Patent Document

BACKGROUND OF THE INVENTION 
     2-methoxyisobutylisonitrile is a key starting material in the preparation of Tc-99 m hexakis (2-methoxyisobutylisonitrile). The preparation of Tc-99 m hexakis (2-methoxyisobutylisonitrile) from 2-methoxyisobutylnitrile has been described by Angelberger, P.; Zbiral, E.; [Ber] OEFZS., 1987, 44. This cationic complex has been reported to be clinically useful as a myocardial perfusion agent by Mousa, S. A.; Maina, M.; Brown, B. A.; Williams, S. J., J. Nucl. Med., 1987, 28, 619 (Abstr.). Mousa, S. A.; Cooney, J. M.; Williams, S. J., J. Nucl. Med., 1987, 28, 620 (Abstr.). Taillefer, R.; Laflamme, L.; Dupras G.; Picard, M.; Phaneuf, D. C.; Leveille, J., Eur. Nucl. Med., 1988, 13 515. The synthesis of hexakis (alkyl isocyanide) and hexakis (arylisocyanide) complexes of technetium(I) have been reported by Abrams, M. J.; Davison, A.; Jones, A. G.; Costello, C. E.; Pang, H., Inorg. Chem., 1983, 22, 2798. Abrams, M. J.; Davison, A.; Brodack, J. W.; Jones, A. G.; Faggiani, R.; Lock, C. J. L., J. Labelled Compd. Radiopharm, 1982, 14, 1596. 
     The synthesis of various isocyanides have been reported by Weber, W. P.; Gokel, G.W.; Ugi, I. K., Angew. Chem., Int. Ed. Engl. 1972, II, 530. Schuster, R. E.; Scott, J. E.; Casanova, J. Jr., &#34;Organic Synthesis&#34;, Wiley; New York, Collect. Vol. V, 1973, 772-774.. Giselher, S.; Ugi, I., Angew. Chem., Int. Ed. Engl. 1977, 16 259. Casanova, J. Jr.; Schuster, R. E.; Werner, N. D., J. Chem. Soc., 1963, 4280. 
     SUMMARY OF THE INVENTION 
     It has now been discovered that 2-methoxyisobutylisonitrile can be prepared from commercially available 2-hydroxyisobutyronitrile in a four step synthesis with a yield of 26%. A synthesis of 2-methoxyisobutylisonitrile has been reported in Angelberger, P.; Zbiral, E., [Ber]OEFZS., 1987, 44, which involves six steps and with no reported yields. European Patent Application No. 233,368 discloses a five step process with an overall yield of 8.1% 
     The process of this invention can be represented by the following diagram: ##STR1## 
     DETAILED DESCRIPTION OF THE INVENTION 
     Etherification of the nitrile compound 1 is effected with anhydrous methanol and freshly fused zinc chloride to give the compound 2. Reduction of compound 2 with lithium aluminum hydride in ether produces the amine compound 3 in good yield in about 8 hours. N-Formylation of compound 3 with ethyl formate and a catalytic amount of p-toluenesulphonic acid produces the amide compound 4. The amide compound 4 is isolated in high yield after distillation. In the final conversion to isonitrile the amide compound 4 is treated with trichloromethylchloroformate (&#34;diphosgene&#34;) at -40° C. in the presence of triethylamine. Isolation of compound 5 is easily achieved after distillation. Compound 5 is reasonably stable and can be stored in a refrigerator for six months. 
    
