經(jīng)典化學(xué)合成反應(yīng)標(biāo)準(zhǔn)操作脲與硫脲的合成

1、經(jīng)典化學(xué)合成反應(yīng)標(biāo)準(zhǔn)操作脲與硫脲的合成目 錄Part I： 脲的合成1、 前言 22、 異氰酸酯與胺反應(yīng)生成脲 22.1. 異氰酸酯與胺反應(yīng)生成脲示例 23、 三光氣（或光氣、雙光氣）與胺反應(yīng)生成脲 33.1. 三光氣與胺反應(yīng)生成脲示例 34、 使用氯甲酰胺與胺反應(yīng)生成脲 44.1 三光氣與仲胺反應(yīng)氯甲酰胺 44.2. 氯甲酰胺與胺反應(yīng)脲 45、 羰基二咪唑 (CDI) 與胺反應(yīng)生成脲55.1 羰基二咪唑與芳香伯胺反應(yīng)生成脲示例一 .55.2羰基二咪唑與胺反應(yīng)生成脲示例二 .66、 氯甲酸酯與胺反應(yīng)生成脲 .66.1利用氯甲酸對硝基苯酯合成脲 6芳香伯胺的對硝基苯氧基碳酰胺和脲的合成示例 7脂

2、肪伯胺的對硝基苯氧基碳酰胺和脲的合成示例 7利用氯甲酸對硝基苯酯一鍋法合成脲示例 8氯甲酸對硝基苯酯用于仲胺的脲合成示例 96.2利用氯甲酸苯酯合成脲 96.2.1芳香伯胺的苯氧基碳酰胺和脲的合成示例 106.2.2脂肪伯胺的苯氧基碳酰胺和脲的合成示例 106.3利用氯甲酸2異丙烯酯合成脲 116.3.1 2-異丙烯氧基碳酰胺的合成 116.3.2 2-異丙烯氧基碳酰胺與胺反應(yīng)合成脲 116.4利用氯甲酸2-三氟乙基酯或氯甲酸2-三氯乙基酯合成脲 126.4.1利用氯甲酸2-三氯乙基酯合成脲示例 127、 異氰酸鉀與胺反應(yīng)生成脲 .137.1異氰酸鉀與胺反應(yīng)生成脲示例 13Part II： 硫

3、脲的合成1、 前言 142、 異硫氰酸酯與胺反應(yīng)生成硫脲 143、 硫光氣（或光氣、雙光氣）與胺反應(yīng)生成硫脲 144、 硫代羰基二咪唑與胺反應(yīng)生成脲155、 利用硫代氯甲基苯酯合成硫脲156、 通過硫代甲巰基碳酰合成硫脲 167、 硫代試劑（如Lawsson試劑）與脲反應(yīng)得到硫脲16Reference 17Part I: 脲的合成1.前言脲Urea在石油化工、醫(yī)藥化工有著廣泛的應(yīng)用前景，很多醫(yī)藥分子中都還有脲的結(jié)構(gòu)片斷。通常含脲的分子可以分為對稱性脲和非對稱性脲兩大類，對稱性脲的合成相對簡單，而非對稱性脲的合成相對難一些。由于非對稱性脲的合成大多適用于對稱性脲的合成，所以我們著重介紹非對稱脲合

4、成的一些常用方法。2. 異氰酸酯與胺反應(yīng)生成脲異氰酸酯與胺反應(yīng)成脲是最為方便的一種方法，特別對于那些可以直接在市場上買到的異氰酸酯，一般這類反應(yīng)收率也很高。但本方法最重要的一點(diǎn)是：反應(yīng)物的用量是取決于底物的活性。通常是等量的底物在非質(zhì)子性溶劑反應(yīng)，加入適量的堿有利于反應(yīng)的進(jìn)行。如果其中一個底物的活性較差的話，可以適當(dāng)增加用量。常用的溶劑有：二氯甲烷、四氫呋喃等。2.1 異氰酸酯與胺反應(yīng)生成脲示例 1To a solution of 3-chloro-4-nitro-phenylamine (1.72 g, 10 mmoL) and triethylamine (3 mL, 20 mmol) i

5、n 100 mL of THF was added isocyanato-benzene (1.19 g, 10 mmol) in 10 mL of THF at 0 oC dropwise. After the addition was completed, the resulting mixture was allowed to raise room temperature and stirred overnight before being poured into water (150 mL). The mixture was extracted with DCM (3 x 100 mL

