Structure of 263400-88-0
*Storage: {[sel_prStorage]}
*Shipping: {[sel_prShipping]}
The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
*For Research Use Only !
Change View
Size | Price | VIP Price | US Stock |
Global Stock |
In Stock | ||
{[ item.pr_size ]} |
Inquiry
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.discount_usd) ]} {[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} |
Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]} | Inquiry {[ item.pr_usastock ]} In Stock Inquiry - | {[ item.pr_chinastock ]} {[ item.pr_remark ]} In Stock 1-2 weeks - Inquiry - | Login | - + | Inquiry |
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days
1-2weeks
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price, item.pr_usd) ]}
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
In Stock
- +
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
CAS No. : | 263400-88-0 |
Formula : | C11H16O5S2 |
M.W : | 292.37 |
SMILES Code : | CC1=CC=C(C=C1)S(=O)(=O)OCCCS(C)(=O)=O |
MDL No. : | MFCD22124592 |
InChI Key : | AXUFUWARAAYMCG-UHFFFAOYSA-N |
Pubchem ID : | 22732325 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.45 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 68.97 |
TPSA ? Topological Polar Surface Area: Calculated from |
94.27 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.98 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.18 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.3 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.66 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.12 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.85 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.25 |
Solubility | 1.66 mg/ml ; 0.00567 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.76 |
Solubility | 0.514 mg/ml ; 0.00176 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.97 |
Solubility | 0.0313 mg/ml ; 0.000107 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.25 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.99 |
* 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 |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h; | Reference Example 17; {2' , 3' ,5' , 6'-tetramethyl-4' - [3- (methylsulfonyl)propoxy]biphenyl-3-yl}methanol; To a solution of 3'- (hydroxymethyl) -2, 3, 5, 6- tetramethylbiphenyl-4-ol (0.616 g, 2.40 mmol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (1.05 g, 3.60 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.597 g, 4.32 mmol), and the mixture was stirred at 9O0C for 12 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 40:60 - 80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.577 g, yield 85%) as colorless crystals, melting point 132-134C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h; | Weigh YZ-2 (2·26g, 10mmol), YZ-1 (3·51g, 12mmol), potassium carbonate (1·8g, 13mmol), was dissolvedIn 20ml N,Nu-dimethylformamide, and the reaction was stirred at 90C in an oil bath for 24 hours, until the reaction was complete feed YZ-2. 150mL was added in the reaction system was diluted with ethyl acetate, washed successively with water, saturated brine, dried over anhydrous sodium sulfate,Filtered, and concentrated to give the crude product was purified by flash column chromatography (30% ethyl acetate / petroleum ether) to give the product YZ-3 (3.05g), yield 88%. |
78% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h;Inert atmosphere; | To a solution of product 20 (1.36g, 6.00mmol) and product 19 (2.1 lg, 7.20mmol) in N, N-dimethylformamide (12mL) was added potassium carbonate (1.08g, 7.80mmol), and the mixture was stirred at 90 C for 24 hr under nitrogen atmosphere .Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: hexane = 40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give a colorless solid product 21 (1.61g, yield 78%). |
77% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h; | Reference Example 18; 2' , 6' -dimethyl-4f - [3- (methylsulfonyl)propoxy]biphenyl-3-carbaldehyde; <n="82"/>To a solution of 4'-hydroxy-2' , 6'-dimethylbiphenyl-3- carbaldehyde (2.26 g, 10.0 itimol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (3.51 g, 12.0 rartiol) in N,N- dimethylformamide (20 mL) was added potassium carbonate (1.80 g, 13.0 mmol) , and the mixture was stirred at 900C for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 40:60 - 80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.68 g, yield 77%) as colorless crystals.MS m/z 347 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h; | Reference Example 26; 3'-fluoro-2' , 6' -dimethyl-4' - [3- (methylsulfonyl) propoxy] biphenyl-3-carbaldehyde; To a solution of 3' -fluoro-4'-hydroxy-2' , 6' - dimethylbiphenyl-3-carbaldehyde (2.44 g, 10.0 mmol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (3.51 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.80 g, 13.0 mmol), and the mixture was stirred at 900C for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced <n="87"/>pressure. The residue was purified by silica gel column chromatography (ethyl acetate rhexane = 40:60 - 80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (3.45 g, yield 95%) as colorless crystals . MS m/z 365 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 21h; | Reference Example 37; {3'- (hydroxymethyl) -6-methyl-4- [3- (methylsulfonyl) propoxy]biphenyl-2-yl }methyl acetate; To a solution of [4-hydroxy-3' - (hydroxymethyl) -6- methylbiphenyl-2-yl]methyl acetate (1.02 g, 3.56 mmol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (1.25 g, 4.27 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.640 g, 4.32 mmol), and the mixture was stirred at 900C for 21 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 50:50 - 100:0) to give the title compound (0.87 g, yield 60%) as a colorless oil.1H NMR (CDCl3) delta: 1.81(1H, t, J=6.0Hz), 2.01(3H, s) , 2.03(3H, <n="93"/>. s) , 2.31-2 .43 (2H, m) , 2.97 (3H, s) , 3.24-3.32 (2H, m) , 4 .16 (2H, t, J=5.7Hz ) , 4 .72 ( 2H, d, J=6. 0Hz) , 4 .76 (2H, s) , 6.78 ( IH, d, J=2.5Hz) , 6. 83 ( IH, d, J=2 . 5Hz) , 7 . 05-7.10 ( 1H, m) , 7. 15 ( 1H, s ) , 7 . 32-7 .43 ( 2H, m) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 70h; | Reference Example 50; 2' , 6' -diethyl-4'- [3- (methylsulfonyl) propoxy] biphenyl-3-carbaldehyde; To a solution of 2' , 6' -diethyl-4' -hydroxybiphenyl-3- carbaldehyde (2.44 g, 9.59 mmol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (3.36 g, 11.5 mmol) in N,N- dimethylformamide (20 mL) was added potassium carbonate (1.73 <n="100"/>g, 12.5 mmol) , and the mixture was stirred at 900C for 70 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate :hexane = 30:70 - 70:30) to give the title compound (2.86 g, yield 80%) as a pale-yellow oil. MS m/z 375 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In methanol; water; ethyl acetate; | A solution of potassium peroxymonosulphate (oxone; 33 g) in water (250 ml) was added to a solution of 3-methylthiopropyl 4-toluenesulphonate (14.29 g) in methanol (1.5 L). The resulting mixture was stirred for 18 hours, filtered and evaporated. The residue was dissolved in ethyl acetate and the solution was washed with brine, dried over magnesium sulphate and evaporated. There was thus obtained 3-methylsulphonylpropyl 4-toluenesulphonate as a solid (10.22 g, 64%); NMR: 2.01 (m, 2H), 2.43 (s, 3H), 2.95 (s, 3H), 3.1 (t, 2H), 4.13 (t, 2H), 7.47 (d, 2H), 7.78 (d, 2H); m/s: M+NH4+ 310. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate; In acetonitrile;Heating / reflux; | 152 (l-r2-(lH-Indazol-4-ylV4-morpholin-4-yl-thienor3.2-d1pyrimidin-6-ylmethyl1- piperidin-4-vU-(3-methanesulfonyl-propylVmethyl-amine.Via [ 1 -(2-chloro-4-morpholin-4-yl-thieno[3 ,2-d]pyrimidin-6-ylmethyl)- piperidin-4-yl]-(3-methanesulfonyl-propyl)-methyl-amine, prepared from (3- methanesulfonyl-propyl)-methyl-piperidin-4-yl-amine. Amine preparation: Toluene-4-sulfonic acid 3-methylsulfanyl-propyl ester was prepared from 3-(methylthio)-l-propanol using standard conditions. Treatment with mCPBA in DCM yielded <strong>[263400-88-0]toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester</strong>. A mixture of 4-methylamino-piperidine- 1-carboxylic acid tert-butyl ester and <strong>[263400-88-0]toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester</strong> was heated in MeCN in the prescence of potassium carbonate to yield 4- [(3-methanesulfonyl-propyl) -methyl- EPO <DP n="82"/>amino]-piperidine-l-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.1H NMR (400MHz, CDCl3) 1.50-1.70 (m, 4H, 2 x CH2), 1.90-1.97 (m, 2H, CH2), 2.00-2.05 (m, 2H, CH2), 2.21 (s, 3H, CH3), 2.38 (m, H, CH), 2.55 (m, 2H, CH2), 2.74 (s, 3H, CH2), 2.96-3.04 (m, 4H, 2 x CH2), 3.75 (s, 2H, CH2), 3.83-3.89 (m, 4H, 2 x CH2), 4.00-4.02 (m, 4H, 2 x CH2), 7.28 (s, H, CH), 7.41 (t, H, ArH, J=7.74Hz), 7.50 (d, H, ArH, J=8.24Hz), 8.18 (d, H, ArH, J=7.05Hz), 8.93 (s, H, ArH); MS (ESI+) 584.39 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With Oxone; In methanol; water; at 0 - 20℃; for 3h; | To a solution of 16A (2.16 g, 8.31 mmol) in MeOH (44 mL) cooled to 0 C was added a solution of OXONE (10.2 g, 16.6 mmol) in water (44 mL). The ice bath was allowed to gradually warm to rt and the reaction mixture was stirred for 3 h. The MeOH was removed under reduced pressure and the reaction mixture was diluted with water. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried (MgS04), and concentrated to give 16B (2.39 g, 8.17 mmol, 98%> yield) as a white solid. LC-MS Anal. Calc'd for CnHi605S2: 292.37, found [M+H] 293.0. |
96% | With Oxone; In methanol; water; at 0℃; for 20h; | To a solution of 3- (methylthio) propyl 4- 5 methylbenzenesulfonate (12.2 g) in methanol, (250 ml) was added EPO <DP n="223"/>dropwise a solution of Oxone (trade name) (57.7 g) in water (250 ml) under ice-cooling. After completion of the dropwise addition, and the mixture was stirred for 20 hr while allowing to warm to room temperature. Methanol was evaporated under reduced pressure, and the mixture was diluted with water. The organic product was extracted with ethyl acetate. The extract was washed with saturated brine, dried (Na2SO4), and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-heptane to give 3- (methylsulfonyl) propyl 4-methylbenzenesul;fonate (13.1 g, yield: 96%) as colorless crystals. MS m/z 293 (MH+). |
96% | With Oxone; In methanol; water; at 0 - 20℃; for 20h; | Reference Example 16; 3- (methylsulfonyl) propyl A- methylbenzenesulfonate; To a solution of 3- (methylthio) propyl A- methylbenzenesulfonate (12.2 g, 46.9 mmol) in methanol (250 mL) was added dropwise a solution of potassium peroxysulfate (trade name: OXONE, 57.7 g, 93.8 mmol) in water (250 mL) under ice-cooling. After completion of the dropwise addition, the mixture was stirred for 20 hr, during which the mixture was allowed to gradually warm to room temperature. Methanol was <n="81"/>evaporated under reduced pressure, and the mixture was diluted with water, and the organic material was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-heptane to give the title compound (13.1 g, yield 96%) as colorless crystals. MS m/z 293 (M + H)+. |
92% | With Oxone; In methanol; water; at 20℃; for 20h;Cooling with ice; | (B) To an ice-cooled solution of 3-(methylthio)propyl 4-methylbenzenesulfonate (3.6 g; 13.8 mmol) in MeOH (70 mL) was added a suspension of monopersulfate compound (17 g; 27.4 mmol) in water (70 mL) in a portion-wise fashion. Upon completion of the addition, the mixture was allowed to warm to rt, and stirring was continued for 20 h. The reaction was partially concentrated to remove the MeOH and the mixture was further diluted with water and extracted with EtOAc (2x). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0- 67% EtOAc in hexanes to afford 3- (methylsulfonyl)propyl 4-methylbenzene-sulfonate (3.72 g, 92%) as a white solid. LC/MS: mass calcd. for C11H16O5S2: 292.38, found 315.1 [M+Na]+. |
92% | With Oxone; In methanol; water; at 20℃; for 20h;Cooling with ice; | (B) To an ice-cooled solution of 3-(methylthio)propyl 4-methylbenzenesulfonate (3.6 g; 13.8 mmol) in MeOH (70 mL) was added a suspension of monopersulfate compound (17 g; 27.4 mmol) in water (70 mL) in a portion-wise fashion. Upon completion of the addition, the mixture was allowed to warm to rt, and stirring was continued for 20 h. The reaction was partially concentrated to remove the MeOH and the mixture was further diluted with water and extracted with EtOAc (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-67% EtOAc in hexanes to afford 3-(methylsulfonyl)propyl 4-methylbenzene-sulfonate (3.72 g, 92%) as a white solid. LC/MS: mass calcd. for C11H16O5S2: 292.38, found 315.1 [M+Na]+. |
92% | With monopersulfate; In methanol; water; at 20℃; for 20h; | (B) To an ice-cooled solution of 350 3-(methylthio)propyl 4-methylbenzenesulfonate (3.6 g; 13.8 mmol) in 21 MeOH (70 mL) was added a suspension of monopersulfate compound (17 g; 27.4 mmol) in 12 water (70 mL) in a portion-wise fashion. Upon completion of the addition, the mixture was allowed to warm to rt, and stirring was continued for 20 h. The reaction was partially concentrated to remove the MeOH and the mixture was further diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-67% EtOAc in hexanes to afford 352 3-(methylsulfonyl)propyl 4-methylbenzene-sulfonate (3.72 g, 92%) as a white solid. LC/MS: mass calcd. for C11H16O5S2: 292.38, found 315.1 [M+Na]+. |
90% | With oxone; In methanol; at 20℃;Cooling with ice; | 3-(methylthio)propyl-4-methylbenzenesulfonate (12.5 g, 48 mmol) was added to 250 mL in an ice bathStirring in a methanol solution, adding Oxone (59 g, 96 mmol) dropwise to the reaction solution, returning to room temperature, and stirring overnight. thenThe reaction solution was concentrated under reduced pressure, and a large amount of a white solid precipitated, which was filtered and washed with water to give a white solid (12.6 g) in a yield of 90%. |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; | 152 (l-r2-(lH-Indazol-4-ylV4-morpholin-4-yl-thienor3.2-d1pyrimidin-6-ylmethyl1- piperidin-4-vU-(3-methanesulfonyl-propylVmethyl-amine.Via [ 1 -(2-chloro-4-morpholin-4-yl-thieno[3 ,2-d]pyrimidin-6-ylmethyl)- piperidin-4-yl]-(3-methanesulfonyl-propyl)-methyl-amine, prepared from (3- methanesulfonyl-propyl)-methyl-piperidin-4-yl-amine. Amine preparation: Toluene-4-sulfonic acid 3-methylsulfanyl-propyl ester was prepared from 3-(methylthio)-l-propanol using standard conditions. Treatment with mCPBA in DCM yielded toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester. A mixture of 4-methylamino-piperidine- 1-carboxylic acid tert-butyl ester and toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester was heated in MeCN in the prescence of potassium carbonate to yield 4- [(3-methanesulfonyl-propyl) -methyl- EPO <DP n="82"/>amino]-piperidine-l-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.1H NMR (400MHz, CDCl3) 1.50-1.70 (m, 4H, 2 x CH2), 1.90-1.97 (m, 2H, CH2), 2.00-2.05 (m, 2H, CH2), 2.21 (s, 3H, CH3), 2.38 (m, H, CH), 2.55 (m, 2H, CH2), 2.74 (s, 3H, CH2), 2.96-3.04 (m, 4H, 2 x CH2), 3.75 (s, 2H, CH2), 3.83-3.89 (m, 4H, 2 x CH2), 4.00-4.02 (m, 4H, 2 x CH2), 7.28 (s, H, CH), 7.41 (t, H, ArH, J=7.74Hz), 7.50 (d, H, ArH, J=8.24Hz), 8.18 (d, H, ArH, J=7.05Hz), 8.93 (s, H, ArH); MS (ESI+) 584.39 (MH+). | |
