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三種策略

直接堿性或者酸性水解，直接金屬催化水解，間接水解（先上醚或者酯等，再去保護）

策略一：金屬催化案例一

To a solution of allylpalladium chloride dimer (65 g,174 mmol, 1.0 equiv), tBuBrettPhos (181 g, 366 mmol, 2.1equiv), and 4-bromobenzotrifluoride (98 mL, 696 mmol, 4.0equiv) in THF (1741 mL, 10 mL/g) in a 5 L jacketed reactor was added a solution of sodium trifluoromethanesulfonate (77 g,435 mmol, 2.5 equiv) in THF (1741 mL, 10 mL/g) under a nitrogen atmosphere. The mixture was stirred at 25 °C for 1 h.

To a separate bottle was added diethyl malonate (79 mL, 522 mmol, 3.0 equiv), THF (1741 mL, 10 mL/g), and sodium tertbutoxide(2.10 M in THF, 199 mL, 418 mmol, 2.4 equiv). The malonate solution was added to the reaction mixture and stirred at 25 °C for 1 h. Agitation was stopped, and inorganic solids were observed to settle to the bottom of the reactor. The bottom sludge was drained, and the main bulk of the catalyst solution was transferred to an inerted drum. A portion (2.5 L) of the THF was charged to the reactor and stirred vigorously for 5 min. The reactor was drained and THF added to the drum. The drum contents were diluted with the remaining THF (6.2 L). The drum was purged with a strong flow of nitrogen, and the contents were used directly in the pilot plant manufacture.

案例二

Bromobenzothiophene 39 (108 kg; 288 mol; 1 equiv) was charged into a reactor at 20 –25 °C followed by deionized water (324 kg), THF (271 kg) and tetrabutylammonium bromide (6.96 kg; 21.6 mol; 0.075 equiv). Then 50% aqueous KOH (95.7 kg; 854 mol; 3equiv) was added to obtain a solidless biphasic mixture. This reaction mixture was degassed. In a second vessel allyl palladium chloride dimer (0.329 kg; 0.9 mol; 0.003equiv) and 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-Bu-X-Phos; 1.22 kg; 2.56 mol; 0.009 equiv) were dissolved in degassed THF (115 kg). This catalyst solution was  added to the reaction mixture and the mixture was heated to IT 60 – 62 °C. The reaction mixture was stirred at that temperature for 3 h until conversion of 39 to 30 was ≥70%. Then another 50% KOH (32.8 kg; 293 mol; 1 equiv) were added and the reaction mixture was stirred for another 12 h at IT 60 – 62 °C. After complete conversion (< 0.1% 39 and< 0.1% chloro impurity 41), a solution of sodium diethyl dithiocarbamate trihydrate (0.8  kg; 3.55 mol; 0.012 equiv) in water (6 kg) was added, the mixture was stirred for 1 h at 64 °C and then the phases were separated. 

策略二：直接酸或者堿水解

案例一

The resulting n-heptane solution was assayed to contain compound 5 in 91.6% assay yield (130.4 kg, 301.8 mol) and 92.1% LCAP. The solution is then concentrated under reduced pressure and finally solvent-switched to t-BuOH (to a final volume between 4 and 6×), keeping the temperature under 45 °C. To this t-BuOH solution is added solid sodium hydroxide (61.7 kg, 1542 mol), and the mixture is heated between 65 and 75 °C for 38 h. After cooling, water (∼750 L) is added keeping the temperature between 25 and 35 °C. The mixture’s pH is then adjusted to 6−7 using 2 N HCl in two portions while keeping the temperature between 25 and 35 °C. More water is then added (900 L), resulting in complete precipitation of crude 6 (supernatant <0.5 LCAP). 

案例二

化合物12制備化合物13

小編：氯水解成羥基，酸性和堿性哪個更好一些呢？需要實際研究

A solution of 12 (31.7 kg, 127 mol), AcOH (133 kg), NaOAc (10.9 kg, 133 mol), and water (31.7 kg) was heated to 100−108 °C, and the batch was aged for 5 h; then HPLC analysis indicated <1% 12 remained (HPLC method A).
Water (256.3 L) was then added to the batch at 38−80 °C; the resulting slurry was heated to 82 °C, and the resulting solution was cooled to 0−5 °C and aged for 19 h. The batch was then filtered, and the residue was washed with water (127 L). Loss to the filtrate was 6%. The wet cake was dried in vacuo at 50 °C to afford the desired 13 at 97.0% purity via HPLC method A (26.6 kg, 90.6% yield)

案例三

2-Bromo-5-nitroterephthalic acid 11 (113 kg, 348 mol, 1 equiv) was added to a solution of sodium hydroxide (138 kg, 3623 mol, 10.4 equiv) in water (565 L). The reaction was stirred for 1 day at reflux. The mixture was diluted with water (450 L) and adjusted to pH 2 with a hydrochloric acid solution. The suspension was filtered, slurred with water (220 L), and dried under vacuum

between 70−80 °C to afford 9 (59 kg, 75%) as a white solid.

策略三：間接策略（先上醚或者酯等，再去保護）

案例一

化合物5的雜環(huán)F原子在酸性條件下很容易水解成羥基，但是產(chǎn)生的HF會腐蝕玻璃反應(yīng)釜。

改變策略，一步變兩步，化合物5先和堿性的叔丁醇鉀，在THF中進行SNAr反應(yīng)，引入叔丁基醚，得到化合物6，釋放的HF被堿吸收，分液處理后，含有化合物6的有機層，用硫酸水解叔丁基，可得水解目標(biāo)物1。

The solution of 5 (42.8 kg, 194 mol, 1.0 equiv) in iPAc was concentrated in vacuo below 50 °C and then solvent-switched to THF (10 total volumes). Solid potassium tert-butoxide (34.8 kg, 311 mol, 1.6 equiv) was added in several portions at 15−25 °C. The mixture was warmed to 25 °C for 5 h. Solid NaHCO3 (16.0 kg) was charged at 25 °C. After stirring for 30 min, 5 wt % aqueous Na2SO4 (353.0 kg) was added to the reaction mixture. After the organic layer was separated, to the resulting THF solution was charged 1 N aqueous H2SO4 solution (336 kg) at 15−30 °C. The mixture was stirred at 20−30 °C for 4.5 h and then adjusted to pH 7 with addition of 30 wt % aqueous NaOH solution (126.0 kg) at 15−30 °C. After MTBE (300 kg) was charged, the reaction solution was adjusted to pH 14 with 30% NaOH aqueous solution (147 kg) at 20−30 °C. The aqueous layer was separated and washed with MTBE (2 × 300kg). To the aqueous solution were charged 2-MeTHF (472 kg) and THF (475 kg), and the reaction mixture was adjusted to pH 10.40−10.60 with concentrated HCl (79.6 kg). The organic layer was separated, and the aqueous layer was extracted with a mixture of 2-MeTHF (231 kg) and THF (231 kg), while maintaining pH 10.40−10.60 (30 wt % aqueous NaOH solution to adjust pH, if necessary). The organic layer was separated, and the aqueous layer was extracted again with a mixture of 2-MeTHF (231 kg) and THF (231 kg). The organic solutions were combined and washed with 5 wt % aqueous  Na2SO4 solution (168 kg). The organic solution was concentrated to ∼100 L. The batch was solvent-switched to 2-MeTHF (210 kg) and then to MTBE (210 kg), resulting in precipitation of 1. The crude 1 was filtered and dried in vacuo for 12 h at 50−55 °C. (36.6 kg, 96.2A% HPLC purity, 83% yield): mp 197.9 °C.

案例二

化合物14先制備化合物15，再水解，其他要求沒有實現(xiàn)，但是思路是經(jīng)叔丁醚，制備羥基

案例三

甲醇鈉作為親核試劑，取代溴得到化合物8，再采用TMSI去除O-甲基

小編：這種策略非常常見，關(guān)鍵是脫O-甲基的問題

化合物7，先引入甲磺酰基得到化合物26，再水解制備化合物3

實際結(jié)果，消旋嚴重

案例四

采用芐醇兩步法，第一步有利，但是需要去除芐基

采用乙酸鉀，可以一鍋法去除乙?；切Ч浅２缓茫╡ntry 1-3）

采用TMSOK，數(shù)據(jù)不是很理想，分析可能是TMSOK中含有氫氧化鉀，內(nèi)酰胺被破壞，雜質(zhì)多（entry 3-8）

采用TMSONa，結(jié)合TMSOK的溶劑對比數(shù)據(jù)，獲得了相對比較好的數(shù)據(jù)

A solution of isoindolinone 9 (201.1 g, 0.67 mol) in 1,2-dimethoxyethane (2.25 L) was loaded in a 5 L roundbottom flask equipped with a stirring bar and a reflux condenser with N2 inlet. The mixture was degassed under vacuum and backfilled with nitrogen three times (degassing by bubbling N2 gas for 20 min can also be used). Solid TMSONa (226.9 g, 2.02 mol) was added to the reaction mixture. The resulting dark red solution was heated to 85 °C and maintained at that temperature for 1 h under stirring.