Реакция #75973

Уравнение реакции

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

Выход 80.0%

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

Выход 80.0%

Растворители

ethylacetate

ethyl acetate

water

isopropanol

water

Условия реакции

Обработка

1. 1
   ТемператураThe resulting suspension was heated
2. 2
   Температураat reflux for 4 hours
3. 3
   ТемператураThis suspension was heated to 50° C.
4. 4
   Фильтрацияfiltered
5. 5
   Промывкаwashed with 100 mL
6. 6
   Температураwarm (55° C.) ethylacetate
7. 7
   ДругоеThe filtrate separated to two phases
8. 8
   ДругоеThe aqueous phase was separated
9. 9
   Другоеthe organic phase was transferred to a 1-L three-neck round bottom flask, to which
10. 10
    ТемператураThe resulting suspension was refluxed for 6 hours
11. 11
    ФильтрацияThe resulting suspension was filtered
12. 12
    Другоеthe organic filtrate was separated
13. 13
    Промывкаwashed with 60 mL water
14. 14
    workup.DISTILLATIONThe organics were distilled to half of the original volume
15. 15
    Температураcooled
16. 16
    Фильтрацияmethyl 4-[(2R)-2-({[(2S)-2-hydroxy-3-phenoxypropyl]amino}methyl)-3,4-dihydro-2H-Chromen-6-yl]benzoate methanesulfonate filtered
17. 17
    Промывкаwashed with ethylacetate

Методика

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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