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CAS No. : | 94594-90-8 | MDL No. : | MFCD00066271 |
Formula : | C10H17NO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 215.31 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 59.0 |
TPSA : | 54.55 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.52 cm/s |
Log Po/w (iLOGP) : | 1.49 |
Log Po/w (XLOGP3) : | 1.54 |
Log Po/w (WLOGP) : | 1.81 |
Log Po/w (MLOGP) : | 1.2 |
Log Po/w (SILICOS-IT) : | 1.23 |
Consensus Log Po/w : | 1.46 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.15 |
Solubility : | 1.54 mg/ml ; 0.00716 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.29 |
Solubility : | 1.09 mg/ml ; 0.00507 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.37 |
Solubility : | 0.927 mg/ml ; 0.00431 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.84 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313 | UN#: | |
Hazard Statements: | H315-H319 | Packing Group: | |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.7% | Stage #1: With potassium hydroxide; dihydrogen peroxide In n-heptane; diethylene glycol dimethyl ether; water at 17℃; for 11 h; Stage #2: With hydrogenchloride; sodium sulfite In diethylene glycol dimethyl ether; water at 5 - 21℃; for 1.58333 h; |
In a round-bottomed flask, 40.00 g (0.105 mol) of (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide and 160 ml of diglyme were placed, and the mixture was cooled to 17° C. while nitrogen was being sent thereto with the intention of limiting the concentration of oxygen to 5percent or less until the end of the reaction. After 0.51 g (0.005 mol) of 35percent hydrogen peroxide solution was inpoured, 15.79 g (0.162 mol) of 35percent aqueous hydrogen peroxide solution and 19.61 g (0.168 mol) of 48percent aqueous potassium hydroxide solution were simultaneously inpoured at 17° C. over 9 hours, followed by stirring at 17° C. for 2 hours, and the end of the reaction was checked by HPLC.Separately, 21.14 g (0.168 mol) of sodium sulfite was dissolved in 110 ml of water in a flask with a stop-cock at room temperature, 58.97 g (0.566 mol) of 35percent hydrochloric acid was added dropwise at 9 to 10° C., and then the above-mentioned reaction mixture was added dropwise thereto at 5 to 12° C. over 1 hour. After the resultant mixture was heated to 21° C. and stirred at the same temperature for 35 min, 200 ml of methyl tert-butyl ether was inpoured thereto, the mixture was stirred for 10 min, and the water layer was removed by separation. The organic layer was washed with saline solution (1.60 g NaCl, 200 ml tap water), 2.40 g of n-heptane and saline solution (1.60 g NaCl, 200 ml tap water) were added thereto, the mixture was stirred for 15 min, the water layer was removed by separation, and the end of washing was checked by GC. The organic layer was concentrated at normal pressures, and 240 ml of n-heptane was added to the obtained residue, which was then vacuum-concentrated until the residue was reduced to about 160 ml. Then, the residue was cooled and stirred at 0 to 10° C. for 30 minutes. The obtained crystal was filtered, washed with 40 ml of n-heptane, and dried under reduced pressure. Thus, 6.48 g of camphorsultam (yield based on (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide: 28.7percent; GC area percentage value: 98.23percent) was obtained. (1S)-2,10-camphorsulfonimine (imine form) was contained in the recovered camphorsultam and couldn't be removed by purification.Meanwhile, the filtrate was concentrated under reduced pressure and n-heptane was added thereto, to obtain 72.17 g (corresponding to 0.105 mol) of (2S)-2-(2-propenyl) octanoic acid/heptane solution. From this of which amount was corresponding to 0.087 mol, cyclohexylamine salt of (2S)-2-(2-propenyl) octanoic acid was derived.In a round-bottomed flask, 241 ml of ethyl acetate, 7.78 g (0.078 mol) of cyclohexylamine were placed and 9.00 g (0.013 mol) of (2S)-2-(2-propenyl) octanoic acid/heptane solution was added dropwise thereto at 20° C. over a 30 minute period, followed by stirring at 20 to 21° C. for 1 hour. Further, 51.00 g (corresponding to 0.074 mol) of (2S)-2-(2-propenyl) octanoic acid/heptane solution was added dropwise thereto at 20° C. over 2 hour 30 min. Then, the mixture was cooled and kept within the range of -3 to 3° C. for 1 hour. The crystal was collected by filtration, washed with 64 ml of cooled ethyl acetate, and dried under reduced pressure. Thus, 20.29 g of cyclohexylamine salt of (2S)-2-(2-propenyl) octanoic acid (yield based on (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide: 82.1percent; optical purity: 100percent) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: With sodium hydride In toluene for 1.5 h; Stage #2: at 20℃; |
Example 2(R)-5-Methyl-4,5-dihydro-pyrazole-1 ,5-dicarboxylic acid 1 -[(4-chloro-phenyl)-amide] 5-[2-fluoro-4- (2-oxo-2H-pyridin-1-yl)-phenyl]-amide}Step 1. Synthesis of (3aS,6R,7aR)-1-methacryloyl-8,8-dimethylhexahydro-3a,6-methano-2,1- benzisothiazole 2,2-dioxide(1 S)-(-)-2,10-camphorsultamProcedure: To a solution of (1S)-(-)-2,10-camphorsultam (1.160g, 5.388 mmoles) in toluene (10ml) was added sodium hydride (60percent in oil, 0.323g, 8.08 mmoles). Stirred for 1.5 hours Added methacryoyl chloride (1.126g, 10.78 mmoles) directly to the reaction mixture. Stirred at room temperature overnight, Evaporated, extracted into ethylacetate, washed with 1 N HCI, dried MgSO4, evaporated in vacuo and purified by chromatography (0-20percent EtOAc in hexane) to afford the desired compound (1.24Og, 81percent) 1 H NMR (400 MHz, DMSO-D6) δ ppm 0.90 (s, 3 H), 1.08 (s, 3 H), 1.23 (m 1 H), 1.42 (m, 1 H), 1.78 (m, 5 H), 1.81 (m, 3H), 3.26 (s, 4 H), 3.56 (d, J=14.04 Hz, 1 H), 3.77 (d, J=14.04 Hz, 1 H)1 3.91 (m, 1 H), 5.48 (s, 1 H)1 5.60 (s,1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: With triethylamine; lithium chloride In tetrahydrofuran at -20℃; for 0.166667 h; Stage #2: at -20 - -10℃; for 0.0833333 h; |
