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Preparation method and application of cangrelor intermediate

A synthetic method and reaction technology, applied in the field of preparation of cangrelor intermediates

Active Publication Date: 2022-04-08
一禾(湖州)生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] In addition, in the patent CN105061431A, although the separation and purification of DEAE-Sephadex A25 ion exchange resin is used once, the yield is also significantly increased to 54%, but the ammonium salt form of the gained has to be further converted into the following formula with sodium iodide or sodium bicarbonate Compound shown by I

Method used

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  • Preparation method and application of cangrelor intermediate
  • Preparation method and application of cangrelor intermediate
  • Preparation method and application of cangrelor intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0082] Example 1: 2-chloro-N-(2-(methylthio)ethyl)-7H-purin-6-amine (2-chloro-N-(2-(methylthio)ethyl)-7H-purin-6 -amine, for the synthesis of the compound shown in formula III)

[0083] In a 100 ml flask, add 2-(methylthio)ethylamine (6.8 g, 57.5 mmol, 1.2 eq), butanol (50 ml), triethylamine (11.6 g, 115 mmol, 2 eq) and 2,6-Dichloropurine (8.96 g, 48 mmol, 1 equiv). The mixture was heated to 100°C and stirred for 6 hours. The mixture was cooled to room temperature and filtered to obtain a white filter cake. The filter cake was added to 150 ml of saturated sodium bicarbonate solution and stirred for 30 minutes, filtered, and the filter cake was washed with water (100 ml). The filter cake was dried in vacuo to obtain 10.9 g of the product, the compound of formula III. Yield 93%, HPLC purity 96%.

[0084] Proton spectrum data of the compound shown as formula III: 1 H NMR (300MHz,D 6 -DMSO)δ12.93(s,1H),8.17(s,1H),8.12(s,1H),3.62(dd,J=13.4,6.4Hz,2H),2.7(q,2H),2.1(s ,3H).

Embodiment 2

[0085] Example 2: Synthesis of 2-chloro-N-(2-(methylthio)ethyl)-7H-purin-6-amine (compound as shown in formula III)

[0086]In a 250 ml flask, add 2-(methylthio)ethylamine (21 g, 230 mmol, 1.5 eq), ethanol (50 ml), triethylamine (39 g, 389 mmol, 2.5 eq) and 2 , 6-Dichloropurine (29 g, 150 mmol, 1 equiv). The mixture was heated to 100°C and stirred for 6 hours. The mixture was cooled to room temperature, 200 ml of water were added and stirring was continued for 30 minutes. Filter to obtain a white filter cake. The filter cake was added to 400 ml of saturated sodium bicarbonate solution and stirred for 30 minutes, filtered, and the filter cake was washed with water (150 ml). The filter cake was dried in vacuo to yield 28.4 g of product, the compound of formula III. Yield 78%, HPLC purity 97%.

Embodiment 3

[0087] Example 3: 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)thio)-9H-purine (compound shown in formula IV )Synthesis

[0088] Compound (0.243 gram, 1 equivalent, 1 mmol) as shown in formula III, isothiourea salt compound (compound as shown in formula VI-2, 0.45 gram, 1.5 equivalent, 1.5 mmol) and sodium hydroxide ( 120 mg, 3 equivalents, 3 mmol) were dissolved in 2 ml of dry DMF, heated to 100°C and stirred for 3 days. If the reaction is not complete, add an isothiouronium salt compound (compound as shown in formula VI-2, 0.3 g, 1 equivalent, 1 mmol) and NaOH (0.08 mg, 2 equivalents, 2 mmol) and continue heating to 115 ° C React for 24 hours. The progress of the reaction was monitored by HPLC, the reaction was cooled to room temperature and water (6 mL) was added. The mixture was stirred for 30 minutes and a pale yellow precipitate formed. The solid was isolated by vacuum filtration and the filtrate was discarded. The filter cake was washed with water (20ml). D...

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Abstract

The invention discloses a preparation method and application of a cangrelor intermediate. The intermediate includes 2-chloro-N-(2-(methylthio)ethyl)-7H-purine-6-amine, which is obtained by reacting 2,6-dichloropurine with 2-methylthioethylamine. In addition, the cangrelor intermediate also includes 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)thio)-9H-purine, and adopts 2‑Chloro‑N‑(2‑(methylthio)ethyl)‑7H‑purin‑6‑amine with S‑3,3,3‑trifluoropropylisothiourea hydrohalide, S‑3, 3,3‑trifluoropropylisothiourea, 3,3,3‑trifluoropropyl‑1‑thiol or 3,3,3‑trifluoropropyl‑1‑thiol alkali metal salt. The technical route of the invention is simple and feasible, the sources of raw materials are wide, the conditions are mild, the production cost is low, the yield is high, the environment is friendly, and a more effective synthesis method is provided for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method and application of a cangrelor intermediate. Background technique [0002] Cangrelor is an intravenous P2Y12 inhibitor that blocks adenosine diphosphate (ADP)-induced platelet activation and aggregation, which is chemically similar to adenosine triphosphate (ATP). It is the first antiplatelet drug for intravenous administration, which is used to prevent coronary artery blockage caused by blood coagulation in adult patients during percutaneous coronary intervention (PCI), and can effectively reduce the risk of myocardial infarction and stent thrombosis . On June 22, 2015, Cangrelor was approved for marketing by the US FDA and authorized The Medicines Company to develop. The formulation specification is 50mg freeze-dried powder injection, and the trade name is KENGREAL TM . [0003] Chemical name of cangrelor: N6-[2-(methylthio)ethyl]-2-[(...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/24C07H19/167C07H1/00C07H19/20
CPCC07D473/24C07H1/00C07H19/167C07H19/20Y02P20/55
Inventor 王郁萱杰森艾伦·戴维李智温进富姚志刚
Owner 一禾(湖州)生物医药科技有限公司
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