Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 335255-43-1 | MDL No. : | MFCD24038830 |
Formula : | C15H18N2O2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JNJJINIJWXHEQQ-UHFFFAOYSA-N |
M.W : | 290.38 | Pubchem ID : | 57717474 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280 | UN#: | N/A |
Hazard Statements: | H302-H312-H332 | 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 |
---|---|---|
100% | With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 2 h; | General procedure: Synthesis oftert-butyl (2-amino~4-(thiophen-2-yl)phenyl)carbamate (9a):Compound 9a was made following the procedure reported in the patent literature ( WO 2009/055917). Compound 8a (0.24 g. 0.75 mmol) was placed in a round bottom flask and 10percent palladium on carbon (catalytic amount, 20 mg) was added into it. The reaction mixture was exposed to a balloon. After purging with the reaction mixture was stirred under balloon for 2 hours at room temperature. It was then filtered through Ceiite and concentrated under vacuum to give the desired amine (0.217 g, 100percent yield).lE NMR (400 MHz, Chloroform-d) δ 7.33 - 7.27 (m, 1H), 7.25 - 7.21 (m, 2H)57.08 - 7.03 (m, 2H), 7.02 (d, J= 2.0 Hz, 1H), 1.52 (s, 9H). |
98% | With palladium on activated charcoal; hydrogen In methanol; ethyl acetate at 20℃; for 20 h; | 4.1.8.1. tert-Butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (16a). Compound 15a (0.53 g, 1.66 mmol) was solubilized in methanol and EtOAc (6 + 16 mL) and stirred at room temperature for 20 h with Pd/C (0.05 g, 10percent w/w) under hydrogen atmosphere. The catalyst was filtered off, and the solvent was removed and washed with PE to give compound 16a as a white solid (0.47 g, 98percent yield). 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.44-7.42 (m, 1H), 7.29 (dd, J = 3.5, 1.2 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.11 (dd, J = 5.3, 3.5 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 8.5, 2.2 Hz, 1H), 5.04 (s, 2H), 1.45 (s, 9H). |
95% | With hydrogen In ethyl acetate at 20℃; for 18 h; | Step 3 : tert-Butyi 2-amino-4-(thiophen-2-yl)phenylcarbamate (4); [0679] Compound 3 was suspended in AcOEt and placed under nitrogen atmosphere; then10percent palladium on carbon (catalytic amount) was added. The reaction mixture was placed under vacuum for a few min then opened up under a balloon of hydrogen and stirred at ambient temperature for 18 h. The reaction mixture was filtered through Celite.(R). and concentrated to give compound 4 (0.393 g, 95percent yield).[0680] 1H NMR (DMSO-d6 δ (ppm): 8.33 (s, IH), 7.42 (dd, J= 4.9, 0.98 Hz, IH), 7.27 (dd,J= 3.5, 0.98 Hz, IH), 7.06 (dd, J= 5.1, 3.7 Hz, IH), 6.95 (d, J= 2.2 Hz, IH), 6.82 (dd, J= 8.0 Hz,2.0 Hz, IH), 5.01 (s, 2H), 1.47 (s, 9H). |
85% | With palladium on activated charcoal; hydrogen In methanol | To a solution of 40a (3.43 g, 10 mmol) in CH3OH (200 mL),was added dry palladium-carbon (0.34 g), the mixture was stirredunder a hydrogen atmosphere overnight. The palladium-carbonwas filtered off over celite, after evaporating the solvent, the residuewas dried under vacuum to give 41a (2.46 g, 85percent), a whitesolid. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.45-7.43 (m,1H), 7.30 (dd, J = 3.6, 1.1 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.08 (dd,J = 5.1, 3.6 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.85 (dd, J = 8.2, 2.1 Hz,1H), 5.01 (s, 2H), 1.47 (s, 9H). ESI-MS m/z: 291.3 [M+H]+. |
83% | at 60℃; for 2 h; | To a solution of tert-butyl (2-nitro-4-(thiophen-2-yl)phe- nyl)carbamate (1.6 g, 4.99 mmol, 1 eq.) in methanol (20 mE)was added hydrazine hydrate (14 mE) and ferric chloride (0.05 g, 0.3 mmol, 0.06 eq.). The resulting mixture was warmed to 60° C. and stirred for 2 h. The reaction was then filtered through Celite, the solids were washed with MeOH. The filtrate was concentrated under reduced pressure. Waterwas added to the residue and the suspension was stirred for 1 h. The obtained solid was filtered, washed with hexanes then dried to yield tert-butyl (2-amino-4-(thiophen-2-yl)phenyl) carbamate (1.2 g, 83percent yield). |
69% | With palladium 10% on activated carbon; hydrogen In methanol; ethanol for 12 h; | To a solution of tert-butyl (2-nitro-4-(thiophen-2-yl)phe- nyl)carbamate (2 g, 6.2 mmol, 1.0 eq.) in ethanol (20 mE) andmethanol (20 mE) was added 10percent Pd/C (0.66 g, 0.1 eq.). The reaction mixture was stirred 12 h under a hydrogen atmosphere. The reaction was filtered and the filtrate was concen120trated under reduced pressure to give tert-butyl (2-amino-4- (thiophen-2-yl)phenyl)carbamate (1.25 g, 69percent yield) as an off-white solid. |
54% | With zinc In 1,4-dioxane; water at 70℃; | Zinc powder (4.75 g) was added to a solution of 16 (6.65 g, 20.74 mmol) in dioxane (180 mL) and H2O (45 mL) and stirred overnight at 70 °C. Upon completion, EtOAc was added and the mixture was washed with H2O (3×100 mL) and brine (1×100 mL). The crude product was purified by column chromatography, eluting with EtOAc:Hexanes (2:1), to obtain 17 (3.95 g, 54 percent yield). 1H NMR (400MHz, CDCl3) δ 7.34–7.20 (m, 3H), 7.10–6.98 (m, 3H), 1.52 (s, 9H). 13C NMR (101MHz, CDCl3) δ 153.7, 144.1, 139.9, 132.2, 127.9, 124.8, 124.4, 122.8, 117.5, 115.0, 80.7, 28.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With pyridine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; for 18h; | Step 6: (R)-ferf -Butyl 2-(4-((3-(dimethylamino)pyrrolidin-l-yl)methyl)benzamido)-4-(thiophen-2-vDphenylcarbamate (8); [0684] A solution of acid 7 (0.20 g, .62 mmol), amine 4 (0.164 g, 0.56 mmol) and BOP reagent (0.30 g, 0.68 mmol) in pyridine (4 mL) was stirred for 18 h, concentrated, diluted withAcOEt, washed with aqueous sodium bicarbonate (NaHCOs), brine, dried over MgSO4, filtered and concentrated. Flash chromatography purification of the residue (eluent: 1 : 1 MeOH: AcOEt with 1% triethylamine) gave compound 8 (0.198 g, 67% yield).[0685] 1H NMR (DMSO-de) delta (ppm): 9.86 (s, IH), 8.72 (s, IH), 7.92 (d, J= 8.2 Hz, 2H),7.79 (d, J= 2.0 Hz, IH), 7.59 (d, J= 8.6 Hz, IH), 7.51 (d, J= 1.2 Hz, IH), 7.50 (d, J= 1.2 Hz, IH),7.46 to 7.43 (m, 3H), 7.11 (dd, J= 5.1, 3.5 Hz, IH), 3.64 (abq, J= 40.5, 13.3 Hz, 2H), 2.84 to 2.75(m, IH), 2.67 to 2.63 (m, IH), 2.33 (m, 2H), 2.13 (s, 6H), 1.99 to 1.88 (m, IH), 1.66 (m, IH),1.45 (s, 9H), 1.25 (m, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With pyridine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; at 20℃; for 18h; | Step 4: (E)-tert-butyl 2-(3-(6-(3,4-dimethoxyphenyl)pyridin-3-yl)acrylamido)-4-(thiophen-2- yPphenylcarbamate (41); [0694] A solution of acid 40 (0.10 g, 0.25 mmol), amine 4 (72.7 mg, 0.25 mmol) and BOP reagent (0.133 g, 3.0 mmol) in pyridine (2 mL) was stirred 18 h at room temperature. The reaction mixture was concentrated and the residue was purified by flash chromatography (eluent:1 :1 hexane: AcOEt) to give title compound 41 (0.14 g, 61% yield).[0695] IH NMR (DMSO-d6) delta (ppm): 9.82 (s, IH), 8.85 (s, IH), 8.61 (s, IH), 8.05 (t, J=12.9 Hz, 2H), 7.89 (s, IH), 7.75 to 7.73 (m, 2H), 7.70 (d, J= 5.9 Hz, IH), 7.66 (m, IH), 7.51 (dd,J= 5.1, 1.2 Hz, IH), 7.48 to 7.46 (m, IH), 7.42 (dd, J= 3.7, 1.2 Hz, IH), 7.12 (dd, J= 5.1, 3.5 Hz,IH), 7.07 (d, J= 8.4 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 1.48 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine; In dichloromethane; at -20 - 20℃; for 1h; | Example 6a; (S)-7V-(2-Amino-5-(thiophen-2-yl)phenyl)-4-((2-(methoxymethyl)pyrrolidin-l- yl)methyl)benzamide (76); Step 1 : tert-Butyi 2-(4-(chloromethyl)benzamido)-4-(thiophen-2-yl)phenylcarbamate (74); [0706] To a suspension of amine 4 (0.45 g, 1.55 mmol) in DCM (6.84 mL), cooled to -20 0C, was added triethylamine (0.65 mL, 4.65 mmol) followed by a solution of 4- (chloromethyl)benzoyl chloride 73 (0.322 g, 1.71 mmol) in DCM (2.28 mL) via canula. The cold bath was then removed and the reaction mixture was stirred at room temperature for 1 h, washed with saturated NH4Cl, saturated NaHCOs, brine, dried over MgSO4, filtered and concentrated. The crude material was recystallized from 30% AcOEt in hexane to give title compound 74 (0.431 g, 63 % yield).[0707] 1H NMR (DMSO-de) delta (ppm): 9.92 (s, IH), 8.73 (s, IH), 7.97 (s, J= 8.2 Hz, 2H), 7.80 (d, J= 1.9 Hz, IH), 7.61 (d, J= 8.4 Hz, IH), 7.60 (d, J= 8.4 Hz, 2H), 7.51 (dd, J= 4.9, 1.0 Hz, IH), 7.50 (dd, J= 5.3, 2.3 Hz, IH), 7.44 (dd, J= 3.7, 1.3 Hz, IH), 7.11 (d, J= 5.1, 3.5 Hz, IH), 4.84 (s, 2H), 1.44 (s, 9H). |
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | 4-(chloromethyl)benzoyl chloride (2 g, 10.58 mmol) was dissolved in THF (20 mL) and a solution of rerr-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (3.38 g, 11.64 mmol) and DEPEA (2.033 mL, 11.64 mmol) in THF (50 mL) was added dropwise at room temperature. After stirring for 1 hour, saturated NaHCtheta3 was added and the products extracted into EtOAc (x2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated in EtOAc to give ferr-butyl [2-[4-(chloromethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate as a beige powder. | |
