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. : | 216574-71-9 | MDL No. : | MFCD08059073 |
Formula : | C10H15NO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FMRKIVIZYXHGAO-UHFFFAOYSA-N |
M.W : | 213.30 | Pubchem ID : | 15541821 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 59.27 |
TPSA : | 80.56 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.21 cm/s |
Log Po/w (iLOGP) : | 2.56 |
Log Po/w (XLOGP3) : | 3.37 |
Log Po/w (WLOGP) : | 2.42 |
Log Po/w (MLOGP) : | 1.59 |
Log Po/w (SILICOS-IT) : | 2.84 |
Consensus Log Po/w : | 2.56 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.35 |
Solubility : | 0.0949 mg/ml ; 0.000445 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.74 |
Solubility : | 0.00388 mg/ml ; 0.0000182 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -2.6 |
Solubility : | 0.535 mg/ml ; 0.00251 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.7 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501 | UN#: | |
Hazard Statements: | H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sulfur; triethylamine In N,N-dimethyl-formamide at 20℃; for 23.1667h; Inert atmosphere; | |
93% | With pyrrolidine; sulfur In N,N-dimethyl-formamide at 50℃; for 0.5h; Microwave irradiation; | General procedure: A mixture of 1 (1 mmol), 2 (1.1 mmol), sulfur (1.1 mmol), corresponding base (1 mmol) and solvent (3mL) was put into a 5 mL microwave reaction vial. The vial was irradiated in the microwave reactor at50 °C for 30 min with the absorbance set to “very high”. After cooling, the reaction mixture was extractedwith EtOAc (3 × 20 mL). The combined organic phase was dried over Na2SO4 and concentrated underreduced pressure and the crude residue purified by flash chromatography on silica gel to give the products3a-3m and 4a-4r. |
70% | Stage #1: methyl 2-cyanoacetate With sulfur; triethylamine In N,N-dimethyl-formamide for 0.5h; Stage #2: 3,3-dimethylbutyrylaldehyde In N,N-dimethyl-formamide at 20℃; | To a 1 L flask containing a mixture of methyl cyanoacetate (MW=99.08, 19.9 g, 201 mmol) and pre-ground sulfur (MW=32.06, 6.45 g, 201 mmol) in 100 mL DMF at r.t. was added TEA (MW=101.19, 10.9 g, 15 mL, 108 mmol, 0.535 eq). The mixture turns brown immediately upon TEA addition. The mixture was stirred until the sulfur had dissolved (ca 30 min). 3,3-dimethylbutraldehyde (MW=100.15, 20.15 g, 201 mmol, d 0.783, 25.2 mL) was added (5 mL DMF used to wash over remaining aldehyde) and the mixture was stirred at r.t. Precipitate formed shortly after aldehyde addition. At ca. 30 min the precipitate was dissolved by mild heating of the reaction with a heat gun, and the solution was stirred for 3 h at rt. Water (1 L) was added slowly to the reaction mixture to form cloudy yellow precipitate, and the mixture was stirred for 30 min. The cloudy orange solution (600 mL) was decanted, and the remaining solution with most of the precipitate was filtered. The solid was washed with water, dried, to give methyl 2-amino-5-tert-butylthiophene-3-carboxylate (MW=213.3) as a yellow solid (30 g, 70%) References: Patent: WO 98/52558To a 250 mL flask containing methyl 2-amino-5-tert-butylthiophene-3-carboxylate (45 g, 210 mmol) in 1:1 mixture of MeOH/water (600 mL) was added 45% KOH (75 g g, 600 mmol), and the reaction mixture was heated to 80° C. for 5 h. The methanol evaporated as the reaction proceeded. The solvent was removed in vacuo and the volume was brought to 600 mL with water and a small amount of insoluble material was filtered. To the vigorously stirred solution was added 20% phosgene in toluene (150 mL, 1.45 eq) over a period of 5 min. A gooey solid was formed during addition of phosgene. The mixture was stirred for 1 h at rt, then filtered and washed with water. The solid was dried in vacuo to provide 6-tert-butyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (39 g, 82%).A solution of 6-tert-butyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (43 gm, 190.9 mmol) in t-BuOH (635 mL) was brought to reflux (90° C.), stirring under N2 