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CAS No. : | 1877-71-0 | MDL No. : | MFCD00029972 |
Formula : | C9H8O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WMZNGTSLFSJHMZ-UHFFFAOYSA-N |
M.W : | 180.16 | Pubchem ID : | 601880 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 44.68 |
TPSA : | 63.6 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.1 cm/s |
Log Po/w (iLOGP) : | 1.53 |
Log Po/w (XLOGP3) : | 1.83 |
Log Po/w (WLOGP) : | 1.17 |
Log Po/w (MLOGP) : | 1.51 |
Log Po/w (SILICOS-IT) : | 1.1 |
Consensus Log Po/w : | 1.43 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.25 |
Solubility : | 1.01 mg/ml ; 0.00558 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.79 |
Solubility : | 0.295 mg/ml ; 0.00164 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.85 |
Solubility : | 2.57 mg/ml ; 0.0143 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.42 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
75% | With N-iodo-succinimide; [4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,N1‘]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(lll) hexafluorophosphate; iodine; caesium carbonate In 1,2-dichloro-ethane at 50℃; for 24 h; Inert atmosphere; Irradiation; Sealed tube | General procedure: To a 15 mL test tube with septum Cs2CO3 (0.6 mmol, 195 mg), aromaticcarboxylic acid (1) (0.3 mmol), [Ir(dF(CF3)ppy)2dtbbpy]PF6 (D) (6 μmmol, 6.7 mg), NIS (1.5mmol, 337.5 mg) and I2 (60 μmol, 20 molpercent) were added. The tube was evacuated and backfilledwith argon for three times, and then 3 mL of dry DCE was added through a syringer under argon.The tube was sealed with Parafilm Mr® and placed in an oil bath with a contact thermometer, andthe reaction was carried out at 50 °C under irradiation with 6 × 5 W blue LEDs (λmax = 455 nm).After 24 h or 36 h, the resulting mixture was filtered through a 2 cm thick pad of silica, and thesilica was washed with DCM) (50 mL). The filtrate was collected and the solvent was removed invacuo. The crude residue was purified by silica gel flash column chromatography to provide thetarget product (2). (Note: The reaction was very sensitive to moisture, and the yields sharplydecreased to less than 5percent when 0.01 equivalent of H2O was added to the reaction system). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With borane-THF In tetrahydrofuran at 0 - 20℃; Inert atmosphere | Mono-methyl isophthalate 22 (2.0 mmol) was placed in a 50 mL round bottom flask and dissolved in dry THF (10 mL) under nitrogen atmosphere. The reaction flask was placed in an ice bath to reach 0°C and 1M borane tetrahydrofuran complex solution (10.0 mmol) was added dropwise. After 15 minutes at 0°C the ice bath was removed and the reaction was stirred at room temperature overnight. After reaction completion ice was carefully added to the reaction, and the mixture extracted three times with diethyl ether. The collected organic phase was washed with brine, dried over anhydrous Na2SO4, and the solvent evaporated in vacuum to obtain 21b (yield 97percent) which needed no further purification. 1H NMR (CDCl3) δ 8.04 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.44 (t, J= 7.8 Hz, 1H), 4.76 (s, 2H), 3.92 (s, 3H) ppm. |
87% | Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 4.25 h; Stage #2: With water In tetrahydrofuran at 0℃; |
EXAMPLE 25 N-((lR,2S)-2-((S)-4-(4-Chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine-l- carbonyl)cyclohexyl)-3-(hydroxymethyl)benzamideStep 1: Methyl 3-(hydroxymethyl)benzoate [00163] A solution of 3-(methoxycarbonyl)benzoic acid (1.05g, 5.83 mmol) in THF (25 mL) was cooled to 0 0C, and then treated with the dropwise addition of 2.0 M borane-methylsulfide complex in THF (14.57 mL, 29.1 mmol) at a rate which did not allow the temperature to exceed 5 0C. The mixture was stirred at 0 0C for 15 minutes, and then allowed to warm to room temperature where it stirred for 4 hours. After this time, the reaction was cooled to 0 0C and then quenched with the addition of small pieces of ice, causing vigorous gas evolution. When gas evolution had ceased, the mixture was diluted with brine and extracted 3X with ethyl acetate. The combined organic phases were washed 3X with diluted bleach to remove residual methyl sulfide, 3X with saturated sodium carbonate to remove any unreacted acid, IX with water, IX with brine, dried over sodium sulfate and then concentrated in vacuo <n="104"/>to yield the methyl 3-(hydroxymethyl)benzoate (845mg, 5.09 mmol, 87 percent yield) as a colorless oil. |
84% | With borane-THF In tetrahydrofuran at 0 - 20℃; for 3 h; | Step A. Methyl 3-(hydroxymethyl)benzoate[00222] To a solution of 3-(methoxycarbonyl)benzoic acid (0.200 g, 1.1 1 mmol) in THF (6.0 mL) at 0 °C was added borane tetrahydrofuran complex (5.55 mL, 5.55 mmol) slowly. The reaction mixture was slowly warmed to room temperature and stirred at for 3 h. After this time, the reaction mixture was diluted with EtOAc and quenched very slowly with water. The organic layer was separated, washed with water and brine, dried over anhydrous MgS04, filtered, and concentrated to afford the title compound (0.16 g, 84percent yield) as a colorless oil. LCMS, [M+H]+ = 167.0. |
84% | Stage #1: With borane-THF In tetrahydrofuran at 18 - 25℃; for 24 h; Stage #2: With methanol In tetrahydrofuran at 18 - 25℃; for 1 h; |
Methyl 3-(hydroxymethyl)benzoate was prepared as follows:mono-Methylisophthalate (8 g, 44.4 mmol, 1 eq) was dissolved in tetrahydrofuran (250 ml) at room temperature. 1.0M Borane-THF solution (222 ml, 222 mmol, 5 eq) was added slowly and the solution stirred for 24 hours at RT. After this time, methanol (30 ml) was slowly added and the reaction stirred at RT for 1 hour after which it was concentrated. The residue was partitioned between ethyl acetate (50 ml) and 10percent aq ammonium hydroxide solution and the organic layer separated. The aqueous layer was washed with ethyl acetate (2.x.50 ml) and the organic layers combined, washed with 10percent aq ammonium hydroxide solution (2.x.50 ml), 2M hydrochloric acid (2.x.50 ml), water (2.x.50 ml), brine (2.x.50 ml) and dried over anhydrous sodium sulphate. The solution was concentrated to give methyl 3-(hydroxymethyl)benzoate as a colourless oil (6.2 g, 84percent).1H NMR (400.132 MHz, DMSO) δ 3.86 (s, 3H), 4.58 (d, 2H), 5.33 (t, 1H), 7.45-7.49 (m, 1H), 7.59 (d, 1H), 7.84 (d, 1H), 7.96 (s, 1H). MS: N/A |
82% | With dimethylsulfide borane complex In tetrahydrofuran at 7 - 20℃; for 6.75 h; Inert atmosphere | In a 3-necked 500 mL round-bottomed flask equipped with a mechanical stirrer was placed dimethyl isophthalate (20.00 g, 0.103 mol, 1 eq.) dissolved in acetone (200 mL). To this mixture was added dropwise over 20 min a sln of NaOH (4.33 g, 0.108 mol, 1.05 eq.) in MeOH (40 mL). The resulting milky suspension was stirred at r.t. overnight. Then, another portion of NaOH (0.433 g, 0.011 mol, 0.1 eq.) was added into the reaction and the suspension was stirred for another 5 hours. The solvent was removed under vacuum and the white precipitate thus obtained was dissolved in water (400 mL). Concentrated HCl (15 mL) was added dropwise until pH~1. Then, the suspension was filtered; the collected precipitate was washed with water (4×100 mL) and dried under vacuum at 65°C for 24 hours to give white solid 18.25 g. The obtained monomethyl isophthalate was used directly without further purification. In a 3 necked 500 mL round-bottomed flask equipped with a magnetic stirrer and a low temperature thermometer under a nitrogen atmosphere was placed monomethyl isophthalate (5.00 g, 0.027 mol, 1 eq.) dissolved in dry THF (125 mL). Then, this solution was placed in an ice-water bath and a solution of BH3•SMe2 (2M in THF, 70 mL, 0.14 mol, 5 eq.) was added dropwise slowly over 90 min to maintain the temperature in the solution below 7°C. After another 15 min, the cooling bath was removed and the solution was allowed to reach ambient temperature. After 5 hours, the reaction was carefully quenched (strong gas evolution) with small pieces of ice while cooling in an ice-water bath. When the gas evolution ceased, brine (50 mL) was added and the resulting mixture was extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with diluted bleach (50 mL, original solution 9.6percent bleach diluted 10 times), brine (50 mL) and dried (MgSO4). The solvent was removed under vacuum to give an oil which contained a small amount of white precipitate. Diethyl ether (20 mL) was added and the solid was removed by filtration and washed with Et2O (2×10 mL). The filtrate was concentrated to yield a pale yellow oil (4.48 g). The crude oil was then purified by silica gel column chromatography (PE:EA, 4:1 to 7:3) to afford methyl 3-hydroxymethylbenzoate (2d) as colorless oil (3.77 g, 82percent). Rf = 0.17 (EtOAc:PE = 1:4); 1H NMR (300 MHz, CDCl3), δ (ppm): 8.00 (s, 1H, HAr), 7.93 (dt, J = 7.7, 1.4 Hz, 1H, HAr), 7.61 – 7.51 (m, 1H, HAr), 7.40 (t, J = 7.7 Hz, 1H, HAr), 4.71 (s, 2H, OCH2), 3.89 (s, 3H, OMe). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With lithium triethylborohydride In tetrahydrofuran for 3 h; | Example 123 3-(Hydroxymethyl)benzoic Acid To 3-[(methyloxy)carbonyl]benzoic acid (0.18 g, 1.0 mmol) was added lithium triethyl borohydride (3.0 mL, 1.0 M in THF, 3.0 mmol) while stirring. The mixture was stirred for 3 h and then quenched with NH4Cl (sat.) and acidified with HCl (aq.). This solution was extracted with EtOAc, and the extract was dried over Na2SO4, filtered and concentrated to afford the title compound 0.136 g (89percent). LC-MS m/z 153 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.2% | With potassium hydroxide In methanol at 20℃; for 15h; | |
98% | With sodium hydroxide In methanol; acetone at 20℃; for 24h; | |
98% | Stage #1: dimethyl Isophthalate With methanol; sodium hydroxide In acetone at 20℃; for 25h; Inert atmosphere; Stage #2: With hydrogenchloride; water |
95% | With sodium hydroxide In methanol at 20℃; for 16h; | |
94% | hydrolysis with pig liver esterase; | |
90% | With sodium hydroxide In methanol; acetone at 25℃; for 9h; Inert atmosphere; Schlenk technique; | |
83% | With methanol; sodium hydroxide at 20℃; | 3-(Methoxycarbonyl)benzoic acid (15) Dimethylisophthalate 14 (9.7 g, 50 mmol) was added to a solution of NaOH (2.3 g, 60 mmol) in dry methanol (75 ml) and stirred at room temperature overnight. The solution so obtained was acidified with conc. HCl and evaporated to dryness. The solid formed was extracted with ethyl acetate (300 ml) and washed with water several times. The clear solution of ethyl acetate was dried over MgSO4 and evaporated to give the half-ester product. Yield (7.44 g, 83%), m.p. 188 °C (lit.27 m.p. 189 °C). 1H NMR (300 MHz, CDCl3): d 8.74 (s, 1H, ArH) 8.27 (d, J = 7.1 Hz, 2H, ArH), 7.55 (t, J = 7.1 Hz, 1H, ArH), 3.94 (s, 3H, CH3O). |
79% | With potassium hydroxide In methanol at 0 - 25℃; for 72h; | |
73% | Stage #1: dimethyl Isophthalate With methanol; sodium hydroxide In acetone at 20℃; for 18h; Stage #2: With hydrogenchloride; water | 9 Example 9; 3-[N'-(2-Nitro-benzoyl)-hydrazinocarbonyl]-benzoic acid methyl ester (26); Isophthalic acid monomethyl ester (24). A solution of dimethyl isophthalate (25 g, 128.75 mmol) was dissolved in acetone (250 mL) and a solution of NaOH (5.4 g, 135 mmol) in methanol (50 mL) was added dropwise. A white precipitated was observed and the slurry was stirred for 18 h at room temperature. Then powdered NaOH (0.5 g) was added. The acetone was evaporated until dryness and the white residue was dissolved in water (250 mL), extracted with diethylether (2×100 mL). The aqueous solution was acidified with concentrated HCl to pH 45 and the white precipitate was filtered, dried under vacuum and the desired monoacid obtained (17 g, 94.36 mmol, 73% yield) as a white solid. |
61% | With sodium hydroxide In methanol | |
55% | With sodium hydroxide In 1,4-dioxane; water at 20℃; Cooling with ice; | |
With sodium hydroxide | ||
With methanol; barium dihydroxide for 15h; | ||
With hydrogenchloride | ||
With sodium hydroxide In methanol at 20℃; | ||
With potassium hydroxide In methanol at 20℃; | ||
With lithium hydroxide; water In tetrahydrofuran; methanol | 32 EXAMPLE 32 This example describes the synthesis of compounds of the formula wherein RR and RS are each independently substituted or unsubstituted aliphatic or aromatic moiety, or RR and RS together form a substituted or unsubstituted cycloaliphatic or aromatic moiety. These compounds are prepared according to Scheme 15 and the procedure below. Esterfication of di-acid 15.2 with TMSCH2N2 gives the corresponding di-methyl ester 15.3. Basic hydrolysis (LiOH, 1 eq) of compound 15.3 yields mono-acid 15.4 which is then coupled with RRNHRS to yield compound 15.5. The basic hydrolysis (LiOH, H2O/THF/MeOH) of 15.5 gives acid 15.1. Compound 15.1, an acid of the formula RCCOOH, are used to make additional compounds of the invention. Table 11 shows exemplary compounds 15.1's. | |
Stage #1: dimethyl Isophthalate With sodium hydroxide In methanol at 20℃; Stage #2: With water | 2 To a solution of compound B2 (60 g, 0.31 mol) in 500 mL of MeOH was added a solution of NaOH (12.4 g, 0.31 mol) in 200 mL of MeOH. The mixture was stirred overnight at room temperature. It was concentrated and the residue was dissolved in 500 mL of water and extracted with Et2O. The aqueous solution was acidified with cone. HCI solution to pH = 2, the formed white precipitate was collected and dried under vacuum to give 46 g of crude compound B3 as a white solid. | |
Stage #1: dimethyl Isophthalate With sodium hydroxide In methanol at 20℃; Stage #2: With hydrogenchloride In water | B3 Synthesis of Compound B3: [Show Image] To a solution of compound B2 (60 g, 0.31 mol) in 500 mL of MeOH was added a solution of NaOH (12.4 g, 0.31 mol) in 200 mL of MeOH. The mixture was stirred overnight at room temperature. It was concentrated and the residue was dissolved in 500 mL of water and extracted with Et2O. The aqueous solution was acidified with conc. HCl solution to pH = 2, the formed white precipitate was collected and dried under vacuum to give 46 g of crude compound B3 as a white solid. | |
18.25 g | Stage #1: dimethyl Isophthalate With sodium hydroxide In methanol; acetone at 20℃; Inert atmosphere; Stage #2: With hydrogenchloride In water at 20℃; Inert atmosphere; | Methyl 3-hydroxymethylbenzoate (2d) In a 3-necked 500 mL round-bottomed flask equipped with a mechanical stirrer was placed dimethyl isophthalate (20.00 g, 0.103 mol, 1 eq.) dissolved in acetone (200 mL). To this mixture was added dropwise over 20 min a sln of NaOH (4.33 g, 0.108 mol, 1.05 eq.) in MeOH (40 mL). The resulting milky suspension was stirred at r.t. overnight. Then, another portion of NaOH (0.433 g, 0.011 mol, 0.1 eq.) was added into the reaction and the suspension was stirred for another 5 hours. The solvent was removed under vacuum and the white precipitate thus obtained was dissolved in water (400 mL). Concentrated HCl (15 mL) was added dropwise until pH~1. Then, the suspension was filtered; the collected precipitate was washed with water (4×100 mL) and dried under vacuum at 65°C for 24 hours to give white solid 18.25 g. The obtained monomethyl isophthalate was used directly without further purification. In a 3 necked 500 mL round-bottomed flask equipped with a magnetic stirrer and a low temperature thermometer under a nitrogen atmosphere was placed monomethyl isophthalate (5.00 g, 0.027 mol, 1 eq.) dissolved in dry THF (125 mL). Then, this solution was placed in an ice-water bath and a solution of BH3•SMe2 (2M in THF, 70 mL, 0.14 mol, 5 eq.) was added dropwise slowly over 90 min to maintain the temperature in the solution below 7°C. After another 15 min, the cooling bath was removed and the solution was allowed to reach ambient temperature. After 5 hours, the reaction was carefully quenched (strong gas evolution) with small pieces of ice while cooling in an ice-water bath. When the gas evolution ceased, brine (50 mL) was added and the resulting mixture was extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with diluted bleach (50 mL, original solution 9.6% bleach diluted 10 times), brine (50 mL) and dried (MgSO4). The solvent was removed under vacuum to give an oil which contained a small amount of white precipitate. Diethyl ether (20 mL) was added and the solid was removed by filtration and washed with Et2O (2×10 mL). The filtrate was concentrated to yield a pale yellow oil (4.48 g). The crude oil was then purified by silica gel column chromatography (PE:EA, 4:1 to 7:3) to afford methyl 3-hydroxymethylbenzoate (2d) as colorless oil (3.77 g, 82%). Rf = 0.17 (EtOAc:PE = 1:4); 1H NMR (300 MHz, CDCl3), δ (ppm): 8.00 (s, 1H, HAr), 7.93 (dt, J = 7.7, 1.4 Hz, 1H, HAr), 7.61 - 7.51 (m, 1H, HAr), 7.40 (t, J = 7.7 Hz, 1H, HAr), 4.71 (s, 2H, OCH2), 3.89 (s, 3H, OMe). |
