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Product Citations

Ramirez, Eduardo ; Min, Sehong ; Ganegamage, Susantha K. , et al. DOI: PubMed ID:

Abstract: Alzheimer's disease (AD) is a multifactorial, chronic neurodegenerative disease characterized by the presence of extracellular beta-amyloid (Abeta) plaques, intraneuronal neurofibrillary tangles (NFTs), activated microglial cells, and an inflammatory state (involving reactive oxygen species production) in the brain. NFTs are comprised of misfolded and hyperphosphorylated forms of the microtubule-binding protein tau. Interestingly, the trimeric form of the 2N4R splice isoform of tau has been found to be more toxic than the trimeric 1N4R isoform in neuron precursor cells. Few drug discovery programs have focused on specific tau isoforms. The present drug discovery project is centered on the anti-aggregation effect of a series of seventeen 4- or 5-aminoindole carboxamides on the 2N4R isoform of tau. The selection of the best compounds was performed using alpha-synuclein (alpha-syn). The anti-oligomer and -fibril activities of newly synthesized aminoindole carboxamide derivatives were evaluated with biophys. methods, such as thioflavin T fluorescence assays, photo-induced crosslinking of unmodified proteins, and transmission electron microscopy. To evaluate the reduction of inclusions and cytoprotective effects, M17D neuroblastoma cells expressing inclusion-forming alpha-syn were treated with the best amide representatives. The 4-aminoindole carboxamide derivatives exhibited a better anti-fibrillar activity compared to their 5-aminoindole counterparts. The amide derivatives 2, 8, and 17 exerted anti-oligomer and anti-fibril activities on alpha-syn and the 2N4R isoform of tau. At a concentration of 40 μM, compound 8 reduced inclusion formation in M17D neuroblastoma cells expressing inclusion-prone alphaSynuclein3K::YFP. Our results demonstrate the potential of 4-aminoindole carboxamide derivatives with regard to inhibiting the oligomer formation of alpha-syn and tau (2N4R isoform) for further optimization prior to pre-clin. studies.

Keywords: Alzheimer's disease ; Amide ; Alpha-synuclein ; Fibril ; Oligomer

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Product Details of [ 527-72-0 ]

CAS No. :527-72-0 MDL No. :MFCD00005437
Formula : C5H4O2S Boiling Point : -
Linear Structure Formula :- InChI Key :QERYCTSHXKAMIS-UHFFFAOYSA-N
M.W : 128.15 Pubchem ID :10700
Synonyms :

Calculated chemistry of [ 527-72-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 31.28
TPSA : 65.54 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.08
Log Po/w (XLOGP3) : 1.57
Log Po/w (WLOGP) : 1.45
Log Po/w (MLOGP) : 0.52
Log Po/w (SILICOS-IT) : 1.94
Consensus Log Po/w : 1.31

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.02
Solubility : 1.22 mg/ml ; 0.00955 mol/l
Class : Soluble
Log S (Ali) : -2.56
Solubility : 0.356 mg/ml ; 0.00278 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.0
Solubility : 12.8 mg/ml ; 0.0998 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.72

Safety of [ 527-72-0 ]

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 [ 527-72-0 ]

* 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 [ 527-72-0 ]
  • Downstream synthetic route of [ 527-72-0 ]

