide, which is then O-substituted to obtain 4-[2-(phthalimido)ethoxy]-3-oxobutyric acid ethyl ester, and finally condense with o-chlorobenzaldehyde and 3-aminocrotonic acid methyl ester to obtain the product.

[0003] In the report of Chinese patent document CN106749187B, phthalic anhydride is first reacted with ethanolamine to obtain N-hydroxyethylphthalimide, which is then condensed with ethyl 4-chloroacetoacetate under sodium hydride conditions to obtain 4-[2-(phthalimido)ethoxy]-3-oxobutyrate, and finally condensed with o-chlorobenzaldehyde and 3-aminocrotonic acid methyl ester to obtain the product. This method uses sodium hydride in the process and requires multi-step separation treatment, which is cumbersome and complicated and has certain safety risks in commercial production.

[0004] In Chinese patent CN102070611B, the authors used 4-[2-(phthalimido)ethoxy]-3-oxobutyric acid ethyl ester to condense with o-chlorobenzaldehyde and 3-aminocrotonic acid methyl ester to successively carry out cyclization reactions to obtain phthaloyl amlodipine. No purification step was performed between the two steps of condensation reaction, but the total yield was low, and the two-step yield was 68.6%. Summary of the invention

[0005] In order to improve the deficiencies in the existing process, the present invention proposes a new process for preparing 4-(2-chlorophenyl)-2-({[2-(phthalimide)ethyl]oxy}methyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester (phthaloyl amlodipine). The characteristic of this method is that sodium tert-butoxide is used as a base in the step of condensing N-hydroxyethylphthalimide with ethyl 4-chloroacetoacetate, avoiding the use of sodium hydride in the prior art, and the whole reaction process is carried out in a one-pot process without the need for an additional separation step. This method is specifically as follows: (1) Take phthalic anhydride, dissolve it in toluene, and add monoethanolamine to the solution. After the addition is completed, stir and heat it to 110-120°C, reflux and react. After the reaction is completed, add a base directly to the reaction solution, the base is selected from one of sodium tert-butoxide, potassium tert-butoxide and sodium methoxide. After the addition is completed, stir and heat it to 110-120°C, reflux and separate the liquids, then cool it to 10±5°C, add ethyl 4-chloroacetoacetate dropwise to the reaction solution, and after the addition is completed, stir and react. After the reaction is completed, add water to quench, separate the liquids to obtain ethyl 4-[2-(phthalimido)ethoxy]-3-oxobutanoate. Toluene solution; (2) Add o-chlorobenzaldehyde and piperidine to the above ethyl 4-[2-(phthalimido)ethoxy]-3-oxobutyrate toluene solution. After the addition is complete, stir and heat to 110-120°C. After the reaction is complete, cool to 30±5°C to obtain ethyl 2-[(2-chlorophenyl)methylidene]-4-{[2-(phthalimido)ethoxy}-3-oxobutyrate. Toluene solution; (3) Add 3-aminocrotonic acid methyl ester to the reaction solution obtained in the previous step, and optionally add methanol, and continue the reflux reaction. After the reaction is completed, add glacial acetic acid to adjust the pH to ≤ 5, cool and stir to crystallize, filter, and dry to obtain phthaloyl amlodipine. .

[0006] Furthermore, in step (1), the equivalent of monoethanolamine used is 1-1.1, the equivalent of base used is 1-1.3; the mass ratio of toluene used to phthalic anhydride is 4:1-10:1; Furthermore, in step (2), the equivalent of piperidine used is 0.3-0.5, preferably 0.3; Furthermore, in step (3), the equivalent of 3-aminocrotonic acid methyl ester is 1-1.2, the temperature of cooling and stirring crystallization is 0-15°C, preferably 0-5°C; the ratio of methanol to toluene is 1:4-2:5; When the above process is adopted, the solvent is not changed in the whole reaction step, and toluene is used for all the steps, and no additional refining process is required in the middle. For the above step (3), methanol can also be selected as the reaction solvent. When methanol is selected, the toluene solution after the reaction of step (2) is concentrated to dryness, and methanol is added to react. After the reaction is completed, glacial acetic acid is added to adjust the pH to ≤ 5, and the temperature is lowered to 0-15°C and stirred for crystallization. The mass of methanol added is calculated based on phthalic anhydride, which is 10 to 15 times the mass of phthalic anhydride.