overnight. The reaction mixture was concentrated by rotovap to remove t-BuOH and the crude product was purified by trituration/recrystallization with ca. 6:1 Hexanes/Acetone in four batches. The solid was vacuum filtered and washed sparingly with ca. 12:1 Hexanes/Acetone to give 37.28 g of white solid, pure by LC. The mother liquor is concentrated to give 11.3 g of beige solid (80% pure by LC), which was recrystallized again to give an additional 3.66 g (95% purity).To a pressure vessel containing a DMF (120 mL) solution of 2-(tert-butoxycarbonyl)-5-tert-butylthiophene-3-carboxylic acid (11.91 gm, 39.78 mmol, 1 eq.) and 3,3-dimethylpiperazine-2-one (5.61 gm, 43.76 mmol, 1.1 eq.) was added TEA (6.11 mL, 43.83 mmol, 1.1 eq.) followed by HATU (16.60 gm, 43.66 mmol, 1.1 eq.). The vessel was sealed and the mixture stirred at 70° C. overnight.The reaction was returned to ambient, diluted with EtOAc, and washed with sat'd. aq. NaHCO3, H2O, and brine. The organics were separated and dried over MgSO4, filtered and concentrated to give an orange solid. The crude material was triturated/partially recrystallized 3× from hot Acetone/Hexanes (ca 1:2), and the solids are washed with hexane. The mother liquor is concentrated and the crystallization procedure is repeated a few times to give 10.28 gm of tert-butyl 5-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)thiophen-2-ylcarbamate (63% yield), as a white solid.To a flask containing tert-butyl 5-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)thiophen-2-ylcarbamate (11.27 gm, 27.52 mmol) was added 50% TFA/DCM (88 mL). The reaction was stirred for 45 min at r.t. and the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed 3× with 1N NaOH, water and brine. The organics were separated, dried over MgSO4, filtered and concentrated. The product precipitated from the mother liquor on the rotovap during the concentration of the organic portion, was filtered and washed copiously with Hexanes to give to off white solid 4-(2-amino-5-tert-butylthiophene-3-carbonyl)-3,3-dimethylpiperazine-2-one.On standing overnight, additional product was observed in the reserved aq. portion. The solid is filtered under vacuum and washed sequentially with water, and Hexanes mixed with a small amount of acetone. The combined off-white solids were dried under vacuum to give a total of 7.27 gm, 85% yield of highly pure 4-(2-amino-5-tert-butylthiophene-3-carbonyl)-3,3-dimethylpiperazine-2-one.To a RB flask containing triphosgene (1.776 g, 0.34 equiv.) in 35 mL DCM, cooled in an ice bath, was added a solution of 4-methyl-3-(5-(morpholinomethyl)pyridin-2-yl)aniline (4.989 g, 1 equiv.) and TEA (2.45 mL, 1 equiv.) in 15 mL DCM over 3 min. An additional 5 mL DCM was used to wash over any remaining material. The ice bath was removed and the mixture was allowed to stir at room temperature for 15 minutes to give a solution of the carbamoyl chloride.To the solution of carbamoyl chloride (1.07 equiv.) in 55 mL DCM, cooled in an ice bath, was added a mixture of ert-butyl 5-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)thiophen-2-ylcarbamate (5.092 g, 1 equiv.) in 50 mL DCM over 3 minutes. A precipitate formed. An additional 10 mL DCM was used to wash over any remaining material (7 mL/mmol DCM total). The ice bath was removed and the solution was stirred at r.t. At 3 min, TEA was added slowly dropwise. After 20.5 h, the reaction volume was reduced by half in vacuo then the mixture was filtered. The solids were washed with a minimal amount of DCM. The solids were taken up in DCM then the mixture was heated while adding MeOH until solids dissolved. The solution was quickly washed with 1M NaOH before solids reformed. The aqueous layer was extracted with DCM (×1). Upon standing, solids precipitated out of the organic layer. More MeOH and heating were applied to dissolve solids then the organic layer was dried over Na2SO4, filtered and solvent removed in vacuo to give 6.984 g (69%) of 1-(5-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)thiophen-2-yl)-3-(4-methyl-3-(5-(morpholinomethyl)pyridin-2-yl)phenyl)urea.The original filtrate from the reaction was washed with 1M NaOH. Remaining product can then be removed by crystallization from DCM or chromatography as 0.5 g or more of product may remain in the filtrate. |