[ 527-72-0 ] Synthesis Path-Upstream   1~39

  • 1
  • [ 527-72-0 ]
  • [ 6324-10-3 ]
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  • 3
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[2] Agricultural and Biological Chemistry, 1982, vol. 46, # 6, p. 1429 - 1438
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  • 6
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  • [ 24065-33-6 ]
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  • 7
  • [ 527-72-0 ]
  • [ 5271-67-0 ]
YieldReaction ConditionsOperation in experiment
81% With thionyl chloride; N,N-dimethyl-formamide; sodium hydroxide In ethyl acetate at 58 - 65℃; for 2.5 h; Inert atmosphere In this experiment, the 2-thiophenecarboxylic acid was the combined solids from Experiments 13.2 and 13.3 of Example 13. [0187] The combined solids of 2-thiophenecarboxylic acid (63.1 g, 493 mmol) was dissolved in ethyl acetate (208 g) in a 3-neck round-bottom flask equipped with a thermocouple, a reflux condenser, and an additional funnel and the system was purged with nitrogen. The reflux condenser outlet was connected to a chilled receiver containing aq. NaOH (20percent, 250 g). A catalytic amount of dimethylformamide (DMF) (0.2 mL, 0.005 eq.) was added and the resulting reaction mixture was heated to 65°C with stirring, followed by a slow addition of thionyl chloride (67.2, 565 mmol, 1.15 eq.). During the addition, gases such as sulfur dioxide (S02) and hydrogen chloride (HC1) were released and the reaction temperature dropped to about 58°C. The reaction completed in 2.5 hours with no detectable unreacted 2-thiophenecarboxylic acid by GC/MS.[0188] After cooling, the flask was fitted with a distillation head and 4-Methoxyphenol (8.9 mg) was added as a stabilizer during the distillation. By vacuum distillation (short path), ethyl acetate and thionyl chloride were distilled from the mixture first under a lower vacuum (approximately 60 to 125 mmHg). The remaining mixture was cooled to room temperature and switched to a higher vacuum. Distillation (short path, approximately 4 mmHg) at a vapor temperature of approximately 63°C afforded 2-thiophenecarbonyl chloride as a clear pale yellow oil (56.5 g, 81percent). GC-FID confirmed that the obtained material was 2-thiophenecarbonyl chloride with a purity of > 98 areapercent.
76% at 20℃; for 1 h; According to Scheme 1 Step 1 : Thiophene-2-carboxylic acid (31.2 mmol, 4.00 g) was slowly added to a solution of thionyl chloride (56.2 mmol, 4.08 mL). The reaction mixture was stirred at room temperature for 1 hour. After evaporation of the thionyl chloride, the crude product was purified by bulb-to-bulb distillation (850C, 14 Torr) to yield thiophene-2-carbonyl chloride (23.7 mmol, 3.48 g, 76percent) as a colorless liquid.
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  • [ 79-37-8 ]
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  • [ 39098-97-0 ]
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  • [ 1918-77-0 ]
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  • 14
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  • [ 64-17-5 ]
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  • [ 60166-85-0 ]
YieldReaction ConditionsOperation in experiment
34% With n-butyllithium; magnesium sulfate; diisopropylamine In tetrahydrofuran; diethyl ether; hexane; water EXAMPLE 3
5-Iodo-2-thiophenecarboxylic acid
The title compound has been described by Schick, J. W., et al., J. Am. Chem. Soc. 70:286 (1948), and was prepared according to the following procedure.