With triethylamine; In dichloromethane; at 20℃; for 1h; | General procedure: Acid 7/8 (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 (3.0 equiv). After stirring for 1 h at room temperature, the solution was extracted with EtOAc, washed with 1N HCl (aq) followed by brine and dried over Na2SO4. Concentrated in vacuo gave the crude product, which was further purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine;dmap; In 1,2-dichloro-ethane; at 20℃; for 72h; | Example 7a; (E)-7V-(2-Amino-5-(thiophen-2-yl)phenyl)-3-(4-(morpholinomethyl)phenyl)acrylamide (96); <n="100"/>Scheme 7; Step 1 : (epsilon)-tert-Buty{ 2-(3-(4-formylphenyl)acrylamido)-4-(thiophen-2-yl)phenyl-carbamate (94); [0712] A suspension of (E)-3-(4-formylphenyl)acrylic acid 93 (1.046g, 5.94 mmol) in 1,2- dichloroethane (30 niL) was treated with neat thionyl chloride (SOCl2) (0.9 rnL, 12.3 mmol) and stirred at 67 0C then dimethyl formamide (0.3 mL) was slowly added; and the reaction mixture was allowed to stir at 67 0C for 30 min, cooled to room temperature, concentrated, diluted with dry benzene (40 mL) and concentrated again. The yellow residue was stored under vacuum for 3 h then suspended in pyridine (25 mL) and treated with amine 4 (1.113g, 3.83 mmol) and A- dimethylamino pyridine (DMAP) (156 mg). The suspension was stirred at room temperature for 3 days, diluted with H2O (10 mL) then stirred for additional 5 h. The solution was diluted with DCM, washed with 5% KHSO4, saturated NaHCO3, dried over MgSO4, filtered and concentrated to provide title compound 94 (0.415 g, 24% yield) after purification by flash chromatography (eluent: 30% to 50% AcOEt in hexanes). LRMS: 448.2 (calc) 471.0 (M+Na, obs) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine;dmap; In N,N-dimethyl-formamide; at 20 - 60℃; for 42h; | Step 3: (E)-ferf-Butyl 2-(3-(6-morpholinopyridin-3-yl)acrylamido)-4-(thiophen-2- vDphenylcarbamate (165); [0766] To a solution of 164 (0.275 g, 1.17 mmol) in DMF (10 mL) was added triethylamine (0.168 mL, 1.21 mmol) and BOP reagent (0.563 g, 1.27 mmol) and the mixture was stirred at room temperature for 30 min. Then amine 4 (0.309 g, 1.06 mmol) and excess triethylamine (0.443 mL, 3.18 mmol) were added and the reaction mixture was allowed to stir for 18 h at room temperature. Then 4-(dimethylamino)pyridine (catalytic amount) was added and the reaction mixture was heated to 50-60 0C for 24 h. The solution was concentrated, diluted with AcOEt, washed with saturated NaHCO3, H2O, brine, dried over MgSO4, filtered and concentrated. The resulting yellow solid was triturated from ethyl ether to give compound 165 (0.435 g, 81% yield).[0767] IH NMR (DMSO-d6) delta (ppm): 9.68 (s, IH), 8.58 (bs, IH), 8.35 (d, J= 2.3 Hz, IH), 7.85 (d, J= 2.0 Hz, IH), 7.82 (d, J= 2.0 Hz, IH), 7.61 (d, J= 9.0 Hz, IH), 7.52 (d, J= 15.5 Hz, IH), 7.51 (dd, J= 5.1, 1.2 Hz, IH), 7.44 (dd, J= 8.4, 2.3 Hz, IH), 7.41 (dd, J= 3.5, 1.2 Hz, IH), 7.11 (dd, J= 5.1, 3.5 Hz, IH), 6.92 (d, J= 9.4 Hz, IH), 6.71 (d, J= 15.4 Hz, IH), 4.02 to 3.97 (m, 4H), 3.69 to 3.67 (m, 4H), 1.45 (s, 9H). LRMS: 506.62 (calc) 507.1 (obs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine; In tetrahydrofuran; at 0℃; for 0.5h; | Step 3: M-(2-Amino-5-(thiophen-2-yl)phenv?-N8-(biphenyl-3-v?octanediamide (184); [0780] Acid 183 (0.103 g, 0.32 mmol) in thionyl chloride (3 mL) with a few drops of DMF was stirred at room temperature for 15 min then concentrated, diluted with dry THF (10 mL), cooled to 0 0C then treated with amine 4 (0.12 g, 0.41 mmol) and triethylamine (0.086 mL, 0.61 mmol). The reaction mixture was stirred at 0 0C for 30 min then quenched with aqueous NH4C1, extracted with AcOEt, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (eluent: 50% AcOEt - hexane) to give the title compound 184 (0.111 g, 52% yield).[0781] IH NMR (DMSO-d6) delta(ppm): 9.97 (s, IH), 9.14 (s, IH), 7.59 to 7.55 (m, 3H), 7.48 to 7.43 (m, 3H), 7.38 to 7.30 (m, 4H), 7.21 to 7.17 (m, 2H), 7.01 (dd, J= 5.1, 3.5 Hz, IH), 6.72 (d, J= 8.2 Hz, IH), 5.06 (s, 2H), 2.32 (t, J= 7.6 Hz, 4H), 1.61 (m, 4H), 1.35 (m, 4H). LRMS: 497.21 (calc) 498.4 (obs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; dichloromethane; at 20℃; for 21h; | Example 35; 7V-(2-Amino-5-(thiophen-2-yl)phenyl)-4-(benzo[d][l,3]dioxol-5-ylmethyl)piperazine-l- carboxamide (316); <n="172"/>Scheme 35; Step 1. tert-Butgammal 2-(4-(benzo[dl[l,31dioxol-5-ylmethyl)piperazine-l-carboxamido)-4-(thiophen-2-yl)phenylcarbamate (315); [0936] A solution of triphosgene (544 mg, 1.83 mmol, 1.05 eq.) in DCM (5 niL) stirred at 00C under nitrogen was treated with a solution of l-(benzo[d][l,3]dioxol-5-ylmethyl)piperazine(314, 1.16g, 5.24 mmol) in anhydrous pyridine (7 mL), added drpwise over 5 min. The resulting mixture was stirred at 0 0C for 3 h and then at room temperature for 30 min, transferred with a syringe into a flask containing solid amine 4 (832 mg, 2.87 mmol), stirred at room temperature for 21 h, diluted with DCM, washed (saturated NaHCO3 then water), dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (elution with 5% isopropyl alcohol in DCM) gave title compound 315 (165 mg, 11% yield) as a yellow solid.[0937] 1H NMR (DMSO-de) delta (ppm): 8.60 (s, IH), 8.30 (s, IH), 7.59 (d, J = 2.2 Hz, IH),7.51 (dd, J = 1.0, 5.0 Hz, IH), 7.46 (d, J = 8.5 Hz, IH), 7.40 (dd, J = 1.0, 3.5 Hz, IH), 7.39 (dd, J= 2.2, 8.5 Hz, IH), 7.11 (dd, J = 3.5, 5.0 Hz, IH), 6.88 (d, J = 1.4 Hz, IH), 6.86 (d, J = 7.8 Hz,IH), 6.76 (dd, J = 1.4, 7.8 Hz, IH), 5.99 (s, 2H), 3.45 (t, J = 4.6 Hz, IH), 3.43 (s, 2H), 2.38 (t, J =4.6 Hz, IH), 1.46 (s, 9H). LRMS: (calc.) 536.2; (obt.) 537.1 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
HOBt (0.22 g, 1.44mmol) was added to a solution of 4- {acetyl {2- (dimethylamino) ethyl] amino} benzoic acid (0.15 g, 1.599 mmol) and EDC (0.276 g, 1.44 mmol) in DMF (4 mL) and allowed to stir for ten min. Tert-butyl (2-amino-4-(2-amino-4-(2-thienyl)phenyl]carbamate (0.435 g, 1.498 mmol) was added to the reaction mixture and continued stirring at 50 0C for overnight. The next day the reaction mixture was purified by preparative HPLC reverse phase (C- 18), eluting with Acetonitrile/Water + 0.05% TFA, to give pure product. MS : cal'd 523 (MH+), exp 523 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 20℃; for 1h; | To a solution of 4- nitrobenzoyl chloride (320 mg, 1.72 mmol) in pyridine (5.0 mL) was added /erf-butyl [2-amino- 4-(2-thienyl)phenyl]carbamate (500 mg, 1.72 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour. The crude reaction mixture was diluted with EtOAc (20 mL) and washed with 2M HCl (10 mL), 2M NaOH (10 mL) and sat.'d aq. NaHCO3 (1 x 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo and gave the desired <n="165"/>ferf-butyl[2-[2-(4-nitrobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate which was confirmed by MS: cal'd 462.1 (MHNa+), exp 462.1 (MHNa+).To a solution of tert-butyl [2-[(4-nitrobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate (598 mg, 1.36 ramol) in 1:1 EtOAc/THF was added 10 mol% Pd/C (136 mg, 1.36 mmol). The reaction mixture was evacuated and refilled with hydrogen (2x). The black reaction mixture was stirred in a parr shaker under 50 psi of hydrogen overnight. The mixture was filtered through a pad of celite (with EtOAc then CH2CI2 washes) and concentrated to provide /erf-butyl [2-[(4- aminobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate which was confirmed by MS : cal'd 410.1 (MH+), exp 410.1 (MH+). | |
To a solution of 4-nitrobenzoyl chloride (320 nig, 1.72 mmol) in pyridine (5.0 mL) was added tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (500 mg, 1.72 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour. The crude reaction mixture was diluted with EtOAc (20 mL) and washed with 2M HCl (10 mL), 2M NaOH (10 mL) and sat'd aq. NaHCObeta (1 x 10 mL). The organic layer was dried over MgSO-1, filtered, and concentrated in vacuo and gave the desired tert-butyl[2-[2-(4~nitrobenzoyl)amino]-4-(2- thienyl)phenyl]carbamate which was confirmed by MS: cal'd 462.1 (MHNa+), exp 462.1 (MHNa+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
HOBt (0.608 g, 3.97 mmol) and EDC (0.761 g, 3.97 mmol) were added to a stirred mixture of 4-(methylamino) benzoic acid(.5 g, 3.31 mmol) in DMF (4 ml) and the mixture was stirred at room temperature for 10 min. tert-hutyl [2-amino-4-(2-thienyl)phenyl]carbamate (1.153 g, 3.97 mmol) was then added and the mixture was heated to 500C overnight. Cool to room temperature and concentrated. The mixture was taken up into ethyl acetate and wash with water. The organic layer was then concentrated and taken on crude to the next step. MS: cal'd 424 (MH+), exp 424 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Diethyl [4-([2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyI]phosphonate. A mixture of 4-(diethoxyphosphoryl)benzoic acid (commercially available, 50 mg, 0.194 mmol), EDCI (44.6 mg, 0.233 mmol), HOBT (31.5 mg, 0.233 mmol) and tert-butyl [2-amino-4-(2- thienyl)phenyl]carbamate (67.7 mg, 0.233 mmol) were taken into DMF (0.58 mL) and stirred for 16 h. Approximately 5 mL of TFA was added to the mixture which was stirred for Ih and concentrated. The product was purified by HPLC (30-90% MeCN in H2O with 0.025% TFA) to afford the requisite product. 1H NMR (DMSO-d6, 600MHz) delta 9.87 (s, IH), 8.11 (dd, J = 7.9, 3.5 Hz, 2H), 7.83 (dd, J = 21.1, 8.2 Hz, 2H), 7.45 (d, J= 2.0 Hz, IH), 7.33 (dd, 7= 5.0, 0.9 Hz, IH), 7.29 (dd, J = 8.2, 2.0 Hz, IH), 7.22 (d, J = 2.9 Hz, IH), 7.03 (dd, J= 5.0, 3.5 Hz, IH), 6.79 (d, J = 8.5 Hz, IH), 5.39 (s, 2H), 3.97-4.16 (m, 4H), 1.33 (t, J= 7.04 Hz, 6H). MS: cal'd 431 (MH+), exp 431 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 4h; | To a solution of 4-(diisopropyl-phosphinoyl)-benzoic acid (700 mg, 2.75 mmol), 2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (959 mg, 3.30 mmol), and HOBT (558 mg, 4.13 mmol) in DMF (5 mL) was addded EDC (792 mg, 4.13 mmol). The reaction mixture was stirred at RT for 4h. The resultant solid was filtered and washed with MeOH to yield the desired material. 1H NMR (CDCl3, 600MHz) delta 10.02 (s, IH), 8.75 (br s, IH), 8.08 (m, 2H), 7.83 (m, 2H), 7.77 (s, IH), 7.62 (d, J= 8.2 Hz, IH), 7.51 (m, 2H), 7.42 (d, J <n="100"/>= 3.0 Hz, IH), 7.21 (dd, J= 8.2, 2.5 Hz, IH), 2.39 (m, 2H), 1.06 (dd, J= 15.0,.7.0 Hz, 6H), 0.90 (dd, J= 16.0 7.0 Hz, 6H). MS: cal'd 527 (MH+), exp 527 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | 4-(l-Methyl-4-oxido-l,4-azaphosphinan-4-yl)benzoic acid (128 mg, 0.51 mmol), 2-amino-4-thiophen-2-yl-phenyl)-carbamic acid terf-butyl ester (176 mg, 0.61 mmol), EDC (116 mg, 0.61 mmol), HOBT (93 mg, 0.61 mmol), and DIPEA (196 mg, 1.52 mmol) were combined and diluted with DMF (2.0 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were washed again with water (2x) then dried (MgSO) and concentrated in vacuo. The residue was purified by MPLC (0-8% MeOH in CH2CI2). Pure fractions were identified, combined, then concentrated in vacuo. The residue was <n="102"/>diluted with 2:1 DCM:TFA and stirred at ambient temperature for 1 h. The mixture was then carefully quenched with sat aq sodium bicarbonate and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated in vacuo to afford the title compound: MS: cal'd 426 (MH+), exp 426 (MH+). 