68% | With sulfur; triethylamine In N,N-dimethyl-formamide at 20 - 50℃; | Compound 27: methyl 2-amino-5-tert-butylthiophene-3-carboxylate: triethylamine (225 mg, 2.5 mmol) was added to a vigorously stirred mixture of cyanoacetic acid methyl ester (500 mg, 5 mmol), sulfur powder (162 mg, 5 mmol) and DMF (10 mL) at 50 °C. 3,3-Dimethylbutyraldehyde (505 mg, 5 mmol) in 4 mL of DMF was added dropwise to this suspension, while maintaining the temperature at 50°C. When the addition was complete, the reaction mixture was allowed to cool to rt and stirred overnight. The reactionmixture was partitioned in water and ether. The ether layer was washed with water (15 mL x 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford a yellow solid, 68% yield. m/z ES+ = 214.08,calcd 214.08; 1H NMR δ ppm 7.15 (s, 2H), 6.48 (s, 1H), 3.69 (s, 3H), 1.25 (s, 9H). |
49% | With hydrogen sulfide; triethylamine In N,N-dimethyl-formamide at 20℃; for 1h; | J.1 Method J Synthesis of 5-tert-Butyl-2-(3-p-tolyl-ureido)-thiophene-3-carboxylic acid methyl ester. (Example 26) [Show Image] Step 1; Triethyl amine (3.04 mL, 21.8 mmol) was added to a solution of methyl cyanoacetate (4.00 g, 40.4 mmol), sulfur (1.29 g, 40.4 mmol) and DMF (20 mL) at ambient temperature. 3,3-dimethyl butraldehyde (5.08 g, 40.4 mmol) was added and stirred 1 h before being poured into water (200 mL). Solids were filtered off and filtrate was extracted with ethyl acetate. The acetate layer was filtered through a plug of silica gel and concentrated in vacuo. Purification via flash chromatography afforded 4.19 g (49%) of methyl 2-amino-5-t-butylthiophene 3-carboxylate. |
49% | With sulfur; triethylamine In DMF (N,N-dimethyl-formamide) for 1h; | P.44.1 To a solution of methyl cyanoacetate (4.00 g, 40.4 mmol), sulfur (1.29 g, 40.4 mmol) and DMF (20 mL) at room temp. was added Et3N ( 3.04 mL, 21.8 mmol). 3,3-Dimethylbutraldehyde (5.08 g, 40.4 mmol) was added and the mixture was stirred 1 h before being poured into water (200 mL). Solids were removed by filteration and the filtrate was extracted with EtOAc. The organic layer was filtered through a plug of silica gel and concentrated under reduced pressure. The crude product was purified via flash chromatrography to afford methyl 2-amino-5-tert-butylthiophene-3-carboxylate (4.19 g, 49%). |
With sulfur; triethylamine In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane for 10h; Heating / reflux; | S.122.1 Metod S; Synthesis of N-(3-carbomethoxy-5-tert-butyl-2-thienyl)-N'-(3-methylphenyl)urea (Example 122); Step 1 To a solution of trichloromethyl chloroformate (diphosgene; 7.0 g, 35.3 mmol) in CH2Cl2 (100 mL) was added methyl 2-amino-5-tert-butylthiophene-3-carboxylate (5.0 g, 23.5 mmol) and pyridine (2.8 g, 35.3 mmol). The reaction mixture was heated to the reflux temp. for 10 h, filtered through a pad of silica, and concentrated under reduced pressure. The residue was dissolved in toluene and the resulting solution was concentrated under reduced pressure to give 3-methoxycarbonyl-5-tert-butylthiophene-2-isocyanate contaminated with a side product. 3-Methoxycarbonyl-5-tert-butylthiophene-2-isocyanate:1H-NMR (CDCl3) δ 1.34 (s, 9H), 3.88 (s, 3H), 6.95 (s, 1H). Side product: 1H-NMR (CDCl3) d 1.37 (s, 9H), 3.89 (s, 3H), 6.88 (s, 1H), 10.92 (br s, 1H). This material was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With methanol; potassium hydroxide; water at 80℃; for 6h; | [0630] The following description provides procedures that were used to prepare certain compounds according to Formula I and certain intermediates to prepare those compounds. [0631] The following provides a procedure used for the preparation of6-tert-butyl- l/f-thieno[2,3- J] [ 1 ,3]oxazine-2,4-dione or 