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Structure of 773-64-8 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Physical Organic Chemistry, 2018, vol. 31, # 2,
[2] Tetrahedron, 1994, vol. 50, # 16, p. 4775 - 4794
[3] Organic Syntheses, 1997, vol. 74, p. 217 - 217
[4] Journal of the American Chemical Society, 1934, vol. 56, p. 696
[5] Recueil des Travaux Chimiques des Pays-Bas, 1935, vol. 54, p. 544,550
[6] Recueil des Travaux Chimiques des Pays-Bas, 1931, vol. 50, p. 60,69, 70
[7] Journal of the American Chemical Society, 1941, vol. 63, p. 3446
[8] Journal of Organic Chemistry USSR (English Translation), 1987, vol. 23, # 11, p. 2144 - 2146[9] Zhurnal Organicheskoi Khimii, 1987, vol. 23, # 11, p. 2429 - 2431
Reference：
[1] Monatshefte fuer Chemie, 1913, vol. 34, p. 576
6
[ 773-64-8 ]
[ 16182-15-3 ]
Reference：
[1] Organic Syntheses, 1997, vol. 74, p. 217 - 217
[2] Antimicrobial Agents and Chemotherapy, 2002, vol. 46, # 8, p. 2450 - 2457
[3] Chemistry - A European Journal, 2012, vol. 18, # 6, p. 1582 - 1585
[4] ACS Combinatorial Science, 2015, vol. 17, # 11, p. 658 - 662
[5] Chemistry - An Asian Journal, 2016, vol. 11, # 4, p. 478 - 481
[6] Medicinal Chemistry Research, 2016, vol. 25, # 7, p. 1425 - 1432
[7] European Journal of Organic Chemistry, 2017, vol. 2017, # 24, p. 3512 - 3515
[8] Research on Chemical Intermediates, 2017, vol. 43, # 11, p. 6601 - 6616
[9] Organic Letters, 2018, vol. 20, # 7, p. 1703 - 1706
7
[ 773-64-8 ]
[ 10576-12-2 ]
[ 38202-27-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;
A solution of ethyl N-hydroxyacetimidate (2.00 g, 19.4 mmol), N,N-diisopropylethylamine (3.01 g, 23.3 mmol) and 4-dimethylaminopyridine (240 mg, 1.96 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0 °C. To this cold solution 2,4,6-trimethylbenzene-1-sulfonyl chloride (4.66 g, 21.3 mmol) was added slowly, warmed to room temperature and stirred for 1 hour. The reaction was quenched with the addition of water (40 mL) and this mixture was extracted with dichloromethane (30 mL, 3 times). The combined dichloromethane layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica flash column chromatography with 5percent ethyl acetate in hexanes as the eluent to obtain 9 as white solid (5.19 g, 94percent). 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 2H), 3.88 (q, J = 7.1 Hz, 2H), 2.62 (s, 6H), 2.28 (s, 3H), 2.00 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 169.1, 143.3, 140.6, 131.5, 130.3, 63.6, 22.8, 21.0, 14.8, 13.9; HRMS (ESI/TOF) m/z calcd for C13H20NO4S+ [M + H]+ 286.1108, found 286.1115.
92%
With triethylamine In N,N-dimethyl-formamide at 0℃;
Ethyl N-hydroxyacetimidate (10.3 g, 47 mmol, 1.1 eq) and triethylamine (25.5 ml, 94 mmol, 2 eq) were dissolved in DMF (40 ml, 2 vol) and the mixture cooled to 0 °C. O-mesitylene chloride (20 g, 47 mmol, 1 eq) was then added portionwise and the mixture stirred at 0 °C for 45 minutes. The above solution was poured into ice water, and solid obtained was filtered and washed with water. Yield : 23 g (92 percent). 1HNMR (400MHz, DMSO-d6): 5 1.16 (t, 3H), 2.03 (s, 3H), 2.31 (s, 3H), 2.64 (s, 6H), 3.89 (q, 2H), 6.96 (s, 2H).
87%
With sodium hydroxide In ethanol at 15 - 25℃; for 2 h;
Into a 500mL reaction flask added ethyl acetohydroxamate (71g, 0.5mol, 1.0eq) and ethanol (284mL, 4P) to form into an ethanol solution of ethyl acetohydroxanoate, into ethyl acetohydroxanoate ethanol solution added sodium hydroxide (24g, 0.6mol, 1.2eq), added the drops of 2,4,6-trimethylbenzenesulfonyl chloride (120.3g, 0.55mol, 1. 1eq), magnetic stirring speeds up the reaction, the reaction temperature is controlled between 15-25 ° C, after the addition is completed, the temperature is maintained between 15-25 ° C for 2 hours, reaction solution added into water (284mL, 4P), the precipitated solid is suction filtered, and then obtained filter cake is washed with ethanol, obtained solid is dried and then obtained 244g of ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetohydroxamate, yield is 87percent
Reference：
[1] RSC Advances, 2018, vol. 8, # 25, p. 13755 - 13763
[2] Synthetic Communications, 2018, vol. 48, # 6, p. 626 - 631
[3] Patent: WO2011/112186, 2011, A1, . Location in patent: Page/Page column 202
[4] Patent: CN108530315, 2018, A, . Location in patent: Paragraph 0100-0102
[5] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 6, p. 1383 - 1387
[6] Organic Letters, 2017, vol. 19, # 19, p. 5490 - 5493
[7] Archiv der Pharmazie, 2006, vol. 339, # 5, p. 262 - 266
[8] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 934 - 945
[9] The Journal of organic chemistry, 1973, vol. 38, # 6, p. 1239 - 1241
[10] Patent: WO2008/9487, 2008, A1, . Location in patent: Page/Page column 68
[11] Journal of the American Chemical Society, 2008, vol. 130, # 30, p. 9642 - 9643
[12] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 2, p. 309 - 316
[13] Angewandte Chemie - International Edition, 2011, vol. 50, # 18, p. 4127 - 4132
[14] Patent: US2012/178913, 2012, A1, . Location in patent: Page/Page column 8
8
[ 773-64-8 ]
[ 36016-38-3 ]
[ 36016-39-4 ]
Yield
Reaction Conditions
Operation in experiment
96%
With triethylamine In tetrahydrofuran at 0℃; for 1.16667 h; Inert atmosphere
MC825 scaffold Step 1-IS08115-029 0-(2,2-dimethylpropano l)-A/-f(mesitylsulfonyl)oxy1hvdroxylamine Procedure: To a solution of 2-mestylenesulphonylchloride (5 g, 22.8 mmol) in dry tetrahydrofuran (75 ml_), N-boc-hydroxylamine (3.34 g, 25.1 mmol) is added and cooled to 0°C. Triethylamine (3.8 mL, 27.4 mmol) is added slowly over 10 min. The reaction mixture is stirred for 1 h at 0°C. The reaction mixture is concentrated and the residue is taken in dichloromethane (75 mL) and washed with water (2 * 75mL), an aqueous solution of NaHC03 (10percent, 75 mL) and dried over MgSO4and concentrated to get the product. Yield: 96 percent (7 g, off white solid). 1H NMR (400 MHz, DMSO-d6): δ [ppm] 11.16 (s, 1H), 7.12 (s, 2H), 2.49 (s, 6H), 2.28 (s, 3H), 1.23 (s, 9H).
93%
With triethylamine In tert-butyl methyl ether at 0 - 20℃; for 2 h;
To a stuffed solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (4.80 g, 22.01mmol) and tert-butyl hydroxycarbamate (3.22 g, 24.21 mmol) in MTBE (45 mL) wasadded triethylamine (3.40 mL, 24.21 mmol) slowly at 0°C. The reaction mixture was stirred at room temperature for 2 h. The resulting solid was filtered and washed with MTBE (100 mL) and hexane. The combined organic layer was dried over sodium sulphate, then concentrated in vacuo, to give the title compound (6.44 g, 93 percent). oH (400MHz, CDC13) 7.57 (s, 1H), 6.99 (s, 2H), 2.68 (s, 6H), 2.32 (s, 3H), 1.32 (s, 9H).
89%
With triethylamine In tert-butyl methyl ether at 0℃; for 0.5 h;
To a 0 °C solutionof 2,4,6-trimethylbenzene-1-sulfonyl chloride (10.0 g, 45.72 mmol) and tert-butyl hydroxycarbamate (6.088 g, 45.72 mmol) in MTBE (100 mL) was added TEA (14.46 mL, 48.01 mmol) drop-wise while stirring. The resulting suspension was stirred at 0 °C for an additional 30 mm and then warmed to ambient temperature. The reaction was then diluted with water (100 mL), adjusted to pH 4 with 1 N HC1(aq). The organic layer was dried (Na2504), filtered and concentrated to yield the title compound initially as a yellowish oil, which upon drying overnight under high vacuum became a white solid (12.89 g, 89percent yield). ‘H NMR (CDC13) 7.66 (br s, 1H), 6.98 (s, 2H), 2.67 (s, 6H), 2.32 (s, 3H), 1.31 (s, 9H).
89%
With triethylamine In tert-butyl methyl ether at 0℃;
To a 0 °C solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (10.0 g, 45.72 mmol) and tert-butyl hydroxycarbamate (6.088 g, 45.72 mmol) in MTBE (100 mL) was added TEA (14.46 mL, 48.01 mmol) dropwise while stirring. The resulting suspension was stirred at 0 °C for an additional 30 mm and then warmed to ambient temperature. The reaction was then diluted with water (100 mL), adjusted to pH 4 with 1 N HC1(aq). The organic layer was dried (Na2504), filtered and concentrated to yield the title compound initially as a yellowish oil, which upon drying overnight under high vacuum became a white solid (12.89 g, 89percent yield). ‘H NIVIR (CDC13) 7.66 (br s, 1H), 6.98 (s, 2H), 2.67 (s, 6H), 2.32 (s, 3H), 1.31 (s, 9H).
89%
With triethylamine In tert-butyl methyl ether at 0℃; for 0.5 h;
Preparation of tert-butyl mesitylsulfonyl)oxycarbamate. To a 0 °C solution of 2,4,6-trimethylbenzene-l-sulfonyl chloride (10.0 g, 45.72 mmol) and tert-butyl hydroxycarbamate (6.088 g, 45.72 mmol) in MTBE (100 mL) was added TEA (14.46 mL, 48.01 mmol) drop-wise while stirring. The resulting suspension was stirred at 0 °C for an additional 30 min and then warmed to ambient temperature. The reaction was then diluted with water (100 mL), adjusted to pH 4 with 1 N HCl(aq). The organic layer was dried (Na2S04), filtered and concentrated to yield the title compound initially as a yellowish oil, which upon drying overnight under high vacuum became a white solid (12.89 g, 89percent yield). NMR (CDCh) δ 7.66 (br s, 1H), 6.98 (s, 2H), 2.67 (s, 6H), 2.32 (s, 3H), 1.31 (s, 9H).
89%
With triethylamine In tert-butyl methyl ether at 0℃; for 0.5 h;
To a 0 °C solution of 2,4,6-trimethylbenzene-l-sulfonyl chloride (10.0 g, 45.72 mmol) and tert-butyl hydroxycarbamate (6.088 g, 45.72 mmol) in MTBE (100 mL) was added TEA (14.46 mL, 48.01 mmol) drop-wise while stirring. The resulting suspension was stirred at 0 °C for an additional 30 min and then warmed to ambient temperature. The reaction was diluted with water (100 mL), adjusted to pH 4 with 1 N HCl(aq). The organic layer was dried (Na2S04), filtered and concentrated to yield the title compound initially as a yellowish oil, which upon drying overnight under high vacuum became a white solid (12.89 g, 89percent yield). MR (CDCh) δ 7.66 (br s, 1H), 6.98 (s, 2H), 2.67 (s, 6H), 2.32 (s, 3H), 1.31 (s, 9H).
88%
With triethylamine In tert-butyl methyl ether at 0 - 3℃; Industrial scale
To a stirred solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (5.5 Kg, 25.14 mol) in MTBE (55 L) is added tert-butyl hydroxycarbamate (4 Kg, 30.17 mol) and cooledto 0 °C. Triethylamine (3.05 Kg, 30.17 mol) is added to the reaction mixture over a period of 1 hour and the reaction mixture is stirred at 0 °C for 2 hours. The reactionmixture is filtered and washed with MTBE (2x5 L). The filtrate is concentrated to a volume of 12 L and n-hexane (6 L) is added and the mixture is redistilled up to a volume of 12 L. To the crude compound 5percent solution of MTBE in n-hexane (60 L) is added andthe mixture is stirred for 2 hours. The reaction mixture is filtered to give the first crop as an off white solid compound (6.13 Kg). The filtrate is concentrated to dryness and 5percentsolution of MTBE in n-hexane (10 L) is added. The reaction mixture is stirred for 30 minutes and filtered to give a second crop of the title compound (0.86 Kg) which is combined with the first crop to give the title compound (6.99 g, 88percent).