Example 3Step 1. Synthesis of (3aS,6R,7aR)-1 -methacιyloyl-8,8-dimethylhexahydro-3a,6-methano-2,1- benzisothiazole 2,2-dioxide.(1 S)-(-)-2,10-camphorsultamProcedure: To a solution of the (1S)-(-)-2,10-camphorsultam (5.00Og, 23.22 mmoles) in anhydrous THF (50ml) at -20° C was added lithium chloride (1.08g, 25.5 mmoles, - small balls), triethylamine (4.21 ml, 30.2 mmoles, 1.30 equivalents.) and then the mixture was allowed to stir for 10 minutes. The lithium chloride did not go into solution. 2-methylacrylic anhydride (4.15 ml, 27.9 mmoles, 1.20 equivalents.) in THF (15ml) was then added. The internal temperature varied between -20° C and -10° C during addition which took about 5 minutes. The thick white mixture was stirred within the cooling bath and allowed to reach room temperature. After stirring overnight the white heterogeneous reaction mixture was added to 350ml of water with stirring. The white crystalline solid (3aS,6R,7aR)-1 -methacryloyl-8,8- dimethylhexahydro-3a,6-methano-2,1-benzisothiazole 2,2-dioxide (6.302g, 96percent yield) was collected and dried under vacuum.-Analytical HPLC run with a Vydac 218TP54 C18 reverse phase column run with solvents A: 0.1percent trifluoroacetic acid in H2O and B: 0.1percent trifluoroacetic acid in acetonitrile. Gradient (0 to 100percentB) over 22 minutes. Retention time 18.166 min (100percent).Optical rotation = 0.02Og in 2ml; c=0.01g/ml (C= 1 (CHCI3)}; measurement -0.226; optical rotation = - 0.226x4000/10 = - 90.4.Combustion Anal sis:Steps 2 through 5 were performed as in Example 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride; mineral oil In toluene at 20℃; for 0.5h; Stage #2: methyl iodide In toluene for 22h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With copper dichloride In benzene for 1h; Heating; | |
85% | With sodium hydride In toluene at 20℃; for 2h; | |
81% | With sodium hydride In toluene; paraffin for 1.5h; Ambient temperature; |
In toluene at 20℃; for 2h; Yield given; | ||
With sodium hydride | ||
With sodium hydride 1) toluene, 30 min; 2) toluene, overnight; Yield given. Multistep reaction; | ||
With n-butyllithium Yield given; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 90% 2: 79% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 96% 2: 50% | With diisobutylaluminium hydride In diethyl ether at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 93% 2: 91% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 88% 2: 75% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 98% 2: 84% | With L-Selectride In tetrahydrofuran for 0.5h; Ambient temperature; | |
72% | With L-Selectride In tetrahydrofuran at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With fluorine; sodium fluoride In chloroform; trichlorofluoromethane at -40℃; for 0.5h; | |
75% | With fluorine; sodium fluoride In chloroform; trichlorofluoromethane at -40℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 93% 2: 64% | With lithium hydroxide In tetrahydrofuran; water at 65℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 91% 2: 61% | With lithium hydroxide In tetrahydrofuran; water at 65℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 95% 2: 73% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0℃; for 3h; | |
73% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0℃; for 3h; Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 91% 2: 42% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0℃; for 3h; | |
42% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0℃; for 3h; Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyridine | |
95% | With pyridine | |
94% | With copper; sodium hydride; copper(l) chloride In toluene |
88% | With sodium hydride; copper(l) chloride In toluene at 0℃; | |
70% | ||
In toluene at 20℃; for 2h; Yield given; | ||
With copper(I) chloride; copper; sodium hydride 1.) mineral oil, toluene, 20 deg C, 2 h, 2.) 20 deg C, 16 h; Yield given. Multistep reaction; | ||
With sodium hydride; copper(l) chloride 1.) toluene, RT, 1 h, 2.) toluene, 15 min; Yield given. Multistep reaction; | ||
With sodium hydride 1) toluene, 30 min; 2) toluene, overnight; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: (2R)-bornane-10,2-sultam With n-butyllithium In toluene at 0 - 20℃; for 2h; Stage #2: pent-4-enoyl chloride In toluene at 20℃; | |
With sodium hydride Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With trimethylaluminum In hexane; toluene at 50℃; for 24h; | |
With trimethylaluminum 1.) hexane, toluene, r.t., 15 min.; 2.) hexane, toluene, 50 deg C, 24 h; Yield given. Multistep reaction; | ||
With trimethylaluminum |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In toluene; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: Hexanoyl chloride In toluene; mineral oil at 20℃; for 2h; Inert atmosphere; | |
88% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In tetrahydrofuran for 1.5h; Inert atmosphere; Cooling with ice; Stage #2: Hexanoyl chloride In tetrahydrofuran Inert atmosphere; | |
With sodium hydride 1.) toluene, RT, 2 h, 2.) 2 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In dichloromethane; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: chloroacetyl chloride In dichloromethane at -60 - 20℃; for 16h; Inert atmosphere; | |
84% | Stage #1: (2R)-bornane-10,2-sultam With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25h; Stage #2: chloroacetyl chloride In tetrahydrofuran; hexane at -78℃; for 0.25h; | |
With n-butyllithium 1.) THF, -78 deg C, 2.) -78 to 25 deg C, 30 min.; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In toluene Stage #2: Cinnamoyl chloride With copper(l) chloride In toluene | |
87% | With silver cyanide In toluene for 8h; Heating; | |
With sodium hydride 1) toluene, 30 min; 2) toluene, overnight; Yield given. Multistep reaction; |
With n-butyllithium Yield given; Multistep reaction; | ||
Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In toluene; mineral oil at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: Cinnamoyl chloride In toluene; mineral oil at 0 - 20℃; for 18h; | ||
With sodium hydride In toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In toluene; mineral oil at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: n-octanoic acid chloride In toluene; mineral oil at 0 - 20℃; for 27h; Inert atmosphere; | |
100% | With dmap; triethylamine In tetrahydrofuran at -5 - 0℃; for 0.5h; Large scale; | |
