* 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 triethylamine; In dichloromethane; at 0℃; for 2h;
To a solution of 3-methanesulfonyl-propan-1-ol (Cambridge) (0.5 g, 3.6 mmol) in dichloromethane (3 mL) at 0 C. was added triethylamine (0.5 g, 5 mmol), and methanesulfonyl chloride (0.3 mL, 4 mmol, Aldrich). The reaction mixture was stirred at 0 C. for 2 h. The mixture was poured into water, extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give crude methanesulfonic acid 3-methanesulfonyl-propyl ester as a yellow oil (Yield 0.7 g, 90%).
With triethylamine; In dichloromethane; at 30℃; for 12h;
To a solution of 3-methylsulfonylpropan-l-ol (200 mg, 1.45 mmol) in DCM (5 mL) was added Et3N (732 mg, 23.5 mmol) and methanesulfonyl chloride (2.84 g, 24.9 mmol). The mixture was stirred at 30 C for 12 hrs, and then partitioned between H20 (20 mL) and DCM (60 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude 3-methylsulfonylpropyl methane sulfonate (300 mg) as a yellow oil, which was used directly in the next step without further purification.
With triethylamine; In dichloromethane; at 20℃; for 1h;
The mixture of the compound 47 (0.100g), methanesulfonyl chloride (0.067 mL), triethylamine (0.120 mL), and a methylene chloride (2.0 mL) was stirred at the room temperature for 1 hour. Water was added to reaction mixed liquor and ethyl acetate extracted. The organic layer was concentrated in vacuum and the rough product of the title compound 48 was obtained. The whole quantity was then used to the next reaction.
Thioacetic S-acid (1.3 g) in dry pyridine (30 ml) was added to impure sulfone methanesulfonate (3.7 g) from step (B) and the reaction mixture stirred at room temperature for 2 days. Chloroform (200 ml) was added and the resultant mixture washed with 2.5% hydrochloric acid (100 ml aliquots) until the aqueous pH remained acidic. The organic layer was dried (MgSO4), filtered and concentrated. Crude sulfone thioacetate was chromatographed on silica gel (250 g) employing 1:1 light petroleum/chloroform (100 ml fractions) for elution. Fractions 53-72 were combined and concentrated yielding clean S-4-thiapentyl thioacetate 4,4-dioxide (0.93 g, 4.7 mmol, 8% from 4-thiapentan-1-ol). Recrystallized (methanol) sulfone thioacetate had m.p. 61.8-62.7 C. (Found: C, 36.8; H, 6.1. C6H1203S2 requires C, 36.7; H, 6.2%). l.r. (KBr) 1690, 1300, 1160, 1130 cm--1. 1H n.m.r.(270 MHz) delta2.15, quin, 2H; 2.36, s, 3H; 2.92, s, 3H; 3.04, m, 4H. m/z 196 (6%, M+'), 116 (39), 43 (100).
Impure sulphide methanesulfonate (3.8 g) from step (A) was dissolved in chloroform (75 ml), and the solution added dropwise to 10% sulfuric acid (104 ml). During the addition, solid potassium permanganate (13.7 g) was also added in small portions. Upon completion of the additions, the reaction mixture was stirred at ambient temperature for 2 days. The reaction mixture was cooled with an ice/water bath and sodium bisulfite added in small portions until the reaction mixture was decolorized. The layers were separated and the aqueous layer was extracted with chloroform (three 100 ml aliquots). The combined organic layers were concentrated affording impure sulfone methanesulfonate (3.7 g).
racemic (2'R,3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione[ No CAS ]
[ 357913-53-2 ]
racemic (2'R,3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1-(3-methanesulfonyl-propyl)-4-piperidinyloxy]-phenyl}spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In ethanol; at 68℃; for 18.0h;
EXAMPLE 12a Preparation of racemic(2'R,3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1-(3-methanesulfonyl-propyl)-4-piperidinyloxy]-phenyl}spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione To a solution of racemic(2'R,3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione (0.1 g, 0.15 mmol) prepared in example 5a in ethanol (2 mL) was <strong>[357913-53-2]methanesulfonic acid 3-methanesulfonyl-propyl ester</strong> (54 mg, 0.25 mmol) (WO2001062668) and triethylamine (0.031 mL, 0.225 mmol). The reaction mixture was heated at 68 C. for 18 h, then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give crude racemic(2'R,3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1-(3-methanesulfonyl-propyl)-4-piperidinyloxy]-phenyl}spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione as a light yellow solid (Yield 0.1 g)
With triethylamine; In dichloromethane; at 0 - 20℃;
4-amino-N-[1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-3-methoxy-benzamide To a cooled (0 degrees) mixture of 3.7 g (0.019 mole) of piperidin-4-yl-carbamic acid tert-butyl ester in 60 mL of dichloromethane, was added 2.1 g (0.020 mole) of triethylamine, followed by 4.2 g (0.017 mole) of <strong>[357913-53-2]3-(methylsulfonyl)-1-propanol-1-methanesulfonate</strong>. The mixture was stirred at room temperature for 18 hours, then diluted with water and the organic layer washed twice with 40 mL of water, once with 40 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluding with dichloromethane-methanol (gradient, 100:0-90:10) to give 3.6 g of [1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester.