88%
With triethylamine In tert-butyl methyl ether at 0℃; for 3 h; Large scale
To a stirred solution of 2,4,6-trimethylbenzene-l-sulfonyl chloride (5.5 Kg, 25.14 mol) in MTBE (55 L) is added tert-butyl hydroxycarbamate (4 Kg, 30.17 mol) and cooled to 0° C. Triethylamine (3.05 Kg, 30.17 mol) is added to the reaction mixture over a period of 1 hour and the reaction mixture is stirred at 0° C. for 2 hours. The reaction mixture is filtered and washed with MTBE (2*5 L). The filtrate is concentrated to a volume of 12 L and n-hexane (6 L) is added and the mixture is redistilled up to a volume of 12 L. To the crude compound 5percent solution of MTBE in n-hexane (60 L) is added and the mixture is stirred for 2 hours. The reaction mixture is filtered to give the first crop as an off white solid compound (6.13 Kg). The filtrate is concentrated to dryness and 5percent solution of MTBE in n-hexane (10 L) is added. The reaction mixture is stirred for 30 minutes and filtered to give a second crop of the title compound (0.86 Kg) which is combined with the first crop to give the title compound (6.99 g, 88percent).
87%
With triethylamine In diethyl ether at 0 - 20℃; Inert atmosphere
Step 6: tert-butyl mesitylsulfonyloxycarbamate To a solution of 2,4,6-trimethylbenzene-1 -sulfonyl chloride (120 g, 0.55 mol, Beiou) and ferf-butyl hydroxycarbamate (73 g, 0.55 mol, Beiou) in Et20 (1 L) was added TEA (58.3 g, 0.57 mol) drop wise at 0 °C under nitrogen atmosphere. Then, the reaction mixture was stirred at rt for overnight. The mixture was filtered and organic layer was concentrated, the crude product was washed with PE (0.5 L) to afford ferf-butyl mesitylsulfonyloxycarbamate (151 .5 g, 0.48mol, 87 percent yield) as a white solid.
76.3%
With triethylamine In diethyl ether at 0℃; for 0.5 h;
[00240] To a mixture of 2,4,6-trimethylbenzenesulfonyl chloride (100 g, 457 mmol) and tert-butyl hydroxycarbamate (60.9 g, 457 mmol) in diethyl ether (1000 mL) was added TEA (46.3 g, 24.9 mmol) at 0°C. The reaction mixture was allowed to stir at 0°C for 30 mm. The reaction mixture was filtered and washed with MTBE (250 mL). The solution was concentrated at 20°C at 150mm Hg to remove the diethyl ether. The reaction mixture was then diluted with petroleum ether (1500 niL) and allowed to stir for 5 mm. The reaction mixture was filtered and washed with petroleum ether (300 mL) to provide tertbutyl [(mesitylsulfonyl)oxy]carbamate (110 g, 76.3percent). 1H NEVER (400 JVEFIz, DMSO-d6) 6 11.19 (s, 1H), 7.14 (s, 2H), 2.54 (s, 6H), 2.30 (s, 3H), 1.25 (s, 9H).
76.3%
With triethylamine In diethyl ether at 0℃; for 0.5 h;
Step 1: tert-butyl [(mesitylsulfonyl)oxy]carbamate To a mixture of 2,4,6-trimethylbenzenesulfonyl chloride (100 g, 457 mmol) and tert-butyl hydroxycarbamate (60.9 g, 457 mmol) in diethyl ether (1000 mL) was added TEA (46.3 g, 24.9 mmol) at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 min. The reaction mixture was filtered and washed with MTBE (250 mL). The solution was concentrated at 20° C. at 150 mm Hg to remove the diethyl ether. The reaction mixture was then diluted with petroleum ether (1500 mL) and allowed to stir for 5 min. The reaction mixture was filtered and washed with petroleum ether (300 mL) to provide tert-butyl [(mesitylsulfonyl)oxy]carbamate (110 g, 76.3percent). 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 7.14 (s, 2H), 2.54 (s, 6H), 2.30 (s, 3H), 1.25 (s, 9H).
73%
With triethylamine In tetrahydrofuran at 0℃; for 1.25 h; Inert atmosphere
N-(tert.-Butoxycarbon l)-0-(mesitylsulfonyl)-hydroxylamineTo a solution of 2-mesitylene sulphonyl chloride (2.0 g, 9.14 mmol) in dry THF (50 ml_), was added N-Boc-hydroxylamine (1.21 g, 9.14 mmol) and cooled to 0 C under N2 atmosphere. The reaction mixture was stirred for 5 minutes. To this mixture triethylamine (1.1 g, 11 mmol) was added slowly over 10 minutes. The reaction mixture was stirred for 1 hour at 0 C and upon completion, the solvent removed in vacuo. The residue was redissolved in dichloromethane (50 ml_) and washed with water (2 x 50 mL), 10percent aqueous NaHCO3 (50 ml_) and dried overMgS04. It was then concentrated under reduced pressure at room temperature to get the product as an off white solid; (2.1 g, 73percent). TLC: pet ether / ethyl acetate (8/2) Rf- 0.4. 1H NMR (DMSO-d6; 400 MHz): δ 11.16 (s, 1 H), 7.12 (s, 2H), 2.49 (s, 6H), 2.28 (s, 3H), 1.23 (s, 9H).
73%
Stage #1: at 0℃; for 0.0833333 h; Inert atmosphere Stage #2: With triethylamine In tetrahydrofuran at 0℃; for 1.16667 h; Inert atmosphere
8.1 N-(tert-butoxy carbonyl)-0-(mesit lsulfonyl)-hydroxylamine To a solution of 2-mesitylene sulphonyl chloride (2.0 g, 0.00914 mol) in dry THF (50 mL) is added N-Boc-hydroxylamine (1.21 g, 0.00914 mol) and cooled to 0°C under N2 atmosphere. The reaction mixture is stirred for 5 minutes. To this mixture triethylamine (1.1 g, 0.011 mol) is added slowly over 10 minutes. The reaction mixture is stirred for 1 hour 0°C and then the solvent is removed in vacuo. The residue is dissolved in dichloromethane (50 mL) and washed with water (2 x 50 mL), 10percent aqueous NaHC03 (50 ml) and dried over MgS04. It is then concentrated under reduced pressure at room temperature to get the product as an off white solid. (2.1 g, 73percent); TLC: Pet ether / Ethyl acetate (8/2) Rf- 0.4; 1H NMR (DMSO-d6; 400 MHz): δ [ppm] 11.16 (s, 1H), 7.12 (s, 2H), 2.49 (s, 6H), 2.28 (s, 3H), 1.23 (s, 9H).
72%
With triethylamine In diethyl ether at 20℃;
(a) O-(Mesitylsulfonyphydroxylamine To a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (30 g, 0.148 mol) and tert-butyl hydroxycarbamate (18 g, 0.148 mol) in Et2O (500 mL) was added Et3N (15 g, 0.148 mol) dropwise over 1 h. The reaction mixture was stirred at room temperature for 4 h, then filtered. The filtrate was concentrated. The product was purified by silica gel column chromatography (5percent v/v EtOAc in PE) to give tert-butyl mesitylsulfonyloxycarbamate as a white solid (31 g, yield 72percent). ESI MS: m/z 338 [M+Na]+.
64%
With triethylamine In hexane; benzene
1st step: Production of t-butyl N-(mesitylenesulphonyloxy)carbamate (Z40) of formula: STR52 with t-Bu=tert-butyl 1 equivalent of triethylamine (3.5 ml-0.025 mol) is added dropwise to 1 equivalent of mesitylenesulphonyl chloride (5.45 g-0.025 mol) and 1 equivalent of t-butyl N-hydroxycarbamate (3.32 g-0.025 mol) dissolved in anhydrous ether (100 ml) at 0° C. During the reaction, a precipitate of triethylamine hydrochloride gradually forms. After 0.5 h of stirring at 0° C., this precipitate is filtered off and washed copiously with ether. The medium is concentrated under vacuum. 5.01 g of pale yellow residue are obtained, which product is recrystallized twice in a minimum amount of hot benzene (8 ml) and of hexane (30 ml). The yield is 64percent. The molecular mass is: M=315.39
Reference：
[1] Organic Process Research and Development, 2009, vol. 13, # 2, p. 263 - 267
[2] Patent: WO2013/124026, 2013, A1, . Location in patent: Page/Page column 80; 81
[3] Patent: WO2015/86502, 2015, A1, . Location in patent: Page/Page column 81
[4] Patent: WO2017/11776, 2017, A1, . Location in patent: Paragraph 00687; 00688; 00689
[5] Patent: WO2018/71447, 2018, A1, . Location in patent: Paragraph 00802; 00803
[6] Patent: WO2018/71454, 2018, A1, . Location in patent: Paragraph 00929; 00932
[7] Patent: WO2018/136661, 2018, A1, . Location in patent: Paragraph 00882
[8] Patent: WO2015/105779, 2015, A1, . Location in patent: Page/Page column 14
[9] Patent: US2016/333005, 2016, A1, . Location in patent: Paragraph 0052-0053
[10] Patent: WO2012/67664, 2012, A1, . Location in patent: Page/Page column 42-43
[11] Patent: WO2015/108861, 2015, A1, . Location in patent: Paragraph 00240
[12] Patent: US2015/225422, 2015, A1, . Location in patent: Paragraph 0328-0329
[13] Organic Letters, 2018, vol. 20, # 22, p. 7131 - 7136
[14] Patent: WO2012/25186, 2012, A1, . Location in patent: Page/Page column 70
[15] Patent: WO2013/131609, 2013, A1, . Location in patent: Page/Page column 95; 96
[16] Patent: US2012/178748, 2012, A1, . Location in patent: Page/Page column 41
[17] Patent: US5296505, 1994, A,
[18] Journal of Organic Chemistry, 2012, vol. 77, # 19, p. 8480 - 8491
[19] Patent: US5521147, 1996, A,
[20] Patent: US5661108, 1997, A,
[21] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 23, p. 11376 - 11391
[22] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 15, p. 4693 - 4699
[23] Patent: WO2011/150156, 2011, A2, . Location in patent: Page/Page column 121
[24] Patent: WO2013/43520, 2013, A1, . Location in patent: Page/Page column 38
[25] Patent: WO2015/97122, 2015, A1, . Location in patent: Page/Page column 102
[26] Patent: WO2016/161572, 2016, A1, . Location in patent: Page/Page column 58
9
[ 773-64-8 ]
[ 58042-39-0 ]
Yield
Reaction Conditions
Operation in experiment
74%
With dmap; hydroxylamine hydrochloride In pyridine at 20℃; for 0.0833333 h; Cooling with ice
General procedure: To a mixture of hydroxylamine hydrochloride (2 equiv.) and DMAP (2 equiv.) in pyridine (20 mL) was added a portion of arylsulfonyl chloride (1 equiv.) on an ice-bath. Then, the mixture was stirred for 5 min at room temperature. The resulting suspension was poured into AcOEt (100 mL) and 1 N HCl aq. (100 mL). The AcOEt layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography under one of the gradient conditions indicated below, and recrystallized from Et2O/n-hexane to give N-hydroxyarylsulfonamide derivatives.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 8, p. 2340 - 2343
10
[ 773-64-8 ]
[ 24807-55-4 ]
[ 74257-00-4 ]
Yield
Reaction Conditions
Operation in experiment
48%
With triethylamine In 1,4-dioxane for 1.5 h; Cooling with ice
An oven dried 1.0 l round-bottomedflask containing a magnetic stir bar was equipped with a Claisen adapter. 3-Nitro-1,2,4-triazole (19.5 g, 0.171 mol), dry dioxane (200 ml) and triethylamine (1.0 equiv., 17.3 g,0.171 mol) was transferred to the reaction flask and the solution was cooled in an ice-bathwith magnetic stirring.47 The Claisen adapter was fitted with a 200 ml pressure-equalizingaddition funnel, containing a dioxane solution (150 ml) of mesitylenesulfonyl chloride(37.4 g, 0.171 mol). The solution of mesitylenesulfonyl chloride was added dropwise overa period of approx. 0.5 h and the final suspension was stirred for an additional 1 h andthen warmed to rt. After removal of the precipitated Et3N·HCl by filtration, the filtratewas concentrated in vacuo to give a yellow solid, which was dissolved in dichloromethane(150 ml) and the solution was washed with water (150 ml).48 The organic layer was driedover anhydrous Na2SO4 and evaporated in vacuo to give a yellow solid. Recrystallizationfrom boiling toluene (20–30 ml) followed by washing with ice-cold toluene and dryingovernight at 1.9 mmHg, provided 24–25 g (46percent–48percent) of the title compound as light yellow solid,49 mp. 131C–133C (lit.37 130C–132C). Rf = 0.23 (20percent hexane in CH2Cl2, UV);1H NMR (300 MHz, CDCl3): δ 8.84 (s, 1H), 7.07 (s, 2H), 2.69 (s, 6H), 2.34 (s, 3H);13C NMR (75 MHz, CDCl3): δ 162.9, 147.5, 145.2, 142.5, 133.0, 127.9, 23.2, 21.3; IR(solid): 3126, 2983, 2947, 1597.Anal. Calcd. for C11H12N4O4S: C, 44.59; H, 4.08; N, 18.91. Found: C, 44.69; H,3.88; N, 18.72. The purity of the product (96percent) established by RP-HPLC, tR = 8.41 min(254 nm).
