CN104817563B - The preparation method of pemetrexed N, N dibenzyl ethylenediamine salt - Google Patents

Abstract

The present invention relates to a preparation method of pemetrexed-N,N-dibenzylethylenediamine salt, the chemical name of the pemetrexed-N,N-dibenzylethylenediamine salt is N-[4 ‑[2‑(2‑amino‑4,7‑dihydro‑4‑oxo‑1H‑pyrrolo[2,3‑d]‑pyrimidin‑5‑yl)ethyl]benzoyl]‑L‑glucose Amino acid-N, N-dibenzylethylenediamine salt, pemetrexed-N, N-dibenzylethylenediamine salt of the present invention has good stability, both anhydrous and hydrate The form of pemetrexed-N, N-dibenzylethylenediamine salt has not been reported in the prior art, which provides a new choice for the dosage form research of pemetrexed; the pemetrexed of the present invention The preparation method of the plug-N,N-dibenzylethylenediamine salt has simple and reasonable steps, the HPLC of the obtained product is more than 99.70%, the single impurity content is less than 0.1%, and the total molar yield reaches 75-80%.

Description

Preparation method of pemetrexed-N,N-dibenzylethylenediamine salt

technical field

The invention relates to a preparation method of pemetrexed-N,N-dibenzylethylenediamine salt.

Background technique

Pemetrexed, a folic acid antagonist, is the world's first and currently only drug for the treatment of malignant pleural mesothelioma. At present, some progress has been made in the research on pemetrexed in the treatment of non-small cell lung cancer. The research structure shows that pemetrexed is very likely to become the first-line drug for the treatment of NSCLC.

At present, the main dosage form of pemetrexed is disodium salt. U.S. Patent No. 5,344,932 discloses the compound patent of pemetrexed and its medicinal salt. The preparation method of pemetrexed disodium salt is also disclosed in U.S. Patent No. 6,013,828 . At home, the Chinese patent "Pemetrexed Salt and Its Preparation Method" (Application No.: CN03138056.5) with publication number CN1552713A discloses a method using pemetrexed divalent metal ion salt, pemetrexed and organic A method for obtaining pemetrexed amine salt compound by reacting amine or inorganic ammonia; the Chinese patent "pemetrexed ethylenediamine salt and its preparation method" (application number: 200610024564.4) with publication number CN101033227A discloses a pemetrexed A method for obtaining pemetrexed ethylenediamine salt compound by reacting stopper with ethylenediamine; the Chinese patent whose authorization notification number is CN100364993C discloses a pemetrexed amine salt compound; the Chinese patent whose publication number is CN104098573A discloses a Pemetrexed organic salt compound.

Although many studies have been done on pemetrexed and its compounds in the prior art, and some salts of pemetrexed have been provided as clinical drugs, but the previous drugs often have problems such as poor stability and complicated preparation process.

Contents of the invention

The technical problem to be solved by the present invention is to provide a preparation method of pemetrexed-N,N-dibenzylethylenediamine salt according to the current situation of the prior art. The preparation method has simple and reasonable steps, and the obtained single impurity content is low , with higher purity and yield.

The technical scheme adopted by the present invention to solve the above-mentioned technical problems is: a pemetrexed-N,N-dibenzylethylenediamine salt, characterized in that: it has the structure of formula (I), and the pemetrexed The chemical name of -N,N-dibenzylethylenediamine salt is N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3- d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid-N,N-dibenzylethylenediamine salt,

Preferably, the pemetrexed-N,N-dibenzylethylenediamine salt contains 0-10 crystal water molecules.

Further preferably, the pemetrexed-N,N-dibenzylethylenediamine salt contains 1 to 7 crystal water molecules.

A preparation method of pemetrexed-N,N-dibenzylethylenediamine salt, characterized in that it comprises the following steps:

(1) Put pemetrexed disodium or its heptahydrate into water or an organic solvent, or a mixture of water and an organic solvent, under the protection of _N2 , the temperature of the control system is 20-35°C;

(2) Add acetic acid or an aqueous solution of acetic acid, or a mixed solution of acetic acid and an organic solvent to the system of step ( ₁ ), under N protection, control the temperature of the system at 20-35°C, and react for 1-1.5 hours; the reaction is complete After suction filtration and rinsing with an organic solvent, the resulting filter cake was vacuum-dried at 40-45°C for 12-16 hours to obtain pemetrexed diacid;

(3) Dissolve the pemetrexed diacid obtained in step (2) in an organic solvent, add N,N-dibenzylethylenediamine, under the protection of _N2 , control the temperature of the system at 20-35°C, and react 3 ~3.5h; after the reaction is completed, reduce the temperature of the reaction system to 10~18°C and keep it warm for 1~1.5h;

(4) Suction filter the mixture obtained in step (3) and rinse with an organic solvent, and dry the resulting filter cake at 40-45°C for 12-16 hours under reduced pressure to obtain the pemetrexed-N,N-di Benzylethylenediamine salt.