98.6% | With dmap; triethylamine In tetrahydrofuran at 0℃; for 1h; |
With sodium hydride 1) toluene, rt, 2 h, 2) toluene, rt, 2 h; Yield given. Multistep reaction; | ||
99.7 %Chromat. | With dmap; triethylamine In tert-butyl methyl ether at 20℃; for 1h; | 1 (1)(3aS,6R,7aR)-8,8-dimethyl-1-octanoylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide In a round-bottomed flask, 80 g of (1S)-(-)-2,10-camphorsultam, 236.4 g of methyl tert-butyl ether, 2.27 g of 4-(dimethylamino)-pyridine and 41.36 g of triethylamine were placed, and to this, 63.46 g of capryloyl chloride was added dropwise at room temperature. After stirring for 1 hour, the reaction solution was added to a mixed solution of 7.75 g of 35% hydrochloric acid and 200 g of water, and the organic layer was separated. The organic layer was washed with 25% aqueous sodium hydroxide solution and subsequently with water, and concentrated under reduced pressure. Thus, 125.34 g of the titled compound was obtained (quality: 99.7% measured by GC).Gas chromatography analysis was carried out using Shimadzu GC-14A (Column: 5% Silicone OV-17 manufactured by GL Science, Detector: FID). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydride In toluene at 20℃; | |
91% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In tetrahydrofuran; toluene at 20℃; for 1h; Stage #2: hydrocinnamic acid chloride In tetrahydrofuran; toluene for 16h; | |
84% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In toluene at 0℃; for 1h; Inert atmosphere; Stage #2: hydrocinnamic acid chloride In toluene at 0℃; for 1h; Inert atmosphere; |
75% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In toluene; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: hydrocinnamic acid chloride In toluene; mineral oil at 20℃; for 2h; Inert atmosphere; | |
With sodium hydride Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Example 2(R)-5-Methyl-4,5-dihydro-pyrazole-1 ,5-dicarboxylic acid 1 -[(4-chloro-phenyl)-amide] 5-[2-fluoro-4- (2-oxo-2H-pyridin-1-yl)-phenyl]-amide}Step 1. Synthesis of (3aS,6R,7aR)-1-methacryloyl-8,8-dimethylhexahydro-3a,6-methano-2,1- benzisothiazole 2,2-dioxide(1 S)-(-)-2,10-camphorsultamProcedure: To a solution of (1S)-(-)-2,10-camphorsultam (1.160g, 5.388 mmoles) in toluene (10ml) was added sodium hydride (60% in oil, 0.323g, 8.08 mmoles). Stirred for 1.5 hours Added methacryoyl chloride (1.126g, 10.78 mmoles) directly to the reaction mixture. Stirred at room temperature overnight, Evaporated, extracted into ethylacetate, washed with 1 N HCI, dried MgSO4, evaporated in vacuo and purified by chromatography (0-20% EtOAc in hexane) to afford the desired compound (1.24Og, 81%) 1 H NMR (400 MHz, DMSO-D6) delta ppm 0.90 (s, 3 H), 1.08 (s, 3 H), 1.23 (m 1 H), 1.42 (m, 1 H), 1.78 (m, 5 H), 1.81 (m, 3H), 3.26 (s, 4 H), 3.56 (d, J=14.04 Hz, 1 H), 3.77 (d, J=14.04 Hz, 1 H)1 3.91 (m, 1 H), 5.48 (s, 1 H)1 5.60 (s,1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tert.-butylnitrite In tetrahydrofuran at 20℃; | |
99% | With tert.-butylnitrite In tetrahydrofuran at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Example 3Step 1. Synthesis of (3aS,6R,7aR)-1 -methaciotayloyl-8,8-dimethylhexahydro-3a,6-methano-2,1- benzisothiazole 2,2-dioxide.(1 S)-(-)-2,10-camphorsultamProcedure: To a solution of the (1S)-(-)-2,10-camphorsultam (5.00Og, 23.22 mmoles) in anhydrous THF (50ml) at -20 C was added lithium chloride (1.08g, 25.5 mmoles, - small balls), triethylamine (4.21 ml, 30.2 mmoles, 1.30 equivalents.) and then the mixture was allowed to stir for 10 minutes. The lithium chloride did not go into solution. 2-methylacrylic anhydride (4.15 ml, 27.9 mmoles, 1.20 equivalents.) in THF (15ml) was then added. The internal temperature varied between -20 C and -10 C during addition which took about 5 minutes. The thick white mixture was stirred within the cooling bath and allowed to reach room temperature. After stirring overnight the white heterogeneous reaction mixture was added to 350ml of water with stirring. The white crystalline solid (3aS,6R,7aR)-1 -methacryloyl-8,8- dimethylhexahydro-3a,6-methano-2,1-benzisothiazole 2,2-dioxide (6.302g, 96% yield) was collected and dried under vacuum.-Analytical HPLC run with a Vydac 218TP54 C18 reverse phase column run with solvents A: 0.1% trifluoroacetic acid in H2O and B: 0.1% trifluoroacetic acid in acetonitrile. Gradient (0 to 100%B) over 22 minutes. Retention time 18.166 min (100%).Optical rotation = 0.02Og in 2ml; c=0.01g/ml (C= 1 (CHCI3)}; measurement -0.226; optical rotation = - 0.226x4000/10 = - 90.4.Combustion Anal sis:Steps 2 through 5 were performed as in Example 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; | |
71% | With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2h; | |
With n-butyllithium In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: bis(trichloromethyl) carbonate; (2R)-bornane-10,2-sultam With N-ethyl-N,N-diisopropylamine In diethyl ether at 0℃; for 0.25h; additional stirring 18 h at 20 deg C; Stage #2: With hydroxylamine hydrochloride; potassium carbonate In diethyl ether; water at 20℃; for 5h; | |
Stage #1: bis(trichloromethyl) carbonate; (2R)-bornane-10,2-sultam With N-ethyl-N,N-diisopropylamine In diethyl ether at 0 - 20℃; for 18h; Stage #2: With hydroxylamine hydrochloride; potassium carbonate for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.1% | Stage #1: (2R)-bornane-10,2-sultam With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25h; Stage #2: C14H23F2O6P In tetrahydrofuran at -78℃; for 1h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With lithium hydroxide; dihydrogen peroxide | |
1: 82% 2: 2.72 g | With lithium hydroxide; dihydrogen peroxide In tetrahydrofuran; water at 55℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In toluene at 20℃; for 1h; Stage #2: 2-bromoisobutyric acid bromide In toluene at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydride In dichloromethane at 0℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
69% | With potassium hexamethylsilazane In tetrahydrofuran; pyridine; toluene at 25℃; for 20h; | |
