霍夫曼降解
1. 3-Aminopicolinic Acid and its Derivatives.
Aqueous sodium hypobromite (from bromine, 56 g., and ice-cold 15% sodium hydroxide solution, 350 ml.) was added to a solution of quinolinimide 7 (50 g.) in ice-cold 10% sodium hydroxide solution (1L.). The mixture was kept
at room temperature for an hour and then at 85" for a further hour ; after cooling, the pH was brought to 5 with 50% sulphuric acid and the mixture kept at 2" for 48 hr. A small amount of 2-aminonicotinic acid was removed by filtration and the filtrate treated with copper acetate (20 g.) in hot water (400 ml.) containing acetic acid (10 ml.). The precipitated copper salt was collected by filtration, washed with water, and resuspended in water (400 ml.), and the suspension saturated with hydrogen sulphide ; copper sulphide was removed by filtration and the filtrate concentrated, 3-Aminopicolinic acid (26 g. ; 56%), m. p. 210", parated on cooling;
a further crop (13 g, ; 28%) of less pure material could be obtained from the mother-liquor by evaporation to dryness.
2.霍夫曼降级反应为什么必须在碱性条件,且先低后高、逐步
升温呢?
3、将6.3g(157.5mmol)NaOH,67mLH2O置于250mL三口瓶中,装上温度计和搅拌器。在冰浴中冷却至0℃加入8.0gBr2(50mmol),温度升至4℃,然后于0℃迅速加入41mmol,温度升至3℃,反应液呈淡黄色。在0℃反应1h后,换冰浴为水浴,加热。随温度的升高,反应液颜色逐渐变深。于71℃反应1h,反应液为红褐色。停止反应,将反应液冷却到25℃,加入由14gNaOH配成的饱和溶液,溶液变黑。用40mL×3乙酸乙酯萃取。乙酸乙酯层加入0.8g无水Na2SO4静置过夜,过滤,在旋转蒸发仪上蒸除乙酸乙酯。真空干燥得暗红色固体3.57g,产率93%。
4. Organic Synthes, Coll. Vol. 10, p.549 (2004); Vol. 78, p.234 (2002).
5.二乙酸碘苯patent (Diacetoxyiodo)benzene hoffman
A.
Example 36 Preparation of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one (Compound of Formula (V)) (Step d) According to the Invention)
(S)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide (10.0 g, 30.5 mmol; enantiomeric purity (S):(R)=99.6:0.4, prepared using the method described in example 34) was suspended in a mixture of tetrahydrofuran (80 mL) and water (80 mL). Under stirring (diacetoxyiodo)benzene (12.75 g, 39.6 mmol) was added in one portion at 20° C. Stirring was continued and a water bath was ud to keep the temperature at 20° C. After a total reaction time of 3.5 h, less than 0.5% starting material was left according to HPLC. To the reaction
mixture ethyl acetate (100 mL) and aqueous 1 N methanesulfonic acid (50 mL) were added. Tetrahydrofuran and ethyl acetate were removed by evaporation in vacuo and another portion of ethyl acetate (100 mL) was added to the residual mixture. The urea type by-product was removed by filtration and washed with some ethyl acetate and water. The filtrate was transferred into a paratory funnel. The aqueous pha was parated
and extracted with ethyl acetate. Each of the organic phas were washed with aqueous 0.1 N methanesulfonic acid (2×40 mL). The aqueous phas were combined and the dissolved ethyl acetate was removed in vacuo. At 0° C. the pH was adjusted to 11 by addition of cold 40% aqueous NaOH and ice. The precipitate was collected by filtration, washed with water until the filtrate was neutral and dried in vacuo to afford
(S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one (7.0 g, 76%), chemical purity as determined by HPLC (area): 98.8%. The product was ud for the following step without further purification.
Example 37 Preparation of
(S)—N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide (Compound of Formula (I)) (Step d) According to the Invention)
In the reaction flask, (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one (7.0 g, 23.3 mmol), prepared as described in the previous example, was charged together wit
h dichloromethane (70 mL). At 40° C., a solution of acetic anhydride (2.97 g, 29.1 mmol) in dichloromethane (10 mL) was added dropwi under stirring over 30 min. After a reaction time of 1.5 h, no starting material was left according to HPLC. Acetone (250 mL) was added and the mixture was concentrated in vacuo to a volume of ?50 mL. The residue was dissolved in acetone (250 mL) at 60° C. The warm solution was treated with charcoal, the resulting suspension filtered and the charcoal washed with warm acetone. The filtrate was concentrated at 60° C. to a volume of ?50 mL when the product started to crystallize. At room temperature, tert-butyl methyl ether (100 mL) was added and the suspension was kept at this temperature overnight. The crystals were collected by filtration, washed with tert-butyl methyl ether and dried in vacuo to afford
(S)—N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide (7.0 g, 88%) as an off-white powder. The purity of the material by HPLC was 99.4% (area) and the enantiomeric ratio (S):(R) was determined as >99.9:0.1. The result of the elemental analys (C,H,N,F,O) corresponded to the expected values.
Example 38 Preparation of
(S)—N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide (Compound of Formula (I)) (Step c) According to the Invention)
To a solution of (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide (20.00 g, 60.91 mmol), (diacetoxyiodo)benzene (25.60 g, 79.48 mmol) und sodium acetate (10.00 g, 12.19 mmol) in acetic acid (190 mL) was added acetic anhydride (20 mL) and the clear solution was heated to 60° C. and stirred at this temperature for 16-20 h. The mixture was cooled to room temperature and 10% aqueous sodium sulfite solution (30 mL)