Reference：
[1] Organic Preparations and Procedures International, 2014, vol. 46, # 3, p. 267 - 271
[2] Tetrahedron Letters, 1986, vol. 27, # 45, p. 5529 - 5532
11
[ 773-64-8 ]
[ 137280-49-0 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 15, p. 5472 - 5478
12
[ 625-82-1 ]
[ 773-64-8 ]
[ 885434-70-8 ]
Yield
Reaction Conditions
Operation in experiment
58%
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 16 h;
To a solution of 2,4-dimethyl-lH-pyrrole (24 mg, 0.25 mmol) and mesitylsulfonyl chloride (218 mg, 1.0 mmol) in 5 mL of THF was added 60percent NaH (40 mg, 1.0 mmol) at 0 °C. The resulting mixture was stirred at r.t. for 16 h. The solution was diluted with EtOAc (50 mL), washed with 1 N HC1 (aq.) (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane/EtOAc = 10/1) to give the desired product as a pale red solid (40 mg, 58percent). H NMR (600 MHz, CDC13) δ 7.01 (s, 1H), 6.95 (s, 2H), 5.77 (s, 1H), 2.49 (s, 6H), 2.31 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H). 13C NMR (150 MHz, CDCI3) δ 143.8, 140.2, 133.8, 132.2, 130.2, 119.7, 119.2, 114.5, 23.4, 21.1, 12.6, 11.8.
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 3, p. 952 - 962
[2] Patent: WO2013/119931, 2013, A1, . Location in patent: Paragraph 0201
With triethylamine; In 1,4-dioxane; for 1.5h;Cooling with ice;
An oven dried 1.0 l round-bottomedflask containing a magnetic stir bar was equipped with a Claisen adapter. 3-Nitro-1,2,4-triazole (19.5 g, 0.171 mol), dry dioxane (200 ml) and triethylamine (1.0 equiv., 17.3 g,0.171 mol) was transferred to the reaction flask and the solution was cooled in an ice-bathwith magnetic stirring.47 The Claisen adapter was fitted with a 200 ml pressure-equalizingaddition funnel, containing a dioxane solution (150 ml) of mesitylenesulfonyl chloride(37.4 g, 0.171 mol). The solution of mesitylenesulfonyl chloride was added dropwise overa period of approx. 0.5 h and the final suspension was stirred for an additional 1 h andthen warmed to rt. After removal of the precipitated Et3N·HCl by filtration, the filtratewas concentrated in vacuo to give a yellow solid, which was dissolved in dichloromethane(150 ml) and the solution was washed with water (150 ml).48 The organic layer was driedover anhydrous Na2SO4 and evaporated in vacuo to give a yellow solid. Recrystallizationfrom boiling toluene (20?30 ml) followed by washing with ice-cold toluene and dryingovernight at 1.9 mmHg, provided 24?25 g (46percent?48percent) of the title compound as light yellow solid,49 mp. 131C?133C (lit.37 130C?132C). Rf = 0.23 (20percent hexane in CH2Cl2, UV);1H NMR (300 MHz, CDCl3): delta 8.84 (s, 1H), 7.07 (s, 2H), 2.69 (s, 6H), 2.34 (s, 3H);13C NMR (75 MHz, CDCl3): delta 162.9, 147.5, 145.2, 142.5, 133.0, 127.9, 23.2, 21.3; IR(solid): 3126, 2983, 2947, 1597.Anal. Calcd. for C11H12N4O4S: C, 44.59; H, 4.08; N, 18.91. Found: C, 44.69; H,3.88; N, 18.72. The purity of the product (96percent) established by RP-HPLC, tR = 8.41 min(254 nm).
2-<strong>[773-64-8]Mesitylenesulfonyl chloride</strong> (54.40 g, 0.249 mol) in CH2Cl2 (300 ml) was added to 1,4-diaminobutane (11.34 g, 0.129 mol) in 1 N NaOH (300 ml) at 0 C., and the biphasic mixture was stirred for 24 hours at room temperature. Organic solvent was evaporated and 2.4 N HCl (250 ml) was added to the combined portions. Solid was filtered, washed with water (250 ml) and recrystallized from aqueous ethanol to give 50.46 g (90%) of (1) as needles: mp 156.5-157.5 C.; NMR (CDCl3/TMS) delta1.36-1.60 (m, 4H), 2.27 (s, 6H), 2.57 (s, 12H), 2.69-2.96 (m, 4H), 4.65 (t, 2H, J=6), 6.89 (s, 4H). Anal. calcd. for C22H32N2O4S2: C, 58.38, H, 7.13, N, 6.19. Found: C, 58.31, H, 7.19, N, 6.14.
With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
A solution of ethyl N-hydroxyacetimidate (2.00 g, 19.4 mmol), N,N-diisopropylethylamine (3.01 g, 23.3 mmol) and 4-dimethylaminopyridine (240 mg, 1.96 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0 C. To this cold solution 2,4,6-trimethylbenzene-1-sulfonyl chloride (4.66 g, 21.3 mmol) was added slowly, warmed to room temperature and stirred for 1 hour. The reaction was quenched with the addition of water (40 mL) and this mixture was extracted with dichloromethane (30 mL, 3 times). The combined dichloromethane layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica flash column chromatography with 5% ethyl acetate in hexanes as the eluent to obtain 9 as white solid (5.19 g, 94%). 1H NMR (400 MHz, CDCl3) delta 6.94 (s, 2H), 3.88 (q, J = 7.1 Hz, 2H), 2.62 (s, 6H), 2.28 (s, 3H), 2.00 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) delta 169.1, 143.3, 140.6, 131.5, 130.3, 63.6, 22.8, 21.0, 14.8, 13.9; HRMS (ESI/TOF) m/z calcd for C13H20NO4S+ [M + H]+ 286.1108, found 286.1115.
92%
With triethylamine; In N,N-dimethyl-formamide; at 0℃;
Ethyl N-hydroxyacetimidate (10.3 g, 47 mmol, 1.1 eq) and triethylamine (25.5 ml, 94 mmol, 2 eq) were dissolved in DMF (40 ml, 2 vol) and the mixture cooled to 0 C. O-mesitylene chloride (20 g, 47 mmol, 1 eq) was then added portionwise and the mixture stirred at 0 C for 45 minutes. The above solution was poured into ice water, and solid obtained was filtered and washed with water. Yield : 23 g (92 %). 1HNMR (400MHz, DMSO-d6): 5 1.16 (t, 3H), 2.03 (s, 3H), 2.31 (s, 3H), 2.64 (s, 6H), 3.89 (q, 2H), 6.96 (s, 2H).
87%
With sodium hydroxide; In ethanol; at 15 - 25℃; for 2h;
Into a 500mL reaction flask added ethyl acetohydroxamate (71g, 0.5mol, 1.0eq) and ethanol (284mL, 4P) to form into an ethanol solution of ethyl acetohydroxanoate, into ethyl acetohydroxanoate ethanol solution added sodium hydroxide (24g, 0.6mol, 1.2eq), added the drops of 2,4,6-trimethylbenzenesulfonyl chloride (120.3g, 0.55mol, 1. 1eq), magnetic stirring speeds up the reaction, the reaction temperature is controlled between 15-25 C, after the addition is completed, the temperature is maintained between 15-25 C for 2 hours, reaction solution added into water (284mL, 4P), the precipitated solid is suction filtered, and then obtained filter cake is washed with ethanol, obtained solid is dried and then obtained 244g of ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetohydroxamate, yield is 87%
With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;
Step 15.2: Ethyl-O-mesitylenesulfonylacetohydroxamate; Prepared according to lit. procedure {Jet. Lett. 1972, 40 , 4133-4135). 15 g (68.6 mMol) Mesitylen-2-sulfonylchloride and 10.5 ml (75.5 mMol) triethyl amine are dissolved in 80 ml DMF. The solution is cooled to 0 C in an ice bath and 7.1 g (68.6 mMol) ethyl-N- hydroxyacetimidate are added in small portions. The reaction mixture is subsequently stirred for 3 h at rt, filtered and concentrated. The residue is first washed with ether and then submitted to aq. workup with EtOAc/H2O. Combined organic extracts are dried and concentrated to give the title compound as yellow oil: MS: [M+1]+ = 286; 1H MNR (CDCI3): delta ppm 7.00 (s, 2H), 3.98 (q, 2H), 2.64 (s, 6H), 2.39 (s, 3H), 2.05 (s, 3H), 1.21 (t, 3H).
With triethylamine; In N,N-dimethyl-formamide; at 0℃; for 0.25h;
Example 13; Preparation of MSH; Part A: Ethyl-O-(mesitylenesulfonyl)acetohydroxamate (MSH Precursor) Ethyl N-hydroxyacetimidate (2.36 g, 22 9 mmol) was dissolved in DMF (6 mL). Triethylamine (3 mL) was added and the stirred solution was cooled to 0 C. 2-Mesitylenesulfonyl chloride (5.00 g, 22 9 mmol) was added in two portions and the resulting white slurry was stirred vigorously for 15 min. The mixture was then diluted with CH2Cl2 (100 mL) and washed repeatedly with H2O. The organic layer was dried (MgSO4), filtered, and the solvent removed under reduced pressure to give the title compound as a white solid that was used without further purification. m.p.=51-53 C. Spectroscopic data was identical to that previously reported (Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii, S.; Ikeda, M., J. Org. Chem. 1973, 38, 1239-1241).
13.12 g
With triethylamine; for 0.75h;Cooling with ice;
Ethylacetohydroxamate (10.23 g, 99.20 mmol) was dissolved in 50 mL of N,N-dimethylformamide at 0 C. Fifteen minutes later, mesitylenesulfonyl chloride (21.70 g, 99.20 mmol) was slowly added along with 0.75 mL of triethylamine (Et3N). The solution stirred at ice bath temperature for forty-five minutes. After forty-five minutes, the reaction was poured over ice and a yellow precipitate formed. After the mixture came to room temperature, the solid, ethyl-O-(mesitylenesulfonyl)-acetohydroxamate was collected by vacuum filtration. Ethyl-O-(mesitylenesulfonyl)acetohydroxamate (13.12 g, 45.98 mmol) was washed three times with 100 mL of distilled water and dried for one hour. The product was hydrolyzed with 70% perchloric acid (HClO4) (4 mL) in p-dioxane (14 mL). This reaction stirred for forty-five minutes at 0 C. The reaction was arrested by the addition of ice and an off white solid, mesitylenesulfonyl hydroxamate (MSH) was collected by vacuum filtration and allowed to dry for thirty minutes. MSH (9.00 g, 41.86 mmol) was dissolved in 30 mL of dichloromethane (CH2C12). The reaction stirred at 0 C. for fifteen minutes. 3-ethylpyridine (4.70 mL, 41.86 mmol) was added dropwise and the mixture reacted for forty-five minutes at 0 C. After forty-five minutes, the 3-ethylpyridinium mesitylenesulfonate was extracted with 100 mL of diethyl ether.
2-Mesitylenesulfonyl chloride (24.78 g, 0.113 mol) in pyridine (60 ml) was added all at once to 4-piperidineethanol (5.58 g, 43.2 mmol) in pyridine (25 ml) at -16 C.; the temperature rose to -11 C. The flask was stored in the refrigerator at 5.5 C. for 44 hours under argon. The reaction mixture was poured into ice (1 kg) and after 3 hours, 16.00 g (75%) of (2) as a yellow solid was filtered off: mp 93.5-94 C.; NMR (CDCl3/TMS) delta1.4-2.1 (m, 7H), 2.27 (s, 6H), 2.44-2.96 (m+s, 14H), 3.37-3.69 (m, 2H), 3.97 (t, 2H, J=5), 6.90 and 6.93 (2s, 4H). Anal. calcd. for C25H35NO5S2: C, 60.82, H, 7.15, N, 2.84. Found: C, 60.90, H, 7.13, N, 2.85.