In the above scheme, the mass ratio of pemetrexed disodium or its heptahydrate to acetic acid is 1:1-10.

In each of the above preferred solutions, the molar ratio of pemetrexed diacid to N,N-dibenzylethylenediamine is 1:1-10.

Preferably, the organic solvent is any one of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, and isopropyl acetate.

Compared with the prior art, the present invention has the advantages of:

The pemetrexed-N,N-dibenzylethylenediamine salt of the present invention has good stability, and can exist in the form of anhydrous or hydrate, and the pemetrexed-N,N- Dibenzylethylenediamine salt has not been reported in the prior art, which provides a new option for the dosage form research of pemetrexed;

The preparation method of the pemetrexed-N,N-dibenzylethylenediamine salt of the present invention has simple and reasonable steps, the HPLC of the obtained product is ≥ 99.70%, the single impurity content is less than 0.1%, and the total molar yield reaches 75-80%.

Description of drawings

Fig. 1 is the HPLC collection of illustrative plates of the product obtained in Example 1 of the present invention;

Fig. 2 is the DSC spectrum of the product obtained in Example 1 of the present invention.

detailed description

The present invention will be further described in detail below in conjunction with the accompanying drawings and embodiments.

Pemetrexed-N, N-dibenzylethylenediamine salt of the present invention has the structure of formula (I), and the chemical name of pemetrexed-N, N-dibenzylethylenediamine salt is N-[ 4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L- Glutamic acid-N,N-dibenzylethylenediamine salt,

The reaction formula of above-mentioned pemetrexed-N, N-dibenzylethylenediamine salt preparation is as follows:

The preparation method of pemetrexed-N,N-dibenzylethylenediamine salt will be specifically described below through Examples 1-5.

Example 1:

In this embodiment, the preparation method of pemetrexed-N,N-dibenzylethylenediamine salt comprises the following steps:

(1) Under the protection of _N2 , put 5.0g of pemetrexed disodium heptahydrate into a 250mL four-necked flask filled with 100mL of purified water, and stir at 20°C until completely dissolved;

(2) Under the protection of _N2 , add 26mL of acetic acid aqueous solution with a volume concentration of 23% to the system of step (1), and the aqueous acetic acid solution will be dripped within 30min; the temperature of the control system is 20°C, and the reaction is stirred for 1h; After the completion of suction filtration, rinse the filter cake with purified water and drain it twice, each time the amount of purified water used is 25mL, then rinse the filter cake with absolute ethanol and drain it twice, each time use absolute ethanol The amount is 10mL; take the obtained filter cake and dry it in vacuum at 40°C for 12h to obtain pemetrexed diacid;

(3) Under the protection of N ₂ , take 3.75 g of pemetrexed diacid obtained in step (2) and put it into a four-necked flask filled with 80 mL of acetone, and stir until completely dissolved at 20° C.; then under N ₂ protection effect, at 20°C, add dropwise a mixed solution of 2.2g N,N-dibenzylethylenediamine and 20mL acetone, finish the dropwise addition within 30min, and keep it warm for 3h after the dropwise addition; after the reaction, lower the temperature of the reaction system to To 10 ℃, keep warm for 1h;

(4) Suction filter the mixture obtained in step (3) and rinse the filter cake with 10°C acetone and drain it twice, each time the amount of acetone used is 10mL; dry the obtained filter cake under reduced pressure at 40°C for 12h, that is The product pemetrexed-N,N-dibenzylethylenediamine salt was obtained.

As shown in Figure 1, the HPLC of the resulting product≥99.74%, the single impurity is less than 0.1%, and the total molar yield is 75～80%; As shown in Figure 2, pemetrexed-N,N-dibenzylethylenediamine Salt has a broad endothermic peak between 78°C and 150°C, a sharp endothermic peak between 180.5°C and 184°C, and a sharp endothermic peak between 227°C and 256°C.