[0007] Beneficial effects: Compared with the existing technology, this solution uses sodium alcohol to replace the sodium hydride used in the traditional process, which avoids safety risks, reduces the intermediate separation steps, increases production continuity, and shortens the production cycle. This process uses conventional materials, has low production safety risks, and is suitable for commercial production. Specific implementation methods Example 1

[0008] Add 44.5g of phthalic anhydride, 300g of toluene and 19.1g of monoethanolamine to a three-necked flask. After the addition is complete, stir and heat to 120°C, reflux for 16h, add 36g of sodium tert-butoxide to the above reaction solution. After the addition is complete, stir and heat to 120°C, reflux and separate the reaction for 2h, cool to 10°C, add 62g of ethyl 4-chloroacetoacetate dropwise to the reaction solution, stir and react for 4h after the addition is complete; take samples for testing, add water to quench the reaction, separate the liquid to obtain 4-[2-(phthalimido)ethoxy]-3-oxobutyric acid ethyl ester toluene solution.

[0009] To the above 4-[2-(phthalimido)ethoxy]-3-oxobutyric acid ethyl ester toluene solution, add 42.1g of o-chlorobenzaldehyde and 8g of piperidine. After the addition, stir and heat to 120°C for 2h. After the reaction is complete, add 34.5g of 3-aminocrotonic acid methyl ester directly to the reaction solution and reflux for 2h. After the reaction is complete, add glacial acetic acid, adjust the pH to ≤5, cool to 5°C, stir and crystallize, filter and dry to obtain 129.9g of phthaloyl amlodipine with a total yield of 81.2%. 1H NMR (400MHz, CDCl3) δ 7.88 (dd, J = 5.5, 3.1 Hz, 2H ), 7.76 (dd, J = 5.6, 3.0 Hz, 2H ), 7.34 (m, 2H ), 7.20 (dd, J = 7.9, 1.4 Hz, 1H ), 7.08 (td, J = 7.5, 1.4 Hz, 1H ), 7.01 (ddd, J = 7.9, 7.3, 1.8 Hz, 1H ), 5.36 (s, 1H ), 4.66 (m, 2H ), 4.01 (m,4H ) , 3.76 (m, 2H ), 3.60(s, 3H ), 2.42(s, 3H ), 1.15 (t, J = 7.1 Hz, 3H). Example 2

[0010] Add 44.5g of phthalic anhydride, 250g of toluene and 19.1g of monoethanolamine to a three-necked flask. After the addition is complete, stir and heat to 120°C, reflux for 16h, add 36g of sodium tert-butoxide to the above reaction solution. After the addition is complete, stir and heat to 120°C, reflux and separate the reaction for 2h, cool to 10°C, add 62g of ethyl 4-chloroacetoacetate dropwise to the reaction solution, stir and react for 4h after the addition is complete; take samples for testing, add water to quench the reaction, separate the liquids to obtain 4-[2-(phthalimido)ethoxy]-3-oxobutyric acid ethyl ester toluene solution.

[0011] To the above 4-[2-(phthalimido)ethoxy]-3-oxobutyric acid ethyl ester toluene solution, add 42.1g of o-chlorobenzaldehyde and 8g of piperidine. After the addition, stir and heat to 120°C for 2h. After the reaction is complete, add 34.5g of methyl 3-aminocrotonate directly to the reaction solution and add 50g of methanol. Reflux for 2h. After the reaction is complete, add glacial acetic acid, adjust the pH to ≤5, cool to 5°C, stir and crystallize, filter and dry to obtain 142.2g of phthaloyl amlodipine with a total yield of 87.8%. Example 3

[0012] Add 44.5g of phthalic anhydride, 300g of toluene and 19.1g of monoethanolamine to a three-necked flask. After the addition is complete, stir and heat to 120°C, reflux for 16h, add 36g of sodium tert-butoxide to the above reaction solution. After the addition is complete, stir and heat to 120°C, reflux and separate the reaction for 2h, cool to 10°C, add 62g of ethyl 4-chloroacetoacetate dropwise to the reaction solution, stir and react for 4h after the addition is complete; take samples for testing, add water to quench the reaction, separate the liquid to obtain 4-[2-(phthalimido)ethoxy]-3-oxobutyric acid ethyl ester toluene solution.