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4.0h;
To a solution of 3-methoxy-4-nitrophenol (0.5 g, 3 mmol) prepared in Example 132 Step A in anhydrous DMF (25 mL) were added K2CO3 (0.8 g, 5.9 mmol) and <strong>[357913-53-2]methanesulfonic acid 3-methanesulfonyl-propyl ester</strong> (0.7 g, 3.2 mmol) sequentially. The reaction mixture was heated at 70 C. for 4 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 2-methoxy-4-(3-(methylsulfonyl)propoxy)-1-nitrobenzene as a off white solid (0.58 g, 68%).
With caesium carbonate; In acetone; for 18.0h;Reflux;
1-({4-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-3-[3-(methylsulfonyl)propoxy]thien-2-yl}carbonyl)-4-phenylpiperidine-4-carboxamide 0.148 g of 3-(methylsulfonyl)propylmethanesulfonate and 0.294 g of Cs2CO3 are added to a mixture of 0.200 g of the compound of preparation 4.1 in 15 ml of acetone. The mixture is refluxed for 18 hours. Filtration by suction and concentration are carried out. The reaction crude is purified by silica gel chromatography, elution being carried out with DCM and then with a DCM/MeOH mixture (97/3; v/v). 0.065 mg of the expected compound is obtained.
methyl {(S)-6-[(R)-5-cyano-4-(4-hydroxy-2,6-dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate[ No CAS ]
[ 357913-53-2 ]
methyl ((S)-6-{(R)-5-cyano-4-[4-(3-methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45 mg
With caesium carbonate; In N,N-dimethyl-formamide; for 3.0h;
{(S)-6-[(R)-5-Cyano-4-(4-hydroxy-2,6-dimethyl-phenyl)-indan-1 -yloxy]-2,3-dihydro- benzofuran-3-yl}-acetic acid methyl ester (1 12 mg), methanesulfonic acid 3- methanesulfonyl-propyl ester (Moltzen, Ejner K et al. Journal of Medicinal Chemistry, 1995 , v o l . 3 8 , 1 1 p . 2 0 0 9 - 2017) ( 73 . 5 m g ) and cesium carbonate (150 mg) are stirred in 2 ml_ of Nu,Nu-dimethylformamide for 3 h. The reaction mixture is concentrated under vacuum, the residue obtained is dissolved in dichloromethane and the organic phase is washed with water, dried over sodium sulfate and concentrated under vacuum The residue is purified by flash chromatography (cyclohexane/ethyl acetate 100:0?70.30) to give the title compound. Yield: 45 mg.
With caesium carbonate; In N,N-dimethyl acetamide; at 80℃; for 3.0h;
5-Bromo-1,3-difluoro-2-(3-methanesulfonyl-propoxy)-benzene A mixture of 4-bromo-2,6-difluoro-phenol (500 mg), <strong>[357913-53-2]methanesulfonic acid 3-methanesulfonyl-propyl ester</strong> (517 mg), and cesium carbonate (1.56 g) in N,N-dimethylacetamide (10 mL) is heated to 80 C. for 3 h. The reaction mixture diluted with water and extracted with ethyl acetate. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0?80:20) to give the title compound.
