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

A technology of aminoethoxy and ethoxy, which is applied in the field of preparation of 2-ethoxy)acetic acid, can solve the problems of many reaction by-products, combustion and explosion, and is not suitable for industrial scale-up production, and achieves product yield and High purity, mild reaction conditions, safe and controllable reaction process

Active Publication Date: 2022-01-07
成都泰和伟业生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the above synthetic method has the following problems: (1) There are many reaction by-products in the step of compound 1 to compound 2, and the target product is difficult to purify; (2) compound 2 In the step of synthesizing compound 3, NaH is used. NaH is a substance with high chemical activity. It is easy to spontaneously ignite in humid air, and it will release heat and hydrogen when it is heated or in contact with moisture and acid substances, which is easy to cause combustion and explosion. , not suitable for industrial scale-up production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1: the preparation method of 2-(2-(2-aminoethoxy) ethoxy) acetic acid

[0034] Prepare 2-(2-(2-aminoethoxy)ethoxy)acetic acid (ie Fmoc-AEEA) according to the following synthetic route:

[0035]

[0036] Step 1: Synthesis of Compound A1

[0037] Add 2-[2-(2-chloroethoxy)ethoxy]ethanol (i.e. compound A0, 843mg, 5.0mmol) in a round bottom flask, K 2 CO 3 (760mg, 5.5mmol) and NaBr (51.4mg, 0.5mmol); then add acetonitrile (13ml) and dibenzylamine (ie Bn 2 NH, 986mg, 5.0mmol), stirred at 80°C for 24 hours. After cooling to room temperature and filtering, the filtrate was evaporated to dryness to obtain 1.45 g of compound A1 with a yield of 88% and a purity of 90%.

[0038] Step 2: Synthesis of Compound A2

[0039] Add compound A1 (1.32 g, 4 mmol) in 40 mL of acetone solution in 15 mL of saturated sodium bicarbonate solution, cool down to 0-5 °C with an ice bath, add NaBr (0.1 g, 1 mmol), TEMPO (ie 2, 2, 6 , 6-tetramethylpiperidine oxide, 0.015g, 0.1mmol), ...

Embodiment 2

[0045]Embodiment 2: the preparation method of 2-(2-(2-aminoethoxy) ethoxy) acetic acid

[0046] Synthesize Fmoc-AEEA according to the route of Example 1, the only difference is that the operation of the first step to synthesize compound A1 is:

[0047] Add 2-[2-(2-chloroethoxy)ethoxy]ethanol (i.e. compound A0, 337mg, 2.0mmol) in a round bottom flask, K 2 CO 3 (414.6mg, 3mmol) and NaBr (30.8mg, 0.3mmol); add acetonitrile (6ml) and dibenzylamine (473.5mg, 2.4mmol) and stir at 50°C for 24 hours. After cooling to room temperature and filtering, the filtrate was evaporated to dryness to obtain 0.5 g of compound A1 with a yield of 75% and a purity of 95%.

[0048] The purity of Fmoc-AEEA synthesized in this example is 99.8%, and the total yield is 75%×91%×93%×91%=57.76%.

Embodiment 3

[0049] Embodiment 3: the preparation method of 2-(2-(2-aminoethoxy) ethoxy) acetic acid

[0050] Synthesize Fmoc-AEEA according to the route of Example 1, the only difference is that the operation of the second step to synthesize compound A2 is:

[0051] Add compound A1 (0.66g, 2mmol) in 20mL acetone solution in 15mL saturated sodium bicarbonate solution, cool down to 0~5℃ with ice bath, add NaBr (0.1g, 1mmol), TEMPO (ie 2,2,6 , 6-tetramethylpiperidine oxide, 0.015g, 0.1mmol), then TCCA (i.e. trichloroisocyanuric acid, 1.87g, 8.0mmol) was added in batches, keeping the temperature of the system at 0-5°C, and the addition was completed Then the system was stirred at room temperature for 3 hours. After the reaction was completed, isopropanol was added and stirred for 30 minutes to quench the reaction. The reaction solution was filtered through diatomaceous earth and concentrated, then added 15 mL of saturated sodium carbonate solution, and extracted twice with 30 mL of ethyl ace...

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Abstract

The invention provides a preparation method of 2-(2-(2-aminoethoxy) ethoxy) acetic acid, and belongs to the field of pharmacy. The method comprises the following steps of: (1) taking a compound A0 and Bn2NH as raw materials to react to prepare a compound A1; (2) taking the compound A1 and an oxidizing agent as raw materials to react to prepare a compound A2; (3) taking the compound A2 and hydrogen as raw materials to react to prepare a compound A3; and (4) taking the compound A3 and fluorenylmethoxycarbonyl succinimide as raw materials to react to prepare the 2-(2-(2-amino ethyoxyl) ethyoxyl) acetic acid. Compared with a preparation method in the prior art, the preparation method disclosed by the invention avoids the use of a dangerous raw material NaH, and is mild in reaction condition, safe and controllable in reaction process, high in product yield and purity and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a preparation method of 2-(2-(2-aminoethoxy)ethoxy)acetic acid. Background technique [0002] Semaglutide, also known as semaglutide, CAS number: 910463-68-2. It is a polypeptide drug synthesized by more than 30 amino acids. From a structural point of view, semaglutide replaces Ala at position 8 on the GLP-1 (7-37) chain with Aib, and Arg at position 34 replaces Lys. , Lys at the 26th position is connected with octadecanoic acid fatty chain, and modified with short-chain polyethylene glycol (PEG), the hydrophilicity is greatly enhanced, not only can be tightly combined with albumin, and cover dipeptidyl peptidase 4 ( DPP-4) hydrolysis site can also reduce renal excretion, prolong biological half-life, and achieve the effect of long circulation. Semaglutide injection is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist developed by Novo Nordisk, Denmark, which wa...

Claims

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Application Information

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IPC IPC(8): C07C269/04C07C271/16C07C213/02C07C213/08C07C217/08
CPCC07C269/04C07C213/02C07C213/08C07C2603/18C07C217/08C07C271/16Y02P20/55
Inventor 冯建祁伟吴逢伟谭康利邓小艳李政洋
Owner 成都泰和伟业生物科技有限公司
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