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[ CAS No. 4651-98-3 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 4651-98-3
Chemical Structure| 4651-98-3
Chemical Structure| 4651-98-3
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Product Details of [ 4651-98-3 ]

CAS No. :4651-98-3 MDL No. :MFCD01070843
Formula : C7H9NO2S Boiling Point : -
Linear Structure Formula :- InChI Key :PLLLBSPBFALBFB-UHFFFAOYSA-N
M.W : 171.22 Pubchem ID :2759773
Synonyms :

Safety of [ 4651-98-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P362-P403+P233-P405-P501 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 4651-98-3 ]

* 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.

  • Downstream synthetic route of [ 4651-98-3 ]

[ 4651-98-3 ] Synthesis Path-Downstream   1~51

  • 1
  • [ 616-45-5 ]
  • [ 4651-98-3 ]
  • [ 126636-92-8 ]
YieldReaction ConditionsOperation in experiment
97% With trichlorophosphate In dichloromethane for 0.166667h; Heating;
  • 2
  • [ 1943-83-5 ]
  • [ 4651-98-3 ]
  • [ 118235-85-1 ]
YieldReaction ConditionsOperation in experiment
97% In ethyl acetate for 2h; Heating;
  • 5
  • [ 4651-98-3 ]
  • [ 32852-81-6 ]
  • [ 179338-12-6 ]
YieldReaction ConditionsOperation in experiment
89% Stage #1: (3-phenoxyphenyl)acetic acid With thionyl chloride In 1,4-dioxane at 78℃; for 3h; Stage #2: 2-amino-4-methylthiophene-3-carboxylic acid methyl ester In 1,4-dioxane at 70 - 98℃;
  • 6
  • [ 4651-98-3 ]
  • 2-chloro-4-hydroxy-3-methyl-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 91 percent / dioxane / 98 °C 2: 89 percent / N-chlorosuccinimide / CHCl3 / Heating 3: 46 percent / KN(Si(CH3)3)2 / tetrahydrofuran; toluene / -65 - 20 °C
  • 7
  • [ 4651-98-3 ]
  • 2-Bromo-4-hydroxy-3-methyl-5-phenyl-7H-thieno[2,3-b]pyridin-6-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 91 percent / dioxane / 98 °C 2: 95 percent / N-bromosuccinimide / CHCl3 / Heating 3: 62 percent / KN(Si(CH3)3)2 / tetrahydrofuran; toluene / -65 - 20 °C
  • 8
  • [ 4651-98-3 ]
  • [ 179337-81-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 91 percent / dioxane / 98 °C 2: 89 percent / N-chlorosuccinimide / CHCl3 / Heating
  • 9
  • [ 4651-98-3 ]
  • [ 179338-05-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 91 percent / dioxane / 98 °C 2: 95 percent / N-bromosuccinimide / CHCl3 / Heating
  • 10
  • [ 4651-98-3 ]
  • 4-hydroxy-3-methyl-5-(3-phenoxy-phenyl)-7<i>H</i>-thieno[2,3-<i>b</i>]pyridin-6-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: SOCl2 / dioxane / 3 h / 78 °C 1.2: 89 percent / dioxane / 70 - 98 °C 2.1: 54 percent / KN(Si(CH3)3)2 / tetrahydrofuran; toluene / -65 - 10 °C
  • 11
  • [ 4651-98-3 ]
  • 2-chloro-4-hydroxy-3-methyl-5-(3-phenoxy-phenyl)-7<i>H</i>-thieno[2,3-<i>b</i>]pyridin-6-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: SOCl2 / dioxane / 3 h / 78 °C 1.2: 89 percent / dioxane / 70 - 98 °C 2.1: 94 percent / N-chlorosuccinimide / CHCl3 / Heating 3.1: 44 percent / KN(Si(CH3)3)2 / tetrahydrofuran; toluene / -65 - 10 °C
  • 12
  • [ 4651-98-3 ]
  • [ 179338-07-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: SOCl2 / dioxane / 3 h / 78 °C 1.2: 89 percent / dioxane / 70 - 98 °C 2.1: 94 percent / N-chlorosuccinimide / CHCl3 / Heating
  • 13
  • [ 4651-98-3 ]
