* 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.
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 15℃; for 3 h; Inert atmosphere
Step 1. Saccharin (10.0 g, 54.6 mmol) was slowly added to solution of LiAlH4 (2.24 g, 59.0 mmol) in 300 mL of THF at 0°C. The reaction mixture was stirred for 3h at 15°C under an inert atmosphere. Upon completion, EtOAc (100 mL) was slowly added followed by addition of 10percent H2S04 (lOOmL). The organic layer was separated and washed with 100 mL of 5percent sodium carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1 (4.4 g, 97percent).
87%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 15℃; for 16.5 h;
tetrahydrofuran (2 mL) was added drop-wise to a 0 °C suspension of lithium aluminum hydride (45.6 mg, 1.20 mmol) in tetrahydrofuran (3 mL). After the reaction mixture had stirred for 30 minutes at 0 °C, it was gradually warmed to 15 °C and stirred at 15 °C for 16 hours. The white suspension was treated with saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide the product as a grey solid. Yield: 160 mg, 0.946 mmol, 87percent. 1H NMR (400 MHz, CDCI3) δ 7.81 (d, J=7.8 Hz, 1 H), 7.63 (dd, half of ABX pattern, J=7.5, 7.3 Hz, 1 H), 7.54 (dd, half of ABX pattern, J=7.5, 7.5 Hz, 1 H), 7.41 (d, J=7.8 Hz, 1 H), 4.95-4.80 (br s, 1 H), 4.55 (s, 2H).
81%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃;
Preparation 16 2,3-Dihydrobenzo[d]isothiazole 1,1-dioxide To a cold solution of lithium aluminum hydride (0.414 g) in anhydrous tetrahydrofuran (30 mL), kept at 0° C. with an external ice bath, was added sulfobenzimide (1 g, 5.5 mmol). The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with the addition of water and 2.5M aqueous sulfuric acid. The mixture was filtered through Celite and washed with ethyl acetate. The organic layer was washed with 1M aqueous sulfuric acid, dried (anhydrous magnesium sulfate), filtered, and concentrated to afford an off-white solid (0.75 g, 81percent). 1H NMR (CDCl3, 300 MHz) δ 7.81-7.78 (d, 1H, J=7.8 Hz), 7.64-7.59 (dt, 1H, J=1.2, 7.5 Hz), 7.52-7.49 (dt, 1H, J=0.75, 7.5 Hz), 7.41-7.37 (d, 1H, J=8.1 Hz), 4.8 (br s, 1H), 4.55-4.54 (d, 1H, J=3.6 Hz).
35.6%
With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether for 48 h;
Example 82 1,2-Benzisothiazoline-1,1-dioxide To a solution of 1,2-benzisothiazoline-3-one-1,1-dioxide (25, 554 mg, 3.02 mmol) in THF (8.0 mL) was slowly added lithium aluminum hydride (1M in ether, 4.09 mL, 4.09 mmol). The solution was stirred for 48 hrs, followed by the slow addition of drops of Na2SO4 10H2O at 0° C. The reaction mixture was filtered through celite, and the filtrate was concentrated to dryness to afford the title compound (182 mg, 35.6percent). 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=7.65 Hz, 1H), 7.67 (d, J=7.49, 1.17 Hz, 1H), 7.58 (t, J=7.44 Hz, 1H), 7.44 (d, J=7.59 Hz, 1H), 4.74 (brs, 1H), 4.59 (s, 2H)
35.6%
With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether for 0.8 h;
Lithium aluminium hydride1 M in ether (4.09 mL) was addedslowly at 0 C to a solution of o-sulfobenzimide (7, 554 mg,3.02 mmol) in THF (8.0 mL), and stirred for 48 min. Subsequently,sodium sulfate hydrate was added to the solution and filteredthrough Celite. The organic layer was concentrated in reducedpressure to afford the title compound (182 mg, 35.6percent); 1H NMR(400 MHz, CDCl3) d 7.85 (d, J = 7.7, 1H), 7.67 (dt, J = 7.5, 1.2 Hz,1H), 7.58 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 4.74 (br, 1H),4.59 (s, 2H).
Reference：
[1] Patent: WO2018/49324, 2018, A1, . Location in patent: Page/Page column 25
[2] Organic Letters, 2014, vol. 16, # 6, p. 1550 - 1553
[3] Patent: WO2017/21805, 2017, A1, . Location in patent: Page/Page column 174
[4] Patent: US2013/303524, 2013, A1, . Location in patent: Paragraph 0268-0269
[5] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8868 - 8878
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5348 - 5355
[7] Tetrahedron, 1996, vol. 52, # 12, p. 4181 - 4198
[8] Journal of Medicinal Chemistry, 1983, vol. 26, # 2, p. 243 - 246
[9] Patent: US2015/329533, 2015, A1, . Location in patent: Paragraph 0294; 0295
[10] Bioorganic and Medicinal Chemistry, 2017,
[11] Mem. Coll. Sci. Kyoto Univ., 1932, vol. <A> 15, p. 151,153
Reference：
[1] Pharmazie, 2005, vol. 60, # 10, p. 723 - 731
[2] Gazzetta Chimica Italiana, 1916, vol. 46 I, p. 234,236
[3] Gazzetta Chimica Italiana, 1915, vol. 45 I, p. 547
[4] Journal of Organic Chemistry, 1951, vol. 16, p. 1582,1585
[5] Journal of Chemical Crystallography, 1994, vol. 24, # 9, p. 581 - 586
[6] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2008, vol. 63, # 7, p. 877 - 879
[7] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2007, vol. 62, # 12, p. 1530 - 1534
[8] Inorganica Chimica Acta, 2018, vol. 479, p. 266 - 274
4
[ 81-07-2 ]
[ 14070-51-0 ]
Yield
Reaction Conditions
Operation in experiment
84%
With tert-butylhypochlorite In methanol at 20℃; for 0.0833333 h;
Saccharin (6.0 g) was reacted in methanol (120 ml) at room temperature for 5 minutes with tert-butyl hypochlorite (5 ml) to give the compoundChloro-saccharin 1a (6.0 g, 84percent); Chloro-saccharin 1a (3.0 g) was reacted with trifluoromethylthio-silver (3.6 g) in acetonitrile (40 ml) at room temperature for 10 min to give Compound 1 (3.3 g, 86percent). Reagent 1 is a white solid at room temperature, soluble in organic solvents such as dichloromethane, chloroform, acetone and acetonitrile.