With water; sodium hydroxide In methanol at 20℃; for 16h; Inert atmosphere; | General procedure A for hydrolysis of diesters No.13a-f. General procedure: An aqueous 1 M NaOH solution (1.0 eq)was added to a solution of diester No.12a-b (1.0 eq) in MeOH (1 mL/0.1 mmol of the diester). Afterstirring at room temperature for 16 h, the solution was acidified with aqueous 5% KHSO4 solution topH 3, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). Combined organic extractswere washed with brine (20 mL), dried over anhydrous Na2SO4 and evaporated under reducedpressure to afford monoester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; N,N-dimethyl-formamide In toluene at 92℃; for 0.833333h; | |
92% | With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 2.5h; Reflux; | |
87% | With oxalyl dichloride In dichloromethane at 40℃; for 1h; | 10a Intermediate 10a: methyl S-fchlorocarbonyDbenzoate.; Into a 250-mL round bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (6.2 g, 34.44 mmol, 1.00 equiv) in dichloromethane (50 mL), oxalyl dichloride (8.74 g, 69.37 mmol, 2.00 equiv), and Ν,Ν-dimethylformamide (cat.). The resulting solution was stirred for 1 h at40°C in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 6.6 g (87%) of methyl 3-(chlorocarbonyl)benzoate as brown oil. |
87% | With oxalyl dichloride In dichloromethane at 40℃; for 40h; | 1 Intermediate la: methyl 3-(chlorocarbonyl benzoate. To 3-(methoxycarbonyl)benzoic acid (6.2 g, 34.44 mmol, 1.00 equiv) in dichloromethane (50 mL) was added oxalyl dichloride (8.74 g, 69.37 mmol, 2.00 equiv) and N,N-dimethylformamide (cat.) and the resulting solution was stirred for 1 h at 40°C in an oil bath. The mixture was concentrated under vacuum to yield 6.6 g (87%) of methyl 3-(chlorocarbonyl)benzoate as brown oil. |
87% | With oxalyl dichloride In dichloromethane at 40℃; for 1h; | 2 Intermediate 2a: Methyl 3-(chlorocarbonyl benzoate. To a solution of 3- (methoxycarbonyl)benzoic acid (6.2 g, 34.44 mmol, 1.00 equiv) in dichloromethane (50 mL) was added oxalyl dichloride (8.74 g, 69.37 mmol, 2.00 equiv) and N,N- dimethylformamide (DMF; cat.) and the resulting solution was stirred for 1 h at 40°C in an oil bath. The resulting mixture was concentrated under vacuum to afford 6.6 g (87%) of intermediate 2a as brown oil. |
87% | With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 40℃; for 1h; | 80a Intermediate 80a: methyl 3-(chlorocarbonyl)benzoate Into a 250-mL round-bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (6.2 g, 34.44 mmol, 1.00 equiv) in dichloromethane (50 mL), oxalyl dichloride (8.74 g, 69.37 mmol, 2.00 equiv), and N,N-dimethylformamide (cat.). The resulting solution was stirred for 1 h at 40° C. in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 6.6 g (87%) of methyl 3-(chlorocarbonyl)benzoate as brown oil |
81% | With thionyl chloride In N,N-dimethyl-formamide at 80℃; for 6h; | |
With thionyl chloride | ||
With thionyl chloride Heating; | ||
With thionyl chloride In chloroform at 80℃; for 2h; Yield given; | ||
With thionyl chloride for 2h; Heating; Yield given; | ||
With thionyl chloride In N,N-dimethyl-formamide for 0.75h; Heating; | ||
With oxalyl dichloride | ||
With oxalyl dichloride In toluene | ||
With thionyl chloride | ||
With thionyl chloride In toluene | ||
With thionyl chloride In toluene at 90 - 95℃; for 1h; | ||
With thionyl chloride for 1h; Heating; | ||
With thionyl chloride; N,N-dimethyl-formamide Heating; | ||
With thionyl chloride In chloroform Heating; | ||
With thionyl chloride In toluene at 80℃; | IV.d.x d)N-allyl-N-cyclopropyl-isophthalamic acid example 11 h A solution of 0.3 g (1.37mmol)N-cyclopropyl-isophthalamic acid in 10ml THF is treated with 142 mg (3.55mmol) NaH (60% suspension in mineral oil) and stirred at25 C. After 2 h 0.27 mi (3.23mmol)allylbromide is added and after 18 h the reaction is quenched with water. The mixture is acidified with 2N HCI and extracted with EtOAc. The organic phase is washed with brine, dried with sodium sulfate and evaporated to yield the title compound that is used in the next step without purification. LC/MS (Nucleosil C-18HD,4x70 mm, 3 M, 20-100% MeCN (6 min), 100% MeCN (1.5 min) ): 3.47 min; MS (ES) MH+= 246.2, MNa+= 268.2 The starting material can be prepared as follows : x) N-cyclopropyl-isophthalamic acid A solution of 0.5 g (2.77mmol) isophthalic acid mono methyl ester, 5ml toluene and 0.8 ml SOCI2 is treated with one drop DMF and heated to80 C till the evolution of gas ceases. After cooling down the mixture is evaporated, dissolved in 2ml DCM and added to an at0 C stirred mixture of 5 mi 10% aqueous Na2CO3, 0.21 ml (3.0mmol) cyclopropyl amine and 5ml DCM. After 1 h the layers are separated and the organic layer is washed with 1 N HCI, brine, dried with sodium sulfate and evaporated. The crude product is crystallized (EtOAc, hexane) to yield N-cyclopropyl-isophthalamic acid methyl ester as off-white crystals. 1H-NMR (400 MHz, CDCl3) : 8. 33 (s, 1H), 8.18 (d, 1H), 8. 05 (d,1H), 7.55 (t,1H), 6.41 (br, 1H), 3.97 (s, 3H), 3.00-2. 91 (m, 1H), 0.98-0. 85 (m, 2H), 0.75-0. 62 (m, 2H) | |
With oxalyl dichloride; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 1.16667h; | 28.1 To a room temperature suspension of monomethyl isophthalate (5.00 g, 27.7 mmol) in 1 ,4-dioxane (40 mL) was added diisopropylethylamine in one portion (5.50 ml_, 31.6 mmol) followed by oxalyl chloride (2.68 ml, 3.91 g, 30.9 mmol) in a drop-wise fashion over 10 minutes. The resulting solution was stirred for 1.0 hour at room temperature, and is designated the first reaction vessel. In a separate, second reaction vessel, a suspension of 5-bromo-2- hydrazinopyridine (4.71 g, 25.1 mmol) in 1 ,4-dioxane (53.3 mL) and toluene (26.6 ml_) was charged with diisopropylethylamine (4.50 ml, 25.8 mmol). The contents of the first reaction vessel were then transferred in one portion to the contents of the second reaction vessel. The resulting combined reaction mixture was matured for 1.0 h, followed by the addition of phosphorus oxychloride (2.68 ml, 30.8 mmol). At this time, the reaction mixture was heated to 95 0C for 9 hours. The reaction was cooled to room temperature and poured into a saturated solution of NaHCO3 (500 mL) and the pH was then further adjusted by the addition of 10 mL of 1.0 N NaOH solution to provide a near pH-7 slurry. The reaction mixture was extracted with 3 x 200 mL ethyl acetate and the organic extracts were sodium sulfate dried, filtered, and concentrated in vacuo. The resulting solution was concentrated to about 200 mL and then removed from vacuum and allowed to crystallize for a period of 12 hours. The resulting solid was collected, ethyl acetate washed (100 mL) to furnish an off-white solid (2.75 g, 33 % yield). 1H NMR (300 MHz, Cf7-DMF) δ 8.98 (s, 1 H), 8.59 (br s, 1 H), 8.38 (br d, J = 8.2 Hz, 1 H), 8.22 (br d, J = 8.2 Hz, 1 H), 7.91 {app d, J = 9.5 Hz, 1 H), 7.85 (t, J = 8.2 Hz, 1 H), 7.63 (dd, J = 9.0 1.2 Hz, 1 H), 4.00 (s, 3H); LC/MS, tr = 2.04 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50 0C), ES- MS m/z 332 (M+H). ES-HRMS m/z 332.0010 (M+H calcd for C14H11BrN3O2 requires 332.0029 | |
With thionyl chloride In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; N,N-dimethyl-formamide | 92.c Step c. Step c. 5-(2-Adamantan-1-yl-ethyl)-4-(3-methoxycarbonyl-benzoylamino)-2-o-tolyl-imidazole-1-carboxylic Acid tert-butyl Ester Isophthalic acid mono methyl ester (200 mg, 1.10 mmol) was heated at reflux for 15 min in the mixture of thionyl chloride (2 ml) and DMF (cat.). The solvent was evaporated in vacuo, the residue was dissolved in DCM (5mi) and the solvent was evaporated to afford 3-chlorocarbonyl-benzoic acid methyl ester. | |
With thionyl chloride at 80℃; for 6h; | 9 3-Chlorocarbonyl-benzoic acid methyl ester (25).; SOCl2 (15 mL) and dry DMF (2 drops) were added to monomethyl isophthalate (5 g, 17.7 mmol), and the reaction mixture was refluxed at 80° C. for 6 hr. The SOCl2 was removed in vacuo, and a colorless oil was obtained and used directly in the next step. | |
With thionyl chloride at 90℃; for 2h; | 2.19 Example 2.19: methyl 3-(isopropyI((4-methylthiazol-2-yl)methyl)carbamoyl)benzoate; [0254] Et3N (1 drop, catalytic) was added to a stirred suspension of 7«oϖo-Methyl isophthalate (0.294 mmol, 1.0 eq) in 2 ml SOCl2 under Ar. The mixture was heated to reflux at 90 0C for 2h. The reaction was cooled to RT, and the solvent was removed in vacuo. The residue was placed under an Ar atmosphere and dissolved in 2 ml anh CH2Cl2. The resulting solution was treated with a solution of N-((4-methylthiazol-2-yl)methyl)propan-2-amine (0.294 mmol, 1.0 eq made from reductive amination of 4-methylthiazole-2-carbaldehyde with isopropylamine) dissolved in 1 ml anh CH2Cl2 under Ar. After stirring at RT for 30 min, the reaction was treated with ET3N (0.294 mmol, 1 eq). After stirring at RT for 30 min, the reaction is poured into a seperatory funnel, washed with sat. NaHCO3 (xl), water (x3), brine (xl), and dried over Na2SO4. The inorganics were removed via filtration, and the solvent was removed in vacuo yielding the crude product in 93% yield. | |
With thionyl chloride In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; N,N-dimethyl-formamide | 92.C N-[5-(2-Adamantan-1-yl-ethyl)-2-o-tolyl-1H-imidazol-4-yl]-isophthalamic Acid Step C. 5-(2-Adamantan-1-yl-ethyl)-4-(3-methoxycarbonyl-benzoylamino)-2-o-tolyl-imidazole-1-carboxylic acid tert-butyl ester. Isophthalic acid mono methyl ester (200 mg, 1.10 mmol) was heated at reflux for 15 min in the mixture of thionyl chloride (2 ml) and DMF (cat.). The solvent was evaporated in vacuo, the residue was dissolved in DCM (5 ml) and the solvent was evaporated to afford 3-chlorocarbonyl-benzoic acid methyl ester. | |
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide Heating; | ||
With oxalyl dichloride In dichloromethane at 20℃; for 48h; | 75.A Step A: Methyl 3-[(2,6-difluorophenyl)amino]carbonyl}benzoate; To a solution of 3-[(methyloxy)carbonyl]benzoic acid (4.0 g, 22 mmol) in DCM (200 ml) was added oxalyl chloride (8.46 g, 66.6 mmol) followed by DMF (1.0 ml_). After stirring at rt for 48 h, solvent was removed, residue resuspended in DCM (200 mL), and the resulting mixture was concentrated again under reduced pressure. After placing the crude acid chloride on the high vacuum for 2 h, the solids were redissolved in DCM (250 mL) and to this was added pyridine (8.79 g, 111 mmol), catalytic DMAP, and 2,6-difluorophenyl amine (8.60 g, 67 mmol). After stirring at rt overnight, the reaction was washed with 1 M HCI (100 mL), organic layer separated, and purified by silica gel chromatography, eluting with a mixture of DCM and MeOH to provide the product (5.57 g, 86%) as an off-white solid. ESIMS (M+H)+ = 292. | |
With oxalyl dichloride In dichloromethane at 20℃; | 10.a To a slurry of 3-[(methyloxy)carbonyl]benzoic acid (1 g, 5.55 mmol) in dichloromethane (16 mL) was slowly added oxalyl chloride (0.97 mL, 11.1 mmol), followed by N,N-dimethylformamide (2 drops) at room temperature. The reaction mixture was stirred for 1 h at room temperature and concentrated to afford methyl 3- (chlorocarbonyl)benzoate which was approximately 80% pure as determined by 1H NMR. The impure methyl 3-(chlorocarbonyl)benzoate was used without purification. Sodium hydride (60% dispersion in oil) (0.25 g, 6.18 mmol) was washed with hexanes, and N,N-dimethylformamide (10 mL) was added. The slurry was cooled to 0 0C. A solution of 5-(methyloxy)-lH-indole (0.65 g, 4.43 mmol) in N5N- dimethylformamide (2 mL) was added slowly to the suspension of sodium hydride and the mixture was stirred for approximately 15 min. A solution of methyl 3-(chlorocarbonyl)benzoate (1.1 g, 5.54 mmol) in N,N-dimethylformamide (2 mL) was slowly added to the reaction mixture and the reaction mixture was stirred at 0 0C for 30 min, then at room temperature for 3 h. The reaction mixture was diluted with water, followed by ethyl acetate. The organic layer was separated, washed several times with water, followed by brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica using a hexanes:ethyl acetate gradient of 0 to 35% ethyl acetate to afford 0.86 g (63%) | |
With thionyl chloride at 70 - 80℃; for 1h; | ||
With thionyl chloride for 1h; Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane | ||
With oxalyl dichloride In chloroform; N,N-dimethyl-formamide at 20℃; for 7h; | 48.1 Chloroform (5 mL) was added to isophthalic acid monomethyl ester (198 mg), and oxalyl chloride (0.12 mL) and N,N-dimethylformamide (1 drop) were added under ice-cooling. After stirring at room temperature for 7 hrs, the mixture was concentrated and azeotroped with toluene to give the title compound. | |
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran for 1h; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane at 0 - 20℃; | 49 Preparation 49: iV-Methoxy-V~methyIisophthaiamic acid methyl ester To isophthalic acid monomethyl ester (5g, 27.7mmol) in DCM (50mL) at 0°C was added oxalyl chloride (2.96mL, 33,3mmol) followed by DMF (0.5mL) dropwise. The mixture was wanned to rt and when effervescence ceased NEt3 (11.6mL, 83.2mmol) and then O, iV-dimethylhydroxylamine hydrochloride (4.06g, 41.6mmol) were added. After 2h DCM was added, the organic phase was washed with sat Na2C03, 1 M HCl, dried (MgS0 ) and the sol vent was removed in vacuo. The residue was purified by column chromatography (35:65 EtOAc :Hexane) to give, after removal of the solvent in vacuo, the title compound: RT = 2.62min; m/z (E8") - 224.2 [ + H]+ | |
With thionyl chloride In dichloromethane for 3h; Reflux; | 38.38a.1 SOCl2 (8.10 mL) was added to a solution of 3-[(methyloxy)carbonyl]benzoic acid (1 g) in dichloromethane (DCM) (15 mL) and the resulting mixture was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in dry DCM. Solvent was evapourated again to afford the acyl chloride as a light yellow solid. This acyl chloride was dissolved in acetone (15 mL) and cooled to 0 °C, to which ammonium thiocyanate (0.845 g) was added. The mixture was then stirred at this temperature for 1.5 hours. Then - (methyloxy)phenyl]methyl} amine (1.571 g, synthesis of this intermediate, see step 1 for preparing intermediate lb) was added at the same temperature and stirred for an additional 30 mins. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (EtOAc : PE = 0-30 %) to afford methyl 3-([(- (methyloxy)phenyl]methyl}amino)carbonothioyl]amino}carbonyl)benzoate (1.307 g) as a brown sticky solid. MS(ES+) m/z 479 (MH+). | |
With thionyl chloride In dichloromethane at 20℃; for 18h; | 21 Example 21 : 3-[4-(3,5-Di-½/-i-butyI-4-hydroxy-phenyIsulfanyl)-4-(3,5-di-te i-butyl-4- methoxy-phenylsulfanyl)-piperidine-l-carbonyl]-benzoic acid methyl esterA 50 mL round bottom flask was charged with mono-methyl isophthalate (0.30 g, 1.66 mmol), 20 mL of anhydrous methylene chloride and 2 drops of anhydrous DMF. Thionyl chloride (0.24 g, 2.0 mmol) was added and the resulting mixture was stirred at ambient temperature for 18 h. The pale yellow solution was concentrated under to an oil, which was diluted with 5 mL of anhydrous THF and charged to 100 mL round bottom flask containing 2,6-di-½ri-butyl-4-[4-(3,5-di-½r/-butyl-4-methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl]- phenol (Ex. 17, 0.86 g, 1.51 mmol), 20 mL of anhydrous THF and diisopropylethylamine (0.78 g, 6.0 mmol). The resulting dark red solution was stirred at ambient temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with IN HCl, water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by chromatography (EtOAc/hexanes, 0-25% gradient). The fractions containing the product were concentrated to dryness and then dried in vacuo (0.70 g, 63%), mp 112-115 °C (dec).'H-NMR (CDCI3) δ 8.07 (dt, 1H, J = 6.8, 1.8 Hz), 8.00 (s, 1H), 7.60 (s, 2H), 7.49 (s, 2H), 7.44 (m, 2H), 5.41 (s, 1H), 3.92 (s, 3H), 3.92 (m, 2H), 3.71 (s, 3H), 3.52 (m, 2H), 1.78 (m, 4H), 1.45 (s, 18H), 1.44 (s, 18H); HRMS (ESI) Calcd. for C43H59NO5S2: 734.3913 (M+H)+. Found: 734.3907. Anal. Calcd for C43H59 05S2: C, 70.36; H, 8.10; N, 1.91; S, 8.74. Found: C, 70.46; H, 8.30; N, 1.86; S, 8.42. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 40℃; Inert atmosphere; | ||
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0℃; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 12h; | ||
With thionyl chloride; N,N-dimethyl-formamide In toluene at 60℃; for 2h; | 4.2. Representative procedure for 4a-d General procedure: Acid 2/3 (1.0 equiv), SOCl2 (6.0 equiv) and DMF (1 drop) were stirred in toluene at 60 °C for 2h. Then the solvent was removed under reduced pressure. The acyl chloride was dissolved in DCM and added dropwise into a solution of corresponding aromatic amine (1.0 equiv) and triethylamine (2.0 equiv). After the addition, the mixture was stirred at room temperature for 1 h and extracted with EtOAc. The organic layer was washed with 1N HCl (aq) followed by 10% Na2CO3 (aq) and dried over Na2SO4. Concentrated in vacuo gave the crude product, which was further purified by crystallization from EtOAc-light petroleum. | |