6-tert-butyl- li7-thieno[3,2-J][l,3]oxazine-2,4-dione. or EPO [0632] To a vial containing methyl 5-tert-butyl-2-aminothiophene-3-carboxylate (0.643 g) in 1:1 methanol: H2O (6 mL) was added KOH (0.5069 g). The vial was capped and the mixture was stirred at 800C for 6 h. The solvent was removed under vacuum and the crude product was dissolved in water (50 mL) and transferred to a 100 mL round bottom flask. To the vigorously stirred aqueous solution was added at room temperature drop wise phosgene (2M toluene, 6 mL) over a 15 minute period. The resulting mixture was stirred at room temperature overnight. The crude reaction mixture was filtered; the precipitate was washed with water, dried and dissolved in ethyl acetate (10 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum to give 654.9 mg (96%) of the expected 6-tert-butyl-lH-thieno[2,3-J][l,3]oxazine-2,4-dione. |
Multi-step reaction with 2 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: 2-amino-5-tert-butylthiophene-3-carboxylic acid methyl ester With hydrogenchloride; sodium nitrite In water at 0℃; for 0.25h; Stage #2: With copper(ll) bromide In water at 100℃; for 2h; | Methyl 2-bromo-5-tert-butylthiophene-3-carboxylate (31) To a solution of 320 (2.0 g, 9.4 mmol) in concentrated HCl (3 mL) and water (3 mL) cooled to 0 °C (ice bath), was slowly added a solution of sodium nitrite (776 mg, 11.3 mmol) in water (2 mL). After stirring for 15 min, a solution of CuBr2 (2.51 g, 11.3 mmol) in water (2 mL) was added, and the reaction was heated at 100 °C for 2 h. The reaction mixture was cooled to room temperature and made basic with aqueous ammonium hydroxide. The resulting precipitate was filtered, dried and purified by silica flash column (1:1 DCM:hexanes) to give 1.48 g (57%) of 31. 1H NMR (400 MHz, acetone-d6) δ 7.12 (s, 1H), 3.83 (s, 3H), 1.37 (s, 9H). |
With hydrogenchloride; copper(I) bromide; sodium nitrite In water at 0 - 100℃; for 2.25h; | Bromide Preparation: To a solution of methyl 5-tert-butyl-3-aminothiophene-2-carboxylate (9.38 mmol) in a mixture of concentrated hydrochloric acid (3 mL) and water (3 mL) cooled to 0°C (ice bath) was slowly added an aqueous solution of sodium nitrite (11.25 mmol in 2 mL) and stirred for 15 minutes. A solution of cuprous bromide (11.3 mmol) in water (2 mL) was added, and the reaction was heated at 100°C for 2 hours. The reaction mixture was cooled down to room temperature and basified with aqueous ammonium hydroxide. The resulting precipitate was filtered, dried and purified by column chromatography (silica gel, 1 :1 dichloromethane:hexane) to afford the desired bromide product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanol; potassium hydroxide; water at 80℃; for 5h; | 123 EXAMPLE 1231 - { 5 -tert-Buty-3 - [4-(2-methoxymethoxyethyl)-5 -oxo- [ 1 ,4] diazep ane- 1 -carbonyl]thiophen-2-yl} -3-(2,3-dichloro-phenyl)urea [0805] 1H NMR (400 MHz, CD3OD): δ 8.02-7.96 (m, IH), 7.25-7.22(m, 2H), 6.59 (s, IH), 4.50 (s, 2H), 3.83-3.78 (m, 2H), 3.74 (t, J = 5.8 Hz, 2H), 3.70-3.65 (m, 2H), 3.58 (s, 4H), 3.28 (s, 3H), 2.81 (t, J = 5.7 Hz, 2H), 1.35 (s, 9H).[0806] Intermediate 5-tert-butyl-2-aminothiophene-3-carboxylic acid was prepared as follows for synthesis of Examples 123-153 and other suitable example: [0807] utyl-2-aminothiophene-3- carboxylate (1.0 mmol) in a 1 :1 methanol:water (3 mL) mixture was added potassium hydroxide (3 mmol). The vial was capped and the resulting mixture was stirred at 80° C for 5 hours. The reaction was cooled down to room temperature and the solvent removed under vacuum. The crude product was dissolved in water, acidified with IM HCl and the resulting mixture extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and solvent removed under vacuum. This material was used without further purification.[0808] Preparation of 5-tert-butyl-2-(3-(2,3- dichlorophenyl)ureido)thiophene-3 -carboxylic acid : EPO [0809] To a vial containing 5-ter?-butyl-2-aminothiophene-3- carboxylic acid (1 mmol) in THF (7 mL) was added 2,3- dichlorophenyl isocyanate (1 mmol). The vial was capped and the solution was stirred at 70 °C for 21 hours. The reaction was cooled down to room temperature and the solvent was removed under vacuum. The oil residue was treated with dichloromethane and the resulting mixture was left to stand at room temperature for 1 hour. The solids were filtered, washed with minimal amount of dichloromethane and dried under vacuum to yield the expected 5-tert-bntyl- 2-(3-(2,3-dichlorophenyl)ureido)thiophene-3-carboxylic acid (317.2 mg, 83%). Coupling with the appropriate amine was performed as described above for Example 1. | |
