Preparation method of 2-(2-(2-aminoethoxy) ethoxy) acetic acid

Abstract

The invention provides a preparation method of 2-(2-(2-amino ethyoxyl) ethyoxyl) acetic acid, which can obtain a product with qualified purity and meet the requirements of structural identification and batch production.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drug synthesis, and particularly relates to a preparation method of 2-(2-(2-aminoethoxy)ethoxy)acetic acid. Background Art

[0002] Semaglutide (also translated as Somaglutide or Semaglutide in China) is a second-generation GLP-1 (glucagon-like peptide-1) analogue developed by diabetes giant Novo Nordisk. It is the 7th GLP-1 receptor agonist launched globally after exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, and benaglutide, and also the third long-acting GLP-1 weekly preparation globally.

[0003] On September 20, 2019, the US FDA officially approved the marketing application of Rybelsus (oral semaglutide) for improving blood glucose control in type II diabetes patients in combination with diet and exercise.

[0004] On April 29, 2021, China officially approved the marketing of semaglutide injection (0.5mg, 1mg prefilled injection pen, Chinese trade name: NovoTai) to assist diet and exercise to improve blood glucose control in type II diabetes patients.

[0005] AEEA, chemically named 2-(2-(2-aminoethoxy)ethoxy)acetic acid, is a key intermediate for the preparation of semaglutide. The structure is shown as the compound of formula (IV):

[0006]

[0007] CN113896656A discloses a preparation method of 2-(2-(2-aminoethoxy)ethoxy)acetic acid, which uses 2-[2-(2-chloroethoxy)ethoxy]ethanol as the starting material and obtains the compound of formula (IV) after amino substitution, hydroxyl oxidation, and amino reduction. However, after substitution with benzylamine in this patent, during amino reduction, the benzyl group as a protecting group has the defect of selective deprotection. The reaction of benzyl group deprotection is incomplete, and the formed impurities are similar in properties to the product, making it difficult to separate and remove. Moreover, an expensive Pd catalyst is required, and the economy is poor. Summary of the Invention

[0008] The present invention provides a preparation method of 2-(2-(2-aminoethoxy)ethoxy)acetic acid, which can obtain a product with qualified purity and meet the requirements of structure identification and batch production.

[0009] In order to achieve the purpose of the present invention, the preparation method of 2-(2-(2-aminoethoxy)ethoxy)acetic acid described in the present invention has the following synthesis route:

[0010]

[0011] Its features include the following steps:

[0012] (1) Reacting the compound of formula (I) with a phthalimide salt to obtain a compound of formula (II);

[0013] (2) Subjecting the compound of formula (II) to an oxidation reaction to obtain a compound of formula (III);

[0014] (3) Subjecting the compound of formula (III) to a reduction reaction to obtain a compound of formula (IV).

[0015] Preferably, the phthalimide salt is directly added in the form of a salt, or added together in the form of phthalimide and a basic compound;

[0016] Preferably, the phthalimide salt is potassium phthalimide, and the basic compound is potassium hydroxide or potassium carbonate;

[0017] Preferably, the molar ratio of the potassium phthalimide salt to the compound of formula (I) is 0.5:1 - 1.50:1;

[0018] Preferably, the solvent for step (1) is N,N-dimethylformamide;

[0019] Preferably, the oxidant for step (2) is 2,2,6,6-tetramethylpiperidine oxide;

[0020] Preferably, the molar ratio of the oxidant for step (2) to the compound of formula (II) is 0.05:1 - 0.15:1;

[0021] Preferably, step (2) is carried out in the presence of sodium bromide and potassium dihydrogen phosphate;

[0022] Preferably, in step (2), the molar ratio of sodium bromide to the compound of formula (II) is 0.05:1 - 0.15:1, the molar ratio of potassium dihydrogen phosphate to the compound of formula (II) is 1.0:1 - 2.0:1, and the solvent is tert-butanol or water;

[0023] Preferably, the reducing agent for step (3) is hydrazine hydrate;

[0024] Preferably, the molar ratio of the reducing agent for step (3) to the compound of formula (III) is 1.0:1 - 1.5:1, and the solvent is absolute ethanol.

