1、經典化學合成反應標準操作磺酰氯合成法 編者： 張國柱藥明康德新藥開發有限公司化學合成部目 錄1. 前言22. 芳香磺酰氯的制備22. 1直接氯磺化法制備芳香磺酰氯22. 2芳香磺酸或鹽氯化制備芳香磺酰氯32. 3芳香硫醇及相關衍生物氯代、氧化合成芳香磺酰氯82. 4. 芳香硫醇的制備112. 5 Sandermeyer 反應由芳胺合成芳香磺酰氯133. 脂肪磺酰氯的制備3. 1 烷基硫醇的合成及通過烷基硫醇合成脂肪磺酰氯143. 2 通過烷基硫脲合成脂肪磺酰氯163. 3 通過烷基異硫氰酸酯合成芳香磺酰氯173. 4 通過羧酸硫醇酯合成芳香磺酰氯173. 5 脂肪磺酰氯合成反應示例18參考文獻

2、：201. 前言磺酰氯是有機化學中非常重要的一類化合物，它們可以作為重要的中間體進行修飾。比如，同胺類化合物作用生成的磺胺類藥物是優良的化學治療劑，開始應用于20世紀30年代。它們能抑制多種細菌，如鏈球菌、葡萄球菌、肺炎球菌、腦膜炎球菌、痢疾桿菌等的生長和繁殖，因此常用以治療由上述細菌所引起的疾病。高碳烷基磺酸鈉類化合物則是優良的合成洗滌劑。磺酰氯主要分為脂肪族磺酰氯和芳香族磺酰氯。芳香磺酰氯的來源有以下幾類：1）由硫酚，各種硫醚在酸性溶劑中導入氯氣制得；2)芳香磺酸類化合物在氯化試劑作用下形成；3）磺化反應。脂肪族磺酰氯的來源主要是硫醇或相關衍生物氯代或氧化。因此，作為磺酰氯的重要前體，磺酸

3、和硫醇類化合物的引入，也是合成磺酰氯基團的重要手段。2. 芳香磺酰氯的制備芳香磺酰氯的制備一般分為以下幾種方法， 直接用氯磺化法制備芳香磺酰氯。 芳香磺酸或鹽經氯化制備芳香磺酰氯。 芳香硫醇及相關衍生物氯化，氧化合成芳香磺酰氯。 Sandermeyer反應由芳胺合成芳香磺酰氯。2. 1直接氯磺化法制備芳香磺酰氯氯磺酸是一類比較常用的直接氯磺化試劑，氯磺酸的活性比濃硫酸大，反應溫度較低，同時可以直接得磺酰氯。氯磺化也是親電反應，選擇性也遵循芳環取代基定位效應及其規則。有規律可循。如果希望反應比較緩和，可以用氯仿或其它鹵代烷烴作為稀釋劑。反應溫度一般都控制在0至20。如果芳環上存在至鈍基團，像羧基

4、等，直接氯磺化的溫度要提的比較高，要達到100多度。1當體系因為位阻，取代基定位效應劣勢等等不能直接完成氯磺化時，就可以選擇分兩步走，先引入磺酸基團。再轉變為磺酰氯。2. 1. 1芳香環磺化反應示例：In a three necked 500 mL round flask equipped with mechanical stirring, was placed with ClSO3H (290 g, 2.49 mol). The system was cooled to 1215 using ice water. N-Phenyl-acetamide (67.5 g, 0.5 mol) wa

5、s added dropwise. The temperature was maintained at 15 oC. After addition, the reaction mixture was heated at 60oC for two hours. The reaction was cooled down to room temperature and poured slowly into 1000 mL of water under finely stirring. The precipitate was collected by filtration, washed with w

6、ater, dried to afford desired 4-Acetylamino-benzenesulfonyl chloride (90 g, 77% yield). This sample could be used in next step without further purification.2. 2芳香磺酸或鹽氯化制備芳香磺酰氯芳香磺酸或鹽可以用氯氣或者某些氯化試劑比如五氯化磷，三氯氧磷，二氯化砜等處理得到芳香磺酰氯。這幾種氯磺化試劑各有優缺點，五氯化磷，三氯氧磷反應效果較好，但是后處理比較繁瑣，反應溫度要求較高。而二氯化砜后處理方便，往往蒸掉溶劑就可以直接投入下一步反應。