A 25 ml (62.5 mmoles) volume of a 2.5M hexane solution of n-butyllithium was slowly added by syringe to a cooled (dry ice/2-propanol) 100 ml tetrahydrofuran solution of 9.0 ml (64.2 mmoles) of diisopropylamine.
The solution was maintained below -60° C. during n-butyllithium addition.
After addition, the cooling bath was removed and the solution allowed to reach room temperature (22° C.), and then cooled again below -60° C.
To the cooled reaction vessel, 3.2 g (25.0 mmol) of 2-thiophenecarboxylic acid dissolved in 100 ml of tetrahydrofuran was slowly added.
Thirty minutes after complete addition of 2-thiophenecarboxylic acid, approximately 17.2 g (87.8 mmoles) of iodotrifluoromethane was condensed into the reaction.
After 5 minutes the cooling bath was removed and the reaction warmed to 0° C. and quenched with 50 ml of water.
The basic aqueous solution was washed with 500 ml of diethyl ether.
The ether solution was extracted with 50 ml of 1N sodium hydroxide and the two aqueous solutions were combined and washed with ether.
The basic solution was acidified and extracted three times with 100 ml of diethyl ether.
Drying of the organic solution with anhydrous magnesium sulfate followed by filtration and concentration gave a crude solid product.
Partial purification was achieved by reprecipitation of the solid product from hot aqueous ethanol to give 3.79 g of slightly impure desired product as a mixture of dark red solid and yellow crystals.
Recrystallization of the solid mixture gave 2.18 g (8.58 mmoles, 34percent yield) of pure title compound as light yellow needles, m.p. 132°-134° C (hexanes).
Analysis:
Calculated for C5 H3 IO2 S: C, 23.64; H, Found: C, 23.86; H, 1.10percent. EIMS (m/z): 254 M+, base), 237 (M+ --OH, 79percent), 209 (M+ --CO H, 5percent), 127 (M+ --I, 18percent) and 82 (C4 H2 S, 36percent); 1 H-NMR (CDCl3)delta, 7.50 (1H, d, J=3.9 Hz) and 7.29 (1H, d, J=3.9 Hz); ir (CHCl3) 2977 br, 2565, 1679 and 1410 cm-1.
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YieldReaction ConditionsOperation in experiment
95%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: With iodine In tetrahydrofuran at -78 - 20℃;
Stage #3: With hydrogenchloride In water
EXAMPLE 1 Preparation of 2- (3-LODOTHIEN-2-VL) CARBOXVLIC acid A solution of 2-thiophenecarboxylic acid (12.8 g, 0.1 mol) in THF AT-78°C is treated dropwise with n-butyl lithium (88 mL of 2.5 M solution in THF, 2.2 equiv), stirred for 0.5 h, treated dropwise with a solution of iodine (28 g) in THF (1.1 equiv. ), allowed to warm to room temperature while stirring, and CONCENTRATED IN VACUO. The resultant residue is dissolved in EtOAc and extracted with 10percent aqueous NA2C03. The aqueous extracts are combined, acidified with conc. HCI and extracted with EtOAc. The EtOAc extracts are combined, dried over MGS04 and concentrated in vacuo to afford the title product as a yellow-orange solid, 23.5 g (95percent yield), identified by HPLC and mass spectral analyses.
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  • [ 89499-43-4 ]
Reference: [1] Patent: US2010/68178, 2010, A1, . Location in patent: Page/Page column 16-17
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  • [ 14597-58-1 ]
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YieldReaction ConditionsOperation in experiment
31%
Stage #1: at 0 - 10℃; for 1.25 h;
Stage #2: at 20℃; Reflux