[0025] The present invention uses a phthalimide salt as an amination reagent. When the resulting intermediate product is subjected to amine reduction, there is no selective deprotection, and the obtained product basically does not contain impurities with incomplete deprotection. Moreover, hydrazine hydrate can be used during amine reduction, greatly improving the economy. Description of the Drawings

[0026] Figure 1 : 1 H-NMR spectrum

[0027] Figure 2 : 1 H-NMR spectrum

[0028] Figure 3 : 1 H-NMR spectrum Detailed Description of the Invention

[0029] The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention to the scope of the described examples.

[0030] Example 1: Synthesis of the Compound of Formula (II)

[0031] 6.0 L of DMF, 1.5 kg of the compound of formula (I) and 1647.7 g of potassium phthalimide were added to a reaction flask. After the addition was complete, the mixture was heated to 110 °C and stirred for 16 h. After the reaction was complete, it was cooled to 25 °C, filtered, and the filter cake was washed with 1.5 L × 3 of ethyl acetate. The filtrate was concentrated to dryness to obtain 2411.5 g of a pale yellow solid with a purity of 87.97% and a yield of 96.2%. Its 1 H-NMR spectrum is as Figure 1 shown.

[0032] Example 2: Synthesis of the Compound of Formula (III)

[0033] 6 L of water, 2000.0 g of the compound of formula (II), 73.7 g of sodium bromide, 111.9 g of Tempo (2,2,6,6-tetramethylpiperidine-N-oxide), 1462 g of potassium dihydrogen phosphate and 100 mL of tert-butanol were added to a reaction flask. The system was cooled to 5 °C, and 9070 g of 10% sodium hypochlorite solution was added. After the reaction was complete, sodium sulfite solution was added, and the mixture was extracted with 5 L × 3 of ethyl acetate. The organic phase was separated and concentrated to dryness to obtain 1337.7 g of an off-white solid with a purity of 99.53% and a yield of 63.7%. Its 1 H-NMR spectrum is as Figure 2 shown.

[0034] Example 3: Synthesis of the Compound of Formula (IV)

[0035] Add 5.6 L of absolute ethanol, 700.0 g of the compound of formula (III), and 154.6 g of hydrazine hydrate to a reaction flask, and stir at 90 °C for 5 h while keeping warm. After the reaction is completed, filter, and wash the filter cake with 500 mL×2 of absolute ethanol. Concentrate the filtrate to obtain 396.25 g of a white solid. Take the above solid, add it to 600 mL of absolute ethanol for pulping, filter, and dry the filter cake in an oven at 45 °C to obtain 275.4 g, with a purity of 98.03% and a yield of 70.7%. Its 1 1H-NMR spectrum is as Figure 3 shown.

[0036] The present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A preparation method of 2-(2-(2-aminoethoxy)ethoxy)acetic acid, which has the following synthesis route: It is characterized in that Comprising the following steps: (1) The compound of formula (I) reacts with phthalimide salt to obtain the compound of formula (II); (2) The compound of formula (II) undergoes an oxidation reaction to obtain the compound of formula (III); (3) The compound of formula (III) undergoes a reduction reaction to obtain the compound of formula (IV).

2. The method according to claim 1, characterized in that, The phthalimide salt is directly added in the form of a salt, or added together in the form of phthalimide and a basic compound.

3. The method according to claim 2, wherein The phthalimide salt is potassium phthalimide, and the basic compound is potassium hydroxide or potassium carbonate.

4. The method according to claim 3, wherein The molar ratio of the potassium phthalimide salt to the compound of formula (I) is 0.5:1 - 1.50:

1.

5. The method according to any one of claims 1-4, characterized in that, The solvent for step (1) is N,N-dimethylformamide.

6. The method according to any one of claims 1 to 4, characterized in that The oxidant for step (2) is 2,2,6,6-tetramethylpiperidine oxide.

7. The method according to claim 6, wherein The molar ratio of the oxidant for step (2) to the compound of formula (II) is 0.05:1 - 0.15:

1.

8. The method according to claim 6, characterized in that, Step (2) reacts in the presence of sodium bromide and potassium dihydrogen phosphate.

9. The method according to any one of claims 1 to 4, characterized in that The reducing agent for step (3) is hydrazine hydrate.

10. The method according to claim 9, wherein The molar ratio of the reducing agent for step (3) to the compound of formula (III) is 1.0:1 - 1.5:1, and the solvent is absolute ethanol.

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