Synthesis of amino-alkoxy-heptanoic alkyl ester

http://www.google.com/patents/EP1756038A1?cl=en

Example 1 (^'lS,2S)-(l-Hydroxymethyl-2-methyl-butyl)-methyl-carbamic acid tert-butyl ester

39.3g Boc-Melle-OH (0.160 mol; Synthetech) were dissolved in 160ml THF and cooled to 0°C. 240ml IM BH₃-THF (0.24 mol; Fluka) were added at 0°C over 1 h and the clear, colorless reaction mixture was warmed up and stirred at RT for 1 h. The reaction mixture was again cooled to 0°C, 100ml deionized water were carefully added at 0 - 5°C over 0.5 h and after warming up to RT stirring was continued for 1 h. To the colorless solution were added 250ml 10% Na₂CO₃ all at once and after stirring for 1 h the reaction mixture was extracted with 1000ml and 500ml ethyl acetate. The organic layers were washed with brine and dried (Na₂Sθ₄). Removal of the solvent by rotary evaporation gave 36.9g (99.7%) product as colorless oil.

Example 2 (lS,2S)-(l-Formyl-2-methyl-butyl -methyl-carbamic acid tert-butyl ester

To a solution of 37.0g Boc-N-methyl-isoleucinol (160 mmol) in 160ml dichloromethane was added a solution of 5.4g NaHCO₃ (64 mmol) and 1.9g KBr (16 mmol) in 160ml deionized water. The reaction mixture was cooled to 0°C and after the addition of 125mg 2,2,6,6-tetramefhyl-piperidin-l-oxyl (TEMPO, 0.8 mmol), 122.6g 10.2% aqueous sodium hypochlorite (176 mmol Cl₂) were added under stirring over 2.5 h at 0-5°. After additional stirring for 30 min the excess of NaOCl was destroyed by the addition of ca. 1ml 38% aqueous sodium bisulfite and the reaction mixture was warmed up to 20°. The aqueous layer was extracted with 160ml dichloromethane and the organic layers were washed with 10% brine and dried (Na₂SO₄). Removal of the solvent by rotary evaporation afforded 35.7g (97.2%) crude product as a light orange oil. 

Example 3 ( 1 S,2S - ( 1 -Dimemoxymethyl-2-methyl-butyl) -methyl- amine hydrochloride

35.6g Crude aldehyde (160 mmol) were dissolved in 200ml methanol and cooled to ~15°C. 111ml 2.8M HCl-MeOH (0.31 mol HCl) were added all at once and the yellowish solution was stirred at RT for 2 h. 155ml Trimethyl orthoformate (1.42 mol; Fluka) were now added and the reaction mixture was stirred at RT over night (18 h). The solvent and the excess of the orthoester were removed by rotary evaporation (40°C/> 10 mbar) and the resulting beige, crystalline residue (33.7g) was dissolved in ca. 310ml isopropyl acetate at ~70°C. After cooling to RT and crystallization at 0°C for 17 h the crystal suspension was filtered and dried (50°C/10 mbar/16 h) affording 29.6g product as white needles, mp. 127-128°C

1H NMR

Example 28

(R)-3-Methoxy-3-fS)-pyrrolidin-2-yl-propionic acid tert-butyl ester hydrochloride

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To a stirred solution of 1.92g of the above described ester (6 mmol) in 30ml ethanol were added 0.20g Pd-C 10% (Degussa) and 0.62g 37% HCl (6.3 mmol). The black suspension was hydrogenated under vigorous stirring at RT for 2 h. The flask was flashed with Ar and the black suspension was filtered. After removal of the solvent by rotary evaporation (40°C/> 10 mbar) the white crystalline residue (1.57g) was dissolved in 7.5ml hot isopropyl acetate at ~80°C. Crystallization at -20°C yielding 1.37g (86%) white crystalline product, [α]o = -36.4 (CHC1₃; c = 1).

1H-NMR:

F.Hoffmann-La Roche Ag

BASEL  SWITZERLAND