In pyridine;
N,O-Bis(2,4,6-trimethylbenzenesulfonyl)-4-piperidineethanol [(2) FIG. 5] 2-Mesitylenesulfonyl chloride (24.78 g, 0.113 mol) in pyridine (60 ml) was added all at once to 4-piperidine-ethanol (5.58 g, 43.2 mmol) in pyridine (25 ml) at -16 C.; the temperature rose to -11 C. The flask was stored in the refrigerator at 5.5 C. for 44 hours under argon. The reaction mixture was poured into ice (1 kg) and after 3 hours, 16.00 g (75%) of (2) as a yellow solid was filtered off: mp 93.5-94 C.; NMR (CDCl3/TMS) delta 1.4-2.1 (m, 7H), 2.27 (s, 6H), 2.44-2.96 (m+s, 14H), 3.37-3.69 (m, 2H), 3.97 (t, 2H, J=5), 6.90 and 6.93 (2s, 4H). Anal. calcd. for C25H35NO5S2: C-60.82, H-7.15, N-2.84. Found: C-60.90, H-7.13, N-2.85.
In pyridine;
N,O-Bis(2,4,6-trimethylbenzenesulfonyl)-4-piperidineethanol [(2) FIG. 5] 2-Mesitylenesulfonyl chloride (24.78 g, 0.113 mol) in pyridine (60 ml) was added all at once to 4-piperidine-ethanol (5.58 g, 43.2 mmol) in pyridine (25 ml) at -16 C.; the temperature rose to -11 C. The flask was stored in the refrigerator at 5.5 C. for 44 hours under argon. The reaction mixture was poured into ice (1 kg) and after 3 hours, 16.00 g (75%) of (2) as a yellow solid was filtered off: mp 93.5-94 C.; NMR (CDCl3/TMS) delta1.4-2.1 (m, 7H), 2.27 (s, 6H), 2.44-2.96 (m+s, 14H), 3.37-3.69 (m, 2H), 3.97 (t, 2H, J=5), 6.90 and 6.93 (2s, 4H). Anal. calcd. for C25H35NO5S2: C-60.82, H-7.15, N-2.84. Found: C-60.90, H-7.13, N-2.85.
With sodium hydroxide; In dichloromethane; at 0 - 20℃; for 24h;
A solution of 2-mesitylenesulfonyl chloride (19.49 g, 89.1 mmol) in CH2Cl2 (100 ml) was added to 4-(aminomethyl)piperidine (1) (5.15 g, 45.1 mmol) in 1 N NaOH (100 ml) at 0 C. After the addition was complete, the biphasic mixture was stirred for 24 hours (0 C. to room temperature). The layers were separated and the aqueous portion was extracted with CHCl3 (2×). The combined organic phase was washed with 0.5 N HCl (200 ml) and H2O (100 ml), dried with sodium sulfate and evaporated in vacuo. Recrystallization from aqueous ethanol produced 18.72 g (88%) of (2) as plates: mp 158.5-160 C.; NMR (CDCl3/TMS) delta0.8-2.0 (m, 5H), 2.25 (s, 6H), 2.46-2.93 (m+2s, 16H), 3.37-3.65 (m, 2H), 4.67 (t, 1H, J=6), 6.90 (s, 4H). Anal. calcd. for C24H34N2O4S2: C, 60.22, H, 7.16, N, 5.85. Found: C, 60.31, H, 7.19, N, 5.86.
2,4,6-trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
EXAMPLE 29 2,4,6-Trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide 2,4,6-Trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from <strong>[33084-49-0]5-amino-4-bromo-3-methylisoxazole</strong> and 2,4,6-trimethylbenzenesulfonyl chloride according to the procedures described in Example 1 b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a pink solid, m.p. 92-95 C., yield 64%.
64%
EXAMPLE 69 2,4,6-Trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide 2,4,6-Trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from <strong>[33084-49-0]5-amino-4-bromo-3-methylisoxazole</strong> and 2,4,6-trimethylbenzenesulfonyl chloride according to the procedures described in Example 40b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a pink solid, m.p. 92-95 C., yield 64%.
With ammonium hydroxide; In methanol; at 20℃; for 5h;
General procedure: Standard Procedure D for the Preparation of Sulfonamides (0054) A solution of sulfonyl chloride in methanol and ammonium hydroxide solution was stirred at 0 C. or room temperature. After the reaction was complete, methanol was removed under reduced pressure. The solution was extracted with ethyl acetate. The combined organic layers were dried over MgSO4(s), filtered, and concentrated to give the desired products without further purification. Step 1. 2,4,6-Trimethylbenzenesulfonamide Following standard procedure D, 2-mesitylenesulfonyl chloride (0.890 g, 4.07 mmol), methanol (8.0 mL), and ammonium hydroxide solution (20 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 5 h and work-up, 2,4,6-trimethylbenzenesulfonamide (0.241 g, 30%) was obtained as a beige solid. 1H NMR (CDCl3, 400 MHz) delta 6.96 (s, 2H), 4.81 (br s, 2H), 2.65 (s, 6H), 2.30 (s, 3H).
With ammonium hydroxide; at 100℃; for 1h;
General procedure: Substituted arylsulfonylchlorides was suspended in 3 mL ammonia water, and thenthe solution was refluxed at 100 C for 1 h. The mixture was cooleddown to room temperature. Substituted arylsulfamides wereobtained by filtration, washing with water and were then driedin vacuo (excepted for the commercially available 4-methylbenzenesulfonamide).
C. N2 -(2,4,6 trimethylbenzenesulfonyl)-<strong>[70-47-3]L-asparagine</strong> L- Asparagine (20.0 g, 0.15 mol) was suspended in a mixture of tetrahydrofuran (130 mL) and water (250 mL). Triethylamine (68 mL, 0.48 mol) was added, followed by mesitylenesulfonyl chloride (49.7 g, 0.23 mol) added over 20 min. The reaction mixture became slightly warmer and the solids dissolved to yield a yellow solution. The reaction mixture was stirred for 3 h at room temperature, then washed twice with ether, and twice with dichloromethane. The aqueous layer was acidified to pH 1.5 with concentrated aqueous HCl, during which time a thick precipitate formed. After being stirred for 30 min the solid was collected by filtration, washed with water and dried to yield the title product (34.1 g, 72%) as a white solid: m.p. 193.5-195 C.; 1 H NMR (DMSO-d6) delta12.58 (bs, 1H), 7.82 (d, 1H), 7.32 (bs, 1H), 6.99 (s, 2H), 6.88 (bs, 1H) 3.98 (m, 1H), 2.55 (s, 6H), 2.45 (dd, 1H), 2.28 (dd, 1H), 2.24 (s, 3H); Mass spectrum (ESI) m/z 315.2, (100%, M+H+).
72%
With triethylamine; In tetrahydrofuran; water;
A. N-(2,4,6 trimethylphenyl)sulfonyl-<strong>[70-47-3]L-asparagine</strong> L-Asparagine (20.0 g, 0.15M) was suspended in a mixture of tetrahydrofuran (l30 mL) and water (250 mL). Triethylamine (49 g, 0.48M) was added followed by mesitylenesulfonyl chloride (49.7 g, 0.227M), The reaction mixture became slightly exothermic and the solids dissolved over a period of 0.5 h. to yield a yellow solution. The reaction mixture was stirred for 3 h at room temperature, then washed with ether, and methylene chloride. The aqueous layer was separated, and acidified to ca. pH=1.5 with conc. HCl, during which time a thick precipitate formed. After 0.5 h. the product was filtered,washed with water and dried to yield a white solid (34 g, 72%). m.p.=193.5 - 1950C 1H NMR (DMSO) delta 2.24 (s, 3H), 2.28 (dd, 1H), 2.45 (dd, 1H), 2.55 (s, 6H, 3.98 (m, 1H), 6.88 (br s, 1H), 6.99 (s, 2H), 7.32 (br s, 1H), 7.82 (d, 2H), 12.58 (br s, 1H). Mass spectrum ESI m/z 315.2, (M+H base peak).
72%
With triethylamine; In tetrahydrofuran; water;
I. N2-(2,4,6 Trimethylbenzenesulfonyl)-<strong>[70-47-3]L-asparagine</strong>. L-Asparagine (20.0 g, 0.15 mol) was suspended in a mixture of tetrahydrofuran (l3OmL) and water (250 mL). Triethylamine (68 mL, 0.48 mol) was added, followed by mesitylenesulfonyl chloride (49.7 g, 0.23 mol) added over 20 min. The reaction mixture became slightly warmer and the solids dissolved to yield a yellow solution. The reaction mixture was stirred for 3 h at room temperature, then washed twice with ether, and twice with dichloromethane. The aqueous layer was acidified to pH 1.5 with concentrated aqueous HCl, during which time a thick precipitate formed. After being stirred for 30 min the solid was collected by filtration, washed with water and dried to yield the title product (34.1 g, 72%) as a white solid: m.p. 193.5-195 C.; 1H NMR (DMSO-d6) d 12.58 (bs, 1H), 7.82 (d, 1H), 7.32 (bs, 1H), 6.99 (s, 2H), 6.88 (bs, 1H), 3.98 (m, 1H), 2.55 (s, 6H), 2.45 (dd, 1H), 2.28 (dd, 1H), 2.24 (s, 3H); Mass spectrum (ESI) m/z 315.2, (100%, M+H+).
General procedure: The sulfonylhydrazides 4a-l were prepared in excellentyields by adding the corresponding arylsulfonyl chloridesdissolved in THF to a slightly excess of hydrazine hydratesolution 80 %, according to the procedure described in theliterature (Audrieth and Brhuchitsch 1956).
With hydrazine hydrate; In tetrahydrofuran; at 0 - 5℃;Inert atmosphere;
General procedure: Hydrazine hydrate (0.25 mol, 2.5 equiv) was added dropwise to a solution of p-toluene sulfonyl chloride or 2, 4, 6 trimethyl benzene sulfonyl chloride (0.1 mol, 1 equiv) in THF (100 mL) at 0 C under an inert atmosphere. After stirring for 0 to 5 C for 30 min, ice-cold ethyl acetate (200 mL) was added to the cooled reaction mixture and the mixture was washed repeatedly with ice cold 10% aqueous sodium chloride (5 x 150 mL). The organic layer was dried over sodium sulfate at 0 C, and was then added slowly to a stirring solution of hexane (1.2 L) during 5 min. Substituted benzene sulfonyl hydrazide precipitated as a white solid and was collected by vacuum filtration. The filter cake was washed with hexanes (2 x 50 mL) and then dried in vacuo yielding the title compound as a white solid (17.61 g, 81%).
With sodium hydroxide; In chloroform; water; at 0 - 20℃; for 2h;
Pentylamine (106, 2.0 g, 22.9 mmol) in 30 ml CHCl3 was mixed at O0C with27 ml 2N NaOH. 2-mesitylenesulfonyl chloride (5, 4.99 g, 22.9 mmol) was added and the reaction mixture was stirred for 2 hrs at room temperature. The reaction was monitored by TLC (silica, hexane:EtOAc 7:3). The CHCl3 phase was separated, washed with NH4Cl (2X), dried, and evaporated to provide 6.16 g (100%) of N-pentyl-mesitylene-2-sulfonamide (107). 13C and 1H NMR confirmed the identity of the product.
100%
With sodium hydroxide; In chloroform; water; at 0 - 20℃; for 2h;
Pentylamine (106, 2.0 g, 22.9 mmol) in 30 ml CHCl3 was mixed at O0C with 27 ml 2N NaOH. 2-mesitylenesulfonyl chloride (5, 4.99 g, 22.9 mmol) was added and the reaction mixture was stirred for 2 hrs at room temperature. The reaction was monitored by TLC (silica, hexane:EtOAc 7:3). The CHCb phase was separated, washed with NH4Cl (2X), dried, and evaporated to provide 6.16 g (100%) of N- pentyl-mesitylene-2-sulfonamide (107). 13C and 1H NMR confirmed the identity of the product.
Part 1 : Preparation of 0-Mesitylenesulfonylhydroxylamine (2) (Literature reference-Tetrahedron Lett. 1972, 40, 4133-4135)To a suspension of ethyl N-hydroxyacetimidate (4.72 g, 45.7 mmol) in DMF (45.7 ml) was added triethylamine (9.53 ml, 68.6 mmol) followed by portionwise addition of mesitylenesulfonyl chloride (1, 1O g, 45.7 mmol). The reaction mixture was stirred for 2 hours at room temperature then poured into ice water (150 mL). The resulting precipitate was collected by vacuum filtration. The collected solids were treated with neat perchloric acid (32.8 ml, 229 mmol) and stirred until homogeneous. Distilled water (30 mL) was used to titurate white crystals of Omesitylenesulfonylhydroxylamine (2, 8.31 g, 38.6 mmol, 84 % yield). MS APCI: [M + H]+ m/z 216.3.; Scheme 1.Preparation of the pyrazolopyridine core of the type 4 began with the preparation of O-mesitylenesulfonylhydroxylamine (1) in two steps from commercial starting materials. This reagent exposed to commercially available pyridines to access appropriately fupsilonnctionalized N- imino-pyridinium mesitylenesulphonate derivates of the type 2. A [3+2] cyclization of 2 with ethyl propiolate yields the pyrazolopyridine core (3). Functionalization of the 6-position of the pyrazolopyridine core is accomplished via a Suzuki coupling reaction to install aryl or heteroaromatic functionality (4) using commercially available boronic acids or esters. To install the thaizole moiety, the ester 4 is first saponified to acid 5 and then converted to the acid chloride 6. Subsequent ketone synthesis is carried out in the presence of aluminum chloride and dialkylzinc to provide 7. alpha-Bromination provides bromoketone 8, which is then subject to condensation with ethylthiooxamate to yield the thiazole 9. Chlorination of the thiazole is accomplished via exposure to NCS to yield 10. A three step sequence of saponification to acid 11, acid chloride synthesis (12) and exposure to an amine, installs the final amide bond to yield target 13.