Example 12: Synthesis of 4-[dimethylamino)diazenyl]thiophene-2-carboxamide (compound 12); Step a:4-Nitrothiophene-2-carboxylic acid: Sulfuric acid (3.0 mL, 5.505 g, 56.17 mmol) was added to nitric acid (2.0 mL, 2.98 g, 49.6 mmol) slowly at 0-10 0C. After completion of the addition, thiophene-2-carboxylic acid (2.8 g, 21.87 mmol) was added to the above nitration mixture slowly for 15 min at the same temperature and stirred the mixture for 1 h. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitated solid was filtered, washed with cold water and dried. The filtrate was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The combined product was stirred with hexane (2 x 50 mL) and filtered the solid and dried to give the product as an off-white solid (2.8 g, 75percent), mp 110-118 0C. The product was a mixture of two compounds by HPLC and 1H NMR and was proceeded to the next step. Step b:Methyl 4-nitrothiophene-2-carboxylate: To a solution of nitrothiophene-2-carboxylic acids (6.8 g, 39.3 mmol) in methanol (50 mL) was added thionyl chloride (6 mL, 78.6 mmol) drop wise under stirring at rt. The reaction mixture was refluxed for 2 h and attained to rt. The mixture was poured into ice cooled water and stirred for 15 min. The precipitated solid was filtered, washed with cold water and dried to give the product as an off-white solid (6.2 g, 85percent). 1H NMR showed that, it is a mixture of two compounds and the crude product was proceded to the next step.; Step c:Methyl 4-aminothiophene-2-carboxylate: To a solution of methyl nitrothiophene-2- carboxylates (7 g, 37.43 mmol) in a mixture of water (150 mL) and methanol (50 mL) was added Cone, hydrochloric acid (4.5 mL). To the above solution was added iron powder (10.5 g, 188 mmol) followed by ammonium chloride (1O g, 187 mmol) at rt. The reaction mixture was stirred and warmed to 70 0C for 1 h and was then allowed to cool to rt. The solution was filtered and basified with saturated sodium bicarbonate solution. The solution was extracted with chloroform (4 x 100 mL). The combined organic layer was dried over sodium sulfate and filtered. Solvent was evaporated and the residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10 and small amount of triethyl amine) as eluent to give methyl 4-aminothiophene-2-carboxylate (1.8 g, 31percent), mp 76-780C. 1H NMR (400 MHz, CDCl3): δ 7.31 (IH, d, JH .6 Hz), 6.40 (IH, d, J=I.6 Hz), 3.85 (3H, s), 3.63 (2H, br s).Further elution of the column with the same solvent system provided methyl 5- aminothiophene-2-carboxylate (0.5 g, 8.5percent), mp 70-720C. 1H NMR (400 MHz, CDCl3): δ 7.45 (IH, d, J=4.0 Hz), 6.09 (IH, d, J=4.0 Hz), 4.29 (2H, br s), 3.81 (3H, s).
Reference: [1] Patent: WO2010/29577, 2010, A2, . Location in patent: Page/Page column 38-39
  • 22
  • [ 527-72-0 ]
  • [ 62224-19-5 ]
Reference: [1] ChemMedChem, 2017, vol. 12, # 24, p. 2044 - 2053
[2] ChemMedChem, 2017, vol. 12, # 24, p. 2044 - 2053
  • 23
  • [ 527-72-0 ]
  • [ 31166-29-7 ]
Reference: [1] Journal of Chemical Research, 2014, vol. 38, # 10, p. 622 - 624
  • 24
  • [ 527-72-0 ]
  • [ 6317-37-9 ]
Reference: [1] Patent: US5519015, 1996, A,
[2] Patent: US5538962, 1996, A,
[3] Patent: US5571805, 1996, A,
[4] Patent: US5527791, 1996, A,
[5] Patent: US2005/222408, 2005, A1,
  • 25
  • [ 527-72-0 ]
  • [ 6317-37-9 ]
  • [ 13138-70-0 ]
YieldReaction ConditionsOperation in experiment
18.2 g at 10 - 20℃; In 100ml three-necked flask was added 32ml fuming nitric acid,Control the temperature ≤ 20 dropwise 24ml concentrated sulfuric acid,Upon completion of the dropwise addition of 22.4 g of 2-thiophenecarboxylic acid,And controlling the temperature does not exceed 20 , plus complete,Control the internal temperature 10 ~ 20 to continue stirring for 3 to 4 hours,The reaction was monitored by TLC (n-hexane: ethyl acetate = 1: 1).The reaction solution was slowly added to 448ml of ice water,Stirring crystallization 1 hour, suction filtration,The filter cake was dried under reduced pressure at 40-45 ° C for 8 hours,18.2 g of 4-nitro-2-thiophenecarboxylic acid was obtainedAnd 5-nitro-2-thiophenecarboxylic acid,Used directly in the next step without purification.
