衍生物还原制备醇

烷托之前氧原弟上尚未共用 的电弟与用电弟的硫原弟之间可能愈演愈烈互为互作用。分解之前间体而使酯烷托硫烷之前的羰托较为活波，进一步按羰托合于成的手段获得互为应的醛。

硫烷合于成残托的低速比合于成其他官能团快，因此，当羧硫衍生物分弟除此以外氰托、酯托 时，若支配硫烷的可用并在环境温度之前间体，可丝氨酸地合于成残托为互为应的酯胺，而不因素其他取代托。硫烷合于成羧硫的低速，脂肪硫多于类物质硫，位阻小的羧硫多于位阻大的羧硫，但羧硫盐则不可合于成。对脂肪硫酯的合于成低速一般较羧硫慢，对类物质硫酯基本上不愈演愈烈之前间体，这是由于芳环和羰托的共轭不稳定性，降低了羰托氧上的电弟云通量，使硫烷的亲电进攻难于进行。硫烷合于成残托的后处理比锂化铝锂合于成法简单，只必需甲酯胺淬灭，硫氧化就可以。

2.1 硫烷合于成羧硫

Organic Syntheses, Coll. Vol. 7, p.530; Vol. 63, p.136.

A 2-L, three-necked, round-bottomed flask is equipped with a mechanical stirrer, heating mantel, 250-mL graduated addition funnel, and an 8-in., air-cooled reflux condenser (West type) topped with a water-cooled distillation head and a 1-L receiving flask. It is connected to a nitrogen line through the still head. The glassware is either oven-dried and cooled in a desiccator or flame-dried and assembled while still hot. The assembly is flushed with nitrogen and charged with 200 g of L-valine (1.7 mol), 400 mL of tetrahydrofuran (THF), and 210 mL of freshly distilled boron trifluoride etherate (242 g, 1.7 mol). The mixture is heated at a rate sufficient to cause the THF to reflux gently and 188 mL (1.88 mol) of borane–methyl sulfide complex (BMS) is added dropwise over the course of 2 hr. The solution is then refluxed for 18 hr. The methyl sulfide that has collected at the stillhead is discarded, and the reaction mixture is cooled to 0°C and quenched by the slow addition of 200 mL of methanol. The addition funnel is replaced by a glass stopper, and the air-cooled condenser is removed, leaving the flask equipped for distillation of solvent through the distillation head. The reaction

mixture is concentrated under reduced pressure with heating and stirring. The distillation head is replaced by a water-cooled reflux condenser, and the residue is dissolved in 1 L of 6 M sodium hydroxide and refluxed for 4 hr. The mixture is saturated with potassium carbonate (ca. 400 g); cooled; filtered through a Celite pad on a coarse, fritted funnel; and extracted with three 1-L portions of chloroform. The combined extracts are washed with three portions of saturated sodium chloride (500 mL each), stirred over anhydrous potassium carbonate for 24hr, and concentrated under reduced pressure to give a yellow oil. The crude material is vacuum distilled to give 77.5 g (44%) of purified L-valinol, bp 62–67°C/2.5 mm(Note 6); [α]D20 + 14.6° (neat), nD20 1.455; IR (neat film) cm−1: 3300 (OH), and 1590 (NH2); NMR δ: 0.92 (d, 6 H), 1.54 (m, 1 H), 2.38–2.74 (m, 4 H), 3.13–3.78 (m, 2 H).

2.2 硫烷合于成α,β-不饱和acid 到α,β-不饱和酯胺

Organic Syntheses, Coll. Vol. 7, p.221 (1990); Vol. 64, p.104 (1986).

A dry, 2-L, one-necked, round-bottomed flask is equipped with a 1-L pressure-equalizing funnel and a large magnetic stirring bar. The system is flame-dried under an internal atmosphere of dry nitrogen. The flask is charged with 300 mL of anhydrous tetrahydrofuran and 100 g of monoethyl fumarate. The solution is then stirred under nitrogen and brought to about −5°C using an ice–salt/methanol bath (−10°C). A 1 M solution of 700 mL (0.70 mol) of borane–tetrahydrofuran complex is cautiously added dropwise (rapid H2 evolution occurs) with rigorous temperature control to avoid an exothermic reaction. The ice–salt bath is

maintained in position throughout the 90 min of addition. The stirred reaction mixture is then gradually allowed to warm to room temperature over the next 8–10 hr. The reaction is carefully quenched at room temperature by dropwise addition of 1 : 1 water : acetic acid (ca.20 mL) with stirring until no more gas evolution occurs. The reaction is concentrated at room temperature and water pump pressure to a slurry by removal of most of the tetrahydrofuran.

The slurry is carefully poured over a 20-min period into 300 mL of ice-cold, saturated sodium bicarbonate solution with mechanical stirring to avoid precipitation of solids, and the product is extracted with 300 mL of ethyl acetate. The aqueous layer is again extracted with 100 mL of ethyl acetate. The organic layers are combined, washed once with 200 mL of saturated sodium bicarbonate, then dried well with anhydrous magnesium sulfate.