With sodium hydroxide; In chloroform; water; at 5℃; for 2h;
Amine 1 (Aldrich) (3. 5g, 21.7 mol) was dissolved in a mixture of chloroform (30 ml) and IN sodium hydroxide (24 ml) and [15ML] of mesitylenesulfonyl chloride dissolved in [1 SML] of chloroform were added at [5C.] The mixture was stirred for 2h, the reaction mixture was then diluted with chloroform (50 ml), the organic layer was separated, washed with a saturated solution of ammonium chloride, dried [(NA2S04),] and evaporated to dryness. The residual oil crystallized after drying and was used in the next step without further purification; 7. 0g (95%) of 2 were obtained [;'HNMR (CDC13)] : [PPM] 1.15 (t, 6H), 1.55 (m, 4H), 2.30 (s, 3H), 2.65 (s, 6H), 2.95 (q, 2H), 3.40-3. 55 [(M,] 4H), 4.40 (t, 1H), 4.90 (t, 1H), 6.95 (s, 2H) [; 13CNMR (CDCL3)] : [PPM] 15.19, 20.80, 22.85, 24.55, 30.83, 42.39, 61.40, 102.41, 131.84, 133.82, 138.99, 141.92.
Under argon, 4-dimethylaminopyridine (3.63 g, 29.71 mmol) is added to a solution of intermediate 15.1 (5.4 g, 28.25 mmol) in anhydrous CH2Cl2 (250 ml) kept at 0 C. by an ice bath, followed after a few minutes, dropwise by 2-mesitylenesulphonyl chloride (6.50 g, 29.71 mmol) in solution in CH2Cl2 (100 ml). The reaction mixture is stirred for 1 h at 0 C. and then overnight at room temperature. Water is added. The reaction mixture is extracted with CH2Cl2. The organic phase is washed with brine, dried over Na2SO4 and evaporated to give a brown solid which is purified by chromatography on silica gel (300 g), eluding with CH2Cl2. A solid separates after concentrating the fractions under vacuum. It is filtered and then washed with diethyl ether and petroleum ether. 5 g of product are obtained in the form of a beige solid.
4-Dimethylaminopyridine (2.21 g, 21 mmol) and a solution of mesitylenesulphonyl chloride (4.60 g, 21 mmol) in anhydrous THF (50 ml) are added to a solution of intermediate 21.1 (20 mmol) in anhydrous THF (200 ml) kept at 0 C. The reaction mixture is stirred at room temperature overnight, and is then filtered and evaporated. The residue is taken up in AcOEt. The organic solution is washed with 1N HCl, H2O and 10% NaHCO3 and then dried and concentrated under vacuum. The residue is purified on silica gel, eluting according to a gradient from AcOEt/petroleum ether (1/9) to AcOEt/petroleum ether (1/4). The purified compound is recrystallized in AcOEt/petroleum ether. 3.60 g of product are obtained in the form of a brown solid.
1-Phenylcyclopropa ne carboxylic acid(1) is reacted with sodium azide and sulfuric acid in CHCl3 to yield 1-phenylcyclopropanamine (2). 1-Phenylcyclopropanamine is then reacted with 2-mesitylenesulfonyl chloride in chloroform under basic conditions to yield the protected derivative (3), N-(I- phenylcyclopropyl)mesitylenesulfonamide. N-(I- phenylcyclopropyl)mesitylenesulfonamide (3) is then reacted with N-(4- bromobutyl)phthalimide (4) in DMF with sodium hydride at room temperature overnight, to yield N-(2-mesitylenesulfonyl)-N-(l-phenylcyclopropyl)-4- phthalimidobutylamine (5).[0092] The phthaloyl group is removed from N-(2-mesitylenesulfonyi)-N-(l- phenylcyclopropyl)-4-phthalimidobutylamine (5) by reaction with hydroxylamine hydrochloride in benzene and sodium methoxide in methanol, to produce N-(4- aminobutyl)-N-(l-phenylcyclopropyl)-2-mesitylenesulfonamide (6). The free amino group is then re-protected with 2-mesitylenesulfonyl chloride in 2N NaOH in CHCl3 to give (7), N-(4-(mesitylene-2-sulfonylamino)butyl)-N-(l-phenylcyclopropyl)~2- mesitylenesulfonamide. (7) is then reacted with l,2-bis(mesitylene-2- --> sulfonyloxymethyl)cyclopropane (8) in DMF with sodium hydride at room temperature overnight to yield (9), the tetra-mesitylene-2-sulfonyl- protected derivative of l,2-bis((N-(l-phenylcyclopropyl)-4- aminobutyl)aminomethyl)cyclopropane. The mesitylene protecting groups are then removed using HBr in acetic acid and phenol in methylene chloride to yield 1,2- bis((N-(l-phenylcyclopropyl)-4-aminobutyl)aminomethyl)cyclopropane (CGC-11255; SL-11255).
A. N-(2,4,6 trimethylphenyl)sulfonyl-<strong>[70-47-3]L-asparagine</strong> L-Asparagine (20.0 g, 0.15M) was suspended in a mixture of tetrahydrofuran (l30 mL) and water (250 mL). Triethylamine (49 g, 0.48M) was added followed by mesitylenesulfonyl chloride (49.7 g, 0.227M), The reaction mixture became slightly exothermic and the solids dissolved over a period of 0.5 h. to yield a yellow solution. The reaction mixture was stirred for 3 h at room temperature, then washed with ether, and methylene chloride. The aqueous layer was separated, and acidified to ca. pH=1.5 with conc. HCl, during which time a thick precipitate formed. After 0.5 h. the product was filtered,washed with water and dried to yield a white solid (34 g, 72%). m.p.=193.5 - 1950C 1H NMR (DMSO) delta 2.24 (s, 3H), 2.28 (dd, 1H), 2.45 (dd, 1H), 2.55 (s, 6H, 3.98 (m, 1H), 6.88 (br s, 1H), 6.99 (s, 2H), 7.32 (br s, 1H), 7.82 (d, 2H), 12.58 (br s, 1H). Mass spectrum ESI m/z 315.2, (M+H base peak).
72%
With triethylamine; In tetrahydrofuran; water;
G. N-(2,4,6 trimethylphenyl)sulfonyl-<strong>[70-47-3]L-asparagine</strong>: L-Asparagine (20.0 g, 0.15M) was suspended in a mixture of tetrahydrofuran (130 mL) and water (250 mL). Triethylamine (49 g, 0.48M) was added followed by mesitylenesulfonyl chloride (49.7 g, 0.227M), The reaction mixture became slightly exothermic and the solids dissolved over a period of 0.5 h. to yield a yellow solution. The reaction mixture was stirred for 3 h at room temperature, then washed with ether, and methylene chloride. The aqueous layer was separated, and acidified to ca. pH=1.5 with conc. HCl, during which time a thick precipitate formed. After 0.5 h. the product was filtered,washed with water and dried to yield a white solid (34 g, 72%). m.p.=193.5-195 C. 1 H NMR (DMSO) delta 2.24 (s, 3H), 2.28 (dd, 1H), 2.45 (dd, 1H), 2.55 (s, 6H), 3.98 (m, 1H), 6.88 (br s, 1H), 6.99 (s, 2H), 7.32 (br s, 1H), 7.82 (d, 2H), 12.58 (br s, 1H). Mass spectrum ESI m/z=315.2, (M+H base peak).
Example 112 Synthesis of 4-[[(2,4,6-Trimethylphenyl)sulfonyl]amino]-L-phenylalanine on Wang Resin 4-Amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine on Wang resin (3.0 g, 2.28 mmol) obtained from Example 62 was suspended in pyridine (15 mL), the slurry was cooled to 0 C. and 2,4,6-trimethylphenylsulfonyl chloride (2.49 g, 11.4 mmol) was added. The resulting mixture was agitated for 2 hr. The mixture was filtered and washed with dichloromethane and methanol. The coupling procedure was repeated. The resulting resin was treated with 25% piperidine in N-methylpyrrolidinone (2*15 min) and was washed with dichloromethane and methanol to give 4-[[(2,4,6-trimethylphenyl)sulfonyl]amino]-L-phenylalanine on Wang resin.
(2) Synthesis of 5-Carboethoxy-3-methyl-1-(2,4,6-trimethylbenzenesulfonyl)indole To a solution of <strong>[73396-90-4]5-carboethoxy-3-methylindole</strong> (601 mg, 2.96 mmol) in DMF, sodium hydride (178 mg, 4.45 mmol) and 2,4,6-trimethylbenzenesulfonyl chloride (971 mg, 4.44 mmol) were added under cooling with ice, followed by stirring for 30 min. The reaction mixture was mixed with a saturated aqueous NH4Cl solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:5) to give the titled compound (1.02 g, 90%). NMR (method a, CDCl3): delta 1.40 (3H, t, J=7.0 Hz), 2.29 (3H, s), 2.32 (3H, s), 2.52 (6H, s), 4.38 (2H, q, J=6.9 Hz), 6.95 (2H, s), 7.35 (1H, s), 7.41 (1H, d, J=8.9 Hz), 7.90 (1H, dd, J=1.4, 8.9 Hz), 8.24 (1H, s).
(ii) To a solution of 6-iodo-1H-indazole (7.35 g, 30.1 mmol, 1 equiv) in THF (100 mL) cooled to 0 C. under argon, was added sodium t-butoxide (2.89 g, 30.1 mmol, 1 equiv). A color change from orange to red was observed. Mesitylenesulfonyl chloride (6.60 g, 30.1 mmol, 1 equiv) was added in one portion and the ice bath was removed allowing the reaction mixture to warm to 23 C. After 40 min the mixture was quenched with saturated ammonium chloride and partitioned between water and ethyl acetate. The aqueous was extracted a total of 3 times with ethyl acetate. The combined organic material was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 6-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole as an orange solid (12.8 g, 100% yield, 2:1 mixture). 1H NMR (CDCl3) 8.51 (s, 1H), 7.95 (s, 0.66H, major isomer), 7.91 (s, 0.33H, minor isomer), 7.47 (d, 0.33H, J=8.4 Hz), 7.29 (d, 0.33H, J=8.4 Hz), 7.26 (d, 0.66H, J=8.9 Hz), 7.18 (d, 0.66H, 8.9 Hz), 6.84 (s, 2H), 2.51 (s, 6H), 2.15 (s, 3H).
With hydrogenchloride; In 1,4-dioxane; sodium hydroxide; aqueous sodium hydroxide (10 ml)-dioxane; water;
EXAMPLE 2 N-mesitylenesulfonyl-<strong>[13485-59-1]L-alanyl-L-proline</strong> <strong>[13485-59-1]L-alanyl-L-proline</strong> (1.86 g, 10 mmole) was dissolved in aqueous sodium hydroxide (10 ml)-dioxane (10 ml), and dioxane (5 ml) solution of mesitylenesulfonylchloride (2.19 g, 10 mmole) was added dropwise to the solution while cooling and stirring while keeping pH value thereof to 10 to 11 with 1N aqueous sodium hydroxide. After that; the mixture was stirred further for 2 hours at room temperature. Water (20 ml) was added thereto and the mixture thus obtained was washed with diethyl ether (40 ml). The water layer was filtered and the filtrate thus obtained was adjusted to pH 2.0 with 1N hydrochloric acid while cooling and stirring to precipitate white solid material. The material was dissolved in 0.5N aqueous sodium hydroxide and the solution thus obtained was crystallized by addition of 1N aqueous hydrochloric acid to give N-mesitylenesulfonyl-<strong>[13485-59-1]L-alanyl-L-proline</strong> yield: 1.67 g, 45.3%). NMR spectrum [DMSO-d6; internal standard: TMS] ppm 1.07 (d.,3H), 1.50-2.06 (m,4H), 2.21 (s,3H), 2.51 (s,6H), 2.92-3.55 (m,2H), 3.56-4.02 (m,2H), 6.89 (s,2H), 7.58 (d,1H), 12.22 (s,1H)
3-Amino-l,l,l-trifluoropropan-2-ol (1.38 g, 10.7 mmol) was dissolved in pyridine (32 mL). 2,4,6-Trimethylbenzensulfonyl chloride (7.0 g, 32 mmol) was added and the mixture was heated at reflux temperature for 18 h. After cooling, the reaction mixture was partitioned between ethyl acetate and ice water. The organic phase was washed with ice- cold saturated aqueous sodium hydrogen carbonate, twice with ice water and dried EPO <DP n="31"/>(Na2SO4). Chromatography (SiO2, ethyl acetate-heptane 1:4) gave the title compound as a gum (4.4 g, 83 %).1H-NMR (300 MHz, DMSO-J15): 7.94 (IH, t), 7.13 (2H, s), 7.03 (2H5 s), 5.00 (IH, sext), 3.27-3-16 (IH, m), 3.14-3.03 (IH, m), 2.52 (6H, s), 2.50 (6H5 s), 2.30 (3H5 s), 2.27 (3H, s)19F-NMR (282 MHz, OMSO-d6 ): delta -74.07 (d) APCI-MS m/z: 494.1 [MH+].