7、因此，芳香磺酸作為引入芳香磺酰氯基團重要的前體得到非常大的重視。2. 2. 1芳香磺酸的制備芳香磺酸的制備有幾種辦法，磺化，有機金屬試劑同三氧化硫加成，Sandermeyer法合成芳香磺酸。這幾種合成芳香磺酸的方法也是各有特色，針對不同的底物也可有不同的選擇。磺化是對芳環體系直接的引入磺酸基團。想把芳鹵轉變成芳香磺酰基團時，就可以考慮用有機金屬試劑置換鹵素后用三氧化硫處理即可以得到芳香磺酸。Sandermeyer法則提供了由芳胺基團轉變為芳香磺酸的一條途徑。2. 2. 1. 1磺化芳烴的磺化通常采用濃硫酸或含有5%-20%三氧化硫的發煙硫酸。磺化反應是一可逆反應，欲得良好產率的磺酸，必須使用過

8、量的磺化劑或者不斷移去生成的水。 對于較難磺化的芳烴可采用三氟化硼，錳鹽，汞鹽，礬鹽做催化劑。苯在室溫下可用濃硫酸磺化生成苯磺酸2；而在70-90oC磺化則生成間苯二磺酸，產率為90% 3；間苯二磺酸鈉在汞鹽的催化下，與15%的發煙硫酸于275oC反應，則以73%產率生成1，3，5-苯三磺酸 4。由于磺化反應是一可逆反應，磺酸基位置隨反應溫度不同而改變 5。例：甲苯的磺化與反應溫度的關系6例：萘的磺化也有類似情況。低溫，小于80oC磺化，主要生成-萘磺酸，這時由動力學控制，一旦達到160 oC 的反應溫度，主要產生-萘磺酸。這時由熱力學控制7。例：磺化反應的可逆性的一個重要應用是將磺酸基先臨時

9、占據芳環某特定位置，然后再進行其他的反應，待反應完成后，再在稀硫酸中加熱，以移去磺酸基。例如-溴代萘的合成8。芳香族化合物磺化時，芳環上存在的羥基，烷氧基，羧基，鹵素等取代基均無影響。芳胺與硫酸反應，首先生成胺鹽，繼而受熱重排成對胺基苯磺酸9。2. 2. 1. 2有機金屬試劑與三氧化硫的加成三氧化硫對碳金屬鍵的插入反應，提供了由芳鹵或烯鹵制備磺酸的又一條途徑。有機鋰是較為典型的試劑。由于三氧化硫在操作中較為不便，而使用三氧化硫吡啶或三氧化硫三甲胺復合試劑能使反應在更為溫和，便利的條件下進行。以三氧化硫三甲胺復合物為起始劑，在無水乙醚或四氫呋喃中與有機鋰化合物反應，控制反應溫度由78oC到室溫，

10、得到磺酸鹽，酸化后即得磺酸10。2. 2. 1. 3芳香硫醇合成方法示例2To 4-bromotoluene (518 mg, 3.1 mmol) was added n-BuLi (2.3 M in hexane, 1.35 mL, 3 mmol) over 10 min with cooling (ice bath). After 6 hours, the supernatant solution used in the next stage. To a stirred suspension of crystalline STTAC (sulfur trioxide-trimethylam

11、ine complex, commercially available) (431 mg, 3.1 mmol) in dry THF (15 mL) at 78 oC was added the preformed hexane solution of p-tolyllithium dropwise over 15 min. The reaction mixture was stirred for 2 hours at 78 oC and then allowed to warm to room temperature over 18 hours. After removal of solve

12、nt, H2O (10 mL) and KOH (3M, 1 mL, 3 mmol) were added to the mixture, which was then extracted with Et2O to remove unreacted 4-bromotoluene. The aqueous solution was evaporated to a white solid. HCl(6 M, 4 mL, 24 mmol) was added. The mixture was extracted with EtOAc (4×20 mL), and the combined