84%
With tert-butylhypochlorite In methanol at 20℃; for 0.0833333 h;
Saccharin (6.0 g of) in methanol (120ml) at room temperature and tert-butyl hypochlorite (5ml) for 5 minutes to give saccharin chloro compound 1a (6.0g, 84percent); chloro saccharin 1a (3.0g) and three difluoromethylthio-silver (3.6 g of) in acetonitrile (40ml) and reacted at room temperature for 10 minutes to give compound 1 (3.3g, 86percent).Reagent 1 at room temperature a white solid was soluble in methylene chloride, chloroform, acetone, and acetonitrile.N - trifluoromethylthio-saccharin (2 - ((Trifluoromethyl) Thio) of benzo [D] isothiazol-3 (2H) -one1,1-dioxide)
84%
With tert-butylhypochlorite In methanol at 20℃; for 0.0833333 h;
Saccharin (6.0 g of) in methanol (120ml) and tert-butyl hypochlorite (5ml) for 5 minutes to give saccharin chloro compound 1a (6.0g, 84percent) at room temperature; chloro saccharin 1a (3.0g) and three difluoromethylthio-silver (3.6 g of) the reaction at room temperature in acetonitrile (40ml) 10 minutes to give compound 1 (3.3g, 86percent).
84%
With tert-butylhypochlorite In methanol at 20℃; for 0.0833333 h; Green chemistry
Saccharin (6.0 g) was reacted with t-butyl hypochlorite (5 ml) in methanol (120 ml) for 5 minutes at room temperature to give the compound chlorosaccharide 1a (6.0 g, 84percent);The chloro saccharin 1a (3.0 g) was reacted with trifluoromethylthio silver (3.6 g) in acetonitrile (40 ml) at room temperature for 10 minutes to give compound II (3.3 g, 86percent).The compound II is a white solid at room temperature and is soluble in an organic solvent such as dichloromethane, chloroform, acetone or acetonitrile.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 15℃; for 3h;Inert atmosphere;
Step 1. Saccharin (10.0 g, 54.6 mmol) was slowly added to solution of LiAlH4 (2.24 g, 59.0 mmol) in 300 mL of THF at 0°C. The reaction mixture was stirred for 3h at 15°C under an inert atmosphere. Upon completion, EtOAc (100 mL) was slowly added followed by addition of 10percent H2S04 (lOOmL). The organic layer was separated and washed with 100 mL of 5percent sodium carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1 (4.4 g, 97percent).
87%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 15℃; for 16.5h;
tetrahydrofuran (2 mL) was added drop-wise to a 0 °C suspension of lithium aluminum hydride (45.6 mg, 1.20 mmol) in tetrahydrofuran (3 mL). After the reaction mixture had stirred for 30 minutes at 0 °C, it was gradually warmed to 15 °C and stirred at 15 °C for 16 hours. The white suspension was treated with saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide the product as a grey solid. Yield: 160 mg, 0.946 mmol, 87percent. 1H NMR (400 MHz, CDCI3) delta 7.81 (d, J=7.8 Hz, 1 H), 7.63 (dd, half of ABX pattern, J=7.5, 7.3 Hz, 1 H), 7.54 (dd, half of ABX pattern, J=7.5, 7.5 Hz, 1 H), 7.41 (d, J=7.8 Hz, 1 H), 4.95-4.80 (br s, 1 H), 4.55 (s, 2H).
81%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃;
Preparation 16 2,3-Dihydrobenzo[d]isothiazole 1,1-dioxide To a cold solution of lithium aluminum hydride (0.414 g) in anhydrous tetrahydrofuran (30 mL), kept at 0° C. with an external ice bath, was added sulfobenzimide (1 g, 5.5 mmol). The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with the addition of water and 2.5M aqueous sulfuric acid. The mixture was filtered through Celite and washed with ethyl acetate. The organic layer was washed with 1M aqueous sulfuric acid, dried (anhydrous magnesium sulfate), filtered, and concentrated to afford an off-white solid (0.75 g, 81percent). 1H NMR (CDCl3, 300 MHz) delta 7.81-7.78 (d, 1H, J=7.8 Hz), 7.64-7.59 (dt, 1H, J=1.2, 7.5 Hz), 7.52-7.49 (dt, 1H, J=0.75, 7.5 Hz), 7.41-7.37 (d, 1H, J=8.1 Hz), 4.8 (br s, 1H), 4.55-4.54 (d, 1H, J=3.6 Hz).
35.6%
With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; for 48h;
Example 82 1,2-Benzisothiazoline-1,1-dioxide To a solution of 1,2-benzisothiazoline-3-one-1,1-dioxide (25, 554 mg, 3.02 mmol) in THF (8.0 mL) was slowly added lithium aluminum hydride (1M in ether, 4.09 mL, 4.09 mmol). The solution was stirred for 48 hrs, followed by the slow addition of drops of Na2SO4 10H2O at 0° C. The reaction mixture was filtered through celite, and the filtrate was concentrated to dryness to afford the title compound (182 mg, 35.6percent). 1H NMR (300 MHz, CDCl3) delta 7.85 (d, J=7.65 Hz, 1H), 7.67 (d, J=7.49, 1.17 Hz, 1H), 7.58 (t, J=7.44 Hz, 1H), 7.44 (d, J=7.59 Hz, 1H), 4.74 (brs, 1H), 4.59 (s, 2H)
35.6%
With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; for 0.8h;
Lithium aluminium hydride1 M in ether (4.09 mL) was addedslowly at 0 C to a solution of o-sulfobenzimide (7, 554 mg,3.02 mmol) in THF (8.0 mL), and stirred for 48 min. Subsequently,sodium sulfate hydrate was added to the solution and filteredthrough Celite. The organic layer was concentrated in reducedpressure to afford the title compound (182 mg, 35.6percent); 1H NMR(400 MHz, CDCl3) d 7.85 (d, J = 7.7, 1H), 7.67 (dt, J = 7.5, 1.2 Hz,1H), 7.58 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 4.74 (br, 1H),4.59 (s, 2H).
