반응 #75973

반응 방정식

Methanesulfonic acid

sodium formate

p-carbomethoxyphenyl boronic acid

K2CO3

(2S)-1-(benzyl{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-3-phenoxy-2-propanol hydrobromide

→

product

수율 80.0%

Methyl 4-[(2R)-2-({[(2S)-2-hydroxy-3-phenoxypropyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate methanesulfonate

수율 80.0%

용매

ethylacetate

ethyl acetate

water

isopropanol

water

반응 조건

후처리

1. 1
   온도The resulting suspension was heated
2. 2
   온도at reflux for 4 hours
3. 3
   온도This suspension was heated to 50° C.
4. 4
   여과filtered
5. 5
   세척washed with 100 mL
6. 6
   온도warm (55° C.) ethylacetate
7. 7
   기타The filtrate separated to two phases
8. 8
   기타The aqueous phase was separated
9. 9
   기타the organic phase was transferred to a 1-L three-neck round bottom flask, to which
10. 10
    온도The resulting suspension was refluxed for 6 hours
11. 11
    여과The resulting suspension was filtered
12. 12
    기타the organic filtrate was separated
13. 13
    세척washed with 60 mL water
14. 14
    workup.DISTILLATIONThe organics were distilled to half of the original volume
15. 15
    온도cooled
16. 16
    여과methyl 4-[(2R)-2-({[(2S)-2-hydroxy-3-phenoxypropyl]amino}methyl)-3,4-dihydro-2H-Chromen-6-yl]benzoate methanesulfonate filtered
17. 17
    세척washed with ethylacetate

실험 절차

In a 500-mL three-neck round bottom flask was dissolved K2CO3 (37.3 g, 270 mmol, 3.8 eq.) in 120 mL water. (2S)-1-(benzyl{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-3-phenoxy-2-propanol hydrobromide (Example 86, 40 g, 180 mmol, 1.0 eq.) was then added. To the resulting suspension was then added 130 mL isopropanol, p-carbomethoxyphenyl boronic acid (20.5 g, 114 mmol, 1.6 eq.) and 10% Pd/C (3.77 g, 1.78 mmol, 0.025 eq.). The resulting suspension was heated at reflux for 4 hours, cooled to 40° C., and 159 mL ethylacetate was added. This suspension was heated to 50° C. and filtered and washed with 100 mL warm (55° C.) ethylacetate. The filtrate separated to two phases. The aqueous phase was separated, and the organic phase was transferred to a 1-L three-neck round bottom flask, to which was added 300 mL ethyl acetate, 10% Pd-C (7.2 g, 0.89 mmol, 0.05 eq.) and a solution of sodium formate (14.4 g, 211 mmol, 3.0 eq.) in 80 mL water. The resulting suspension was refluxed for 6 hours. Methanesulfonic acid (28 g, 146 mmol, 4.1 eq.) was added to the reaction at a temperature ≧50° C. The resulting suspension was filtered; the organic filtrate was separated and washed with 60 mL water. The organics were distilled to half of the original volume, cooled and methyl 4-[(2R)-2-({[(2S)-2-hydroxy-3-phenoxypropyl]amino}methyl)-3,4-dihydro-2H-Chromen-6-yl]benzoate methanesulfonate filtered and washed with ethylacetate. The dry white crystalline product (15.5 g, 80% yield) was used without further purification. NMR (DMSO-d6) δ1.77 (m, 1H), 2.10 (m 1H), 2.42 (s, 3H, HSO3CH3), 2.90 (m, 2H), 3.12 (dd, J=8, 1.8 Hz, 1H), 3.36 (m, 2H), 3.85) (s, 3H), 4.02 (m, 2H), 4.25 (m, 1H), 4.50 (tt, J=7, 1.5 Hz, 1H), 5.87 (bs, 1H, OH), 6.95 (m, 4H, ArH), 7.33 (t, J=7 Hz, 2H, ArH), 7.52 (m, 2H, ArH), 7.77 (d, J=8 Hz, 2H, ArH), 7.95 (d, J=8 Hz, 2H, ArH); MS (EI): m/z 448 (MH+).

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