13、organic extract was dried (MgSO4) and evaporated to give a moist solid. Et2O (15 mL) was added and some white solid precipitated. This was washed with further Et2O (2×10 mL). The combined Et2O extracts were concentrated to give white crystals (383 mg, 62%) of the monohydrate.2. 2. 1. 4 Sanderme

14、yer反應合成芳香磺酸Sandermeyer反應的應用之一就是將芳香化重氮鹽轉化為芳香磺酸。這是一類很經典的反應。具體操作是將芳胺經重氮鹽在二價金屬離子催化下（一般是二價銅）用液態二氧化硫處理，就可以得到芳香磺酸。2. 2. 2 芳香磺酸或鹽氯化制備芳香磺酰氯示例A mixture of sodium 4'-cyanobiphenyl-4-sulfonate (251 g) and phosphorous oxychloride was refluxed for 16 h. The reaction mixture was poured into a large quantity of

15、 ice/water and the resulting slurry was extracted with dichloromethane (1*1.8 L).The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated to approximately 200 mL. Hexanes (200 mL) was added. The slurry was stirred for 30 min, filtered, washed with 1:1 dichl

16、oromethane/hexanes, and dried to give product (82.1 g).The mother liquor was concentrated and further purified by flash chromatography on silica gel (40->70percent dichloromethane/hexanes) to give an additional 16.2 g of white solid.2. 2. 3 芳香環磺化反應示例2-Nitro-phenylamine (13.8 g) are dissolved in c

17、onc. H2SO4(75 mL), H3PO4 (100 mL) and water (50 mL). The solution of NaNO2 (8.3 g) in water (25 mL) was slowly added dropwise under ice-water cooling. The temperature was maintained at 1015 oC. NH3-SO3H was added in batches to remove the extra formed HNO2. The reaction was cooled down to -10 oC, liq

18、uid SO2 (50 mL) was added dropwise. The reaction mixture was poured into another mixture of FeSO4.7H2O (55.7 g) and Cu (1 g). Half an hour later, the reaction was filtered, the residue cake was washed with mixture of ether (750 mL) and CH2Cl2 (750 mL). The combined filtrate and washings were washed

19、with brine, dried and concentrated. The residue was precipitated in water (50 mL), then diluted ammonia was used to adjust pH equal 9 under stirring. Filtered, the filtrate was acidified with HCl (6 N), the precipitate was collected by filtration and dried to afford desired 2-Nitro-benzenesulfonic a

20、cid, (9.4 g, 65% yield.) 2. 3芳香硫醇及相關衍生物氯代、氧化合成芳香磺酰氯芳香硫醇及相關衍生物，比如硫醚，二硫化物在氧化性氯化試劑存在下，均能夠較容易的轉變成磺酰氯。因此，芳香硫醇及其衍生物也是合成芳香磺酰氯的一類重要前體。 文獻報道：對硝基硫酚在以下兩種條件下都可以很容易的轉變成對硝基苯磺酰氯11：Andrews, Stephen P. 報道：將如下底物懸浮于醋酸水中，導入氯氣，就能以76的收率得到磺酰氯12。二硫化物也是一類可以通過氯氣處理轉化成磺酰氯的重要前體。如Berryman, K. A. 報道132. 3. 1硫酚變磺酰氯合成方法示例4-Nitro-3-

21、trifluoromethyl-benzenethiol 47g was dissolved in AcOH (100 mL), chlorine gas was bubbled into the mixture at 010 oC, TLC indicate the reaction completed. The precipitate was collected by filtration, washed with water. Taken into CH2Cl2 (200 mL). Dried upon anhydrous MgSO4, filtered, concentrated to

22、 afford the desired sulfonyl chloride (22.3 g) as an yellow oil, this sample could be used in next step without further purification. 2. 3. 2芳香硫醇相關衍生物氯代、氧化合成芳香磺酰氯舉例Chlorine gas was bubbled through a suspension of methyl 4-benzylsulfanyl-3-nitrobenzoate (25.4 g, 83.7 mmol) in acetic acid/water (2:3,