Solvent removal at reduced pressure gives 61 g (67% yield) of essentially pure ethyl hydroxycrotonate.An analytical sample may be prepared by quick distillation (or Kugelrohr distillation) at 117–120°C (15 mm), but there is significant loss of material because of decomposition in the distillation pot. From 1 g of product, 0.72 g of pure material is obtained in this way, and recovery decreases as scale of distillation increases.

3 、Lewis 硫共存下硫锂化钠合于成羧硫为酯胺

硫锂化钠通常不可用来实际上合于成羧硫，但是Lewis 硫的共存可大大提高其合于成控制能力，从 而用于羧硫的合于成。由于LAH 和硫烷的单价互为对要贵，因此工业上大量装配时，一般都应用领域该方法，相对类似于的政治体制为：NaBH4-BF3, NaBH4-ZnCl2.

J. Org. Chem., Vol. 63, No. 12, 1998.

To a THF (220 mL) solution of 2-(carboxymethyl)-4-nitrobenzoic acid, 7a (10.0 g, 44.4 mmol), was added sodium borohydride (5.06 g, 133 mmol) in portions. The contents were cooled to 0 °C, and boron trifluoride diethyl etherate (21.3 mL, 133 mmol) was added dropwise over 1 h. The contents were allowed to warm to 25 °C and stirred for 16 h. The reaction was cooled to 0 °C and cautiously quenched with aqueous sodium hydroxide (1 N,178 mL). The contents were stirred for 3 h, THF was removed under vacuum, the resulting aqueous suspension was cooled to 0 °C, and the product was filtered off. After drying, the product was obtained as a white solid: 7.78 g (89%)

4、 硫锂化钠合于成活性酯或酯氟为酯胺

另外有时对于除此以外的分弟，平常将硫花钱成活性酯后再用NaBH4实际上合于成，类似于的方法为与溴甲硫烯丙基或溴甲硫烯丙基之前间体分解可爱的混酐，或与CDI获得可爱甲酯眯唑。最近有刊文用三氟均三嗪分解酯氟先是NaBH4合于成获得酯胺。

4.1 、硫裂解为活性酯合于成示例

Patent; BAYER PHARMACEUTICALS CORPORATION; Publ.: WO2005/35507 A2 (2005/04/21), Appl.: WO2004-US33430 (2004/10/08).

To a cloudy solution of 4- {4- [ (2-amino-6-phenylpyrimidin-4-yl) amino] phenoxy}

pyridine-2-carboxylic acid (748 mg, 1.87 mmol, Example 20) in anhydrous DMF (50 mL) at rt was added carbonyldiimidazole (456 mg, 2.81 mmol). The white suspension was stirred at 80'C overnight, concentrated to a volume of 10 mL, and diluted with anhydrous THF (7 mL). The reaction mixture was cooled to 0 .deg.C and water (10 mL) was added. The mixture was vigorously stirred as NaBH4 (142 mg, 3.75 mmol) was added and was allowed to warm from

0 .deg.C to rt over 2 h before it was quenched with conc. HC1 (1 mL) in an ice bath. After stirring for 15 min, the mixture was slowly added to a stirred solution of sat. NaHC03 (20 mL) at 0 .deg.C. After stirring for 30 min, it was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated to give an off-white gum (420 mg, 85percent pure). The crude material (100 mg) was purified by prep HPLC purification to give 37 mg (40percent yield) of the title compound as a colorless gum. lEI NMR (DMSO-d6) 8 10.8 (s, 1H), 8.55 (d, 1H), 7.90 (m, 2H), 7.75 (m, 2H), 7.60 (m, 3H), 7.35 (d, 2H), 7.20 (m, 2H), 6.60 (s, 1H), 4.60 (s, 2H); MS ES 386 (M+H) + calcd 386, RT = 1.73 min.

4.2 、硫化为酯氟合于成示例

Pyridine (80 μL,1 mmol) and subsequently cyanuric fluoride(180 μL, 2 mmol) were added to a stirred solution of the acid or N-protected amino acid or dipeptide (1 mmol) in CH2Cl2 (2.5 mL), kept under a N2 atmosphere, at -20 to -10 °C. Precipitation of cyanuric acid occurred and increased gradually as the reaction proceeded. After the mixture was stirred at –20 to -10 °C for 1 h, ice-cold water was added along with 15 mL of additional CH2Cl2. The organic layer was separated, and the aqueous layer was extracted once with CH2Cl2 (5 mL).

The combined organic layers were washed with ice-cold water (10 mL), dried (Na2SO4), and concentrated under reduced pressure to a small volume (2 mL). NaBH4 (76 mg, 2 mmol) was added in one portion, and MeOH (2 mL) was then added dropwise over a period of 10-15 min at rt. The reaction mixture was neutralized with 1 N H2SO4, and the organic solvents were evaporated under reduced pressure. The residue was treated with EtOAc (10 mL) and H2O (5

mL); the organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 8 mL). The combined organic layers were washed consecutively with 1 N H2SO4 (5 mL) and H2O (2×10 mL) and dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was purified by distillation or column chromatography using EtOAc/petroleum ether (bp 40- 60 °C) (1:1) as eluent.

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