Triethylamine → 1-Ethoxy-4-fluoro-2-(methoxymethoxy)benzene

5′-Fluoro-2′-hydroxyacetophenone (9.38 g, 61 mmole), iodoethane (7.3 ml, 91 mmole) and K2CO3 (12.6 g, 91 mmole) in acetone (100 ml) was stirred at 60° C. overnight. The mixture was filtered, evaporated, dissolved in hexane/ethyl acetate, washed with 2M NaOH (2×20 ml) and water, dried (MgSO4) and evaporated to give 2′-ethoxy-5′-fluoroacetophenone. A solution of mCPBA )19.3 g, 112 mmole) in CH2Cl2 (500 ml) was dried with MgSO4. 2′-Ethoxy-5′-fluoro-acetophenone (10.2 g, 56 mmole) was added and the mixture was stirred for 3 days. More mCPBA (5 g, 29 mmole) and MgSO4 was added and stirring was continued for 2 days. The mixture was filtered, diluted with ethyl acetate, washed with 2 M NaOH (2×70 ml), NH4Cl (sat, 50 ml), dried (MgSO4) and evaporated. The residue (10.45 g,) was dissolved in ethanol (100 ml). KOH (8.9 g, 160 mmole) was dissolved in water (50 ml). The solutions were combined and stirred for 1 h. The mixture was washed with diethyl ether/hexane 2×(50+25 ml), acidified with HCl (konc), extracted with ethyl acetate (3×100 ml), dried (MgSO4) and evaporated. The residue (8.22 g) was dissolved in CH2Cl2 (100 ml). Triethylamine 11.7 ml, 84 mmole) and bromomethyl methyl ether (6.45 ml, 79 mmole) were added and the solution was refluxed for 2 hrs. More triethylamine 11.7 ml, 84 mmole) and bromomethyl methyl ether (6.45 ml, 79 mmole) were added and refluxing was continued overnight. The solution was evaporated, CH2Cl (200 ml) was added and the solution was washed with water, 2M NaOH and NH4Cl. Drying (MgSO4) and evaporation provided 4.0 g of 1-ethoxy-4-fluoro-2-methoxymethoxybenzene. This compound was reacted in a manner analogous to Example 39 to give (+,−)-N-(cis-2-(3-ethoxy-6-fluoro-2-methoxymethoxyphenyl)-cyclopropyl)-N′-(5-chloropyrid-2-yl)-urea. Finally deprotection with 2 M HCl in dioxane gave the titled compound. 1NMR (250 MHz, DMSO-D6) δ 1.04-1.14 (m, 1H), 1.41-1.56 (m+t, 4H), 1.96-2.06 (m, 1H), 3.05-3.15 (m, 1H), 4.06-4.19 (m, 2H), 6.64 (t, 1H), 6.94 (dd, 1H), 7.19 (d, 1H), 7.82 (dd, 1H), 8.10 (d, 1H), 8.61 (br.s, 1H), 9.08 (br.s, 1H), 9.57 (br.s, 1H).

1. dry with materialA solution of mCPBA )19.3 g, 112 mmole) in CH2Cl2 (500 ml) was dried with MgSO4
2. stirringstirring
3. waitwas continued for 2 days
4. filtrationThe mixture was filtered
5. additiondiluted with ethyl acetate
6. washwashed with 2 M NaOH (2×70 ml), NH4Cl (sat, 50 ml)
7. dry with materialdried (MgSO4)
8. customevaporated
9. dissolutionThe residue (10.45 g,) was dissolved in ethanol (100 ml)
10. stirringstirred for 1 h
11. washThe mixture was washed with diethyl ether/hexane 2×(50+25 ml)
12. extractionextracted with ethyl acetate (3×100 ml)
13. dry with materialdried (MgSO4)
14. customevaporated
15. dissolutionThe residue (8.22 g) was dissolved in CH2Cl2 (100 ml)
16. temperaturethe solution was refluxed for 2 hrs
17. temperaturerefluxing
18. waitwas continued overnight
19. customThe solution was evaporated
20. additionCH2Cl (200 ml) was added
21. washthe solution was washed with water, 2M NaOH and NH4Cl
22. customDrying
23. custom(MgSO4) and evaporation

ORD record

ord-ec9c2d5a65a844c2bf0299c5151d637b

Source dataset

uspto-grants-2002_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06376492B1