With water; potassium hydroxide In methanol at 80℃; for 4.5h; | 6-tert-butyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (5) General procedure: To a vial containing methyl 5-tert-butyl-2-aminothiophene-3-carboxylate, 3, (639.6 mg, 3 mmol) in 1:1 methanol:water (6 mL) was added KOH (496.4 mg, 8.8 mmol). The vial was capped and the mixture was stirred at 80 °C until no starting material was seen by TLC (4.5 h) The solvent was removed under vacuum, and the crude product was transferred to a 100 mL round bottom flask using water (50 mL). To the vigorously stirred aqueous solution was added phosgene (2M in toluene, 6 mL, 11 mmol) dropwise over a six minute period. The resulting mixture was stirred at room temperature overnight. The mixture was filtered, and the gummy solids were washed with water then dissolved in ethyl acetate (EtOAc). The organic solution was dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum to give 626.9 mg (93%) of 5 as a tan solid. The material was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 70℃; for 21h; | 123 EXAMPLE 1231 - { 5 -tert-Buty-3 - [4-(2-methoxymethoxyethyl)-5 -oxo- [ 1 ,4] diazep ane- 1 -carbonyl]thiophen-2-yl} -3-(2,3-dichloro-phenyl)urea [0805] 1H NMR (400 MHz, CD3OD): δ 8.02-7.96 (m, IH), 7.25-7.22(m, 2H), 6.59 (s, IH), 4.50 (s, 2H), 3.83-3.78 (m, 2H), 3.74 (t, J = 5.8 Hz, 2H), 3.70-3.65 (m, 2H), 3.58 (s, 4H), 3.28 (s, 3H), 2.81 (t, J = 5.7 Hz, 2H), 1.35 (s, 9H).[0806] Intermediate 5-tert-butyl-2-aminothiophene-3-carboxylic acid was prepared as follows for synthesis of Examples 123-153 and other suitable example: [0807] utyl-2-aminothiophene-3- carboxylate (1.0 mmol) in a 1 :1 methanol:water (3 mL) mixture was added potassium hydroxide (3 mmol). The vial was capped and the resulting mixture was stirred at 80° C for 5 hours. The reaction was cooled down to room temperature and the solvent removed under vacuum. The crude product was dissolved in water, acidified with IM HCl and the resulting mixture extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and solvent removed under vacuum. This material was used without further purification.[0808] Preparation of 5-tert-butyl-2-(3-(2,3- dichlorophenyl)ureido)thiophene-3 -carboxylic acid : EPO [0809] To a vial containing 5-ter?-butyl-2-aminothiophene-3- carboxylic acid (1 mmol) in THF (7 mL) was added 2,3- dichlorophenyl isocyanate (1 mmol). The vial was capped and the solution was stirred at 70 °C for 21 hours. The reaction was cooled down to room temperature and the solvent was removed under vacuum. The oil residue was treated with dichloromethane and the resulting mixture was left to stand at room temperature for 1 hour. The solids were filtered, washed with minimal amount of dichloromethane and dried under vacuum to yield the expected 5-tert-bntyl- 2-(3-(2,3-dichlorophenyl)ureido)thiophene-3-carboxylic acid (317.2 mg, 83%). Coupling with the appropriate amine was performed as described above for Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | P.2 Step 2 Step 2 Methyl 2-amino-5-tert-butylthiophene-3-carboxylate was condensed with 4-methylphenyl isocyanate in a manner similar to that described in Method A, Step 2 to produce N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N'-(4-methylphenyl)urea (0.029 g, 18%): mp 109-111° C.; 1H NMR (CDCl3) δ1.38 (s, 9H), 2.34 (s, 3H), 3.81 (s, 3H), 6.75 (bs, 1H), 6.82 (s, 1H), 7.16 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 10.37 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: methyl 2-amino-5-tert-butylthiophene-3-carboxylate With potassium hydroxide In methanol; water at 80℃; for 5h; Stage #2: phosgene In methanol; water; toluene at 20℃; | To a 1 L flask containing a mixture of methyl cyanoacetate (MW=99.08, 19.9 g, 201 mmol) and pre-ground sulfur (MW=32.06, 6.45 g, 201 mmol) in 100 mL DMF at r.t. was added TEA (MW=101.19, 10.9 g, 15 mL, 108 mmol, 0.535 eq). The mixture turns brown immediately upon TEA addition. The mixture was stirred until the sulfur had dissolved (ca 30 min). 