69% | With pyridine; copper(l) iodide; potassium hexamethylsilazane In toluene at 20℃; for 20.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With trimethylaluminum In toluene at 60℃; for 30h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: phthalimidyl 2-diazopropanoate In tetrahydrofuran at 20℃; for 2h; | |
1.78 g | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: phthalimidyl 2-diazopropanoate In tetrahydrofuran; mineral oil at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: (4-bromo-phenyl)-diazo-acetic acid 1,3-dioxo-1,3-dihydro-isoindol-2-yl ester In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: diazo-(3,4-dichloro-phenyl)-acetic acid 1,3-dioxo-1,3-dihydro-isoindol-2-yl ester In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: succinimidyl diazoacetate In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With trimethylaluminum In 1,2-dichloro-ethane at 85℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In toluene at 0 - 20℃; for 2h; Stage #2: (E)-2,4-Dimethyl-2-pentenoic acid chloride In toluene at 20℃; for 4h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In dichloromethane at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 88% 2: 91% | With lithium hydroxide; dihydrogen peroxide In tetrahydrofuran; water at 0℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: (2R)-bornane-10,2-sultam With methylmagnesium bromide In tetrahydrofuran; diethyl ether at 0℃; for 0.5h; Stage #2: (E)-3-benzyloxypropenoyl chloride In tetrahydrofuran; diethyl ether at 0℃; for 1h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: (2R)-bornane-10,2-sultam With methylmagnesium bromide In tetrahydrofuran; diethyl ether at 0℃; for 0.5h; Stage #2: (E)-Hept-2-enoyl chloride In tetrahydrofuran; diethyl ether at 0℃; for 1h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 99 percent / thionyl chloride / DMF / 3 h / 20 °C 2: 100 percent / ammonium hydroxide / dioxane / 6 h / 20 - 95 °C 3: 66 percent / sodium borohydride / methanol; H2O / 1 h / 5 °C | ||
Multi-step reaction with 3 steps 1: SOCl2 2: NH3 / dioxane; H2O 3: 93 percent / NaBH4 / methanol; H2O | ||
Multi-step reaction with 2 steps 1: 1.) SOCl2, DMF, 2.) conc. NH3 / 1.) 115 deg C, 2.) 1,4-dioxane, a) RT, 2 h, b) 90 deg C, 4 h 2: 74 percent / NaBH4 / methanol; H2O / 5 °C |
Multi-step reaction with 4 steps 1: SOCl2 / 3 h / Heating 2: NH3 / CHCl3 / 7 h / 0 °C 3: 100 percent / 4 h / 170 °C 4: 85 percent / LiAlH4 / tetrahydrofuran / 12 h / 20 °C | ||
Multi-step reaction with 2 steps 1: SOCl2; aqueous NH3; concentrated aqueous HCl / aufeinanderfolgendes Behandeln 2: Raney nickel; ethanol / Hydrogenation | ||
Multi-step reaction with 2 steps 1.1: thionyl chloride / chloroform / 16.75 h / 80 °C 1.2: 3 h / 0 - 20 °C 1.3: Amberlyst 15 / 4 h / 100 °C / Dean-Stark 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 6 h / 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 50 percent / toluene / 72 h / Heating 2: 70 percent / LiAlH4 / diethyl ether / 0.25 h / 0 °C | ||
Multi-step reaction with 2 steps 1: 29 percent / toluene / 72 h / Heating 2: 70 percent / LiAlH4 / diethyl ether / 0.25 h / 0 °C | ||
Multi-step reaction with 2 steps 1: 720 percent / hexane 2: L-Selectride / tetrahydrofuran / 25 °C |
Multi-step reaction with 2 steps 1: 73 percent / CH2Cl2 2: L-Selectride / tetrahydrofuran / 25 °C | ||
Multi-step reaction with 2 steps 1: 74 percent / hexane 2: L-Selectride / tetrahydrofuran / 25 °C | ||
Multi-step reaction with 2 steps 1: 59 percent / hexane 2: L-Selectride / tetrahydrofuran / 25 °C | ||
Multi-step reaction with 3 steps 1: toluene / 24 h 2: p-TsOH / diethyl ether / 1 h 3: 92 percent / L-selectride / tetrahydrofuran / 0.33 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: 2.) p-TsOH / 1.) toluene, 24 h, 2.) CH2Cl2, 1 h 2: 98 percent / L-selectride / tetrahydrofuran / 0.5 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: (2R)-bornane-10,2-sultam With trimethylaluminum In n-heptane; dichloromethane at 20℃; for 0.5h; Stage #2: methyl 2-(2-phenylthiazol-4-yl)acetate In n-heptane; dichloromethane for 24h; Heating; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With lithium chloride In tetrahydrofuran at -20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In toluene; mineral oil for 0.166667h; Inert atmosphere; Stage #2: 2-furancarbonyl chloride In toluene; mineral oil for 16h; Inert atmosphere; | |
64% | With sodium hydride In toluene; mineral oil at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: N-[(2S)-2-hexyl-4-pentenoyl]-(1S)-(-)-10,2-camphorsultam With calcium hydroxide In n-heptane; water; isopropyl alcohol at 82℃; for 16h; Stage #2: With hydrogenchloride In tert-butyl methyl ether; water; isopropyl alcohol at 10 - 24℃; | 1.1 Calcium Hydroxide Method In a round-bottomed flask, 40.00 g (0.104 mol) of (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide, 200 ml of isopropanol, 76 ml of water and 15.53 g (0.210 mol) of calcium hydroxide were placed. The mixture was heated to the reflux temperature (about 82° C.), and was maintained at the same temperature for 16 hours. The reaction mixture was added dropwise into a liquid mixture of 80 ml of water and 54.60 g (0.524 mol) of 35% hydrochloric acid at 10 to 24° C., and then 200 ml of methyl tert-butyl ether was inpoured thereto. After the mixture was stirred for 10 min, the water layer was removed by separation, and then the organic layer was washed twice with 200 ml of water. After the organic layer of which amount was corresponding to 0.103 mol was vacuum-concentrated, an operation cycle of adding 135 ml of n-heptane to the residue and vacuum concentration was repeated three times. Next, 135 ml of n-heptane was added to the concentrate, and then the crystal was filtered. The obtained crystal was washed with 39.7 ml of n-heptane, and then dried under reduced pressure. Thus, 21.34 g of (1S)-(-)-2,10-camphorsultam (95.0% based on (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide; GC area percentage value: 99.47%) was recovered.Meanwhile, the filtrate was concentrated, and n-heptane was added thereto, to obtain 71.69 g (corresponding to 0.103 mol) of (2S)-2-(2-propenyl) octanoic acid heptane solution. From