The synthetic method of carboxyamidotriazole

A carboxylamine triazole and a synthesis method technology are applied in the field of pharmaceutical synthesis, and can solve the problems that product purity, operability and safety are difficult to apply to industrial production, and total impurity content is difficult to meet the requirements of drug marketization, and achieves high production efficiency. , High safety and strong operability

Active Publication Date: 2021-04-13
GUANGDONG YINZHU PHARMACEUTICAL TECHNOLOGY CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The applicant found in the actual application process that the product purity, operability, safety, etc. involved in the synthesis process of intermediates 5 to TM in the above synthesis route are difficult to apply to industrial production
And more importantly, in the carboxylaminotriazole prepared by this synthetic route, the control of the residues of raw material intermediates in each step and the total impurity content produced in the process is difficult to meet the requirements of drug marketization

Method used

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  • The synthetic method of carboxyamidotriazole
  • The synthetic method of carboxyamidotriazole
  • The synthetic method of carboxyamidotriazole

Examples

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preparation example Construction

[0029] The invention provides a synthesis method of carboxyaminotriazole, comprising steps (1) to (4).

[0030] The structural formulas of compound SM1, compound int-1, compound int-2 and carboxyaminotriazole involved therein are as follows:

[0031] .

[0032] Step (1) and step (2) adopt "one-pot method" to carry out halogenation reaction and azide substitution reaction sequentially. Among them, step (1) uses N,N-dimethylformamide (abbreviated as DMF, the same below) as solvent, thionyl chloride and (4-chlorophenyl)-[2,6-dichloro-4- (Hydroxymethyl)phenyl]-methanone (compound SM1) undergoes a substitution reaction, and the reaction solution is added with anhydrous potassium carbonate to adjust the base to obtain a reaction solution system containing compound int-1.

[0033] In one example, step (1) includes the following steps:

[0034] Add compound SM1 to N,N-dimethylformamide, stir to dissolve, then add thionyl chloride to carry out halogenation reaction; the obtained r...

Embodiment 1

[0068] This embodiment provides a kind of synthetic method of carboxyamine triazole, and the steps are as follows:

[0069] Step 1 and Step 2: Preparation of compound int-1 (SASZ-int1) and compound int-2 (SASZ-int2)

[0070]

[0071] 1. Ratio of materials (Table 1)

[0072] Table 1 The list of ingredients prepared by compound int-1 and compound int-2 in this example

[0073]

[0074] 2. Operation content

[0075] Preparation of 4% sodium chloride solution: Add 73kg of drinking water and 3.04kg of sodium chloride into a 500L reaction tank, stir until dissolved, and release for later use.

[0076] Drinking water pre-cooling: Add 114kg of drinking water to the 500L reaction tank, cool to 0°C, and set aside.

[0077] Add 21.66kg of dimethylformamide to a 200L reaction tank, then add 7.60kg of compound SM1 (SASZ-SM1), start stirring, and after the solution is clear, cool down to an internal temperature of 0°C. Slowly add 5.48 kg of thionyl chloride, control the internal t...

Embodiment 2

[0114] This example provides a synthesis method of carboxyaminotriazole, the steps of which are the same as those in Example 1, the main difference being that during the preparation of compound int-1 (SASZ-int1), potassium carbonate was added in 4 batches, each time The amount accounts for 25% of the total amount of potassium carbonate" and is adjusted to "add potassium carbonate in 4 batches, and the amount of each addition accounts for 15%, 15%, 35%, and 35% of the total amount of potassium carbonate successively".

[0115] details as follows:

[0116] Preparation of 4% sodium chloride solution: Add 73kg of drinking water and 3.04kg of sodium chloride into a 500L reaction tank, stir until dissolved, and release for later use.

[0117] Drinking water pre-cooling: Add 114kg of drinking water to the 500L reaction tank, cool to 0°C, and set aside.

[0118] Add 21.66kg of dimethylformamide to a 200L reaction tank, then add 7.60kg of compound SM1 (SASZ-SM1), start stirring, and a...

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Abstract

The present invention relates to a kind of synthetic method of carboxyamine triazole. The synthetic method of carboxyaminotriazole comprises the following steps: step (1) adopts " one pot method " to carry out halogenation reaction and azide substitution reaction successively; Step (2) uses DMSO as solvent, in potassium carbonate (K 2 CO 3 ) under the action of cyanoacetamide and compound int‑2 to undergo a Click ring-forming reaction; step (3) refines the product of step (2), and the raw material ratio, feeding sequence, feeding temperature, post-treatment and other multiple nodes for optimal control, so that the related substances in the prepared carboxyaminotriazole product can meet the requirements of drug quality and industrial production of drugs, and the synthesis method has high yield, low process cost, good stability, and is easy to use. Carry out industrialized scale-up production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis method of carboxyamine triazole. Background technique [0002] Inhibition of angiogenesis in cancerous tissue is an effective approach in the treatment of solid tumors. Carboxyamidotriazole (CAI) is one of the most representative anti-angiogenic drugs. It specifically inhibits calcium ion-mediated signal transduction pathways, thereby inhibiting angiogenesis in cancerous tissues and reducing the invasion of cancer cells. Force and motility, affect the proliferation and metastasis of cancer cells. [0003] At present, the synthesis method of carboxytriazole mainly refers to "Wu Xiaofeng, Fang Gang, etc., Synthesis of New Anticancer Drug L-651582 [J], China Journal of Pharmaceutical Industry, 2006, 37 (3): 147-149", and its synthesis route is as follows Shown: [0004] [0005] The applicant found in the actual application process that the product purity, o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/04
CPCC07D249/04
Inventor 叶菜英李宗森池研生
Owner GUANGDONG YINZHU PHARMACEUTICAL TECHNOLOGY CO LTD
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