Resolving method of medicine lesinurad axial chiral enantiomer

An enantiomeric and axial chirality technology, applied in organic chemistry and other directions, can solve the problems of high cost, high resolution difficulty, and unsuitable for industrial production.

Inactive Publication Date: 2017-08-29
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As far as the current industrial technology level is concerned, the cost of this split method is high and it is not suitable for industrial production
Moreover, the steric hind

Method used

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  • Resolving method of medicine lesinurad axial chiral enantiomer
  • Resolving method of medicine lesinurad axial chiral enantiomer
  • Resolving method of medicine lesinurad axial chiral enantiomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Preparation of racemic lesinurad

[0081] Referring to WO2014008295A1, lesinurad was synthesized. Proceed as follows:

[0082]

[0083] Add 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (Compound A, 5g, 0.018mol), potassium carbonate (3.74 g, 0.027mol, 1.5eq), DMF (50mL). Ethyl bromoacetate (3.3 g, 0.022 mol, 1.2 eq) was added dropwise with stirring. After dropping, stir the reaction at room temperature for 1.5h. After the reaction of raw materials was detected by sampling, 100 mL of ice water was dripped into the reaction solution under stirring, and a white solid was precipitated. Stir for 30min, filter with suction and wash with water. After the filter cake was dried, it was recrystallized with ethyl acetate to obtain 4 g of white solid, namely Intermediate B.

[0084] 1 HNMR (CDCl 3 ): δ8.54(dd, J=8Hz, 1H), 8.31(S, 1H), 7.66(m, 1H), 7.57(m, 1H), 7.40(dd, J=8Hz, 1H), 7.34(m ,2H),4.08(m,2H),3.72(s,3H),2.42(m,1H),1.16(m,2H),0.85(m,2H)

[0085]...

Embodiment 2

[0094]

[0095] (1S,2R)-2-Amino-1,2-diphenylethanol

[0096] Mix 10g of racemic lesinurad (1.0eq), 5g of chiral aminoalcohol derivative (1S,2R)-2-amino-1,2-diphenylethanol (1.0eq), and 65mL of acetone, and heat in an oil bath to 60°C, dissolve until clear. React at 60°C for 1h, stop heating, slowly cool to 7-8°C in an oil bath, filter, and wash the filter cake with ethyl acetate (EA) to obtain 4.05g of white solid powder A (salt of lesinurad in R configuration) , ee=98.6%. The filtrate was concentrated by rotary evaporation and dried to obtain 10.9 g of white solid C, ee=24.4% (the crude salt of S configuration lesinurad).

[0097] Add 4.05g of the white solid powder A in the above step to 230mL of ethyl acetate / acetone=10 / 1 mixed solvent, set the oil bath at 70°C, heat and dissolve until clear, stop heating after 1h, and slowly cool in the oil bath To 7-8°C, filter, and wash the filter cake with ethyl acetate to obtain 3.57 g of white solid powder B (salt of lesinurad i...

Embodiment 3

[0100]

[0101] (1S,2R)-2-Amino-1,2-diphenylethanol

[0102] Referring to Example 2, 5g racemic lesinurad (1.0eq), 3.9g chiral aminoalcohol derivative (1S,2R)-2-amino-1,2-diphenylethanol (1.5eq), 250mL ethyl acetate / acetone=10 / 1 mixed, heated to 80°C in an oil bath, dissolved until clear. React at 80° C. for 1 h, stop heating, slowly cool to 28° C. in an oil bath, filter, and wash the filter cake with ethyl acetate to obtain 2.2 g of white solid powder (salt of lesinurad in R configuration), ee=96.5%.

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Abstract

The invention discloses a resolving method of a medicine lesinurad axial chiral enantiomer. An alkamine derivative with optical activity is used as a resolving agent and reacts with a lesinurad racemic body in an organic solvent to form salts; the salts are dissociated to obtain (R)- or (S)-2-(5-bromo-4-(4-cyclopropylnaphthalene-1-yl-4H-1,2,4-triazole-3-sulfenyl)acetic acid with optical activity is obtained. By the method, an S configuration axial chiral enantiomer and an R configuration axial chiral enantiomer with the optical activity ee reaching 93 percent or higher can be obtained.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to medicine Lesinurad (2-(5-bromo-4-(4-cyclopropylnaphthalene-1-yl)-4H-1,2,4-triazol-3-ylsulfanyl) ) A resolution method for the axial chiral enantiomer of acetic acid). Background technique [0002] Ardea Biosciences has developed a novel URAT1 inhibitor, lesinurad, whose structure is shown in formula I, chemical name: 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1, 2,4-triazol-3-ylthio)acetic acid, or 2-[[5-bromo-4-(4-cyclopropyl-1-naphthalene)-4H-1,2,4-triazole-3 -yl]thio]acetic acid, CAS: 878672-00-5. Lesinurad is an oral uricosurgic agent that inhibits the renal proximal tubule uric acid transporter URAT1 for the treatment of gouty patients with hyperuricemia. [0003] [0004] In 2012, AstraZeneca acquired the drug with a huge investment of 1.26 billion US dollars to acquire Ardea Biosciences, and launched a clinical trial of lesinurad 200mg or 400mg tablets combined with xanth...

Claims

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Application Information

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IPC IPC(8): C07D249/12
CPCC07D249/12
Inventor 戴向前黄悦
Owner ZHEJIANG JINGXIN PHARMA
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