this of which amount was corresponding to 0.099 mol, cyclohexylamine salt of (2S)-2-(2-propenyl) octanoic acid was derived.To be more specific, 273 ml of ethyl acetate and 8.81 g (0.089 mol) of cyclohexylamine were placed in a round-bottomed flask, and 10.19 g (corresponding to 0.015 mol) of the above-obtained (2S)-2-(2-propenyl) octanoic acid/heptane solution was added dropwise thereto at 20° C. over a 30 minute period, followed by stirring at 20 to 21° C. for 1 hour. Further, 57.76 g (corresponding to 0.084 mol) of (2S)-2-(2-propenyl) octanoic acid/heptane solution was added dropwise thereto at 20 to 21° C. over 2 hours and 30 min. Then, the resultant mixture was cooled and kept within the range of -3 to 3° C. for 1 hour. The precipitated crystal was collected by filtration, washed with 73 ml of cooled ethyl acetate, and dried under reduced pressure. Thus, 23.03 g of cyclohexylamine salt of (2S)-2-(2-propenyl) octanoic acid (yield based on (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide: 82.3%; optical purity: 100%) was obtained. |
86.1% | Stage #1: N-[(2S)-2-hexyl-4-pentenoyl]-(1S)-(-)-10,2-camphorsultam With barium dihydroxide In n-heptane; water; isopropyl alcohol at 50 - 82℃; for 3h; Stage #2: With hydrogenchloride In tert-butyl methyl ether; water; isopropyl alcohol at 10 - 24℃; | 2.1; 3; 4 Barium Hydroxide Method In a round-bottomed flask, 40.00 g (0.104 mol) of (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide, 200 ml of isopropanol, 45.8 ml of water and 66.14 g (0.210 mol) of barium hydroxide octahydrate were placed. The mixture was heated to 50° C., and was maintained at the same temperature for 3 hours. The reaction mixture was added dropwise into a liquid mixture of 160 ml of water and 54.60 g (0.524 mol) of 35% hydrochloric acid at 10 to 24° C., and then 200 ml of methyl tert-butyl ether was inpoured thereto. After the mixture was stirred for 10 min, the water layer was removed by separation, and then the organic layer was washed once with 200 ml of water and once with 202.0 g of saline solution (200 ml of water, 2.0 g of NaCl). After the organic layer of which amount was corresponding to 0.103 mol was vacuum-concentrated, 135 ml of n-heptane was added to the residue, and vacuum concentration was carried out again. Next, 135 ml of n-heptane was added to the concentrate, and then the crystal was filtered. The obtained crystal was washed with 39.7 ml of n-heptane, and then dried under reduced pressure. Thus, 19.94 g of (3aS,6R,7aR)-8,8-dimethylhexahydro-3a,6-methano-2,1-benzois othiazole 2,2-dioxide, i.e. (1S)-(-)-2,10-camphorsultam was recovered (88.9% to (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide; GC area percentage: 99.14%). Meanwhile, the filtrate was concentrated, and n-heptane was added thereto, to obtain 71.69 g (corresponding to 0.103 mol) of (2S)-2-(2-propenyl) octanoic acid/heptane solution. From this of which amount was corresponding to 0.099 mol, cyclohexylamine salt of (2S)-2-(2-propenyl) octanoic acid was derived.Separately, 273 ml of ethyl acetate and 8.81 g (0.089 mol) of cyclohexylamine were placed in a round-bottomed flask, and 10.19 g (corresponding to 0.015 mol) of the (2S)-2-(2-propenyl) octanoic acid/heptane solution was added dropwise thereto at 20° C. over a 30 minute period, followed by stirring at 20 to 21° C. for 1 hour. Further, 57.76 g (corresponding to 0.084 mol) of (2S)-2-(2-propenyl) octanoic acid/heptane solution was added dropwise thereto at 20 to 21° C. over 2 hours and 30 min. Then, the resultant mixture was cooled and kept within the range of -3 to 3° C. for 1 hour. The crystal was collected by filtration, washed with 73 ml of cooled ethyl acetate, and dried under reduced pressure. Thus, 22.67 g of cyclohexylamine salt of (2S)-2-(2-propenyl) octanoic acid (yield based on (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide: 81.0%; optical purity: 100%) was obtained.; According to the same manner as in Example 1 or 2, hydrolysis was performed using 100 parts of (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide, under the conditions shown in the following Table 1. The amount of (2S)-2-(2-propenyl) octanoic acid produced in the reaction solution was measured by LC, and the production rate thereof was calculated. The results are shown in the following Table 1. TABLE 1 Solvent Water Base Example Part by Part by Part by Reaction Reaction Production No. Type volume volume Type mol Temperature Time Rate (%) 3 IPA 500 194Ba(OH)2 2.0 82° C. 1 h 86.1 (Reflux) 4 IPA 500 194Ba(OH)2 2.0 60° C. 1 h 87.5 5 t-BuOH 500 194Ba(OH)2 2.0 50° C. 4 h 82.3 6 IPA 500 194Sr(OH)2 2.0 82° C. 4 h 88.0 (Reflux) The IPA and t-BuOH in the table represent isopropanol and tertiary butanol respectively. (2S)-2-(2-propenyl) octanoic acid produced in Examples 3 to 6 was derived to cyclohexylamine salt. The optical purity measured was 100% in each Example. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.7% | In a round-bottomed flask, 40.00 g (0.105 mol) of (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide and 160 ml of diglyme were placed, and the mixture was cooled to 17 C. while nitrogen was being sent thereto with the intention of limiting the concentration of oxygen to 5% or less until the end of the reaction. After 0.51 g (0.005 mol) of 35% hydrogen peroxide solution was inpoured, 15.79 g (0.162 mol) of 35% aqueous hydrogen peroxide solution and 19.61 g (0.168 mol) of 48% aqueous potassium hydroxide solution were simultaneously inpoured at 17 C. over 9 hours, followed by stirring at 17 C. for 2 hours, and the end of the reaction was checked by HPLC.Separately, 21.14 g (0.168 mol) of sodium sulfite was dissolved in 110 ml of water in a flask with a stop-cock at room temperature, 58.97 g (0.566 mol) of 35% hydrochloric acid was added dropwise at 9 to 10 C., and then the above-mentioned reaction mixture was added dropwise thereto at 5 to 12 C. over 1 hour. After the resultant mixture was heated to 21 C. and stirred at the same temperature for 35 min, 200 ml of methyl tert-butyl ether was inpoured thereto, the mixture was stirred for 10 min, and the water layer was removed by