With Oxone; In methanol; at 6 - 20℃; for 16h;Product distribution / selectivity; | Reference Example 6Synthesis of 3- (methylsulfonyl) propyl 4-methylbenzenesunfonate; [0414][0415]3- (Methylthio) propyl 4-methylbenzenesunfonate (29.4 g) was dissolved in methanol, and the mixture was cooled to 6C or below. While cooling to 6C or below, oxone (registered trade mark; 105.2 g) dissolved in water (400 mL) was added dropwise over 1 hr. After stirring at 6C or below for 1 hr, the mixture was stirred at room temperature for 14 hr. Water (800 mL) was added, and the mixture was stirred at 6C or below for 1 hr. The precipitated solid was collected by filtration, and washed twice with water (400 mL) . The solid was suspended in methanol (150 mL) , and the suspension was heated to 65C.Water (150 mL) was added dropwise over 30 min, and the mixture was cooled to room temperature and stirred at 6C or below for 1 hr. The solid was collected by filtration, and washed twice with water (150 mL) . The solid was vacuum-dried at 50C to give white title compound (25.21 g) .1H NMR (300MHz, CDC13) : delta 2.17-2.28 (2H, m) , 2.46 (3H, s) , 2.91 (3H, s), 3.07-3.15 (2H, m) , 4.18 (2H, t, J=5.9 Hz), 7.34-7.37 (2H, d, J=8.0 Hz), 7.78-7.80 (2H, d, J=8.3 Hz). | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 21h; | Step B: 3 -(methylsulfonyl)propyl 4-methylbenzenesulfonate (34-2)To a solution of 34-1 (35 g, 135 mmol) in dry DCM (400 mL) with ice-bath cooling was added MCPBA (46.5 g, 270 mmol) portionwise. The resulting mixture was stirred at 0 C for lh, and then warmed to the room temperature and stirred for 20 h. The reaction was quenched byaddition of aqueous solution of NaHSO3 and the DCM layer was washed with Na2CO3 (aq.), water and brine, respectively, and concentrated to afford a residue, which was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 3/1) to give compound 34-2. | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 21h; | To a solution of34-1 (35 g, 135 mmol) in dry DCM (400 mL) with ice-bath cooling was addedMCPBA(46.5 g, 270 mmol) portionwise. The resulting mixture was stirred at 0 oc for 1h, andthen warmed to the room temperature and stirred for 20 h. The reaction was quenched by5 addition of aqueous solution ofNaHS03 and the DCM layer was washed with Na2C03 (aq.),water and brine, respectively, and concentrated to afford a residue, which was purified bychromatography on silica gel (petroleum ether:ethyl acetate= 3/1) to give compound 34-2. | |
With oxone; In methanol; water; at 20℃; for 20h;Cooling with ice; | To a solution of product 18 (7.32g, 28.1mmol) in methanol (150mL) was added dropwise a solution of potassium peroxysulfate (34.6g, 56.3mmol) in water (150mL) under ice-cooling. After completion of the dropwise addition, the mixture was stirred for 20 hr, during which the mixture was allowed to gradually warm to room temperature. Methanol was evaporated under reduced pressure, and the mixture was diluted with water, and the organic material was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-heptane to give a colorless crystal product 19 (7.86g, yield 95%). | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 21h; | To a solution of product from Step A (35 g, 135 mmol) in dry DCM (400 mL) in an ice-bath was added MCPBA (46.5 g, 270 mmol) portionwise. The resulting mixture was stirred at 0 C for lh, and then warmed to the room temperature and stirred for 20 h. The reaction was quenched by addition of aqueous solution of NaHS( and the DCM layer was washed with Na2C( (aq.), water and brine, respectively, and concentrated to afford a residue, which was purified by chromatography on silica gel (eluting with PE:EA=3: 1) to give the title compound. | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 21h; | To a solution of product from Step A (35 g, 135 mmol) in dry DCM (400 mL) in an ice-bath was added MCPBA (46.5 g, 270 mmol) portionwise. The resulting mixture was stirred at 0for 1h, and then warmed to the room temperature and stirred for 20 h. The reaction was quenched by addition of aqueous solution of NaHSO3 and the DCM layer was washed with Na2CO3 (aq. ) , water and brine, respectively, and concentrated to afford a residue, which was purified by chromatography on silica gel (eluting with PE:EA3:1) to give the title compound. | |
With Oxone; In tetrahydrofuran; water; at 20℃; for 12h;Inert atmosphere; | 62 g of 3-(methylthio)propyl 4-methylbenzenesulfonate obtained in step 1) was loaded in THF/distilled water (150/100 ml) in a flask in nitrogen atmosphere, followed by stirring for dissolving them. Then, 310 g of oxone was added thereto. The mixture was stirred for 12 hours at room temperature. Upon completion of the reaction, distilled water was slowly added thereto, followed by extraction using ethylacetate. The extract was washed with brine, dried over anhydrous MgSO4, and concentrated to give the target compound. (0288) 1H NMR (400 MHz, CDCl3): delta 7.81 (2H, d), 7.38 (2H, d), 4.20 (2H, m), 3.13 (2H, m), 2.93 (3H, s), 2.48 (3H, s), 2.23 (2H, m). | |
With Oxone; In methanol; at 20 - 30℃; for 2h;Inert atmosphere; | A solution of 3- (methylthio) propyl p-toluenesulfonate 24a (10.0 g, 38.40 mmol) was dissolved in 100 mL of methanol,100 mL of a solution containing Oxone reagent (35.42 g, 57.60 mmol), and the reaction was stirred at room temperature for 2 hours.The reaction mixture was concentrated under reduced pressure, 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL of X 2) and the combined organic layers were washed with water (30 mL of X 3) and saturated sodium chloride solution Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 3- (methylsulfonyl) propyl p-toluenesulfonate 24b (8.0 g, white solid) The purification was carried out directly to the next reaction. | |
1.95 g | With oxone; In methanol; water; at 0 - 20℃; for 20h; | Step 1: Preparation of 3-methylsulfonylpropyl 4-methylbenzenesulfonate To a solution of 3-methylsulfanylpropyl 4-methylbenzenesulfonate (2 g, 7.7 mmol) in methanol (50 mL) was added a solution of oxone (9.47 g, 15.4 mmol) in water (50 mL) dropwise at 0 oC. After being warmed to rt and stirred at rt for 20 hrs, the mixture was filtered and the filtrate was extracted with EA (50 mL) for three times. The combined organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to give 3- methylsulfonylpropyl 4-methylbenzenesulfonate as a white solid (1.95 g) which was used in the next step directly without further purification. |
38 g | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0℃; | To a solution of 3-(Methylthio)-1-propanol (20g, 0.19mol) and TEA (66ml, 0.48mol) in DCM (800mL) cooled at 0C was added p-toluenesulfonyl chloride (44g, 0.23mol, dissoloved in 200mL DCM) dropwise. After addtion, the mixture was then stirred at r.t. overnight. After the reaction was complete, the resluting solution was washed with saturated Na2CO3 solution, brine, dried over MgSO4 and concentrated in vacuo to give the crude of 3-methylsulfanylpropyl 4-methylbenzenesulfonate, which was used in the next step without further purification. To the solution of the crude of 3-methylsulfanylpropyl 4-methylbenzenesulfonate (prepared above) in DCM (200 mL) cooled at 0oC was added m-CPBA (66g, 0.39mol) slowly and the mixture was then stirred at rt overnight. After the reaction was complete, the mixture was washed with saturated sodium thiosulfate (300mL) 3 times , saturated sodium bicarbonate (300mL) 3 times, dried over MgSO4 and then concentrated in vacuo to give 3-methylsulfonylpropyl 4-methylbenzenesulfonate (11b, 38g, 69% yield over 2 steps) as a white solid. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF(5mL) cooled at 0oC was added NaH( 169 mg, 4.4 mmol). The mixture was then stirred at rt for 30mins. Then to the resulting solution was added 3-methylsulfonylpropyl 4-methylbenzenesulfonate (11b, 750 mg, 2.6 mmol) and the mixture was stirred at 50oC overnight. After the reaction was complete, to the mixture was added water (30 mL) and the resulting mixture was extracted with DCM (50 mL) 3 times. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with DCM:MeOH 20 :1) to give tert-butyl N-(4-chloro-2-nitro-phenyl)-N-(3-methylsulfonylpropyl)carbamate(11c, 360 mg, 69% yield). To a soltuion of tert-butyl N-(4-chloro-2-nitro-phenyl)-N-(3-methylsulfonylpropyl)carbamate (11c, 360 mg, 1.45 mol) in MeOH (10 mL) was added 2% Pt/C (50mg) under N2 atmosphere, the mixture wa then hydrogenated at rt for 3 hours. After the reaction was complete, the mixture was filtred and the filtrate was concentrated in vacuo to give the crude of tert-butyl N-(2-amino-4-chloro-phenyl) -N-(3-methylsulfonylpropyl)carbamate (11d, 330 mg, 100% yield), which was used in the next step directly without further purificaton. A mixture of tert-butyl N-(2-amino-4-chloro-phenyl)-N-(3-methylsulfonylpropyl)carbamate (11d, 320 mg, 0.92mmol) and sodium chloroacetate (130 mg, 1.1 mmol) in 4N HCl (15 mL) was stirred to 100oC overnight. After the reaction was complete, The reaction was concentrated in vacuo and the residue was redissoved in DCM (100 mL). The resulting soltuion was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column crhomatography on silica gel (elution with DCM/EtOAc=3/1) to give 5-chloro-2-(chloromethyl) -1-(3-methylsulfonylpropyl)benzimidazole (11e, 130 mg, 44% yield). To a mixture of 2-(methylsulfonyl)-1H-indole (72 mg, 0.37 mmol) and 5-chloro-2-(chloromethyl) -1-(2- (methylsulfonyl)ethyl)-1H-benzo[d]imidazole (11e, 120 mg, 0.37mmol) in DMF (3 mL) was added K2CO3 (104 mg, 0.74 mmol) and the mixture was stirred at rt overnight. After the reaction was completed, the mixture was filtered and the filtrate was purified by preparative HPLC to give 5-chloro-2-[(3-methylsulfonylindol-1-yl)methyl]-1-(3-methylsulfonylpropyl)benzimidazole (11, 100 mg, 78%). MS: calcd (MH+) 480.1, exp (MH+) 480.1. 1H NMR(DMSO-d6, 400MHz):delta8.29(s, 1H), 7.80-7.86(m, 1H), 7.65-7.73(m, 3H), 7.26-7.34(m, 3H), 5.92(s, 2H), 4.86(t, J=7.6Hz, 2H), 3,73(br, 3H), 3.19(t, J=8.0Hz, 2H), 2.96(s, 3H), 2.08(t, J=7.6Hz, 2H); 13C NMR (101MHz, DMSO-d6) delta151.4, 143.2, 137.3, 134.7, 134.6, 126.9, 124.2, 123.8, 123.3, 122.6, 119.5, 119.2, 115.5, 112.4, 112.3, 51.1, 45.6, 43.6, 42.3, 23.1. |
With Oxone; In tetrahydrofuran; water; at 0 - 20℃; for 12h;Inert atmosphere; | Under a nitrogen atmosphere, 62 g of 3-(methylthio)propyl 4-methylbenzenesulfonate obtained in step 1 was added in THF/distilled water (150/100 mL) in a flask and stirred to dissolve, and then 310 g of oxone was added dropwise at 0?. After stirring at room temperature for 12 hours or longer, upon completion of the reaction, distilled water was slowly added dropwise, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate to give the title compound. (0182) 1H NMR (400MHz, CDCl3) : delta 7.81 (2H, d) , 7. 38 (2H, d) , 4.20(2H, m), 3.13(2H, m), 2.93(3H, s), 2.48(3H, s), 2.23(2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 3h; | To a solution of ethyl (2E) -3- (2-{ [3-chloro-5- (trifluoromethyl) pyridin-2-yl] oxy}-4-hydroxyphenyl) acrylate (5.00 g) in N,N-dimethylformamide (50 ml) were added potassium carbonate (2.67 g) and 3- (methylsulfonyl) propyl 4- methybenzenesulfonate (4.46 g) , and the mixture was stirred at 500C for 3 hr. After allowing to cool to room temperature, '1N hydrochloric acid was added to the reaction mixture, the resulting solid was collected by filtration and washed with water to give ethyl (2E) -3-{2-{ [3-chloro-5- (trifluoromethyl) pyridin-2-yl] oxy}-4- [3-(methylsulfonyl)propoxy] phenyl}acrylate (6.34 g, yield: 97%) as a white solid. Recrystallization from ethyl acetate-hexane gave white crystals, melting point 190.6-191.00C. |
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 4h; | General procedure: To a stirred solution of 33b (0.68 g, 1.74 mmol) and K2CO3 (322 mg, 2.33 mmol) in DMF (15 mL) was added 2-chloro-N,N-diethylacetamide (0.31 g, 2.07 mmol) and the mixture was stirred at room temperature for 2 h, at 50 C for 30 min, and at 80 C for 1 h. Then, additional 2-chloro-N,N-diethylacetamide (0.30 g, 2.01 mmol) was added to the mixture, which was stirred at 80 C for additional 30 min. After being cooled to room temperature, the reaction was acidified with 1 M HCl, and extracted with EtOAc, and the combined organic layer was washed with sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-EtOAc, 9:1 to 1:2) to give crude 7c (1.39 g, quant.) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; sodium iodide; In water; N,N-dimethyl-formamide; at 100℃; for 2h; | Example 802-[3-(Methylsulfonyl)propyl]sulfanyl}-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; A 1 M aqueous solution of sodium hydrogen carbonate (1.0 ml) was added to a mixture of 2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (341 mg) obtained by the method of Example 2, or a method pursuant to thereto, <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (292 mg) obtained by a method described in a published document, WO 08/1931, or a method pursuant to thereto, sodium iodide (150 mg) and N,N-dimethylformamide (10 ml), and the resulting mixture was stirred for 2 hours at 100 C. The reaction mixture was returned to room temperature, and then the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, and the dilution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by chromatography, and then was recrystallized from ethyl acetate. Thus, the title compound (235 mg) was obtained as a white powder.1H NMR (300 MHz, DMSO-d6) delta ppm 2.00-2.12 (2H, m), 2.98 (3H, s), 3.17 (4H, t, J=7.4 Hz), 4.87 (2H, q, J=8.7 Hz), 6.35 (1H, d, J=3.0 Hz), 7.14-7.25 (2H, m), 7.30-7.44 (3H, m), 12.14 (1H, br. s.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; sodium iodide; In water; N,N-dimethyl-formamide; at 100℃; for 15h; | Example 1543-[4-(Cyclopropylmethoxy)phenyl]-2-[3-(methylsulfonyl)propyl]sulfanyl}-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; A 1 M aqueous solution of sodium hydrogen carbonate (0.64 ml) was added to a mixture of 3-[4-(cyclopropylmethoxy)phenyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (200 mg) obtained by the method of Example 6, or a method pursuant to thereto, <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (187 mg) obtained by a method described in a published document, WO 08/1931, or a method pursuant to thereto, sodium iodide (96 mg) and N,N-dimethylformamide (10 ml), and the resulting mixture was stirred for 15 hours at 100 C. The reaction mixture was returned to room temperature, and then was diluted with ethyl acetate. The dilution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by chromatography, and then was recrystallized from a mixed solvent of ethyl acetate/hexane. Thus, the title compound (164 mg) was obtained as a white powder.1H NMR (300 MHz, DMSO-d6) delta ppm 0.33-0.39 (2H, m), 0.57-0.64 (2H, m), 1.19-1.34 (1H, m), 2.00-2.12 (2H, m), 2.97 (3H, s), 3.10-3.23 (4H, m), 3.89 (2H, d, J=6.8 Hz), 6.34 (1H, d, J=2.8 Hz), 7.04 (2H, d, J=9.1 Hz), 7.25 (2H, d, J=9.1 Hz), 7.39 (1H, d, J=2.8 Hz), 12.12(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; sodium iodide; In water; N,N-dimethyl-formamide; at 100℃; | Example 1512-[3-(Methylsulfonyl)propyl]sulfanyl}-3-{4-[(2,2,2-trifluoroethoxy)methyl]phenyl}-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; A mixture of 2-thioxo-3-{4-[(2,2,2-trifluoroethoxy)methyl]phenyl}-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (250 mg) obtained in Example 16, <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (225 mg) obtained by the method described in a published document, WO 08/1931, or a method pursuant to thereto, sodium iodide (149 mg), a 1 M aqueous solution of sodium hydrogen carbonate (1.0 ml) and N,N-dimethylformamide (10 ml), was stirred overnight at 100 C., and then was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography, and then was recrystallized from ethyl acetate. Thus, the title compound (187 mg) was obtained as a white solid.1H NMR (300 MHz, DMSO-d6) delta ppm 2.00-2.12 (2H, m), 2.97 (3H, s), 3.13-3.21 (4H, m), 4.20 (2H, q, J=9.5 Hz), 4.77 (2H, s), 6.36 (1H, d, J=2.3 Hz), 7.37-7.43 (3H, m), 7.51 (2H, d, J=8.3 Hz), 12.17(1H, br. s.