23、500 mL) for 1.5 h. The mixture was stirred under the chlorine atmosphere for 19 h when the system was purged with nitrogen and the solvent was concentrated in vacuo. The resulting yellow precipitate was collected by filtration, washed with hexane (2 × 50 mL), and recrystallized from chloroform/

24、hexane to afford the sulfonyl chloride as a white crystal (17.8 g, 76%).2.3. 3應用硝酸鉀-SO2Cl2的反應示例 To above compound 1 (6.55 g, 14.4 mmol) and potassium nitrate (4.37 g, 43.0 mmol) in acetonitrile (45 mL) was added sulfuryl chloride (3.45 mL, 43.0 mmol) dropwise over 7 min and the reaction mixture was

25、stirred at room temperature. After 5 h sodium bicarbonate (500 mL, aq satd) was added and the solution extracted with ethyl acetate (600 mL). The organic phase was washed with brine (400 mL), dried with magnesium sulfate, and evaporated in vacuo to give the title compound (6.6 g, 78%) as an oil. Use

26、d without further purification. 2. 4. 芳香硫醇的制備有機鎂與有機鋰試劑與硫發生插入反應，生成物進一步水解，則生成硫醇或硫酚。由于硫醇可由多種其他方法制得。因此，本法合成硫酚更具有實用價值。例：苯基鋰與硫發生放熱反應，生成物進一步水解則生成苯硫酚14。二硫化物很容易被多種還原試劑還原成硫醇。二硫化物本身也能被氯化試劑作用直接得到磺酰氯。鋅乙酸15，氫化鋁鋰16 等均為常用的還原試劑。若為硝基取代的二芳基二硫化物被鋅乙酸還原時，硝基亦被還原成氨基。但用二硫化鈉做還原劑時，硝基不受影響。鋁二氯化鎳，四叔丁基硼氫化物也能還原二硫醚成硫酚。作為Sandermeyer

27、直接芳磺化的一種替代方法，在某些二氧化硫不適宜的情況下，成為了一種變通的選擇。鄰氨基苯甲酸形成的重氮鹽與二硫化鈉反應，生成相應的二硫化物。它與鋅乙酸共回流，則被還原生成鄰巰基苯甲酸15。經過氯氣處理，即可生成相應的磺酰氯。2. 4. 1. 1芳香硫醇合成方法示例2,4-Dibromo-6-methyl-benzothiazole（3.1 g） and NaHS (1.0 g) in methanol (30 mL) was heated to reflux for 1 hour. TLC indicated the reaction completed. The solvent was rem

28、oved under reduced pressure. Water (30 mL) was added. The water layer was extracted with CH2Cl2 (100 mL) three times. Combined organic layer was washed with brine. Dried upon anhydrous Na2SO4, concentrated to afford desired product.2. 5 Sandermeyer 反應由芳胺合成芳香磺酰氯Sandermeyer反應的另一個應用是直接得到芳香磺酰氯。這種反應對催化劑，

29、反應條件的要求及控制都比成磺酸高。市場上有二氧化硫醋酸溶液出售。將芳胺做成重氮鹽，以亞銅鹽作為催化劑，醋酸做溶劑，再用二氧化硫處理就能夠以較好的收率得到芳香磺酰氯。172. 5. 1 芳香環磺化反應示例 To a suspension of 4-amino-2-chloro-3-methyl-benzonitrile (500 mg, 3.00 mmol) in 1.8 mL of 6 N HCl at room temperature was added 2 mL of water followed by a solution of NaNO2 (220 mg, 3.13 mmol) in

30、1 mL of water dropwise and the suspension stirred at room temperature for 20 min. The suspension was added to a solution of SO2 in acetic acid (prepared by bubbling SO2 gas into acetic acid until saturation at room temperature) and copper(II) chloride dihydrate (60 mg, 3.52 mmol) in 0.15 mL of water

31、. The suspension was stirred at room temperature for 1.25 h and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/Hexanes, 50:50, 75:25 and 100