With tert-butylhypochlorite; In methanol; at 20℃; for 0.0833333h;
Saccharin (6.0 g) was reacted in methanol (120 ml) at room temperature for 5 minutes with tert-butyl hypochlorite (5 ml) to give the compoundChloro-saccharin 1a (6.0 g, 84%); Chloro-saccharin 1a (3.0 g) was reacted with trifluoromethylthio-silver (3.6 g) in acetonitrile (40 ml) at room temperature for 10 min to give Compound 1 (3.3 g, 86%). Reagent 1 is a white solid at room temperature, soluble in organic solvents such as dichloromethane, chloroform, acetone and acetonitrile.
84%
With tert-butylhypochlorite; In methanol; at 20℃; for 0.0833333h;
Saccharin (6.0 g of) in methanol (120ml) at room temperature and tert-butyl hypochlorite (5ml) for 5 minutes to give saccharin chloro compound 1a (6.0g, 84%); chloro saccharin 1a (3.0g) and three difluoromethylthio-silver (3.6 g of) in acetonitrile (40ml) and reacted at room temperature for 10 minutes to give compound 1 (3.3g, 86%).Reagent 1 at room temperature a white solid was soluble in methylene chloride, chloroform, acetone, and acetonitrile.N - trifluoromethylthio-saccharin (2 - ((Trifluoromethyl) Thio) of benzo [D] isothiazol-3 (2H) -one1,1-dioxide)
84%
With tert-butylhypochlorite; In methanol; at 20℃; for 0.0833333h;
Saccharin (6.0 g of) in methanol (120ml) and tert-butyl hypochlorite (5ml) for 5 minutes to give saccharin chloro compound 1a (6.0g, 84%) at room temperature; chloro saccharin 1a (3.0g) and three difluoromethylthio-silver (3.6 g of) the reaction at room temperature in acetonitrile (40ml) 10 minutes to give compound 1 (3.3g, 86%).
84%
With tert-butylhypochlorite; In methanol; at 20℃; for 0.0833333h;Green chemistry;
Saccharin (6.0 g) was reacted with t-butyl hypochlorite (5 ml) in methanol (120 ml) for 5 minutes at room temperature to give the compound chlorosaccharide 1a (6.0 g, 84%);The chloro saccharin 1a (3.0 g) was reacted with trifluoromethylthio silver (3.6 g) in acetonitrile (40 ml) at room temperature for 10 minutes to give compound II (3.3 g, 86%).The compound II is a white solid at room temperature and is soluble in an organic solvent such as dichloromethane, chloroform, acetone or acetonitrile.
[0111] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 19 mg (0.1037 mmol) saccharin were dissolved in approximately 4 mL ethanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/saccharin cocrystal, as shown in FIG. 12. Solubility measurements indicate that this multiple-component crystal of <strong>[298-46-4]carbamazepin</strong>e has improved solubility over previously known forms of <strong>[298-46-4]carbamazepin</strong>e (e.g., increased molar solubility and in aqueous solutions). [0112] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C22H17N3O4S1, M=419.45, triclinic P-1; a=7.5140(11), b=10.4538(15), c=12.6826(18) , a=83.642(2), beta=85.697(2), gamma=75.411(2) , U=957.0(2) 3, T=200(2) K, Z=2, mu(Mo-Kalpha)=0.206 mm-1, Dc=1.456 Mg/m3, k=0.71073 3, F(000)=436, 2thetamax=56.200; 8426 reflections measured, 4372 unique (R1.t 0.0305). Final residuals for 283 parameters were R1=0.0458, wR2=0.1142 for I>2?(I), and R1=0.0562, wR2=0.1204 for all 4372 data. [0113] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. The 2 amines of the saccharin are hydrogen bonded to the carbonyl of the CBZ on each side forming a tetramer. The crystal has a space group of P-i with n-g interactions between the phenyl groups of the CBZ and the saccharin phenyl groups. [0114] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts up to 3495 cm1 accounting for 10 amines; CO aliphatic stretching was shifted up to 1726 cm-1; N-H in-plane bending at 1649 cm; CC stretching shifted down to 1561 cm-1; (OSO) sulfonyl peak at 1330 cm-1 C-N aliphatic stretching 1175 cm-1. [0115] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 75.310 C (endotherm) and 177.32 C. (endotherm), m.p.=148-155 C. (MEL-TEMP); (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.20 C, saccharin m.p.=228.8 C.). [0116] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 3.342% weight loss starting at 67.03 C. and a 55.09% weight loss starting at 118.71 C. followed by complete decomposition. [0117] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD derived from the single crystal data, experimental (calculated): 6.9 (7.0); 12.2 (12.2); 13.6 (13.8); 14.0 (14.1); 14.1 (14.4); 15.3 (15.6); 15.9 (15.9); 18.1 (18.2); 18.7 (18.8); 20.2 (20.3); 21.3 (21.5); 23.7 (23.9); 26.3 (26.4); 28.3 (28.3).
Following the procedure of Example 1 the following compositions of encapsulated aspartame and saccharin were also prepared.
42
[ 29490-19-5 ]
[ 81-07-2 ]
[ 81589-00-6 ]
Yield
Reaction Conditions
Operation in experiment
91.3%
With 1,1,1,3,3,3-hexamethyl-disilazane; In toluene;
(a) 15.6 ml (0.075 mmole) of hexamethyldisilazane were added to a refluxing solution of 13.2 g (0.1 mole) of 5-mercapto-2-methyl-1,3,4-thiadiazole and 92 mg (0.5 mole) of saccharin in 25 ml of toluene and the reaction was completed after 30 minutes. Toluene was removed by distillation at normal pressure and the residue was vacuum distilled to obtain 18.63 g (91.3% yield) of 2-methyl-5-trimethylsilylthio-1,3,4-thiadiazole with a boiling point of 150-152 C. at 15 mg Hg and the distillate solidified to a solid melting at 67-69 C.