  • 4-hydroxy-3-methyl-5-(2-thienyl)thieno[2,3-b]pyridin-6(7H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 91 percent / dioxane / 98 °C 2: 79 percent / KN(Si(CH3)3)2 / tetrahydrofuran; toluene / -65 - 20 °C
Multi-step reaction with 2 steps 1: 91 percent / dioxane / Heating 2: 79 percent / KN[Si(CH3)3]2 / tetrahydrofuran; toluene / -70 - 20 °C
  • 14
  • [ 4651-98-3 ]
  • 4-hydroxy-3-methyl-5-phenylthieno[2,3-b]pyridin-6(7H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 91 percent / dioxane / 98 °C 2: 45 percent / KN(Si(CH3)3)2 / tetrahydrofuran; toluene / -65 - 20 °C
Multi-step reaction with 2 steps 1: 91 percent / dioxane / Heating 2: 45 percent / KN[Si(CH3)3]2 / tetrahydrofuran; toluene / -70 - 20 °C
  • 15
  • [ 4651-98-3 ]
  • 2-(3-allyloxy-2-hydroxy-propylsulfanyl)-3,5-dimethyl-3<i>H</i>-thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dimethylsulfoxide / 20 h / 100 °C 2.1: P-BEMP / dimethylsulfoxide; dimethylformamide / 25 - 50 °C 2.2: dimethylsulfoxide / 20 °C
  • 16
  • [ 4651-98-3 ]
  • 3-allyl-2-(3-allyloxy-2-hydroxy-propylsulfanyl)-5-methyl-3<i>H</i>-thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dimethylsulfoxide / 20 h / 100 °C 2.1: P-BEMP / dimethylsulfoxide; dimethylformamide / 25 - 50 °C 2.2: dimethylsulfoxide / 20 °C
  • 17
  • [ 4651-98-3 ]
  • 2-(3-allyloxy-2-hydroxy-propylsulfanyl)-3-(2-methoxy-ethyl)-5-methyl-3<i>H</i>-thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dimethylsulfoxide / 20 h / 100 °C 2.1: P-BEMP / dimethylsulfoxide; dimethylformamide / 25 - 50 °C 2.2: dimethylsulfoxide / 20 °C
  • 18
  • [ 4651-98-3 ]
  • 2-(3-allyloxy-2-hydroxy-propylsulfanyl)-3-(4-methoxy-phenyl)-5-methyl-3<i>H</i>-thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dimethylsulfoxide / 20 h / 100 °C 2.1: P-BEMP / dimethylsulfoxide; dimethylformamide / 25 - 50 °C 2.2: dimethylsulfoxide / 20 °C
  • 19
  • [ 4651-98-3 ]
  • 2-(3-allyloxy-2-hydroxy-propylsulfanyl)-3-(3-chloro-benzyl)-5-methyl-3<i>H</i>-thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dimethylsulfoxide / 20 h / 100 °C 2.1: P-BEMP / dimethylsulfoxide; dimethylformamide / 25 - 50 °C 2.2: dimethylsulfoxide / 20 °C
  • 20
  • [ 4651-98-3 ]
  • 2-(3-allyloxy-2-hydroxy-propylsulfanyl)-3-(3,4-dichloro-phenyl)-5-methyl-3<i>H</i>-thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dimethylsulfoxide / 20 h / 100 °C 2.1: P-BEMP / dimethylsulfoxide; dimethylformamide / 25 - 50 °C 2.2: dimethylsulfoxide / 20 °C
  • 21
  • [ 4651-98-3 ]
  • 2-(3-allyloxy-2-hydroxy-propylsulfanyl)-5-methyl-3-(2-morpholin-4-yl-ethyl)-3<i>H</i>-thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dimethylsulfoxide / 20 h / 100 °C 2.1: P-BEMP / dimethylsulfoxide; dimethylformamide / 25 - 50 °C 2.2: dimethylsulfoxide / 20 °C
  • 22
  • [ 4651-98-3 ]
  • 2-(3-allyloxy-2-hydroxy-propylsulfanyl)-3-benzo[1,3]dioxol-5-ylmethyl-5-methyl-3<i>H</i>-thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dimethylsulfoxide / 20 h / 100 °C 2.1: P-BEMP / dimethylsulfoxide; dimethylformamide / 25 - 50 °C 2.2: dimethylsulfoxide / 20 °C
  • 23
  • [ 4651-98-3 ]
  • [ 60100-09-6 ]
  • 5-methylthieno[2,3-d]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