6、). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford 2.4 g of 1-(3-chloro-4-nitro-phenyl)-3- phenyl-urea (80 %)3. 三光氣（或光氣、雙光氣）與胺反應(yīng)生成脲除了一些常用的伯胺的異氰酸酯可以購買到以外，在藥物化學(xué)

7、中決大多數(shù)異氰酸酯是無法購得的，因此需要自己合成異氰酸酯。 常用異氰酸酯的合成方法是伯胺與三光氣反在堿性條件下生成異氰酸酯，而后異氰酸酯與另一分子胺反應(yīng)生成脲，第二步反應(yīng)其實(shí)同前。對于低沸點(diǎn)的異氰酸酯，第一步反應(yīng)完后最好將其蒸餾出來，再投第二步反應(yīng)，這樣下一步產(chǎn)物相對干凈。如果異氰酸酯沸點(diǎn)很高，一般生成異氰酸酯后，直接一鍋用到下一部，但必須嚴(yán)格控制三光氣的用量 （注意三光氣用底物胺的1/3的量）。光氣與雙光氣也適用本方法，但考慮到使用的方便性和安全問題，一般使用三光氣。3.1三光氣與胺反應(yīng)生成脲示例 2To a stirred solution of 3-chloro-4-nitro-phen

8、ylamine (1.72 g, 10 mmoL) and diisopropyl ethylamine (2.1 g, 20 mmol) in 100 mL of dry DCM was added a solution of triphosgene (0.99 g, 3.3 mmol) in 10 mL of DCM. The resulting mixture was stirred at 0 oC for 3 hours and then treated with aniline (930 mg, 10 mmol). The reaction mixture was allowed t

9、o warm to room temperature overnight. After removal of the solvent, the residue partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to the residue, which was

10、purified by column chromatography on silica to afford 1.9 g of the 1-(3-chloro-4-nitro-phenyl)-3- phenyl-urea (65 %).4. 使用氯甲酰胺與胺反應(yīng)生成脲對于仲胺由于無法形成異氰酸酯，我們可以通過其與三光氣反應(yīng)得到氯甲酰胺然后再與另一個胺反應(yīng)。 一般仲胺的氯甲酰胺中間體對水是穩(wěn)定的，可以分離純化出來。4.1三光氣與仲胺反應(yīng)氯甲酰胺 3To a solution of 2-allyl-piperidine (0.63 g, 5 mmol) and pyridine (0.52 g, 6

11、.6 mmol) in 50 mL of dichloromethane was added a solution of triphosgene (0.66 g, 2.2 mmol) in 10 mL of dichloromethane at 0 oC dropwise over 40 min. The resulting mixture was then warmed to room temperature and stirred overnight. The reaction mixture was added 50 mL of 1 N of aqueous HCl solution d

12、ropwise. After separation, the aqueous phase was extracted with DCM (3 x 50 mL). The combined organic phases were washed with a saturated NaHCO3 solution and brine ( 3 x 50 mL ), then dried over MgSO4. After removal of the solvent, the crude product was taken into Et2O and the solids were filtered.

13、The filtrate was concentrated to 860 mg of carbamoyl chloride as yellow oil (92 %).4.2氯甲酰胺與胺反應(yīng)脲A solution of 2-allyl-piperidine-1-carbonyl chloride (1.87 g, 10 mmol), triethylamine (5 mL), and 4-chloro-3-fluoro-phenylamine (1.7 g, 12 mmol) in 100 mL of anhydrous dioxane was stirred at room temperatu

14、re under nitrogen for 26 h and then concentrated to dry under vacuum. The residue was dissolved in 100 mL of dichloromethane, and washed with 0.5 N of aqueous HCl solution and brine, After dried over anhydrous Na2SO4 and filtered, the filtrate was concentrated to the crude product, which was purifie

15、d by flash column chromatography to afford 2-Allyl-piperidine-1-carboxylic acid (4-chloro-3-fluoro-phenyl)-amide (2.3g, 77 %) 5. 羰基二咪唑 (CDI) 與胺反應(yīng)生成脲胺也可以先與羰基二咪唑 (CDI)反應(yīng)，形成一個中間體，然后與另一分子胺反應(yīng)生成脲。本方法適用范圍也很廣，對那些底物很昂貴、或較難得到的，本方法也很適用。但由于CDI不穩(wěn)定，放置時間長，遇水會分解，造成加料不準(zhǔn)確，容易生成較難分離的二聚體。因此反應(yīng)前確定CDI的質(zhì)量尤為關(guān)鍵。5.1 羰基二咪唑與芳香伯胺