With thionyl chloride In N,N-dimethyl-formamide at 25℃; for 3h; Reflux; | To 3-(methoxycarbonyl)benzoic acid intermediate 1 ( 10 g, 55.5 mmol) was added thionyl chloride ( 16.2 1 mL, 222 mmol) in smal l portions at 25 °C fol lowed by a drop of dimethylformamide. The reaction mixture was stirred under refluxing for 3 h. Excess thionyl chloride was evaporated under reduced pressure at 100 °C. The 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride intermediate 2 ( 12.19 g, 69.4 mmol) was dissolved in 1 00 mL of water, to that added solution of sodium hydroxide (4.44 g, 1 1 1 mmol) in 25 mL of water. Free base of 4,5,6,7- tetrahydrothieno[3,2-c]pyridine was extracted in dichloromethane (75 mL), dried over anhydrous potassium carbonate. The acid chloride was dissolved in anhydrous dichloromethane (75 mL) and cooled to 0 °C. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.333333h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 1.5h; Reflux; | ||
With thionyl chloride at 20℃; for 2h; | ||
With thionyl chloride for 2h; Reflux; | ||
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere; | Synthesis of methyl 3-(5-chloro-2-hexyl-1-methyl-1H-indole-3-carbonyl)benzoate (31) To a stirred solution of 27 (360 mg, 2.4 mmol) in dichloromethane (10 ml) was added one drop of DMF followed by 2.4 ml of oxalyl chloride solution (2.0 M in dichloromethane, 4.80 mmol) at 0 °C. The reaction mixture was stirred for 16 h in rt and the crude was evaporated under reduced pressure to obtain 29, which was used without further purification. To a stirred solution of 25 (500 mg, 2.0 mmol) in dichloromethane was added Me2AlCl (1.0 M in hexane, 4 ml, 4 mmol) at 0 °C. After stirred at rt for 2 h, the reaction was quenched with water, extracted with EtOAc, the organic layers were combined, washed with brine and dried over Na2SO4. The solvents were evaporated under reduced pressure and the crude was purified by silica gel chromatography using 20% EtOAc/Hex as eluent to afford 31 (666 mg, 85%). | |
With thionyl chloride at 90℃; for 1h; | ||
Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With oxalyl dichloride In dichloromethane at 0 - 40℃; for 0.583333h; Stage #2: With N,N-dimethyl-formamide In dichloromethane at 40℃; for 0.5h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; for 2h; Inert atmosphere; Schlenk technique; | ||
With oxalyl dichloride; N,N-dimethyl-formamide at 20℃; for 2h; | Methyl 1-[3-(methoxycarbonyl)benzoyl]aziridine-2-carboxylate (6d) and methyl 3-[(3-methoxy-3-oxoprop-1-en-2-yl)carbamoyl]benzoate (8d). Oxalyl chloride (0.16 ml,1.83 mmol) and 3 drops of DMF were added to a stirredsolution of 3-(methoxycarbonyl)benzoic acid (3d) (300 mg,1.66 mmol) in CH2Cl2 (7 ml), and the mixture was stirredat room temperature for 2 h. The solvent and oxalylchloride excess were evaporated under reduced pressure togive desired acid chloride 4d as a yellow solid which wasthen dissolved in MeCN (2 ml) and added dropwise to asolution of methyl aziridine-2-carboxylate (1b) (168 mg,1.66 mmol) and Et3N (0.51 ml, 3.66 mmol) in MeCN (6 ml) at-5°C temperature. After 30 min, the ice bath was removed,and the reaction mixture was stirred at room temperatureovernight. The precipitate was filtered off and washed withMe2CO. The filtrate was concentrated under reducedpressure, and the residue was purified by flash chromatographyon silica gel (eluent petroleum ether - EtOAc, 3:1)to elute compound 8d and then compound 6d. Methyl 1-[3-(methoxycarbonyl)benzoyl]aziridine-2-carboxylate (6d). Yield 227 mg (51%), yellow oil.1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 8.66 (1H, t, J = 1.8, H-2 Ar); 8.25-8.17 (2H, m, H-4,6 Ar); 7.55 (1H, t,J = 7.8, H-5 Ar); 3.95 (3H, s, OCH3); 3.74 (3H, s, OCH3);3.33 (1H, dd, J = 5.7, J = 3.2, NCH); 2.82 (1H, dd, J = 3.2,J = 1.3) and 2.70 (1H, dd, J = 5.7, J = 1.3, NCH2).13C NMR spectrum (CDCl3), δ, ppm: 175.8 (NC=O); 168.9(NCCO2CH3); 166.1 (ArCO2Me); 133.9 (C-1 Ar); 133.0(C-3 Ar); 132.8 (C-4 Ar); 130.7 (C-5 Ar); 129.9 (C-2 Ar);128.8 (C-6 Ar); 52.7 (OCH3); 52.4 (OCH3); 35.5 (C-2 aziridine);31.4 (C-3 aziridine). Mass spectrum, m/z (Irel, %): 264[M+H]+ (100). Found, %: C 59.14; H 4.96; N 5.25.C13H13NO5. Calculated, %: C 59.31; H 4.98; N 5.32.Methyl 3-[(3-oxobut-1-en-2-yl)carbamoyl]benzoate (8d).Yield 112 mg (25%), light-yellow solid. 1H NMR spectrum(CDCl3), δ, ppm (J, Hz): 8.55 (1H, br. s, NH); 8.47 (1H, td,J = 1.6, J = 0.6, H-2 Ar); 8.22 (1H, dt, J = 7.8, J = 1.4, H-6 Ar);8.05 (1H, ddd, J = 7.8, J = 1.8, J = 1.2, H-4 Ar); 7.58 (1H,td, J = 7.8, J = 0.6, H-5); 6.81 (1H, s) and 6.04 (1H, d,J = 1.4, =CH2); 3.96 (3H, s, OCH3); 3.91 (3H, s, OCH3).13C NMR spectrum (CDCl3), δ, ppm: 166.2 (C=O); 164.9(C=O); 164.8 (C=O); 134.8 (C-3 Ar); 133.1 (C-4 Ar);131.6 (C=CH2); 131.1 (C-1 Ar); 131.0 (C-6 Ar); 129.2(C-4 Ar); 127.9 (C-2 Ar); 109.6 (C=CH2); 53.3 (OCH3);52.6 (OCH3). Mass spectrum, m/z: (Irel, %) 264 [M+H]+(100). Found, %: C 59.39; H 4.97; N 5.27. C13H13NO5.Calculated, %: C 59.31; H 4.98; N 5.32. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With borane-THF; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | Mono-methyl isophthalate 22 (2.0 mmol) was placed in a 50 mL round bottom flask and dissolved in dry THF (10 mL) under nitrogen atmosphere. The reaction flask was placed in an ice bath to reach 0C and 1M borane tetrahydrofuran complex solution (10.0 mmol) was added dropwise. After 15 minutes at 0C the ice bath was removed and the reaction was stirred at room temperature overnight. After reaction completion ice was carefully added to the reaction, and the mixture extracted three times with diethyl ether. The collected organic phase was washed with brine, dried over anhydrous Na2SO4, and the solvent evaporated in vacuum to obtain 21b (yield 97%) which needed no further purification. 1H NMR (CDCl3) delta 8.04 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.44 (t, J= 7.8 Hz, 1H), 4.76 (s, 2H), 3.92 (s, 3H) ppm. |
91% | With borane-THF; In tetrahydrofuran; at 0 - 30℃; for 16h;Inert atmosphere; | To a mixture of 3-(methoxycarbonyl)benzoic acid (5 g, 27.78 mmol, 1.0 eq) in dry THF (20 mL) was added BH3/THF (1 M in THF, 55 mL, 55.5 mmol, 2.0 eq) at 0C. The mixture was stirred at 30C. for 16 h under nitrogen atmosphere. Then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound PI-23a (4.2 g, 91%). |
91% | With borane-THF; In tetrahydrofuran; at 0 - 25℃; for 16h;Inert atmosphere; | To a solution of 162 (20.0 g, 111 mmol) in THF (300 mL) was added BH3THF (333 mL, 333 mmol). The mixture was stirred at 0 C. for 0.5 h. Then the mixture was warmed to 25 C. for 15.5 h. The mixture was combined with a second lot and quenched with MeOH (400 mL) and concentrated in vacuum. The residue was diluted with H2O (200 mL), the aqueous phase was extracted with EA (3×400 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give colorless oil (21.0 g, 91% yield). |
87% | EXAMPLE 25 N-((lR,2S)-2-((S)-4-(4-Chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine-l- carbonyl)cyclohexyl)-3-(hydroxymethyl)benzamideStep 1: Methyl 3-(hydroxymethyl)benzoate [00163] A solution of 3-(methoxycarbonyl)benzoic acid (1.05g, 5.83 mmol) in THF (25 mL) was cooled to 0 0C, and then treated with the dropwise addition of 2.0 M borane-methylsulfide complex in THF (14.57 mL, 29.1 mmol) at a rate which did not allow the temperature to exceed 5 0C. The mixture was stirred at 0 0C for 15 minutes, and then allowed to warm to room temperature where it stirred for 4 hours. After this time, the reaction was cooled to 0 0C and then quenched with the addition of small pieces of ice, causing vigorous gas evolution. When gas evolution had ceased, the mixture was diluted with brine and extracted 3X with ethyl acetate. The combined organic phases were washed 3X with diluted bleach to remove residual methyl sulfide, 3X with saturated sodium carbonate to remove any unreacted acid, IX with water, IX with brine, dried over sodium sulfate and then concentrated in vacuo <n="104"/>to yield the methyl 3-(hydroxymethyl)benzoate (845mg, 5.09 mmol, 87 % yield) as a colorless oil. | |
84% | With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 3h; | Step A. Methyl 3-(hydroxymethyl)benzoate[00222] To a solution of 3-(methoxycarbonyl)benzoic acid (0.200 g, 1.1 1 mmol) in THF (6.0 mL) at 0 C was added borane tetrahydrofuran complex (5.55 mL, 5.55 mmol) slowly. The reaction mixture was slowly warmed to room temperature and stirred at for 3 h. After this time, the reaction mixture was diluted with EtOAc and quenched very slowly with water. The organic layer was separated, washed with water and brine, dried over anhydrous MgS04, filtered, and concentrated to afford the title compound (0.16 g, 84% yield) as a colorless oil. LCMS, [M+H]+ = 167.0. |
84% | Methyl 3-(hydroxymethyl)benzoate was prepared as follows:mono-Methylisophthalate (8 g, 44.4 mmol, 1 eq) was dissolved in tetrahydrofuran (250 ml) at room temperature. 1.0M Borane-THF solution (222 ml, 222 mmol, 5 eq) was added slowly and the solution stirred for 24 hours at RT. After this time, methanol (30 ml) was slowly added and the reaction stirred at RT for 1 hour after which it was concentrated. The residue was partitioned between ethyl acetate (50 ml) and 10% aq ammonium hydroxide solution and the organic layer separated. The aqueous layer was washed with ethyl acetate (2×50 ml) and the organic layers combined, washed with 10% aq ammonium hydroxide solution (2×50 ml), 2M hydrochloric acid (2×50 ml), water (2×50 ml), brine (2×50 ml) and dried over anhydrous sodium sulphate. The solution was concentrated to give methyl 3-(hydroxymethyl)benzoate as a colourless oil (6.2 g, 84%).1H NMR (400.132 MHz, DMSO) delta 3.86 (s, 3H), 4.58 (d, 2H), 5.33 (t, 1H), 7.45-7.49 (m, 1H), 7.59 (d, 1H), 7.84 (d, 1H), 7.96 (s, 1H). MS: N/A | |
82% | With dimethylsulfide borane complex; In tetrahydrofuran; at 7 - 20℃; for 6.75h;Inert atmosphere; | In a 3-necked 500 mL round-bottomed flask equipped with a mechanical stirrer was placed dimethyl isophthalate (20.00 g, 0.103 mol, 1 eq.) dissolved in acetone (200 mL). To this mixture was added dropwise over 20 min a sln of NaOH (4.33 g, 0.108 mol, 1.05 eq.) in MeOH (40 mL). The resulting milky suspension was stirred at r.t. overnight. Then, another portion of NaOH (0.433 g, 0.011 mol, 0.1 eq.) was added into the reaction and the suspension was stirred for another 5 hours. The solvent was removed under vacuum and the white precipitate thus obtained was dissolved in water (400 mL). Concentrated HCl (15 mL) was added dropwise until pH~1. Then, the suspension was filtered; the collected precipitate was washed with water (4×100 mL) and dried under vacuum at 65C for 24 hours to give white solid 18.25 g. The obtained monomethyl isophthalate was used directly without further purification. In a 3 necked 500 mL round-bottomed flask equipped with a magnetic stirrer and a low temperature thermometer under a nitrogen atmosphere was placed monomethyl isophthalate (5.00 g, 0.027 mol, 1 eq.) dissolved in dry THF (125 mL). Then, this solution was placed in an ice-water bath and a solution of BH3?SMe2 (2M in THF, 70 mL, 0.14 mol, 5 eq.) was added dropwise slowly over 90 min to maintain the temperature in the solution below 7C. After another 15 min, the cooling bath was removed and the solution was allowed to reach ambient temperature. After 5 hours, the reaction was carefully quenched (strong gas evolution) with small pieces of ice while cooling in an ice-water bath. When the gas evolution ceased, brine (50 mL) was added and the resulting mixture was extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with diluted bleach (50 mL, original solution 9.6% bleach diluted 10 times), brine (50 mL) and dried (MgSO4). The solvent was removed under vacuum to give an oil which contained a small amount of white precipitate. Diethyl ether (20 mL) was added and the solid was removed by filtration and washed with Et2O (2×10 mL). The filtrate was concentrated to yield a pale yellow oil (4.48 g). The crude oil was then purified by silica gel column chromatography (PE:EA, 4:1 to 7:3) to afford methyl 3-hydroxymethylbenzoate (2d) as colorless oil (3.77 g, 82%). Rf = 0.17 (EtOAc:PE = 1:4); 1H NMR (300 MHz, CDCl3), delta (ppm): 8.00 (s, 1H, HAr), 7.93 (dt, J = 7.7, 1.4 Hz, 1H, HAr), 7.61 - 7.51 (m, 1H, HAr), 7.40 (t, J = 7.7 Hz, 1H, HAr), 4.71 (s, 2H, OCH2), 3.89 (s, 3H, OMe). |
With sodium borohydrid; trifluoroborane diethyl ether; In tetrahydrofuran; | To a suspension of 3-methoxycarbonylbenzoic acid (4.68 g, prepared by the method of Kasina and Nematollahi, Tetrahedron Lett. (1978) 1403) in tetrahydrofuran (12.5 mL) at 0 C. was added dropwise borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 25 mL) over 40 min. The reaction mixture, which had become a solution, was allowed to warm slowly to room temperature as it was stirred overnight. When examination by TLC after 24 h showed little conversion to the alcohol, the reaction mixture was cooled with an ice bath and the reaction quenched with water (20 mL). The mixture was saturated with potassium carbonate and the phases were separated. The organic phase was washed (saturated potassium carbonate solution) and evaporated. The aqueous phase was extracted with ethyl acetate; and the ethyl acetate solution was used to redissolve the residue from the tetrahydrofuran solution. The resulting ethyl acetate solution was washed (water), dried and evaporated to afford a portion of crude alcohol. The original aqueous phase was acidified with 10% aqueous hydrochloric acid to pH 2, resulting in precipitation of unreacted acid as a white solid, which was filtered, washed with water and ether, and dried under vacuum to provided recovered starting acid (2.7 g). To a suspension of the recovered acid (2.7 g) in tetrahydrofuran was added sodium borohydride (0.49 g), resulting in evolution of gas. To the mixture was added dropwise boron trifluoride etherate (2.05 mL) over 5 min, causing further gas evolution. The reaction mixture, which was heated to a gentle reflux by the exothermic reaction, was stirred 4 h, quenched with water (2.5 mL) and evaporated. The residue was partitioned between dichloromethane and water. After the aqueous phase was further extracted with dichloromethane, the combined extracts were washed (brine), dried and evaporated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution; and the organic phase was washed (brine), dried and evaporated to afford crude alcohol which was combined with the material obtained from the borane reduction for purification by chromatography, eluding with dichloromethane:ethyl acetate (gradient, 100:0, 95:5, 91.5:9.5, 91:1, 85:15) to afford methyl 3-hydroxymethylbenzoate; TLC: 0.42, dichloromethane:ethyl acetate (9:1); MS: m/z=167(M+1). | |
With borane-THF; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | To a solution of compound B3 (46 g, 0.3 mol) in 700 mL of dry THF was added a solution of BH3 in THF (1 M, 600 mL, 0.60 mol) at 0C under N2 atmosphere over 20 min. Then the solution was stirred overnight at room temperature. To quench the reaction, 50% aqueous solution of acetic acid (400 mL) was added slowly. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic phase was washed with 10% aqueous Na2CO3 solution, H2O, and brine consecutively. It was dried over Na2SO4, filtered, concentrated under reduced pressure and purified by chromatography on silica gel (eluent: PE/EtOAc = 10/1) to give 28 g of compound B4 as a white solid (Yield in three steps: 54%). | |
Synthesis of Compound B4: [Show Image] To a solution of compound B3 (46 g, 0.3 mol) in 700 mL of dry THF was added a solution of BH3 in THF (1 M, 600 mL, 0.60 mol) at 0C under N2 atmosphere over 20 min. Then the solution was stirred overnight at room temperature. To quench the reaction, 50% aqueous solution of acetic acid (400 mL) was added slowly. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic phase was washed with 10% aqueous Na2CO3 solution, H2O, and brine consecutively. It was dried over Na2SO4, filtered, concentrated under reduced pressure and purified by chromatography on silica gel (eluent: PE/EtOAc = 10/1) to give 28 g of compound B4 as a white solid (Yield in three steps: 54%). | ||
With diborane; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere; | To a cooled (0 C) solution of mono-methyl isophthalate (5 g, 28 mmol) in anhydrous THF (55 ml) was slowly added borane in THF solution (1 M, 55 ml) under nitrogen atmosphere. The reaction mixture was allowed to gradually reached room temperature and stirred for 2 hours. The reaction was slowly quenched with 50% aqueous acetic acid solution (30 ml). Reaction mixture was concentrated under vaccum and the resulting suspension was partitioned between ethyl acetate and water. The organic phase was washed with 10% aqueous Na2CO3 and brine, then dried with sodium sulphate and evaporated to yield 3 as colorless,viscous oil (4.6 g, 99%). The product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 3-(5,5-dimethyl-1,3,2-dioxaborinanyl)-1-methoxycarbonylbenzene; carbon dioxide With [Ni(N,N'-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]imidazole-2-ylidene)(allyl)Cl]; potassium <i>tert</i>-butylate In toluene at 100℃; for 15h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride In water; ethyl acetate; toluene at 20℃; | |