at 220℃; for 0.333333h; Microwave irradation; 34 Formamide (4 ml) was added to methyl 2-amino-4-methyl-thiophene-3-carboxylate (400 mg), and the mixture was stirred with a microwave reactor at 220°C for 20 min. The above reaction was carried out using the same amount of starting materials by additional two batches. The reaction mixtures were cooled to room temperature and were combined together. Water was added thereto, and the organic layer was extracted with methanol/chloroform and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue (1.35 g) as such was used in the next reaction without further purification. A part (300 mg) of the residue was suspended in diisopropylethylamine (1.57 ml). Phosphorus oxychloride (0.84 ml) was added to the suspension, and the mixture was stirred at 100°C for one hr. The solvent was removed by distillation under the reduced pressure. Water was then added to the reaction mixture under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution. The organic layer was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give 4-chloro-5-methyl-thieno[2,3-d]pyrimidine (231 mg, yield 87%) (2 steps).
  • 24
  • [ 4651-98-3 ]
  • [ 87-13-8 ]
  • diethyl (3-methoxycarbonyl-4-methylthienyl)aminomethylenemalonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
R.23 REFERENCE EXAMPLE 23 REFERENCE EXAMPLE 23 Reaction of methyl 2-amino-4-methylthiophene-3-carboxylate with diethyl ethoxymethylenemalonate in a manner similar to that used in Reference Example 10 yields diethyl (3-methoxycarbonyl-4-methylthienyl)aminomethylenemalonate as crystals melting at 105.5°-106°C.
  • 25
  • 5-nitro-furan-2-iminocarboxylic acid ether ester [ No CAS ]
  • [ 4651-98-3 ]
  • 5-methyl-2-(5'-nitro-2'-furyl)-4-hydroxy-thieno[2,3-d]pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
In <i>N</i>-methyl-acetamide A.a 2-(5'-Nitro-2'-furyl)-4-hydroxy-thieno[2,3-d]pyrimidine a. 5-Methyl-2-(5'-nitro-2'-furyl)-4-hydroxy-thieno[2,3-d]pyrimidine, m. p. >300°C. (from dimethylformamide), from 5-nitro-furan-2-iminocarboxylic acid ether ester and 2-amino-4-methyl-thiophene-3-carboxylic acid methyl ester.
  • 26
  • [ 110-89-4 ]
  • 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane [ No CAS ]
  • [ 105-34-0 ]
  • [ 4651-98-3 ]
YieldReaction ConditionsOperation in experiment
In diethyl ether; ethanol E.a 4-Chloro-5-Methylthieno[2,3-d]pyrimidine a) To 17 g of 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane and 17 g of methyl cyanoacetate in 170 mL of ethanol was added 14.6 g of piperidine in portions. The mixture was heated to 50°C with stirring for one hour. The mixture was then concentrated, and treated with diethyl ether. The solids were collected, and washed with cold diethyl ether to give 18.1 g of methyl 2-amino-4-methylthiophene-3-carboxylate.
  • 27
  • [ 4651-98-3 ]
  • methyl 2-formamido-4-methylthiophene-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With formic acid; acetic anhydride In diethyl ether E.b 4-Chloro-5-Methylthieno[2,3-d]pyrimidine b) To 40 mL of acetic anhydride was slowly added 40 mL of 97% formic acid while holding the temperature at 25-30°C with mild ice cooling. Then 24 g of methyl 2-amino-4-methylthiophene-3-carboxylate was added, and the mixture was stirred for hour hours at room temperature. The mixture was then concentrated by evaporation, and the residue was treated with diethyl ether and filtered to give 26.2 g of methyl 2-formamido-4-methylthiophene-3-carboxylate. M.P. 78-81°C.
