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High-purity selexipag

A high-purity technology of Selexipah, which is applied in the field of high-efficiency preparation of prostacyclin receptor agonist Selexipah, achieves the effect of low cost, high purity and simple operation

Active Publication Date: 2017-11-21
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] In summary, none of the currently disclosed technical solutions can meet the requirements of high preparation yield and high purity of Selexipah at the same time, especially for the most widely disclosed class of intermediates with (S-I) reaction, so it is necessary to develop new methods to prepare high-purity Selexipah with high yield

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Add 5-bromo-2,3-diphenylpyrazine (100g, 0.32mol), 4-isopropylamino-1-butanol (127g, 0.96mol) and potassium iodide (15.9g, 0.096mol) in the reaction flask , heated to 150°C for 16 hours. After the system was cooled to room temperature, ethyl acetate (800 mL) was added, washed with water (800 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with dichloromethane / heptane (1.2 L, v / v =1:5) recrystallized to obtain 4-((5,6-diphenylpyrazin-2-yl)-(isopropyl)amino)-1-butanol (75.5 g, yield: 65.3%) .

[0053] 1 H NMR (400MHz, CDCl 3 )δ8.01 (s, 1H), 7.45 (d, J = 5.8Hz, 2H), 7.35 (d, J = 6.8Hz, 2H), 7.28–7.21 (m, 6H), 4.79 (hept, J = 6.6 Hz,1H),3.68(t,J=6.3Hz,2H),3.47–3.38(m,2H),1.86(s,1H),1.80–1.72(m,2H),1.69–1.58(m,2H) ,1.27(d,J=6.7Hz,6H).

[0054] 13 C NMR (100MHz, CDCl 3 )δ151.6, 149.0, 139.6, 139.5, 139.0, 129.8, 129.3, 128.1, 128.0, 127.9, 127.1, 126.9, 62.4, 46.2, 42.2, 30.0, 25.7, ...

Embodiment 2

[0056] Add 4-((5,6-diphenylpyrazin-2-yl)-isopropylamino)-1-butanol (72.3g, 0.20mol), toluene (200mL), tetrabutylsulfuric acid in the reaction flask Ammonium hydrogen (33.9g, 0.10mol) and 40% potassium hydroxide solution (150mL, w%) were added dropwise with tert-butyl bromoacetate (78.0g, 0.40mol) under an ice-water bath, and the reaction was continued for 20 hours after dropping . Add concentrated hydrochloric acid dropwise to adjust the pH of the system to 5-6, extract with ethyl acetate (500mL), wash with water (500mL×2), and concentrate under reduced pressure to obtain 2-(4-((5,6-diphenylpyrazinyl ) (isopropyl) amino) butoxy) tert-butyl acetate crude product, directly carry out next step reaction.

Embodiment 3

[0058] Tetrahydrofuran (300 mL) and 10% sodium hydroxide solution (300 mL, w%) were added to the crude product obtained in Example 2 above, heated to reflux, and the reaction was complete as detected by TLC. Concentrate under reduced pressure to remove tetrahydrofuran, extract the aqueous phase with methyl tert-butyl ether (300mL×2), then adjust the pH to 2-3 with 1N hydrochloric acid, extract with ethyl acetate (800mL), concentrate under reduced pressure, and wash the residue with acetic acid Ethyl ester (500 mL) was recrystallized to give 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (S-I) (55.8 g, two steps Yield: 66.5%).

[0059] 1 H NMR (400MHz, CDCl 3 )δ8.10(s,1H),7.42(dd,J=7.6,1.8Hz,2H),7.32(dd,J=7.4,2.1Hz,2H),7.27–7.21(m,6H),4.85(hept ,J=6.6Hz,1H),4.07(s,2H),3.61(t,J=6.0Hz,2H),3.48–3.39(m,2H),1.81–1.70(m,4H),1.26(d, J=6.7Hz,6H).

[0060] 13 C NMR (400MHz, CDCl 3 )δ173.3, 152.0, 149.6, 139.4, 138.8, 138.4, 129.9, 129.5, 128.1, 128.0, 127.9, ...

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Abstract

The invention discloses high-purity selexipag. The selexipag is prepared by performing a reaction on a key intermediate 2-(4-((5,6-diphenylpyrazin-2-yl)isopropylamino)butoxy)acetic acid with CDI and disulfamide in an organic solvent in the presence of an organic alkali. The reaction is simple to operate, low in cost, friendly to the environment and high in yield (greater than 95%), and thus, is suitable for industrial production. The prepared selexipag has the purity of greater than or equal to 99.9%, and can well satisfy the requirements of drug production. The prepared selexipag has high purity, thereby being beneficial to obtaining drugs with higher grade afterwards.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a high-efficiency preparation method of prostacyclin receptor agonist Selexipah. The purity of the obtained Selexipah is more than or equal to 99.9%, and the yield is more than or equal to 95%. Background technique [0002] Selexipag (Selexipag) is a new type of oral long-acting PGI2 receptor agonist developed by Actelion Biopharmaceutical Company of Switzerland and approved by the US FDA in 2015 for the treatment of pulmonary hypertension in adults. The chemical name of Selexipa is: 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}-N-(methylsulfonyl ) Acetamide has the following structural formula: [0003] [0004] The compound of formula (S-I) is an important intermediate of Selexipah, and many documents have reported the process of preparing Selexipah by reacting it with methanesulfonamide. [0005] [0006] WO2002088084 (Heterocyclic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/20
CPCC07D241/20
Inventor 张倩倩屈晓霞
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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