3,3-dimethylbutraldehyde (MW=100.15, 20.15 g, 201 mmol, d 0.783, 25.2 mL) was added (5 mL DMF used to wash over remaining aldehyde) and the mixture was stirred at r.t. Precipitate formed shortly after aldehyde addition. At ca. 30 min the precipitate was dissolved by mild heating of the reaction with a heat gun, and the solution was stirred for 3 h at rt. Water (1 L) was added slowly to the reaction mixture to form cloudy yellow precipitate, and the mixture was stirred for 30 min. The cloudy orange solution (600 mL) was decanted, and the remaining solution with most of the precipitate was filtered. The solid was washed with water, dried, to give methyl 2-amino-5-tert-butylthiophene-3-carboxylate (MW=213.3) as a yellow solid (30 g, 70%) References: Patent: WO 98/52558To a 250 mL flask containing methyl 2-amino-5-tert-butylthiophene-3-carboxylate (45 g, 210 mmol) in 1:1 mixture of MeOH/water (600 mL) was added 45% KOH (75 g g, 600 mmol), and the reaction mixture was heated to 80° C. for 5 h. The methanol evaporated as the reaction proceeded. The solvent was removed in vacuo and the volume was brought to 600 mL with water and a small amount of insoluble material was filtered. To the vigorously stirred solution was added 20% phosgene in toluene (150 mL, 1.45 eq) over a period of 5 min. A gooey solid was formed during addition of phosgene. The mixture was stirred for 1 h at rt, then filtered and washed with water. The solid was dried in vacuo to provide 6-tert-butyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (39 g, 82%).A solution of 6-tert-butyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (43 gm, 190.9 mmol) in t-BuOH (635 mL) was brought to reflux (90° C.), stirring under N2 overnight. The reaction mixture was concentrated by rotovap to remove t-BuOH and the crude product was purified by trituration/recrystallization with ca. 6:1 Hexanes/Acetone in four batches. The solid was vacuum filtered and washed sparingly with ca. 12:1 Hexanes/Acetone to give 37.28 g of white solid, pure by LC. The mother liquor is concentrated to give 11.3 g of beige solid (80% pure by LC), which was recrystallized again to give an additional 3.66 g (95% purity).To a pressure vessel containing a DMF (120 mL) solution of 2-(tert-butoxycarbonyl)-5-tert-butylthiophene-3-carboxylic acid (11.91 gm, 39.78 mmol, 1 eq.) and 3,3-dimethylpiperazine-2-one (5.61 gm, 43.76 mmol, 1.1 eq.) was added TEA (6.11 mL, 43.83 mmol, 1.1 eq.) followed by HATU (16.60 gm, 43.66 mmol, 1.1 eq.). The vessel was sealed and the mixture stirred at 70° C. overnight.The reaction was returned to ambient, diluted with EtOAc, and washed with sat'd. aq. NaHCO3, H2O, and brine. The organics were separated and dried over MgSO4, filtered and concentrated to give an orange solid. The crude material was triturated/partially recrystallized 3× from hot Acetone/Hexanes (ca 1:2), and the solids are washed with hexane. The mother liquor is concentrated and the crystallization procedure is repeated a few times to give 10.28 gm of tert-butyl 5-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)thiophen-2-ylcarbamate (63% yield), as a white solid.To a flask containing tert-butyl 5-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)thiophen-2-ylcarbamate (11.27 gm, 27.52 mmol) was added 50% TFA/DCM (88 mL). The reaction was stirred for 45 min at r.t. and the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed 3× with 1N NaOH, water