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; sodium iodide; In water; N,N-dimethyl-formamide; at 100℃; for 15h; | Example 2153-[4-(Cyclopropylmethoxy)phenyl]-2-[3-(methylsulfonyl)propyl]sulfanyl}-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; A 1 M aqueous solution of sodium hydrogen carbonate (0.64 ml) was added to a mixture of 3-[4-(cyclopropylmethoxy)phenyl]-2-thioxo-1,2,3, 7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (200 mg) obtained by the method of Example 31, or a method pursuant to thereto, <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (187 mg) obtained by the method described in a published document, WO 08/1931, or a method pursuant to thereto, sodium iodide (96 mg) and N,N-dimethylformamide (10 ml), and the resulting mixture was stirred for 15 hours at 100 C. The reaction mixture was returned to room temperature, and then was diluted with ethyl acetate. The dilution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by chromatography, and then was recrystallized from a mixed solvent of ethyl acetate/hexane. Thus, the title compound (160 mg) was obtained as a white powder.1H NMR (300 MHz, DMSO-d6) delta ppm 0.32-0.39 (2H, m), 0.57-0.64 (2H, m), 1.21-1.32 (1H, m), 2.01-2.13 (2H, m), 2.97 (3H, s), 3.12-3.21 (4H, m), 3.88(2H, d, J=6.8 Hz), 6.43 (1H, d, J=3.4 Hz), 6.98 (1H, d, J=3.4 Hz), 7.04 (2H, d, J=9.1 Hz), 7.22 (2H, d, J=9.1 Hz), 11.84 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Example 181{ (3S) -6- [ (3-{2-ethoxy-4- [3- (methylsulfonyl) propoxy] -IH- benzimidazol-1-yl } -2-methylbenzyl ) amino] -2 , 3-dihydro-l- benzofuran-3-yl} acetic acid; [ 1203 ][1204]Methyl [ (3S) -6-{ [3- (2-ethoxy-4-hydroxy-lH-benzimidazol-l- yl) -2-methylbenzyl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate (116 mg, 0.2 mmol) , 3- (methylsulfonyl) propyl p-toluenesulfonate (88 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol) were suspended in N, N- dimethylformamide (3 mL) and the suspension was stirred at 60C for 2 hr. The reaction mixture was allowed to cool, diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 40:60) to give an oil (130 mg) . The obtained oil was dissolved in methanol (5 mL) -tetrahydrofuran (5 mL) , 1 M aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at 5O0C for 1 hr. Water (10 mL) was added, and the volatile component was evaporated under reduced pressure. 1 M Aqueous hydrochloric acid solution (0.5 mL) was added, and the mixture was diluted with saturated brine, extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure to give the title compound (77 mg, yield 65%) as a white solid.1H NMR (300 MHz, DMSO-d6) delta 1.32 (3H, t, J = 7.0 Hz), 1.93 (3H, s), 2.17-2.29 (2H, m) , 2.36-2.47 (IH, m) , 2.57-2.69 (IH, m) , 3.05 (3H, s), 3.34-3.39 (3H, m) , 3.54-3.67 (IH, m) , 4.05-4.14 (IH, m) , 4.22-4.40 (4H, m) , 4.46-4.65 (3H, m) , 6.00-6.19 (3H, m) , 6.43 (IH, d, J = 7.9 Hz), 6.76 (IH, d, J = 7.9 Hz), 6.88- 7.04 (2H, in) , 7.20-7.26 (IH, m) , 7.34 (IH, t, J = 7.5 Hz), 7.42-7.48 (IH, m) . MS m/z 594 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h;Inert atmosphere; | To a solution of 4-bromo-3,5-dimethylphenol (2.01g, lOmmol) and 3 -(methyl sulfonyl)propyl 4-methylbenzenesulfonate (3.5 lg, 12.0mmol) in N,N-dimethylformamide (20mL) was added potassium carbonate (1.80g, 13.0mmol), and the mixture was stirred at 90 C for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate : hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give a colorless crystals product 25 (2.73g, yield 85%). |
67% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h; | Weighing 4-bromo-3,5(dimethyl)phenol (2.0g, 10mmol), YZ-1 (2.92g, 10mmol), potassium carbonate (2.76g, 20mmol), dissolved in 20ml N,N-dimethyl formamide, in the reaction system 90 C stirring in oil bath 24 hours. In the reaction system by adding 150 ml ethyl acetate dilution, water sequentially, saturated salt water washing, anhydrous sulfuric acid nano dry, filtered, concentrated to obtain crude products, rapid column chromatography purification (petroleum ether: ethyl acetate: dichloromethane = 1:1:1), to obtain the product 12e (2.15g), yield 67%. |
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 46h;Product distribution / selectivity; | Example 9Synthesis of 2-bromo-l, 3-dimethyl-5- [3- (methylsulfonyl) propoxy] benzene; [0420][0421]4-Bromo-3, 5-dimethylphenol (40.00 g) , 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (72.71 g) and potassium carbonate (35.75 g) were added toN, N-dimethylformamide (400 mL) , and the mixture was stirred. The mixture was heated to 70C, stirred for 46 hr, and cooled to 5C. Water (200 mL) was added dropwise at 10C or below, seed crystal (60 mg) was added, and water (400 mL) was continuously added. After stirring for 2 hr, the precipitated crystals were collected by filtration, washed with water (400 mL) and dried to give the title compound (63.08 g) .XH NMR (300 MHz, CDC13) : delta 2.28-2.36 (m, 2H) , 2.38 (s, 6H) , 2.93-2.97 (m, 3H) , 3.20-3.26 (m, 2H) , 4.07 (t, J=5.8 Hz, 2H) , 6.63 (s, 2H) , 7.26 (s, 1H) . |
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 18h; | Step C: 2-bromo- 1,3 -dimethyl-5 -(3 -(methylsulfonyl)propoxy)benzene (34-3)To a solution of compound 34-2 (32.1 g, 110 mmol) in DMF (300 mL) was added 4-bromo-3,5- dimethylphenol (20.1 g, 100 mmol), and K2C03 (16.5 g, 120 mmol). The resulting mixture was stirred at 100 C for 18 hours. Then water was added and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine, dried and concentrated to give a residue. The residue was purified by chromatography on silica gel(petroleum ether:ethyl acetate = 3/1) to give compound 34-3. MS (ESI) m1z(M+H):32 1.0/323.0. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 18h; | To a solution of compound 34-2 (32.1 g, 110 mmol) in DMF (300 mL) was added 4-bromo-3,5-dimethylphenol (20.1 g, 100 mmol), and K2C03 (16.5 g, 120 mmol). The resulting mixture wasstirred at 100 C for 18 hours. Then water was added and the mixture was extracted with ethylacetate (150 mL x 3). The combined organic layers were washed with brine, dried andconcentrated to give a residue. The residue was purified by chromatography on silica gel15 (petroleum ether:ethyl acetate= 3/1) to give compound 34-3. MS (ESI) m/z(M+Hf:321.0/323.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; | A mixture of 2-amino-3-hydroxy-5-( isopropylsulfonyl) benzonitrile (0.73 g) , 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (1.06 g) , potassium carbonate (0.50 g) and N,N-dimethylformamide (10 mL) was stirred overnight at 700C. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: ethyl acetate) to give the title compound (0.95 g, yield 87%) as colorless crystals. Melting point 142-143C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.50 g | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 13h; | A mixed solution of <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (1.86 g) that can be obtained by a publicly known method, 4-bromophenol (1.0 g), potassium carbonate (1.20 g), and N,N-dimethylformamide (15 mL) was heated with stirring at 80 C. for 13 hours. The reaction mixture was left to reach room temperature, and to the reaction mixture, water was added, followed by filtering the deposited solid to obtain the subject compound (1.50 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | Step 1 c Synthesis of (2'-Methyl-4'-(3-(methylsulfonyl) propoxy)-[1 , 1 '-biphenyl]-3-yl) methanol To a solution of 3'-(hydroxymethyl)-2-methyl-[1 , 1 '-biphenyl]-4-ol (compound of Step 1 b, 50 mg, 0.233 mM) and <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (75 mg, 0.257 mM) in anhydrous DMF (2 ml), cesium carbonate (76 mg, 0.233 mM) was added at RT. The reaction mixture was stirred at RT for 2 h. Reaction was then quenched by addition of water (5 ml) and allowed to stir for 10 min and then extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography (silica gel, 40% ethyl acetate in n-hexane) to obtain the compound ethyl 2-(3-(4-((2'-methyl-4'- (3-(methylsulfonyl) propoxy)-[1 , 1 '-biphenyl]-3-yl) methoxy) phenyl) oxetan-3-yl) acetate (98 mg, 0.170 mM) as colorless oil. Yield: 99%; 1 H NMR (300 MHz, CDCI3): delta 7.44-7.39 (m, 1 H), 7.39-7.31 (m, 2H), 7.25 (d, J= 7.5 Hz, 1 H), 7.18 (d, J= 8.4 Hz, 1 H), 6.81 (d, J= 5.4 Hz, 1 H), 6.77 (s, 1 H), 4.76 (d, J= 4.8 Hz, 2H), 4.18-4.14 (t, J= 5.4, 1 1 .1 Hz, 2H), 3.32-3.27 (t, J= 15.6, 15.3 Hz, 2H), 2.98 (s, 3H), 2.40-2.35 (m, 2H), 2.27 (s, 3H), 1 .70 (t, J= 5.4, 1 1 .1 Hz, 1 H) ; MS: (m/z) 357 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With caesium carbonate; In N,N-dimethyl-formamide; for 2h; | Step 1 b Synthesis of 3', 5'-Dimethyl-4'-(3-(methylsulfonyl) propoxy)-[1 , 1 '-biphenyl]-3- carbaldehyde A mixture of 4'-hydroxy-3',5'-dimethyl-[1 ,1 '-biphenyl]-3-carbaldehyde (compound of Step 1 a, 50 mg, 0.221 mM), 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (78 mg, 0.265 mM) and cesium carbonate (108 mg, 0.331 mM) in DMF was stirred for 2 h. The reaction mixture was concentrated. The crude compound was purified by column chromatography to obtain the compound 3', 5'- dimethyl-4'-(3-(methylsulfonyl) propoxy)-[1 , 1 '-biphenyl]-3-carbaldehyde (55 mg) as colorless liquid. Yield: 71 %; 1 HNMR (300 MHz, CDCI3): delta 10.08 (s,1 H), 8.15 (s, 1 H), 7.98 (d, J= 7.8 Hz, 1 H), 7.87 (d, J= 7.5 Hz, 1 H), 7.81 (d, J= 8.1 Hz, 1 H), 7.68-7.63 (t, J= 7.5, 15 Hz, 1 H), 7.51 (d, J= 8.1 Hz. 1 H), 3.91 -3.87 (t, J= 6, 12Hz, 2H), 3.40-3.37 (m, 2H), 3.04 (s, 3H), 2.31 (s, 6H), 2.20-2.15 (m, 2H); MS: (m/z) 369 (M+Na) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | Example 80 Ethyl 2-(3-(4-((3'-methoxy-4'-(3-(methylsulfonyl) propoxy)-[1 , 1 '-biphenyl]-3-yl) methoxy) phenyl) oxetan-3-yl) acetate (Compound 80) To a solution of ethyl 2-(3-(4-((4'-hydroxy-3'-methoxy-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (40 mg, 0.089 mM; prepared by the method analogus to method described in Step 1 d of Example 1 ) and 3-(methyl sulfonyl)propyl 4-methylbenzenesulfonate (28.7 mg, 0.098 mM) in anhydrous DMF (2 ml), cesium carbonate (58 mg, 0.178 mM) was added at RT. The reaction mixture was stirred at RT for 2 h and then quenched by addition of 5 ml water, stirred for 10 min and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography (silica gel, 40% ethyl acetate in n-hexane) to obtain the compound ethyl 2-(3-(4-((3'- methoxy-4'-(3-(methylsulfonyl) propoxy)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl) oxetan- 3-yl)acetate (50 mg, 0.087 mM) as colorless oil. Yield: 98 %; 1 H NMR (300 MHz, DMSO-de): delta 7.72 (s, 1 H), 7.62 (d, J= 7.2 Hz, 1 H), 7.47 (d, J= 7.5 Hz, 1 H), 7.42-7.38 (t, J= 6.9 Hz, 1 H), 7.24 (s, 1 H),7.18-7.16 (m, 3H), 7.07 (d, J= 8.1 , 1 H), 7.02 (d, J= 8.4 Hz, 2H), 5.15 (s, 2H), 4.75 (s, 4H), 4.14-4.10 (t, J= 6Hz, 2H), 3.93-3.88 (m, 2H), 3.86 (s, 3H), 3.28-3.26(m, 2H), 3.08 (s, 2H), 3.03 (s, 3H), 2.15 (s, 2H), 1 .04 (t, J= 7.2 Hz, 3H); MS: (m/z) 569 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | Step 1 c Synthesis of (4'-(3-(Methylsulfonyl) propoxy)-3'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl) methanol To a solution of 3'-(hydroxymethyl)-3-(trifluoromethyl)-[1 , 1 '-biphenyl]-4-ol (compound of Step 1 b, 100 mg, 0.373 mM) in DMF (2 ml), Cs2C03 (121 mg, 0.373 mM) was added, followed by addition of 3-(methylsulfonyl) propyl 4- methylbenzenesulfonate (120 mg, 0.410 mM) and allowed to stir at RT for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate, concentrated and purified by column chromatography to obtain the pure compound (4'-(3-(methylsulfonyl) propoxy)-3'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl) methanol (122.5 mg, 0.302 mM). Yield: 81 %; 1 H NMR (300 MHz, DMSO-d6): delta 7.94 (d, J= 8.4 Hz, 1 H), 7.83 (s, 1 H), 7.61 (s, 1 H), 7.55 (d, J= 7.5 Hz, 1 H), 7.44 (d, J= 7.5 Hz, 1 H), 7.38-7.30 (m, 2H), 5.27 (t, J= 5.4 Hz, 1 H), 4.58 (d, J= 5.4 Hz, 2H), 4.31 (t, J= 5.7 Hz, 2H), 3.28-3.23 (m, 2H), 3.03 (s, 3H), 2.22 (t, J= 7.5 Hz, 2H); MS: (m/z) 41 1 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; | Step 1 b Ethyl 2-(3-(4-((3-(6-(3-(methylsulfonyl)propoxy)pyridin-3-yl)benzyl)oxy) phenyl) oxetan-3-yl)acetate (Compound 109) To a solution of ethyl 2-(3-(4-((3-(6-hydroxypyridin-3-yl)benzyl) oxy)phenyl) oxetan-3-yl)acetate (compound of Step 1 a, 40 mg, 0.095 mM) and 3- (methylsulfonyl)propyl 4-methylbenzenesulfonate (30.7 mg, 0.105 mM) dissolved in DMF (3 ml), cesium carbonate (62.07 mg, 0.322 mM) was added and stirred at 80 QC for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate, concentrated and purified by column chromatography to obtain the compound ethyl 2-(3-(4-((3-(6-(3-(methylsulfonyl) propoxy)pyridin-3-yl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (42 mg) as pale yellow semisolid. Yield: 81 %; 1 HNMR (300 MHz, DMSO-d6) delta: 8.47 (s, 1 H), 8.04-8.01 (m, 1 H) 7.73 (s, 1 H), 7.63-742 (m, 1 H), 7.52-7.34 (m, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.7 Hz, 1 H), 5.15 (s, 2H), 4.75 (s, 4H), 4.40 (t, J = 6.0 Hz, 2H), 3.99 (q, J = 6.9 Hz, 2H), 3.30-3.25 (m, 2H), 3.07 (s, 2H), 3.02 (s, 3H), 2.19- 1 .198 (m, 2H), 1 .01 (t, J = 6.9 Hz, 3H); MS: (e/z) 540.2 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Example 61 Ethyl 2-(3-(4-((2'-chloro-4'-(3-(methylsulf onyl)propoxy)-[1 , 1 '-biphenyl]-3-yl)methoxy) phenyl)oxetan-3-yl)acetate (Compound 61 ) To the stirred solution of ethyl 2-(3-(4-((2'-chloro-4'-hydroxy-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (compound of Example 60, 405 mg, 0.894 mM) and <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (314 mg, 1 .073 mM) dissolved in DMF (5 ml), cesium carbonate (583 mg, 1 .788 mM) was added and stirred at 60 QC for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate, concentrated and purified by column chromatography to obtain the compound, ethyl 2-(3-(4-((2'-chloro-4'-(3-(methylsulfonyl)propoxy)-[1 ,1 '-biphenyl]- 3-yl)methoxy) phenyl) oxetan-3-yl)acetate (465 mg, 0.810 mM). Yield: 91 %; 1 H NMR (300 MHz, CDCI3) delta: 7.48-7.42 (m, 4H), 7.27 (d, J = 2.5 Hz, 1 H), 7.13 (d, 1 H), 7.07 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 2.1 Hz, 2 H), 6.89 (dd, J = 8.3 Hz, 2.5 Hz, 1 H), 5.1 1 (s, 2H), 5.01 (d, J = 6.0 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 4.18 (t, J = 5.3 Hz, 2H), 4.05 (q, J = 5.3 Hz, 2H), 3.28 (t, J = 7.2 Hz, 2H), 3.1 1 (s, 3H), 2.99 (s, 2H), 2.39-2.35 (m, 2H), 1 .13 (t, J = 7.2 Hz, 3 H); MS: m/z: 573 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine; In dichloromethane; for 12h;Inert atmosphere; | 4-Methylbenzene-1-sulfonyl chloride (759 mg, 3.98 mmol), 3-(methylsulfonyl)propan- 1-ol (500 mg, 3.62 mmol) and triethyl amine (0.555 ml_, 3,98 mmol) were dissolved in Dichloromethane Dry (5 mL) under nitrogen atmosphere, and the mixture was stirred for 12 hours. The solvent was removed under reduced pressure and the residue was purified by semi-preparative HPLC-UV, to afford 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (881 mg, Y = 83%) as a white solid. MS (ESi+) m/z: 293.1 [M+H]+. (0255) Tert-butyl (4-hydroxy-2,6-dimethylphenyl)carbamate (which was synthesized as reported in the synthesis of compound 34) (269 mg, 1.13 mmol), 3- (methysulfonyl)propyl 4-methybenzenesulfonate (398 mg, 1.36 mmol) and potassium carbonate (188 mg, 1.36 mmol) were dissolved in N,N-Dimethylformamide Dry (2.5 ml) and the mixture was stirred at 80C under nitrogen atmosphere for 12 hours. AcOEt (20 mL) was added, and the mixture was washed with brine (2 x 0 mL). The organic layer was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV, to afford tert-butyl (2,6-dimethyl-4-(3- (methylsulfonyl)propoxy)pheny[)carbamate (375 mg, Y = 93%) as a white solid. MS (ESI+) m/z: 380.2 [ +Naf . (0256) Starting from tert-butyl (2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)carbamate (375 mg, 1.05 mmol), 2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)aniline, hydrochloride salt (309 mg, Y = quant.) was obtained as reported in the synthesis of compound 34. MS (ESI+) m/z: 258.1 [M+H]+. (0257) Starting from 2,6-dimethyl-4-(3-(methysulfonyl)propoxy)aniline, hydrochloride salt (46.1 mg, 0.157 mmoi) methyl 7-(3-(N-(2,6-dimethyl-4-(3- (methylsulfonyl)propoxy)phenyl)sulfamoyl) (0258) phenyl)heptanoate was obtained (33 mg, Y = 39%) as described in Procedure A. MS (ESI+) m/z: 562.3 [M+Na]+. (0259) Compound 35 was then obtained by hydrolysis of the ester derivative (20 mg, 0.046 mmol) as described for compound 1 , as a white solid (23 mg, Y = 83%). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.24 - 1.43 (m, 4 H) 1.51 - 1 .67 (m, 4 H) 1 .96 (s, 6 H) 2.26 - 2.41 (m, 4 H) 2.61 (t, J=7.58 Hz, 2 H) 2.97 (s, 3 H) 3.22 - 3.31 (m, 2 H) 4.04 (t, .7=5.68 Hz, 2 H) 6.32 (br s, 1 H) 6.52 (s, 2 H) 7.33 - 7.41 (m, 2 H) 7.48 - 7.58 (m, 2 H) 9.36 (br s, 2 H). MS (ESI+) m/z: 526.2 [M+H]+. |