68% | With 1,3-bis-(diphenylphosphino)propane; cesium fluoride In 1,4-dioxane at 60℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester; di-n-propylamine With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | General procedure B for the synthesis of amides No.14a-s; 16b-g. General procedure: An oven-dried 20 mL pressurevial was charged with monoester No.13a-f (1.0 eq) and dissolved in anhydrous DMF (0.5 mL/0.1mmol of the monoester). The corresponding amine (1.2 eq) was added, followed by HBTU (1.0 eq).The resulting solution was stirred at 0 °C for 5 min, then TEA (2.0 eq) was added and stirring at 0 °Cwas continued for 0.5 h. The resulting mixture was warmed to room temperature and stirring wascontinued for 2 h. The brownish solution was diluted with water (20 mL) and extracted with EtOAc(3 x 15 mL). Combined organic extracts were washed with water (15 mL), brine (15 mL), dried overanhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gelcolumn chromatography. |
92% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 8h; | |
91% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 4h; |
With HATU In N,N-dimethyl-formamide at 20℃; | E.1 Step E (1): Methyl 3-(dipropylcarbamoyl)benzoate.; To a solution of 3- (methoxycarbonyl)benzoic acid (6.7 g, 37.2 mmol) in DMF (60 niL) was added HATU (17.0 g, 44.7 mmol) and dipropylamine (9.4 g, 93 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (600 mL) was added and the mixture was washed with H2O, dried and concentrated to give the title compound was used in the next step without purification. | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h; | Step 1. (3-(methoxycarbonyl)phenyl)(3-(/ert-butoxycarbonylamino)pyrrolidin-1- yl)methanone. A mixture of wowo-methyl isophthalate (0.5180 g, 2.87 mmol, 1.0 equiv), lambda/-Boc-3- aminopyrrolidine (0.6680 g, 3.58 mmol, 1.24 equiv), EDCI-ICl ( 1.005 g, 5.24 mmol, 1.8 equiv), HOBt (0.610 g, 4.5 mmol, 1.57 equiv), and DIEA (5 mL, 28.7 miriol, 10 equiv) in CH2Cl2 (30 mL) was stirred at rt for 24 h. The reaction mixture was diluted with CH2Cl2, washed with 1 N HCI and 10% Na2CO3, and dried over Na2SO4. After the solvent was removed, the crude product (0.7387 g, 74%) was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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87% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; | 11 Synthesis of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]isophthalic acid Example 11 Synthesis of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]isophthalic acid A mixture of 2.00 g (6.44 mmol) of 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine, 1.75 g (9.71 mmol) of isophthalic acid monomethyl ester, 2.7 mL of triethylamine, 1.00 g of 1-hydroxybenzotriazole hydrate, and 2.00 g of WSC hydrochloride, was suspended in 15 mL of dimethylformamide, followed by stirring at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. After filtration, the residue obtained by solvent distillation under reduced pressure was then subjected to silica gel column chromatography (ethyl acetate-heptane). Thereafter, a solid precipitated with ethyl acetate-hexane was collected by filtration, and dried under aeration to yield 2.65 g of the titled compound (yield: 87%). 1H-NMR (DMSO-d6) δ (ppm): 2.91 (3H, d, J=4.8 Hz), 3.76 (3H, s), 3.92 (3H, s), 3.93 (3H, s), 7.01 (1H, s), 7.02 (1H, brs), 7.19 (1H, s), 7.48 (1H, brd, J=8.0 Hz), 7.57 (1H, t, J=8.0 Hz), 7.72 (1H, t, J=8.0 Hz), 7.92 (1H, brd, J=8.0 Hz), 8.17 (1H, brd, J=8.0 Hz), 8.22 (1H, t, J=1.6 Hz), 8.26 (1H, brd, J=8.0 Hz), 8.56 (1H, t, J=1.6 Hz), 10.67 (1H, s). |
87% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; | 11 Example 11 Synthesis of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]isophthalic acid A mixture of 2.00 g (6.44 mmol) of 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine, 1.75 g (9.71 mmol) of isophthalic acid monomethyl ester, 2.7 mL of triethylamine, 1.00 g of 1-hydroxybenzotriazole hydrate, and 2.00 g of WSC hydrochloride, was suspended in 15 mL of dimethylformamide, followed by stirring at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. After filtration, the residue obtained by solvent distillation under reduced pressure was then subjected to silica gel column chromatography (ethyl acetate-heptane). Thereafter, a solid precipitated with ethyl acetate-hexane was collected by filtration, and dried under aeration to yield 2.65 g of the titled compound (yield: 87%). 1H-NMR (DMSO-d6) δ (ppm): 2.91 (3H, d, J = 4.8 Hz), 3.76 (3H, s), 3.92 (3H, s), 3.93 (3H, s), 7.01 (1H, s), 7.02 (1H, brs), 7.19 (1H, s), 7.48 (1H, brd, J = 8.0 Hz), 7.57 (1H, t, J = 8.0 Hz), 7.72 (1H, t, J = 8.0 Hz), 7.92 (1H, brd, J = 8.0 Hz), 8.17 (1H, brd, J = 8.0 Hz), 8.22 (1H, t, J = 1.6 Hz), 8.26 (1H, brd, J = 8.0 Hz), 8.56 (1H, t, J = 1.6 Hz), 10.67 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester; chlorobenzene With 3 A molecular sieve; caesium carbonate In N,N-dimethyl-formamide at 20 - 145℃; for 26h; Stage #2: diazomethyl-trimethyl-silane In methanol at 0℃; for 5h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; | 5.1.57. Methyl 3-carbamoylbenzoate (23) A solution of mono-methyl isophthalate 22 (150 mg, 0.83 mmol,1.0 equiv.), HOBt.NH3 (190 mg, 1.25 mmol, 1.5 equiv.) and EDC(192 mg, 1.00 mmol, 1.2 equiv.) in DMF (1.5 mL) was stirred at rtovernight. The reaction media was diluted with water and theaqueous phase was extracted 3 times with EtOAc. The combinedorganic layers were washed with a saturated solution of NaHCO3and brine, dried over Na2SO4, filtered and concentrated undervacuum, to yield 23 as white solid (108 mg, 0.60 mmol, 72%). 1HNMR (400 MHz, MeOD) δ ppm 3.94 (s, 3H), 7.59 (t, 1H, J 7.8 Hz),8.10 (ddd, 1H, J 1.3 Hz, J 1.9 Hz, J 7.8 Hz), 8.17 (dt, 1H, J 1.3 Hz,J 7.8 Hz), 8.53 (t, 1H, J 1.9 Hz); 13C NMR (101 MHz, MeOD) δ ppm51.4, 128.3, 128.5, 130.4, 131.7, 132.2, 134.2, 166.3, 169.8. |
Multi-step reaction with 2 steps 1: thionyl chloride 2: conc. NH4OH | ||
Multi-step reaction with 2 steps 1: thionyl chloride 2: concentrated aqueous ammonia |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 21h; | 8 Referential Example 8: methyl 3-(N,N-dimethylcarbamoyl)benzoate Referential Example 8: methyl 3-(N,N-dimethylcarbamoyl)benzoate To a methylene chloride (20 ml) solution of monomethyl isophthalate (317 mg, 1.76 mmol) were added dimethylamine hydrochloride (172 mg, 2.11 mmol), 1-hydroxybenzotriazole (287 mg, 1.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (404 mg, 2.11 mmol) and N-methylmorpholine (0.23 ml, 2.11 mmol) and the resulting mixture was stirred at room temperature for 21 hours.. The reaction mixture was concentrated under reduced pressure.. ethyl acetate was added to the residue.. The resulting mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and brine, and dried over anhydrous sodium sulfate.. After filtration, the filtrate was concentrated under reduced pressure.. The residue was subjected to chromatography on a silica gel column and the fraction obtained from the methanol:methylene chloride (=1:50) elude was concentrated under reduced pressure, whereby the title compound (290 mg, 80%) was obtained as a colorless oil. IR (ATR) ν: 1720, 1633, 1583, 1500, 1436, 1392, 1286, 1255, 1205, 1112, 1076, 979, 933, 823, 773, 730, 696, 669, 638, 580, 489, 439 cm-1.1H-NMR (400MHz, CDCl3) δ: 2.99(3H,s), 3.13(3H,s), 3.93(3H,s), 7.49(1H,t,J=8.2Hz), 7.63(1H,t,J=7.6Hz), 8.05-8.15(2H,m). MS (m/z): 208 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With methanol; triethylamine;palladium diacetate; 1,3-bis-(diphenylphosphino)propane; at 100℃; under 25858.1 Torr; for 15h; | The following were introduced into a vessel: [10.] Og (40.3 mmol) of <strong>[618-89-3]methyl 3-bromobenzoate</strong>, 2.5g (mmol) of 1, 3-bis (diphenylphosphino) propane ("DPPP"), 14 mL of triethylamine, 0.905 g of palladium acetate, and 140 ml of methanol. The vessel was sealed and pressurized with carbon monoxide to a pressure of 500 psi. The vessel was heated to [100 C] for 15 hours. The mixture was then cooled and concentrated on a rotary evaporator before partitioning between EtOAc and 2M HC1. The layers were separated, and the aqueous layer was extracted with EtOAc [(LX).] The organic extracts were combined and washed with saturated aqueous [NACL] solution and dried [(MGSO4).] Concentration provided a solid, which is slurred in hexane and filtered. The material is dried in a vacuum oven at- 10mmHg at [70 C] ; yield 5.9g [(82%).] NMR: [DMSO'H 8] (ppm) 3.54 (3H, s); 7. [18-7.] 21 [(1H,] m); 7. [34- 7.] 40 [(1H,] m); 7. 46- 7.49 (1H m); 7. [87- 7.] 89 [(1H,] m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; | 2 1.8 g (5.5 mmol) of isophthalic acid monomethyl ester from Preparation 1,3. 5g (18.5 mmol) [OF EDAC-HCI,] 2. 5g (18.5 mmol) of HOBt, and 3.1 g (15.4 mmol) of [2-AMINO-L- (4-METHOXY-PHENYL)-ETHANONE] hydrochloride were dissolved in 20 mL of [DIMETHYLFORMAMIDE.] [1.] 9g (15.4 mmo 1) of di-isopropyl ethylamin was then added. Stirring was continued overnight at room temperature. Water (60 [ML)] was added, and the product was filtered, washed with water. The resulting solid was triturated in hot methanol, filtered and dried in a vacuum oven overnight at 70 °C to provide 3.5 g (69%) desired product. MS: m/z (APCI, AP+) [328] [[M]] +NMR : [DMSO'H 8] (ppm) 3.84 (3H, s); 3. 88 (3H, s); 4.73 (2H, d, J = 5. 6 [HZ)] ; 7. [04- 7.] 08 (2H m); 7.63-7. 66 [(1H,] t, J = 7. 8 [HZ)] ; 7. [99- 8.] 027 (2H, m); 8. 097-8.16 (2H, m); 8.47-8. 48 [(LH,] m); 9.00-9. 03 [(1H,] t, [J] = 5. [8] [HZ).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: N-BOC-1,2-diaminoethane In N,N-dimethyl-formamide at 20℃; for 2.5h; | 35.1 Step 1. Synthesis of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)benzoate (Compound 124): A solution of 3-(methoxycarbonyl)benzoic acid (Compound 123; 1.0 g, 5.55 mmol),HATU (2.53 g, 6.7 mmol) and DIEPA (1.44 mL, 8.31 mmol) I nDMF (15 mL) was stirredat room temperature for 10 minutes, then a solution of tert-butyl (2-aminoethyl)carbamate (1.07 g, 6.68 mmol) in DMF (4 mL) was added and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and the organic layer was washed with sat. NaHCO3, water (2x), brine, dried over Na2SO4 and concentrated to obtain methyl 3-((2-(Qert-butoxycarbonyl)amino)ethyl)carbamoyl)benzoate (Compound 124; 1.69 g, 94%) as a red solid. MS (ESI) calcd for C16H22N205: 322.15. |
87% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; | 10.8-1 Step 8-1: Synthesis of Methyl-3-[(2-tert-butoxycarbonylamino)ethylcarbamoyl]benzoic Acid Ester (112) Step 8-1: Synthesis of Methyl-3-[(2-tert-butoxycarbonylamino)ethylcarbamoyl]benzoic Acid Ester (112) Monomethylisophthalic acid (111) (1.01 g) was dissolved in N,N-dimethylformamide (25 ml). To the solution were added EDCI·HCl (1.60 g), HOBt·H2O (1.26 g), triethylamine (848 mg), and N-tert-butoxycarbonyl-1,2-diaminoethane (1.00 g), and the mixture was stirred at room temperature for 16 hours. The reaction liquid was diluted with chloroform (100 ml), washed with water (300 ml), saturated aqueous sodium bicarbonate (300 ml), and brine (300 ml), dried over anhydrous sodium sulfate, and filtered. After that, the filtrate was concentrated and the residue was purified by silica gel flash column chromatography (developing solvent: n-hexane:ethyl acetate=17:50 to n-hexane:ethyl acetate=3:5) to give a compound (112) (1.47 g, yield: 81%) as a white solid. 1H NMR data on the compound (112) is shown below. 1H-NMR (DMSO-d6, 500MHz, δ; ppm) 8.69-8.68 (1H, m), 8.43 (1H, s), 8.11-8.09 (2H, m), 7.63 (1H, t, J = 7.74 Hz), 6.94-6.91 (1H, m), 3.89 (3H, s), 3.31-3.28 (2H, m), 3.12 (2H, q, J = 5.82 Hz), 1.37 (9H, s). |
81% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; |
72% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 1 N-(2-tert-Butoxycarbonylaminoethyl)isophthalamic Acid Methyl Ester Preparation 1 N-(2-tert-Butoxycarbonylaminoethyl)isophthalamic Acid Methyl Ester Mono-methyl isophthalate (10.0 g, 55.5 mmol), t-butyl n-(2-aminoethyl) carbamate (8.89 g, 55.5 mmol, 1.0 eq) and EDCI (12.2 g, 63.8 mmol, 1.15 eq) were dissolved in 270 mL DCM, followed by the addition of DIPEA (29.0 mL, 166 mmol, 3.0 eq). The reaction was allowed to stir at room temperature overnight. It was then taken up in 100 mL of DCM, washed with a 1:1 solution of 1.0 N HCl in brine, water, and a 1:1 solution of brine in saturated NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to afford the product as a light yellow solid (12.81 g, 72%). |
72% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 1 Preparation 1 N-(2-tert-Butoxycarbonylaminoethyl)isophthalamic Acid Methyl Ester Mono-methyl isophthalate (10.0 g, 55.5 mmol), t-butyl n-(2-aminoethyl)carbamate (8.89 g, 55.5 mmol, 1.0 eq) and EDCI (12.2 g, 63.8 mmol, 1.15 eq) were dissolved in 270 mL DCM, followed by the addition of DIPEA (29.0 mL, 166 mmol, 3.0 eq). The reaction was allowed to stir at room temperature overnight. It was then taken up in 100 mL of DCM, washed with a 1:1 solution of 1.0 N HCl in brine, water, and a 1:1 solution of brine in saturated NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to afford the product as a light yellow solid (12.81 g, 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | 237 (2,2-dimethoxyethyl)carbamoyl]benzoate A mixture of 3-(methoxycarbonyl)benzoic acid (500 mg, 2.77 mmol), 1-Hydroxybenzotriazole hydrate (397 mg, 2.94 mmol), A/-(3-Dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride (564 mg, 2.94 mmol), and TEA (1.16 mL, 8.31 mmol) in DCM (15 mL) was stirred at 0 °C for 10 min, then 2,2-dimethoxyethan-1 -amine (0.301 mL, 2.77 mmol) was added and the mixture was left stirring at RT O/N. It was washed with NaHC03 (x1), NH4CI (x3) and Brine, organic phase was separated, dried and concentrated under reduced pressure affording methyl 3- [(2,2-dimethoxyethyl)carbamoyl]benzoate (p237, 548 mg, y= 74%) that was used as such in the next step. MS (m/z): 268.2 [MH]+. |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; | 9 N-(2,2-Dimethoxyethyl)isophthalamic Acid Methyl Ester Preparation 9 N-(2,2-Dimethoxyethyl)isophthalamic Acid Methyl Ester Mono-methyl isophthalate (1 g, 5.55 mmol), amino acetaldehyde dimethyl acetal (569 μL, 5.28 mmol) and EDCI (1.52 g, 7.92 mmol) were dissolved in 55 mL DCM, followed by the addition of DIPEA (1.84 mL, 10.56 mmol). The reaction was allowed to stir at room temperature for 2 hours. It was then taken up in 50 mL of DCM, washed with saturated NaHCO3 solution (100 mL), and brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford the crude product (1.48 g) as a clear oil which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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71% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester; di-n-propylamine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 15h; Stage #2: With lithium hydroxide; water In tetrahydrofuran for 1.5h; Stage #3: With hydrogenchloride In tetrahydrofuran; water | 2.8 Example 2.8: Synthesis of Isophthalic Acid [0306] To a stirred solution of mono-methyl isophthalate (0.25 g, 1.4 mmol) in dichloromethane (16 mL) was added HOBt (0.21 g, 1.6 mmol), EDCI (0.30 g, 1.6 mmol) and Pr2NH (0.24 mL, 1.75 mmol). The resulting mixture was stirred at room temperature for 15h under argon followed by quenching with NaHCO3. The layers were separated and the aqueous layer was extracted with CHCl3 (2 x 20 mL). The combined organic layer was dried with Na2SO4 and concentrated under reduced pressure. The resulting oil was dissolved in THF (5 mL) to which was added 3 mL of l.ON LiOH(aq). The resulting mixture was stirred rapidly for 1.5 h. The volatiles were removed via rotary evaporation and the resulting aqueous solution was extracted with CHCl3 (x3). The aqueous solution was then acidified EPO to pH 1 with IN HCl(aq) and extracted with CHCl3 (x3). The combined organic layer was dried with Na2SO4 and concentrated under reduced pressure to provide 8e (0.25 g, 71%) as an amorphous solid; 1HNMR (300 MHz5 CDCl3): δ 11.98 (bs, IH), 8.08-8.16 (m, 2H), 7.62-7.67 (m, IH), 7.49-7.56 (m, IH), 3.44-3.56 (m, 2H), 3.11-3.24 (m, 2H), 1.48-1.80 (m, 4H), 0.95-1.07 (m, 3H), 0.72-0.83 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium borohydrid; trifluoroborane diethyl ether; In tetrahydrofuran; water; | EXAMPLE 5 Preparation of Methyl m-Hydroxymethylbenzoate (Me mHMB). To a stirred suspension of 21.0 g. of monomethylisophthalate (97% pure, 114 millimoles) and sodium borohydride (4.0 g., 105 millimoles) in tetrahydrofuran (120 ml.), boron trifluoride etherate (20.0 g., 140 millimoles) was added at rate to maintain gentle reflux. The mixture was stirred at room temperature for 4 hours. Water (25 ml.) was added and the solvents were removed on a rotary evaporator. The residue was taken up in water (100 ml.) and extracted with dichloromethane (four 50 ml. portions). The combined organic layer was extracted with 5% sodium bicarbonate (100 ml.), water (100 ml.), and dried. Removal of solvent in vacuo left 18.75 g. (97% yield) of a clear colorless oil; acetylation gc, Me mHMB (99.1%), m-xylenediol (0.26%), high-boilers (0.05%). Fractional distillation gave 90% yield of a center-cut fraction: b.p. 123 C./1.0 torr; acetylation gc, Me mHMB (99.80%), m-xylenediol (0.11%), methyl 3-carboxybenzaldehyde (0.06%), and high-boilers (0.03%); ir (neat) 3425, 1725, 1712 (shoulder), 1455, 1440, 1300, 1210, 1115, and 755 cm.-1; nmr (CCl4) 8.0-7.0 (m, 2H), 7.6-7.2 (m, 2H), 4.52 (m, 2H), 4.46 (m, 1H), and 3.80 (s, 3H); mass spectrum m/e 166 (parent ion), 135 (base peak). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With ethylenediamine In methanol | 8.a (a) (a) 3-(Aminoethylcarbamoyl)benzoic acid: A solution of 9 g of isophthalic acid monomethyl ester and 1.5 ml of ethylenediamine in 90 ml of methanol is stirred for 18 hours and then concentrated to dryness. The residue is washed with ice-cold methanol. Yield: 91% |