With 1,1,1,3,3,3-hexamethyl-disilazane; In N,N,N,N,N,N-hexamethylphosphoric triamide; water; toluene; Petroleum ether;
EXAMPLE 28 A mixture consisting of 2.85 g (25 mmoles) of 1-methyl-2-mercaptoimidazole, 22 mg (0.12 mmoles) of saccharin, 20 ml of toluene and 5.2 ml (25 mmoles) of hexamethyldisilazane was refluxed for 1 hour and after cooling to room temperature, 5.40 g (25 mmoles) of 4-nitrobenzyl bromide and then 5 ml of hexamethylphosphoric triamide were added to the mixture which contained 1-methyl-2-(trimethylsilylthio)-imidazole. After stirring for 2 hours at room temperature, the mixture was diluted to 150 ml with ethyl acetate and the solution thus obtained was washed three times with 50 ml of a saturated sodium bicarbonate solution and then twice with 20 ml of water. The organic layer was dried, filtered and evaporated to dryness and the crystalline residue was washed with 100 ml of petroleum ether (boiling range 60-80 C.) and then vacuum dried to obtain 5.54 g (89% yield) of 1-methyl-2-(4-nitrobenzylthio)-imidazole melting to 74-77 C. Crystallization of a sample from ethanol raised the melting point to 77.5-78.0 C.
In water; at 70 - 80℃;Product distribution / selectivity;
Example 2:Step 1 : Saccharin (183.2 mg) was added to water (20 ml) and mixed in a water bath at 70 -80 C. After a clear solution was obtained, ODV base (263.4 mg) was added and mixed until dissolved.Step 2: The water from the resulting solution was partially evaporated using a hot water bath at 50-80C until sedimentation was observed. The resulting solid material was separated by vaccum filtration, and dried in an oven at 45C for about 1 hour. Example 3:Step 1: Saccharin (183.2 mg) was added to water (10 ml) and mixed in a water bath at 70 -80C. After a clear solution was obtained, ODV base (263.4 mg) was added and mixed until dissolved.Step 2: The water from the resulting solution was partially evaporated using a hot water bath at 50-80C until sedimentation was observed. The resulting solid material was separated by vaccum filtration, and dried in an oven at 45 C for about 1 hour.
In acetone; at 0 - 50℃;Product distribution / selectivity;
Example 8; A mixture of 80.00 g adefovir dipivoxil (0.1595 moles) and 29.52 g saccharin (1.01 equivalents) in 550 mL acetone in a 1 L round bottom flask was stirred and heated to 45-50 C. Total dissolution was achieved within 25 minutes. The solution was slowly cooled to 20-25 C. in a controlled manner (over about 4 hours). During the cooling phase precipitation of a white solid was observed. Stirring at room temperature was continued for 16 hours. The slurry was then cooled to 0-5 C. and stirred at that temperature for 5 hours. The salt crystals were collected by suction filtration and dried in vacuo to give 97.88 g (90%) of ADE:SAC salt.
In ethanol; at 25℃; for 0.166667h;
Form I of AD-SAC cocrystal was prepared according to our previouslyreported method (Gao et al., 2011). Briefly, equimolar AD andSAC (7.5 mmol) was dissolved in 50 mL of ethanol. The mixture wasstirred at 25 C for 10 min and form I of AD-SAC cocrystal precipitated.After suction filtration, the form I was obtained.
To a solution of 100 mg (0.58 mmol) <strong>[136236-51-6]rasagiline</strong> in 1.5 ml acetone a solution of 106 mg (0.58 mmol, 1.0 eq) saccharin in 1.5 ml acetone was added. The solution was stirred over night. Evaporation of the solvent in vacuo and drying in high vacuum yielded a white, solid foam (208 mg, 0.58 mmol, quant.).
63%
In isopropyl alcohol; at 20℃;Cooling with ice;
500 mg (2.920 mmoles) of <strong>[136236-51-6]rasagiline</strong> base are dissolved in 6.0 ml of isopropyl alcohol whereupon 534 mg (2.915 mmoles) of saccharine are added. The solution is allowed to stand overnight at room temperature. The solvent is evaporated in vacuo, the residue is treated with a mixture of diisopropyl acetate and diisopropyl ether and the precipitated solid substance is filtered. Thus 826 mg of the title compound are obtained which is dissolved in 4.0 ml of hot isopropanol, to the solution 5.0 ml of diisopropyl ether are added and the product is crystallized by slow cooling of the solution. The suspension is cooled with icecold water, the precipitated crystals are filtered off and finally washed with cold diisopropyl ether. Yield 653 mg (63 %), off-white crystals.Melting point: 107.0-108..5 CElementary analysis for the Formula: C19H18N2O3S (354.43) :Calculated [%] C: 64.39 H: 5.12 N: 7.90 S: 9.05 O: 13.54 Found [%] C: 64.34 H: 5.08 N: 7.98 S: 9.13IR (KBr): 3289, 2953, 2830, 2731, 1622, 1583, 1455, 1271, 1152, 1118 cm"1.1H-NMR (DMSO-t , 400 MHz) delta 7.66 (m, 1H), 7.60 (m, 4H), 7.38 (m, 1H), 7.37 (m, 1H), 7.31 (t, 1H), 4.81 (dd, 1H, J = 7.3, 4.2 Hz), 4.00 (m, 2H), 3.75 (m, 1H), 3.10 (m, 1H), 2.89 (m, 1H), 2.43 (m, 1H), 2.19 (m, lH) ppm.HPLC purity: >99.8%[a] 22D =+13.5 (c=l; EtOH)
5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl saccharinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetone; at 40℃;
1.0g of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl and 0.5g of saccharin were dissolved in 20ml of acetone at 40 C. The solution was cooled to 5 C to crystallize the desired saccharin salt.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;
General procedure: Diisopropyl azodicarboxylate (DIAD, 4.5 mmol) was placed in a 50 mL round-bottomed flask equipped with a stirring bar. Then triphenylphosphine (Ph3P, 4.5 mmol) and dry tetrahydrofuran (THF, 20 mL) were added and the solution was cooled in an ice bath. Then the alcohol(3.0 mmol) was added. The mixture was then stirred for 10 minand a solution of saccharin (3.0 mmol) in dry THF (5 mL) was added dropwise. After being stirred for 30 min, the flask was removed from the ice bath and the solution was stirred at room temperature, and monitored by TLC. When the reaction was judged to be complete, the organic solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/EtOAc (v/v = 10:1) as the eluent to give the products. All the isolated products were characterised by physical and spectroscopic data and also by comparison with authentic samples. 5,7-10 The physicaland spectral data of the products are shown as follows. 2-Methyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless solid,m.p. 132-133 C (lit.7 129-130 C); 1H NMR (400 MHz, CDCl3):delta 3.26 (s, 3H), 7.83 (m, 2H), 7.93 (dd, J = 7.2, 1.6 Hz, 1H), 8.05 (dd,J = 7.2, 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): delta 23.2, 120.9,125.1, 127.5, 134.3, 134.6, 137.5, 158.6.
