A method for preparing a mosapride citrate intermediate and a method for preparing mosapride citrate

Abstract

The present invention discloses a method for preparing a mosapride citrate intermediate and a method for preparing mosapride citrate, and belongs to the field of biomedicine technology. The method for preparing the mosapride citrate intermediate comprises the following steps: reacting 2-aminomethylmorpholine and 4-fluorobenzyl chloride under the action of butyllithium and lithium carbonate to obtain a mosapride citrate intermediate represented by Formula I. The mosapride citrate intermediate prepared by the preparation method has high yield and purity, and can significantly improve production efficiency. The method is used for the preparation of mosapride citrate, which can significantly improve its preparation efficiency and promote low-cost, large-scale industrial production of mosapride citrate.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a method for preparing a mosapride citrate intermediate and a method for preparing mosapride citrate. Background Art

[0002] Mosapride citrate, a third-generation prokinetic drug, is a potent, selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist. It stimulates 5-HT4 receptors on cholinergic interneurons and myenteric nerves in the gastrointestinal tract, promoting the release of acetylcholine, thereby enhancing gastrointestinal motility and improving gastrointestinal symptoms in patients with functional dyspepsia without affecting gastric acid secretion. As a prokinetic drug without dopamine receptor antagonism, mosapride citrate offers advantages such as strong receptor selectivity, good pharmacokinetics, low dosage, safety, and high efficacy. Due to its excellent clinical efficacy and low side effects, it has been widely used both domestically and internationally, providing patients with options and assistance in relieving pain and restoring health.

[0003] The prior art discloses a variety of methods for preparing mosapride citrate. Among them, 4-(4-fluorobenzyl)-2-aminomethylmorpholine having a structure of Formula I is an important intermediate that affects the quality of the final product and is referred to as Intermediate 1.

[0004]

[0005] Patent CN108129414A discloses the preparation route of the above intermediate as follows:

[0006]

[0007] However, the above method requires the use of intermediate 2, (4-fluorobenzylamino)ethanol, which is relatively expensive and increases the synthesis cost of intermediate 1. In addition, the synthesis yield and purity of intermediate 1 are low. The above problems have affected the large-scale industrial preparation of mosapride citrate.

[0008] Therefore, researching and developing a new method for preparing 4-(4-fluorobenzyl)-2-aminomethylmorpholine is of great significance for the application of mosapride citrate. Summary of the Invention

[0009] In view of this, the technical problem to be solved by the present invention is to provide a method for preparing a mosapride citrate intermediate and a method for preparing mosapride citrate. The mosapride citrate intermediate prepared by the preparation method has high yield and purity, and can significantly improve production efficiency.

[0010] In order to achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0011] The present invention provides a method for preparing a mosapride citrate intermediate, comprising the following steps: reacting 2-aminomethylmorpholine and 4-fluorobenzyl chloride under the action of butyl lithium and lithium carbonate to obtain the mosapride citrate intermediate shown in formula I;

[0012]

[0013] Preferably, the molar ratio of butyl lithium to lithium carbonate is 10:(0.5-8); more preferably 10:(1-5). In some specific embodiments of the present invention, it is preferably 10:1 or 10:2 or 10:3 or 10:4 or 10:5.

[0014] Preferably, the molar ratio of butyl lithium to 2-aminomethylmorpholine is 10:(0.5-2); more preferably 10:(1-1.5); further preferably 10:1.

[0015] Preferably, the molar ratio of 2-aminomethylmorpholine to 4-fluorobenzyl chloride is (1-3):1; more preferably (1-2):1; further preferably 1:1.

[0016] Preferably, the solvent of the reaction is selected from one or more of acetonitrile, DMF, hexamethylphosphoramide, methanol, and ethanol; more preferably, acetonitrile.

[0017] Preferably, the reaction temperature is 80°C to 100°C, more preferably 80°C to 90°C. In some specific embodiments of the present invention, the reaction temperature is preferably 80°C.

[0018] The present invention also provides a method for preparing mosapride citrate, comprising the following steps:

[0019] 1) In the presence of butyl lithium and lithium carbonate, 2-aminomethylmorpholine and 4-fluorobenzyl chloride are reacted to obtain the mosapride citrate intermediate shown in formula I;

[0020] 2) reacting the mosapride citrate intermediate to obtain mosapride citrate represented by formula a;

[0021]

[0022] Preferably, the molar ratio of butyl lithium to lithium carbonate is 10:(0.5-8), more preferably 10:(1-5). In some specific embodiments of the present invention, it is preferably 10:1 or 10:2 or 10:3 or 10:4 or 10:5.