Yield | Reaction Conditions | Operation in experiment |
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52% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 80℃; for 18h; | 13-III Employing 229 mg (0.10 mmole) of 4-iodobenzonitrile as starting material, 259 mg (96 percent) of benzonitrile compound was obtained by the same procedure as in the synthesis of the synthetic intermediate of Embodiment Compound 16-III. 0.045 mL (0.738 mmole) of 50 percent hydroxylamine was added to a 4 mL ethanol solution of 100 mg (0.369 mmole) of the above intermediate and the mixture was stirred for 16 hours at 60° C. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure, yielding 110 mg (98 percent) of amideoxime compound. 36 mg (0.197 mmole) of isophthalic acid monomethyl ester and 38 mg (0.197 mmole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to a 2 mL N,N-dimethylformamide solution of 30 mg (0.099 mmole) of above intermediate 2-III and the mixture was stirred for one hour at room temperature and then for 17 hours at 80° C. The solvent was removed under reduced pressure, ethyl acetate and water were added, and the mixture was extracted. The organic layer was sequentially washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was slurry washed with diethylether and hexane, yielding 23 mg (52 percent) of ester compound. 1 mL of 1N lithium hydroxide was added to a mixed solution (2 mL of methanol and 1 mL of tetrahydrofuran) of 22 mg (0.049 mmole) of the intermediate of 3-III and the mixture was stirred for one hour at 50° C. The mixture was cooled to room temperature and then neutralized with 1 mL of 1N hydrochloric acid. Next, 10 percent monosodium dihydrogen phosphate aqueous solution was added to adjust the pH to 3-4 and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure, yielding 17 mg (80 percent) of Embodiment Compound 27-III. |
Yield | Reaction Conditions | Operation in experiment |
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83% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,4-dioxane at 20 - 95℃; for 21h; | 36-IV 1 mL of isoamylamine was added to a 2 mL diisopropylethylamine solution of 182 mg (1.0 mmole) of 4-chloro-3-nitrobenzonitrile, the mixture was stirred for 15 hours at 90° C., 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure, yielding 250 mg of aniline compound (1B-11). 0.3 mL (50 mmole) of 50 percent hydroxylamine aqueous solution was added to a mixed solution (2 mL of tetrahydrofuran and 8 mL ethanol) of 240 mg (1.0 mmole) of aniline compound (1B-9) and the mixture was stirred for 14 hours at 50° C. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and 256 mg (a yield of 96 percent) of amideoxime compound (1B-12) was obtained from the ethyl acetate-hexane (1:1) fraction. 221 mg (1.23 mmole) of isophthalic acid monomethyl ester and 217 mg (1.13 mmoles) of WSC hydrochloride were added to a 10 mL dioxane solution of 251 mg (0.943 mmole) of the above amideoxime. The mixture was stilled for 3 hours at room temperature and then stirred for 18 hours at 95° C.. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and 319 mg (an 83 percent yield) of oxadiazole compound (1B-13) was obtained from the ethyl acetate-hexane (1:3) fraction. 2 mL of 1N lithium hydroxide was added to a solution (2 mL of methanol and 5 mL of tetrahydrofuran) of 319 mg (0.366 mmole) of the above oxadiazole compound (1B-13), the mixture was stirred for 15 hours at room temperature, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure, yielding 137 mg (a 97 percent yield) of benzoic, acid compound (1B-14). To a solution of 130 mg (0.328 mmole) of benzoic acid compound (1B-14) in 2 mL of N,N-dimethylformamide were sequentially added 13 uL (0.122 mmole) of dimethylsulfamoyl chloride, 26 uL (0.183 mmole) of butyldimethylamine, 4 mg (0.030 mmole) of pyridine, and 21 mg (0.122 mmole) of benzenesulfonamide and the mixture was stirred for 14 hours at room temperature. The solvent was removed under reduced pressure, after which 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography and 78 mg (a 44 percent yield) of the compound of Embodiment 36-IV was obtained from the ethyl acetate-hexane (2:1) fraction. |
Yield | Reaction Conditions | Operation in experiment |
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64% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; | 15 Example 15; 8-(5-Fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-(3-methoxycarbonylbenzoyloxy)phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No.15-1) A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No.11, 25.3 mg, 0.0562 mmol), monomethyl isophthalate (20.5 mg, 0.114 mmol), N,N-diisopropylethylamine (38.8 µL, 0.223 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (43.4 mg, 0.114 mmol) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (15 mL). The mixture was washed with water (15 mL) and saturated saturated brine (15 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (22.0 mg) as a colorless solid. (Yield 64%) |
Yield | Reaction Conditions | Operation in experiment |
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84% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Stage #2: 2,6-difluoroaniline With pyridine; dmap In dichloromethane | 1.A 3-[(Methyloxy)carbonyl]benzoic acid (11.0 g, 61.1 mmol) was dissolved in 600 mL of dichloromethane with stirring. Oxalyl chloride (16.3 mL, 183.2 mmol) was added dropwise by addition funnel as a solution in 100 mL of DCM. DMF (3.0 mL) was added via syringe. The reaction was stirred overnight at rt and then concentrated in vacuo.The resultant solid was further dried under high vacuum pressure. The solid was dissolved in 600 mL of DCM with stirring. Pyridine (24.5 mL, 305.3 mmol), (4-dimethylamino)-pyridine (3.7 g, 30.5 mmol), and 2,6-difluoroaniline (19.7 mL, 183.2 mmol) were added to the solution. The reaction was stirred overnight and poured into 1N HCl. The layers were separated, and the aqueous layer was washed twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography. The clean fractions (by TLC) were concentrated in vacuo to afford 14.87 g (84%) of the desired product. 1H NMR (400 MHz, DMSO-d6): δ10.40 (s, 1H), 8.58 (s, 1H), 8.24 (m, 1H), 8.18 (m, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.25-7.18 (m, 2H), 3.89 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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80% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In acetonitrile at 20℃; for 5h; | A17.a 4-(4-Aminophenyl)-l-piperazinecarboxylic acid 1,1-dimethylethyl ester (1.00 g, 3.61 mmol), 1,3-benzenedicarboxylic acid 1 -methyl ester (4.33 mmol), O-benzotriazolyl tetramethylisouronium tetrafluoroborate (TBTU) (5.03 mmol) and Et3N (1.50 ml, 10.7 mmol) were mixted in CH3CN (10 ml) and stirred at room temperature for 5 hours. The crystalline product was filtered off from the reaction mixture, washed with H2O and dried on the air. Yield: 1.262 g of intermediate 42 (80 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With diethyl cyanophosphonate; triethylamine In dichloromethane at 20℃; for 18h; | B12 DECP (1.167 ml, 0.00703 mol) was added to a stirring solution of intermediate 38 (2.1 g, 0.00468 mol) (prepared according to Al l.d-2) and 1,3-benzenedicarboxylic acid 1 -methyl ester (0.886 g, 0.00492 mol) in Et3N (1.316 ml, 0.00937 mol) and CH2Cl2 (100 ml; p. a.). The reaction mixture was stirred for 18 hours at room temperature and then an aqueous saturated NaHCO3 solution (50 ml) and CH2Cl2/Me0H 1/1 (40 ml) was added. The mixture was stirred for 15 minutes. The layers were separated and the organic layer was stirred with H2O (50 ml) and left standing overnight in a separated funnel. The precipitate in the organic layer was filtered off, washed (CH2Cl2) and dried (50 0C, in vacuo), yielding 0.54 g of compound 140 (19 %). The filtrate was evaporated and the residue was stirred in acetone, filtered off, washed (acetone) and dried (50 0C, in vacuo), yielding 1 g of compound 140 (35 %). |
Yield | Reaction Conditions | Operation in experiment |
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80% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With oxalyl dichloride In dichloromethane at 20℃; for 1h; Stage #2: (+/-)-cis-propane-2-sulfonic acid [2-(4-amino-phenyl)-cyclopentyl]-amide With triethylamine In tetrahydrofuran at 20℃; for 1h; | 69.IV.C Preparation of (+,-) Cis-4'-[2-(Propane-2-sulfonylamino)-cyclopentyl]-biphenyl-3-carboxylic Acid Methyl Ester EXAMPLE 69 Preparation of (+,-) Cis-4'-[2-(Propane-2-sulfonylamino)-cyclopentyl]-biphenyl-3-carboxylic Acid Methyl Ester Scheme IV, step C: Monomethyl isophthalate (140 mg, 0.78 mmol) and methylene chloride (4.7 mL) were combined in a 15 mL round bottomed flask, fitted with a y-tube, capped by a rubber stopper, and nitrogen gas, and stirbar. Next, by syringe, oxalyl chloride (0.2 mL, 3.106 mmol) was added, and stirred at room temperature for one hour. After one hour the reaction mixture was reduced under vacuum and to it was added the amine from example 23 (200 mg, 0.706 mmol), triethylamine (0.11 mL, 0.776 mmol), and anhydrous tetrahydrofuran (4.7 mL). The reaction mixture was then stirred under same conditions for an additional hour. Next the reaction mixture was quenched with water, and extracted with methylene chloride (25 mL*3). The organic layer was dried (MgSO4), filtered, and concentrated under reduced vacuum, yielding 385 mg of a brown foam. This material was purified via silica gel chromatography, utilizing a Chromatotron with a 4000 uM rotor in a 3:1 hexane:ethyl acetate solvent system, yielding the title compound (277 mg, 80%) as white crystals. Electrospray-MS 446.0 (M*+1); Analysis; Theory: C 62.14; H 6.35; N 6.30; Found: C 61.80; H 6.22; N 6.32. |
Yield | Reaction Conditions | Operation in experiment |
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65% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: (4-methylaminomethyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 16h; | 1-34 Example 1-34General Procedure (A)N-Methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzyl]-isophthalamic Acid To a solution of isophthalic acid monomethyl ester (72 mg, 0.4 mmol) in THF (10 mL) was added with stirring HOBt (54 mg, 0.4 mmol) followed by EDAC (77 mg, 0.4 mmol) and the mixture was stirred for 30 min. at ambient temperature. To the resulting mixture was added (4-methylaminomethyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (100 mg, 0.33 mmol, Example 1) and DIPEA (70 μL, 0.4 mmol). The reaction mixture was stirred for 16 h. at ambient temperature. The solvent was evaporated and the residue purified using preparative HPLC (Method Z4): Amount isolated=100 mg (65%) of N-Methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzyl]-isophthalamic acid methyl ester as an oil.To a solution of the ester (100 mg) in EtOH (5 mL) was added water (2 mL) and 1N NaOH (0.5 mL). The mixture was stirred at ambient temperature for 6 h and the volatiles evaporated. The residue was dissolved in water (5 mL) and washed with Et2O (2×10 mL) and pH adjusted to 1 by 1N HCl. The aqueous phase was extracted with EtOAc (3×10 mL), the combined organic phases dried (MgSO4) and evaporated which afforded 73 mg (49%) of the title compound as a solid.1H NMR (400 MHz, CDCl3) δ 0.95 (d, 3H), 1.05 (s, 3H), 1.14 (d, 3H), 1.33-1.49 (m, 3.5H), 1.58 (m, 1H), 1.79 (m, 1H), 2.27 (m, 0.5H), 2.88+3.08 (2×s, 3H, rotamers), 3.28 (m, 1.5H), 3.63 (d, 0.5H), 4.02 (m, 0.5H), 4.53-4.79 (m, 2.5H), 7.21-7.70 (m, 6H), 8.15 (m, 2H). HPLC-MS (Method Z1): m/z=449 (M+1); tr=1.76 min. |
Yield | Reaction Conditions | Operation in experiment |
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68% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In tetrahydrofuran at 20℃; for 65h; | 125 Example 125 Methyl 3-[[(3-bromo-4-fluorophenyl)methyl](methyl)amino]carbonyl}benzoate To a solution of [(3-bromo-4-fluorophenyl)methyl]methylamine (0.355 g, 1.63 mmol) in THF (16 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (0.294 g, 1.63 mmol), HBTU (0.929 g, 2.45 mmol), Et3N (0.458 mL, 3.26 mmol) and stirred at room temperature for 65 h, and then quenched with H2O. The organic layer was loaded onto silica gel cartridge and purified by CombiFlash chromatograph to afford the title compound 0.419 g (68%). LC-MS m/z 380 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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93% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 18h; | 110 Example 110 1,1-Dimethylethyl 4-[(2'-fluoro-5'-[({3-[(methyloxy)carbonyl]phenyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperazinecarboxylate To a solution of 1,1-dimethylethyl 4-[5'-(aminomethyl)-2'-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.200 g, 0.5 mmol) in CH2Cl2 (5 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (0.0901 g, 0.5 mmol), HBTU (0.19 g, 0.5 mmol), and Et3N (0.0703 mL, 0.5 mmol). The mixture was stirred at room temperature for 18 h and then quenched with H2O. The organic layer was separated, concentrated and purified by CombiFlash chromatograph to afford the title compound 0.26 g (93%). LC-MS m/z 562 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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60% | Example 169 Amethyl 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoate; To a solution of 3-(methoxycarbonyl)benzoic acid (0.9 g, 5 mmol) in dichloromethane (20 mL), 1-hydroxybenzotriazole (0.75 g, 5.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.06 g, 5.5 mmol) and triethyl amine (2 mL) were added. The mixture was stirred at room temperature for 30 min, and then <strong>[59878-57-8]cyclopropyl(piperazin-1-yl)methanone</strong> (1.0 g, 5 mmol) was added and the mixture was stirred at room temperature for 16 h. The resulting mixture was added water (50 mL) and extracted with dichloromethane (100 mL×3), the organic phase was washed with sodium bicarbonate, brine and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20:1 to 2:1), 0.95 g of methyl 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoate as an oil was obtained, Yield 60%. 1H-NMR (400 MHz, CDCl3) 0.80-0.82 (m, 2H), 1.00-1.04 (m, 2H), 1.24-1.27 (m, 1H), 3.25-3.78 (m, 8H), 3.94 (s, 3H), 7.52-7.55 (t, J=7.6 Hz, 1H), 7.63-7.65 (d, J=7.6 Hz, 1H), 8.09-8.14 (m, 2H); LC-MS (ESI) m/z: 317(M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: 1-(2-methylpropionyl)piperazine In dichloromethane at 20℃; for 16h; | 168.A Example 168 Amethyl 3-(4-isobutyrylpiperazine-1-carbonyl)benzoate; To a solution of 3-(methoxycarbonyl)benzoic acid (0.9 g, 5 mmol) in dichloromethane (20 mL), 1-hydroxybenzotriazole (0.75 g, 5.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.06 g, 5.5 mmol) and triethyl amine (2 mL) was added. The mixture was stirred at room temperature for 30 min, then 2-methyl-1-(piperazin-1-yl)propan-1-one (1.0 g, 5 mmol) was added and the mixture was stirred at room temperature for 16 h. The resulting mixture was added water (50 mL) and extracted with dichloromethane (100 mL×3). The organic phase was washed with sodium bicarbonate and brine and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20:1 to 2:1) to give 1.25 g of methyl 3-(4-isobutyrylpiperazine-1-carbonyl)benzoate as an oil. Yield 94%. 1H-NMR (400 MHz, CDCl3) 1.14-1.15 (d, J=6.4 Hz, 6H), 2.81 (brs, 1H), 3.44-3.80 (m, 8H), 3.94 (s, 3H), 7.52-7.55 (t, J=7.6 Hz, 1H), 7.62-7.64 (d, J=8.0 Hz, 1H), 8.08-8.14 (m, 2H); LC-MS (ESI) m/z: 319(M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 4-HYDROXYPIPERIDINE In dichloromethane at 20℃; for 16h; | 96 Methyl 3-[(4-hydroxy-1-piperidinyl)carbonyl]benzoate Example 96 Methyl 3-[(4-hydroxy-1-piperidinyl)carbonyl]benzoate To 3-[(methyloxy)carbonyl]benzoic acid (0.901 g, 5 mmol) in DCM (25 mL) was added TEA (0.697 mL, 5.00 mmol), EtOCOCl (0.480 mL, 5.0 mmol). This mixture was stirred at 0° C. for 10 mins and then 4-piperidinol (0.506 g, 5.00 mmol) was added. Stirring was continued at room temperature for 16 h. The reaction mixture was diluted with DCM (35 mL), washed with HOAc (20 mL, 10%), NaHCO3 (20 mL, 10%), water (20 mL), dried over Na2SO4, filtered and concentrated and purified by CombiFlash chomatograph to afford the title compound (0.696 g, 53%). LC-MS m/z 264 (M+H)+. |
53% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 4-HYDROXYPIPERIDINE In dichloromethane at 20℃; for 16h; | 96 Methyl 3-[(4-hydroxy-1-piperidinyl)carbonyl]benzoate Example 96 Methyl 3-[(4-hydroxy-1-piperidinyl)carbonyl]benzoate To 3-[(methyloxy)carbonyl]benzoic acid (0.901 g, 5 mmol) in DCM (25 mL) was added TEA (0.697 mL, 5.00 mmol), EtOCOCl (0.480 mL, 5.0 mmol). This mixture was stirred at 0° C. for 10 mins and then 4-piperidinol (0.506 g, 5.00 mmol) was added. Stirring was continued at room temperature for 16 h. The reaction mixture was diluted with DCM (35 mL), washed with HOAc (20 mL, 10%), NaHCO3 (20 mL, 10%), water (20 mL), dried over Na2SO4, filtered and concentrated and purified by CombiFlash chomatograph to afford the title compound (0.696 g, 53%). LC-MS m/z 264 (M+H)+. |
53% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 4-HYDROXYPIPERIDINE In dichloromethane at 0 - 20℃; | 169 Example 169 Methyl 3-[(4-hydroxy-1-piperidinyl)carbonyl]benzoate To 3-[(methyloxy)carbonyl]benzoic acid (0.901 g, 5 mmol) in DCM (25 mL) was added TEA (0.697 mL, 5.00 mmol), and EtOCOCl (0.480 mL, 5.0 mmol), stirred at 0° C. for 10 min. and then 4-piperidinol (0.506 g, 5.00 mmol) was added. This mixture was then stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (35 mL), washed with HOAc (20 mL, 10%), NaHCO3 (20 mL, 10%), water (20 mL), dried over Na2SO4, filtered and concentrated and purified by CombiFlash chromatograph to afford the title compound (0.696 g, 53%). LC-MS m/z 264 (M+H)+. |
53% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 4-HYDROXYPIPERIDINE In dichloromethane at 20℃; for 16h; | 96 Example 96 Methyl 3-[(4-hydroxy-l-piperidinyl)carbonyl]benzoateTo 3-[(methyloxy)carbonyl]benzoic acid (0.901 g, 5 mmol) in DCM (25 mL) was addedTEA (0.697 mL, 5.00 mmol), EtOCOCl (0.480 mL, 5.0 mmol). This mixture was stirred at 0 0C for 10 mins and then 4-piperidinol (0.506 g, 5.00 mmol) was added. Stirring was continued at room temperature for 16 h. The reaction mixture was diluted with DCM (35 mL), washed with HOAc (20 mL, 10%), NaHCO3 (20 mL, 10%), water (20 mL), dried over Na2SO4, filtered and concentrated and purified by CombiFlash chomatograph to afford the title compound (0.696 g, 53 %). LC-MS m/z 264 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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89% | With lithium triethylborohydride; In tetrahydrofuran; for 3h; | Example 123 3-(Hydroxymethyl)benzoic Acid To 3-[(methyloxy)carbonyl]benzoic acid (0.18 g, 1.0 mmol) was added lithium triethyl borohydride (3.0 mL, 1.0 M in THF, 3.0 mmol) while stirring. The mixture was stirred for 3 h and then quenched with NH4Cl (sat.) and acidified with HCl (aq.). This solution was extracted with EtOAc, and the extract was dried over Na2SO4, filtered and concentrated to afford the title compound 0.136 g (89%). LC-MS m/z 153 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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91% | With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine In dichloromethane at 25℃; for 20h; | 3 EXAMPLE 3 Methyl 3-((lR,2S)-2-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine- l-carbonyl)cyclohexylcarbamoyl)benzoate[00124] (( 1 S,2R)-2-Aminocyclohexyl)((S)-4-(4-chlorophenyl)-4-hydroxy-3,3 - dimethylpiperidin- 1 -yl)methanone, HCl salt (50 mg, 0.125 mmol), 3- (metrioxycarbonyl)benzoic acid (22.44 mg, 0.125 mmol), HOBt (38.2 mg, 0.249 mmol), EDC (47.8 mg, 0.249 mmol) and triethylamine (0.087 mL, 0.623 mmol) were mixed in methylene chloride (3 mL) at 25 0C and stirred for 20 hours. The reaction was worked up by adding methylene chloride followed by rinsing with saturated sodium carbonate (IX). The methylene chloride layer was dried over sodium sulfate and concentrated to give a colorless oil. The colorless oil was purified over silica gel in 3 : 1 to 1 : 1 hexanes/EtOAc to 100% EtOAc to yield Example 3 (60 mg, 0.114 mmol, 91 % yield) as a white glass. MS (ESI+) = 525.55 (M+H)+ 1H NMR (CD3OD, 400 MHz) (NMR shows several rotamers) δ 8.39 (s, 1 H), 8.20 (d, 0.5H, J = 8.0 Hz), 8.16 (d, 0.5H, J = 8.0 Hz), 8.00 (d, 0.5H, J = 8.0 Hz), 7.98 (d, 0.5H, J = 8.0 Hz), 7.62 (app. t, 0.5H, J = 8.0 Hz), 7.58 (app. t, 0.5H, J = 8.0 Hz), 7.48 (d, IH, J = 8.0 Hz), 7.35 (d, IH, J = 8.0 Hz), 7.30 (d, IH, J = 8.0 Hz), 7.23 (d, IH, J = 8.0 Hz), 4.56 (m, 0.5H), 4.42 (m, 0.5H), 4.20 (m, 0.5H), 4.08-3.90 (m, IH), 3.96 (s, 0.5 x 3H), 3.94 (s, 0.5 x 3H), 3.68-3.56 (m, IH), 3.46-3.34 (m, 2H), 3.15-3.00 (m, IH), 2.74 (m, 0.5H), 2.50 (m, IH), 2.20 (m, 0.5H), 2.06 (m, IH), 1.90 (m, 0.5H), 1.82-1.66 (m, 3.5H), 1.66-1.43 (m, 3.5H), 0.78 (s, 0.5 x 3H), 0.77 (s, 0.5 x 3H), 0.74 (s, 0.5 x 3H), 0.65 (s, 0.5 x 3H). [LCMS method: Inj. Vol. = 10 uL; Start % B = O; Final % B = 100; Gradient Time = 2 min; Flow Rate = 5 ml/min; Wavelength = 220 nm; Solvent A = 10% MeOH - 90% H2O - 0.1% TFA; Solvent B = 90% MeOH - 10% H2O - 0.1% TFA; Column 1 = Waters Sunfire S5 C18 4.6 x 50 mm (2 min. grad); Retention Time = 2.02 minutes.] |
Yield | Reaction Conditions | Operation in experiment |
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87% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; | 11 Synthesis of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]isophthalic acid Production example 11 Synthesis of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]isophthalic acid A mixture of 2.00 g (6.44 mmol) of 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine, 1.75 g (9.71 mmol) of isophthalic acid monomethyl ester, 2.7 mL of triethylamine, 1.00 g of 1-hydroxybenzotriazole hydrate, and 2.00 g of WSC hydrochloride, was suspended in 15 mL of dimethylformamide, followed by stirring at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. After filtration, the residue obtained by solvent distillation under reduced pressure was then subjected to silica gel column chromatography (ethyl acetate-heptane). Thereafter, a solid precipitated with ethyl acetate-hexane was collected by filtration, and dried under aeration to give 2.65 g of the titled compound (yield: 87%). 1H-NMR (DMSO-d6) δ (ppm): 2.91 (3H, d, J = 4.8 Hz), 3.76 (3H, s), 3.92 (3H, s), 3.93 (3H, s), 7.01 (1H, s), 7.02 (1H, brs), 7.19 (1H, s), 7.48 (1H, brd, J = 8.0 Hz), 7.57 (1H, t, J = 8.0 Hz), 7.72 (1H, t, J = 8.0 Hz), 7.92 (1H, brd, J = 8.0 Hz), 8.17 (1H, brd, J = 8.0 Hz), 8.22 (1H, t, J = 1.6 Hz), 8.26 (1H, brd, J = 8.0 Hz), 8.56 (1H, t, J = 1.6 Hz), 10.67(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
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100% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In tetrahydrofuran Stage #2: benzyl-methyl-amine In tetrahydrofuran at 20℃; | 3.a 1.0 g (5.6 mmol) monomethyl isophthalate were combined in 30 ml THF with 1.8 g (5.6 mmol) TBTU and 781.0 μl (5.6 mmol) triethylamine, then 723 μl (5.6 mmol) benzylmethylamine was added and the mixture was stirred overnight at ambient temperature. The reaction solution was extracted with sat. NaCl solution and ethyl acetate. The organic phases were dried and evaporated to dryness i. vac. Quantitative yield of 3-a. RF=0.64 (silica gel; petroleum ether/ethyl acetate 1:1) |
Yield | Reaction Conditions | Operation in experiment |
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76% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 2,3-Diaminopyridine In N,N-dimethyl-formamide at 200℃; for 0.166667h; | 69.69a Example 69 (a) Methyl 3-(3H-imidazo[4,5-b]pyridin-2-yl)benzoateA suspension of isophtalic acid monomethyl ester (5.0 g, 28 mmol) and CDI (4.5 g, 28 mmol) in DMF (10 mL) was stirred at 0 0C for 30 min. Pyridine-2,3-diamine (2,52 g, 23 mmol) was added and the reaction mixture was heated to +200 0C for 10 minutes. Water io was added and the product precipitated at r.t. and was filtered, washed with water and dried to afford 4.1 g (76% yield) of the title compound. MS (APPI) m/z 254 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
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71% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 4-(4-methoxyphenyl)pyridine-2,3-diamine In N,N-dimethyl-formamide at 200℃; for 0.166667h; | 68.68a Methyl 3-[7-(4-methoxyphenyl)-3H-imidazo[4, 5-b]pyridin-2-A suspension of isophtalic acid monomethyl ester (0.460 g, 2.56 mmol) and CDI (0.414 g, 2.56 mmol) in DMF (3 mL) was stirred at 0 0C for 30 mins. 4-(4-methoxyphenyl)pyridine- 2,3-diamine (obtained from Example l(c)) (0.500 g, 2.32 mmol) was added and the reaction mixture was heated to +200 0C for 10 minutes. Water was added and the product EPO precipitated at r.t. and was filtered, washed with water and dried to afford 0.59 g (71% yield) of the title compound. MS (APPI) m/z 360 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
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94% | With triethylamine; HATU In N,N-dimethyl-formamide at 25℃; for 5h; | 4.5 Step 5 To a solution of 3- (methoxycarbonyl) benzoic acid (52.0 mg, 0.289 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate hexafluorophosphate salt (127 mg, 0.333 mmol) in dimethylformamide (1.0 mL), Compound I-108 (60.0 mg, 0.222 mmol) and triethylamine (0.062 mL, 0.444 mmol) were added. The solution was then stirred at 25°C for 5 hours. Water (5.0 mL) was then added to the reaction solution. The precipitated powder was filtered, washed with water, and then dried. The resulting powder was further washed with ethyl acetate and hexane to yield subject compound 1-120 (90.0 mg, 94%) as a white powder.1H-NMR (DMSO-d.6) 612.11 (1H, s), 11.07 (1H br s) 8.56 (1H, s), 8.24 (1H, d, J=7.8Hz), 8.15 (1H, d, J = 7.8 Hz) 7.69-7.73 (3H, m), 7.43 (1H, d, J = 8.7 Hz), 7.27-7.33 (3H, m), 7.03 (1H, d, J = 7.2 Hz), 4.25 (2H, t, J = 4.2 Hz), 4.05 (2H, t, J = 4.2 Hz), 3.90 (3H, s) LC/MS (Method A): 2.21 min, [M+H]+ = 433.3. |
Yield | Reaction Conditions | Operation in experiment |
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51% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 25℃; | 5a Intermediate 5a: methyl 3-((2-(2-hvdroxyethoxy)ethyl carbamoyl)benzoate.; Into a 1000-mL round bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (20 g, 111.11 mmol, 1.00 equiv) in N,N-dimethylformamide (500 mL), HATU (63.2 g, 166.32 mmol, 1.50 equiv), N,N-diisopropylethylamine (21.5 g, 166.67 mmol, 1.50 equiv), and 2-(2-aminoethoxy)ethanol (23.3 g, 221.90 mmol, 2.00 equiv). The resulting solution was stirred for overnight at 25°C. The resulting mixture was concentrated under vacuum. The resulting solution was dissolved in 200 mL of ethyl acetate. The resulting mixture was washed with 10x200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (100: 1). This resulted in 15 g (51%) of methyl 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoate as red oil. |
51% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 25℃; | 10 Intermediate 10a: methyl 3-((2-(,2-hvdroxyethoxy)ethyl)carbamoyl benzoate. Into a 1000-mL round bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (20 g, 111.11 mmol, 1.00 equiv) in N,N-dimethylformamide (500 mL), HATU (63.2 g, 166.32 mmol, 1.50 equiv), N,N-diisopropylethylamine (21.5 g, 166.67 mmol, 1.50 equiv), and 2-(2-aminoethoxy)ethanol (23.3 g, 221.90 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25°C. The resulting mixture was concentrated under vacuum. The resulting solution was dissolved in 200 mL of ethyl acetate. The resulting mixture was washed with 10x200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (100:1). This resulted in 15 g (51%) of methyl 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoate as red oil. |
51% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; | 64a Intermediate 64a: methyl 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoate Into a 1000-mL round bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (20 g, 111.11 mmol, 1.00 equiv) in N,N-dimethylformamide (500 mL), HATU (63.2 g, 166.32 mmol, 1.50 equiv), N,N-diisopropylethylamine (21.5 g, 166.67 mmol, 1.50 equiv), 2-(2-aminoethoxy)ethanol (23.3 g, 221.90 mmol, 2.00 equiv). The resulting solution was stirred for overnight at 25° C. The resulting mixture was concentrated under vacuum. The resulting solution was dissolved in 200 mL of ethyl acetate. The resulting mixture was washed with 10*200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (100:1). This resulted in 15 g (51%) of methyl 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoate as red oil. |
Yield | Reaction Conditions | Operation in experiment |
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60% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 3h; | 15c Intermediate 15c: methyl 3-("2-(2-phenylpyrimidin-5-ylcarbamoyl)-4-(piperidin-l-yl - phenylcarbamovQbenzoate.; To a solution of 2-amino-N-(2-phenylpyrimidin-5-yl)-5- (piperidin-l-yl)benzamide (2 g, 3.75 mmol, 1.00 equiv, 70%) in dichloromethane (30 mL) was added 3-(methoxycarbonyl)benzoic acid (1 160 mg, 6.12 mmol, 1.20 equiv, 95%), EDC.HC1 (2040 mg, 10.20 mmol, 2.00 equiv, 95%), and 4- dimethylaminopyridine (660 mg, 5.14 mmol, 1.00 equiv, 95%) and the resulting solution was stirred for 3 h at 25°C in an oil bath. The mixture was concentrated under vacuum, diluted with 100 mL of ethyl acetate, washed with 1x100 mL of brine and then the organic layer was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (2:1) to afford 1200 mg (60%) of product as a green to yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 16h; | 3 To a solution of 71 isophthalic acid mono methyl ester 7a (133mg, 0.74mmol), EDCI (283mg, 1.48mmol) and 10 HOBt (200mg, 1.48mmol) in anhydrous 54 CH2Cl2 (8mL) was added a solution of 72 (R)-2-(4-methylthiazol-2-yl)pyrrolidine 11a (124mg, 0.74mmol) and 11 diisopropylethylamine (0.77mL, 4.44mmol) in anhydrous CH2Cl2 (2mL) at 0°C under argon atmosphere and it was allowed to stir for 16h at 23°C. The reaction mixture was quenched with 73 water and extracted with CH2Cl2. The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH 9:1) to furnish 74 3-[(R)-2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl]benzoic acid methyl ester (80%) as a colorless oil. 1H NMR (300MHz, CDCl3) δ 8.26 (s, 1H), 8.13 (d, 1H, J=7.5Hz), 7.80 (d, 1H, J=7.5Hz), 7.53 (t, 1H, J=7.5Hz), 6.80 (s, 1H), 5.68 (dd, 1H, J=7.2 and 5.4Hz), 3.94 (s, 3H), 3.82-3.74 (m, 1H), 3.57-3.49 (m, 1H), 2.51-2.35 (m, 2H), 2.45 (s, 3H), 2.17-2.03 (m, 2H); 13C NMR (75MHz, CDCl3) δ 171.5, 169.0, 166.1, 152.4, 136.6, 131.6, 131.0, 130.0, 128.5, 128.1, 112.7, 58.6, 52.1, 50.0, 32.1, 24.9, 17.0. |
Yield | Reaction Conditions | Operation in experiment |
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78% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With pivaloyl chloride In dichloromethane at 0℃; for 1h; Stage #2: piperidine With triethylamine In dichloromethane at 0 - 20℃; | Methyl 3-(piperidine-1-carbonyl)benzoate To a solution of 3-(methoxycarbonyl)benzoic acid ( 1.08 g, 6 mmol) and triethylamine (0.92 ml, 6.6 mmol) in dichloromethane (15 ml) was added a solution of pivaloyl chloride ( 0.74 ml, 6.0 mmol) in dichloromethane (5 ml) at 0 °C. The reaction mixture was stirred at 0 oC for 1 h. A solution of triethylamine (0.92 ml, 6.6 mmol) and piperidine (0.65 ml, 6.6 mmol) in dichloromethane (10 ml) was slowly added at 0 °C. The reaction mixture was stirred at room temperature overnight. The dichloromethane solution was washed with 30% aqueous citric acid, brine, and saturated aqueous NaHCO3, the dried (Na2SO4) and evaporated. The crude product was purified by column chromatography (30% petroleum ether in EtOAc) to give the product as a viscous oil (1.10 g, 78 %). 1H NMR (300 MHz, CDCl3): δ 8.02-8.05 (m, 2H), 7.52-7.58 (m, 1H), 7.42 (m, 1H), 3.89 (s, 3H), 3.63 (bs, 2H), 3.29 (bs, 2H), 1.65 (bs, 4H), 1.51 (bs, 2H). The 1H NMR data was in agreement with that reported by Martinelli et al.4 |
63% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With 1,1'-carbonyldiimidazole In dichloromethane at 20 - 25℃; for 2h; Stage #2: CH4O3S*C20H20N2O3 With triethylamine In dichloromethane at 20 - 25℃; | 44.1 Step 1 : Preparation of C227. A suspension of 3-(methoxycarbonyl)benzoic acid (2.91 g, 16.1 mmol) in dichloromethane (50 ml.) at ambient temperature was treated with 1 ,1 '- carbonyldiimidazole (2.62 g, 16.1 mmol). The reaction mixture became clear after stirring for 5 minutes. After 2 hours stirring the reaction mixture was treated with C26- mesylate (7.05 g, 14.7 mmol) and triethylamine (3.10 ml_, 22.0 mmol) and stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, brine and then dried over magnesium sulfate. The suspension was filtered and the filtrate was concentrated in vacuoto afford C227 as an off-white solid. Yield: 6.57 g, 13.1 mmol, 90%. LCMS m/z 499.2 (M+H)+. 1 H NMR (400 MHz, CD3OH) δ 8.51 (t, J=1 .4 Hz, 1 H), 8.19 (dt, J=7.9, 1.4 Hz, 1 H), 8.08 (dt, J=7.9, 1 .4 Hz, 1 H), 7.77 (s, 1 H), 7.60 (t, J=7.9 Hz, 1 H), 7.46-7.29 (m, 10H), 6.32 (s, 1 H), 5.31 (s, 2H), 5.01 (s, 2H), 4.47 (s, 2H), 3.92 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium hydroxide In methanol at 0 - 20℃; for 26h; | 2 Synthesis of 6-(methoxycarbonyl)pyridine-2-carboxylic acid (2) A solution of 1 (5.85 g, 30.0 mmol) in methanol (150 mL) was cooled to 0 °C. After KOH pellets (1.76 g, 31.0 mmol) were added, the reaction mixture was stirred at 0 °C for 2 h and then at room temperature for 24 h. The solvent was removed under reduced pressure, and the residue was suspended in H2O (100 mL) and extracted with ethyl acetate (3 × 30 mL). The aqueous layers were acidified to pH 3 with 1 M diluted HCl solution and extracted with chloroform (5 × 30 mL). The collected organic layers were dried over anhydrous Na2SO4. The chloroform was removed in vacuo to provide the desired product 2 (2.80 g, 52%) as a white solid: m.p. 144-146 °C. 1HNMR (DMSO-d6): δH 8.12-8.24 (m, Py-3,4,5, 3H) 3.93 (s, -CH3,3H); 13CNMR(DMSO-d6): δ = 52.2, 127.4, 127.7, 139.0,147.4, 148.9, 164.9, 165.8 ppm; IR (KBr), v/cm-1: 3073, 2964, 2852, 1725,1581, 1325 |