PREPARATION 2 Ethyl (1E)-N-(2,4,6-trimethylphenyl)sulfonyloxyethanimidate To a solution of ethyl (1E)-N-hydroxyethanimidate (8.4 g, 81.5 mmol) in DMF (20 mL) is added triethylamine (12 mL, 86.24 mmol) and the mixture is stirred for 20 minutes. 2,4,6-Trimethylbenzene-1-sulfonyl chloride (20 g, 81.5 mmol) is added and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic extracts are dried over sodium sulphate, filtered, and evaporated to dryness to give the title compound as white solid (15 g, 64%). The crude material is used without further purification.
To a stirred solution of N-hydroxy-acetimidic acid ethyl ester (42g, 183 mmol) in DMF (100 mL) is added triethylamine (49.2 mL, 366 mmol) at 0 C. The reaction mixture is stirred at room temperature for 10 minutes and cooled again to 0 C. 2,4,6- Trimethyl-benzenesulfonyl chloride (40 g, 183 mmol) is added portion wise. The reaction mixture is stirred overnight at room temperature. The reaction mixture is diluted with EtOAc (100 mL), washed with ice water (2x500 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, filtered, and evaporated to give the title compound as a pale yellow solid (40 g, crude) that is used without further purification. LC-MS m/z286.1 [M+Hj.
With triethylamine; In N,N-dimethyl-formamide; at 0℃; for 0.783333h;
A solution of ethyl N-hydroxyacetimidate (10.37 g, 101 mmol) and triethylamine (25.5 ml, 183 mmol) in DMF (40 ml) was cooled to 0C. To the mixture was added solid 2-mesitylenesulfonyl chloride (20 g, 91 mmol) in portions over 2 min. It was stirred at 0C for 45 min and the reaction mixture was poured into ice water (300 g). The solid precipitation was filtered and washed with water (3x20 mL). It was dried under vacuum to give (E)-ethyl N(mesitylsulfonyl)oxyacetimidate
To a stirred solution of N-hydroxy-acetimidic acid ethyl ester (42g, 183 mmol) in DMF (100 mL) is added triethylamine (49.2 mL, 366 mmol) at 0 C. The reaction mixture is stirred at room temperature for 10 minutes and cooled again to 0 C. 2,4,6-Trimethyl-benzenesulfonyl chloride (40 g, 183 mmol) is added portion wise. The reaction mixture is stirred overnight at room temperature. The reaction mixture is diluted with EtOAc (100 mL), washed with ice water (2*500 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, filtered, and evaporated to give the title compound as a pale yellow solid (40 g, crude) that is used without further purification. LC-MS m/z 286.1 [M+H]+.
Reference Example 11 1-(mesitylsulfonyl)-<strong>[68282-47-3]2-phenyl-1H-imidazole-4-carbaldehyde</strong> To a solution of <strong>[68282-47-3]2-phenyl-1H-imidazole-4-carbaldehyde</strong> (1.73 g) in N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 523 mg) at room temperature, and the mixture was stirred for 1 hr. Mesitylsulfonyl chloride (2.42 g) was added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3?3:2) to give the title compound as a pale-yellow oil (yield 1.76 g, 49%). 1H-NMR (CDCl3) delta: 2.17 (6H, s), 2.26 (3H, s), 6.78 (2H, s), 7.15-7.23 (4H, m), 7.34-7.38 (1H, m), 8.33 (1H, s), 9.96 (1H, s).
With N,N,N'N'-tetramethyl-1,3-propanediamine; In tetrahydrofuran; at 20℃; for 3h;
(vi) 2-Amino-5-(4-[3-(?grt-butyldimethylsilyloxy propoxy1-2-methoxybenzyl)-6- methylpyrimidin-4-yl 2.4,6-trimethylbenzenesulfonate2-<strong>[773-64-8]Mesitylenesulfonyl chloride</strong> (4.96 g, 22.7 mmol) was added to a solution of N,NJV',N'- tetramethyl-l ,3-propanediamine (3.79 mL, 22.7 mmol) and the product from step (v) (6.55 g, 15.1 mmol) in THF (66 mL) and the mixture was stirred at r.t. for 3h. The resulting mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with brine, dried (Na2S04) and concentrated. Purification by FCC, eluting with hexane / EtOAc gave 8.87 g (14.4 mmol, 95%) of the sub-title compound as a white solid; NMR: 6.93 (2H, s), 6.71 (1H, d), 6.41 (1H, d), 6.33 (1H, dd), 4.66 (2H, br s), 4.02 (2H, t), 3.78 (3H, s), 3.77-3.82 (2H, m), 3.75 (2H, s), 2.59 (6H, s), 2.31 (3H, s), 2.25 (3H, s), 1.93- 2.01 (2H, m), 0.89 (9H, s), 0.05 (6H, s); LC-MS: m/z = 616 [MH+] (T = 2.99).
With N,N,N'N'-tetramethyl-1,3-propanediamine; In tetrahydrofuran; at 20℃; for 22h;
N1,N1,N3N3-tetramethylpropane- 1,3 -diamine (0.88 mL) and 2,4,6-trimethylbenzene-l- sulfonyl chloride (1.15 g) were added to the solution of the product from step (iv) (1.52 g) in THF (15 mL) and the mixture was stirred at r.t. After 22 h, 0. IN HCl aq. (45 mL) was added and the mixture was then extracted twice with CHCl3. The organic layer was dried (MgSO4) and concentrated. The resulting residue was purified by FCC to give the subtitle compound as pale yellow oil (1.92 g); 1H NMR (CDCl3): 6.94 (2H, s), 6.71 (IH, d). 6.41 (IH, d), 6.33 (IH, dd), 4.72 (2H, br s), 4.02 (2H, t), 3.81 (2H, t), 3.79 (3H, s), 3.76 (2H, s), 2.61 (6H, s), 2.31 (3H, s), 2.26 (3H, s), 1.98 (2H, tt), 0.89 (9H, s), 0.05 (6H, s); LC-MS m/z 616 ESI.
With N,N,N'N'-tetramethyl-1,3-propanediamine; In tetrahydrofuran; at 20℃; for 3h;
2-<strong>[773-64-8]Mesitylenesulfonyl chloride</strong> (4.96 g) was added to a solution of N,N,N',N'-tetramethyl- 1,3-propanediamine (3.79 mL) and 2-amino-5-{4-[3-(tert-butyldimethylsilyloxy)propoxy]- 2-methoxybenzyl}-6-methylpyrimidin-4-ol (6.55 g) in THF (66 mL) and the mixture was stirred at RT for 3h. The mixture was then diluted with water and extracted with EtOAc. The combined organic solutions were washed with brine, dried (Na2S04) and concentrated in vacuo. Purification by FCC, eluting with 23-44% EtOAc in hexane, gave the sub-title compound (8.8 g) as a white solid: 1H NMR (CDCI3): 6.93 (s, 2H), 6.71 (d, 1H), 6.41 (d, 1H), 6.33 (dd, 1H), 4.66 (br s, 2H), 4.02 (t, 2H), 3.78 (s, 3H), 3.77-3.82 (m, 2H), 3.75 (s, 2H), 2.59 (s, 6H), 2.31 (s, 3H), 2.25 (s, 3H), 1.93-2.01 (m, 2H), 0.89 (s, 9H), 0.05 (s, 6H); LC-MS: m/z = 616 [MH ].
8.87 g
With N,N,N'N'-tetramethyl-1,3-propanediamine; In tetrahydrofuran; at 20℃; for 3h;
2-<strong>[773-64-8]Mesitylenesulfonyl chloride</strong> (4.96 g, 22.7 mmol) was added to a solution of N, N, ' , N' -tetramethyl-1 , 3-propanediamine (3.79 mL, 22.7 mmol) and the product of example 8 step step (v) (6.55 g, 15.1 mmol) in THF (66 mL) and the mixture was stirred at RT for 3h. The resulting mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with brine, dried and concentrated. The residue was purified via chromatography on silica to give 8.87 g of the subtitle compound as a white solid; XH N R (CDC13) ; 6.93 (2H, s), 6.71 (1H, d), 6.41 (1H, d) , 6.33 (1H, dd) , 4.66 (2H, br s), 4.02 (2H, t), 3.78 (3H, s), 3.77-3.82 (2H, m) , 3.75 (2H, s), 2.59 (6H, s), 2.31 (3H, s), 2.25 (3H, s), 1.93-2.01 (2H, m) , 0.89 (9H, s), 0.05 (6H, s); LC-MS: m/z 616.
With triethylamine; In dichloromethane; for 3h;Reflux;
General procedure: To the solution of 11 or 20 or 32 or 38 (0.5 mmol) and Et3N (1.4 mmol) in dichloromethane was added dropwise corresponding carbonyl or sulfonyl chloride (0.9 mmol), then stirred at room temperature or reflux for 3 h. After cooling to room temperature, the mixture was washed with saturated aq. NaHCO3 (50 mL), brine (50 mL), and dried with anhydrous Na2SO4, then concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to afford title compounds.
With sodium hydroxide; In chloroform; water; at 0 - 20℃; for 2h;
N-Adamantan-1-yl-methylamine (119, 1.88 g, 11.39 mmol) in 30 ml CHCl3 was mixed at 00C with 14 ml 2N NaOH. 2-mesitylenesulfonyl chloride (5, 2.48 g, 11.39 mmol) was added and the reaction mixture was stirred for 2 hrs to room temperature. The reaction was monitored by TLC (silica, hexane:EtOAc 8:2). The CHCl3 phase was separated, washed with NH4Cl solution (2X), dried, and evaporated to provide N-Adamantan-1- ylmethyl-mesitylene-2-sulfonamide (120, 3.77 g, 95%). 1H and 13C NMR confirmed the identity of the product.
With aluminum (III) chloride; In dichloromethane; at 20℃; for 2h;
A mixture of mesitylsulfonyl chloride (219 mg, 1.0 mmol), 1,2,4-trimethyl- benzene (125 mg, 1.05 mmol) and AICI3 (266 mg, 2.0 mmol) in DCM (5 mL) was stirred for 2 hours at room temperature. The mixture was then poured into 10 mL of 5% HCl (aq.), and extracted by DCM (30 mL). The organic phase was washed by aqueous KHCO3, brine, and dried over anhydrous Na2SC>4. The resulting solution was evaporated, and the residue waspurified by silica gel column chromatography (Hexane/EtOAc = 10/1) to give the desired product as a white solid (290 mg, 96%). NMR (600 MHz, CDC13) delta 7.81 (s, 1H), 6.95 (s, 1H), 6.90 (s, 2H), 2.48 (s, 6H), 2.28 (s, 6H), 2.25 (s, 3H), 2.17 (s, 3H). 1 C NMR (150 MHz, CDCI3) delta 142.9, 142.1, 139.5, 139.0, 134.9, 134.3, 134.1, 133.8, 132.1, 129.1, 22.6, 21.1, 19.7, 19.4, 18.6.
With aluminum (III) chloride; In dichloromethane; at 20℃; for 2h;
A mixture of mesitylsulfonyl chloride (147 mg, 0.68 mmol), pentyl-benzene (100 mg, 0.68 mmol) and AlCl3 (181 mg, 1.36 mmol) in DCM (3 mL) was stirred for 2 hours at room temperature. The mixture was then poured into 10 mL of 5% HCl (aq.), and extracted by DCM (30 mL). The organic phase was washed by aqueous KHCO3, brine, and dried over anhydrous Na2SC>4. The resulting solution was evaporated, and the residue was purified by silica gel column chromatography (Hexane/EtOAc = 10/1) to give the desired product as a pale yellow oil (200 mg, 90%). NMR (600 MHz, CDCI3) delta 7.68 (d, 2H, J= 7.2 Hz), 7.25 (d, 2H, J= 6.6 Hz), 6.93 (s, 2H), 2.63 (t, 2H, J= 7.2 Hz), 2.49 (s, 6H), 2.28 (s, 3H), 1.57-1.62 (m, 2H), 1.28-1.32 (m, 4H), 0.88 (t, 2H, J = 6.6 Hz). 13C NMR (150 MHz, CDCI3) delta 148.4, 143.3, 140.9, 140.1, 134.3, 132.3, 128.9, 126.4, 35.9, 31.5, 30.8, 22.9, 22.6, 21.1, 14.1.