16、反應(yīng)生成脲示例一 4To a solution of 3-chloro-4-nitro-phenylamine (1.72 g, 10 mmoL) and triethylamine (1.0 g, 10 mmol) in 50 mL of DMF was added CDI (1.61 g, 10 mmol) at room temperature under N2 atmosphere. The mixture was stirred at that temperature for 1 h and then added a solution of aniline (1.0 g, 11 mm

17、ol) in 5 mL of DMF. After stirred for another 10 h, the reaction mixture was poured into water (100 mL) and extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (5 x 100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude produ

18、ct, which was purified by column to afford 2.0 g of 1-(3-chloro-4-nitro-phenyl)-3- phenyl-urea (68 % yield)5.2 羰基二咪唑與胺反應(yīng)生成脲示例二 5To a solution of 3-(3-piperidin-1-ylmethyl-phenoxy)-propylamine (2.48 g, 10 mmoL) and diisopropylethylamine (1. 4 mL, 10 mmol) in DMF (50 mL) was added CDI (1.61 g, 10 mmol

19、) at room temperature under N2 atmosphere. The mixture was stirred at that temperature for 1 h and then a solution of i-BuNH2 (146 mg, 20 mmol) in 5 mL of DMF was added to the mixture. The reaction mixture was stirred at room temperature overnight before poured into water (100 mL). The mixture was e

20、xtracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (5 x 100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford 2.75 g of 1-isobutyl-3-3-(3-piperidin-1-ylmethyl-phenoxy)-propyl-u

21、rea (80 %).6. 氯甲酸酯與胺反應(yīng)生成脲胺先與氯甲酸酯反應(yīng)得到相應(yīng)的烷氧基碳酰胺，然后再與另一分子胺反應(yīng)生成脲。本方法適用范圍也很廣，對那些底物很昂貴、或較難得到的，本方法尤為適用。一般來說比較常用的為氯甲酸對硝基苯酯和氯甲酸苯酯。6.1 利用氯甲酸對硝基苯酯合成脲氯甲酸對硝基苯酯主要用于伯胺的反應(yīng)，其反應(yīng)機(jī)理是中間體對硝基苯氧基碳酰胺在堿性條件下，脫去對硝基苯酚得到相應(yīng)的異氰酸酯，然后再與另一分子胺反應(yīng)得到脲。使用本方法一個主要的注意點(diǎn)是第一步對硝基苯氧基碳酰胺的制備，一定要選擇好相應(yīng)的堿，用好當(dāng)量。另外也有文獻(xiàn)在第一步用過量的堿生成異氰酸酯的溶液，馬上再與另一分子胺反應(yīng)。該法的一

22、個缺點(diǎn)就是有時產(chǎn)生的黃色的副產(chǎn)物對硝基苯酚，不易除干凈（一般用強(qiáng)堿洗）。 氯甲酸對硝基苯酯也可以與仲胺反應(yīng)生成脲，一般在DMAP-CH3CN，加熱體系進(jìn)行胺交換。6.1.1 芳香伯胺的對硝基苯氧基碳酰胺和脲的合成示例 6To a solution of methyl 3-aminobenzoate (1.0 g, 6.5 mmol) and pyridine (1.0 mL) in 100 mL of dichloromethane was added a solution of 4- nitrophenylchloroformate (1.4 g, 6.7 mmol) in 10 mL of

23、 dichloromethane dropwise at 0 oC under N2 atmosphere. The resulting mixture was stirred at r.t. for 20 h before poured into ice-water. The mixture was extracted with DCM (3 x 100 mL). The combined organic phases were washed with 0.5 N aq. HC1 and brine, dried over anhydrous Na2SO4 and filtered. The

24、 filtrate was concentrated to give the crude product, which was purified by column to afford 2.1 g of 3-3-(4-tert-Butyl-phenyl)-ureido-benzoic acid methyl ester (94 %)6.1.2 脂肪伯胺的對硝基苯氧基碳酰胺和脲的合成示例 7To a solution of 4-nitrophenyl chloroformate (2.3 g, 11 mmol) in 20 mL of CH2Cl2 was added a solution of