1H NMR (CD3OD^, 600MHz) 5 8.18 (d, J =6.2 Hz, 2H), 7.98 (dd, J = 11.2 Hz, J= 8.2 Hz, 2H), 7.50 (d, J= 1.8 Hz, IH), 7.37 (dd, J=8.2 Hz, J= 1.8 Hz, IH), 7.22 (dd, J= 12.6 Hz, J= 5.0 Hz, 2H), 7.01 (m , IH), 6.91 (d, J=8.2 Hz, IH), 3.06-2.96 (m, 2H), 2.92-2.82 (m, 2H), 2.46-2.36 (m, 5H), 2.17-2.07 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78 - 20℃; for 18h; | 4-Bromomethyl-benzoyl bromide (0.70 g, 2.52 mmol) was made 0.21 M in anhydrous DCM and cooled to -78C. To this stirring solution was added (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid /er/-butyl ester (0.73 g, 2.52 mmol) followed by DIPEA (0.98 g, 7.56 mmol). The resulting solution was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was then diluted with 0.1 N HCl and extracted with EtOAc. The organic layer was then washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), and concentrated in vacuo to afford the title compound: 1H NMR (DMSO-d6, 600MHz) delta 9.90 (s, IH), 8.72 (s, IH), 7.94 (d, J= 7.8 Hz, 2H), 7.78-7.80 (m, IH), 7.57-7.62 (m, 3H), 7.47-7.51 (m , 2H), 7.42-7.44 (m, IH), 7.09-7.12 (m, IH), 4.77 (s, 2H), 1.43 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | 4-(5,5-Dimethyl-2-oxo-2lambda -[l,3,2]dioxaphosphinan-2-ylmethyl)- benzoic acid (100 mg, 0.35 mmol), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid ferf-butyl ester (123 mg, 0.42 mmol), EDC (81 mg, 0.42 mmol), HOBT (54 mg, 0.35 mmol), and DIPEA (136 mg, 1.05 mmol) were combined and diluted with DMF (1.4 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were identified, combined and concentrated in vacuo. The residue was diluted with 10:1 DCM:TFA and stirred at ambient temperature for 2 hours. The mixture was then concentrated in vacuo to afford the title compound: 1H NMR (DMSO-d6, 600MHz) delta 9.85 (s, IH), 7.93 (d, J= 7.2 Hz, 2H), 7.50 (s, IH), 7.43 (d, J=7.2 Hz, 2H), 7.34-7.40 (m, 2H), 7.28-7.30 (m , IH), 7.03-7.06 (m, IH), 6.90-6.92 (m, IH), 4.20-4.25 (m, 2H), 4.01 (br-s, 2H), 3.87-3.94 (m, 2H), 3.52 (d, J =20.4 Hz, 2H), 1.08 (s, 3H), 0.84 (s, 3H). MS: cal'd 457 (MH+), exp 457 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; | To a solution of 4-(ethoxy-methyl-phosphinoylmethyl)-benzoic acid (1.0 g, 4.13 mmol) and (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-buty ester (1.44 g, 4.95 mmol) in DMF (20 mL) was added HOBT (1.27 g, 8.26 mmol) and EDC (1.58 g, 8.26 mmol). The reaction mixture was stirred over the weekend. The solvent was removed and the residue was purified by column chromatography on silica gel, eluting with CHClbeta/MeOH(2.5% to 20%) to give a glassy yellow solid. At this stage, the enantiomers can be separated via chiral chromatography and deprotected to generate both enantiomers. Spectral data for Boc- protected racemate;eta NMR (CDCl3, 600MHz) delta 9.31 (br s, IH), 8.00 (m, 2H), 7.95 (d, J= 8.2 Hz, 2H), 7.40 (dd, J= 8.2, 2.0 Hz, IH), 7.37 (dd, J= 8.2, 2.0 Hz, 2H), 7.32 (d, J= 8.2 Hz, IH), 7.28 (dd, J= 3.5, 2.3 Hz, IH), 7.26 (m, IH), 7.04 (dd, J= 5.0, 3.5 Hz, IH), 6.95 (br s, IH), 4.05- 3.96 (m, 2H), 3.22 (dd, J= 18.2, 14.4 Hz, IH), 3.19 (dd, J= 18.2, 14.4 Hz, IH), 1.37 (d, J= 13.8 Hz, 3H), 1.27 (t, J= 7.0 Hz, 3H). MS: cal'd 415 (MH+; -Boc), exp 415 (MH+; -Boc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 72h; | A mixture of 6-[(Diethoxyphosphoryl)methyl]nicotinic acid (55.5 mg, 0.188 mmol), tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (65.5 mg, 0.226 mmol) HOBT (30.5 mg, 0.226 mmol), and EDC (43.3 mg, 0.226 mmol) was taken into DMF (1.32 mL) and stirred for 3 days. The mixture was diluted with EtOAc and washed with 50% saturated aqueous NaHCtheta3 3x, brine, dried (MgStheta4) and concentrated to afford a residue taken into DCM (2 mL) and TFA (1 mL) and stirred for Ih. This mixture was concentrated via rotovap, dissolved in minimum MeOH and purified via HPLC (10-100% MeCN in water with 0.025% TFA) to afford fractions poured into saturated aqueous NaHCtheta3 and extracted with EtOAc 2x. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to afford 36.5 mg of the requisite product as a light yellow solid. 1H NMR (DMSO-de, 600MHz) delta 9.84 (s, IH), 9.04 (s, IH), 8.26 (dd, J = 7.9, 2.0 Hz, IH), 7.47 (dd, J= 8.2, 1.8 Hz, IH), 7.44 (d, J= 2.0 Hz, IH), 7.33 (dd, J= 5.0, 0.9 Hz, IH), 7.28 (dd, J= 8.8, 2.3 Hz, IH), 7.22 (dd, J= 3.5, 1.2 Hz, IH), 7.2 (dd, J = 5.0, 3.5 Hz, IH), 6.78 (d, J= 8.2 Hz, IH), 5.22 (s, 2H), 3.95 (dt, J= 7.3, 7.3 Hz, 4H), 3.53 (d, J= 22.3 Hz, 2H), 1.19 Hz (t, J= 7.0 Hz, 3H). MS: cal'd 446 (MH+), exp 446 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | 4-[l-(Dimethoxy-phosphoryl)-l-fluoro-ethyl]-benzoic acid (50 mg, 0.18 mmol), (2-Amino-4-thiophen-2-yl-phenyl)-carbamic acid /erf-butyl ester (63 mg, 0.22 mmol), BOP (96 mg, 0.22 mmol), and DIPEA (70 mg, 0.54 mmol) were combined and diluted with DMF (0.72 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were identified, combined, and concentrated in vacuo. The residue was diluted with 5:1 CH2C^TFA. The resulting solution was stirred at ambient temperature for Ih then concentrated in vacuo to afford the title compound: 1H NMR (DMSO-dbeta, 600MHz) £ 10.15 (s, IH), 8.05 (d, J= 9.0 Hz, 2H), 7.56-7.62 (m, 3H), 7.43-7.48 (m, 2H), 7.37 (d, J =3.5 Hz, IH), 7.06-7.09 (m , 2H), 3.72 (d, J=10.8 Hz, 3H), 3.57 (d, J=10.8 Hz, 3H), 1.86-1.96 (m, 3H). MS: cal'd 449 (MH+), exp 449 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | 4-[(Dimethoxy-phosphoryl)-fluoro-methyl]-benzoic acid (52 mg, 0.198 mmol), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (69 mg, 0.238 mmol), EDC (57 mg, 0.298 mmol), HOBT (36 mg, 0.238 mmol), and DEPEA (77 mg, 0.595 mmol) were combined and diluted with DMF (0.79 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were combined and concentrated in vacuo. The residue was diluted with 10:1 DCM:TFA and stirred at ambient temperature. After 2 hours the deprotection was complete and the mixture was concentrated in vacuo to give the title compound: 1H NMR (DMSO-d6, 600MHz) delta 9.87 (br-s, IH), 8.05 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 7.8 Hz , 2H), 7.48 (s, IH), 7.37 (d, J=5.0 Hz, IH), 7.32 (d, J=8.4 Hz, IH), 7.24-7.27 (m , IH), 7.04 (dd, J =3.6 Hz, J=5.0 Hz, IH), 6.86 (d, J=8.4 Hz, IH), 6.33 (dd, J=SA Hz, J =43.8 Hz, IH), 3.64-3.71 (m, 6H). MS: cal'd 435 (MH+), exp 435 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | 4-[rerf-Butoxycarbonylamino-(dimethoxy-phosphoryl)-methyl]-benzoic acid (76 mg, 0.212 mmol), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (74 mg, 0.254 mmol), EDC (61 mg, 0.317 mmol), HOBT (39 mg, 0.254 mmol), and DIPEA (82 mg, 0.635 mmol) were combined and diluted with DMF (0.85 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were identified, combined, then concentrated in vacuo. The residue was diluted with 10:1 DCM:TFA and stirred at ambient temperature. After 2 h the mixture was concentrated in vacuo to give the title compound: 1H NMR (DMSO-dbeta, 600MHz) delta 9.81 (s, IH), 9.06 (br-s, 2H), 8.05 (d, J =9.0 Hz, 2H), 7.62 (d, J=9.0 Hz, 2H), 7.44-7.46 (m, IH), 7.34-7.36 (m, IH), 7.29-7.32 (m, IH), 7.22-7.24 (m, IH), 7.03- 7.05 (m, IH), 6.82 (d, 7=7.8 Hz, 2H), 5.20 (d, J=17.4 Hz, IH), 3.73 (d, J=10.8 Hz, 3H), 3.58 (d, 7=10.8 Hz, 3H). MS: cal'd 432 (MH+), exp 432 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; | A mixture of ter/-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (600 mg, 2.07 mmol) and 6- chloronicotinyl chloride (380 mg, 2.16 mmol) in 5 mL of pyridine was stirred overnight, poured into EtOAc and washed with saturated NaHCO3, dried (Na2SO4) and concentrated giving the BOC-protected chloronicotinamide. 1H NMR (600 MHz, CD3OD): delta 8.95 (d, J = 2.3 Hz, IH), 8.35 (dd, J = 8.2 Hz, 2.3 Hz, IH), 7.85 (br s, IH), 7.62 (d, J = 8.5 Hz, IH), 7.55-7.51 (m, 2H), 7.37-7.35 (m, 2H), 7.07 (dd, J= 5.0 Hz, 3.5 Hz, IH), 4.59 (s, IH), 1.49 (s, 9H). MS: cal'd 452 (MNa+), exp 452 (MNa+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | 4-[(Dimethoxyphosphoryl)amino]benzoic acid (100 mg, 0.41 mmol), 2-amino-4-thiophen-2-yl- phenyl)-carbamic acid ter/-butyl ester (142 mg, 0.49 mmol), EDC (94 mg, 0.49 mmol), HOBT (75 mg, 0.49 mmol), and DIPEA (158 mg, 1.22 mmol) were combined and diluted with DMF (1.6 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were washed again with water (2x) then dried (MgStheta4) and concentrated in vacuo. The residue was purified by MPLC (0-8% MeOH in CH2CI2). Pure fractions were identified, combined, then concentrated in vacuo. The residue was diluted with 2:1 DCM:TFA and stirred at ambient temperature for 1 h. The mixture was then carefully quenched with sat aq sodium bicarbonate and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated in vacuo to afford the title compound: MS: cal'd 418 (MH+), exp 418 (MH+). 1H NMR (DMSO-d, 600MHz) delta 9.52 (s, IH), 8.46 (d, J= 9.1 Hz, IH), 7.87 (d, J =8.2 Hz, 2H), 7.42 (s, IH), 7.33 (d, J=5.0 Hz, IH), 7.26 (d, J= 8.2 Hz, IH), 7.21 (d , J=3.5 Hz, IH), 7.08 (d, J=8.5 Hz, 2H), 7.03- 7.01 (m, IH), 6.78 (d, J=8.2 Hz, IH), 5.09 (s, 2H), 3.65 (d, J=I 1.2 Hz, 6H). MS: cal'd 418 (MH+), exp 418 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | 4- {3-[(ethyloxy)(methyl)phosphoryl] propanoyl} benzoic acid (1 g, 3.52 mmol), 1,1-dimethylethyl [2-amino-4-(2- thienyl)phenyl]carbamate (1.532 g, 5.28 mmol), DDPEA (0.922 mL, 5.28 mmol) and BOP (2.334 g, 5.28 mmol) were stirred in DMF (10 mL) at room temperature overnight. Saturated NaHCObeta was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with water and brine, dried over MgStheta4 and concentrated in vacuo. Purification of the residue by MPLC (0-20% MeOH-EtOAc) gave ethyl {3-[4-([2-([(l,l-dimethylethyl)oxy] carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]-3-oxopropyl}methylphosphinate as an orange solid. MS: cal'd 457 (MH+ - Boc), exp 457 (MH+ - Boc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 60℃; | 2£)-3-[3-(dimethoxyphosphoryl)phenyl]acrylic acid (0.0735 g, 0.287 mmot) was dissolved in DMF (3 ml). EDC (0.0706 g, 0.368 mmol) and HOBT (0.0993 g, 0.648 mmol) were added. The mixture was allowed to stir briefly, ferf-butyl [2- amino-4-(2-thienyl)phenyl]carbamate (0.1333 g, 0.459 mmol) was added. The reaction was allowed to stir at 60 0C. After approximately six hours EDC (0.0912 g, 0.476 mmol) and HOBT (0.0906 g, 0.592 mmol) were added. The reaction was allowed to stir over the weekend at 60 0C. The reaction was filtered and diluted with methanol. The residue was purified by preparative HPLC Reverse phase (C- 18), eluting with Acetonitrile/Water (+0.025% TFA). Fractions containing the product were diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated. MS: calc'd 429 (MH+-Boc), exp 429 (MH+-Boc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridine; at 20℃; for 4h; | Step 4: tert-butyl 2- (3-METHOXYBENZAMIDO)-4- (THIOPHEN-2-YL) PHENYLCARBAMATE (180) [0344] 3-Methoxybenzoyl chloride 179 (0.20g, 1.17 MMOL) and 178 (0.34g, 1.17 MMOL) were stirred in pyridine (15 mL) at rt for 4 hrs then the pyridine was removed by rotary evaporation and the crude material was purified by column chromatography (25% ethyl acetate in hexanes) to provide the title compound 180 (0.44g, 89% yield NMR: (DMSO) 8 (ppm): 400 MHz, (DMSO) d (ppm): 9.88 (s, 1H), 8.72 (s, 1H), 7.80 (s, 1H), 7.60 (d, J= 8.4 Hz, 1H), 7.43 to 7.55 (m, 6H), 7.17 (dd, J= 7.6, 1.8 Hz, 1H), 7.11 (dd, J= 4.9, 3.5 Hz, 1H), 3.84 (s, 3H), 1.46 (s, 9H). MS: (CALC.) 424.15 ; (obt.) 425.1 (MH) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In pyridine; at 20℃; | Step 1: Acetic acid 4-(2-TERT-BUTOXYCARBONYLAMINO-5-THIOPHEN-2-YL-PHENYLCARBAMOYL)-PHENYL ester (183) [0346] TERTBUTYL 2-AMINO-4-(THIOPHEN-2-YL) PHENYLCARBAMATE 178 (0.198g, 0.68 MMOL), BENZOTRIAZOL-1-YLOXY-TRIS (DIMETHYLAMINO) PHOSPHONIUM HEXAFLUOROPHOSPHATE (BOP) (0.302g, 0.68 MMOL) and 4-acetoxybenzoic acid (182) (0. 