With aluminum (III) chloride; In dichloromethane; at 20℃; for 2h;
A mixture of mesitylsulfonyl chloride (219 mg, 1.0 mmol), cyclohexyl-benzene (160 mg, 1.0 mmol) and AICI3 (200 mg, 1.5 mmol) in DCM (10 mL) was stirred for 2 hours at room temperature. The mixture was then poured into 10 mL of 5% HCl (aq.), and extracted by DCM (30 mL). The organic phase was washed by aqueous KHCO3, brine, and dried over anhydrous Na2SC>4. The resulting solution was evaporated, and the residue was purified by silica gel column chromatography (Hexane/EtOAc = 10/1) to give the desired product as a white solid (255 mg, 75%). H NMR (600 MHz, CDCI3) delta 7.69 (d, 2H, J= 8.4 Hz), 7.27 (d, 2H, J = 8.4 Hz), 6.93 (s, 2H), 2.60 (s, 6H), 2.52-2.55 (m, 1H), 2.27 (s, 3H), 1.82-1.83 (m, 4H), 1.73-1.75 (m, 1H), 1.34-1.41 (m, 4H), 1.22-1.26 (m, 1H). 13C NMR (150 MHz, CDCI3) delta 153.3, 143.2, 141.0, 140.0, 134.3, 132.2, 127.4, 126.4, 44.6, 34.2, 26.7, 26.0, 22.9, 21.0.
1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 16h;
To a solution of lH-Indole (117 mg, 1.0 mmol) and mesitylsulfonyl chloride (219 mg, 1.0 mmol) in 5 mL of THF was added 60% NaH (50 mg, 1.25 mmol) at 0 C. The resulting mixture was stirred at r.t. for 16 h. The solution was diluted with EtOAc (50 mL),washed with 1 N HC1 (aq.) (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2S0 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane/EtOAc = 10/1) to give the desired product as a white solid (250 mg, 84%). H NMR (600 MHz, CDC13) delta 7.59-7.61 (m, 1H), 7.54-7.55 (m, 1H), 7.34-7.35 (m, 1H), 7.17 (s, 2H), 6.93 (s, 2H), 6.61-6.62 (m, 1H), 2.52 (s, 6H), 2.26 (s, 3H). 13C NMR (150 MHz, CDC13) delta 144.1, 140.3, 134.7, 133.1, 132.5, 130.3, 126.8, 124.2, 122.8, 121.5, 112.5, 106.5, 22.7, 21.1.
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 16h;
To a solution of lH-Pyrrolo[3,2-]pyridine (35 mg, 0.3 mmol) and mesitylsulfonyl chloride (88 mg, 0.4 mmol) in 4 mL of THF was added 60% NaH (16 mg, 0.4 mmol) at 0 C. The resulting mixture was stirred at r.t. for 16 h. The solution was diluted with EtOAc (50 mL), washed with 1 N HC1 (aq.) (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane/EtOAc = 1/1) to give the desired product as a white solid (86 mg, 96%). H NMR (600 MHz, CDC13) delta 8.48 (d, 1H, J = 3.6 Hz), 7.74-7.75 (m, 1H), 7.71 (d, 1H, J = 8.4 Hz), 7.09-7.11 (m, 1H), 6.94 (s, 2H), 6.81 (d, 1H, J = 3.0 Hz), 2.50 (s, 6H), 2.25 (s, 3H). 13C NMR (150 MHz, CDC13) delta 148.1, 145.8, 144.7, 140.4, 132.6, 132.5, 129.6, 128.3, 119.8, 118.7, 107.8, 22.7, 21.1.
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 16h;
To a solution of lH-Pyrrolo[2,3-c]pyridine (35 mg, 0.3 mmol) and mesitylsulfonyl chloride (66 mg, 0.3 mmol) in 4 mL of THF was added 60% NaH (16 mg, 0.4 mmol) at 0 C. The resulting mixture was stirred at r.t. for 16 h. The solution was diluted with EtOAc (50 mL), washed with 1 N HC1 (aq.) (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane/EtOAc = 1/1) to give the desired product as a white solid (78 mg, 87%). H NMR (600 MHz, CDC13) delta 8.69 (s, 1H), 8.35 (d, 1H, J = 5.4 Hz), 7.73 (d, 1H, J= 3.6 Hz), 7.48 (d, 1H, J= 5.4 Hz), 6.96 (s, 2H), 6.63 (d, 1H, J = 3.0 Hz), 2.53 (s, 6H), 2.28 (s, 3H). 13C NMR (150 MHz, CDC13) delta 144.9, 142.1, 140.6, 135.8, 135.1, 132.8, 132.4, 131.8, 130.0, 115.9, 105.5, 22.7, 21.2.
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 16h;
To a solution of lH-Pyrrolo[2,3-]pyridine (59 mg, 0.5 mmol) and mesitylsulfonyl chloride (110 mg, 0.5 mmol) in 4 mL of THF was added 60% NaH (24 mg, 0.6 mmol) at 0 C. The resulting mixture was stirred at r.t. for 16 h. The solution was dilutedwith EtOAc (50 mL), washed with 1 N HC1 (aq.) (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane/EtOAc = 7/1) to give the desired product as a white solid (130 mg, 87%). H NMR (600 MHz, CDC13) delta 8.22 (d, 1H, J = 4.2 Hz), 7.85 (d, 1H, J = 3.0 Hz), 7.83 (d, 1H, J = 7.8 Hz), 7.08-7.11 (m, 1H), 6.93 (s, 2H), 6.57 (d, 1H, J = 3.0 Hz), 2.71 (s, 6H), 2.27 (s, 3H). 13C NMR (150 MHz, CDC13) delta 147.6, 144.7, 144.0, 141.3, 132.8, 132.1, 129.3, 126.9, 122.4, 118.6, 103.8, 23.0, 21.2.
With dmap; hydroxylamine hydrochloride; In pyridine; at 20.0℃; for 0.08333330000000001h;Cooling with ice;
General procedure: To a mixture of hydroxylamine hydrochloride (2 equiv.) and DMAP (2 equiv.) in pyridine (20 mL) was added a portion of arylsulfonyl chloride (1 equiv.) on an ice-bath. Then, the mixture was stirred for 5 min at room temperature. The resulting suspension was poured into AcOEt (100 mL) and 1 N HCl aq. (100 mL). The AcOEt layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography under one of the gradient conditions indicated below, and recrystallized from Et2O/n-hexane to give N-hydroxyarylsulfonamide derivatives.
With bis(benzonitrile)palladium(II) dichloride; oxygen; potassium carbonate; In 1,4-dioxane; at 120℃; under 760.051 Torr; for 24h;Molecular sieve;
General procedure: A 10 ml dried round bottom flask was charged sequentially with a stirring bar, Pd(PhCN)2Cl2 (0.02 mmol, 10 mol %), K2CO3 (05 equiv), p-toluene sulfonyl chloride (1.5 equiv) and 4 ? molecular sieve (50 mg). Dry dioxane (1 ml) and alpha-methyl vinyl pyridine (0.2 mmol, 1 equiv) were added into the mixture in sequence, and the resultant mixture was stirred at 120 C under 1 atm of oxygen (balloon pressure) for 24 h. After cooling down, the mixture was diluted with ethyl acetate and filtered via Celite. After removing the organic solvent under reduced pressure, the crudeproduct was purified by silica gel flash column chromatography (EtOAc/hexane mixtures). And 3a was obtained in 71% yield as a white solid. Mp=98-99 C; Rf=0.35 (EA/Hexane=3:7). 1H NMR (300 MHz, CDCl3) delta 8.58 (d, J=4.23 Hz, 1H), 7.87 (d, J=8.25 Hz, 2H), 7.68-7.74 (td, J=7.77, 1.70 Hz, 1H), 7.50 (d, J=7.95 Hz, 1H), 7.34 (d, J=8.25 Hz, 2H), 7.25-7.29 (m, 2H), 2.59 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) delta 155.8, 149.6, 149.3, 144.2, 139.0, 136.8, 129.9, 127.4, 124.1, 121.0, 21.5, 15.0; IR (film, cm-1): 3020, 1597, 1581, 1568, 1465, 1431, 1311, 1301, 1215, 1145, 1085; HRMS m/z calculated for C14H13O2 [M+H]+: 213.2887; found 213.2882.
With triethylamine; In dichloromethane; at 20℃; for 1h;
To a solution of <strong>[13078-79-0]2-(3-chlorophenyl)ethanamine</strong> (0.778 g, 5 mmol) and triethyl amine (1.05 mL, 7.5 mmol) in dichloromethane, was added 2,4,6- trimethylbenzene- l-sulfonyl chloride (1.09 g, 5 mmol) portion wise. The mixture was allowed to stir for 1 h at ambient temperature. The reaction mixture was washed with HC1 (2N) (3 x 50 mL), water and brine. The organic layer was dried over anhydrous MgS04 and concentrated in vacuo to obtain the title compound.
With triethylamine; In dichloromethane; at 20℃; for 1h;
To a solution of (4-bromophenyl)methanamine (0.93 g, 5 mmol) and triethyl amine (1.05 mL, 7.5 mmol) in dichloromethane, was added 2,4,6- trimethylbenzene- l-sulfonyl chloride (1.09 g, 5 mmol) portion wise. The mixture was allowed to stir for 1 h at ambient temperature. The reaction mixture was washed with HC1 (2N) (3 x 50 mL), water and brine. The organic layer was dried over anhydrous MgS04 and concentrated in vacuo to obtain the title compound as colorless prisms (98%); 1 H NMR (400 MHz, Chloroform-if) delta (ppm) 7.38 - 7.32 (m, 2H), 7.07 - 7.01 (m, 2H), 6.94 (s, 2H), 4.90 (t, J= 6.2 Hz, 1H), 4.03 (d, J= 6.2 Hz, 2H), 2.61 (s, 6H), 2.31 (s, 3H); 13C NMR (100 MHz, Chloroform-i/) delta (ppm) 142.6, 139.2, 135.6, 133.7, 132.1, 131.8, 129.6, 121.9, 46.3, 23.1, 21.1 ; HRMS calculated for Ci6Hi8BrN02S (M+H)+ : 368.0314, Found: 368.0319.
With triethylamine; In dichloromethane; at 20℃; for 1h;
To a solution of 2,4,6-trimethylbenzenesulfonyl chloride (5.86 g, 27 mmol) and TEA (4.1 g, 40 mmol) in DCM (100 mL) was added (4-bromophenyl)methanamine (5.0 g, 27 mmol) portionwise. The mixture was allowed to stir for 1 h at rt, washed with HCI (2N, 100 mL), water and brine. The organic layer was dried over Na2S04 and concentrated to obtain compound 1a. 1H-NMR (CDCI3, 300 MHz): delta 7.38-7.35 (m, 2H), 7.05-7.02 (m, 2H), 6.94 (s, 2H), 4.76 (t, J = 6.0 Hz, 1H), 4.04 (d, J = 6.0 Hz, 2H), 2.62 (s, 6H), 2.31 (s, 3H).
3-(mesitylsulfonyl)-1,7-dimethyl-2-propyl-1H,3H-2,5-bibenzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With tetrabutylammomium bromide; sodium hydroxide; In benzene; at 0 - 20℃;
General procedure: To a solution of 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazole 3 (2 mmol) and tetrabutylammonium bromide (0.2 mmol) in benzene (25 mL), a solution of 50% NaOH (25 mL) was added at 0 C followed by the addition of sulfonyl chloride 4 (2.2 mmol). The reaction mixture was stirred vigorously at room temperature for 5-6 h and the reaction was monitored by TLC. After the completion of the reaction, aqueous phase was separated and the organic phase was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate and concentrated to give crude products which were purified by column chromatography over silica gel using hexane-EtOAc (6:4) mixture as eluent.
tert-butyl 2-(N, 2, 4, 6-tetramethylphenylsulfonamido)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With potassium carbonate; In acetonitrile; at 0 - 20℃;Inert atmosphere;
A solution of amino acid f-butyl ester (1 eq) and K2C03 (1.1 eq) were dissolved in anhydrous acetonitrile and cooled to 0 C before sulfonyl chloride (1 eq) was added. The resultant solution was allowed to stir overnight at rt. The reaction was concentrated in vacuo and residue was dissolved in CH2CI2. The organics were combined and then washed sequentially with 0.1 M HCI, saturated NaHC03 and brine. The organics were then dried over Na2S04 and concentrated in vacuo to furnish derivatives 7 & 8 with no further purification.; Derivative 5 synthesized using general procedure d (77 %): 5H (400 MHz, CDCI3) 1.37 (s, 9H, CH3) 2.30 (s, 3H, CH3), 2.61 (s, 6H, CH3) 2.82 (s, 3H, CH3), 3.99 (s, 2H, CH2), 6.95 (s, 2H, CH); 5C (400 MHz, CDCI3) 21.0, 22.9, 27.5, 35.1 , 51.6, 130.6, 137.4, 141.3, 145.5, 70.2; LRMS (ES+) calculated for [Ci6H25N04S + H] 285.10, found 286.22.