1.6 g | With pyridine; In dichloromethane; at 0 - 20℃; for 12h; | To a solution of 3-(methylsulfonyl)propan-1 -ol (1 .0 g) in dichloromethane (10 mL) and pyridine (1 .5 mL) is added at 0C p-toluene-sulfonylchloride (1 .38 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCI solution and brine. After drying (MgSO4) the solvent is evaporated to give the title compound. Yield: 1 .6 g; LC (method 1 ): tR = 0.82 min; Mass spectrum (ESI+): m/z = 293 [M+H]+. |
With dmap; triethylamine; In tetrahydrofuran; at 50℃; for 14h; | Step C. 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate 3-(Methylsulfonyl)propan-l-ol (102 mg, 0.737 mmol), DMAP (0.88 g, 7.2 mmol), and TEA (6.1 ml, 43.4 mmol) were dissolved in THF (29.0 ml). Tosyl chloride (6.1 g, 31.8 mmol) was added and the mixture heated at 50C for 14 hours. The mixture was cooled to RT, diluted with water (300 ml), and extracted with EtOAc (3 x 150 ml). The organic fractions were combined, washed with brine, dried over magnesium sulfate, filtered and the volatiles removed in vacuo. The crude product was purified by column chromotagraphy on silica gel, BIOTAGE (Uppsala, Sweden) HP 340 g, using a gradient eluant of 5-100% EtOAc:Hexanes to the title compound. MS Ret: (m/z): 293 (M+H)+- |
With dmap; triethylamine; In tetrahydrofuran; at 50℃; for 14h; | Step C. 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate 3-(Methylsulfonyl)propan-l-ol (102 mg, 0.737 mmol), DMAP (0.88 g, 7.2 mmol), and TEA (6.1 ml, 43.4 mmol) were dissolved in THF (29.0 ml). Tosyl chloride (6.1 g, 31.8 mmol) was added and the mixture heated at 50C for 14 hours. The mixture was cooled to RT, diluted with water (300 ml), and extracted with EtOAc (3 x 150 ml). The organic fractions were combined, washed with brine, dried over magnesium sulfate, filtered and the volatiles removed in vacuo. The crude product was purified by column chromotagraphy on silica gel, BIOTAGE (Uppsala, Sweden) HP 340 g, using a gradient eluant of 5-100% EtOAc:Hexanes to the title compound. MS Ret: (m/z): 293 (M+H)+- | |
With triethylamine; In dichloromethane; at 0 - 15℃; for 12h; | To a stirred solution of 3-methylsulfonylpropan-1-ol (500 mg, 3.62 mmol) in DCM (10 mL) was added triethylamine (549 mg, 5.43 mmol). Then to the mixture was added a solution of tosyl chloride (759 mg, 3.98 mmol) in DCM (10 mL) at 0 C. The resulting mixture was stirred at 15 C for 12 hrs, and then partitioned between DCM and H20. The separated organic layer was washed sequentially with water, hydrochloric acid and brine, then dried over anhydrous Na2SO4 and concentrated under reduced pressure give 3-methylsulfonylpropyl 4-methylbenzenesulfonate (900 mg) as a light yellow oil, which was used directly in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
268 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h; | To a solution of 3-bromo-4-methylphenol (200 mg) and K2CO3 (1 93 mg) in N,N- dimethylformamide (5 mL) is added 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (375 mg). The mixture is stirred for 12 hours at 90C and then partitioned between water and ethyl acetate. The organic phase is washed with brine and dried (MgSO4) . Th e solvent is eva porated a nd th e res id u e is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20?20:80) to give the title compound. Yield: 268 mg; LC (method 1 ): tR = 1 .12 min; Mass spectrum (ESI+): m/z = 307 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Step 1: synthesis of (4-chloro-2-nitro-phenyl)-(3-methanesulfonyl-propyl)-carbamic acid tertbutyl ester (4-Chloro-2-nitro-phenyl)- (3-methanesulfonyl-propyl)-carbamic acid tert-butyl ester was prepared according to Scheme 1. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF (5 mL) was added NaH (170 mg, 4.3 mmol, 60 wt%). The mixturewas stilTed for 30 mm at RT, then <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (0.75 g,2.56 mmol) was added. The solution was heated to 50 C and stirred for overnight. After cooledto RT, H20 (30 mL) was added and the solution was extracted with DCM (40 mLx3). Theorganic layer was dried over anhydrous and concentrated. The residue was purified by prep-TLC(DCM) to give tert-butyl 4-chloro-2-nitrophenyl(3-(methylsulfonyl)propyl)carbamate (360 mg, yield: 69%) as pale oil. MS obsd. (ESIj [(M+H)]: 393.0. | |
69% | To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF (5 mL) was added NaH (170 mg, 4.3 mmol, 60 wt %). The mixture was stirred for 30 min at RT, then <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (0.75 g, 2.56 mmol) was added. The solution was heated to 50 C. and stirred for overnight. After cooled to RT, H2O (30 mL) was added and the solution was extracted with DCM (40 mL*3). The organic layer was dried over anhydrous and concentrated. The residue was purified by prep-TLC (DCM) to give tert-butyl 4-chloro-2-nitrophenyl(3-(methylsulfonyl)propyl)carbamate (360 mg, yield: 69%) as pale oil. MS obsd. (ESI+) [(M+H)+]: 393.0. | |
69% | (4-Chloro-2-nitro-phenyl)-(3-methanesulfonyl-propyl)-carbamic acid tert-butyl ester was prepared according to Scheme 1. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF (5 mL) was added NaH (170 mg, 4.3 mmol, 60 wt %). The mixture was stirred for 30 min at RT, then <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (0.75 g, 2.56 mmol) was added. The solution was heated to 50 C. and stirred for overnight. After cooled to RT, H2O (30 mL) was added and the solution was extracted with DCM (40 mL×3). The organic layer was dried over anhydrous and concentrated. The residue was purified by prep-TLC (DCM) to give tert-butyl 4-chloro-2-nitrophenyl(3-(methylsulfonyl)propyl)carbamate (360 mg, yield: 69%) as pale oil. MS obsd. (ESI+) [(M+H)+]: 393.0. |
69% | To a solution of 3-(Methylthio)-1-propanol (20g, 0.19mol) and TEA (66ml, 0.48mol) in DCM (800mL) cooled at 0C was added p-toluenesulfonyl chloride (44g, 0.23mol, dissoloved in 200mL DCM) dropwise. After addtion, the mixture was then stirred at r.t. overnight. After the reaction was complete, the resluting solution was washed with saturated Na2CO3 solution, brine, dried over MgSO4 and concentrated in vacuo to give the crude of 3-methylsulfanylpropyl 4-methylbenzenesulfonate, which was used in the next step without further purification. To the solution of the crude of 3-methylsulfanylpropyl 4-methylbenzenesulfonate (prepared above) in DCM (200 mL) cooled at 0oC was added m-CPBA (66g, 0.39mol) slowly and the mixture was then stirred at rt overnight. After the reaction was complete, the mixture was washed with saturated sodium thiosulfate (300mL) 3 times , saturated sodium bicarbonate (300mL) 3 times, dried over MgSO4 and then concentrated in vacuo to give <strong>[263400-88-0]3-methylsulfonylpropyl 4-methylbenzenesulfonate</strong> (11b, 38g, 69% yield over 2 steps) as a white solid. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF(5mL) cooled at 0oC was added NaH( 169 mg, 4.4 mmol). The mixture was then stirred at rt for 30mins. Then to the resulting solution was added <strong>[263400-88-0]3-methylsulfonylpropyl 4-methylbenzenesulfonate</strong> (11b, 750 mg, 2.6 mmol) and the mixture was stirred at 50oC overnight. After the reaction was complete, to the mixture was added water (30 mL) and the resulting mixture was extracted with DCM (50 mL) 3 times. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with DCM:MeOH 20 :1) to give tert-butyl N-(4-chloro-2-nitro-phenyl)-N-(3-methylsulfonylpropyl)carbamate(11c, 360 mg, 69% yield). To a soltuion of tert-butyl N-(4-chloro-2-nitro-phenyl)-N-(3-methylsulfonylpropyl)carbamate (11c, 360 mg, 1.45 mol) in MeOH (10 mL) was added 2% Pt/C (50mg) under N2 atmosphere, the mixture wa then hydrogenated at rt for 3 hours. After the reaction was complete, the mixture was filtred and the filtrate was concentrated in vacuo to give the crude of tert-butyl N-(2-amino-4-chloro-phenyl) -N-(3-methylsulfonylpropyl)carbamate (11d, 330 mg, 100% yield), which was used in the next step directly without further purificaton. A mixture of tert-butyl N-(2-amino-4-chloro-phenyl)-N-(3-methylsulfonylpropyl)carbamate (11d, 320 mg, 0.92mmol) and sodium chloroacetate (130 mg, 1.1 mmol) in 4N HCl (15 mL) was stirred to 100oC overnight. After the reaction was complete, The reaction was concentrated in vacuo and the residue was redissoved in DCM (100 mL). The resulting soltuion was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column crhomatography on silica gel (elution with DCM/EtOAc=3/1) to give 5-chloro-2-(chloromethyl) -1-(3-methylsulfonylpropyl)benzimidazole (11e, 130 mg, 44% yield). To a mixture of 2-(methylsulfonyl)-1H-indole (72 mg, 0.37 mmol) and 5-chloro-2-(chloromethyl) -1-(2- (methylsulfonyl)ethyl)-1H-benzo[d]imidazole (11e, 120 mg, 0.37mmol) in DMF (3 mL) was added K2CO3 (104 mg, 0.74 mmol) and the mixture was stirred at rt overnight. After the reaction was completed, the mixture was filtered and the filtrate was purified by preparative HPLC to give 5-chloro-2-[(3-methylsulfonylindol-1-yl)methyl]-1-(3-methylsulfonylpropyl)benzimidazole (11, 100 mg, 78%). MS: calcd (MH+) 480.1, exp (MH+) 480.1. 1H NMR(DMSO-d6, 400MHz):delta8.29(s, 1H), 7.80-7.86(m, 1H), 7.65-7.73(m, 3H), 7.26-7.34(m, 3H), 5.92(s, 2H), 4.86(t, J=7.6Hz, 2H), 3,73(br, 3H), 3.19(t, J=8.0Hz, 2H), 2.96(s, 3H), 2.08(t, J=7.6Hz, 2H); 13C NMR (101MHz, DMSO-d6) delta151.4, 143.2, 137.3, 134.7, 134.6, 126.9, 124.2, 123.8, 123.3, 122.6, 119.5, 119.2, 115.5, 112.4, 112.3, 51.1, 45.6, 43.6, 42.3, 23.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 18h; | Step A: 1 -fluoro-3 -(3 -(methylsulfonyl)propoxy)-5 -(trifluoromethyl)benzene (10-2)To a solution of compound 10-1 (400 mg, 2.22 mmol) in DMF (5.0 mL) was added compound la (973 mg, 3.33 mmol), and K2C03 (613 mg, 4.44 mmol). The resulting mixture was stirred at 100 C for 18 hours. H20 was added and the resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried and concentrated to give a residue, which was purified by preparative TLC on silica gel eluted with petroleum ether:ethylacetate (5:1) to give compound 10-2. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 18h; | To a solution of compound 10-1 (400 mg, 2.22 mmol) in DMF (5.0 mL) was added compound 1a(973 mg, 3.33 mmol), and K2C03 (613 mg, 4.44 mmol). The resulting mixture was stirred at 100C for 18 hours. H20 was added and the resulting mixture was extracted with EtOAc (15 mL x3). The combined organic layers were washed with brine, dried and concentrated to give aresidue, which was purified by preparative TLC on silica gel eluted with petroleum ether:ethyl15 acetate ( 5: 1) to give compound 10-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | (Reference Example 28) (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-d imethyl-2-(1-{5-[3-(methylsulfonyl)propoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetr ahydroquinolin-5-ol To a solution of 145 mg (0.224 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.7 ml of N,N-dimethylformamide, 130 mg (0.445 mmol) of 3-(methylsulfonyl)propyl p-toluenesulfonate and 135 mg (0.977 mmol) of potassium carbonate were added, and the mixture was stirred at 80C for 4 hours. 44 mg (0.337 mmol) of 2-chloro-5-hydroxypyrimidine was further added thereto, and the mixture was stirred at 80C for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate = 55/45-25/75 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 137.0 mg of the title compound as a white solid (yield: 80%). 1H-NMR spectrum (400 MHz, CD2 Cl2) delta: 8.03 (2H, s), 7.68-7.63 (2H, m), 7.42-7.36 (2H, m), 7.22 (1H, d, J = 47 Hz), 5.17-5.09 (1H, m), 4.69-4.62 (1H, m), 4.41-4.33 (1H, m), 4.04 (2H, t, J = 6 Hz), 3.69-3.59 (1H, m), 3.20 (2H, t, J = 8 Hz), 2.91 (3H, s), 2.83-2.56 (4H, m), 2.33-1.56 (17H, m), 1.13 (3H, s), 1.00 (3H, s), 0.65-0.58 (1H, m). Mass spectrum (EI, m/z): 768 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.8% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; | To a mixture of 4-bromo-3-(trifluoromethyl)phenol (commercial source, 570 mg, 2.365 mmol) and <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (commercial source, 691 mg, 2.365 mmol) in anhydrous DMF was added cesium carbonate (1926 mg, 5.91 mmol) and reaction was stirred overnight at RT. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic solvent was removed and the residue was purified by column chromatography to obtain the title compound (630 mg) as white solid. Yield: 73.8 % yield; 1 H NMR (CDCI3, 300 MHZ): delta 7.62 (d, J = 8.2 Hz, 1 H), 7.22 (d, J= 1 .6 Hz, 1 H), 6.91 (d, J = 8.2 Hz, 1 H), 4.17 (t, J = 6.0 Hz, 2H), 3.28 (t, J = 7.5 Hz, 2H), 2.99 (s, 3H), 2.42 -2.37 (m, 2H); MS: (m/z) 383.5 [M+ Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.6 g | With caesium carbonate; In acetonitrile;Reflux; | A mixture of 4-chloro-2-nitroaniline (3.44 g, 20.0 mmol), 3-(methylsulfonyl)propyl 4- methylbenzenesulfonate (5.53 g, 20.0 mmol) and cesium carbonate (9.78 g, 30.0 mmol) in acetonitrile (40 mL) was heated with stirring under reflux overnight. The resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 0 - 8% methanol in dichloromethane) to afford 4.60 g of 4-chloro-N-[2- (methylsulfonyl)propyl]-2-nitroaniline as an orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.3% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h; | Cs2CO3 (72.4 mg, 0.222 mmol) was added to a solution of ethyl 2-(3-(4-(2-(3-(4- hydroxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetate (Compound 76, 70.54 mg, 0.171 mmol) in DMF. The reaction mixture was stirred at RT for 10 minutes, followed by the addition of <strong>[263400-88-0]3-(methylsulfonyl)propyl 4-methylbenzenesulfonate</strong> (50 mg, 0.171 mmol). The reaction mixture was refluxed at 80 C for 1 h. After completion of reaction, the solvent was evaporated and the residue was dissolved in EtOAc. The organic layer was washed with water, dried over anhydrous Na2504 and concentrated. The crude compound was purified by flash column chromatography (1-50 % EtOAc in petroleum ether as eluent) to obtain the title compound (68 mg) as sticky liquid. Yield: 74.3 %; 1H NMR (CDC13, 300 MHz): 7.05 (d, J = 9.0 Hz, 2H), 6.99 (d, J =9.0Hz, 2H), 6.84 (d, J = 9.0Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 5.01 (d, J = 6.0Hz, 2H), 4.96 (d, J = 6.0 Hz, 2H), 4.88 (d, J = 9.0 Hz, 2H), 4.84 (d, J = 6.0 Hz, 2H), 4.11 (t, J= 6.0, 6.0 Hz, 2H), 3.99-4.06 (m, 2H), 3.75 (t, J= 6.0, 6.0 Hz, 2H), 3.27 (t, J=9.0, 9.0 Hz, 2H), 3.09 (s, 2H), 2.97 (s, 3H), 2.52 (t, J = 6.0, 6.0 Hz, 2H), 2.33-2.38 (m, 2H),1.15 (t, J= 6.0, 6.0 Hz, 3H); MS (mlz): 555.1 [M+ Na]. |
A148325 [599-91-7]
Propyl 4-methylbenzenesulfonate
Similarity: 0.87
A167649 [778-28-9]
Butyl 4-methylbenzenesulfonate
Similarity: 0.86
A259226 [5469-66-9]
Propane-1,3-diyl bis(4-methylbenzenesulfonate)
Similarity: 0.86
A225237 [40412-06-4]
2-(Thiophen-2-yl)ethyl 4-methylbenzenesulfonate
Similarity: 0.86
A216764 [80-40-0]
Ethyl 4-methylbenzenesulfonate
Similarity: 0.86
A148325 [599-91-7]
Propyl 4-methylbenzenesulfonate
Similarity: 0.87
A167649 [778-28-9]
Butyl 4-methylbenzenesulfonate
Similarity: 0.86
A259226 [5469-66-9]
Propane-1,3-diyl bis(4-methylbenzenesulfonate)
Similarity: 0.86
A225237 [40412-06-4]
2-(Thiophen-2-yl)ethyl 4-methylbenzenesulfonate
Similarity: 0.86
A216764 [80-40-0]
Ethyl 4-methylbenzenesulfonate
Similarity: 0.86
A126721 [357913-53-2]
3-(Methylsulfonyl)propyl methanesulfonate
Similarity: 0.57
A120919 [3185-99-7]
1-Methyl-4-(methylsulfonyl)benzene
Similarity: 0.54
A670469 [22821-77-8]
4-(Methylsulfonyl)benzyl Alcohol
Similarity: 0.54
A169001 [220798-39-0]
(3-(Methylsulfonyl)phenyl)methanol
Similarity: 0.54