N3-[6-chloro-4'-(piperidin-4-yloxy)-2-trifluoromethylbiphenyl-4-yl]-1H-[1,2,4]triazole-3,5-diamine hydrochloride[ No CAS ]
[ 357913-53-2 ]
N3-{6-chloro-4'-[1-(3-methanesulfonylpropyl)piperidin-4-yloxy]-2-trifluoromethylbiphenyl-4-yl}-1H-[1,2,4]triazole-3,5-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 20.0h;
To a suspension of compound 139, N3-(2-chloro-4'-(piperidin-4-yloxy)-6- (trifiuoromethyl)biphenyl-4-yl)-lH-l ,2,4-triazole-3,5-diamine hydrochloride (80 mg, 1 63 iimol. Eq: 1 .00) in dichloromethane (3.00 ml ) were added 3-(methylsulfonyi)propyl methanesuifonate ( 1 06 mg, 490 iimol, Eq : 3) and. N-ethyi-N-isopropylpropan-2-amine ( 1 06 mg, 142 mu, 817 iimol, Eq: 5). The reaction mixture was stirred at room temperature for 20 h. DMF (3 mL) was added. The reaction mixture was heated at 80 C for 5 h. It was diluted with dichloromethane (50 mL), washed with water (2x20 m L). brine ( 1 0 mL), dried over MgS04and concentrated. The residue was purified by flash chromatography (silica gel, 12 g, 2% to 13% methanol in dichloromethane) to give free amine as a white solid. To the solution of free amine in dichloromethane (2 mL ) was added a freshly made 1 mL of HQ (prepared from 0.3 m L of acetyl chloride added to 3 ml, of methanol ). The reaction mixture was stirred at room temperature for 2 h, and then concentrated in vacuo. The residue was triturated with methanol methyl tert-butyl ether. The resulting solid was filtered, washed with methyl tert-butyl ether and dried to afford 1 7 mg (17%) of the desired product as an off-white solid.MS +m/z: 573.0 ( M + H )
ethyl 9-hydroxy-10-methoxy-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylate[ No CAS ]
[ 357913-53-2 ]
ethyl 10-methoxy-9-(3-methylsulfonylpropoxy)-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 30℃; for 12.0h;
To a solution of ethyl 9-hydroxy-10-methoxy-2-oxo-6-(2-thienyl)-6,7- dihydrobenzo[a]quinolizine-3-carboxylate (100 mg, 0.251 mmol) in DMF (3 mL) was added K2CO3 (69.6 mg, 0.503 mmol) and 3-methylsulfonylpropyl methane sulfonate (81.6 mg, 0.377 mmol). The mixture was stirred at 30 C for 12 hrs, and then partitioned between H20 (50 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude ethyl 10-methoxy-9- (3-methylsulfonylpropoxy)-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylate (90 mg) as a yellow oil, which was used directly in the next step without further purification.
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2.0h;
Compound I-k (0.048g), the compound 48 of the reference example 15, cesium carbonate (0.088g), and the mixture of DMF (1.0 mL) were stirred at 90 degrees C for 2 hours. Water was added to reaction mixed liquor and ethyl acetate extracted. the rough product of compound II-k obtained by concentrating an organic layer in vacuum after drying with anhydrous sodium sulfate -- the whole quantity -- it used to the next reaction.
With triethylamine; In dichloromethane; at 20℃; for 16.0h;
General procedure: TEA 4.4 mL (32 mmol) and methanesulfonyl chloride 1.4 mL (18 mmol) were added to a methylene chloride (30 mL) solution of ethylene fluorohydrin 1.0 g (16 mmol), and the mixture was stirred at room temperature for 16 hours. After the completion of the reaction, water was added to the reaction mixture, and followed by extraction with methylene chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product 2.23 g including the title compound as a light yellow oil. Mass spectrum (CI, m/z):143[M+1]+. 1H-NMR spectrum (400MHz, CDCl3) delta:4.76 - 4.60 (m, 2H), 4.53 - 4.41 (m, 2H), 3.08 (s, 3H).
15
ethyl 3-(2-fluoro-4-((7-hydroxychroman-2-yl)methoxy)phenyl)propanoate[ No CAS ]
[ 357913-53-2 ]
ethyl 3-(2-fluoro-4-((7-(3-(methylsulfonyl)propoxy)chroman-2-yl)methoxy)phenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3.0h;
General procedure: To a DMF (5mL) solution of compound 18 (100mg, 0.27mmol) were added potassium carbonate powder (75mg, 0.54mmol) and MeI (0.025mL, 0.41mmol). The resulting suspension was heated to 60C for 3h. The reaction mixture was cooled to ambient temperature and added AcOEt and water. The extracts are combined, dried over anhydrous Na2SO4. The mixture was concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether=1:10) to give compound19a(89mg, 85%) as a colorless oil.
91%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3.0h;
General procedure: ethyl 3-(4-((7-hydroxychroman-2-yl)methoxy)-2-fluorophenyl)propanoate (100 mg, 0.27 mmol) was dissolved in dry N,N -dimethylformamide (5 mL), Potassium carbonate (75 mg, 0.54 mmol) and iodomethane (0.025 mL, 0.41 mmol) were added and heated to 60 C. After 3 h, The reaction was monitored by TLC (petroleum ether/ethyl acetate = 5/1) and the starting material was completely reacted. Cooled to room temperature, diluted with water, the reaction solution was extracted twice with ethyl acetate, combined and washed with water and saturated brine, dry over anhydrous sodium sulfate and filtered. The solvent was evaporated, column chromatography (petroleum ether / ethyl acetate = 10/1) to give 89 mg of colorless liquid, yield 85%.
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