Example 2:

In this embodiment, the preparation method of pemetrexed-N,N-dibenzylethylenediamine salt comprises the following steps:

(1) Under the protection of _N2 , put 5.0 g of pemetrexed disodium heptahydrate into a 250 mL four-neck flask filled with 100 mL of absolute ethanol, and stir at 35 ° C until completely dissolved;

(2) Under _N2 protection, add 52mL volumetric concentration to the system of step (1) and be 23% acetic acid ethanol solution, this acetic acid ethanol solution drops in 30min; The temperature of control system is 35 ℃, stirring reaction 1.5 h; After the reaction is completed, filter with suction, rinse the filter cake with purified water and drain it twice, each time the amount of purified water used is 25mL, then rinse the filter cake with absolute ethanol and drain it twice, each time without The amount of water and ethanol used was 10 mL; the resulting filter cake was vacuum-dried at 45°C for 16 hours to obtain pemetrexed diacid;

( ₃ ) Under N protection, get 3.75g of pemetrexed diacid obtained in step (2) and drop into a four-necked flask filled with 80mL ethyl acetate, and stir until completely dissolved at 35°C; ₂ Protective effect, at 35°C, add dropwise a mixed solution of 4.4g N,N-dibenzylethylenediamine and 20mL ethyl acetate, dropwise within 30min, and keep warm for 3.5h after the dropwise addition; Lower the temperature of the reaction system to 18°C and keep it warm for 1.5h;

(4) Suction filter the mixture obtained in step (3) and rinse the filter cake with ethyl acetate at 20°C and drain it twice, each time the amount of ethyl acetate used is 10mL; depressurize the obtained filter cake at 45°C After drying for 16 hours, the product pemetrexed-N,N-dibenzylethylenediamine salt was obtained.

Example 3:

In this embodiment, the preparation method of pemetrexed-N,N-dibenzylethylenediamine salt comprises the following steps:

(1) Under the protection of _N2 , 5.0 g of pemetrexed disodium heptahydrate was dropped into a four-necked flask filled with 100 mL of 50% ethanol aqueous solution, and stirred at 25° C. until completely dissolved;

(2) Under the protection of _N2 , add 78mL of acetic acid aqueous solution with a volume concentration of 23% to the system of step (1), and the aqueous acetic acid solution will be dripped within 30min; the temperature of the control system is 25°C, and the reaction is stirred for 1.2h; After the reaction is completed, filter with suction, rinse the filter cake with purified water and drain twice, each time the amount of purified water used is 25mL, then rinse the filter cake with absolute ethanol and drain twice, each time with absolute ethanol The usage amount is 10 mL; the obtained filter cake is vacuum-dried at 42°C for 14 hours to obtain pemetrexed diacid;

(3) Under the protection of N ₂ , take 3.75 g of the pemetrexed diacid obtained in step (2) and put it into a four-necked flask filled with 80 mL of tetrahydrofuran, and stir at 25° C. until completely dissolved; then under N ₂ protection At 25°C, add dropwise a mixed solution consisting of 6.6g N,N-dibenzylethylenediamine and 20mL tetrahydrofuran, and finish the dropwise addition within 30 minutes. After the dropwise addition, keep it warm for 3.2 hours; Lower to 15°C, keep warm for 1.2h;

(4) Suction filter the mixture obtained in step (3) and rinse the filter cake with acetone at 15°C and drain it twice, the amount of acetone used each time is 10mL; the obtained filter cake is dried under reduced pressure at 43°C for 13h, namely The product pemetrexed-N,N-dibenzylethylenediamine salt was obtained.

Embodiment 4: The preparation method of pemetrexed-N,N-dibenzylethylenediamine salt in this embodiment comprises the following steps:

(1) Under the protection of _N2 , put 5.0g of pemetrexed disodium heptahydrate into a 250mL four-neck flask filled with 100mL of purified water, and stir at 23°C until completely dissolved;

(2) Under the protection of _N2 , add 218.6mL of acetic acid methanol solution with a volume concentration of 23% to the system of step (1), and the acetate methanol solution will be dripped within 30min; the temperature of the control system is 23°C, and the reaction is stirred 1.3h; After the reaction is completed, filter with suction, rinse the filter cake with purified water and drain it twice, each time the amount of purified water is 25mL, then rinse the filter cake with absolute ethanol and drain it twice, each time The amount of absolute ethanol used was 10 mL; the resulting filter cake was vacuum-dried at 44°C for 13 hours to obtain pemetrexed diacid;