and brine. The organics were separated, dried over MgSO4, filtered and concentrated. The product precipitated from the mother liquor on the rotovap during the concentration of the organic portion, was filtered and washed copiously with Hexanes to give to off white solid 4-(2-amino-5-tert-butylthiophene-3-carbonyl)-3,3-dimethylpiperazine-2-one.On standing overnight, additional product was observed in the reserved aq. portion. The solid is filtered under vacuum and washed sequentially with water, and Hexanes mixed with a small amount of acetone. The combined off-white solids were dried under vacuum to give a total of 7.27 gm, 85% yield of highly pure 4-(2-amino-5-tert-butylthiophene-3-carbonyl)-3,3-dimethylpiperazine-2-one.To a RB flask containing triphosgene (1.776 g, 0.34 equiv.) in 35 mL DCM, cooled in an ice bath, was added a solution of 4-methyl-3-(5-(morpholinomethyl)pyridin-2-yl)aniline (4.989 g, 1 equiv.) and TEA (2.45 mL, 1 equiv.) in 15 mL DCM over 3 min. An additional 5 mL DCM was used to wash over any remaining material. The ice bath was removed and the mixture was allowed to stir at room temperature for 15 minutes to give a solution of the carbamoyl chloride.To the solution of carbamoyl chloride (1.07 equiv.) in 55 mL DCM, cooled in an ice bath, was added a mixture of ert-butyl 5-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)thiophen-2-ylcarbamate (5.092 g, 1 equiv.) in 50 mL DCM over 3 minutes. A precipitate formed. An additional 10 mL DCM was used to wash over any remaining material (7 mL/mmol DCM total). The ice bath was removed and the solution was stirred at r.t. At 3 min, TEA was added slowly dropwise. After 20.5 h, the reaction volume was reduced by half in vacuo then the mixture was filtered. The solids were washed with a minimal amount of DCM. The solids were taken up in DCM then the mixture was heated while adding MeOH until solids dissolved. The solution was quickly washed with 1M NaOH before solids reformed. The aqueous layer was extracted with DCM (×1). Upon standing, solids precipitated out of the organic layer. More MeOH and heating were applied to dissolve solids then the organic layer was dried over Na2SO4, filtered and solvent removed in vacuo to give 6.984 g (69%) of 1-(5-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)thiophen-2-yl)-3-(4-methyl-3-(5-(morpholinomethyl)pyridin-2-yl)phenyl)urea.The original filtrate from the reaction was washed with 1M NaOH. Remaining product can then be removed by crystallization from DCM or chromatography as 0.5 g or more of product may remain in the filtrate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | at 210℃; for 2.5h; | |
at 210℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: water; sodium hydroxide / 0.5 h / 150 °C / Microwave irradiation 1.2: 2 h / 20 °C 2.1: triethylamine / acetonitrile / 0.5 h / 100 °C / Microwave irradiation 3.1: 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: water; sodium hydroxide / 0.5 h / 150 °C / Microwave irradiation 1.2: 2 h / 20 °C 2.1: triethylamine / acetonitrile / 0.5 h / 100 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: water; sodium hydroxide / 0.5 h / 150 °C / Microwave irradiation 1.2: 2 h / 20 °C 2.1: triethylamine / acetonitrile / 0.5 h / 100 °C / Microwave irradiation 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: methyl 2-amino-5-tert-butylthiophene-3-carboxylate With water; sodium hydroxide at 150℃; for 0.5h; Microwave irradiation; Stage #2: bis(trichloromethyl) carbonate In toluene at 20℃; for 2h; | Compound 29: 6-tert-butyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione: compound 27 (63 mg, 0.30 mmol), 2-aminothiophene and 0.6 mL of 1 M NaOH aqueous solution were combined in a conical bottom microwave vial. The slurry was irradiated under microwave at 150 °C for 30 min. Triphosgene(44 mg, 0.15 mmol) in 1 mL toluene was added slowly with vigorous stirring. The resulting mixture was allowed to stir at rt for 2 h. The precipitate was filtered and washed successively with water, hexane