separation. The organic layer was washed with saline solution (1.60 g NaCl, 200 ml tap water), 2.40 g of n-heptane and saline solution (1.60 g NaCl, 200 ml tap water) were added thereto, the mixture was stirred for 15 min, the water layer was removed by separation, and the end of washing was checked by GC. The organic layer was concentrated at normal pressures, and 240 ml of n-heptane was added to the obtained residue, which was then vacuum-concentrated until the residue was reduced to about 160 ml. Then, the residue was cooled and stirred at 0 to 10 C. for 30 minutes. The obtained crystal was filtered, washed with 40 ml of n-heptane, and dried under reduced pressure. Thus, 6.48 g of camphorsultam (yield based on (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide: 28.7%; GC area percentage value: 98.23%) was obtained. (1S)-2,10-camphorsulfonimine (imine form) was contained in the recovered camphorsultam and couldn't be removed by purification.Meanwhile, the filtrate was concentrated under reduced pressure and n-heptane was added thereto, to obtain 72.17 g (corresponding to 0.105 mol) of (2S)-2-(2-propenyl) octanoic acid/heptane solution. From this of which amount was corresponding to 0.087 mol, cyclohexylamine salt of (2S)-2-(2-propenyl) octanoic acid was derived.In a round-bottomed flask, 241 ml of ethyl acetate, 7.78 g (0.078 mol) of cyclohexylamine were placed and 9.00 g (0.013 mol) of (2S)-2-(2-propenyl) octanoic acid/heptane solution was added dropwise thereto at 20 C. over a 30 minute period, followed by stirring at 20 to 21 C. for 1 hour. Further, 51.00 g (corresponding to 0.074 mol) of (2S)-2-(2-propenyl) octanoic acid/heptane solution was added dropwise thereto at 20 C. over 2 hour 30 min. Then, the mixture was cooled and kept within the range of -3 to 3 C. for 1 hour. The crystal was collected by filtration, washed with 64 ml of cooled ethyl acetate, and dried under reduced pressure. Thus, 20.29 g of cyclohexylamine salt of (2S)-2-(2-propenyl) octanoic acid (yield based on (3aS,6R,7aR)-1-[(2S)-2-allyloctanoyl]-8,8-dimethylhexahydro-3a,6-methano-2,1-benzoisothiazole 2,2-dioxide: 82.1%; optical purity: 100%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: (2R)-bornane-10,2-sultam With trimethylaluminum In hexane; toluene at 20℃; Stage #2: (5Z)-methyl 6,10-dimethyl-2-methyleneundeca-5,9-dienoate In hexane; toluene for 41h; Reflux; | |
60% | Stage #1: (5Z)-methyl 6,10-dimethyl-2-methyleneundeca-5,9-dienoate; (2R)-bornane-10,2-sultam With trimethylaluminum In toluene at 20℃; for 0.25h; Stage #2: In toluene at 130℃; for 1h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: phthalimidyl 2-diazobutanoate In tetrahydrofuran; mineral oil at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine In dichloromethane at 0 - 20℃; for 3h; | 1.18 [00124] [3aS-[1(E),3a,6,7a]]-1-[3-(3,4-difluorophenyl)-1-oxo-2-propenyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,l-benzisothiazole-2,2-dioxide: At 0-5 0C, a solution of 3-(3,4-difluoro-phenyl)-acryloyl chloride in dichloromethane (30 mL) was added to a mixture of (2R)-bornane-10,2-sultam (14.5 g, 67.35 mmol, 1.00 equiv), triethylamine (20.4 g, 201.98 mmol, 3.00 equiv), and dichloromethane (120 mL). The resulting solution was stirred at ambient temperature for about 3 hours and then water (40 mL) was added. Standard extractive workup with dichloromethane (2 x 40 mL) gave the title product as an off-white solid (18.5 g; yield = 72 %). 1H NMR (300 MHz, CDCl3) δ: 7.68 (d, / = 15.6 Hz, 1 H), 7.15- 7.45 (m, 3 H), 7.19 (d, J = 15.6 Hz, 1 H), 4.00 (m, 1 H), 3.55 (q, J1 =13.8 Hz, J2 = 24.0 Hz ), 2.18 (m, 2 H), 1.93 (m, 2 H), 1.37-1.48 (m, 2 H), 1.22 (s, 3 H), 0.96 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 87% 2: 89% | Stage #1: (3S,4S,6S)-7-(8,8-dimethyl-2,2-dioxidotetrahydro-3a,6-methano-2,1-benzisothiazol-1(4H)-yl)-2,4,6-trimethyl-7-oxoheptan-3-ol With lithium hydroxide monohydrate; dihydrogen peroxide In tetrahydrofuran; water at 0 - 20℃; for 17h; Stage #2: With hydrogenchloride In water at 20℃; for 1h; | 4.9. (3S,6S)-Tetrahydro-6-isopropyl-3-methyl-5-methylenepyran-2-one 49b General procedure: At first, LiOH*H2O (403 mg, 9.69 mmol) and 34% aq H2O2 (1.3 mL, 19.2 mmol) were added to a stirred solution of 13 (1.12 g, 2.40 mmol) in THF (16 mL) and water (4 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C and then for 16 h at rt. Then water (10 mL) and CHCl3 (20 mL) were added. The organic layer was separated and the aqueous layer was extracted with CHCl3. The aqueous layer was acidified with 3 M HCl to pH 1, stirred for 1 h at rt and extracted with ethyl acetate (3 × 20 mL). The combined ethyl acetate extracts were washed with water, saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated under reduced pressure. Compound 4 (359 mg, 84%) was isolated by column chromatography on silica gel (petroleum ether/ethyl acetate) as a colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 84% 2: 89% | Stage #1: 8,8-dimethyl-1-{(2S)-2-methyl-4-[(1S)-2-methyl-1-(tetrahydro-2H-pyran-2-yloxy)propyl]pent-4-enoyl}hexahydro-3a,6-methano-2,1-benzisothiazole 2,2-dioxide With lithium hydroxide monohydrate; dihydrogen peroxide In tetrahydrofuran; water at 0 - 20℃; for 17h; Stage #2: With hydrogenchloride In water at 20℃; for 1h; | 4.9. (3S,6S)-Tetrahydro-6-isopropyl-3-methyl-5-methylenepyran-2-one 49b At first, LiOH*H2O (403 mg, 9.69 mmol) and 34% aq H2O2 (1.3 mL, 19.2 mmol) were added to a stirred solution of 13 (1.12 g, 2.40 mmol) in THF (16 mL) and water (4 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C and then for 16 h at rt. Then water (10 mL) and CHCl3 (20 mL) were added. The organic layer was separated and the aqueous layer was extracted with CHCl3. The aqueous layer was acidified with 3 M HCl to pH 1, stirred for 1 h at rt and extracted with ethyl acetate (3 × 20 mL). The combined ethyl acetate extracts were washed with water, saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated under reduced pressure. Compound 4 (359 mg, 84%) was isolated by column chromatography on silica gel (petroleum ether/ethyl acetate) as a colourless oil; [α]D = +34.1 (c 2.32, CHCl3); 1H NMR (CDCl3) d 0.96 (d, J = 6.5 Hz, 3H, 7-Me), 1.02 (d, J = 6.5 Hz, 3H, 7-Me), 1.24 (d, J = 6.9 Hz, 3H, 3-Me), 2.00 (d of sept., J = 6.9, 6.5 Hz, 1H, 6-H), 2.16-2.25 (m, 1H, 4-H), 2.66-2.81 (m, 2H, 3-H, 4-H), 4.50 (d, J = 6.9 Hz, 1H, 6-H), 4.97-5.39 (m, 1H, C=CHH), 5.05-5.10 (m, 1H, C=CHH); 13C NMR (CDCl3) d 17.2, 17.6, 19.2, 32.9, 34.4, 35.1, 88.3, 113.4, 138.9, 174.6; IR (CCl4) νmax: 3086, 1742, 1655 cm-1; MS (EI): m/z (%) = 168 (M+, 4.8), 125 (100.0), 97 (80.0), 41 (41.9). Anal. Calcd for C10H16O2: C, 71.39; H, 9.59. Found: C, 71.34; H, 9.64. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 1h; Inert atmosphere; | 4.2.1 Methyl 3-{(1S,5R,7R)-10,10-dimethyl-3,3-dioxo-3λ6-thia-4-azatricyclo[5.2.1.01,5]decane-4-carbonyl}but-3-enate (2) To a stirred solution of 4-methyl itaconate (1) (864 mg, 6.0 mmol) in dry CH2Cl2 (23 ml) were added 4-(dimethylamino)pyridine (161 mg, 1.3 mmol) and (S)-(-)-2,10-camphorsultam (15) (431 mg, 2.0 mmol). The mixture was cooled to 0 °C and N,N′-dicyclohexylcarbodiimide (1.36 g, 6.6 mmol) was added. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The solution was warmed to room temperature and further stirred overnight. The resulting precipitates of N,N′-dicyclohexylurea were filtered off and the filtrate was washed successively with 5% aqueous NaHCO3, water, 1 N HCl, water and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel [ SiO2 51 g; hexane-EtOAc (5:1 then 3:1 v/v)] to afford amide 2 (612 mg, 90%) as a colourless solid. Mp 86.2 °C (from diethyl ether); [α]D22 -82.9 (c 1.95, CHCl3); IR (KBr) 3119, 1738, 1674, 1633, 1436, 1328, 1175, 1132, 1114, 1063, 979, 764 cm-1; 1H NMR (600 MHz) δ 6.05 (1H, d, J=1.0 Hz, =CHH), 5.88 (1H, d, J=1.0 Hz, =CHH), 4.06 (1H, dd, J=7.5, 4.9 Hz, NCH), 3.69 (3H, s, OMe), 3.52 (1H, d, J=13.7 Hz, CHHSO2), 3.47 (1H, d, J=16.1 Hz, CHHCO2Me), 3.45 (1H, d, J=13.7 Hz, CHHSO2), 3.25 (1H, d, J=16.1 Hz, CHHCO2Me), 2.05-2.00 (2H, m, CH2), 2.00-1.85 (3H, m, CH, CH2), 1.49-1.29 (2H, m, CH2), 1.22 (3H, s, Me), 1.00 (3H, s, Me); 13C NMR (100 MHz) δ 169.9, 169.0, 135.6, 127.7, 65.4, 53.2, 51.8, 47.8, 47.5, 44.9, 38.0, 32.9, 26.2, 20.9, 19.7; MS (EI+) (m/z) 341 (M+, 1%), 310 (15), 277 (16), 218 (19), 127 (100), 99 (72), 69 (32), 59 (25); HRMS calcd for C16H24NO5S (MH+) 342.1375, found 342.1396. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: (2R)-bornane-10,2-sultam With trimethylaluminum In hexane; toluene at 20℃; for 0.25h; Stage #2: methyl 6-methyl-2-methylidene-5-heptenoate In hexane; toluene for 41h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 3,4-methoxycinnamic acid With pivaloyl chloride; triethylamine In tetrahydrofuran at -78 - 0℃; for 1.08333h; Inert atmosphere; Stage #2: (2R)-bornane-10,2-sultam With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 3-(4-chlorophenyl)propanoic acid With pivaloyl chloride; triethylamine In tetrahydrofuran at -78 - 0℃; for 1.08333h; Inert atmosphere; Stage #2: (2R)-bornane-10,2-sultam With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 10 - 25℃; for 18h; | 3.2 Take 30 g of the resulting intermediate, add 250 mL of dichloromethane. After stirring to clarify,37 g of camphorsulfonamide and 9. 6 g of N, N'-4-dimethylaminopyridine (DMAP) were added and the reaction was cooled to 10 ° C. A solution of 75 g of N, N'-dicyclohexylcarbodiimide (DCC) and 50 mL of DCM was added dropwise, and the temperature of the dropping process was below 20 ° C. After completion of the dropwise addition, the reaction was carried out at 20 ° C to 25 ° C for 18 hours. After completion of the reaction, the reaction solution was filtered and the resulting filtrate was washed once with 50 mL of water and once with 25 mL of saturated brine. After the dichloromethane phase was concentrated, 300 mL of n-heptane was added to precipitate a solid. Filtered and then dried to give 56 g of a solid, 99.8% purity, 91% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
415 g | Stage #1: phosgene; (2R)-bornane-10,2-sultam With triethylamine In dichloromethane at 0℃; for 2.5h; Reflux; Stage #2: With hydrogenchloride; hydroxylamine hydrochloride In dichloromethane; water at 20℃; for 3.5h; Reflux; | 1 Example 1 Preparation of Compound (14) 1) Under room temperature and stirring conditions,Disperse 323 g of D-(-)-camphor sulfonamide (15) and 220 g of solid phosgene in 5 liters of dichloromethane.When the temperature of the waiting liquid drops to 0 5 , the temperature should be controlled below 10 .Slowly add 610 grams of triethylamine dropwise;Control 5 10 and stir for 30 minutes,Stir at reflux for 2 hours;2) 120 grams of hydroxylamine hydrochloride are added in portions,Continue stirring at reflux for 3 hours; drop to room temperature,Slowly add 2 liters of 5% hydrochloric acid in water;Stir for 30 minutes at room temperature, then stand still to separate layers;3) After the separated organic phase is washed with 1 liter of water,The solvent was removed by concentration under reduced pressure to obtain 415 g of a crude product of compound (14); the crude product did not require further purification.Directly used in the next reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: (2R)-bornane-10,2-sultam With trimethylaluminum In hexane; toluene at 20℃; for 0.25h; Inert atmosphere; Stage #2: ethyl N-diphenylmethylene glycine In hexane; toluene at 40℃; for 20h; | 1-5 ccording to the molar ratio of L-camphorsulfonamide: dibenzylideneglycine ethyl ester: trimethylaluminum = 1.0:1.1:1.2, the following reaction is carried out: Dissolve 0.5 g of L-camphorsulfonamide in 5 mL of toluene, and add 2.8 mL of trimethylaluminum n-hexane solution (1.0 mol/L) dropwise at room temperature under nitrogen protection. After the above reaction solution was continuously stirred at room temperature for 15 minutes, 0.58 g of a toluene solution (5 mL) of ethyl benzhydrylglycine was added dropwise to the reaction solution, the temperature was raised to 40° C., and the reaction was carried out for 20 hours. TLC detects the end of the reaction. Add 10mL saturated sodium bicarbonate and 10mL water successively, separate the liquids, extract the aqueous phase with 20mL ethyl acetate, combine the organic phases, wash three times with water, concentrate the organic phase, and purify by column chromatography (petroleum ether: ethyl acetate = 4:1) 0.91 g of light yellow oily substance was obtained with a yield of 90.0%. |