Yield | Reaction Conditions | Operation in experiment |
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45% | General procedure: Mono-Methyl Isophthalate (II) To a solution of acrylic acid (0.206 mL, 3 mmol), distilled to remove polymerized material, in toluene (5 mL, 0.2 M) was added N,N- diisopropylethylamine (0.174 mL, 1 mmol) dropwise at rt. The mixture was stirred for 30 min after which <strong>[6018-41-3]methyl coumalate</strong> (0.152 g, 1 mmol) was added, followed by 10% Pd/C (0.038 g, 25% / mass). The reaction was heated to 140C for 15 h, then cooled and quenched with sat. aq. NH4C1 solution ( 10 mL). The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine and dried over MgS04. Filtration and concentration in vacuo gave the crude product which was purified via flash column chromatography (5: 1 - 3: 1 hexanes:EtOAc) to give mono-methyl isophthalate in 45% yield as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; | |
76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; | 11.9-1 Step 9-1: Synthesis of Methyl-3-(4-tert-butoxycarbonylpiperazine-1-carbonyl)benzoic Acid Ester (115) Step 9-1: Synthesis of Methyl-3-(4-tert-butoxycarbonylpiperazine-1-carbonyl)benzoic Acid Ester (115) (0184) Monomethylisophthalic acid (111) (1.01 g) was dissolved in N,N-dimethylformamide (20 ml). To the solution were added EDCI·HCl (1.61 g), HOBt·H2O (1.28 g), triethylamine (847 mg), and 4-tert-butoxycarbonylpiperazine (1.16 g), and the mixture was stirred at room temperature for 16 hours. The reaction liquid was diluted with chloroform (100 ml), washed with water (300 ml), saturated aqueous sodium bicarbonate (300 ml), and brine (300 ml), dried over anhydrous sodium sulfate, and filtered. After that, the filtrate was concentrated and the residue was purified by silica gel flash column chromatography (developing solvent: n-hexane:ethyl acetate=3:10 to n-hexane:ethyl acetate=3:5) to give a compound (115) (1.49 g, yield: 76%) as a white solid. 1H NMR data on the compound (115) is shown below. 1H-NMR (CD3OD, 500MHz, δ; ppm) 8.12 (1H, d, J = 7.99 Hz), 8.06 (1H, s), 7.67 (1H, d, J = 7.49 Hz), 7.59 (1H, t, J = 7.74 Hz), 3.92 (3H, s), 3.74 (2H, s), 3.54-3.41 (6H,m), 1.46 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With dmap; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In dichloromethane at 0 - 20℃; for 2h; | Compound 1: Methyl 3-((3-((3-(isoquinolin-5-ylamino)pyrrolidin- I -yl)methyl)phenyl)carbamoyl) benzo ate To a suspension of intermediate 14 (1 g, 3.14 mmol) and 3-(methoxycarbonyl)benzoic acid (0.594 g, 3.30 mmol, 1.05 eq) in DCM (15 mL) was added at 000 the 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (5.61 ml, 9.42 mmol, 3 eq) and the N,N-dimethylpyridin-4-amine (1.535 g, 12.56 mmol, 4 eq). The reaction mixture was stirred at rt for 2h, diluted in EtOAc, washed with sat.NaHCO3 and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluting with Water/ACN 100/0 to 0/1 00 to give the title compound (1 g, 66%) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester; 5-(N-(3-amino-4-methylbenzyl) piperidin-3-ylamino)-indazole-1-carboxylic acid tertbutyl ester With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In dichloromethane at 0℃; for 0.0833333h; Stage #2: With dmap In dichloromethane at 0 - 20℃; Stage #3: With hydrogenchloride In dichloromethane for 1.08333h; | Compound 3: Methyl 3-((5-((3-((I H-indazol-5-yl)amino)piperidin- I -yl)methyl)-2-methylphenyl)carbamoyl)benzoate dihydrochloride To a solution of intermediate 15 (100 mg, 0.230 mmol, 1.0 eq) and 3-(methoxycarbonyl)benzoic acid (41 mg, 0.230 mmol, 1.0 eq) in DCM (1.5 mL) was added at 000 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (0.410 mL, 0.689 mmol, 3.0 eq). After 5 minutes of stirring at 0 c DMAP (112 mg, 0.918 mmol, 4.0 eq) was added and the solution stirred at 0°C for 1 hour, then slowly allowed to warm to room temperature and stirred overnight. The solution was diluted with EtOAc, washed with sat. NaHCO3, sat. NH4CI (x 2) and brine, then dried over Na2SO4, filtered and concentrated under vacuum. The residue was dissolved in DCM and purified by flash chromatography eluting with (DCM: MeOH = 98:2) to give the Boc-compound 3.To a solution of Boc-compound 3 in DCM (5 mL) was bubbled HCI gas for 5 mm. The resulting mixture was stirred for 1 hour and concentrated under vacuum. The residue was purified by reversed phase flash chromatography eluting with ACN/H20(0.1% TFA), 0/1 00 to 30/70 to give the compound 3 (76 mg, 58%) as a beige powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 30.1 Part 1- Synthesis of tert-Butyl 2-(3-(methoxycarbonyl)benzoyl)hydrazine-1-carboxylate ] Into a 100-mL round-bottom flask was placed a solution of 3- (methoxycarbonyl)benzoic acid (4 g, 22.20 mmol, 1.00 equiv) in dichloromethane (50 mL). 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (5.11 g, 26.66 mmol, 1.20 equiv), 4- dimethylaminopyridine (3.25 g, 26.60 mmol, 1.20 equiv), and (tert-butoxy)carbohydrazide (3.52 g, 26.63 mmol, 1.20 equiv) were added to the reaction mixture. The resulting solution was stirred overnight at room temperature. The resulting mixture was washed with 3x50 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum to provide a residue, which was then purified by a silica gel column with ethyl acetate/petroleum ether (1:1) as eluent to furnish 6 g (92%) of tert-butyl 2-(3-(methoxycarbonyl)benzoyl)hydrazine-1- carboxylate as a white solid |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; | [003701 To a stirred solution of Compound AD17 (4 g, 22.2 mmol) and Compound AD12-1 (0.3.52 g, 26.64 mmol) in DCM (50 mL) was added EDCI (5.11 g, 26.64 mmol) and DMAP (3.25 g, 26.64 mmol) in one portion at r.t., then the mixture was stirred at r.t. for 1 h. TLC showed the reaction was completed. The reaction mixture was concentrated and purified by column to afford the Compound AD18 (5.9 g, purity: 90% on TLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In acetonitrile at 20℃; for 2h; | 4.a Methyl 3-(morpholine-4-carbonyl)benzoate Morpholine (958 μL, 1 1.1 mmol, 1 equiv), mono-methyl isophthalate (2.00 g, 1 1 .1 mmol, 1 equiv), MeCN (50 mL), DIPEA (5.80 mL, 33.3 mmol, 3 equiv) and HATU (4.64 g, 12.2 mmol, 1.1 equiv) were stirred at room temperature. After two hours the mixture was quenched with 5 % w/v aqueous sodium carbonate (50 mL) and the organic solvents removed in vacuo. The aqueous residue was extracted with ethyl acetate (3 * 50 mL), and the pooled organic extracts washed with water (2 x 50 mL), dried over sodium sulfate and evaporated. Chromatography (40 g silica cartridge, 0-50 % ethyl acetate in petroleum benzine) and collection of the suspected product fractions gave the title compound (2.718 g, 98 % yield) as a pale brown oil. LCMS-B: rt 3.32 min, m/z 250 [M+H]+ |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tert.-butylhydroperoxide; sodium acetate; tetra-(n-butyl)ammonium iodide In tetrahydrofuran; water at 80℃; for 12h; | 34 example 34 TBAI in the reaction bottle (0.3mmol, 148 mg), compound1s (2mmol, 360 mg), compound2 (4mmol, 341 mg), NaOAc (4mmol, 164 mg), TBHP (0.60 ml), water (4.0 ml), tetrahydrofuran (4.0 ml). Then the system in the air 80 °C heating under the conditions of about 12 hours, quenched with saturated sodium sulfite solution, extraction with ethyl acetate (40 ml × 3), silica gel adsorption, through the simple column chromatography can get product3s,yield 92%. The prepared test data mainly of the product are as follows, can be known through the analysis, the actual synthetic product is consistent with the theoretical analysis. |
88% | With tert.-butylhydroperoxide; sodium acetate; tetra-(n-butyl)ammonium iodide In tetrahydrofuran; water at 80℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 3'-amino-4'-bromoacetophenone With thionyl chloride; N,N-dimethyl-formamide In dichloromethane; toluene for 3h; Reflux; Inert atmosphere; Schlenk technique; Stage #2: benzene 1,3-dicarboxylic acid monomethyl ester In dichloromethane; toluene at 25℃; for 12h; | 3 Methyl 3-((5-acetyl-2-bromophenyl)carbamoyl)benzoate To a solution of the carboxylic acid (1.0 eq) in toluene (1.0 M) thionyl chloride (2.0 eq) andone drop of DMF were added. The solution was refluxed for 3 h, concentrated and dissolvedin DCM (0.50 M). The corresponding aniline (1.2 eq) was added and the reaction mixture was stirred at 25 00 for 12h. The reaction mixture was concentrated and purified by flash column chromatography (hex:EtOAc, 2:1) obtaining the desired amides in pure form. This method was used to obtain intermediates methyl 3-((5-acetyl-2-bromophenyl)carbamoyl)benzoate, methyl 3-((5-acetyl-2-propoxyphenyl)carbamoyl )benzoate, methyl 3-((5-acetyl-2- isobutoxyphenyl)carbamoyl)benzoate, methyl 3-((5-acetyl-2-(cyclopropylmethoxy)phenyl) carbamoyl )benzoate, methyl 3-((5-acetyl-2-(benzyloxy)phenyl)carbamoyl )benzoate, methyl 3-((5-acetyl-2-morphol inophenyl)carbamoyl )benzoate, methyl 3-(5-acetyl-2- ethoxybenzamido)benzoate, methyl 3-((5-acetyl-2-ethoxyphenyl)carbamoyl)-5-nitrobenzoateand methyl 3-((5-acetyl-2-ethoxyphenyl)carbamoyl)-4-bromobenzoate. In the case of methyl 3-((5-acetyl-2-ethoxyphenyl)carbamoyl)-5-nitrobenzoate and methyl 3-((5-acetyl-2-ethoxyphenyl)carbamoyl)-4-bromobenzoate, after work up, Et20 was added tothe obtained residue and the desired amides precipitated. It was filtered off and washed withEt20 affording the desired products in pure form. Methyl 3-((5-acetyl-2-bromophenyl)carbamoyl)benzoate‘Qr White solid; Yield: 60 %; mp 133-135 00; MS (ESI), m/z: calcd forHMeO2C . N C17H14BrNNaO4, 397.9998; found, 397.9996. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; | 4.1d Intermediate 4.1d: 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoate Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(piperidin-1-yl)phenyl)-isonicotinamide (300 mg, 0.66 mmol, 1.00 equiv) in dichloromethane (15 mL), EDC.HCl (153 mg, 0.80 mmol, 1.21 equiv), 4-dimethylaminopyridine (96.75 mg, 0.79 mmol, 1.20 equiv), and 3-(methoxycarbonyl)benzoic acid (130.8 mg, 0.73 mmol, 1.10 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 2*50 mL of NH4Cl aq. and 1*50 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (3:1˜2:1). This resulted in 360 mg (88%) of methyl 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoate as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | 126 Intermediate 126f Into a 250-mL round-bottom flask, was placed a solution of 2-(2-amino-5-(piperidin-1-yl)phenyl)-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide (4.3 g, 10.09 mmol, 1.00 equiv) in dichloromethane (100 mL), 3-(methoxycarbonyl)benzoic acid (2.08 g, 11.56 mmol, 1.10 equiv), EDCI (2.87 g, 14.97 mmol, 1.50 equiv), 4-dimethylaminopyridine (1.83 g, 14.98 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2*20 ml of dichloromethane and the organic layers combined. The resulting mixture was washed with 1*20 mL of water and 1*20 ml of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 5.8 g (98%) of methyl 3-((2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoate as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 2h; | 65c Intermediate 65c: methyl 3-((2-(6-(3-(trifluoromethyl)benzylamino)pyrimidin-4-yl)-4-chlorophenyl)carbamoyl)benzoate Into a 100-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-6-(2-amino-5-chlorophenyl)pyrimidin-4-amine (500 mg, 1.32 mmol, 1.00 equiv) in dichloromethane (30 mL), EDC.HCl (380 mg, 1.98 mmol, 1.50 equiv), N,N-dimethylpyridin-4-amine (242 mg, 1.98 mmol, 1.50 equiv), and 3-(methoxycarbonyl)benzoic acid (357 mg, 1.98 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 30° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (2:1). The product was obtained as 400 mg (56%) of a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | To a stirred solution of 3-(methoxycarbonyl)benzoic acid 1 (500 mg, 2.78 mmol) in DMF (5 mL) at 0 C, were added 2-(methylsulfonyl)ethan-l-amine hydrochloride (443 mg, 2.78 mmol), HATU (1.58 g, 4.17 mmol), and DIEA (1.45 mL, 8.33 mmol). The reaction mixture was gradually warmed to RT and stirred for 16 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2S04), filtered and concentrated. The residue was purified (silica gel; eluting 3% MeOH/CH2Cl2) to afford compound 2 (450 mg, 57%) as an off white solid. 1H MR (500MHz, DMSO-i): delta 8.93 (m, 1H), 8.42 (s, 1H), 8.06 - 8.11 (m, 2H), 7.63 (m, 1H), 3.88 (s, 3H), 3.68 (m, 2H), 3.38 (m, 2H), 3.02 (s, 3H); LCMS Mass: 285.9 (M + H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | <strong>[777-12-8]6-(trifluoromethyl)benzo[d]thiazol-2-amine</strong> (commercially available or prepared according to Step 1 and 2 of Example 1) (1 eq), 3-(methoxycarbonyl)benzoic acid (1.05eq) and DIPEA (5 eq) were dissolved in DMF (2 ml). HI3TU(1.2 eq) was added and the reaction were stirred overnightat ambient temperature before extraction with ethylacetate,washed thoroughly 2 times with dilute acid and dried. Thecrude product, methyl 3-((6-(trifluoromethyl)benzo[d]thi-azol-2-yl)carbamoyl)benzoate, was isolated by evaporationof the solvent under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane for 0.0833333h; Stage #2: ethyl 1-(6-amino-2-butoxy-5-nitropyrimidin-4-yl)-1,4-diazepane-2-carboxylate In dichloromethane at 20℃; | Ethyl 1-(6-amino-2-butoxy-5-nitropyn'midin-4-yl)-4-[3-(methoxycarbonyl)benzoyl]-1,4- diazepane-2-carboxylate 7bxiv A solution of 3-(methoxycarbonyl)benzoic acid (38 mg, 0.21 mmol) in DCM (5 mL) was treated with Et3N (0.09 mL, 0.63 mmol), EDC.HCI (60 mg, 0.31 mmol) and HOBt hydrate (42 mg, 0.31 mmol). The solution was stirred for 5 min followed by the addition of ethyl 1- (6-amino-2-butoxy-5-nitropyrirnidin-4-yl)-1 ,4-diazepane-2-carboxylate 6b (80 mg, 0.21 mmol). The solution was allowed to stir overnight at room temperature. The reaction was quenched by addition of a saturated aqueous solution of NH4CI (50 mL). The phases were separated and the aqueous phase extracted with DCM (2 x 40 mL). The combined organic phases were dried over MgS04 and the solvent removed in vacuo to provide ethyl 1-(6- amino-2-butoxy-5-nitropyrimidin-4-yl)-4-[3-(methoxycarbonyl)benzoyl]-1 ,4-diazepane-2- carboxylate (85 mg, 75%) as a yellow oil; LC-MS (Method F) 545.5 [MH+]; RT 2.99 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 18h; | 35 A mixture of thiazolidine (500 mg, 2.77 mmol), HATU (i.26g, 3.32 mmol), 3- (methoxycarbonyl)benzoic acid (235mg, 2.63 mmol) and DIPEA (i.07g, 8.3i mmol) in DMF (10 ml) was stirred at room temperature for i8h. The mixture was then diluted with water and ethyl acetate. Organic layer was washed with saturated aqueous sodium bicarbonate, water, brine and dried. Crude residue was purified by column chromatography to yield methyl 3-(thiazolidine-3-carbonyl)benzoate in 85% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a solution of mono-methyl isophthalate (0.50 g, 2.77 mmol) in DMF (5 mL) was added DIPEA (0.55 mL, 3 mmol) and HATU (1.15 g, 3.0 mmol) and the mixture stirred at room temperature for 45 minutes. 4,4-Diethoxybutan-l -amine (0.375 g, 2.3 mmol) was added and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium carbonate (x2) and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated at reduced pressure to afford the title compound (0.95 g, >100%). 