32、:0) to afford the title compound (305 mg) as a white solid.3. 脂肪磺酰氯的制備脂肪磺酰氯大部分是由相應的硫醇及其衍生物用氯磺化試劑（比如氯氣）作用得來。因此，硫醇及其衍生物的引入是合成脂肪族磺酰氯的重要手段。硫類得衍生物有多種，包括硫脲，異硫氰酸酯，硫代乙酸酯，磺原酸酯等等。3. 1 烷基硫醇的合成及通過烷基硫醇合成脂肪磺酰氯3. 1. 1 硫醇的合成硫醇可由硫氫化鈉（鉀）或硫化氫與烴化試劑進行親核取代反應而制取。常用的烴化試劑有鹵代烴，醇，硫酸酯等。將硫化氫通到乙醇鈉的乙醇液中，首先得到的是硫氫化鈉，繼而與1，7-二溴庚烷反應，以

33、88%的產率生成1，7-庚二硫醇19。-氨基腈在室溫下就可以同硫化氫反應，高產率的生成硫醇。-氨基腈易由相應的醛，酮制得。因此，本法是由醛酮合成硫醇的良好方法。例：3，4-二甲氧基苯甲醛與焦亞硫酸鈉及叔丁胺在室溫反應10分鐘后加入氰化鈉，就生成了氨基晴。它在三乙胺或吡啶的存在下，通入硫化氫，室溫反應就能以92%的產率生成3，4-二甲氧基苯甲硫醇20。硫脲很容易烴化反應生成硫-烴基異硫脲鹽，進一步用堿水解，就能以良好產率生成硫醇。例：1，2-二溴乙烷滴入到熱的硫脲乙醇溶液中，馬上形成硫-烴基異硫脲鹽，再與氫氧化鉀水溶液一同回流，就可以得到硫醇21。 羧酸硫醇酯在酸性或堿性試劑催化下，均可水解成硫

34、醇。例：對甲苯磺酸酯與硫代乙酸鉀在乙醇或丙酮中共熱，生成乙酸硫醇酯，再在5%氫氧化鉀乙醇溶液中回流，就可以生成硫醇22。 黃原酸乙酯單鉀鹽可由氫氧化鉀與二硫化碳在乙醇中反應制得。它與鹵代烴，磺酸酯等烴化試劑反應生成黃原酸酯，進一步氨解或水解，就能生成硫醇。本法適用于水溶性鹵化物如氯乙酸合成相應的硫醇。例：黃原酸乙酯單鉀鹽在丙酮中與-苯基溴乙烷于室溫下反應，即生成黃原酸酯。將黃原酸酯與氫化鋁鋰在乙醚中共熱，即生成硫醇23。烯烴與硫化氫在壓力下加熱則生成硫醇，加成方向按馬氏法則。例：在干冰冷卻下將烯烴與硫化氫置于壓力瓶中，然后于150oC加熱，即生成硫醇24。3. 1. 2 通過硫醇合成芳香磺酰氯

35、 目前有兩種常用的方法將脂肪硫醇轉變為脂肪磺酰氯，一是用NaClO4在酸性溶液中處理得來。另一種是在酸性介質中通入氯氣制得。如：3. 2 通過烷基硫脲合成脂肪磺酰氯3. 2. 1烷基硫脲的合成硫脲極易發生烴化反應生成S烴基異硫脲鹽，收率一般在（4090）。烷基硫脲是所有脂肪類硫醇衍生物中最重要的一類，它可以從前體鹵代烷烴經硫脲處理得來。反應條件比較溫和。如下例所示：本法的一種改良是在濃鹽酸或濃氫溴酸存在下，醇與硫脲直接反應，即可生成S烴基異硫脲鹽，不必由醇制備鹵代烴再進行反應。3. 2. 2 通過烷基硫脲合成芳香磺酰氯 目前有兩種常用的方法將脂肪硫脲轉變為脂肪磺酰氯，一是用NaClO4在酸性溶