123G, 0.68 MMOL) were stirred in pyridine at rt overnight then solvent evaporated and purified by flash chromatography (35% ethyl acetate in hexanes) to provide 183 (O. 11g, 36%). 1H NMR: (DMSO) 5 (ppm): 400 MHz, (DMSO) d (ppm): 9.91 (s, 1H), 8.72 (s, 1H), 8.01 (d, J= 8.8 Hz, 2H), 7.78 (d, J= 1.8 Hz, 1H), 7.63 (d, J= 8. 4 Hz, 1H), 7.51 (dd, J= 4.9, 0.98 Hz, 2H), 7.44 (dd, J= 3.7, 0.98 Hz, 1H), 7.30 (d, J= 8.6 Hz, 1H), 7.11 (dd, J= 5.1 Hz, 1H), 2.32 (s, 3H), 1.46 (s, 9H). MS: (CALC.) 452.14 ; (obt. ) 475 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In dichloromethane; | Example 24 3-(4-Oxo-7-thiophen-2-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile Prepared from (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example G18) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (108 mg). MS (EI) 343 (M+); mp>250 C. (dec.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 2h; | General procedure: Synthesis oftert-butyl (2-amino~4-(thiophen-2-yl)phenyl)carbamate (9a):Compound 9a was made following the procedure reported in the patent literature ( WO 2009/055917). Compound 8a (0.24 g. 0.75 mmol) was placed in a round bottom flask and 10% palladium on carbon (catalytic amount, 20 mg) was added into it. The reaction mixture was exposed to a balloon. After purging with the reaction mixture was stirred under balloon for 2 hours at room temperature. It was then filtered through Ceiite and concentrated under vacuum to give the desired amine (0.217 g, 100% yield).lE NMR (400 MHz, Chloroform-d) delta 7.33 - 7.27 (m, 1H), 7.25 - 7.21 (m, 2H)57.08 - 7.03 (m, 2H), 7.02 (d, J= 2.0 Hz, 1H), 1.52 (s, 9H). |
98% | With palladium on activated charcoal; hydrogen; In methanol; ethyl acetate; at 20℃; for 20h; | 4.1.8.1. tert-Butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (16a). Compound 15a (0.53 g, 1.66 mmol) was solubilized in methanol and EtOAc (6 + 16 mL) and stirred at room temperature for 20 h with Pd/C (0.05 g, 10% w/w) under hydrogen atmosphere. The catalyst was filtered off, and the solvent was removed and washed with PE to give compound 16a as a white solid (0.47 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.34 (s, 1H), 7.44-7.42 (m, 1H), 7.29 (dd, J = 3.5, 1.2 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.11 (dd, J = 5.3, 3.5 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 8.5, 2.2 Hz, 1H), 5.04 (s, 2H), 1.45 (s, 9H). |
95% | With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 20℃; for 18h; | Step 3 : tert-Butyi 2-amino-4-(thiophen-2-yl)phenylcarbamate (4); [0679] Compound 3 was suspended in AcOEt and placed under nitrogen atmosphere; then10% palladium on carbon (catalytic amount) was added. The reaction mixture was placed under vacuum for a few min then opened up under a balloon of hydrogen and stirred at ambient temperature for 18 h. The reaction mixture was filtered through Celite and concentrated to give compound 4 (0.393 g, 95% yield).[0680] 1H NMR (DMSO-d6 delta (ppm): 8.33 (s, IH), 7.42 (dd, J= 4.9, 0.98 Hz, IH), 7.27 (dd,J= 3.5, 0.98 Hz, IH), 7.06 (dd, J= 5.1, 3.7 Hz, IH), 6.95 (d, J= 2.2 Hz, IH), 6.82 (dd, J= 8.0 Hz,2.0 Hz, IH), 5.01 (s, 2H), 1.47 (s, 9H). |
85% | With palladium on activated charcoal; hydrogen; In methanol; | To a solution of 40a (3.43 g, 10 mmol) in CH3OH (200 mL),was added dry palladium-carbon (0.34 g), the mixture was stirredunder a hydrogen atmosphere overnight. The palladium-carbonwas filtered off over celite, after evaporating the solvent, the residuewas dried under vacuum to give 41a (2.46 g, 85%), a whitesolid. 1H NMR (400 MHz, DMSO-d6) delta 8.35 (s, 1H), 7.45-7.43 (m,1H), 7.30 (dd, J = 3.6, 1.1 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.08 (dd,J = 5.1, 3.6 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.85 (dd, J = 8.2, 2.1 Hz,1H), 5.01 (s, 2H), 1.47 (s, 9H). ESI-MS m/z: 291.3 [M+H]+. |
83% | With methanol; iron(III) chloride; hydrazine hydrate; at 60℃; for 2h; | To a solution of tert-butyl (2-nitro-4-(thiophen-2-yl)phe- nyl)carbamate (1.6 g, 4.99 mmol, 1 eq.) in methanol (20 mE)was added hydrazine hydrate (14 mE) and ferric chloride (0.05 g, 0.3 mmol, 0.06 eq.). The resulting mixture was warmed to 60 C. and stirred for 2 h. The reaction was then filtered through Celite, the solids were washed with MeOH. The filtrate was concentrated under reduced pressure. Waterwas added to the residue and the suspension was stirred for 1 h. The obtained solid was filtered, washed with hexanes then dried to yield tert-butyl (2-amino-4-(thiophen-2-yl)phenyl) carbamate (1.2 g, 83% yield). |
69% | With palladium 10% on activated carbon; hydrogen; In methanol; ethanol; for 12h; | To a solution of tert-butyl (2-nitro-4-(thiophen-2-yl)phe- nyl)carbamate (2 g, 6.2 mmol, 1.0 eq.) in ethanol (20 mE) andmethanol (20 mE) was added 10% Pd/C (0.66 g, 0.1 eq.). The reaction mixture was stirred 12 h under a hydrogen atmosphere. The reaction was filtered and the filtrate was concen120trated under reduced pressure to give tert-butyl (2-amino-4- (thiophen-2-yl)phenyl)carbamate (1.25 g, 69% yield) as an off-white solid. |
54% | With zinc; In 1,4-dioxane; water; at 70℃; | Zinc powder (4.75 g) was added to a solution of 16 (6.65 g, 20.74 mmol) in dioxane (180 mL) and H2O (45 mL) and stirred overnight at 70 C. Upon completion, EtOAc was added and the mixture was washed with H2O (3×100 mL) and brine (1×100 mL). The crude product was purified by column chromatography, eluting with EtOAc:Hexanes (2:1), to obtain 17 (3.95 g, 54 % yield). 1H NMR (400MHz, CDCl3) delta 7.34-7.20 (m, 3H), 7.10-6.98 (m, 3H), 1.52 (s, 9H). 13C NMR (101MHz, CDCl3) delta 153.7, 144.1, 139.9, 132.2, 127.9, 124.8, 124.4, 122.8, 117.5, 115.0, 80.7, 28.3 |
palladium-carbon; | Example G18 (2-Amino-4-thiophen-2-yl-phenyl)-carbamic Acid tert.-Butyl Ester Prepared from (2-nitro-4-thiophen-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example C3) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a beige powder (151 mg). MS (ISP) 291 [(M+H)+]. | |
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; | A solution of N-BOC 2-nitro-4-(2-thienyl)aniline (18.0 g) in 350 mL of EtOAc was evacuated and refilled with nitrogen (2×). To the solution was added 10% Pd/C (4.46 g), and the reaction mixture was evacuated and refilled with hydrogen (2×). The black reaction mixture was stirred under an atmosphere of hydrogen overnight. The mixture was filtered through a pad of celite (with EtOAc then CH2Cl2 washes) and concentrated to provide a brownish-white solid. The solid was triturated with ether and filtered to provide the off-white tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (E): 1H NMR (600 MHz, DMSO-d6) delta 8.31 (br, 1 H), 7.41 (dd, J=5.0, 0.9 Hz, 1 H), 7.26 (dd, J=3.5, 1.2 Hz, 1 H), 7.23 (br d, J=8.5 Hz, 1 H), 7.05 (dd, J=5.0, 3.5 Hz, 1 H), 6.94 (d, J=2.1 Hz, 1 H), 6.81 (dd, J=8.2, 2.1 Hz, 1 H), 4.98 (s, 2 H), 1.43 (s, 9 H); MS (ESI+): cal'd [M+Na]+ 291.1, obs'd 291.1. | |
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; | A solution of N-BOC 2-nitro-4-(2-thienyl)aniline (18.0 g) in 350 mL of EtOAc was evacuated and refilled with nitrogen (2x). To the solution was added 10% Pd/C (4.46 g), and the reaction mixture was evacuated and refilled with hydrogen (2x). The black reaction mixture was stirred under an atmosphere of hydrogen overnight. The mixture was filtered through a pad of celite (with EtOAc then CH2CI2 washes) and concentrated to provide a brownish-white solid. The solid was triturated with ether and filtered to provide the off-white tert-bniyl [2-amino-4-(2- thienyl)phenyl]carbamate (E): 1H NMR (600 MHz, DMSO-rftf) delta 8.31 (br, 1 H), 7.41 (dd, J= 5.0, 0.9 Hz, 1 H), 7.26 (dd, J= 3.5, 1.2 Hz, 1 H), 7.23 (br d, J= 8.5 Hz, 1 H), 7.05 (dd, J= 5.0, 3.5 Hz, 1 H), 6.94 (d, J= 2.1 Hz, 1 H), 6.81 (dd, J= 8.2, 2.1 Hz, 1 H), 4.98 (s, 2 H), 1.43 (s, 9 H); MS (ESI+): cal'd [M+Na]+ 291.1, obs'd 291.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | To a solution of ^carbamoyl-fluoro-methy^-benzofbjthiophene^-carboxylic acid (100 mg, 0.40 mmol), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (172 mg, 0.59 mmol) andN,N-diisopropylethylamine (0.103 mL, 0.59 mmol) in DMF (2.0 mL) was added (1H-1,2,3- benzotriazol-l-yloxy)(triisopropyl)phosphonium hexafluorophosphate (262 mg, 0.59 mmol) and the reaction was stirred overnight. The solvent was removed and the residue was purified by reverse phase chromatography (10-100% ACN/Eta2O). The fractions were extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated in vacuo. ESIMS calcd 526 (M+ + H), found 526 (M+ + H). | |
With (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | To a solution of 6-(carbamoyl-fluoro-methyl)-benzo[b]thiophene-2-carboxylic acid (100 mg, 0.40 mmol), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (172 mg, 0.59 mmol) and N,N-diisopropylethylamine (0.103 mL, 0.59 mmol) in DMF (2.0 mL) was added (IH-1, 2,3- benzotriazol-l-yloxy)(triisopropyl)phosphonium hexafluorophosphate (262 mg, 0.59 mmol) and the reaction was stirred overnight. The solvent was removed and the residue was purified by reverse phase EPO <DP n="115"/>chromatography (10-100% ACN/H2O). The fractions were extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated in vacuo. ESMS calcd 526 (M+ + H), found 526 (M+ + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 14h; | 2-(5-[(2-amino-5-tbien-2-yIphenyl)ainino]carbonyI}thien-3-yl)-Nu,Nu'-diphenylmalonamide4-[2-anilino-l-(anilinocarbonyl)-2-oxoethyl]thiophene-2-carboxylic acid (37 mg, 0.1 mmol) was made 0.25 M in anhydrous dichloromethane and stirred at O0C. To this stirring solution was added thionyl chloride (35 mg, 0.3 mmol) followed by catalytic DMF. The resulting mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture was then concentrated in vacuo and azeotroped once with 5 mL anhydrous toluene. The residue was then diluted with 0.25 mL anhydrous dichloromethane and treated with tert-butyl 2-amino-4-thien-2-ylphenylcarbamate (34 mg, 0.12 mmol). The resulting mixture was stirred at ambient temperature. After 14 hours the reaction mixture was diluted with 2: 1 DCM:TFA and stirred for 1 hour. After that time the mixture was concentrated in vacuo. The residue was then purified by reverse phase chromatography to yield the desired product as the TFA salt. MS: cal'd 553 (MH+), exp 553 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; | Preparation of tert-Butyl [2-[(6-Chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]-carbamate (F) A mixture of tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (E) (600 mg, 2.07 mmol) and 6-chloronicotinyl chloride (380 mg, 2.16 mmol) in 5 mL of pyridine was stirred overnight, poured into EtOAc and washed with saturated NaHCO3, dried (Na2SO4) and concentrated giving the BOC-protected chloronicotinamide (F): 1H NMR (600 MHz, CD3OD): delta 8.95 (d, J=2.3 Hz, 1H), 8.35 (dd, J=8.2 Hz, 2.3 Hz, 1H), 7.85 (br s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.55-7.51 (m, 2H), 7.37-7.35 (m, 2H), 7.07 (dd, J=5.0 Hz, 3.5 Hz, 1H), 4.59 (s, 1H), 1.49 (s, 9H); MS (ESI+): cal'd [M+Na]+ 452.1, obs'd 452.1. | |