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine saccharinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.706 g
In methanol; at 50℃; for 18h;
Methanol (1 mL) was added to a mixture of <strong>[183321-74-6]erlotinib</strong> free base (0.4 g) and saccharin (0.366 g) and slurried for 18 hours at 50C. The solvent was evaporated at 25C to 30C and the solid obtained was dried at 55C in a vacuum tray drier for 6 hours to obtain the title compound. Yield: 0.706 g
Example 5 LSCBTN 2H20 The dihydrate of the 1:1 cocrystal of lithium saccharinate and <strong>[107-43-7]betaine</strong> [00127 ] Lithium hydroxide (>98%, anhydrous, used as received from Sigma Aldrich, 23.9mg, 1 .0 mmol), saccharin (>99% used as received from Sigma Aldrich, 183.1 mg, 1 .0 mmol) and <strong>[107-43-7]betaine</strong> (99+% pure, used as received from Aldrich, 1 17.1 mg, 1 .0 mmol) were dissolved in 4.0 mL of deionised water. The solution was evaporated on a hot plate until crystals emerged from solution. Colorless plates (127.0mg) were collected from the hot solution. [00128 ] Crystals of LSCBTN-2H2O were characterized by single crystal x-ray crystallography (Table 5) and powder x-ray diffraction (Brucker D8 advance, Cu radiation) (Figure 16; calculated (top) and experimental (bottom)). As can be seen from Figure 16, major peaks lie at about the following positions: 5.2, 14.7, 15.2, 18.5, 21 .6, 22.7, 24.3, 25.0 and 26.4. [00129] Figure 17 shows a comparison of the experimental and calculated powder x-ray diffraction patterns of LSCBTN -2H2O. [00130 ] Figure 18 shows a digital microscope image of LSCBTN-2H2O crystals. [00131 ] The single crystal x-ray structure reveals that LSCBTN-2H2O is a 1 :1 cocrystal of lithium saccharinate and <strong>[107-43-7]betaine</strong> with two water molecules in the crystal lattice. Each lithiunn cation is bridged by two carboxylate moieties of <strong>[107-43-7]betaine</strong> (Li-O bond distances: 1 .921 A, 1 .940 A) to form a liner chain and is also coordinated by two water molecules (Li-O bond distances: 1 .955 A and 1.893 A). These water molecules form hydrogen bonds with the carbonyl and basic nitrogen of saccharinate anions. [00132] Figure 19 shows the crystal packing diagram of LSCBTN-2H2O. Table 5: Single crystal X-ray diffraction data for LSCBTN.2H2O (Bruker-AXS APEX2 CCD diffracto meter) Crystallographic data Empirical formula Ci2 H19LiN207S Formula weight 342.29 Temperature 296 (2) K Wavelength 1.54178 A Crystal system Orthorhombic Space group P b c a Unit cell dimensions a = 11.9004 (2) A a=90 b = 8.1845 (10) A beta= 90 c c = 33.2368 (2) A gamma =90 Volume 3237.22 (8) A3 Z 8 Density (calculated) 1.405 Mg/m3 Reflections collected 26918 Independent reflections 2941 [R(int) = 0.0524] Final R indices [I>2sigma(I)] Rl = 0.0358, wR2 = 0.0925 R indices (all data) Rl = 0.0440, wR2 = 0.0978
With 1,10-Phenanthroline; potassium carbonate; Selectfluor; copper(l) chloride; In nitromethane; at 90℃; for 6h;Sealed tube;
General procedure: To a 5 mL screw-capped vial equipped with a 15×10 mm spinvane triangular-shaped Teflon stirbar, simple arene 1(0.5 mmol), saccharin (1.0 mmol), Selectfluor (1.0 mmol), K2CO3 (1.0 mmol) and CuCl (0.1 mmol) were added in nitromethane (3.0 mL). The mixture was sealed with aTeflon-lined cap and stirred at 90 C for 6.0 h (monitoredby TLC), extracted with dichloromethane (5×3 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash silica gel column chromatography to give aromatic amine 2. The characterizations of aromatic amines 2 and 4 were listed in the Supporting Information online.
4-(1-pyrrolidinyl)pyridinium saccharinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
In tetrahydrofuran; at 60℃;
General procedure: The 100mL round bottomed flask was charged with pyridine derivatives (or pyridine) (4.09mmol) and equimolar of saccharin (4.09mmol, 500mg) followed by the addition of 20mL THF as solvent. Then the reaction mixture was set to react in THF, at ca. 60°C for overnight. After the reaction, the solvent was removed by vacuum. The crude product was then obtained. Recrystallization proceeded with dissolution of crude product in methanol to form a saturated solution, to which a hexane overlayer (ca. 10cm high) was added. Solvent diffusion over a period of a week at room temperature afforded white crystals of the desired salt.
2-N,N-dimethylaminopyridinium saccharinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.4%
In tetrahydrofuran; at 60℃;
General procedure: The 100mL round bottomed flask was charged with pyridine derivatives (or pyridine) (4.09mmol) and equimolar of saccharin (4.09mmol, 500mg) followed by the addition of 20mL THF as solvent. Then the reaction mixture was set to react in THF, at ca. 60C for overnight. After the reaction, the solvent was removed by vacuum. The crude product was then obtained. Recrystallization proceeded with dissolution of crude product in methanol to form a saturated solution, to which a hexane overlayer (ca. 10cm high) was added. Solvent diffusion over a period of a week at room temperature afforded white crystals of the desired salt.