86% | Stage #1: (2R)-bornane-10,2-sultam With trimethylaluminum In hexane; toluene at 20℃; for 0.5h; Inert atmosphere; Stage #2: ethyl N-diphenylmethylene glycine In hexane; toluene at 50℃; for 24h; Inert atmosphere; | isothiazol-1(4H)-yl)-2-((diphenylmethylene)amino)ethan-1-one (6) S-Camphorsultam 4 (1.5 g, 6.96 mmol) was dissolved in anhydrous toluene (30 mL). Asolution of Me3Al in hexane (8.4 mL, 8.4 mmol) was added dropwise at room temperatureunder argon. The reaction mixture was stirred for 30 minutes, followed by additionof a solution of the benzophenone imine of glycine ethyl ester 5 (2.04 g, 7.65 mmol) intoluene (25 mL). The reaction mixture was heated to 50 C and stirred for an additional24 hours. The reaction was cooled in an ice bath and quenched by addition of saturatedsodium bicarbonate (40 mL). The mixture was transferred to a separatory funnel. Theaqueous phase was extracted with ethyl acetate (3 x 50mL). The combined organic phasewas washed with 5% sodium carbonate solution, water and brine, then evaporated to drynessunder reduced pressure. The residue was purified by flash column chromatography onsilica gel eluting with petroleum ether/EtOAc to give 2.61 g (86%) 6 as a light yellow oil. Rf 0.30 (silica gel, petroleum ether/EtOAc 4/1); 1H NMR (500MHz, CDCl3) d 7.66 (dd,J5.2, 3.3Hz, 2H), 7.47-7.43 (m, 3H), 7.40-7.38 (m, 1H), 7.34-7.31 (m, 2H),7.20-7.18 (m,2H), 4.63 (d, J4.5Hz, 2H), 3.90 (dd, J7.8, 4.9Hz, 1H), 3.42 (d, J12.3Hz, 2H),2.11-2.05 (m, 1H), 1.41-1.38(m, 1H), 1.35 (d, J6.7Hz, 1H), 1.13 (s, 4H), 0.95 (s, 6H). |
86% | With trimethylaluminum In toluene at 50℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: (2R)-bornane-10,2-sultam With sodium hydride In toluene; mineral oil Resolution of racemate; Stage #2: C17H11BrClNO In toluene; mineral oil at 25 - 28℃; for 3h; Schlenk technique; Resolution of racemate; | Ra,1S and Sa,1S sultam imide A dry 50-mL three-necked round-bottom flask was charged with(S)-camphorsultam (943 mg, 4.38 mmol), 60 wt% NaH (304 mg, 7.60 mmol), and toluene (140 mL). To this was transferred a toluene solution of (±)-Br-Naph-PyCOCl (3.0 mL, prepared from(±)-Br-Naph-PyCOOH (1.00 g, 2.92 mmol) and SOCl2 (1.06 mL)) in a 20-mL Schlenk tube, and thetube was washed with toluene (2 mL and 1 mL) to complete the transfer process. After a 3-hstirring of the whole mixture at rt, sat aq NH4Cl (10 mL) and AcOH (1 mL) was added. The aqlayer was then extracted with CH2Cl2 (10 mL x 3), and the combined organic layers were dried overNa2SO4 (30 g). Filtration/evaporation gave a brown solid (2 g), which was purified bySiO2-chromatography (100 g, 1.5:3:1 EtOAc-hexane-toluene eluent) to give(R)-6-(2-bromonaphthalen-1-yl)-5-methylpyridine-2-carbonyl (S)-camphorsultam imide (Ra,1Sisomer) (300 mg, 19% yield) as a white solid and(S)-6-(2-bromonaphthalen-1-yl)-5-methylpyridine-2-carbonyl (S)-camphorsultam imide (Sa,1Sisomer) (300 mg, 19% yield) as a yellow oil, respectively |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | Stage #1: monofluoromethylbenzyl thioether With chlorine In chloroform at -40 - 23℃; for 25h; Schlenk technique; Darkness; Stage #2: (2R)-bornane-10,2-sultam With sodium hydride In chloroform; toluene at -40 - 23℃; for 3h; Schlenk technique; Inert atmosphere; | 1.4. General procedure for the synthesis of sodium (1S)-(-)-2,10-camphorsultam General procedure: To a solution of (1S)-(-)-2,10-camphorsultam (1.29 g, 6.00 mmol, 1.20 equiv.) in toluene (50.0 mL) was added NaH (240 mg, 6.00 mmol, 1.20 equiv., 60%) under an argon atmosphere at 0 °C. The solution was then stirred at room temperature for 1 h to give a suspension of sodium (1S)-(-)-2,10-camphorsultam. The mixture can be used for the next step directly. 1.5. General procedure for the synthesis of (1S)-(-)-N-monofluoromethylthio-2,10-camphorsultam Into a 2.0 L of Schlenk tube was added anhydrous CHCl3 (1.5 L) and get weighed. Chlorine gas was bubbled slowly for 15 min. The concentration of Cl2 in CHCl3 was then determined to be 1.0 mol/L by weighing the Schlenk tube before and after bubbling of the chlorine gas. An aliquot of Cl2 in CHCl3 (5.0 mL, 1.0 M) was added into a solution of monofluoromethylbenzyl thioether (5.0 mmol,1.0equiv.) in anhydrous CHCl3 (15.0 mL) in a 100 mL three-neck roundbottom flask at -40 °C in the dark. The mixture was warmed to 23 °C and was further stirred for 1 h in the dark. The mixture was then cooled to -40 °C, and the suspension of sodium (1S)-(-)-2,10-camphorsultam (6.0 mmol, 1.2 equiv.) was added at -40 °C. The mixture was then warmed to 23 °C, and was further stirred at room temperature for 3 h. The mixture was extracted with Et2O (25.0 mL x 3). The combined organic phase was separated and dried over anhydrous Na2SO4. After filtration, the solvent was removed under vacuum. The residue was purified by flash chromatography to give (1S)-(-)-N-monofluoromethylthio-2,10-camphorsultam 1a as a white solid (237 mg, 17% yield). 1.5.1. (3aR,6R,7aR)-1-((Fluoromethyl)thio)-8,8-dimethylhexahydro-3H-3a,6-methanobenzo[c]isothiazole 2,2-dioxide (1a) Yield 17%, white solid. 1H NMR (400 MHz, CDCl3) d 5.87 (dd,J 53.2, 11.5 Hz, 1H), 5.47 (dd, J 52.3, 11.5 Hz, 1H), 3.41 (dd, J 8.0,4.4 Hz, 1H), 3.22 (q, J 13.7 Hz, 2H), 2.31e2.14 (m, 1H), 1.94 (t,J 3.8 Hz, 1H), 1.92-1.82 (m, 2H), 1.78 (dd, J 13.4, 8.1 Hz, 1H), 1.43(t, J 9.2 Hz, 1H), 1.36e1.27 (m, 1H), 1.02 (s, 3H), 0.92 (s, 3H); 19F NMR (376 MHz, CDCl3) d 182.27 (br, 1 F); 13C NMR (101 MHz,CDCl3) d 90.95 (d, J 219.1 Hz), 68.34, 50.66, 49.19, 47.72, 44.13,34.46, 32.02, 27.09, 20.12, 19.94 ppm. IR (KBr): nmax 2950, 2880,1457, 1410, 1299, 1140, 1122, 1071, 956 cm-1. MS (DART POS): 297.1(M NH4); HRMS (DART POS): C11H22O2N2FS2 (M NH4) Calcd:297.1101, Found: 297.1102. Mp: 127.0-128.5 °C. |
Tags: 94594-90-8 synthesis path| 94594-90-8 SDS| 94594-90-8 COA| 94594-90-8 purity| 94594-90-8 application| 94594-90-8 NMR| 94594-90-8 COA| 94594-90-8 structure
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