Reference: [1] Journal of the American Chemical Society, 1999, vol. 121, # 34, p. 7751 - 7759
[2] Patent: WO2010/29577, 2010, A2, . Location in patent: Page/Page column 38-39
[3] Patent: CN107400110, 2017, A, . Location in patent: Paragraph 0019; 0040; 0041; 0057; 0072; 0087
[4] Patent: CN107616976, 2018, A, . Location in patent: Paragraph 0049; 0050
  • 26
  • [ 527-72-0 ]
  • [ 7697-37-2 ]
  • [ 108-24-7 ]
  • [ 609-40-5 ]
  • [ 6317-37-9 ]
  • [ 13138-70-0 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 1134,1141
[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1958, vol. 246, p. 2003[3] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1959, vol. 248, p. 1182
  • 27
  • [ 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
  • 28
  • [ 527-72-0 ]
  • [ 6148-64-7 ]
  • [ 13669-10-8 ]
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
  • 29
  • [ 527-72-0 ]
  • [ 13669-10-8 ]
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 11, p. 2333 - 2336
  • 30
  • [ 615-07-6 ]
  • [ 98-03-3 ]
  • [ 527-72-0 ]
  • [ 326-91-0 ]
  • [ 76-05-1 ]
Reference: [1] Journal of Photochemistry and Photobiology A: Chemistry, 2018, vol. 364, p. 303 - 308
  • 31
  • [ 527-72-0 ]
  • [ 699-89-8 ]
Reference: [1] Patent: US6689883, 2004, B1,
  • 32
  • [ 527-72-0 ]
  • [ 32431-84-8 ]
YieldReaction ConditionsOperation in experiment
40%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h;
Stage #2: With N-fluorobis(benzenesulfon)imide In tetrahydrofuran; hexane at -78 - 20℃; for 10 h;
2-Thiophene-carboxylic acid (1.7 g, 13.3 mmol) was dissolved in anhydrous THF (30 mL) and the solution was cooled to -78° C. under Ar, with stirring. n-Butyllithium (18.3 mL, 29.3 mmol) in hexanes was added to the above solution and the mixture was stirred for 30 min. A solution of N-fluorobenzenesulfonimide (5 g, 15.9 mmol) in THF (30 mL) was then added and the resulting solution was stirred at -78° C. for 4 h and allowed to warm to ambient temperature over a period of 6 h. The reaction was diluted with diethyl ether (100 mL), cooled to 0° C., and 1 N HCl (15 mL) was added to give a biphasic mixture. The aqueous layer was isolated and washed with diethyl ether (3.x.50 mL). The combined ethereal layers were dried over MgSO4, filtered, and concentrated in vacuo to yield an orange oil. The oil was subjected to column chromatography on silica gel using 1:1 hexanes/ethyl acetate as the eluent. (14) was obtained as a slightly brown solid (0.777 g) in 40percent yield. TLC (1:1 ethyl acetate/hexanes) Rf 0.17; 1H NMR (CDCl3) δ 10.7 (s, 1H), 7.53 (dd, J=5.4, 3.6 Hz, 1H), 6.89 (d, J=5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.2 (d, J=3.5 Hz), 161.5 (d, J=278 Hz), 132.0 (d, J=10 Hz), 118.9 (d, J=24.7 Hz), 113.6; 19FNMR (282 MHz, CDCl3, CFCl3) δ -65.2 (d, J=6 Hz); EI-MS m/e 145.9838 (M+calcd 145.9838 for C5H3FO2S).
Reference: [1] Organic Preparations and Procedures International, 1997, vol. 29, # 2, p. 221 - 223
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 20, p. 4333 - 4340
[3] Patent: US2009/155202, 2009, A1, . Location in patent: Page/Page column 16
[4] Macromolecules, 2017, vol. 50, # 16, p. 6098 - 6107
[5] Patent: WO2010/148488, 2010, A1, . Location in patent: Page/Page column 29
[6] Patent: WO2012/139425, 2012, A1, . Location in patent: Page/Page column 121
[7] Patent: US2018/127401, 2018, A1, . Location in patent: Paragraph 0507-0510