and ether, then dried invacuo to give compound 29 with 83% yield. m/z ES+ = 226.09, calcd 226.05; 1H NMR δ ppm 12.60 (s, 1H), 6.92 (s, 1H), 1.23 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: tetrahydrofuran / 19 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: tetrahydrofuran / 24 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: 1,4-dioxane / 25 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: 48 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: 1,4-dioxane / 25 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: 1,4-dioxane / 25 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: 1,4-dioxane / 25 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3.1: sodium hydroxide / water; ethyl acetate / 0.5 h / 5 - 15 °C 3.2: 5 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; N,N-dimethyl-formamide / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: 1,4-dioxane / 25 h / 80 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: 1,4-dioxane / 25 h / 80 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: 1,4-dioxane / 25 h / 80 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; N,N-dimethyl-formamide / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; N,N-dimethyl-formamide / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; N,N-dimethyl-formamide / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3: toluene / 0.67 h / 80 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; N,N-dimethyl-formamide / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: tetrahydrofuran / 19 h / 70 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; N,N-dimethyl-formamide / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: tetrahydrofuran / 24 h / 70 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; N,N-dimethyl-formamide / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3.1: sodium hydroxide / water; ethyl acetate / 0.5 h / 5 - 15 °C 3.2: 5 - 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3.1: sodium hydroxide / water; ethyl acetate / 0.5 h / 5 - 15 °C 3.2: 5 - 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3: tetrahydrofuran / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3: tetrahydrofuran / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: 48 h / 70 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3: toluene / 0.67 h / 80 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3: toluene / 0.67 h / 80 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3: toluene / 0.67 h / 80 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C 3: tetrahydrofuran / 25 h / 70 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: water; potassium hydroxide / methanol / 4.5 h / 80 °C 2: water; toluene / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2-ethoxy-ethanol Reflux; | 2 Example 2 Example 2 Synthesis of the intermediate (II) (to be illustrated by taking the synthesis of 6-tert-butyl-4-chloro-thieno[2,3-d]pyrimidine as an example) 2.13g (10mmol) of methyl 3-amino-5-tert-butyl thiophen-2-carboxylate was added in a 250ml single-necked round-bottom flask. Then 100ml 2-ethoxyethanol and 2.14g (20mmol) formamidine acetate were added. The system is refluxed und stirring. After the completion of the reaction monitored by TLC, the reaction mixture was refluxed under stirring, the system was cooled down, distilled under reduced pressure until the residual ethylene glycol monomethyl ether was 30 ml, and said system was refrigerated for several hours so that a great unmber of solids was precipited. The precipitation was filtered out and the filter cake was washed with cold ethyl ether several times, and dried under vacuum. The dried filter cake was directly used in the next reaction. |
Tags: 216574-71-9 synthesis path| 216574-71-9 SDS| 216574-71-9 COA| 216574-71-9 purity| 216574-71-9 application| 216574-71-9 NMR| 216574-71-9 COA| 216574-71-9 structure
[ 65416-85-5 ]
Ethyl 2-amino-5-isopropylthiophene-3-carboxylate
Similarity: 0.96
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 :