6-bromo-5-fluoro-1-(mesitylsulfonyl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
To a mixture of 6-bromo-5- fluoro-lH-indole (890 mg, 4.16 mmol) in dry THF (15 mL) under N2 at 0C was added NaH (500 mg, 60% wt, 12.5 mmol). The mixture was stirred for 0.5 hr at 20C, followed by addition of 2,4,6- trimethylbenzenesulfonyl chloride (1.09 g, 5.0 mmol) in portions. The resulting mixture was stirred for 0.5 hr at 20C then quenched with water (50 mL) and extracted with EtOAc. The organic layer was separated, washed with brine (100 mL), dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give the desired product (1.5 g, 82% yield) as white solid. LC-MS: m/z 396 (M+H)+.
6-bromo-1-(2,4,6-trimethylbenzenesulfonyl)indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92.6%
0 C,To a solution of <strong>[79762-54-2]6-bromoindazole</strong> (7.35 g, 37.3 mmol) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (3.65 g, 38.1 mmol) and stirred for 30 minutes.2,4,6-trimethylbenzenesulfonyl chloride (8.35 g, 38.1 mmol) was added in one portion to the reaction system and stirred at room temperature for 40 minutes.The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate.The organic phase was washed with saturated brine,Dried over anhydrous sodium sulfate, and concentrated to give the title compound (13.1 g, 92.6%).
N-(3-(dimethylamino)propyl)-2,4,6-trimethylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98.5%
With triethylamine; In dichloromethane; at 20℃; for 3h;Cooling with ice;
To a flame dried, round bottom flask on ice bath equipped with a stir bar containing 40 - 50 mL of anhydrous DCM , 1.0 equivalent of respective sulfonyl chloride was added followed by 1.5 equivalents of Et3N, and dropwise addition of 1.5 equivalents of 3-(dimethylamino)propylamine. The reaction mixture was taken off ice bath and allowed to stir for the indicated time at room temperature. The reaction was then transferred to a separatory funnel and extracted with a 30 - 70 mL of distilled water. Volatiles and/or solvent were removed from the organic phase using a rotary evaporator followed by drying under 10"3 mm Hg vacuum. This compound was synthesized according to General Method 1 using 2,4,6-trimethylbenzene-l- sulfonyl chloride (2 g, 9.14 mmol), triethylamine (1.9 mL, 13.72 mmol, 1.5 eqv.), and 3- (dimethylamino)propylamine (1.7 mL, 13.72 mmol, 1.5 eqv.) in DCM (50 mL) for 3 hours yielding a clear solution. The solution was then extracted using distilled water (75 mL), the extracted organic layer was dried using rotary evaporator yielding a clear oil; which was further dried under 10"3 mm Hg vacuum yielding in pale white waxy solid product. Yield 98.5 % (2.56 g). NMR (CDCI3, 400 MHz, delta): 7.04 (br. s, 1H, H7), 6.93 (s, 2H, H3), 2.94 (t, 2H, J8-9 = 5.7 Hz, H8), 2.61 (s, 6H, H4), 2.32 (t, 2H, J10-9 = 5.6 Hz, H10), 2.27 (s, 3H, HI), 2.18 (s, 6H, Hl l), 1.69- 1.56 (m, 2H, H9)ppm; 13C {} NMR (CDCI3, 100 MHz, delta): 141.74 (C6), 139.07 (C2), 133.80 (C5), 131.87 (C3), 59.66 (CIO), 45.48 (CI 1), 43.72 (C8), 24.99 (C9), 22.88 (C4), 20.95 (CI) ppm. HRMS-ESI-TOF (m/z): [M+ + H+] calculated for C14H25N2O2S1, 285.4255, found, 285.1643.
2-{1-[(((2,4,6-trimethylphenyl)sulfonyl)amino)methyl]cyclohexyl}acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium carbonate; In water; at 20℃;pH 8 - 9;Green chemistry;
General procedure: Following this, the general procedure has been adoptedfor the synthesis of sulfonamides: gabapentin (1 eq, 1.169mmol) was suspended in dist. water (15 ml) and Na2CO3solution, to adjust the pH at 8-9, followed by the addition ofsulfonyl chloride (1 eq, 1.169 mmol), was suspended in thedrug solution. The evolution of reaction was scrutinized byTLC. The reaction was completed when the suspensionturned into a clear solution. The reaction mixture was acidifiedto obtain white precipitate. The products were separated,rinsed with dist. water and recrystallized in MeOH.
75%
With sodium carbonate; In water; at 20℃; for 3h;pH 8.0;
General procedure: To a solution of Gabapentin (0.171 g, 1.00 mmol) and water(10 mL), 1 M sodium carbonate was added to adjust thepH 8. Then added 4-acetamidobenzenesulfonyl chloride(0.233 g, 1.00 mmol) and the mixture was stirred at roomtemperature keeping the pH of the mixture up to 8.0 by using sodium carbonate solution. Progress and completion of thereaction was confirmed by TLC. After 3 h, the pH of mixturewas adjusted to 2.0 by 1 M HCl. White precipitates wereproduced, filtered and washed with distilled water. Colorlesscrystals were obtained after recrystallization from methanol.Yield 64%.
With pyridine; In dichloromethane; at 0 - 20℃; for 8h;Cooling with ice;
General procedure: To a solution of compound 11a (154 mg, 1.0 mmol) in anhydrous CH2Cl2 (10 mL) was added 3,5-dichlorobenzoyl chloride (209 mg, 1.0 mmol) and pyridine (241 mL 3.0 mmol) under ice bath. After stirring at room temperature for about 8 h, the solvent was removed in vacuum. The resulting residue was dissolved in NaOH (1 M) water solution (3 mL) and CH3OH (3 mL) and stirred for another 2 h. Then the solvent was removed under vacuum, and the residue was acidied to pH 2 or below with HCl (1 M) water solution. The solution was extracted with ethyl acetate twice and the combined organics were dried over anhydrous sodium sulfate and concentrated in vacuum. The resulting residue was puried by silica gel chromatography to give the desired compound as a white solid (234 mg, yield 85.0%)
4-mesityl-1-methyl-3-(phenylsulfonyl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With water; sodium carbonate; eosin y; In acetonitrile; at 100℃; under 760.051 Torr; for 20h;Schlenk technique; Irradiation; Inert atmosphere;
General procedure: To a Schlenk tube were added 1 (0.2 mmol), 2 (1.5 eqiuv, 0.3 mmol), Eosin Y (2mol %, 0.004 mmol), Na2CO3 (2 eqiuv, 0.4 mmol), H2O (4.0 equiv, 0.8 mmol) CH3CN (2 mL). Then the mixture was stirred at 100 C (oil bath temperature) in argon atmosphere (1 atm) under 5 W blue LED light for 20 h until complete consumption of starting material as monitored by TLC and GC-MS analysis. After the reaction was finished, the reaction mixture was washed with brine. The aqueous phase was re-extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuum. The residue was purified by silica gel flash column chromatography (hexane/ethyl acetate = 3 : 1 to 1 : 1) to afford the desired products 3.
(4-((2,4,6-trimethylphenyl)sulfonylamino)phenyl)carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With triethylamine; In toluene; at 20℃; for 4h;
tert-Butyl (4-aminophenyl)carbamate (2 g, 10 mmol) and mesitylenesulfonyl chloride (2.2 g, 10 mmol)Dissolve in 200 mL of toluene, add 2 mL of triethylamine, and react at room temperature for 4 hours.A large amount of solid precipitated, and after suction filtration, it was washed with 100 mL of water and dried.A purple solid was obtained in an amount of 3.5 g, yield 89%.
N-[2-(2-fluorophenyl)ethyl]-2,4,6-trimethylbenzene-1-sulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
With triethylamine; In dichloromethane; at 20℃; for 2h;
2,4,6-Trimethylbenzenesulfonyl chloride (38 mg, 0.17 mmol) was dissolved in DCM (2 mL) and <strong>[52721-69-4]2-(2-fluorophenyl)ethanamine</strong> (41.1 mg, 0.30 mmol) was added followed by triethylamine (50 pL, 0.35 mmol). The reaction mixture was stirred for 2 hours at room temperature. Water (1 mL) was added. The layers were separated and the organic phase was concentrated. Purification by preparative HPLC (XBridge Cl 8 19 x 50 mm; 0.1 % TFA(aq)/MeCN; 80:20 to 30:70) afforded the title compound as a white solid (4.6 mg, 8 %). MS ESI+ m/z 322 [M+H]+.
With triethylamine; In acetonitrile; at 25℃; for 24h;
(1) 1 mmol of latinosyl N, N-dimethylamino-3-methylindole shown in Formula 1, 1.5mmol of mesitylenesulfonyl chloride as shown in Formula 2e was added to a 50mL flask, Add 10mL CH3CN to completely dissolve, slowly add 1.5mmol Et3N, The reaction was stirred at 25 C for 24h to obtain a reaction solution; the reaction formula is as follows: (2) concentrated the reaction solution under reduced pressure, Add CH2Cl2 and water, Extraction, combining organic phases, It was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated and evaporated to dryness, and then separated by silica gel column chromatography to obtain N, N-dimethylsulfonamide derivatives as shown in formula 3e.
pent-1-yn-3-yl 2,4,6-trimethylbenzenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 25h;
General procedure: To a solution of 7a (6.0 g, 37.5 mmol,1.0 equiv) in CH2Cl2 (120 mL) was added DMAP (0.46 g, 3.75 mmol, 0.1 equiv) and triethylamine (6.2 mL, 45mmol, 1.2 equiv). The reaction mixture was cooled to 0 oC, then 2,4,6-trimethylbenzenesulfonyl chloride (8.6 g,39.3 mmol, 1.05 equiv) was added. After stirring for 1 h at 0 oC, the reaction mixture was allowed to warm toroom temperature and stirred for 24 h. The resulting suspension was quenched with saturated aqueous NH4Cland extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, andconcentrated. The residue was purified by flash column chromatography to give the propargyl sulfonate 1d.
1-(5-fluoro-2-(methylthio)pyrimidin-4-yl)piperidin-4-amine[ No CAS ]
N-(1-(5-fluoro-2-(methylthio)pyrimidin-4-yl)piperidin-4-yl)-2,4,6-trimethylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With triethylamine; In dichloromethane; at 0 - 20℃; for 10h;
General procedure: Substituted sulphonyl chloride (1.0 eq) was added to compound 4(1.0 eq) and mixed with triethyl amine (3.0 eq) and dichloromethane(10 volume) at 0-5 C. The obtained mixture was magnetically stirredat room temperature for 10 h and reaction was monitored using TLC.Then the reaction mixture was transferred into a separating funneland brine solution was added, then dried with anhydrous sodium sulphate,and finally evaporation of the solvent get the crude product. Silicagel (60-120 mesh) was used to purify the obtained product with 8:2ratio of hexane: ethyl acetate as an eluent in a column chromatography.Scheme for the synthesis of 5-fluoro-2- methylthio substituted pyrimidinederivatives is presented in Fig. 1.2.2.4.1. Synthesis of N-(1-(5-fluoro-2-(methylthio)pyrimidin-4-yl)piperidin-4-yl)-2,4,6-trimethylbenzenesulfonamide (F1). Yield: 81%. IR(nu/cm-1): 1677 (CN), 3389 (NH), 1373 (SO2). 1H NMR (DMSO-d6): delta1.34-1.38 (m, 2H, C-CH2), 1.58-1.61 (m, 2H, C-CH2), 2.25 (s, 3H, s-CH3), 2.39 (s, 3H, Ar-CH3), 2.55 (s, 6H, Ar-CH3), 3.06 (q, J = 11.28 Hz,2H, N-CH2), 3.26 (s, 1H, CH2-CH), 4.14 (q, J = 10.26 Hz, 2H, N-CH2),7.02 (s, 2H, NH, ArH), 7.60 (d, J = 8.31 Hz, 1H, ArH), 8.08 (d, J =6.96 Hz, 1H, ArH). MS, m/z: 425 (M + 1). Elemental analyses found(calculated) for C17H12BrN3O2S (%): C, 53.75 (53.88); H, 5.94 (6.12);N, 13.20 (13.33).
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