<strong>[171596-29-5]Tadalafil</strong> (purchased from Pall Pharma) (1000mg) and Saccharin (purchased from Aldrich) (940.8 mg) was added to acetonitrile (ACN) solvent (280 ml) and stirred at 25 C for about 30 minutes to prepare a mixed solution in which tadalafil and saccharin were dissolved. The solution was rotary evaporated at 25C for 1 hour and 40 minutes, and the resulting powder was dried (60 , 24 hours) in a drying oven to obtain a talar flav: saccharin (1: 2) co-crystal.
Example 3: Preparation and Characterization of tenofovir alafenamide saccharin Tenofovir alafenamide free base was suspended in 5 volumes of butyl acetate and 1 equivalent of saccharin was added as a solid. The slurry was treated by sonication. The solid obtained was isolated by filtration to give crystalline tenofovir alafenamide saccharin. NMR spectrum indicated 1 equivalent of saccharin. The XRPD is shown in Figure 9. The same XRPD pattern was obtained after storage at 40 °C 75percentRH for 14 days. Prominent peaks were selected from observed peaks by identifying substantially non- overlapping, low-angle peaks with strong intensity. The prominent peaks of tenofovir alafenamide saccharin include: 7.3, 14.4, 16.0, and 18.6 ± 0.2° 2 Theta. The observed peaks of tenofovir alafenamide saccharin are shown in Table 3. Table 3. Observed peaks in the XRPD pattern of tenofovir alafenamide saccharin Figure 23 shows the experimental differential scanning calorimetry (DSC) and Thermo- gravimetric Analysis (TGA) of TAF saccharin. TGA indicated no weight loss upon heating. DSC showed a sharp endotherm with melting onset at aboutl25 °C.
2-(5-bromoquinolin-2-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With C10H3F6IO4; In ethyl acetate; at 60℃; for 8h;
General procedure: quinoline 1a (64.5 mg, 0.5 mmol), saccharin 2a (100.6 mg, 0.55 mmol) and PhI(OCOCF3)2 (430.0 mg, 1.0 mmol) were added to EtOAc2 (3 mL). The mixture was stirred at 60 oC for 8.0 h (monitored by TLC), quenched with water, extracted with dichloromethane (5×3 ml), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by a shot flash silica gel column chromatography (EtOAc/petro ether = 1:6) to give compound 3a as a white solid (97.2 mg, 79%).
2-(6-fluoroquinolin-2-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With C10H3F6IO4; In ethyl acetate; at 60℃; for 8h;
General procedure: quinoline 1a (64.5 mg, 0.5 mmol), saccharin 2a (100.6 mg, 0.55 mmol) and PhI(OCOCF3)2 (430.0 mg, 1.0 mmol) were added to EtOAc2 (3 mL). The mixture was stirred at 60 oC for 8.0 h (monitored by TLC), quenched with water, extracted with dichloromethane (5×3 ml), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by a shot flash silica gel column chromatography (EtOAc/petro ether = 1:6) to give compound 3a as a white solid (97.2 mg, 79percent).
2-(8-fluoroquinolin-2-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With C10H3F6IO4; In ethyl acetate; at 60℃; for 8h;
General procedure: quinoline 1a (64.5 mg, 0.5 mmol), saccharin 2a (100.6 mg, 0.55 mmol) and PhI(OCOCF3)2 (430.0 mg, 1.0 mmol) were added to EtOAc2 (3 mL). The mixture was stirred at 60 oC for 8.0 h (monitored by TLC), quenched with water, extracted with dichloromethane (5×3 ml), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by a shot flash silica gel column chromatography (EtOAc/petro ether = 1:6) to give compound 3a as a white solid (97.2 mg, 79percent).
2-(8-chloroquinolin-2-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With C10H3F6IO4; In ethyl acetate; at 60℃; for 8h;
General procedure: quinoline 1a (64.5 mg, 0.5 mmol), saccharin 2a (100.6 mg, 0.55 mmol) and PhI(OCOCF3)2 (430.0 mg, 1.0 mmol) were added to EtOAc2 (3 mL). The mixture was stirred at 60 oC for 8.0 h (monitored by TLC), quenched with water, extracted with dichloromethane (5×3 ml), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by a shot flash silica gel column chromatography (EtOAc/petro ether = 1:6) to give compound 3a as a white solid (97.2 mg, 79%).
2-(quinazolin-2-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With C10H3F6IO4; In ethyl acetate; at 60℃; for 8h;
General procedure: <strong>[253-82-7]qui</strong>noline 1a (64.5 mg, 0.5 mmol), saccharin 2a (100.6 mg, 0.55 mmol) and PhI(OCOCF3)2 (430.0 mg, 1.0 mmol) were added to EtOAc2 (3 mL). The mixture was stirred at 60 oC for 8.0 h (monitored by TLC), quenched with water, extracted with dichloromethane (5×3 ml), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by a shot flash silica gel column chromatography (EtOAc/petro ether = 1:6) to give compound 3a as a white solid (97.2 mg, 79%).
tert-butyl 2-({2-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfamoyl]benzoyl}methylamino)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
General procedure: A mixture of Ph3P (3148 mg, 12 mmol, 1 equiv) and hexachloroethane (2982 mg, 12.6 mmol, 1.05 equiv) in CHCl3 (total volume 40 mL) was stirred at 65 C for 8 h. After cooling to r.t., under N2, to the mixture was added saccharin (7690 mg, 42.0 mmol, 3.5 equiv) in one portion, followed by the addition of the stock solution of DIPEA in CHCl3 (1.32 M, 59 mL, 78 mmol, 6.5 equiv). The resulting mixture was heated under N2 at 60 C for 6 h. The mixture was cooled to r.t. and filtered under N2. The solid crude was washed with CHCl3 (3 × 5 mL) and dried under vacuum. The dry solid (5410 mg) was kept under N2. No further separation was attempted, and the resulting solid was used directly in the parallel chemistry. The total yield from Ph3P to the solid was assumed to be 100%, thus the theoretical amount of the ?active? mixture of 13 and 14 was 451 mg/mol. Parallel Chemistry; General Procedure (Scheme 5) Under N2, to a mixture of the dry solid 13/14 (226 mg, 0.5 mmol) was added a stock solution of DIPEA (1.5 M, 2.17 mL, 3.25 mmol, 6.5 equiv) in CHCl3 at r.t. The mixture was stirred at r.t. for 5 min before a solution of the appropriate amine (1.0 mmol, 2 equiv) in CHCl3 (2 mL) was added. If the amine was in the form of HCl salt, 1 equiv extra of DIPEA was added to the reaction mixture. The resulting mixture was stirred at r.t. for 20 h, and then heated at 60 C for 15 min. The solvents were evaporated, and the dry residue was dissolved in DMSO (4 mL). The DMSO solution was submitted to purification group for isolation.