( ₃ ) Under N protection, get 3.75g of pemetrexed diacid obtained in step (2) and drop into a four-necked flask filled with 80mL of isopropyl acetate, and stir until completely dissolved at 23°C; Under _N2 protection, at 23°C, add dropwise a mixed solution consisting of 10.6g N,N-dibenzylethylenediamine and 20mL isopropyl acetate, dropwise within 30min, and keep warm for 3.2h after the dropwise addition; After completion, the temperature of the reaction system was lowered to 12°C and kept for 1.4h;

(4) Suction filter the mixture obtained in step (3) and rinse the filter cake with isopropyl acetate at 17°C and drain it twice, the amount of isopropyl acetate used each time is 10mL; put the obtained filter cake at 44°C After drying under reduced pressure for 15 hours, the product pemetrexed-N,N-dibenzylethylenediamine salt was obtained.

Example 5:

In this embodiment, the preparation method of pemetrexed-N,N-dibenzylethylenediamine salt comprises the following steps:

(1) Under the protection of _N2 , put 5.0g of pemetrexed disodium into a 250mL four-necked flask filled with 100mL of anhydrous methanol, and stir at 30°C until completely dissolved;

(2) Under the protection of _N2 , add 437.2mL of acetic acid methanol solution with a volume concentration of 23% to the system of step (1), and the acetic acid methanol solution will be dripped within 30min; the temperature of the control system is 30°C, and the reaction is stirred 1.1h; After the reaction is completed, filter with suction, rinse the filter cake with purified water and drain it twice, each time the amount of purified water is 25mL, then rinse the filter cake with anhydrous methanol and drain it twice, each time The amount of anhydrous methanol used was 10 mL; the resulting filter cake was vacuum-dried at 42°C for 15 hours to obtain pemetrexed diacid;

(3) Under the protection of N ₂ , take 3.75 g of pemetrexed diacid obtained in step (2) and put it into a four-neck flask filled with 80 mL of methyl ethyl ketone, and stir at 22°C until completely dissolved; then under N ₂ protection effect, at 22°C, add dropwise a mixed solution of 21.1g N,N-dibenzylethylenediamine and 20mL methyl ethyl ketone, dropwise within 30min, and keep warm for 3.1h after the dropwise addition; Lower to 15°C, keep warm for 1.4h;

(4) Suction filter the mixture obtained in step (3) and rinse the filter cake with methyl ethyl ketone at 12°C and drain it twice, each time using 10 mL of methyl ethyl ketone; dry the obtained filter cake at 44°C for 15 hours under reduced pressure, that is The product pemetrexed-N,N-dibenzylethylenediamine salt was obtained.

Claims (2)

1. a preparation method of pemetrexed-N, N-dibenzylethylenediamine salt, it is characterized in that: described pemetrexed-N, N-dibenzylethylenediamine salt has formula (I ), the chemical name is N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl) Ethyl]benzoyl]-L-glutamic acid-N,N-dibenzylethylenediamine salt, Described preparation method comprises the following steps: (1) Put pemetrexed disodium or its heptahydrate into water or an organic solvent, or a mixture of water and an organic solvent, under _N2 protection, the temperature of the control system is 20 to 35°C; The mass ratio of metrexed disodium or its heptahydrate to acetic acid is 1:1-10; (2) Add acetic acid or an aqueous solution of acetic acid, or a mixed solution of acetic acid and an organic solvent to the system of step ( ₁ ), under N protection, control the temperature of the system at 20-35°C, and react for 1-1.5 hours; the reaction is complete After suction filtration and rinsing with an organic solvent, the resulting filter cake was vacuum-dried at 40-45°C for 12-16 hours to obtain pemetrexed diacid; (3) Dissolve the pemetrexed diacid obtained in step (2) in an organic solvent, add N,N-dibenzylethylenediamine, under the protection of _N2 , control the temperature of the system at 20-35°C, and react 3 ~3.5h; after the reaction is completed, reduce the temperature of the reaction system to 10~18°C and keep it warm for 1~1.5h; the molar ratio of pemetrexed diacid to N,N-dibenzylethylenediamine is 1:1 ~10; (4) Suction filter the mixture obtained in step (3) and rinse with an organic solvent, and dry the resulting filter cake at 40-45°C for 12-16 hours under reduced pressure to obtain the pemetrexed-N,N-di Benzylethylenediamine salt. 2. the preparation method of pemetrexed-N,N-dibenzylethylenediamine salt according to claim 1 is characterized in that: described organic solvent is methyl alcohol, ethanol, Virahol, THF, acetic acid Any one of ethyl ester and isopropyl acetate.