25、 benzyl glycinate (0.62 g, 3.8 mmol) in 4 mL of 1:1 CH2Cl2/ pyridine at 0 C dropwise. The solution was stirred for 30 min and then diluted with 100 mL of CH2Cl2. The reaction mixture was washed with 1 M NaHSO4 (3 x 50 mL) and brine (3 x 50 mL). The organic phase was concentrated to the crude product

26、, which was purified by column chromatography to afford 0.81 g of N-(4-nitrophenyloxycarbonyl)benzyl glycinate (65%) as white solid. To the solution of N-(4-nitrophenyloxycarbonyl)benzyl glycinate (0.79 g, 2.4 mmol) in 10 mL of benzene were added 1,6-aminohexanol (0.34 g, 2.9 mmol), DMAP (88 mg, 0.7

27、2 mmol) and diisopropylethylamine (0.46 g, 3.6 mmol) at room temperature. The reaction mixture was stirred at for 30 min before diluted with 50 mL of CH2Cl2. The mixture was washed with 1 M NaHSO4 (3 x 50 mL), 2% Na2CO3 (3 x 50 mL) and brine (3 x 50 mL). The organic phase was dried and concentrated

28、to the crude product, which was purified by column chromatography to afford 0.61 g of 3-(6-hydroxyhexyl)ureidoacetic acid benzyl Ester (86%) as white solid.6.1.3 利用氯甲酸對硝基苯酯一鍋法合成脲示例 8To a solution of 1-(2,6-dichloro-benzyl)-3-pyrrolidin-1-ylmethyl-1H-indazol-6-ylamine (374 mg, 1.0 mmol) and diisoprop

29、ylethylamine (640 mg, 5.0 mmol) in 100 mL of DCM was added a solution of 4-nitrophenyl chloroformate (220 mg, 1.1 mmol) in 10 mL of DCM at 20 oC under N2 atmosphere. The resulting mixture was stirred for 30 min and then added 3-amino-4-(3,4-difluoro-phenyl)-1-phenyl-butan-2-one (275 mg, 1.0 mmol). A

30、fter stirred at 20 oC for 30 min, the mixture was warmed to room temperature and then stirred for another 6 h before poured into water. The reaction mixture was extracted with DCM (3 x 100 mL). The combined organic phases were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4 and filtered.

31、The filtrate was concentrated to the crude product, which was purified by column chromatography to afford 175 mg of 1-1-(2,6-dichloro-benzyl)-3-pyrrolidin-1-ylmethyl- 1H-indazol-6-yl-3-1-(3,4-difluoro-benzyl)-2-oxo-3-phenyl-propyl-urea (26 %)6.1.4 氯甲酸對硝基苯酯用于仲胺的脲合成示例 9To a solution of 5-oxo-5-piperid

32、in-3-yl-3-pyridin-3-yl-pentanoic acid methyl ester (2.9 g, 10 mmol) in DCM (200 mL) was added 4-nitrophenylchloroformate (2.0 g, 10 mmol) and NMM (6.0 mL, 30 mmol) at 0 oC. The resulting mixture was stirred for 2 h before poured into water (15 mL). After separated, the organic layer was dried over a

33、nhydrous Na2SO4 and evaporated to oil, which was dissolved in 100 mL of MeCN. The solution was then treated by 4,4bipiperidinyl-1-carboxylic acid tert-butyl ester (4.3 g, 15 mmol) and DMAP (1.2 g, 10 mmol), and heated to reflux for 24 h. After removal of the solvent, the residue was dissolved in EtO

34、Ac (200 mL). The organic phase was washed with 1 N NaOH (3 x 100 mL), brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtered, the filtrate was concentrated to the crude product, which was purified by silica gel chromatography to afford 4.1 g of 1-3-(4-methoxycarbonyl-3-pyridin-3-yl-butyr

35、yl)-piperidine-1-carbonyl-4,4bipiperidinyl-1-carboxylic acid tert-butyl ester (69 %)6.2 利用氯甲酸苯酯合成脲氯甲酸苯酯也是一般用于伯胺脲的合成，其首先與胺的反應(yīng)苯氧基碳酰胺，在堿性條件下，高溫條件下與另一分子胺反應(yīng)生成脲。其特點(diǎn)是相應(yīng)的中間體苯氧基碳酰胺，較為穩(wěn)定，易于制備及純化。若將氯甲酸苯酯用于仲胺的脲的合成，在第二步反應(yīng)一般用第二個胺的負(fù)離子反應(yīng)。6.2.1 芳香伯胺的苯氧基碳酰胺和脲的合成示例 10To a solution of pyridin-3-ylamine (940 mg, 10 mmol