2-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfamoyl]-N-[(4-methoxyphenyl)methyl]-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
General procedure: A mixture of Ph3P (3148 mg, 12 mmol, 1 equiv) and hexachloroethane (2982 mg, 12.6 mmol, 1.05 equiv) in CHCl3 (total volume 40 mL) was stirred at 65 °C for 8 h. After cooling to r.t., under N2, to the mixture was added saccharin (7690 mg, 42.0 mmol, 3.5 equiv) in one portion, followed by the addition of the stock solution of DIPEA in CHCl3 (1.32 M, 59 mL, 78 mmol, 6.5 equiv). The resulting mixture was heated under N2 at 60 °C for 6 h. The mixture was cooled to r.t. and filtered under N2. The solid crude was washed with CHCl3 (3 × 5 mL) and dried under vacuum. The dry solid (5410 mg) was kept under N2. No further separation was attempted, and the resulting solid was used directly in the parallel chemistry. The total yield from Ph3P to the solid was assumed to be 100percent, thus the theoretical amount of the ?active? mixture of 13 and 14 was 451 mg/mol. Parallel Chemistry; General Procedure (Scheme 5) Under N2, to a mixture of the dry solid 13/14 (226 mg, 0.5 mmol) was added a stock solution of DIPEA (1.5 M, 2.17 mL, 3.25 mmol, 6.5 equiv) in CHCl3 at r.t. The mixture was stirred at r.t. for 5 min before a solution of the appropriate amine (1.0 mmol, 2 equiv) in CHCl3 (2 mL) was added. If the amine was in the form of HCl salt, 1 equiv extra of DIPEA was added to the reaction mixture. The resulting mixture was stirred at r.t. for 20 h, and then heated at 60 °C for 15 min. The solvents were evaporated, and the dry residue was dissolved in DMSO (4 mL). The DMSO solution was submitted to purification group for isolation.
2-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfamoyl]-N-(4-hydroxybutyl)-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
General procedure: A mixture of Ph3P (3148 mg, 12 mmol, 1 equiv) and hexachloroethane (2982 mg, 12.6 mmol, 1.05 equiv) in CHCl3 (total volume 40 mL) was stirred at 65 C for 8 h. After cooling to r.t., under N2, to the mixture was added saccharin (7690 mg, 42.0 mmol, 3.5 equiv) in one portion, followed by the addition of the stock solution of DIPEA in CHCl3 (1.32 M, 59 mL, 78 mmol, 6.5 equiv). The resulting mixture was heated under N2 at 60 C for 6 h. The mixture was cooled to r.t. and filtered under N2. The solid crude was washed with CHCl3 (3 × 5 mL) and dried under vacuum. The dry solid (5410 mg) was kept under N2. No further separation was attempted, and the resulting solid was used directly in the parallel chemistry. The total yield from Ph3P to the solid was assumed to be 100%, thus the theoretical amount of the ?active? mixture of 13 and 14 was 451 mg/mol. Parallel Chemistry; General Procedure (Scheme 5) Under N2, to a mixture of the dry solid 13/14 (226 mg, 0.5 mmol) was added a stock solution of DIPEA (1.5 M, 2.17 mL, 3.25 mmol, 6.5 equiv) in CHCl3 at r.t. The mixture was stirred at r.t. for 5 min before a solution of the appropriate amine (1.0 mmol, 2 equiv) in CHCl3 (2 mL) was added. If the amine was in the form of HCl salt, 1 equiv extra of DIPEA was added to the reaction mixture. The resulting mixture was stirred at r.t. for 20 h, and then heated at 60 C for 15 min. The solvents were evaporated, and the dry residue was dissolved in DMSO (4 mL). The DMSO solution was submitted to purification group for isolation.
N-(1,3-dihydroisobenzofuran-5-yl)-2-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfamoyl]benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
General procedure: A mixture of Ph3P (3148 mg, 12 mmol, 1 equiv) and hexachloroethane (2982 mg, 12.6 mmol, 1.05 equiv) in CHCl3 (total volume 40 mL) was stirred at 65 C for 8 h. After cooling to r.t., under N2, to the mixture was added saccharin (7690 mg, 42.0 mmol, 3.5 equiv) in one portion, followed by the addition of the stock solution of DIPEA in CHCl3 (1.32 M, 59 mL, 78 mmol, 6.5 equiv). The resulting mixture was heated under N2 at 60 C for 6 h. The mixture was cooled to r.t. and filtered under N2. The solid crude was washed with CHCl3 (3 × 5 mL) and dried under vacuum. The dry solid (5410 mg) was kept under N2. No further separation was attempted, and the resulting solid was used directly in the parallel chemistry. The total yield from Ph3P to the solid was assumed to be 100%, thus the theoretical amount of the ?active? mixture of 13 and 14 was 451 mg/mol. Parallel Chemistry; General Procedure (Scheme 5) Under N2, to a mixture of the dry solid 13/14 (226 mg, 0.5 mmol) was added a stock solution of DIPEA (1.5 M, 2.17 mL, 3.25 mmol, 6.5 equiv) in CHCl3 at r.t. The mixture was stirred at r.t. for 5 min before a solution of the appropriate amine (1.0 mmol, 2 equiv) in CHCl3 (2 mL) was added. If the amine was in the form of HCl salt, 1 equiv extra of DIPEA was added to the reaction mixture. The resulting mixture was stirred at r.t. for 20 h, and then heated at 60 C for 15 min. The solvents were evaporated, and the dry residue was dissolved in DMSO (4 mL). The DMSO solution was submitted to purification group for isolation.