    
     The following examples are specific embodiments of this invention. 
     EXAMPLE 1 
     2-Methoxyisobutyronitrile 
     To a solution of freshly fused zinc chloride (149 g, 1.09 mol) in anhydrous methanol (100 ml) was added 2-hydroxyisobutyronitrile (commercially available) (100 ml, 93 g, 1.09 mol). The mixture was heated (60° C.) in an oil bath for 12 hours. After cooling to room temperature, the reaction mixture was poured onto ice. It was then extracted with ether (3×200 ml) and the combined extracts dried (Na 2  SO 4 ). Removal of the solvent and distillation of the residue afforded 52 g (51%) of 2-methoxyisobutyronitrile, bp 117°-118° C. 
       1  H-NMR (CDCl 3 ) 1.31 (s, 6H (CH 3 ) 2  C), 3.25 (s, 3H, OCH 3 ).  13  C-NMR (CDCl 3 ) 26.23 (CH 3  --), 53.12 (OCH 3 ), 71.12 (--C--), 120.28 (CN). 
     EXAMPLE 2 
     2-Methoxyisobutylamine 
     To a well stirred slurry of lithium aluminum hydride (9.0 g, 0.24 mol) in dry ether (500 ml) was added dropwise a solution of 2-methoxyisobutyronitrile (19.8 g, 0.2 mol) in dry ether (150 ml). The mixture was stirred under reflux for 8 hours. Excess hydride was carefully destroyed by the dropwise addition of water. The mixture was filtered and the filter cake washed with ether (6×150 ml). The combined ether solution was dried (Na 2  SO 4 ). After removal of ether, the residual liquid was distilled to give 16.8 g (82.0%) of the title compound, bp 124°-125° C. 
       1  H-NMR (CDCl 3 ) 1.16 (s, 6H, (CH 3 ) 2  C), 1.6 (s, 2H, NH 2 ), 2.65 (s, 2H, CH 2 ), 3.26 (s, 3H, OCH 3 ). 
       13  C-NMR (CDCl 3 ) 22.31 (CH 3 ), 49.15 (CH 2 ), 50.38 OCH 3 ), 74.77 (C) MS: m/e 104 (M+1). 
     Anal. Calculated for C 5  H 13  NO: C, 58:21; H, 12.70; N, 13.58. Found: C, 58.17; H, 12.84; N, 13.74. 
     EXAMPLE 3 
     N-Formyl-2-methoxyisobutylamine 
     To a stirred solution of 2-methoxyisobutylamine (16.4 g, 0.16 mol) and a catalytic amount of p-toluenesulphonic acid (75 mg) at 0° C. was added slowly ethylformate (11.79 g, 12.92 ml, 0.16 mol). After the slightly exothermic reaction ceased, the solution was refluxed for 16 hours, and distilled through a Vigreux column to give 19.36 g (93%) of N-formyl-2-methoxyisobutylamine, bp 74° C./15 mm. 
       1  H-NMR (CDCl 3 ) 1.13 (s, 6H, (CH 3 ) 2  C), 3.15 (s, 3H, OCH 3 , 3.27 (d, 2H J=5.8 Hz, CH 2 ) 6.0 (bs, 1H, NH), 8.19 (s, 1H, CHO). 
       13  C-NMR (CDCl 3 ) 22.65 (CH 3 ), 46.26 (CH 2 ) 49.60 (OCH 3 ), 161.53 (CHO). MS: m/e 132 (M+1) 
     Anal. Calculated for C 6  H 13  NO 2  -1H 2  O: C, 54.08; H, 10.01; N, 10.51. Found: C, 53.90; H, 9.85; N, 10.59. 
     EXAMPLE 4 
     2-Methoxyisobutylisonitrile 
     To a cooled (-40° C.) solution of N-formyl-2-methoxyisobutylamine (9.0 g, 0.69 mol) and triethylamine (19.5 ml, 14.16 g, 0.14 mol) in dry dichloromethane (100 ml) was added dropwise trichloromethylchloroformate (&#34;diphosgene&#34;) (4.15 ml, 6.8 g, 0.035 mol) in dry dichloromethane (50 ml) over a period of 1 hour. After the addition was complete, the temperature of the reaction mixture was allowed to rise to 0° C. and stirred for 1 hour, and at reflux temperature for 0.5 hour. Water (25 ml) was added and the organic layer separated. The organic layer was washed with a saturated solution of sodium bicarbonate (25 ml), water (25 ml) and dried (Na 2  SO 4 ). Evaporation of the methylene chloride left a dark brown liquid. The dark brown liquid obtained was distilled under vacuum to give 5.2 g (66.7%) of the title compound as a colorless liquid b.p. 60°-61° C./22 mm. 
       1  H-NMR (CDCl 3 ) 1.25 (s, 6H), (CH 3 ) 2  C), 3.22 (s, 3H, OCH 3 ), 3.38 (m, 2H, CH 2 ). 
       13  C-NMR (CDCl 3  22.23 (CH 3 ), 49.69 (OCH 3 ), 50.32 (CH 2 ), 73.06 (C), 157.49 (NC) MS: m/e 114 (M+1). 
     Anal. Calculated for C 6  H 11  NO: C, 63.68; H, 9.80; N, 12.38. Found: C, 63.72; H, 9.89; N, 12.70.

Technology Category: c