36、) and triethylamine (2.0. g, 20 mmol) in 50 ml of DMF was added 2.94 g of (2-tert-Butyl-5-cyano-phenyl)-carbamic acid phenyl ester at room temperature under N2 atmosphere. The resulting mixture was heated to 100 oC for 5 h before poured into 200 mL of water. The mixture was extracted with DCM (3 x 1

37、00 mL). The combined organic phases were washed with 0.5 N of HCl aqueous solution (3 x 100 mL) and brine (3 x100 mL). After dried over anhydrous Na2SO4 and filtered, the filtrate was concentrated to the crude product, which was purified by column to afford 1.9 g of 1-(2-tert-Butyl-5-cyano-phenyl)-3

38、-pyridin-3-yl-urea (64 %).6.2.2 脂肪伯胺的苯氧基碳酰胺和脲的合成示例 11To a solution of isobutylamine (7.3 g, 0.1 mol) and triethylamine (10.1 g, 0.1 mol) in 200 ml of N,N-methylpyrrolidone was added 24.9 g of octyl-carbamic acid phenyl ester at room temperature under N2 atmosphere. The resulting mixture was heated t

39、o 60 oC for 5 h before cooled to 40 oC. The reaction mixture was put into 500 mL of methanol and then further cooled to room temperature. The solid was collected and washed with methanol to afford 18.9 g of 1-isobutyl-3-octyl-urea (83 %).6.3 利用氯甲酸2異丙烯酯合成脲最近也有文獻(xiàn)報(bào)道，用氯甲酸2異丙烯酯與伯胺生成異丙烯氧基碳酰胺，其在N-甲基四氫吡咯的催化

40、下與另一分子胺反應(yīng)可以高收率的得到相應(yīng)的脲，且許多反應(yīng)經(jīng)過簡單后處理后就可得到較好的純度。6.3.1. 2-異丙烯氧基碳酰胺的合成 12To an aqueous solution of sodium hydroxide (8 mL, 2.5 M in water) was added a solution of 3,5-Dimethylaniline (1.2g, 10 mmol) in 20 mL of EtOAc at 5 oC dropwise. The resulting mixture was stirred at 5 oC for 30 min before added isop

41、ropenyl chloroformate (1.1 mL, 14 mmol). The reaction mixture was stirred at r.t. for 1 h and then the mixture was separated. The aqueous phase was extracted with EtOAc (3 X 20 mL). The combined organic phases were washed with brine (3 X 50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate

42、 was concentrated to the crude product, which was recrystallization from EtOAc:Heptane (1:2) to afford 1.2 g of (3,5-Dimethyl-phenyl)-carbamic acid isopropenyl ester (58 %).6.3.2 2-異丙烯氧基碳酰胺與胺反應(yīng)合成脲A mixture of (3,5-Dimethyl-phenyl)-carbamic acid isopropenyl ester (1.2 g, 5.8 mmol) and benzylamine (0.

43、6 g, 5.8 mmol) in 50 mL of THF was added N-Methylpyrrolidine (0.06mL). The reaction mixture was stirred at 55 oC for 21 h before poured into ice-water. The mixture was extracted with DCM (3 X 100 mL). The combined organic phases were washed with 0.5 N aq. HC1 and brine, dried over anhydrous Na2SO4 a

44、nd filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford 1.5 g of 1-Benzyl-3-(3,5-dimethyl-phenyl)-urea (98 %)6.4 利用氯甲酸2-三氟乙基酯或氯甲酸2-三氯乙基酯合成脲用2-三氟乙基酯或氯甲酸2-三氯乙基酯合成脲也是一個較好的方法，在成脲時反應(yīng)一般較為干凈，易于后處理。6.4.1 利用氯甲酸2-三氯乙基酯合成脲示例 13To an ice-cold suspension of 3-