36、液中處理得來。另一種是在酸性介質中通入氯氣制得。文獻報道：183. 3 通過烷基異硫氰酸酯合成芳香磺酰氯3. 3. 1烷基異硫氰酸酯的合成烷基異硫氰酸酯是脂肪硫醇的另一類重要的衍生物。它也可以由烷基鹵代烴作為前體與異硫氰酸鉀反應生成。如：3. 3. 2 通過烷基異硫氰酸酯合成芳香磺酰氯異硫氰酸酯類化合物用氯氣處理后也能得到磺酰氯：3. 4 通過羧酸硫醇酯合成芳香磺酰氯3. 4. 1 羧酸硫醇酯的合成 羧酸硫醇酯的制備一般都是通過鹵代烷烴同乙酸硫醇鉀反應生成。如：3. 4. 2 通過羧酸硫醇酯合成脂肪磺酰氯羧酸硫醇酯也是通過氯氣的處理得到脂肪磺酰氯。如：3. 5 脂肪磺酰氯合成反應示例 脂肪族磺

37、化反應示例1A solution of 4-(7-Bromo-2-ethoxymethyl-imidazo4,5-cquinolin-1-yl)-butane-1-thiol (1.73 g, 4.39 mmol) in concentrated hydrochloric acid (7.5 ML) and water (5 mL) was cooled to 0 oC. A solution of sodium chlorate (0.61 g, 5.7 mmol) in water (2. 5 mL) was added dropwise with vigourous stirring o

38、ver a period of three minutes. The reaction was stirred at 0 oC for 90 minutes then diluted with dichloromethane (50 mL). Aqueous potassium carbonate (8 mL of 6M) was slowly added to adjust the mixture to pH equal 5. Dichloromethane (100 mL) and water (75 mL) were added, and the reaction was allowed

39、 to warm to ambient temperature with stirring. The aqueous layer was separated and extracted with dichloromethane (3 x 40 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.61 g of 4-(7-Bromo-2-ethoxymethyl-imidazo4,5

40、-cquinolin-1-yl)-butane-1-sulfonyl chloride as a tan solid.脂肪族磺化反應示例2To a solution of methylthioglycolate (1.3kg, 12.25mol) in dichloromethane (9 litres) was added ice (4.5 litres). Chlorine gas was bubbled gently through the solution, maintaining the temperature below 5.deg.C until the solution mai

41、ntained a slight green colouration. The solution was degassed with nitrogen to remove excess chlorine, the organic phase collected and the solvent removed under reduced pressure to give the subtitle compound (1.758 kg, 83 percent) which was used without further purification. 烷基硫醇衍生物合成反應示例3-4-(4-chlo

42、rophenoxy)phenyl-7-iodo-hept-2-enoate (59.8 g) and thiourea (9.39 g) in ethanol (123 ml) was refluxed for 24 hours. The resulting mixture was cooled and evaporated to give ethyl 7-amidinothio-3-4-(4-chlorophenoxy)phenylhept-2-enoate hydroiodide (70.2 g) (E:Z = 1:1 mixture) as slightly yellow oil. Th

43、is sample was then dissolved in AcOH (1000 mL), chlorine gas was bubbled into the mixture at 010 oC, TLC indicate the reaction completed. The precipitate was collected by filtration, washed with water. Re-dissolved in CH2Cl2 (1000 mL). Dried upon anhydrous MgSO4, filtered, concentrated to afford the

44、 target sulfonyl chloride (52 g, 65 %). 烷基硫醇衍生物合成脂肪磺酰氯反應示例A mixture of 1-iodo-3-methylbutane (12 g) and potassium thiocyanate (5.9 g) in acetone (110 ml) was refluxed for 4 hours. After precipitate was filtered off, the filtrate was evaporated in vacuo. Water was added to the residue followed by ext

45、raction with chloroform. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give the thiocyanate (8.3 g). A solution of above thiocyanate was bubbled with chlorine gas for 1 hour under ice-cooling (below 0.deg. C.) with stirring followed by extraction with diisopro

46、pyl ether. After extract was dried over sodium sulfate, the solvent was evaporated in vacuo to give sulfonyl chloride (9.0 g). To a 28percent ammonium hydroxide (50 ml) was added dropwise crude sulfonyl chloride in dichloromethane (15 ml) over 20 minutes at approximately 0.deg. C. The reaction mixture was stirred vigorously overnight at ambient temperature. The phases were separated. The aqueous phase was extracted with chloroform/methanol (5/1). The combined organic extracts were washed with half-brine, dried over magnesium sulfate and evaporated under reduced pressur