'HNMR (400 MHz, DMSO-d6); delta 8.69 (dd, J=5.5, 5.5 Hz, 1H), 8.44 (dd, J=1.6, 1.6 Hz, 1H), 8.12 - 8.08 (m, 2H), 7.63 (dd, J=7.8, 7.8 Hz, 1H), 4.51 - 4.47 (m, 1H), 3.90 (s, 3H), 3.56 (ddd, J=7.1, 9.5, 14.1 Hz, 2H), 3.43 (ddd, J=7.0, 9.5, 14.1 Hz, 2H), 3.29 - 3.26 (m, 2H), 1.57 - 1.54 (m, 4H), 1.11 (dd, J=7.1, 7.1 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 16h; | 4 General procedure: To a solution of 71 isophthalic acid mono methyl ester 7a (133mg, 0.74mmol), EDCI (283mg, 1.48mmol) and 10 HOBt (200mg, 1.48mmol) in anhydrous 54 CH2Cl2 (8mL) was added a solution of 72 (R)-2-(4-methylthiazol-2-yl)pyrrolidine 11a (124mg, 0.74mmol) and 11 diisopropylethylamine (0.77mL, 4.44mmol) in anhydrous CH2Cl2 (2mL) at 0°C under argon atmosphere and it was allowed to stir for 16h at 23°C. The reaction mixture was quenched with 73 water and extracted with CH2Cl2. The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 16h; | 4 General procedure: To a solution of 71 isophthalic acid mono methyl ester 7a (133mg, 0.74mmol), EDCI (283mg, 1.48mmol) and 10 HOBt (200mg, 1.48mmol) in anhydrous 54 CH2Cl2 (8mL) was added a solution of 72 (R)-2-(4-methylthiazol-2-yl)pyrrolidine 11a (124mg, 0.74mmol) and 11 diisopropylethylamine (0.77mL, 4.44mmol) in anhydrous CH2Cl2 (2mL) at 0°C under argon atmosphere and it was allowed to stir for 16h at 23°C. The reaction mixture was quenched with 73 water and extracted with CH2Cl2. The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25.0℃; for 16h; | General procedure: To a solution of 7c (45mg, 0.215mmol) in dry CH2Cl2 (2mL), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDCI) (62mg, 0.322mmol), and 1-hydroxybenzotriazole hydrate (HOBt) (50mg, 0.322mmol) were added followed by amine 10a (27mg, 0.215mmol) and diisopropylethylamine (225μL, 1.290mmol). The reaction mixture was stirred at 25C for 16h then CH2Cl2 was added and the resulting solution was washed with saturated aqueous NH4Cl and water. The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/n-hexane 1:4) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 16h; | 4 General procedure: To a solution of 71 isophthalic acid mono methyl ester 7a (133mg, 0.74mmol), EDCI (283mg, 1.48mmol) and 10 HOBt (200mg, 1.48mmol) in anhydrous 54 CH2Cl2 (8mL) was added a solution of 72 (R)-2-(4-methylthiazol-2-yl)pyrrolidine 11a (124mg, 0.74mmol) and 11 diisopropylethylamine (0.77mL, 4.44mmol) in anhydrous CH2Cl2 (2mL) at 0°C under argon atmosphere and it was allowed to stir for 16h at 23°C. The reaction mixture was quenched with 73 water and extracted with CH2Cl2. The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h; | General procedure for synthesis of compounds 5a-c: Compound 4 (213 mg, 1.0mmol) and 3-substituted benzoic acid (1.0mmol) were dissolved in 10mL of dry N,N-dimethylformamide (DMF), HBTU (417mg, 1.1mmol) and DIPEA (258mg, 2.0mmol) were added, and the reaction mixture was stirred at RT for 18h. Then the reaction mixture was concentrated in vacuo. The residue was washed with water, and dried in air to give crude product, which was purified by column chromatography on silica gel with eluent (1:99 to 5:95 MeOH/CH2Cl2) to afford a white solid 5.Methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate (5a): Yield 63%, Rf=0.52 (1:13 MeOH/CH2Cl2), mp 252-254°C. 1H NMR (acetone-d6): 3.90 (s, 3H, OCH3), 7.35 (s, 2H, Ph-H), 7.71 (t, J=8.0Hz, 1H, Ph-H), 8.23 (dt, J=1.5, 8.0Hz, 1H, Ph-H), 8.39 (dt, J=1.5, 8.0Hz, 1H, Ph-H), 8.72 (t, J=1.5Hz, 1H, Ph-H). MS (ESI): 376 ([M+H]+, 25%); MS (ESI): 374 ([M-H]-, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-iodo-succinimide; [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; iodine; caesium carbonate; In 1,2-dichloro-ethane; at 50℃; for 24h;Inert atmosphere; Irradiation; Sealed tube; | General procedure: To a 15 mL test tube with septum Cs2CO3 (0.6 mmol, 195 mg), aromaticcarboxylic acid (1) (0.3 mmol), [Ir(dF(CF3)ppy)2dtbbpy]PF6 (D) (6 mummol, 6.7 mg), NIS (1.5mmol, 337.5 mg) and I2 (60 mumol, 20 mol%) were added. The tube was evacuated and backfilledwith argon for three times, and then 3 mL of dry DCE was added through a syringer under argon.The tube was sealed with Parafilm Mr and placed in an oil bath with a contact thermometer, andthe reaction was carried out at 50 C under irradiation with 6 × 5 W blue LEDs (lambdamax = 455 nm).After 24 h or 36 h, the resulting mixture was filtered through a 2 cm thick pad of silica, and thesilica was washed with DCM) (50 mL). The filtrate was collected and the solvent was removed invacuo. The crude residue was purified by silica gel flash column chromatography to provide thetarget product (2). (Note: The reaction was very sensitive to moisture, and the yields sharplydecreased to less than 5% when 0.01 equivalent of H2O was added to the reaction system). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 18h; Inert atmosphere; | 3 (R)-Methyl-2-((l-(4-(4-chlorophenyl)piperidin-l-yl)-3-methyl-l-oxobutan-2- yl)carbamoyl)benzoate: Under a nitrogen atmostphere, a solution of 2-(methoxycarbonyl)benzoic acid (272 mg, 1.509 mmol) and HATU (603 mg, 1.585 mmol) and HOBt (23.11 mg, 0.151 mmol) dissolved in dichloromethane (DCM) (5031 μ) was prepared at room temperature in a small microwave vial. The mixture was treated with DIEA (791 μ, 4.53 mmol) and appeared to be some what homogeneous. Afterwards, to the mixture was added (R)-2 -amino- l-(4-(4-chlorophenyl)piperidin-l-yl)-3-methylbutan-l -one, Hydrochloride (500 mg, 1.509 mmol). Finally, the reaction was stirred at room temperature for 18 hr. The progress was checked by Open Access LCMS [Shimadzu 10A PE (LC) coupled with SciexSingle Quadrupole 150EX (MS) and Sedere Sedex 75C (ELS)] ((Thermo Hypersil Gold C18, 20x2.1 mm, 1.9 u particle diam.), 1.6 niL/min, gradient from 5-92% CH3CN (0.02 % TFA) / H20 (0.02 %TFA)). The spectra confirmed that the reaction was progressed fairly cleanly and was about 100% complete. The reaction mixture was diluted with DCM and treated with an aqueous work up using 1 : 1 mixture of saturated sodium bicarbonate and water and brine. The organic layer was passed through a phase separator and concentrated to give the crude product, which was purified by flash chromatography using a Biotage Isolera. A 120g silica column was used along with a gradient of 0%(3cv)-0-40%(20CV) 40%(4CV) ehtyl acetate/ hexanes at a flow rate of 100 mL/ min. All fractions containing the desired product were combined and concentrated to give the desired product, (N43755- 5-101) (R)-methyl 2-((l-(4-(4-chlorophenyl)piperidin-l-yl)-3-methyl-l-oxobutan-2- yl)carbamoyl)benzoate (553 mg, 1.210 mmol, 80 % yield) , as an off-white solid. Purity was judged >95% and the analytical characterization data of the final material was consistent with the assigned structure . All of this material was carried on as a synthetic intermediate._MS (ES) m/e 457 [M+H]+, rt = 1.19 mins. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; | 1.12 (12) Preparing methyl 3-(2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-7-azaspiro[3.5]nonan-7-carbo nyl)benzoate. 4-(((7-azaspiro[3.5]nonan-2-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (100 mg, 0.25 mmol) is dissolved in dichloromethane(5 mL), followed by successively adding mono-methyl isophthalate (57 mg, 0.32 mmol), triethylamine (104 μL, 0.75 mmol) and HATU (131 mg, 0.34 mmol), and the reaction mixture is stirred overnight at room temperature. Then, the reaction mixture is poured into water (15 mL) and the mixture is extracted with dichloromethane (15 mL * 2), then the organic solution is dried with anhydrous Na2SO4, filtered, rotated to dryness and purified by column chromatography (PE : EA = 3 : 1), so as to obtain a white solid of 95 mg, that is 3-(2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-7-azaspiro[3.5]nonan-7-carbo nyl)benzoate, with a yield of 68%. Spectrum is: 1H NMR (400 MHz, CDCl3) δ: 8.10(m, 1H), 8.05(m, 1H), 7.59(m, 1H), 7.51(t, J = 7.6 Hz, 1H), 7.45-7.43(m, 2H), 7.39-7.35(m, 1H), 4.18(s, 2H), 3.95(m, 4H), 3.63(m, 2H), 3.22(m, 2H), 2.15(m, 1H), 2.05(m, 2H), 1.61-1.44(m, 6H), 1.29(m, 2H), 1.14(m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: 3,3,3-trifluoropropylamine; benzene 1,3-dicarboxylic acid monomethyl ester With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | General procedure B for the synthesis of amides No.14a-s; 16b-g. General procedure: An oven-dried 20 mL pressurevial was charged with monoester No.13a-f (1.0 eq) and dissolved in anhydrous DMF (0.5 mL/0.1mmol of the monoester). The corresponding amine (1.2 eq) was added, followed by HBTU (1.0 eq).The resulting solution was stirred at 0 °C for 5 min, then TEA (2.0 eq) was added and stirring at 0 °Cwas continued for 0.5 h. The resulting mixture was warmed to room temperature and stirring wascontinued for 2 h. The brownish solution was diluted with water (20 mL) and extracted with EtOAc(3 x 15 mL). Combined organic extracts were washed with water (15 mL), brine (15 mL), dried overanhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gelcolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 2.2-dimethylpropylamine; benzene 1,3-dicarboxylic acid monomethyl ester With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | General procedure B for the synthesis of amides No.14a-s; 16b-g. General procedure: An oven-dried 20 mL pressurevial was charged with monoester No.13a-f (1.0 eq) and dissolved in anhydrous DMF (0.5 mL/0.1mmol of the monoester). The corresponding amine (1.2 eq) was added, followed by HBTU (1.0 eq).The resulting solution was stirred at 0 °C for 5 min, then TEA (2.0 eq) was added and stirring at 0 °Cwas continued for 0.5 h. The resulting mixture was warmed to room temperature and stirring wascontinued for 2 h. The brownish solution was diluted with water (20 mL) and extracted with EtOAc(3 x 15 mL). Combined organic extracts were washed with water (15 mL), brine (15 mL), dried overanhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gelcolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dipotassium hydrogenphosphate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; 2,4,6-Triisopropylthiophenol; water-d2; triphenylphosphine In dichloromethane at 20℃; for 36h; Inert atmosphere; Irradiation; Schlenk technique; Sealed tube; | |
73% | With dipotassium hydrogenphosphate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; 2,4,6-Triisopropylthiophenol; water-d2; triphenylphosphine In dichloromethane at 20℃; for 36h; Irradiation; Inert atmosphere; Sealed tube; | 11 Example 11 Weighed first (36.0mg, 0.2mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.3mg, 0.002mmol), Κ2ΗΡΟ4 (34.8mg, 1.0equiν.), and Ρh3Ρ (0.22mmol, 57.6mg, 1.1equiv.) was added to the reaction tube, and the gas was exchanged three times through a vacuum line. Under an argon atmosphere, DCM/D2O (2.0 mL, 1: 1 ν/ν) was added. Then, 2,4,6-triisopropylthiophenol (0.03 mmol, 7.1 mg) was carefully added, and then the tube was sealed and placed under a 5W blue LEDs lamp and allowed to react at room temperature for 36 hours. At the end of the reaction. The reaction completed, the mixture was quenched with water, and extracted with DCM (3x10mL). Rotary evaporated organic phase was dried over anhydrous Na2SO4 the solvent was removed by dry-like, column chromatography (300-400 mesh silica gel chromatography) (eluent: petroleum ether - ethyl acetate, volume ratio: 40-10: 1) to give 24.1mg, 73% yield of product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0℃; | Compound 6 To a stirred solution of 3-(methoxycarbonyl)benzoic acid 5 (135.1 mg, 0.75 mmol),1-hydroxybenzotriazole (HOBt) (101.3 mg, 0.75 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (143.8 mg, 0.75 mmol), and triethylamine (0.28 mL, 2 mmol) inDMF (2.5 mL) at 0 °C was added the obtained amine hydrochloride (175.4 mg, 0.5 mmol). After 17 h,the reaction was quenched with sat. aq. NH4Cl solution and diluted with AcOEt. The resulting mixturewas washed with 1M aq. HCl solution, sat. aq. NaHCO3 solution, and brine, and then dried over Na2SO4.After concentration under reduced pressure, the residue was recrystallized from AcOEt-hexane to givecompound 6 as white solid (135 mg, 56% yield). [α]20D -9.8 (c 0.23, CHCl3); Mp 142-143 °C; 1H NMR(400 MHz, CDCl3) δ 1.47-1.60 (m, 2H), 1.70-2.08 (m, 4H), 2.95 (s, 3H), 3.91 (s, 3H), 4.13-4.25 (m, 2H),4.36 (dd, J = 5.6 Hz, 14.8 Hz, 1H), 4.46 (dd, J = 5.6 Hz, 14.8 Hz, 1H), 4.70-4.82 (m, 1H), 7.10-7.37 (m,7H), 7.43-7.48 (m, 1H), 7.93 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 1.2 Hz, 1H); 13CNMR (100 MHz, CDCl3) δ 21.5, 28.6, 31.9, 37.3, 43.5, 52.3, 53.4, 69.6, 127.5, 127.6 (2C), 127.9, 128.6(2C), 128.8, 130.5, 131.7, 132.7, 133.9, 137.8, 166.1, 166.5, 171.3; IR (ATR) ν 1721, 1631, 1532, 1347,1252, 1163, 956, 821, 694 cm-1; (+)-ESI-HRMS. Calcd for C23H28N2NaO7S+ (M+Na+): 499.1509. Found:499.1529 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-pivalamido-4-oxo-6-(methylaminomethyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine hydrochloric salt In N,N-dimethyl-formamide at 20℃; for 12h; | 6.7. Methyl 4-[N-methyl-(2-pivalamido-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-methylamino]-carbonyl}-phenylcarboxylate (24a) General procedure: To a solution of 4-methoxycarbonyl phenyl carboxylic acid (180 mg,1 mmol) in DMF (1 mL) was added N-methyl morpholine (310 mg,3 mmol), EDCI (240 mg, 1.2 mmol) and HOAt (183 mg, 1.05 mmol).The mixture was stirred at rt for 1 h. Compound 23 (313 mg, 1 mmol)was added and stirring was continued overnight. The solvent was removedand the residue was purified by a silica column with CHCl3 andMeOH to provide 316 mg of 24a as a semi-solid in 72% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; | 1 Step-1: Synthesis of Methyl 3-((4-methoxy-2-methylphenyl)carbamoyl)benzoate (3). To a stirred solution of 3-(methoxycarbonyl)benzoic acid 2 (1 g, 5.55 mmol) in CH2CI2 (15 mL) were added 4-methoxy-2-methylanibne 1 (0.71 mL, 5.55 mmol), HATU (2.53 g, 6.66 mmol) and ethyldiisopropylamine (2.42 mL, 13.87 mmol) at 0 °C under inert atmosphere. The reaction mixture was gradually warmed to RT and stirred for 16 h. The progress of the reaction was monitored by TLC; after the completion, the reaction mixture was diluted with water (30 mL) and extracted with CH2CI2 (2 x 40 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAcri? -hexanes) to afford compound 3 (1.5 g, 5.01 mmol, 90%) as an off white solid. NMR (500 MHz, CDCh): d 8.50 (br s, 1H), 8.21 (br d, J= 7.8 Hz, 1H), 8.13 (br d, J= 7.3 Hz, 1H), 7.66 (br s, 1H), 7.61-7.55 (m, 2H), 6.82-6.76 (m, 2H), 3.96 (s, 3H), 3.81 (s, 3H), 2.31 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With 2.9-dimethyl-1,10-phenanthroline; neocuproine; zinc In dimethyl sulfoxide at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 2-(N-tert-butoxycarbonylamino)-6-(O-methanesulfonyl)-N-benzylhexanamide With hydrogenchloride In 1,4-dioxane; dichloromethane at 0 - 20℃; for 1h; Stage #2: benzene 1,3-dicarboxylic acid monomethyl ester With 4-methyl-morpholine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 12h; | 6B To a solution of compound 1 (649.7 mg, 1.55 mmol) synthesized by the known approach (Angew. Chem. Int. Ed. 2013, 52, 8620) in CH2Cl2 (6.2 mL), 4 N HCl in dioxane (3.9 mL) was added at 0° C. The reaction solution was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure to obtain corresponding hydrochloride. To a solution of 3-(methoxycarbonyl)benzoic acid (279 mg 1.55 mmol), COMU (633.8 mg, 1.55 mmol), and N-methylmorpholine (0.68 mL, 6.2 mmol) in DMF (5 mL), a solution of the obtained hydrochloride in DMF (2.8 mL) was added at 0° C. 12 hours later, the reaction was terminated with a saturated aqueous solution of ammonium chloride, and ethyl acetate was added thereto. The mixed solution was washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and then, the organic phase was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and then, the residue was recrystallized (ethyl acetate/hexane) to obtain compound 2 (480.9 mg, 65% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | General procedures (GP2) General procedure: To a stirred aromatic compounds (1.5 eq) in DCM (2 mL/mmol), EDCI (1 eq), HOBt (1 eq) and triethylamine (1.5 eq)were added, followed by compound 13 (1 eq).The clearsolution was stirred at room temperature 20-24 h. Thereaction mixture was diluted with DCM (30 mL), andwashed with 1-N HCl and water. The organic layer wasdried over anhydrous Na2SO4, filtered, and concentrated invacuum to give the crude product. The residue was purified by column chromatography on silica gel to afford the correspondingproducts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.8% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 0℃; for 0.5h; Stage #2: (S)-2-amino-N-(1,3-benzothiazol-5-yl)-N-methyl-3-amphetamine With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h; | 4.1.4. Methyl (S)-3-((1-(benzo[d]thiazol-5-yl(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)benzoate (5) To a solution of 3-methoxycarbonylbenzoic acid (0.48 g,2.67 mmol) in 20 mL dichloromethane, HATU was added (1.27 g,3.33 mmol) at 0 C, and the mixture was stirred for 0.5 h. Subsequently,intermediate 4 (0.69 g, 2.22 mmol) and DIEA (0.57 g,4.44 mmol) were added to the mixture and then stirred at roomtemperature for another 3 h (monitored by TLC). The resultingmixture was evaporated under reduced pressure, and the residue was initially washed by 1 N HCl and extracted with ethyl acetate(3 20 mL). Then, the combined organic layer was washed withsaturated sodium bicarbonate (3 20 mL), dried over anhydrousNa2SO4, filtered, and concentrated under reduced pressure to affordthe corresponding crude product, which was purified by flashcolumn chromatography (EA:PE 1:3) to obtain intermediate 5 asa yellow solid with the yield of 60.8%. 1H NMR (400 MHz, DMSO-d6)d 9.50 (s, 1H, CH), 9.03 (d, J 7.6 Hz, 1H, NH), 8.42 (s, 1H, Ph-H), 8.27(d, J 8.5 Hz, 1H, Ph-H), 8.15e8.02 (m, 3H, Ph-H), 7.61 (t, J 7.8 Hz,1H, Ph-H), 7.46 (d, J 8.6 Hz, 1H, Ph-H), 7.09 (d, J 5.1 Hz, 3H, Ph-H), 6.90e6.77 (m, 2H, Ph-H), 4.66 (d, J 6.5 Hz, 1H, CH), 3.90 (s, 3H,OCH3), 3.26 (s, 3H, NCH3), 3.10e2.92 (m, 2H, PhCH2). ESI-MS: m/z474.02 [MH]. C26H23N3O4S (473.14). |
Tags: 1877-71-0 synthesis path| 1877-71-0 SDS| 1877-71-0 COA| 1877-71-0 purity| 1877-71-0 application| 1877-71-0 NMR| 1877-71-0 COA| 1877-71-0 structure
[ 713-57-5 ]
4-(Ethoxycarbonyl)benzoic acid
Similarity: 0.95
[ 713-57-5 ]
4-(Ethoxycarbonyl)benzoic acid
Similarity: 0.95
[ 4376-18-5 ]
2-(Methoxycarbonyl)benzoic acid
Similarity: 0.93
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Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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