  • 28
  • [ 4651-98-3 ]
  • [ 108-24-7 ]
  • [ 4651-80-3 ]
YieldReaction ConditionsOperation in experiment
95% With Mg(ClO4)2*2H20 at 140℃; for 3h;
  • 29
  • [ 4651-98-3 ]
  • [ 110-13-4 ]
  • [ 1009639-27-3 ]
YieldReaction ConditionsOperation in experiment
42% With bismuth (III) nitrate pentahydrate In dichloromethane at 20℃; for 24h;
  • 33
  • [ 1003-31-2 ]
  • [ 4651-98-3 ]
  • C11H8N2OS2 [ No CAS ]
  • 35
  • [ 4651-98-3 ]
  • [ 19673-94-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: 1-methyl-pyrrolidin-2-one / 24 h / 135 °C / Inert atmosphere 2.1: acetic acid; bromine / 3 h / 20 °C 3.1: trichlorophosphate / 2 h / Reflux 4.1: hydrogenchloride / tetrahydrofuran / 0.5 h 4.2: 24 h / 110 °C / Inert atmosphere
  • 36
  • [ 4651-98-3 ]
  • 6-bromo-5-methyl-4-(pyridin-4-yl)thieno[2,3-d]pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: 1-methyl-pyrrolidin-2-one / 24 h / 135 °C / Inert atmosphere 2.1: acetic acid; bromine / 3 h / 20 °C 3.1: trichlorophosphate / 2 h / Reflux 4.1: hydrogenchloride / tetrahydrofuran / 0.5 h 4.2: 24 h / 110 °C / Inert atmosphere 5.1: potassium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water / 16 h / 100 °C / Inert atmosphere
  • 37
  • [ 4651-98-3 ]
  • N-(2-methoxy-5-(5-methyl-4-(pyridin-4-yl)thieno[2,3-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: 1-methyl-pyrrolidin-2-one / 24 h / 135 °C / Inert atmosphere 2.1: acetic acid; bromine / 3 h / 20 °C 3.1: trichlorophosphate / 2 h / Reflux 4.1: hydrogenchloride / tetrahydrofuran / 0.5 h 4.2: 24 h / 110 °C / Inert atmosphere 5.1: potassium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water / 16 h / 100 °C / Inert atmosphere 6.1: potassium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water / 5 h / 100 °C / Inert atmosphere
  • 38
  • [ 4651-98-3 ]
  • 6-bromo-5-methylthieno[2,3-d]pyrimidin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1-methyl-pyrrolidin-2-one / 24 h / 135 °C / Inert atmosphere 2: acetic acid; bromine / 3 h / 20 °C
  • 39
  • [ 4651-98-3 ]
  • [ 19673-93-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-methyl-pyrrolidin-2-one / 24 h / 135 °C / Inert atmosphere 2: acetic acid; bromine / 3 h / 20 °C 3: trichlorophosphate / 2 h / Reflux
  • 40
  • [ 4651-98-3 ]
  • [ 1070-34-4 ]
  • methyl 2-(3-(3-ethoxy-3-oxopropyl)ureido)-4-methylthiophene-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
55.3% To a solution of 4-ethoxy-4-oxobutanoic acid (713 mg, 5.4 mmol) in toluene was added diphenylphosphoryl azide (1.48 g, 5.4 mmol) followed by TEA (600 mg, 5.94 mmol). The reaction was stirred at RT for 30 min then methyl 2-amino-4-methylthiophene-3-carboxylate (500 mg, 2.7 mmol) was added. The reaction was heated at reflux for 4 h, cooled to RT then diluted with EA (20 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried with Na2SC>4 and concentrated to a residue which was purified by chromatography eluted with DCM/MeOH (50: 1) to give 2-(3-(3-ethoxy-3-oxopropyl)ureido)-4-methylthiophene-3- carboxylate (470 mg, 55.3% yield) as a yellow solid. LCMS: MH+315 and TR= 1.589 min.
  • 41
  • [ 67-64-1 ]
  • [ 105-34-0 ]
  • [ 4651-98-3 ]
YieldReaction ConditionsOperation in experiment
13.6% With morpholine; sulfur In N,N-dimethyl-formamide at 50℃; 38.a a) 2-amino-4-methylthiophene-3-carboxylic acid methyl ester (38a) The sulfur powder (640.0mg, 20.0mmol) to a single-neck flask,4 mL of DMF was added,Were successively added methyl cyanoacetate (1.98g, 20.0mmol),Morpholine (1.74 g, 20.0 mmol),The solution was dark brown,Acetone (4.62 g, 80.0 mmol) was added,50 ° C overnight.After completion of the reaction, the mixture was cooled to room temperature,Add appropriate amount of water,Ethyl acetate was extracted three times,The combined organic phases were washed with saturated brine,Dried over anhydrous magnesium sulfate,The crude product was distilled under reduced pressure.Separation and purification by column chromatography,To give a pale yellow solid.Yield: 13.6%
13.6% With morpholine; sulfur In N,N-dimethyl-formamide at 50℃; Inert atmosphere;
  • 42
  • [ 4651-98-3 ]
  • [ 57-13-6 ]
  • [ 75860-79-6 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; In water; at 200℃; for 5h;Reflux; The compound 38a (500.0 mg, 2.90 mmol),Urea (1.37 g, 22.80 mmol) in a single-necked flask,200 reaction 2h,After cooling,Add 8% aqueous solution of 20% NaOH,Heating reflux 5h,Hot filter,Remove insoluble matter,Ice bath,With 2N HCl adjusted to pH = 3,Precipitation of solids,Filtration to obtain brown crude product.Yield: 97.1%
  • 43
  • [ 4651-98-3 ]
  • [ 32315-10-9 ]
  • [ 109666-88-8 ]
YieldReaction ConditionsOperation in experiment
61% Stage #1: 2-amino-4-methylthiophene-3-carboxylic acid methyl ester With water; potassium hydroxide In water at 90℃; for 2h; Stage #2: bis(trichloromethyl) carbonate In water; toluene at 0 - 20℃; for 2.16667h; 5-methyl-lH-thieno[2.3-dl[1.31oxazine-2.4-dione 5-methyl-lH-thieno[2.3-dl[1.31oxazine-2.4-dione ) in H20 (20 mL) was added methyl 2- (1.0 g, 5.84 mmol) at rt. The resulting reaction was heated to 90°C for 2 h and then cooled to 0°C. A solution of triphosgene (0.866 g, 2.92 mmol) in PhMe (12 mL) was added dropwise over 10 min. The resulting solution was gradually warmed to rt and stirred for 2 h. The resulting solid was filtered, washed with H20 and dried to afford the title compound as a light pink solid (0.65 g, 61%). NMR (400 MHz, CDsOD) δ 6.65 (d, J=2 Ηζ,ΙΗ), 2.42 (d, J=2 Hz, 3H); MS ESI [M + H]+ 184.0, calcd for
  • 44
  • [ 4651-98-3 ]
  • [ 72784-42-0 ]
  • C13H16N2O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% Stage #1: 2-amino-4-methylthiophene-3-carboxylic acid methyl ester With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; Stage #2: methyl 1-aminocyclopropane-1-carboxylate hydrochloride With triethylamine In dichloromethane at 20℃; 1.5 the fifth stepDissolve 2-amino-4-methyl-thiophene-3-carboxylic acid methyl ester 1f (17.12g, 100mmol, 1.0eq) in dichloromethane (200mL), and add carbonyldiimidazole (17.84g, 110 mmol, 1.1 eq), react overnight at room temperature. TLC showed that compound If completely disappeared. Triethylamine (12.14g, 120mmol, 1.2eq) was added to the reaction solution, and stirred at room temperature for 1 hour, then 1-aminocyclopropanecarboxylic acid methyl ester hydrochloride was added for 1h (18.19g, 120mmol, 1.2eq), and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column, eluting with petroleum ether: ethyl acetate = 90:10 to 0: 100 to obtain compound 1i (21.23 g, yield: 68%) as an off-white solid.
  • 45
  • [ 4651-98-3 ]
  • [ 32315-10-9 ]
  • methyl 3-amino-1-methylcyclobutanecarboxylate [ No CAS ]
  • ethyl 2-(3-(3-(methoxycarbonyl)-3-methylcyclobutyl)ureido)-4-methylthiophene-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% Stage #1: 2-amino-4-methylthiophene-3-carboxylic acid methyl ester; bis(trichloromethyl) carbonate With triethylamine In dichloromethane at -5 - 20℃; for 1h; Stage #2: methyl 3-amino-1-methylcyclobutanecarboxylate In dichloromethane at 20℃; 3.4 Step 4:
Preparation of Ethyl 2-(3-(3-(methoxycarbonyl)-3-methylcyclobutyl)ureido)-4-methylthiophene-3-carboxylate
In a 1000 mL single-necked flask, triphosgene (9.56 g, 32.2 mmol) was dissolved in anhydrous dichloromethane (70 mL) and the mixture was put at -5° C. Methyl 2-amino-4-methylthiophene-3-carboxylate (5.97 g, 32.2 mmol) and triethylamine (13.0 g, 128.8 mmol) were dissolved in anhydrous dichloromethane (140 mL), which was added dropwise to the above solution of triphosgene in dichloromethane. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 h, and then methyl 3-amino-1-methylcyclobutylcarboxylate (4.6 g, 32.2 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated, mixed with water (250 mL) and extracted with ethyl acetate (250 mL*3). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and subjected to silica-gel column chromatography (dichloromethane:methanol=40:1) to obtain 5.2 g of the title compound with a yield of 46%. MS (ESI) m/z 355.1 [M+H]+.
  • 46
  • [ 4651-98-3 ]
  • [ 24424-99-5 ]
  • methyl 2-[(tert-butoxy)carbonyl]amino-4-methylthiophene-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
56.8% With dmap In 1,4-dioxane for 16h; Reflux; 122.A (1305) (1306) [00767] Step A: DMAP (642 19 mg, 5.26 mmol) was added to a stirred solution of compound 102 (9.0 g, 52.56 mmol) and B0C2O (13.77 g, 63.08 mmol) in 108 mL of dioxane, and refluxed overnight. After 16 h reaction was complete (monitored by NMR). The mixture was concentrated and purified by column chromatography (eluted by Hex:EtOAc 10: 1). The product 143 was obtained as
56.8% With dmap In 1,4-dioxane for 16h; Reflux; 31.A [00707] Step A: Methyl 2-[(tert-butoxy)carbonyl]amino-4-methylthiophene-3-carboxylate [00708] DMAP (642.19 mg, 5.26 mmol) was added to a stirred solution of methyl 2-amino-4-methylthiophene-3-carboxylate 31A (9.0 g, 52.56 mmol) and Boc2O (13.77 g, 63.08 mmol) in 108 mL of dioxane. The mixture was refluxed overnight. After 16 h reaction was complete (monitored by NMR). The mixture was concentrated under reduced pressure and purified by column chromatography (Eluted by Hex:EtOAc 10:1). Methyl 2-[(tert-butoxy)carbonyl]amino-4-methylthiophene-3-carboxylate 31B (8.1 g, 29.85 mmol, 56.8% yield) was obtained as white solid.
56.8% With dmap In 1,4-dioxane for 16h; Reflux; 31.A [00707] Step A: Methyl 2-[(tert-butoxy)carbonyl]amino-4-methylthiophene-3-carboxylate [00708] DMAP (642.19 mg, 5.26 mmol) was added to a stirred solution of methyl 2-amino-4-methylthiophene-3-carboxylate 31A (9.0 g, 52.56 mmol) and Boc2O (13.77 g, 63.08 mmol) in 108 mL of dioxane. The mixture was refluxed overnight. After 16 h reaction was complete (monitored by NMR). The mixture was concentrated under reduced pressure and purified by column chromatography (Eluted by Hex:EtOAc 10:1). Methyl 2-[(tert-butoxy)carbonyl]amino-4-methylthiophene-3-carboxylate 31B (8.1 g, 29.85 mmol, 56.8% yield) was obtained as white solid.
  • 47
  • [ 4651-98-3 ]
  • [ 45515-45-5 ]
  • C11H10N4OS [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With potassium <i>tert</i>-butylate In methanol at 20℃; for 16h; Reflux; 101.A General procedure: [00716] Step A: General procedure: To a stirred solution of methyl 2-amino-4- methyithiophene-3-carboxylate 102 (1 eq.) in dry methanol (20 mL) was added the appropriate corresponding cyanoimidazole (1.5 eq.) at room temperature and then potassium / -butylate (3 eq.) was added portion-wise. The reaction mixture was refluxed for 16 h, cooled to room temperature and the precipitate (potassium salt of the product) was filtered. The precipitate was dissolved in wter (50 mL), acidified by acetic acid (10 mL) and stirred at room temperature for 15 min. The precipitate was filtered, washed with water and air dried. Starting with (1229) cyanoimidazole l-methyl-lfT-imidazole-2-carbonitrile 91 gave compound 103 as white solid (1.2 g, 69% yield).
  • 48
  • [ 4651-98-3 ]
  • 3,4‐dimethylthiophen‐2‐amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 75℃; for 2.5h; 1 Step 1.3,4-Dimethylthiophen-2-amine o a solution of lithium aluminium hydride (122 mg, 3.21 mmol) in THF (10 ml) cooled to 0° C was added dropwise a solution of methyl 2-amino-4-methyl-thiophene-3-carboxylate (250 mg, 1.46 mmol) in THF (10 ml). The solution was stirred at 0° C for 30 min, then heated at 75° C for 2 h. The reaction was cooled and quenched by addition of water (0.12 ml), followed by 15 % aq. NaOH (0.12 ml). The resulting mixture was filtered and the filtrate concentrated under reduced pressure to give 3,4-dimethylthiophen-2-amine as a yellow oil. This was used directly without purification.1H NMR (400 MHz, chloroform-d) d 6.19 (s, 1H), 2.08 (s, 3H), 1.96 (s, 3H).
  • 49
  • [ 29745-44-6 ]
  • [ 4651-98-3 ]
  • methyl 4-methyl-2-(picolinamido)thiophene-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.54 g With triethylamine In dichloromethane at 20℃; for 1h; 1.37.2 Step 1 and Step 2: To a solution of picolinic acid (1.23 g, 10.0 mmol) in (COCl)2 (10 mL) was added 2 drops of DMF. The resulting mixture was stirred at room temperature for 0.5 hr. Then the mixture was concentrated in vacuum to give picolinoyl chloride as a white solid, which was dissolved in dry DCM (40 mL). Then methyl 2-amino-4-methylthiophene-3-carboxylate (2.05 g, 12.0 mmol) was added, followed by TEA (3.03 g, 30.0 mmol). The resulting mixture was stirred at room temperature for 1 hr. The reaction was monitored by LCMS and TLC. Then the reaction mixture was concentrated in vacuum to give a residue, which was purified by silica gel column (DMC) to afford methyl 4-methyl-2-(picolinamido)thiophene-3-carboxylate (2.54 g, yield: 92%) as a brown solid.
  • 50
  • [ 4651-98-3 ]
  • [ 120-92-3 ]
  • methyl 2-(cyclopentylamino)-4-methylthiophene-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
62.9% With sodium tris(acetoxy)borohydride; glacial acetic acid In 1,2-dichloro-ethane at 20℃; for 18h; 1.1 Step 1 : Methyl 2-(cy cl opentylamino)-4-methylthiophene-3 -carboxylate NaBH(OAc)3 (18.382 g, 86.7 mmol, 2.50 equiv.) was added portionwise to a solution of methyl 2-amino-4-methylthiophene-3-carboxylate (5.940 g, 34.7 mmol, 1.00 equiv.), cyclo- pentanone (7.556 g, 86.7 mmol, 2.50 equiv.), and acetic acid (5.209 g, 86.7 mmol, 2.50 equiv.) in DCE (120 mL). The resulting suspension was stirred at ambient temperature for 18 h. The reaction mixture was slowly poured over 10% Na2CO3 solution (200 mL) and stirred until gas evolution ceased. The organic layer was separated, and the aqueous layer extracted with DCM (50 mL x 3). The combined organic phase was washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (80 g) (0 - 5% MTBE in heptanes) to give the title compound (5.221 g, 21.8 mmol, 62.9% yield) as colorless oil. Rf = 0.6 (10% MTBE in heptanes). LCMS calc, for C12H18NO2S [M+H]+: m/z = 240.1; Found: 240.0.
62.9% With sodium tris(acetoxy)borohydride; glacial acetic acid In 1,2-dichloro-ethane at 20℃; for 18h; 1.1 Step 1 : Methyl 2-(cy cl opentylamino)-4-methylthiophene-3 -carboxylate NaBH(OAc)3 (18.382 g, 86.7 mmol, 2.50 equiv.) was added portionwise to a solution of methyl 2-amino-4-methylthiophene-3-carboxylate (5.940 g, 34.7 mmol, 1.00 equiv.), cyclo- pentanone (7.556 g, 86.7 mmol, 2.50 equiv.), and acetic acid (5.209 g, 86.7 mmol, 2.50 equiv.) in DCE (120 mL). The resulting suspension was stirred at ambient temperature for 18 h. The reaction mixture was slowly poured over 10% Na2CO3 solution (200 mL) and stirred until gas evolution ceased. The organic layer was separated, and the aqueous layer extracted with DCM (50 mL x 3). The combined organic phase was washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (80 g) (0 - 5% MTBE in heptanes) to give the title compound (5.221 g, 21.8 mmol, 62.9% yield) as colorless oil. Rf = 0.6 (10% MTBE in heptanes). LCMS calc, for C12H18NO2S [M+H]+: m/z = 240.1; Found: 240.0.
  • 51
  • [ 4651-98-3 ]
  • [ 116-11-0 ]
  • methyl 2-(isopropylamino)-4-methylthiophene-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
86.1% With sodium tris(acetoxy)borohydride; glacial acetic acid In 1,2-dichloro-ethane for 4h; 52.1 Step 1. Methyl 2-(isopropylamino)-4-methylthiophene-3-carboxylate Sodium triacetoxyborohydride (13.5 g, 63.7 mmol) was added in portions to a mixture of methyl 2-amino-4-methylthiophene-3-carboxylate (7.27 g, 42.5 mmol), 2-methoxyprop-l-ene (4.6 g, 63.7 mmol), and acetic acid (3.64 mL, 63.7 mmol) in DCE (140 mL). The resulting mixture was stirred for 4 h. The reaction mixture was slowly poured into 10% Na2CO3 (aq) and stirred until gas evolution ceased (30 min). The organic layer was separated, and the aqueous layer extracted with DCM (60 mL x 3). The combined organic layers were washed with 10% Na2CO3 (aq) (60 mL), water (60 mL), and brine (60 mL); dried over Na2SO4; filtered; and concentrated. The crude product was purified by silica gel chromatography (0-10% MTBE/heptanes) to give the title compound (7.81 g, 36.6 mmol, 86.1% yield) as colorless oil. LCMS calc, for C10H16NO2S [M+H]+: m/z =214.1; Found: 214.2.
86.1% With sodium tris(acetoxy)borohydride; glacial acetic acid In 1,2-dichloro-ethane for 4h; 52.1 Step 1. Methyl 2-(isopropylamino)-4-methylthiophene-3-carboxylate Sodium triacetoxyborohydride (13.5 g, 63.7 mmol) was added in portions to a mixture of methyl 2-amino-4-methylthiophene-3-carboxylate (7.27 g, 42.5 mmol), 2-methoxyprop-l-ene (4.6 g, 63.7 mmol), and acetic acid (3.64 mL, 63.7 mmol) in DCE (140 mL). The resulting mixture was stirred for 4 h. The reaction mixture was slowly poured into 10% Na2CO3 (aq) and stirred until gas evolution ceased (30 min). The organic layer was separated, and the aqueous layer extracted with DCM (60 mL x 3). The combined organic layers were washed with 10% Na2CO3 (aq) (60 mL), water (60 mL), and brine (60 mL); dried over Na2SO4; filtered; and concentrated. The crude product was purified by silica gel chromatography (0-10% MTBE/heptanes) to give the title compound (7.81 g, 36.6 mmol, 86.1% yield) as colorless oil. LCMS calc, for C10H16NO2S [M+H]+: m/z =214.1; Found: 214.2.
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