N-allyl-2-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfamoyl]-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
General procedure: A mixture of Ph3P (3148 mg, 12 mmol, 1 equiv) and hexachloroethane (2982 mg, 12.6 mmol, 1.05 equiv) in CHCl3 (total volume 40 mL) was stirred at 65 C for 8 h. After cooling to r.t., under N2, to the mixture was added saccharin (7690 mg, 42.0 mmol, 3.5 equiv) in one portion, followed by the addition of the stock solution of DIPEA in CHCl3 (1.32 M, 59 mL, 78 mmol, 6.5 equiv). The resulting mixture was heated under N2 at 60 C for 6 h. The mixture was cooled to r.t. and filtered under N2. The solid crude was washed with CHCl3 (3 × 5 mL) and dried under vacuum. The dry solid (5410 mg) was kept under N2. No further separation was attempted, and the resulting solid was used directly in the parallel chemistry. The total yield from Ph3P to the solid was assumed to be 100%, thus the theoretical amount of the ?active? mixture of 13 and 14 was 451 mg/mol. Parallel Chemistry; General Procedure (Scheme 5) Under N2, to a mixture of the dry solid 13/14 (226 mg, 0.5 mmol) was added a stock solution of DIPEA (1.5 M, 2.17 mL, 3.25 mmol, 6.5 equiv) in CHCl3 at r.t. The mixture was stirred at r.t. for 5 min before a solution of the appropriate amine (1.0 mmol, 2 equiv) in CHCl3 (2 mL) was added. If the amine was in the form of HCl salt, 1 equiv extra of DIPEA was added to the reaction mixture. The resulting mixture was stirred at r.t. for 20 h, and then heated at 60 C for 15 min. The solvents were evaporated, and the dry residue was dissolved in DMSO (4 mL). The DMSO solution was submitted to purification group for isolation.
A suspension of <strong>[641571-10-0]Nilotinib</strong> (12.08 g, 22.81 mmol) in methanol (250 mL) was heated to 30 C. To this suspension was added saccharin (9.64 g, 52.62 mmol) and the suspension was heated to 60 C. The clear solution was maintained at 60 C for 1 hour, cooled to 50 C and maintained for 1 .5 hours. The slurry was then cooled to 40 C and maintained for 1 hour. The slurry was again cooled to 30 C, maintained for 1 hour, cooled to 20 C and maintained for 1 hour further. The white suspension was filtered and the filter cake was washed with cold (0 C) methanol (3 x 15 mL). The damp solid was dried under high vacuum at 30 C for 13 hours to afford <strong>[641571-10-0]Nilotinib</strong> saccharinate Form APO-II as a white solid (14.14 g, 87 % yield). Figure 8 depicts a PXRD diffractogram of a sample prepared by this method.
[Pd(saccharinate)2(1,4-bis(diphenylphosphino)butane)]*DMF[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
General procedure: A 5mL aqueous solution of SacH (0.5mmol) and a 50mL solution of Pd(OAc)2 (0.25mmol) in MeCN were mixed and stirred for 30minat rt. Then, dppp or <strong>[7688-25-7]dppb</strong> (0.25mmol) dissolved in MeCN (10mL) was added this solution and stirred for 6h. The powders of neutral Pd(II) complexes (1 and 5) were obtained after removal of the solvents using a rotary evaporator. Then, 1 was crystallized from a mixture of MeOH/CHCl3, while 5 was crystallized from DMF.
With scandium tris(trifluoromethanesulfonate); at 150℃; for 24.0h;Sealed tube;
174 mg of <strong>[1117-31-3]1,3-butanediol diacetate</strong> 1u was sequentially added to a 5 mL sample vial.91.5 mg saccharin 2f, 5.0 mg bismuth triflate.The seal was heated to 150 C and stirred for 24 hours.Saccharin 2f replaces the ester group of <strong>[1117-31-3]1,3-butanediol diacetate</strong> 1u,Column chromatography (petroleum ether: ethyl acetate = 5:1) gave the product 3uf.In the amino alcohol derivative, the amino group is derivatized as a sulfonamide group.And retain at least one carboxylate group. The isolated yield was 12%.
Weigh 1.43 g of <strong>[122320-73-4]rosiglitazone</strong> and 0.73 g of saccharin, add 20 mL of acetone to obtain a suspension, and place the suspension in the room.After stirring for 5 h, it was filtered, and the obtained white solid was dried at 70 C for 48 h to obtain a solid sample of <strong>[122320-73-4]rosiglitazone</strong> saccharin salt.
General procedure: Complexes 4, 6, 8 and 10-12 were prepared by the following method. SacH (0.5mmol, 91.6mg) in water (5mL) was added to a solution of Pd(OAc)2 (0.25mmol, 56.1mg) in MeCN (10mL) and the solution was stirred for 30min at rt. Then, the corresponding phosphine (0.5mmol) in MeOH (10mL) was added to this solution and the resulting solutions were refluxed over a day. Complexes 2, 5 and 9 were synthesized using the same procedure, but the SacH/phosphine ratio was 2:1. In the case of 9, DMSO (10mL) was added to the reaction medium to dissolve the solid particles. The powders of these complexes were obtained after removal of the solvents using a rotary evaporator.
General procedure: Complexes 4, 6, 8 and 10-12 were prepared by the following method. SacH (0.5mmol, 91.6mg) in water (5mL) was added to a solution of Pd(OAc)2 (0.25mmol, 56.1mg) in MeCN (10mL) and the solution was stirred for 30min at rt. Then, the corresponding phosphine (0.5mmol) in MeOH (10mL) was added to this solution and the resulting solutions were refluxed over a day. Complexes 2, 5 and 9 were synthesized using the same procedure, but the SacH/phosphine ratio was 2:1. In the case of 9, DMSO (10mL) was added to the reaction medium to dissolve the solid particles. The powders of these complexes were obtained after removal of the solvents using a rotary evaporator.
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