[0023] Preferably, the molar ratio of butyl lithium to 2-aminomethylmorpholine is 10:(0.5-2); more preferably 10:(1-1.5); further preferably 10:1.

[0024] Preferably, the molar ratio of 2-aminomethylmorpholine to 4-fluorobenzyl chloride is (1-3):1; more preferably (1-2):1; further preferably 1:1.

[0025] Preferably, the reaction temperature is 80°C to 100°C, more preferably 80°C to 90°C. In some specific embodiments of the present invention, it is preferably 80°C.

[0026] Preferably, the solvent of the reaction is selected from one or more of acetonitrile, DMF, hexamethylphosphoramide, methanol, and ethanol; more preferably acetonitrile or ethanol.

[0027] The 2-aminomethylmorpholine in the above-mentioned preparation method of the mosapride citrate intermediate and the preparation method of mosapride citrate can be purchased or prepared.

[0028] The preparation method of the 2-aminomethylmorpholine is shown in the following synthetic route:

[0029]

[0030] Wherein, the conditions of step (a) and step (b) are to react in an alkaline environment;

[0031] Preferably, the alkaline environment is independently provided by one or more of sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyl lithium, phenyl lithium, lithium diisopropylamide (LDA), and lithium hexamethyldisilazide (LiHMDS).

[0032] The conditions of step (c) in route 1 are to carry out the reaction in an acidic environment;

[0033] Preferably, the acidic environment is provided by one or more of sulfuric acid, hydrochloric acid, and nitric acid.

[0034] Compared with the prior art, the present invention provides a method for preparing a mosapride citrate intermediate, comprising the following steps: reacting 2-aminomethylmorpholine and 4-fluorobenzyl chloride in the presence of butyl lithium and lithium carbonate to obtain a mosapride citrate intermediate represented by Formula I. The mosapride citrate intermediate prepared by the preparation method has a high yield and purity, significantly improving production efficiency. Application of the method to the preparation of mosapride citrate significantly improves its production efficiency and promotes low-cost, large-scale industrial production of mosapride citrate. DETAILED DESCRIPTION

[0035] To further illustrate the present invention, the preparation method of the mosapride citrate intermediate and the preparation method of mosapride citrate provided by the present invention are described in detail below with reference to the examples.

[0036] Example 1

[0037] 1 mmol of 2-aminomethylmorpholine and 1 mmol of 4-fluorobenzyl chloride were dissolved in acetonitrile, and 10 mmol of butyl lithium and 1 mmol of lithium carbonate were added. The reaction was carried out at 100°C for 10 hours. After the reaction was completed, the temperature was cooled to room temperature and ethyl acetate was added for extraction. The organic phase was evaporated to dryness and concentrated under reduced pressure, and then recrystallized from ethanol to obtain intermediate 1, i.e., 4-(4-fluorobenzyl)-2-aminomethylmorpholine, with a purity of 99.5% and a yield of 95.2%. 1 H NMR: (400MHz, CDCl3) δ1.43-1.71(br,2H),1.85(t,J=9Hz,1H),2.15(m,1H),2.56-2.75(m,4H ),3.34-3.51(m,3H),3.68(m,1H),3.81-3.94(m,1H),7.04(t,J=10Hz,2H),7.26-7.37(m,2H).

[0038] Example 2

[0039] 1 mmol of 2-aminomethylmorpholine and 1 mmol of 4-fluorobenzyl chloride were dissolved in acetonitrile, and 10 mmol of butyl lithium and 2 mmol of lithium carbonate were added. The reaction was carried out at 100°C for 10 hours. After the reaction was completed, the temperature was cooled to room temperature and ethyl acetate was added for extraction. The organic phase was evaporated to dryness and concentrated under reduced pressure, and then recrystallized from ethanol to obtain intermediate 1, i.e., 4-(4-fluorobenzyl)-2-aminomethylmorpholine, with a purity of 99.4% and a yield of 93.7%.

