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A process for the preparation of regadenoson

A technology of regardson and compound, applied in the field of preparing regardson, can solve the problems of difficult removal, metal pollution of regardson, etc., and achieve the effect of low toxicity

Inactive Publication Date: 2016-08-17
SCINOPHARM TAIWAN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Furthermore, WO2012 / 149196 uses the catalyst IDAAR-Cu 2+ (iminodiacetate-copper(II)), which can be difficult to remove, resulting in metal contamination in the final regadepine

Method used

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  • A process for the preparation of regadenoson
  • A process for the preparation of regadenoson
  • A process for the preparation of regadenoson

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0075] Embodiment 2 prepares Regadeson with formula IIb compound

[0076] 2-Chloro-2',3'-O-isopropylidene-adenosine (IIb) was prepared according to Scheme 2.

[0077] Process 2

[0078]

[0079] in N 2(g) 2-chloroadenosine (IIa, 20g, 66.3mmol), 2,2-dimethoxypropane (DMOP, 60mL) and HClO 4 The aqueous solution (70 wt%, 3 mL) was stirred at room temperature for 8 h. with NaHCO 3 Saturated aqueous solution (about 120 mL) slowly adjusted the pH of the reaction mixture to 7-9. After stirring in an ice bath for 2 h, the mixture was filtered, washed with water (50 mL) and then dried under vacuum at 50° C. for 6 h to afford the compound of formula lib with 99% purity in 88% yield.

[0080] 1 H NMR (400MHz, DMSO-d6) δ8.36(s, 1H), δ7.87(s, 2H), δ6.06(d, J=2.4Hz, 1H), δ5.28(dd, J=6Hz ,2.4Hz,1H),δ5.08(t,J=5.6Hz,1H),δ4.94(dd,J=6Hz,2Hz,1H),δ4.21(m,1H),δ3.54(m ,2H), δ1.54(s,3H), δ1.33(s,3H).

[0081] 13 C NMR (100 MHz, DMSO-d6) δ 157.3, 153.6, 150.4, 140.4, 118.6, 113.6, 89.8,...

Embodiment 3

[0092] Embodiment 3 prepares Regadeson with formula IId compound

[0093] 2-Chloro-2',3'-O-cyclohexylidene-adenosine (IId) was prepared according to Scheme 5.

[0094] Process 5

[0095]

[0096] in N 2(g) 2-chloroadenosine (IIa, 5g, 16.58mmol), cyclohexanone (50mL) and HClO 4 (70 wt%, 0.75 mL) was stirred at room temperature for 24 h. The pH of the reaction mixture was slowly adjusted to 7-9 with 6N KOH (3 mL) and diluted with water (100 mL). The aqueous phase was extracted twice with DCM (50 mL x 2). The combined organic phases were washed with water (100 mL) and then washed with anhydrous Na 2 SO 4dry. The separated dry organic phase was evaporated to dryness under vacuum at 50°C. The residue was passed through a silica gel column to obtain the compound of formula IId with 99% purity in 51% yield.

[0097] 1 H NMR (400MHz, CDCl 3 )δ7.82(s,1H),5.97(s,2H),5.81(d,J=5.0Hz,1H),5.40(dd,J=11.6,2.0Hz,1H),5.20(t,J=5.4 Hz,1H),5.10(dd,J=5.9,1.1Hz,1H),4.53(s,1H),4.00(d...

Embodiment 4

[0109] Embodiment 4 prepares Regadeson with the compound of formula IIe

[0110] 2-Chloro-2',3'-O-isopropylidene-5'-O-(2-methoxy-propan-2-yl)-adenosine (IIe) was prepared according to Scheme 8.

[0111] Process 8

[0112]

[0113] in N 2(g) , the compound of formula IIb (5 g, 16.58 mmol), 2,2-dimethoxypropane (DMOP, 25 mL) and TfOH (0.28 g) were stirred at reflux temperature for 3 h. with Et 3 The reaction was quenched with N (1 mL) and evaporated to dryness under vacuum at 50 °C. The residue was suspended in EtOAc / toluene (20 mL) in a ratio of 1:1 (v / v). The isolated precipitate was passed through a silica gel column to afford Ile with 98% purity in 35% yield.

[0114] 1 H NMR (400MHz, DMSO-d6) δ8.32(s, 1H), 7.85(s, 2H), 6.12(s, 1H), 5.39(dd, J=6.1, 2.2Hz, 1H), 4.97(dd, J=6.1, 2.9Hz, 1H), 4.31(td, J=5.2, 3.0Hz, 1H), 3.56-3.39(m, 2H), 2.95(s, 3H), 1.54(s, 3H), 1.34(s ,3H), 1.20(s,3H), 1.17(s,3H).

[0115] 13 C NMR (100 MHz, DMSO-d6) δ 157.3, 153.6, 150.3, 140.6,...

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Abstract

The present invention provides novel processes for the preparation of regadenoson having the formula (I). In some embodiments, the intermediates for the synthesis of regadenoson are also provided.

Description

[0001] Cross References to Related Applications [0002] Not applicable [0003] Statement Concerning Rights to Inventions Made Pursuant to Federally Sponsored Research and Development [0004] Not applicable [0005] REFERENCE TO SEQUENCE LISTINGS, TABLES OR COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON CD-ROM [0006] Not applicable Background technique [0007] Regadenoson (regadenoson) (2-{4-[(methylamino)carbonyl]-1H-pyrazol-1-yl}adenosine) is A 2A Adenosine receptor agonists and indicated for radionuclide myocardial perfusion imaging (MPI) in patients unable to withstand adequate exercise stress. It was approved by the United States Food and Drug Administration in 2008 and marketed under the brand name Lexiscan. [0008] US Patent No. 6,403,567, US Patent No. 7,732,595 and US Publication No. 20110144320 describe a series of methods for preparing 2-adenosine N-pyrazole compounds including regadezone. However, these methods involve the reaction of genotoxic hydrazin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/167
CPCC07H19/167C07H19/16
Inventor 张孝恒梅丽君
Owner SCINOPHARM TAIWAN LTD
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