[0013] To the above 4-[2-(phthalimido)ethoxy]-3-oxobutyric acid ethyl ester toluene solution, add 42.1g of o-chlorobenzaldehyde and 8g of piperidine. After the addition, stir and heat to 120°C for 2h. After the reaction is completed, concentrate the reaction solution, add 34.5g of 3-aminocrotonic acid methyl ester and 600g of methanol to the reaction solution, reflux for 2h. After the reaction is completed, add glacial acetic acid, adjust the pH to ≤5, cool to 15°C, stir and crystallize, filter and dry to obtain 144.3 phthaloyl amlodipine with a total yield of 89.1%. Example 4

[0014] Add 44.5g of phthalic anhydride, 250g of toluene and 19.1g of monoethanolamine to a three-necked flask. After the addition is complete, stir and heat to 120°C, reflux for 16h, add 20.3g of sodium methoxide to the above reaction solution. After the addition is complete, stir and heat to 120°C, reflux and separate the reaction for 2h, cool to 10°C, add 62g of ethyl 4-chloroacetoacetate dropwise to the reaction solution, stir and react for 4h after the addition is complete; take samples for testing, add water to quench the reaction, separate the liquids to obtain a toluene solution of ethyl 4-[2-(phthalimido)ethoxy]-3-oxobutanoate.

[0015] To the above 4-[2-(phthalimido)ethoxy]-3-oxobutyric acid ethyl ester toluene solution, add 42.1g of o-chlorobenzaldehyde and 8g of piperidine. After the addition, stir and heat to 120°C for 2h. After the reaction is complete, add 34.5g of 3-aminocrotonic acid methyl ester directly to the reaction solution, and add 50g of methanol. Reflux for 2h. After the reaction is complete, add glacial acetic acid, adjust the pH to ≤5, cool to 5°C, stir and crystallize, filter and dry to obtain 133.1g of phthaloyl amlodipine with a total yield of 82.3%.

Claims

1. An amlodipine intermediate 4-(2-chlorophenyl)-2-({[2-(phthalimido)ethyl]oxy}methyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester The preparation method is characterized in that The one-pot method includes: (1) Phthalic anhydride is dissolved in toluene, and monoethanolamine is added to the solution. After the addition, the temperature is raised to 110-120°C for reaction. After the reaction is completed, a base selected from sodium tert-butoxide, potassium tert-butoxide or sodium methoxide is directly added to the reaction solution, and the reaction is separated at 110-120°C. Subsequently, ethyl 4-chloroacetoacetate is added to the reaction solution, and the reaction is carried out at 110-120°C. After the reaction is completed, the reaction is quenched and the solution is separated to obtain ethyl 4-[2-(phthalimido)ethoxy]-3-oxobutanoate. Toluene solution; (2) Add o-chlorobenzaldehyde and piperidine to a toluene solution of ethyl 4-[2-(phthalimido)ethoxy]-3-oxobutyrate. After the addition is complete, heat the mixture to 110-120°C to obtain ethyl 2-[(2-chlorophenyl)methylidene]-4-{[2-(phthalimido)ethoxy}-3-oxobutyrate. Toluene solution; (3) Ethyl 2-[(2-chlorophenyl)methylidene]-4-{[2-(phthalimido)ethoxy}-3-oxobutanoate The reaction was carried out with 3-aminocrotonic acid methyl ester in an organic solvent and crystallized to obtain 4-(2-chlorophenyl)-2-({[2-(phthalimido)ethyl]oxy}methyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester. .

2. The method according to claim 1, characterized in that: In step (1), the molar ratio of monoethanolamine to phthalic anhydride is 1-1.1, and the molar ratio of alkali to phthalic anhydride is 1-1.3; the mass ratio of toluene to phthalic anhydride is 4:1-10:

1.

3. The method according to claim 1, characterized in that: The ratio of the amount of piperidine in step (2) to the amount of phthalic anhydride in step (1) is 0.3-0.

5.

4. The method according to claim 1, characterized in that: The organic solvent in step (3) is selected from toluene, methanol or a mixture thereof.

5. The method according to claim 1, characterized in that: The ratio of the amount of 3-aminocrotonic acid methyl ester in step (3) to the amount of phthalic anhydride in step (1) is 1-1.2, and the temperature of the cooling and stirring crystallization is 0-15°C.

6. The method according to claim 4, characterized in that When a mixture of methanol and toluene is used as the solvent in step (3), the mass ratio of methanol to toluene is 1:4-2:5.

Images