With pyridine; | tert-Butyl ^-[(theta-Chloropyridiii-S-ylJcarbonylJaminoJ-^Z-thienyOphenyl]- carbamate (F). A mixture of tert-bntyl [2-amino-4-(2-thienyl)phenyl]carbamate (E) (600 mg, 2.07 mmol) and 6-chloronicotinyl chloride (380 mg, 2.16 mmol) in 5 mL of pyridine was stirred overnight, poured into EtOAc and washed with saturated NaHCO3, dried (Na2SO4) and <n="53"/>concentrated giving the BOC-protected chloronicotinamide (F): 1H NMR (600 MHz3 CD3OD): delta 8.95 (d, J= 2.3 Hz, IH), 8.35 (dd, J = 8.2 Hz, 2.3 Hz, IH), 7.85 (br s, IH), 7.62 (d, J= 8.5 Hz, IH), 7.55-7.51 (m, 2H), 7.37-7.35 (rn, 2H), 7.07 (dd, J= 5.0 Hz, 3.5 Hz, IH)54.59 (s, IH), 1.49 (s, 9H); MS (ESI+): cal'd [M+Naf 452.1, obs'd 452.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)-1,3-thiazole-5-carboxylic acid (60 mg, 0.16 mmol) was made 0.25 M in anhydrous DCM and to this stirring solution was added catalytic DMF followed by 3 equivalents thionyl chloride (179 mg, 1.5 mmol). The resulting solution was stirred at ambient temperature under nitrogen for 1 hour. The reaction mixture was then concentrated in vacuo and azeotroped once with toluene to remove excess thionyl chloride. The residue was made 0.5M in anhydrous DCM and to this stirring solution was added 3 equivalents triethylamine (48 mg, 0.48 mmol) followed by 1 equivalent tert-butyl 2-amino-4-thien-2-ylphenylcarbamate (30 mg, 0.16 mmol). The resulting mixture was stirred at ambient temperature for 14 hours. The reaction mixture was then diluted with 4M TFA in DCM and allowed to stir at ambient temperature. After one hour the reaction mixture was concentrated in vacuo and purified by reverse phase chromatography: MS (ESI+): cal'd [M+H]+ 531.1, obs'd 531.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine; at 20℃; for 15h; | Example A5. a) Preparation of intermediate 12. A solution of intermediate 11 (0.0003 mol) in CH2Cl2 (3ml) was added dropwise to a solution of [2-amino-4-(2-thienyl)phenyl]-l,l-dimethylethyl ester carbamic acid (0.0006 mol) in pyridine (7ml). The mixture was stirred at room temperature for 15 hours, then evaporated to dryness. The residue was taken up in CH2Cl2. The organic layer was washed with H2O several times, dried (MgSO4), filtered and the solvent was evaporated. This fraction (0.35g) was purified by column chromatography over silica gel (eluent: CH2C12/CH3OH/NH4OH 99/1/0 to 97/3/0.1; 15-40mum). The pure fractions were collected and the solvent was evaporated, yielding 0.2g (80%) of intermediate 12 (E-configuration). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[4-(2-tert-Butoxycarbonylamino-5-thiophen-2-yI-phenyIcarbamoyl)-phenyl]-hydroxy-acetic acid methyl ester. 4-(Hydroxy-methoxycarbonyl-methyl)-benzoic acid (1.135 g, 5.40 mmol), EDCI (1.553 g, 8.10 mmol), and HOBT (949 mg, 7.02 mmol) were combined in DMF (40 mL) and stirred for 10 minutes before adding (2-amino-4-thiophen-2-yl-rhohenyl)-carbamic acid tert-butyl ester (1.647 g, 5.67 mmol). The reaction was then stirred at 600C for 14h. Additional EDCI (500 mg) and HOBT (300 mg) were added, and the solution was stirred at 60 0C for another 5h. The solvent was evaporated, and the resulting <n="62"/>residue was dissolved in EtOAc, washed (water, sat. NaHCO3, brine), dried (MgSO4), and concentrated. Flash chromatography on silica (5-60% EtOAc/hexanes) afforded [4-(2-tert-butoxycarbonylamino-5- thiophen-2-ylphihenylcarbamoyl)-phenyl]-hydroxy-acetic acid methyl ester as a pale yellow powder. 1H NMR (CDCl3) delta 9.24 (s, IH), 8.03 (s, IH), 7.96 (d, J= 8.2 Hz, 2H), 7.53 (d, J= 8.5 Hz, 2H), 7.37 (dd, J = 8.4, 2.2 Hz, IH), 7.27 - 7.23 (m, 3H), 7.04 (dd, J= 4.8, 3.7 Hz, IH), 6.85 (s, IH), 5.25 (s, IH), 3.78 (s, 3H), 1.50 (s, 9H). cal'd 483.1 (MH+), exp 483.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 14h; | N-(2-tert-Butoxycarbonylamino-5-thiophen-2-yl-phenyl)-terephthaIamic acid methyl ester. Methyl4-(chlorocarbonyl)benzoate (0.75 g, 3.79 mmol) and anhydrous DCM (0.25 M) was treated with tert- butyl 2-amino-4-thien-2-ylphenylcarbamate (1.0 g, 3.44 mmol). The resulting solution was stirred at ambient temperature for 14 hours. The reaction mixture was quenched with a solution of aqueous NaOH (IM) and partitioned between ethyl acetate and water. The organic layer was washed with water, saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was carried on without further purification | |
With pyridine; at 20℃; for 18h; | Methyl 4-(chlorocarbonyl)benzoate (1.40 g, 7.07 mmol) and /er/-butyl [2-amino-4-(2- thienyl)phenyl]carbamate (2.05 g, 7.07 mmol) were combined in pyridine (10 mL) and stirred at room temperature for 18 h. The reaction mixture was poured into 3:1 CHCl3:MeOH, washed with 2 N HCl and 2 N NaOH, dried (Na2SO4), and evaporated to give the desired product as a colorless solid. MS: cal'd 475 (MNa+), exp 475 (MNa+). | |
Methyl 4-(chlorocarbonyl)benzoate (0.75 g, 3.79 mmol) and anhydrous DCM (0.25 M) was treated with tert-butyl 2-amino-4-thien-2-ylphenylcarbamate (1.0 g, 3.44 mmol). The resulting solution was stirred at ambient temperature for 14 hours. The reaction mixture was quenched with a solution of aqueous NaOH (IM) and partitioned between ethyl acetate and water. The organic layer was washed with water, saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was carried on without further purification. |
With triethylamine; In dichloromethane; at 20℃; for 1h; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 20℃; for 15h; | d) Preparation of intermediate 21. A solution of intermediate 20 (0.0002 mol) in CH2Cl2 (2ml) was added dropwise at 5C to a solution of [2-amino-4-(2-thienyl)phenyl]- 1 , 1 -dimethylethyl ester carbamic acid (0.0003 mol) in pyridine (6ml). The mixture was stirred at room temperature for 15 hours. Pyridine was evaporated. The residue was taken up in CH2Cl2. The organic layer was washed with H2O, dried (MgSO4), filtered and the solvent was evaporated. The obtained residue (0.2g) was purified by column chromatography over silica gel (eluent: CH2C12/CH3OH 98/2; 15-40mum). The desired fractions were collected and the solvent was evaporated, yielding: 0.12g of intermediate 21 (E-configuration). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; triethylamine; In tetrahydrofuran; dichloromethane; at 20℃; for 48h; | Triethylamine (0.002 mol) was added at room temperature to a solution of intermediate 49 (0.0005 mol), [2-amino-4-(2-thienyl)phenyl]- carbamic acid, 1,1-dimethylethyl ester (0.001 mol) and PyBOP (0.0011 mol) in THF (3ml) and DCM (3ml). The mixture was stirred at room temperature for 48 hours, poured out into water and extracted with <n="50"/>DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (Ig) was purified by column chromatography over silica gel (15-40mum) (eluent: DCM/MeOH/NH4OH 93/7/0.5). The pure fractions were collected and the solvent was evaporated, yielding 0.14g (43%) of intermediate 50. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; | Coupling; {2-[4-(l-Hydroxy-l-methyIcarbamoyI-ethyl)-benzoylamino]-4-thiophen-2-yl- phenylj-carbamic acid tert-butyl ester. To a solution of 4-(l -hydroxy- 1-methylcarbamoyl-ethyl)- benzoic acid (77 mg, 0.345 mmol), (2-ammo-4-thiophen-2-yl-phenyl)-carbarnic acid tert-butyl ester (150 mg, 0.52 mmol), and HOBt (69.9 mg, 0.52 mmol) in DMF (4.0 mL) was added EDCI (99 mg, 0.52 mmol) and the reaction was stirred overnight. The solvent was removed. The residue was dissolved in EtOAc and washed with H2O, 0.5 N HCl, sat. NaHCO3, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was used without further purification, cal'd 497 (MH+), exp 497 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h; | Ethyl [(tert-butoxycarbonyl)amino][4-([2-[(tert-butoxycarbonyl)amino]-5-(2- thienyl)phenyl]amino}carbonyl)phenyl]acetate. 4-{l-[(tert-butoxycarbonyl)amino]-2-ethoxy-2- oxoethyl}benzoic acid (1.2 g, 3.71 mmol), tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (1.293 g, 4.45 mmol), BOP (2.462 g, 5.57 mmol) and DIPEA (0.972 mL, 5.57 mmol) were stirred in DMF (10 mL) at room temperature for 3 days. Saturated NaHCO3 was added and the products extracted into EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product as a pale yellow powder. 1H NMR (d-DMSO, 600 MHz) delta 9.89 (s, IH), 8.71 (br s, IH), 7.93 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.4 Hz, IH), 7.83 (d, J= 1.8 Hz, IH), 7.60 (d, J= 8.4 Hz, IH), 7.54 (d, J= 8.4 Hz, 2H), 7.50 (m, 2H), 7.42 (d, J= 3.6 Hz, IH), 7.10 (dd, J= 5.4 and 3.6 Hz, IH), 5.27 (d, J= 8.4 Hz, IH), 4.08 (m, 2H), 1.43 (s, 9H), 1.38 (s, 9H), 1.11 (t, J= 7.2 Hz, 3H). MS: cal'd 440 (MH+ - Boc - 'Bu), exp 440 (MH+ - Boc - 'Bu). | |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h; | Step B: Ethyl [(tert-butoxycarbonyl)amino][4-([2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]acetate. 4-{1-[(tert-butoxycarbonyl)amino]-2-ethoxy-2-oxoethyl}benzoic acid (1.2 g, 3.71 mmol), tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (1.293 g, 4.45 mmol), BOP (2.462 g, 5.57 mmol) and DIPEA (0.972 mL, 5.57 mmol) were stirred in DMF (10 ml) at room temperature for 3 days. Saturated NaHCO3 was added and the products extracted into EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product as a pale yellow powder. 