[0040] Example 3

[0041] 1 mmol of 2-aminomethylmorpholine and 1 mmol of 4-fluorobenzyl chloride were dissolved in acetonitrile, and 10 mmol of butyl lithium and 5 mmol of lithium carbonate were added. The reaction was carried out at 100°C for 10 hours. After the reaction was completed, the temperature was cooled to room temperature and ethyl acetate was added for extraction. The organic phase was evaporated to dryness and concentrated under reduced pressure, and then recrystallized from ethanol to obtain intermediate 1, i.e., 4-(4-fluorobenzyl)-2-aminomethylmorpholine, with a purity of 99.1% and a yield of 93.4%. 1 H NMR:

[0042] Example 4

[0043] 1 mmol of 2-aminomethylmorpholine and 1 mmol of 4-fluorobenzyl chloride were dissolved in acetonitrile, and 10 mmol of butyl lithium and 3 mmol of lithium carbonate were added. The reaction was carried out at 100°C for 10 hours. After the reaction was completed, the temperature was cooled to room temperature and ethyl acetate was added for extraction. The organic phase was evaporated to dryness and concentrated under reduced pressure, and then recrystallized from ethanol to obtain intermediate 1, i.e., 4-(4-fluorobenzyl)-2-aminomethylmorpholine, with a purity of 99.7% and a yield of 95.2%.

[0044] Example 5

[0045] 1 mmol of 2-aminomethylmorpholine and 1 mmol of 4-fluorobenzyl chloride were dissolved in acetonitrile, and 10 mmol of butyl lithium and 4 mmol of lithium carbonate were added. The reaction was carried out at 100°C for 10 hours. After the reaction was completed, the temperature was cooled to room temperature and ethyl acetate was added for extraction. The organic phase was evaporated to dryness and concentrated under reduced pressure, and then recrystallized from ethanol to obtain intermediate 1, i.e., 4-(4-fluorobenzyl)-2-aminomethylmorpholine, with a purity of 99.5% and a yield of 94.6%.

[0046] Example 6

[0047] 1 mmol of 2-aminomethylmorpholine and 1 mmol of 4-fluorobenzyl chloride were dissolved in acetonitrile, and 10 mmol of butyl lithium and 4 mmol of lithium carbonate were added. The mixture was reacted at 80°C for 10 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was evaporated to dryness and concentrated under reduced pressure, and then recrystallized from ethanol to obtain intermediate 1, i.e., 4-(4-fluorobenzyl)-2-aminomethylmorpholine, with a purity of 99.8% and a yield of 95.1%.

[0048] The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by those skilled in the art, and such improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing a mosapride citrate intermediate, characterized in that: The following steps are involved: Under the action of butyl lithium and lithium carbonate, 2-aminomethylmorpholine and 4-fluorobenzyl chloride react to obtain the mosapride citrate intermediate shown in formula I; 2. The preparation method according to claim 1, characterized in that The molar ratio of the butyl lithium to the lithium carbonate is 10:(0.5-8).

3. The preparation method according to claim 1, characterized in that The molar ratio of butyl lithium to 2-aminomethylmorpholine is 10:(0.5-2); The molar ratio of 2-aminomethylmorpholine to 4-fluorobenzyl chloride is (1-3):

1.

4. The preparation method according to claim 1, characterized in that The solvent of the reaction is selected from one or more of acetonitrile, DMF, hexamethylphosphoramide, methanol and ethanol.

5. The preparation method according to claim 1, characterized in that The reaction temperature is 80°C to 100°C.

6. A method for preparing mosapride citrate, characterized in that: The following steps are involved: 1) In the presence of butyl lithium and lithium carbonate, 2-aminomethylmorpholine and 4-fluorobenzyl chloride are reacted to obtain the mosapride citrate intermediate shown in formula I; 2) reacting the mosapride citrate intermediate to obtain mosapride citrate represented by formula a; 7. The preparation method according to claim 6, characterized in that The molar ratio of the butyl lithium to the lithium carbonate is 10:(0.5-8).

8. The preparation method according to claim 6, characterized in that The molar ratio of the butyl lithium to 2-aminomethylmorpholine is 10:(0.5-2).

9. The preparation method according to claim 6, characterized in that The reaction temperature is 80°C to 100°C.

10. The preparation method according to claim 6, characterized in that The solvent of the reaction is selected from one or more of acetonitrile, DMF, hexamethylphosphoramide, methanol and ethanol.

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