45、chloro-4-nitro-phenylamine (1.72 g, 10 mmoL) in EtOAc (50 mL) was added 3M NaOH (25 mmol, 2.50 eq). The resulting biphasic mixture was stirred briskly at 0-5 C for 30 min. Troc-Cl (175 mg, 1.40 eq) was added dropwise. The ice bath was removed and the reaction was stirred at rt by which time the raw

46、material was disappeared as check by LC/MS. The layers were separated and the aqueous phase was extracted with EtOAc (3 X 50 mL). The combined EtOAc layers were washed with H2O (250 mL), brine (250 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to the crude product, whi

47、ch was used for the next reaction without further purification. A mixture of crude (3-chloro-4-nitro-phenyl)-carbamic acid trichloromethyl ester (4.2 g) and indan-1-ylaminein (1.3 g, 10 mmol) in 20 mL of DMSO was heated to 55oC. The reaction mixture was stirred for 3 h when the material was disappea

48、red as checked by LCMS. The reaction mixture was poured into ice-water and extracted with DCM (3 X 50 mL). The combined organic phases were washed with brine (5 X 50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column t

49、o afford 1.9 g of 1-(3-chloro-4-nitro-phenyl)-3-indan-1-yl-urea (57 %)7. 異氰酸鉀與胺反應(yīng)生成脲對于沒有任何取代基的脲，一般主要通過氰酸鉀與胺反應(yīng)得到，一般這類反應(yīng)在水和醋酸的混合溶劑中進(jìn)行。7.1異氰酸鉀與胺反應(yīng)生成脲示例 14To a solution of o-aminophenol (1.1 g, 10 mmol) in 20 mL of glacial acetic acid and water (1:1) was added a solution of potassium cyanate (1.6g, 20 m

50、mol) in water dropwise. The resulting solution was stirred at r.t. for 3 h. After removal of the solvent, the residue was dissolved in EtOAc (100 mL). The organic phase was washed with sodium bicarbonate solution and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to t

51、he crude product, which was recrystallized once from methanol and then several times from acetone-hexane to afford 1.2 g of white needles (2-Hydroxy-phenyl)-urea (80 %).Part II: 硫脲的合成1. 前言硫脲Thiourea在石油化工、醫(yī)藥化工同樣具有泛的應(yīng)用前景，很多醫(yī)藥分子中都還有硫脲的結(jié)構(gòu)片斷。例如目前市場上很多口服降糖藥、抗甲狀腺藥都屬于硫脲類分子。硫脲的化學(xué)合成通常有下列一些方法。2. 異硫氰酸酯與胺反應(yīng)生成硫脲

52、15To a solution of tert-butylisothiocyanate (5.0 mL, 39 mmol) in dichloromethane (200 mL) were added isopropylamine (4.0 mL, 47 mmol) and diisopropylethylamine (DIEA) (6.8 mL, 39 mmol), and the mixture was stirred at rt for 2h. The reaction mixture was diluted with EtOAc, washed with 10 percent citr

53、ic acid (2x), saturated NaHCO3 (2x), H20 (2x), and brine (1x). The organic layer was dried (MgS04) and evaporated to the crude product, which was purified by column to afford 1-tert-butyl-3-isopropyl-thiourea (3.3 g, 52 %).3. 硫光氣與胺反應(yīng)生成硫脲 16To a solution of 8.5 g of 3-chloro-5-fluoroaniline in 150 ml

54、 of benzene was added a solution of 2.2 g of thiophosgene in 10 ml of benzene dropwise at room temperature under nitrogen. The resulting mixture was stirred at 60 oC for 3 hours and then cooled to room temperature. After filtered, the filtrate was concentrated to the oil, which was followed by a sol

55、ution of t-pentylamine (3.4 g ) in 30 ml of benzene. The mixture was stirred at room temperature for another 30 minutes. The reaction mixture was evaporated in vacuo and the resulting solid recrystallized from cyclohexane to give 2.2 g of the title compound as colorless needles 1-(3-chloro-5-fluoro-

56、phenyl)-3-(2,2-dimethyl-propyl)-thiourea4. 硫代羰基二咪唑與胺反應(yīng)生成硫脲 17To a mixture of 1,1-thiocarbonyldiimidazole (535 mg) and acetonitrile (7 ml) was added a solution of 3-(N,N-Dimethyl) aniline (272 mg) in acetonitrile (7 ml) dropwise over period of 15 minutes at 0oC under nitrogen. After stirring for 2 hours at ambient temperature, 2-(amino