1H NMR (DMSO-d6, 600 MHz) delta 9.89 (s, 1H), 8.71 (br s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.50 (m, 2H), 7.42 (d, J=3.6 Hz, 1H), 7.10 (dd, J=5.4 and 3.6 Hz, 1H), 5.27 (d, J=8.4 Hz, 1H), 4.08 (m, 2H), 1.43 (s, 9H), 1.38 (s, 9H), 1.11 (t, J=7.2 Hz, 3H). MS: cal'd 596 (MH+), exp 440, 484, 496 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | {4-Thiophen-2-yI-2- [(5-trimethylsilanyl-f ur an-2-carbonyl)-amino] -phenyl}-car bamic acid tert-butyl ester. To a solution of 5-trimethylsilanyl-furan-2-carboxylic acid (98.4 mg, 0.534 mmol) and (2-amino- 4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (186 mg, 0.641 mmol) in DMF (2 mL) was added DIPEA (0.093 mL, 0.534 mmol) BOP (236 mg, 0.534 mmol) and the resultant solution were stirred at room temperature overnight. The material was purified by HPLC (40-100% MeCN-H2O; 0.025%TFA) to yield the desired product. 1H NMR (d6-DMSO, 600 MHz) delta 9.69 (s, IH), 8.87 (br s, IH), 7.84 (d, J= 1.4 Hz, IH), 7.53 (dd, J= 5.0, 1.2 Hz, IH), 7.48 (m, 2H), 7.43 (dd, J= 3.8, 1.2 Hz, 2H), 7.25 (d, J= 3.5 Hz, IH), 7.10 (dd, J= 5.0, 3.3 Hz, IH), 6.92 (d, J= 3.5 Hz), 1.44 (s, 9H), 0.30 (s, 9H). MS cal'd 357 (MH+ - Boc), exp 357 (MH+ - Boc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 60℃; for 6h; | [4-({2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]acetic acid. To a solution of ter/-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (0.300 g, 1.03 mmol) in DCM (5 mL) was added DIPEA (0.170 mL, 1.03 mmol), BOP (0.456 g, 1.03 mmol) and 4-(2-methoxy-2-oxoethyl)benzoic acid (0.200 g, 1.03 mmol). The reaction was allowed to stir at 60 0C for 6 h, diluted with EtOAc, washed with sat'd NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The filtrate was purified by reverse phase HPLC (30-100percent MeCN-H2O) to give methyl [4-({2-[(tert-butoxycarbonyl)amino]-5-(2- thienyl)phenyl]amino}carbonyl)phenyl]acetate. MS: cal'd 367 (MH+ - Boc), exp 367 (MH+ - Boc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; | lambda'-[2-aimno-5-(2-thienyl)phenyl]-4-(trimethylsUyl)benzamide. A mixture of 4-(trimethylsilyl)benzoic acid (68.6 mg, 0.353 mmol), 1,1-dimethylethyl [2-amino-4-(2-thienyl)phenyl]carbamate (123 mg, 0.424 mmol), EDC (81.2 mg, 0.424 mol), and HOBT (57.3 mg, 0.424 mmol) were taken into DMF (1.06 mL) and stirred overnight. About 3 mL TFA was added and the reaction was stirred Ih, then concentrated and purified via HPLC (20-100% MeCN in water with 0.025% TFA) to afford fractions poured into saturated aqueous NaHCO3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to afford the title compound as a light tan solid. 1H NMR (d6- DMSO, 600 MHz) delta 9.70 (s, IH), 7.95 (d, J= 7.9 Hz, 2H), 7.64 (d, J= 8.2 Hz, 2H), 7.46 (s, IH), 7.33 (dd, J= 5.0, 0.9 Hz, IH), 7.28 (dd, J= 8.2, 2.1 Hz, IH), 7.22 (d, J= 3.5 Hz, IH), 7.02 (dd, J= 5.0, 2.5 Hz, IH), 6.79 (d, J= 8.2 Hz, IH), 5.12 (s, 2H), 0.37 (s, 9H). MS: cal'd 367 (MH+), exp 367 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | Dissolved in 30 mL of DMF and treated with tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (3.25 g, 11.2 mmol) followed by BOP (11.0 g, 24.9 mmol), stirred overnight at RT. Poured into EtOAc and washed with 2 N HCl, 2 N NaOH, water, dried (Na2SO4), cone. Chromatography on SiO2 (0-50% EtOAc/hexanes) gave the intermediate vinyl silane biaryl amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 60℃; for 18h; | To a solution of tert-bvAy [2-amino-4-(2-thienyl)phenyl]carbamate in DCM (5 mL) was added Et3N ( 0.32 mL, 2.26 mmol), BOP (0.67 g, 1.51 mmol) and 4-[3- <n="72"/>trimethylsilyl)propanoyl]amino}benzoic acid (0.200 g, 0.754 mmol). The reaction was allowed to stir at 60 0C for 18 h, diluted with EtOAc, washed with sat'd NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The filtrate was purified by MPLC (0-100% DCM/EtOAc) to give tert-butyl {4-(2-thienyl)-2- (4-[3-(trimethylsilyl)propanoyl]amino}benzoyl))amino]phenyl}carbamate. MS: cal'd 438 (MH+ - Boc), exp 438 (MH+ - Boc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; | N-[2-Amino-5-(2-thienyl)phenylJ-4-[hydroxy(dimethyl)silyl]benzamide. A mixture of 4- [hydroxy(dimethyl)silyl]benzoic acid (88.4 mg, 0.420 mmol), EDC (96.7 mg, 0.504 mmol), HOBT (681 mg, 0.504 mmol) and 1,1-dimethylethyl [2-amino-4-(2-thienyl)phenyl]carbamate (146 mg, 0.504 mmol) were taken into DMF (1.2 mL) and stirred overnight. Aproximately 2 mL TFA added and the reaction was stirred for Ih, then concentrated and purified via HPLC (25-100% MeCN in water with 0.025% TFA) to afford fractions poured into saturated aqueous NaHCC>3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to afford the requisite product as a light yellow solid. 1H NMR (d6-DMSO, 600 MHz) delta 9.7 (s, IH), 7.94 (d, J= 7.9 Hz, 2H), 7.66 (d, 8.2 Hz, 2H), 7.46 (s, IH), 7.33 (d, J= 5.0 Hz, IH), 7.28 (dd, J= 8.2, 2.1 Hz, IH), 7.22 (d, J = 2.6 Hz, IH), 7.12 (dd, / = 5.0, 3.5 Hz, IH), 6.79 (d, J= 8.5 Hz, IH), 6.12 (s, IH), 5.13 (s, 2H), 0.36 (s, 6H). MS: cal'd 369 (MH+), exp 369 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,1-dimethylethyl [2-([4-(4,4-dimethyl-l,4-azasilinan-l-yl)phenyl]carbonyl}amino)-4-(2- thienyl)pheny I] carbamate. 4-(4,4-dimethyl-l,4-azasilinan-l-yl)benzoic acid (0.375 g, 1.032 mmol) was taken up in DCM (4 mL) and cooled to 0 0C. Oxalyl chloride, 2 M in DCM (0.568 mL, 1.135 mmol) was added followed by 2 drops of DMF. After stirring for 1 hour, a further portion of oxalyl chloride, 2 M in DCM (0.258 mL, 0.516 mmol) was added and stirring continued for 2 hours. The solvent was removed in vacuo and the residue dissolved in THF (4 mL). DIPEA (0.451 mL, 2.58 mmol) was added followed by 1,1-dimethylethyl [2-amino-4-(2-thienyl)phenyl]carbamate (0.300 g, 1.032 mmol). The mixture was <n="69"/>stirred at room temperature for 3 days. Water was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue twice by MPLC (6-50% EtOAc-hexanes) gave 1,1-dimethylethyl [2-([4-(4,4- dimethyl-l,4-azasilinan-l-yl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate as a beige solid. 1H NMR (d6-DMSO, 600 MHz) delta 9.64 (s, IH), 8.63 (d, J= 2.4 Hz, IH), 7.82 (d, 7= 8.4 Hz, 2H), 7.76 (d, J = 2.4 Hz, IH), 7.57 (d, J= 8.4 Hz, IH), 7.50 (dd, J= 4.8 and 1.2 Hz, IH), 7.46 (dd, / = 8.4 and 2.4 Hz, IH), 7.42 (dd, J= 3.6 and 1.2 Hz, IH), 7.10 (dd, J= 4.8 and 3.6 Hz, IH), 6.90 (d, J = 8.4 Hz, 2H), 3.72 (m, 4H), 1.44 (s, 9H), 0.72 (m, 4H), 0.06 (s, 6H). MS: cal'd 522 (MH+), exp 522 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; HATU; at 50℃; for 48h; | To the above acid (1.0 equiv) in NMP (5 mL), was added HATU (1.5 equiv), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (1.5 equiv.) and NMM (6.0 equiv). The reaction mixture was then stirred at 50 C. for 48 hours. The reaction mixture was diluted with water and acetonitrile and the resulting solid was filtered, washed with water, and dried to give [2-({5-[5-fluoro-4-(3-isopropyl-2-methyl-3H-imidazol-4-yl)-pyrimidin-2-ylamino]-thiophene-2-carbonyl}-amino)-4-thiophen-2-yl-phenyl]-carbamic acid tert-butyl ester. MS found for C31H32FN7O3S2 as (M+H)+ 633.97. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 3 N-(2-amino-5-thiophen-2-yl-phenyl)-4-[4-(1-isopropyl-2-methylimidazol-5-yl)-pyrimidin-2-ylamino]-benzamide To Int-3 (75 mg, 0.3 mmol) in DMF (4 mL) were added HATU (110 mg, 0.29 mmol), <strong>[335255-43-1]tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate</strong> (84 mg, 0.29 mmol) and NMM (0.08 mL, 0.67 mmol) and stirred at room temperature. After 2 hours, additional <strong>[335255-43-1]tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate</strong> (65 mg, 0.22 mmol) and NMM (0.08 mL, 0.67 mmol) were added and stirred at room temperature. After 16 hours, the reaction mixture was concentrated in vacuo and 4.0 M HCl in dioxane (1 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was then concentrated and diluted with water and acetonitrile and purified by preparative HPLC affording Compound 6, after lyophilization. MS found for C28H27N7OS as (M+H)+ 510.1. 1H NMR (400 MHz, dmso-d6): delta 9.81 (s, 1H); 9.58 (s, 1H); 8.46 (d, J=5.6 Hz, 1H); 7.93 (d, J=8.8 Hz, 2H); 7.84 (d, J=8.8 Hz, 2H); 7.50 (s, 1H); 7.44-7.33 (m, 1H); 7.33-7.21 (m, 3H); 7.12 (d, J=5.6 Hz, 1H); 7.03-7.00 (m, 1H); 6.79 (d, J=8.4 Hz, 1H); 5.73 (m, 1H); 2.50 (s, 3H); 1.49 (d, J=7.2 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 45℃; | Example 64N-(2-amino-5-thiophen-2-yl-phenyl)-4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzamide Methyl 4-(cyanomethyl)-benzoic acid methyl ester (1.92 g, 11.01 mmol) and 1-bromo-2-(2-bromo-ethoxy)-ethane (12.56 mL, 55.04 mmol) were combined in THF (15 mL) and cooled down to 0 C. Potassium bis(trimethylsilyl)-amide (0.5M in toluene, 48.3 mL, 24.21 mmol, 2.2 eq) was added over a period of 15 minutes and then warmed up to room temperature and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried with MgSO4 and evaporated under vacuum. The crude product was purified by chromatography on silica gel (25% EtOAc/hexanes) to afford 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester. To a solution of 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (1.55 g 6.32 mmol) in MeOH (10 mL) was added Et3N (3 mL). H2S was bubbled into the solution. The reaction vessel was stirred at room temperature for 3 days. The reaction mixture was then evaporated and purified by silica gel chromatography (33% EtOAc/hexanes) to afford 4-(4-thiocarbamoyl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester.The above compound was dissolved in DMF. Chloro-acetaldehyde in water (1.2 eq) was added and heated with microwave at 85 C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried with MgSO4 and evaporated under vacuum. This product was used for next step without purification. The solid 4-[4-(4-hydroxy-4,5-dihydro-thiazol-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid methyl ester was dissolved in MeOH and an excess of p-TsOH was added and heated in the microwave for 20 minutes at 70 C. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution. The organic phase was dried with MgSO4, evaporated under vacuum and purified by silica gel chromatography (33% EtOAc/hexanes).Compound 4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (1.00 g, 3.3 mmol) was dissolved in MeOH (5 mL) and treated with 1N NaOH. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution mixture was evaporated, suspended in water, and acidified with 1N HCl. 4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoic acid was collected as precipitate, dried under vacuum, and used for next step without further purification.A solution of 4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoic acid (0.9 g, 3.11 mmol), 2-Amino-4-thiophen-2-yl-phenyl-carbamic acid tert-butyl ester (1.08 g, 1.1 eq), HATU (1.42 g, 1.2 eq), and DIPEA (1.04 mL, 2.0 eq) were dissolved in DMF and stirred at 45 C. overnight. After the reaction was complete, it was cooled down and precipitated with water and a saturated solution of NaHCO3. The solid formed was collected and used for next step without further purification. Solid {2-[4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoylamino]-4-thiophen-2-yl-phenyl}-carbamic acid tert-butyl ester was re-dissolved in DCM/TFA (1:1) and stirred for 1 hour. After the reaction was complete, the reaction mixture was evaporated and purified by reverse phase chromatography to afford title compound, Example 64. MS found for C28H26N7FOS as (M+H)+ 461.12. 1H NMR (400 MHz, dmso-d6): 1H-NMR (DMSO) delta: 9.74 (s, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.44 (s, 1H), 7.32 (d, J=5.2 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.21 (d, J=3.6 Hz, 1H), 7.01 (q, J=3.6, 4.8 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.14 (s, 1H), 4.02-4.00 (m, 2H), 3.69-3.65 (m, 2H), 2.11-2.08 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In N,N-dimethyl-formamide; | Example 37N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-ethoxythiazol-2-yl)tetrahydropyran-4-yl)benzamide; Compound A (0.49 g, 1.8 mmol) and ethyl chloroacetate (1.11 mL, 10.4 mmol) were dissolved in EtOH (15 mL). The resulting mixture was heated at 60 C. overnight, concentrated, and purified by silica gel chromatography (1% MeOH/DCM) to afford Compound B (0.35 g, 58%). MS m/z: 348 (MH+). Compound B (0.35 g, 1.0 mmol) was hydrolyzed with 2N aqueous NaOH (5 mL) and THF (2 mL) to afford corresponding acid Compound C (0.30 g, 90%). MS m/z: 334 (MH+). Compound C (0.20 g, 0.6 mmol) was coupled with amine Compound D (0.18 g, 0.6 mmol) in the presence of HATU (0.46 g, 1.2 mmol) and triethylamine (0.25 mL, 1.8 mmol) in DMF (10 mL) to afford crude amide Compound E. MS m/z: 606 (MH+). Crude Compound E was treated with 4N HCl/dioxane, concentrated and purified by preparative HPLC to afford Example 37 (0.041 g, 13% for two steps). MS (C27H27N3O3S2) m/z: 506 (MH+). NMR 1H NMR (dmso-d6): delta 9.66 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.42 (s, 1H), 7.31 (d, J=5.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.02 (t, J=3.2 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.41 (s, 1H), 5.12 (s, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.68 (m, 2H), 3.58 (m, 2H), 2.53 (m, 2H), 2.31 (m, 2H), 1.28 (t, J=7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; HATU; In 1-methyl-pyrrolidin-2-one; at 50℃; for 16h; | Example 51N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(5-(pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide To the mixture of methyl 4-(4-(thiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate (570 mg, 1.88 mmol) in DMF (5 mL) was added a 1M solution of bromine in DMF (1.9 mL, 1.88 mmol). After 2 hours, additional 1M solution of bromine in DMF (1.9 mL, 1.88 mmol) was added. The reaction mixture was then concentrated to half its volume and poured into water (25 mL). The resulting solid was filtered and washed with water and dried to give methyl 4-(4-(5-bromothiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate. 1H NMR (400 MHz, dmso-d6): delta 7.99 (d, J=8.0 Hz, 2H); 7.58 (s, 1H); 7.41 (d, J=8.0 Hz, 2H); 3.87 (s, 3H); 3.91-3.84 (m, 2H); 3.73-3.68 (m, 2H); 2.63-2.59 (m, 2H); 2.41-2.37 (m, 2H); MS found for C16H16BrNO3S (m/z): 3840.3 [M++1].A mixture pyridin-3-ylboronic acid (128 mg, 1.05 mmol), methyl 4-(4-(5-bromothiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate (200 mg, 0.52 mmol), potassium carbonate (144 mg, 1.05 mmol), and PdCl2(dppf) (76 mg, 0.11 mmol) in toluene/ethanol/water (2 mL/1 mL/1 mL) was heated in microwave (Emry's Optimizer) at 100 C. for 20 minutes. The reaction mixture was then poured into EtOAc/hexanes mixture and the resultant solid was filtered and dried. The dried solid was used for next step without purification. MS found for C21H20N2O3S (m/z): 381.20 [M++1]. To the above crude ester in methanol (5 mL) and THF (2 mL), NaOH (1.0 M, 5.0 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was then diluted with water and acidified with 1N HCl to about pH 7. The aqueous solution was then concentrated and diluted with methanol. The solids were filtered. The filtrate was then concentrated and used for next step. MS found for C20H18N2O3S (m/z): 367.39 [M++1]. To the above crude carboxylic acid in NMP (3 mL), was added HATU (300 mg, 0.76 mmol), <strong>[335255-43-1]tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate</strong> (303 mg, 1.05 mmol) and N-methylmorpholine (NMM) (0.3 mL, 2.62 mmol) and stirred at 50 C. for 16 hours. The reaction mixture was then diluted with water and acetonitrile/methanol and the resulting solid was filtered and washed with water and dried to give tert-butyl 2-(4-(4-(5-(pyridin-3-yl)thiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzamido)-4-(thiophen-2-yl)phenylcarbamate. MS found for C35H34N4O4S2 as (M+H)+ 639.17. To the above butoxycarbonyl (Boc) protected compound was added 4.0 M HCl dioxane (6.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated and diluted with water and acetonitrile and directly purified by preparative HPLC followed by lyophilization to give the title compound. MS found for C30H26N4O2S2 as (M+H)+ 538.91. 1H NMR (400 MHz, dmso-d6): delta 9.68 (s, 1H); 8.82 (s, 1H); 8.50 (d, J=3.6 Hz, 1H); 8.25 (s, 1H); 7.99-7.95 (m, 3H); 7.59 (d, J=8.8 Hz, 2H) 7.41-7.39 (m, 2H); 7.32-7.19 (m, 4H); 7.02-7.00 (m, 1H); 6.77 (d, J=8.4 Hz, 1H); 5.12 (brs, 2H); 3.76-3.73 (m, 2H); 3.65-3.60 (m, 2H); 2.66-2.63 (m, 2H); 2.41-2.39 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 50℃; | Example 22N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-(pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide; 1-Pyridin-3-yl-ethanone (2 g, 16.52 mmol) was dissolved in a mixture of AcOH (8 mL) and HBr (4 mL). After stirring for 20 minutes, Br2 (1.0 eq) in CHCl3 (3 mL) was added in a period of 5 minutes. When the reaction was completed, the solids were filtered out and washed with water and extracted with EtOAc. The organic phase was dried, evaporated, and used for next step. Compound 4-(4-thiocarbamoyl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (300 mg, 1.075 mmol) was dissolved in MeOH (7 mL) and 2-Bromo-1-pyridin-3-yl-ethanone (1.2 eq) was added and refluxed at 85 C. for 30 minutes. The reaction mixture was washed with saturated aqueous solution of NaHCO3 and then extracted with EtOAc. The organic phase was dried, evaporated and used for next step without any purification. Compound 4-[4-(4-pyridin-3-yl-thiazol-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid methyl ester (200 mg, 0.52 mmol) was dissolved in MeOH and 1N NaOH was added. After reaction was complete, the mixture was evaporated and acidified slowly with 1N HCl. The formed solid was filtered out and used for next step without purification. Compound 4-[4-(4-Pyridin-3-yl-thiazol-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid HATU (171 mg, 1.1 eq), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (136 mg, 1.1 eq), and DIPEA (0.14 mL, 2.0 eq) were dissolved in DMF and heated at 50 C. overnight. The reaction mixture was washed with water and extracted with EtOAc. The organic phase was dried, evaporated, and re-dissolved in a mixture of DCM and TFA (1:1). After stirring for 1 hour at room temperature the mixture was evaporated and purified by reverse phase chromatography to give Example 22. MS found for C30H26N4O2S2 as (M+H)+ 539.12. 1H NMR (400 MHz, dmso-d6): delta: 9.64 (s, 1H), 9.12 (d, J=1.6 Hz, 1H), 8.49 (dd, J=4.8, 3.2 Hz, 1H), 8.26-8.23 (m, 1H), 8.17 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.43-7.28 (m, 2H), 7.27 (t, J=4.4 Hz, 1H), 7.22 (dd, J=8.4, 6.1 Hz, 1H), 7.16-7.15 (m, 1H), 6.97 (dd, J=5.2, 1.6 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.09 (s, 2H), 3.73-3.70 (m, 2H), 3.63-3.58 (m, 2H), 2.67-2.64 (m, 2H), 2.42-2.36 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In pyridine; at 20℃; for 48h; | To a solution of 2'-(ethoxycarbonyl)biphenyl-3-carboxylic acid 56 (0.166 g, 0.614 mmol) in pyridine (3 ml), <strong>[335255-43-1]tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate</strong> 61 (0.4 g,1.378 mmol) and BOP (0.815 g, 1.843 mmol) were added. The reaction mixture was stirred at rt for 2 days, concentrated and diluted with DCM then washed with NaHCO3, brine and dried with Na2SO4. Flash purification (5% EtOAc/DCM) afforded the tert-Boc intermediate (0.333 g, 0.614 mmol) which was taken up in DCM (1.75 mL). Neat trifluoroacetic acid (0.946 mL,12.28 mmol) was added and the reaction mixture was allowed to stir at room temperature for1 h then diluted with DCM and a solution of KOH in brine (0.672 g, in 10 mL brine) and stirred until pH>9. The organic phase was separated and dried over Na2SO4. Flash purification (15% EtOAc/DCM) afforded title compound 62 (0.195g, 72% yield) as a light brown solid. 1H NMR: (DMSO) d(ppm) IH: 9.83 (s, IH), 8.02 (d, IH), 7.98 (s, IH), 7.80(dd, IH), 7.66 (t, IH), 7.55 (m, 4H), 7.45 (d, IH), 7.36 (dd, IH), 7.31 (dd, IH), 7.24 (dd, IH),7.05 (dd, IH), 6.82 (d, IH), 5.15 (s, 2H), 4.09 (m, 2H), 1.02 (t, 3H). LRMS(ESI): (calc.)442.53 (found) 443.2 (MH)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; LiOH; DIPEA; sodium hydrogencarbonate; benzotriazol-1-ol; triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; methanol; dichloromethane; water; ethyl acetate; trifluoroacetic acid; | Synthesis of (E)-3-(3-(2-amino-5-(thiophen-2-yl)phenylamino)-3-oxoprop-1-enyl)benzamide (BRD-3636) A mixture of methyl 3-bromobenzoate (10.8 g, 50.2 mmol, 1.0 eq), t-butyl acrylate (8.05 g, 62.8 mmol, 1.25 eq), triethylamine (10.16 g, 100 mmol, 2.0 eq), triacetoxylpalladium (0.14 g, 0.50 mmol, 0.01 eq) and tri-o-tolylphosphine (0.61 g, 2.0 mmol, 0.04 eq) was heated at 100 C. for 2 h under nitrogen atmosphere. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The organic phase was adjusted to pH~3 with a 1M aqueous solution of HCl. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow solid (11 g, 84% yield). A mixture (E)-methyl 3-(3-tert-butoxy-3-oxoprop-1-enyl)benzoate (12.0 g, 45.7 mmol) in TFA (100 mL) was stirred at room temperature for 20 h. The solvent was removed under reduced pressure. The residue obtained was washed with ethyl acetate to give a white solid (8.5 g, 90% yield). A mixture of (E)-3-(3-(methoxycarbonyl)phenyl)acrylic acid (5.56 g, 27 mmol, 1.5 eq), <strong>[335255-43-1]tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate</strong> (5.22 g, 17.98 mmol, 1.0 eq), HATU (10.30, 42.7 mmol, 2.37 eq) and DIPEA (6.96 g, 98 mmol, 5.45 eq) in THF (80 ml) was stirred at room temperature for 20 h. The reaction was then concentrated. The residue was diluted with ethyl acetate and washed with water, then brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (silica gel, 50% PE/CH2Cl2) to afford a yellow solid (6.0 g, 64.9% yield). To a solution of (E)-methyl 3-(3-(2-(tert-butoxycarbonylamino)-5-(thiophen-2-yl)phenylamino)-3-oxoprop-1-enyl)benzoate (5.5 g, 11.49 mmol, 1.0 eq) in THF (60 mL) was added a solution of LiOH (0.69 g, 28.7 mmol, 2.5 eq) in water (60 mL). The reaction was stirred at room temperature for 20 h. The reaction was extracted with ethyl acetate. The aqueous layer was separated and acidified with a 1N aqueous solution of HCl to pH~2. The precipitate formed was filtered and rinsed subsequently with water (200 mL), then methanol (100 mL) to afford a white solid (4.2 g, 79% yield). A mixture of ammonia hydrochloride (0.02 g, 0.43 mmol, 2.0 eq), (E)-3-(3-(2-(tert-butoxycarbonylamino)-5-(thiophen-2-yl)phenylamino)-3-oxoprop-1-enyl)benzoic acid (0.10 g, 0.21 mmol, 1.0 eq), HATU (0.08 g, 0.32 mmol, 1.5 eq), HOBt (0.043 g, 0.32 mmol, 1.5 eq) and DIPEA (0.11 g, 0.86 mmol, 4.0 eq) in THF (10 mL) was stirred at room temperature for 20 h. The reaction was then concentrated. The residue was diluted with ethyl acetate and washed with water, then brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (silica gel, 10% MeOH/CH2Cl2) to afford the desired product (0.08 g, 80% yield). A solution of (E)-tert-butyl 2-(3-(3-carbamoylphenyl)acrylamido)-4-(thiophen-2-yl)phenylcarbamate (0.08 g, 0.17 mmol, 1.0 eq) in CH2Cl2 was treated with trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 1 h. The reaction was then concentrated. The residue was dissolved in ethyl acetate (20 mL). The solution was washed with a saturated aqueous solution of sodium bicarbonate (10 mL), then water (10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The product was washed with ether (2 mL) to give the target compound (0.05 g, 73% yield). ESI+ MS: m/z (rel intensity) 364 (92.63, M+H), 1H NMR (500 MHz, d6-DMSO): delta 9.48 (s, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.80-7.70 (m, 2H), 7.62 (d, J=16 Hz, 1H), 7.54 (t, J=8 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J=5 Hz, 1H), 7.29-7.19 (m, 2H), 7.10-6.59 (m, 2H), 6.79 (d, J=8 Hz, 1H), 5.24 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With DIPEA; sodium hydrogencarbonate; trifluoroacetic acid; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | Synthesis of N-(2-amino-5-(thiophen-2-yl)phenyl)-4-sulfamoylbenzamide (BRD-7726) A solution of <strong>[335255-43-1]tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate</strong> (0.30 g, 1.03 mmol, 1 eq), 4-sulfamoylbenzoic acid (0.42 g, 2.06 mmol, 2 eq), HATU (780 mg, 2.06 mmol, 2.0 eq.), and DIPEA (0.45 mL, 2.58 mmol, 2.5 eq) in DMF (5 mL) was stirred for 15 h at room temperature. The reaction was quenched with a saturated solution of sodium bicarbonate. The solid obtained was filtered and dried under reduced pressure. The product was purified by column chromatography (silica gel, 3% MeOH/CH2Cl2) to afford the desired product (0.25 g, 51% yield). To a stirred solution of tert-butyl 2-(4-sulfamoylbenzamido)-4-(thiophen-2-yl)phenylcarbamate (0.15 g, 0.32 mmol, 1 eq) in CH2Cl2 (2 mL) was added TFA (1 mL) at 0 C. The reaction was stirred at room temperature for 2 h. The reaction was then concentrated. The residue was dissolved in EtOAc. The solution was washed with a saturated solution of sodium bicarbonate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The product was purified by column chromatography (silica gel, 3% MeOH/CH2Cl2) to afford the desired product (0.03 g, 24.9% yield). ESI+ MS: m/z (rel intensity) 374 (98.32, M+H), 1H NMR (500 MHz, d6-DMSO): delta 8.15 (d, J=8.5 Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.49 (s, 1H), 7.36 (d, J=4.5 Hz, 1H), 7.31 (dd, J=8.5, 2 Hz, 1H), 7.44 (d, J=2.5 Hz, 1H), 7.05 (t, J=3.5 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 5.21 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Genral procedure: To a solution of substituted benzoic acid 3-8 (1.1 equiv) in anhydrous DMF (5 mL/mmol of amine) was added EDCI (1.2 equiv) followed by HOBt (1.2 equiv) and stirred at room temperature for 1 h. Thereafter protected phenylendiamine 9-11 (1 equiv) was added and the mixture heated at 78 C overnight. After completion of the reaction as confirmed by TLC, saturated sodium bicarbonate solution (20 mL/mmoL of amine) was added and the mixture was extracted with ethylacetate (30 mL/mmol of amine). The organic layer was washed with water (30 mL/mmol of amine), dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified using flash chromatography (silica gel, hexane/ethylacetate gradient) to yield the N-Boc protected probes. The Boc group was subsequently removed by treating N-Boc protected compound with a mixture of TFA/DCM (1:1 v/v) at room temperature for 1 h. The solvent was removed in vacuo and the residue purified using flash chromatography (silica gel, hexane/ethylacetate gradient) to yield the final probes as solids in 70-80% over all yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Genral procedure: To a solution of substituted benzoic acid 3-8 (1.1 equiv) in anhydrous DMF (5 mL/mmol of amine) was added EDCI (1.2 equiv) followed by HOBt (1.2 equiv) and stirred at room temperature for 1 h. Thereafter protected phenylendiamine 9-11 (1 equiv) was added and the mixture heated at 78 C overnight. After completion of the reaction as confirmed by TLC, saturated sodium bicarbonate solution (20 mL/mmoL of amine) was added and the mixture was extracted with ethylacetate (30 mL/mmol of amine). The organic layer was washed with water (30 mL/mmol of amine), dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified using flash chromatography (silica gel, hexane/ethylacetate gradient) to yield the N-Boc protected probes. The Boc group was subsequently removed by treating N-Boc protected compound with a mixture of TFA/DCM (1:1 v/v) at room temperature for 1 h. The solvent was removed in vacuo and the residue purified using flash chromatography (silica gel, hexane/ethylacetate gradient) to yield the final probes as solids in 70-80% over all yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Genral procedure: To a solution of substituted benzoic acid 3-8 (1.1 equiv) in anhydrous DMF (5 mL/mmol of amine) was added EDCI (1.2 equiv) followed by HOBt (1.2 equiv) and stirred at room temperature for 1 h. Thereafter protected phenylendiamine 9-11 (1 equiv) was added and the mixture heated at 78 C overnight. After completion of the reaction as confirmed by TLC, saturated sodium bicarbonate solution (20 mL/mmoL of amine) was added and the mixture was extracted with ethylacetate (30 mL/mmol of amine). The organic layer was washed with water (30 mL/mmol of amine), dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified using flash chromatography (silica gel, hexane/ethylacetate gradient) to yield the N-Boc protected probes. The Boc group was subsequently removed by treating N-Boc protected compound with a mixture of TFA/DCM (1:1 v/v) at room temperature for 1 h. The solvent was removed in vacuo and the residue purified using flash chromatography (silica gel, hexane/ethylacetate gradient) to yield the final probes as solids in 70-80% over all yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Genral procedure: To a solution of substituted benzoic acid 3-8 (1.1 equiv) in anhydrous DMF (5 mL/mmol of amine) was added EDCI (1.2 equiv) followed by HOBt (1.2 equiv) and stirred at room temperature for 1 h. Thereafter protected phenylendiamine 9-11 (1 equiv) was added and the mixture heated at 78 C overnight. After completion of the reaction as confirmed by TLC, saturated sodium bicarbonate solution (20 mL/mmoL of amine) was added and the mixture was extracted with ethylacetate (30 mL/mmol of amine). The organic layer was washed with water (30 mL/mmol of amine), dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified using flash chromatography (silica gel, hexane/ethylacetate gradient) to yield the N-Boc protected probes. The Boc group was subsequently removed by treating N-Boc protected compound with a mixture of TFA/DCM (1:1 v/v) at room temperature for 1 h. The solvent was removed in vacuo and the residue purified using flash chromatography (silica gel, hexane/ethylacetate gradient) to yield the final probes as solids in 70-80% over all yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 55℃; | A mixture of compound 8 (120 mg, 0.0003 mol), <strong>[335255-43-1]tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate</strong> (88 mg, 0.0003 mol), HOAT (61 mg, 0.00045 mol), EDCI (115 mg, 0.0006 mol), and DIPEA (155 mg, 0.0012 mol) in DMF (5 ml) was stirred at 55 C. for overnight. Water (20 ml) was added to the mixture, and extracted with EA (25 ml×2). The organic layers were separated, dried, filtered, and concentrated to get a residue, which was purified by Prep-TLC to afford compound 10 (170 mg, 84%) as a yellow solid. |
Tags: 335255-43-1 synthesis path| 335255-43-1 SDS| 335255-43-1 COA| 335255-43-1 purity| 335255-43-1 application| 335255-43-1 NMR| 335255-43-1 COA| 335255-43-1 structure
[ 118684-31-4 ]
tert-Butyl (3-(hydroxymethyl)phenyl)carbamate
Similarity: 0.67
[ 144072-29-7 ]
tert-Butyl (4-(hydroxymethyl)phenyl)carbamate
Similarity: 0.67
[ 205318-52-1 ]
3-(Aminomethyl)-1-N-Boc-aniline
Similarity: 0.66
[ 104060-23-3 ]
N-Boc-2-(4-Aminophenyl)ethanol
Similarity: 0.65
[ 263403-72-1 ]
tert-Butyl 2-Boc-aminobenzylcarbamate
Similarity: 0.64
[ 89673-36-9 ]
tert-Butyl benzo[b]thiophen-2-ylcarbamate
Similarity: 0.73
[ 1251734-12-9 ]
tert-Butyl (5-methylthiophen-3-yl)carbamate
Similarity: 0.72
[ 230301-73-2 ]
tert-Butyl 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate
Similarity: 0.67
[ 118684-31-4 ]
tert-Butyl (3-(hydroxymethyl)phenyl)carbamate
Similarity: 0.67
[ 144072-29-7 ]
tert-Butyl (4-(hydroxymethyl)phenyl)carbamate
Similarity: 0.67
[ 89673-36-9 ]
tert-Butyl benzo[b]thiophen-2-ylcarbamate
Similarity: 0.73
[ 1251734-12-9 ]
tert-Butyl (5-methylthiophen-3-yl)carbamate
Similarity: 0.72
[ 118684-31-4 ]
tert-Butyl (3-(hydroxymethyl)phenyl)carbamate
Similarity: 0.67
[ 144072-29-7 ]
tert-Butyl (4-(hydroxymethyl)phenyl)carbamate
Similarity: 0.67
[ 205318-52-1 ]
3-(Aminomethyl)-1-N-Boc-aniline
Similarity: 0.66
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :