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Chemical Structure| 13669-10-8
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Product Details of [ 13669-10-8 ]

CAS No. :13669-10-8 MDL No. :MFCD00542649
Formula : C9H10O3S Boiling Point : -
Linear Structure Formula :- InChI Key :VKSDKUXHVLZDHO-UHFFFAOYSA-N
M.W : 198.24 Pubchem ID :255159
Synonyms :

Calculated chemistry of [ 13669-10-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.33
Num. rotatable bonds : 5
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 50.22
TPSA : 71.61 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.08 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.0
Log Po/w (XLOGP3) : 2.01
Log Po/w (WLOGP) : 1.88
Log Po/w (MLOGP) : 0.67
Log Po/w (SILICOS-IT) : 2.92
Consensus Log Po/w : 1.9

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.29
Solubility : 1.02 mg/ml ; 0.00513 mol/l
Class : Soluble
Log S (Ali) : -3.14
Solubility : 0.143 mg/ml ; 0.000723 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.51
Solubility : 0.618 mg/ml ; 0.00312 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.23

Safety of [ 13669-10-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 13669-10-8 ]

* 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.

  • Upstream synthesis route of [ 13669-10-8 ]
  • Downstream synthetic route of [ 13669-10-8 ]

[ 13669-10-8 ] Synthesis Path-Upstream   1~13

  • 1
  • [ 88-15-3 ]
  • [ 105-58-8 ]
  • [ 13669-10-8 ]
YieldReaction ConditionsOperation in experiment
98% With sodium hydride In tetrahydrofuran at 35℃; Preparation of ethyl-3-oxo [3-(2-THIOPHENYL)] propanoate Sodium hydride (60percent dispersion in mineral oil, 100g, 2.5 mol) was washed with anhydrous hexane (2 x 250 [ML)] under a nitrogen atmosphere at room temperature. Anhydrous tetrahydrofuran (THF) (340 [ML)] was then added with stirring followed by 2- acetyl thiophene (136 ml, 1.25 mol) in anhydrous THF (340 ml) over period of 20 minutes. The reaction mixture was then warmed to [35°C.] After 30 minutes diethyl carbonate (305.5 ml, 2.5 mol) in anhydrous THF (660 mi) was added over a period of 1 hour. After an additional hour the reaction mixture was cooled [TO-10°C,] quenched with water (475 [ML)] and glacial acetic acid (145 mi) was added. The mixture was stirred for 20 minutes and then warmed to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 200 [ML).] The combined organic extracts were washed with brine (2 x 200 [ML),] dried with [NA2SO4] and concentrated under reduced pressure to give the title compound as a crude dark orange oil in 98percent yield (242.8g).
91%
Stage #1: at 0 - 71℃;
Stage #2: With acetic acid In waterCooling with ice
Step 1; [00218] To a solution of l-(thiophen-2-yl)ethanone (2.944 g, 23.3 mmol) and Diethyl carbonate (70 mL) at 0 0C was added sodium hydride (1.86 g, 46.6 mmol). The resulting off-white slurry solution was gradually warmed to 71 0C, and stirred for 1.5 hour. The reaction mixture was poured into ice-HOAc-H2O, and extracted with ethyl acetate. The organic phase was washed (brine), dried (MgSO4) and concentrated to give a brown liquid. The crude product was purified via flash chromatography (silica gel cartridge with eluent of 0-3percent ethyl acetate/hexane) to afford ethyl 3-oxo-3-(thiophen-2-yl)propanoate as an amble liquid, 4.193 g (91percent). LCMS m/z 388.99, 390.09 (M+23); HPLC: Rt 2.01 min. (4.0 min. gradient, Column: YMC Combiscreen C- 18, Method A).
89%
Stage #1: With sodium hydride In toluene; mineral oil at 0℃; for 0.166667 h; Inert atmosphere
Stage #2: for 2 h; Inert atmosphere; Reflux
Under a nitrogen atmosphere, a magneticallystirred solution of 2-acetylthiophene (12.6 g, 100 mmol) in toluene (100 mL)cooled to 0 °C was slowly added sodium hydride (60percent in mineral oil, 4.8 g, 120 mmol). The formedmixture was stirred for 10 min followed by slow addition of diethyl carbonate (13 mL, 110 mmol). After the addition was complete, the stirredsolution was heated to reflux for 2 h. The resulting mixture was poured into icewater/acetic acid, and extracted with ethyl acetate (3 × 200 mL). The combined organicsolution were washed with saturatedbrine solution, dried over anhydrous sodium sulfate, and concentrated to give abrown liquid. The crude product was further purified via flash chromatography(hexane/ethyl acetate) to afford the corresponding product 2d.
83% With sodium hydride In tetrahydrofuran at 24 - 79℃; for 1.25 - 1.83333 h; Heating / reflux A 0.254 g portion of 60percent sodium hydride and 1.95 g of diethyl carbonate were charged using 1.0 ml of tetrahydrofuran at 24°C and then the temperature was increased to carry out reflux. At said temperature (79°C), a solution prepared by dissolving 0.5 g of 2-acetylthiophene in 1 ml of tetrahydrofuran was added dropwise thereto spending 15 minutes. Thereafter, the mixture was stirred at said temperature for 1 hour, and when the reaction was completed, the reaction solution was analyzed by a liquid chromatography under the same conditions of the aforementioned Production Example 1 to find that the reaction yield was 89percent.(Reference Example 1) A 0.254 g portion of 60percent sodium hydride was charged using 1.5 ml of tetrahydrofuran at 24°C. At said temperature (79°C), a solution prepared by dissolving 1.95 g of diethyl carbonate and 0.5 g of 2-acetylthiophene in 1 ml of tetrahydrofuran was added dropwise thereto spending 15 minutes. Thereafter, the mixture was stirred at said temperature for 1 hour, and when the reaction was completed, the reaction solution was analyzed by a liquid chromatography under the same conditions of the aforementioned Production Example 1 to find that the reaction yield was 83percent.
83%
Stage #1: at 60 - 65℃; for 1 h;
Stage #2: at 75 - 80℃; for 2 h;
A 71.1 g (0.63 mol) portion of tert-butoxy potassium was added to 194.7 g (1.65 mol) of diethyl carbonate at 60 to 65°C and stirred at 60 to 65°C for 1 hour, and then 180 ml of toluene solution containing 50 g (0.40 mol) of 2-acetylthiophene was added dropwise thereto at 75 to 80°C and stirred at 75 to 80°C for 2 hours. The reaction solution was cooled down to room temperature, mixed with 725 g of water, extracted with 600 ml of ethyl acetate, washed with saturated brine, concentrated and then distilled under a reduced pressure to obtain 65.2 g of 3-oxo-3-(2-thienyl)propionic acid ethyl ester (yield 83percent).
81%
Stage #1: at 20 - 35℃; for 0.833333 h;
Stage #2: at 35℃; for 2 h;
[0098] A three necks-round bottom flask, equipped with addition funnel, nitrogen inlet and (0154) temperature probe was charged with anhydrous THF and NaH (60percent dispersion in mineral oil, 2 equiv. c = 1.25 M, concentration referred to moles of NaH). The suspension was stirred at room temperature for 10 min and then a THF solution of 2-acetylthiophene (25 mmol, 1 equiv. c = 0.62 M) was added dropwise over a period of 20 min. A slight (4-5 °C) increase of the temperature was observed during the addition, and then the reaction mixture was warmed to 35 °C and stirred for 30 min. A THF solution of diethyl carbonate (50 mmol, 2 equiv., c = 1.70 M) was added over a period of 1 hour. After one additional hour, the reaction mixture was cooled down to -10 °C and quenched with slow addition of water (5-10 ml), and then glacial acetic (3 ml) was added. The mixture was stirred for 20 min and then warmed to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x 50 ml). The combined organic layers were washed with brine, dried with anhydrous Na2S04 and concentrated under reduced pressure. Purification was done by automated flash chromatography using silica gel column and a mixture of hexanes and ethyl acetate as eluent. Hexanes (100percent) was used to elute the excess of diethyl carbonate, and the amount of ethyl acetate was progressively increased from 20percent to 50percent to elute the title compound.
74% With sodium hydride In tetrahydrofuran at 24 - 79℃; for 1.25 - 1.83333 h; Heating / reflux A 10.16 g portion of 60percent sodium hydride and 78 g of diethyl carbonate were charged using 60 ml of tetrahydrofuran at 24°C and then the temperature was increased to carry out reflux. At said temperature (79°C), a solution prepared by dissolving 20 g of 2-acetylthiophene in 20 ml of tetrahydrofuran was added dropwise thereto spending 50 minutes. Thereafter, the mixture was stirred at said temperature for 1 hour and then ice-cooled when the reaction was completed. When the reaction solution was analyzed by a liquid chromatography, the reaction yield was 94percent. A 63 ml portion of 4 N hydrochloric acid aqueous solution was ice-cooled in advance, and the ice-cooled reaction solution was added dropwise thereto in such a manner that the solution temperature was kept at about 10°C. The pH value after the dropwise addition was 6. Next, separation of layers was carried out, and the water layer was further extracted three times with 40 ml of toluene, combined with the first organic layer and washed with 20 ml of saturated brine. Thereafter, this was partially concentrated and then subjected to rectification by attaching a condenser, thereby obtaining 26.9 g (purity 87percent, yield 74percent) of 3-oxo-(2-thienyl)propionic acid ethyl ester containing the sodium hydride-derived oil component from a fraction of 128 to 130°C (distillation under 4 mmHg). 1H-NMR (CDCl3) δ 1.27 (t, 3 H, J = 8 Hz), 3.92 (s, 2 H), 4.21 (q, 2 H, J = 8 Hz), 7.15 (dd, 1 H, J = 5 Hz, 1 Hz), 7.70 (d, 1 H, J = 5 Hz), 7.74 (d, 1 H, J = 1 Hz) In this connection, the liquid chromatography conditions are as follows. MCI-Gel ODS 15 cm (mfd. by Mitsubishi Kagaku) 40°C Acetonitrile : 50 mM ammonium acetate aqueous solution = 50:50 (0.7 ml/min) Detection wavelength UV 254 nm(Production Example 2) Synthesis of 3-oxo-(2-thienyl) propionic acid ethyl ester A 13.31 g portion of 60percent sodium hydride and 56.1 g of diethyl carbonate were charged using 105 ml of tetrahydrofuran at 24°C and then the temperature was increased to 60°C. At said temperature, a solution prepared by dissolving 30 g of 2-acetylthiophene in 15 ml of tetrahydrofuran was added dropwise thereto spending 20 minutes. Thereafter, the mixture was stirred at said temperature for 1 hour and then ice-cooled when the reaction was completed. When the reaction solution was analyzed by a liquid chromatography under the same conditions of the aforementioned Production Example 1, the reaction yield was 99percent. A 87.4 ml portion of 4 N hydrochloric acid aqueous solution was ice-cooled in advance, and the ice-cooled reaction solution was added dropwise thereto in such a manner that the solution temperature was kept at about 10°C. Since the pH value after the dropwise addition was 1.5, the pH was adjusted to 7 with 25percent sodium hydroxide aqueous solution. Separation of layers was carried out, and the water layer was further extracted once with 30 ml of toluene, combined with the first organic layer and washed with 30 ml of 25percent brine. The thus obtained organic layer was concentrated to a pressure of 50 mmHg. Next, in order to separate the oil component originated from NaH, 30 ml of acetonitrile and 30 ml of heptane were added at 25°C and stirred for 30 minutes, and then the heptane layer was separated to remove the oil component. By concentrating the acetonitrile layer (under a pressure of 5 mmHg), 46.3 g (purity 92percent, yield 90percent) of 3-oxo-3-(2-thienyl)propionic acid ethyl ester was obtained.
69%
Stage #1: With sodium hydride In mineral oil; benzene for 3 h; Reflux
Stage #2: With water; acetic acid In mineral oil; benzene
Example 13 Ethyl 3-Oxo-3-(thiophen-2-yl)propanoate (36). To a suspension of sodium hydride (7.13 g, 178 mmol, 60 percent in mineral oil) in benzene (100 mL) was added diethyl carbonate (14.0 g, 118 mmol). The mixture was heated to reflux and a solution of 2-acetylthiophene (7.48 g, 59.4 mmol) in benzene (20 mL) was added dropwise over 1 hour. When addition was complete, the mixture was refluxed for a further 3 hours, after which hydrogen evolution had ceased. The reaction was quenched with acetic acid (15 mL) and then with ice-cold water (45 mL). The organic phase was separated, the aqueous layer was extracted with benzene and the combined extracts were washed with cold water, dried (Na2SO4) and concentrated under reduced pressure. The residue was distilled under high vacuum to give 36 (8.15 g, 69 percent) as a colorless oil: bp 130 °C (0.3 torr): IR (neat) 2925, 2848, 1742,1669, 1459, 1373, 1030, 851, 723 cm"1; 1H NMR (400 MHz, CHCl3) δ 1.28 (t, 3H, J = 7 Hz), 3.93 (s, 2H), 4.25 (q, J= Hz, 2H), 7.16 (m, IH), 7.71-7.76 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 14.1, 46.5, 61.6, 128.3, 133.2, 134.9, 142.4, 167.0, 185.2: HRMS (EI) m/z 198.0349 (calcd for C9Hi0O3S 198.0351).
64% With sodium hydride In toluene; mineral oil at 70℃; for 1 h; Inert atmosphere To a suspension of 630mg NaH (15.85mmol, 60percent dispersion in mineral oil) in 40ml of dry toluene under a nitrogen atmosphere was slowly added diethyl carbonate (1.92ml, 15.85mmol) and 2-acetylthiophene (1.00g, 7.93mmol). The reaction mixture was heated to 70°C for 1 h, cooled, 200ml of water was slowly added followed by 2ml of AcOH and the mixture was extracted with 3x200ml of EtOAc. The combined organic layers were washed with 100ml of water, 300 ml of brine, dried over magnesium sulfate and evaporated to give a crude oil that was purified by column chromatography (silica, 10percent EtOAc in PE 40-60) to give 1 .00g (5.04mmol, 64percent) of 3-thiophen-2-yl-3- oxopropionic acid ethyl ester. 1H-NMR (CDCI3): δ 8.15 (s, 1 H), 7.55 (m, 1 H), 7.35 (m, 1 H), 4.20 (q, 2H), 3.90 (s, 2H), 1.25 (t, 3H). A solution of 870mg (5.25mmol) of benzothiazol-2-yl-hydrazine and 1 .04g (5.25mmol) of 3-thiophen-2-yl-3-oxopropionic acid ethyl ester in 15ml of ethanol was refluxed for 18h under a nitrogen atmosphere, cooled, the solids were filtered, washed with a little cold EtOH and dried to give 1 .38g (4.61 mmol, 88percent) of 2-benzothiazol-2-yl-5-thiophen- 2-yl-1 ,2-dihydropyrazol-3-one. 1H-NMR {DMSO-d6)\ δ 12.90 (bs, 1 H), 8.05 (d, 1 H), 7.90 (d, 1 H), 7.65 (m, 2H), 7.50 (t, 1 H), 7.40 (t, 1 H), 7.10 (s, 1 H), 5.95 (s, 1 H). To a solution of 720mg (2.41 mmol) of 2-benzothiazol-2-yl-5-thiophen-2-yl-1 ,2- dihydropyrazol-3-one in 10ml of THF was added N,N-dimethylformamide dimethylacetal (350μΙ, 2.56mmol). The reaction was stirred for 2h at room temperature under a nitrogen atmosphere. Diethyl ether was added to induce precipitation after which the solids were filtered off, washed with diethyl ether and dried to give 753mg (2.12mmol, 88percent) of 2-benzothiazol-2-yl-4-[1 -dimethylaminomethylidene]-5-thiophen-2- yl-2,4-dihydropyrazol-3-one as a mixture of isomers. In order to obtain one of the isomers pure, 5ml of DCM was added to the solid isomeric mixture, stirred thoroughly and the liquid decanted from the remaining solids. The liquid was concentrated, the solids filtered and washed with 2ml of DCM. The combined solids after two DCM washing cycles weighed 82mg and consisted of one single isomer. 1H-NMR (DMSO- d6): δ 8.00 (m, 2H), 7.85 (m, 1 H), 7.75 (s, 1 H), 7.50 (s, 1 H), 7.45 (m, 1 H), 7.30 (m, 1 H), 7.25 (s, 1 H), 3.75 (s, 3H), 3.50 (s, 3H). A suspension of 500mg (1.41 mmol) of 2-benzothiazol-2-yl-4-[1 - dimethylaminomethylidene]-5-thiophen-2-yl-2,4-dihydropyrazol-3-one in 5ml EtOH and 5ml of 25percent aqueous ammonia solution was heated to 60°C for 1 h. After cooling to room temperature, the solids were filtered, washed with a little EtOH and dried to give 357mg (1 .09mmol, 78percent) of 4-[1 -aminomethylidene]-2-benzothiazol-2-yl-5-thiophen-2- yl-2,4-dihydropyrazol-3-one. 1H-NMR {DMSO-d6)\ δ 9.40 (bs, 2H), 8.30 (s, 1 H), 8.05 (d, 1 H), 7.90 (d, 1 H), 7.75 (d, 1 H), 7.65 (m, 1 H), 7.50 (t, 1 H), 7.35 (t, 1 H), 7.25 (m, 1 H).

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[6] Patent: EP1486493, 2004, A1, . Location in patent: Page 22
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[14] Journal of Medicinal Chemistry, 1999, vol. 42, # 20, p. 4081 - 4087
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[23] Patent: US2630437, 1947, ,
  • 2
  • [ 527-72-0 ]
  • [ 2033-24-1 ]
  • [ 13669-10-8 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 2 h;
Stage #2: With toluene-4-sulfonic acid In ethanol for 1 h; Heating / reflux
Step 1.
Preparation of ethyl-2-(thiophene-2-oyl)acetate.
A solution of thiophene-2-carboxylic acid (8.9 g, 68.5 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (12.0 g, 81.6 mmol), and 4-dimethylaminopyridine (17.0 g, 138 mmol) in dry CH2Cl2 (100 mL) was cooled to 0° C. and treated with a solution of 1,3-dicyclohexylcarbodiimide (75 mL, 1.0 M in CH2Cl2, 75 mmol).
The reaction was allowed to stir at room temperature for 2 h and the dicyclohexylurea was then filtered and washed with CH2Cl2.
The filtrate was concentrated at reduced pressure and the residue was dissolved in absolute ethanol (400 mL).
The solution was then treated with a solution of p-toluenesulfonic acid monohydate (32 g, 168 mmol) in absolute ethanol (100 mL) and refluxed under argon for 1 h.
At this time, the ethanol was removed at reduced pressure and the residue was dissolved in EtOAc and washed sequentially with H2O (300 mL), saturated NaHCO3 (200 mL), 1 N HCl (200 mL), saturated NaCl, and dried (MgSO4).
The solvent was removed at reduced pressure and the residue was filtered through a pad of silica with 10percent EtOAc/90percent hexanes to afford the desired product as an oil (13 g, 96percent). TLC (20percent EtOAc/80percent hexane) Rf 0.21; 1H-NMR (DMSO-d6) δ 1.17 (t, J=7.01, 3H), 4.06-4.14 (m, 4H), 7.25 (t, J=5.1 Hz, 1H), 7.98 (d, J=3.8 Hz, 1H), 8.06 (d, J=4.9 Hz, 1H).
96%
Stage #1: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 2 h;
Stage #2: With toluene-4-sulfonic acid In ethanol for 1 h; Heating / reflux
A solution of thiophene-2-carboxylic acid (8.9 g, 68.5 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (12.0 g, 81.6 mmol), and 4-dimethylaminopyridine (17.0 g, 138 mmol) in dry CH2Cl2 (100 mL) was cooled to 0° C. and treated with a solution of 1,3-dicyclohexylcarbodiimide (75 mL, 1.0 M in CH2Cl2, 75 mmol).
The reaction was allowed to stir at room temperature for 2 h and the dicyclohexylurea was then filtered and washed with CH2Cl2.
The filtrate was concentrated at reduced pressure and the residue was dissolved in absolute ethanol (400 mL).
The solution was then treated with a solution of p-toluenesulfonic acid monohydate (32 g, 168 mmol) in absolute ethanol (100 mL) and refluxed under argon for 1 h.
At this time, the ethanol was removed at reduced pressure and the residue was dissolved in EtOAc and washed sequentially with H2O (300 mL), saturated NaHCO3 (200 mL), 1 N HCl (200 mL), saturated NaCl, and dried (MgSO4).
The solvent was removed at reduced pressure and the residue was filtered through a pad of silica with 10percent EtOAc/90percent hexanes to afford the desired product as an oil (13 g, 96percent). TLC (20percent EtOAc/80percent hexane) Rf0.21; 1H-NMR (DMSO-d6) δ1.17 (t, J=7.01, 3H), 4.06-4.14 (m, 4H), 7.25 (t, J=5.1 Hz, 1H), 7.98 (d, J=3.8 Hz, 1H), 8.06 (d, J=4.9 Hz, 1H).
27%
Stage #1: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 2 h;
Stage #2: With toluene-4-sulfonic acid In ethanol for 1 h; Heating / reflux
Intermediate 1D : Preparation of 4-chloro-6- (2-thienyl) pyrimidin-2-amine; Step 1: Preparation of ethyl 3-oxo-3- (2-thienyl) propanoate; A solution of 2, 2-dimethyl-1, 3-dioxane-4,6-dione (12 g, 83.26 mmol) and thiophene- 2-carboxylic acid (8.97 g, 70.0 mmol) and DMAP (17.10 g, 140 mmol) in methylene chloride (100 mL) was cooled in an ice bath and treated with a solution of DCC (15.88 g, 76.96 mmol) in methylene chloride (50 mL). The reaction was stirred at rt for 2 h. The resulting precipitate was filtered and the filtrate was concentrated and re-dissolved in EtOH (400 mL). To this solution was addedp-toluenesulfonic acid (32 g) and the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo to afford the crude organic concentrate which was dissolved in ethyl acetate (1000 mL) and washed with water (300 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (200 mL), IN hydrochloric acid (200 mL), saturated aqueous sodium chloride, dried (Na2S04), and concentrated. The residue was purified using silica gel column chromatography (0-7percent ethyl acetate in hexane) to furnish the desired product as a colorless oil (3.67 g, 27percent). MS ES 199 (M+H) +, calcd 199; RT = 2.12 min; TLC (25percent ethyl acetate in hexane) Rf= 0.50.
27%
Stage #1: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2 h;
Stage #2: With toluene-4-sulfonic acid In ethanol for 1 h; Heating / reflux
A solution of 2,2-dimethyl-l,3-dioxane-4,6-dione (12 g, 83.26 mmol) and thiophene- 2-carboxylic acid (8.97 g, 70.0 mmol) and DMAP (17.10 g, 140 mmol) in methylene chloride (100 rnL) was cooled in an ice bath and treated with a solution of DCC (15.88 g, 76.96 mmol) in methylene chloride (50 mL). The reaction was stirred at rt for 2 h. The resulting precipitate was filtered and the filtrate was concentrated and re-dissolved in EtOH (400 mL). To this solution was added /?-toluenesulfonic acid (32 g) and the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo to afford the crude organic concentrate which was dissolved in ethyl acetate (1000 mL) and washed with water (300 EPO <DP n="40"/>mL). The organic layer was washed with saturated aqueous sodium bicarbonate (200 niL), IN hydrochloric acid (200 mL), saturated aqueous sodium chloride, dried (Na2SO4), and concentrated. The residue was purified using silica gel column chromatography (0-7percent ethyl acetate in hexane) to furnish the desired product as a colorless oil (3.67 g, 27percent). MS ES 199 5 (M+H)+, calcd 199; RT = 2.12 min; TLC (25percent ethyl acetate in hexane) Rf = 0.50.

Reference: [1] Patent: US2004/2507, 2004, A1, . Location in patent: Page/Page column 8
[2] Patent: US2004/2508, 2004, A1, . Location in patent: Page/Page column 11-12
[3] Patent: WO2005/35507, 2005, A2, . Location in patent: Page/Page column 53
[4] Patent: WO2006/99231, 2006, A1, . Location in patent: Page/Page column 38-39
  • 3
  • [ 88-15-3 ]
  • [ 13669-10-8 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With potassium <i>tert</i>-butylate In toluene at 60 - 65℃; for 0.5 h;
Stage #2: at 75 - 80℃; for 0.75 h;
PREPARATION 17; No. Chromatographic method B.; Ethyl 3-oxo-3-thiophen-2-ylpropionate; Diethyl carbonate (39.6 ml, 327 mmol) in toluene (20 ml) was heated to 60°C. At this temperature, potassium tert-butoxide (14.3g, 128 mmol) was portionwise added and, once the addition was over, heated at 65°C for half an hour. Then the temperature was raised to 75°C and 2-acethylthiophene (1 0.0g, 79 mmol) in toluene (20 ml) was dropwise added. The reaction mixture was heated at 80°C for 45 min, then allowed to reach room temperature and finally poured into water. After successive extractions with ethyl acetate, the organic phase was dried over sodium sulfate, filtered and evaporated. 14.2 g of a dark oil were obtained as the desired final product (90percent yield). No. (CDCl3): 1.25 (t, 3H), 3.90 (s, 2H), 4.20 (q, 2H), 7.1 (m, 1 H), 7.70 (m, 1 H), 7.75 (m, 1 H).
Reference: [1] Patent: WO2005/123693, 2005, A1, . Location in patent: Page/Page column 55-56
[2] Journal of the American Chemical Society, 1944, vol. 66, p. 1768
[3] Journal of Organic Chemistry, 1948, vol. 13, p. 161,162
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YieldReaction ConditionsOperation in experiment
90%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.666667 h;
Stage #2: at -78 - 20℃; for 0.5 h;
To a stirred solution of DIPA (7.6 mL, 54 mmol) in THF (53 mL) was added n-BuLi (21.6 mL) at 0 °C. Stirring was continued at this temperature 10 minutes. The mixture was then cooled to -78 °C and EtOAc (2.4 mL, 27 mmol) was added dropwise. Stirring was continued at this temperature 30 minutes. After that, a solution of compound 13.1 (3 mL, 27 mmol) in THF (20 mL) was added dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The crude of reaction was poured in water and extracted with EtOAc (3 x 30 mL). The collected organic phase were washed with brine, dried over Na S04 and concentrated under vacuum. The title compound 13.2 was obtained as brownish oil (4.8 g, 24.3 mmol). Yield 90percent.
Reference: [1] Patent: WO2016/30534, 2016, A1, . Location in patent: Page/Page column 110
[2] Patent: WO2017/136450, 2017, A2, . Location in patent: Sheet 105/122
[3] Patent: WO2018/6074, 2018, A2, . Location in patent: Paragraph 0076; 00629
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  • [ 527-72-0 ]
  • [ 6148-64-7 ]
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YieldReaction ConditionsOperation in experiment
78%
Stage #1: With Carbonyldiimidazole In tetrahydrofuran at 5 - 10℃;
Stage #2: With magnesium chloride In tetrahydrofuran at 50℃; for 2 h; Room temperature overnigth stirring
To a suspension of [2-THIOPHENECARBOXYLIC] acid (6.48 g, 50.57 mmol) in tetra- [HYDROFURANE] (100 ml) at 5. was added [L, LAPOS;-CARBONYLDIIMIDAZOLE] (8.61 g, 53. [09 MMOL)] by portions. The mixture was allowed to warm to room temperature, and the stirring was continued for 1 hour. The reaction mixture was added into a suspension mixture of magnesium chloride (4.86 g, 51. [07 MMOL)] and pottasium 3- ethoxy-3-oxopropanoate (12.91 g, 75.85 mmol) in [TETRAHYDROFURANE] (50 ml). After being stirred at 50. for 2 hours and at room temperature overnight, the reaction mixture was poured into water, and then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (ethyl acetate/hexane, 15/85) to give ethyl [3-OXO-3- (2-THIENYL)] propanoate [- (7.] 83 g, 78percent yield) as a yellow oil.
Reference: [1] Patent: WO2004/29055, 2004, A1, . Location in patent: Page 205-206
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  • [ 105-36-2 ]
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Reference: [1] Green Chemistry, 2017, vol. 19, # 6, p. 1420 - 1424
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  • [ 1003-09-4 ]
  • [ 6148-64-7 ]
  • [ 82102-37-2 ]
  • [ 13669-10-8 ]
Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 37, p. 9763 - 9766[2] Angew. Chem., 2013, vol. 125, # 37, p. 9945 - 9948
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  • [ 29813-41-0 ]
  • [ 105-58-8 ]
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Reference: [1] Organic Letters, 2017, vol. 19, # 23, p. 6344 - 6347
  • 9
  • [ 98-03-3 ]
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Reference: [1] RSC Advances, 2013, vol. 3, # 31, p. 12616 - 12620
  • 10
  • [ 527-72-0 ]
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Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 11, p. 2333 - 2336
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  • [ 141-97-9 ]
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Reference: [1] Patent: US2710867, 1954, ,
[2] Patent: US2710867, 1954, ,
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  • [ 64-17-5 ]
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Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 11, p. 2333 - 2336
  • 13
  • [ 2810-04-0 ]
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Reference: [1] Bulletin de la Societe Chimique de France, 1954, p. 492,494
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