  • 33
  • [ 527-72-0 ]
  • [ 109-72-8 ]
  • [ 133745-75-2 ]
  • [ 32431-84-8 ]
Reference: [1] Patent: US7452730, 2008, B2,
  • 34
  • [ 527-72-0 ]
  • [ 75-65-0 ]
  • [ 56267-50-6 ]
YieldReaction ConditionsOperation in experiment
69% for 5 h; Heating / reflux A solution of thiophene2-carboxylic acid (1.00 g, 7.8 mmol), diphenylphosphoryl azide (2.15 g, 7.80 mmol) and triethylamine (1.1 mL, 7.8 mmol) in tert-butanol (20 mL) was heated at reflux for 5 hours, at which time thin layer chromatography (DCM/Hexanes) indicates the reaction is complete. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether (3.x.). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate, and then concentrated to afford a beige solid. Purification by column chromatography (SiO2, DCM/Hexanes) afforded compound 113 as a white solid 1.07 g (69percent). 1H-NMR (400 MHz, DMSO-d6)δ 6.87(dd, 1H), 6.77 (m, 1H), 6.5 (dd, 1H), 1.46 (s, 9H).
69% for 5 h; Heating / reflux Example 113; A solution of thiophene2-carboxylic acid (1.00 g, 7.8 mmol), diphenylphosphoryl azide (2.15 g, 7.80 mmol) and triethylamine (1.1 mL, 7.8 mmol) in tert-butanol (20 mL) was heated at reflux for 5 hours, at which time thin layer chromatography (DCM/Hexanes) indicates the reaction is complete. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether (3.x.). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate, and then concentrated to afford a beige solid. Purification by column chromatography (SiO2, DCM/Hexanes) afforded compound 113 as a white solid 1.07 g (69percent). 1H-NMR (400 MHz, DMSO-d6)δ 6.87 (dd, 1H), 6.77 (m, 1H), 6.5 (dd, 1H), 1.46 (s, 9H).
50% at 90℃; for 4 h; To a solution of thiophenecarboxylic acid (0.5 g, 3.90 mmol) in tBuOH (10 ml) was added Et3N (0.571 ml, 4.10 mmol) and DPPA (0.883 ml, 4.10 mmol). The solution was heated at 90 °C for 4 hours. The reaction mixture was cooled to RT and the solvent was removed in vacuo. The residue was treated with benzene and then the solution was washed with 5percent citric acid, and sat'd NaHCO3. Solid was filtered off and the filtrate was washed with brine. The organic layer was dried (MgSO4), concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc/hexanes) to obtain tert-butyl thiophen-2-ylcarbamate (0.39 g, 50percent yield). 1H NMR (400 MHz, DMSO-d6): δ 10.4 (brs, 1H), 6.84 (dd, J = 1.6, and 5.2 Hz, 1H), 6.75 (dd, J = 4.0, and 5.6 Hz, 1H), 6.48 (dd, J= 1.6, and 4.0 Hz, 2H), 1.45 (s, 9H); MS (ESI) m/z: 222.0 (M+22+H+).
Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 5, p. 1594 - 1605
[2] Patent: US2007/105864, 2007, A1, . Location in patent: Page/Page column 151
[3] Patent: US2007/117804, 2007, A1, . Location in patent: Page/Page column 77
[4] Journal of Medicinal Chemistry, 2002, vol. 45, # 20, p. 4513 - 4523
[5] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4898 - 4908
[6] Patent: WO2010/51373, 2010, A1, . Location in patent: Page/Page column 100
[7] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 21, p. 5567 - 5571
  • 35
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  • [ 89281-29-8 ]
Reference: [1] Journal of Chemical Research, 2014, vol. 38, # 10, p. 622 - 624
  • 36
  • [ 527-72-0 ]
  • [ 112887-68-0 ]
Reference: [1] Patent: CN107616976, 2018, A,
[2] Patent: CN107616976, 2018, A,
  • 37
  • [ 527-72-0 ]
  • [ 14597-58-1 ]
  • [ 89499-43-4 ]
Reference: [1] Patent: US2010/68178, 2010, A1, . Location in patent: Page/Page column 16-17
  • 38
  • [ 67-56-1 ]
  • [ 527-72-0 ]
  • [ 14597-58-1 ]
  • [ 89499-43-4 ]
YieldReaction ConditionsOperation in experiment
31%
Stage #1: at 0 - 10℃; for 1.25 h;
Stage #2: at 20℃; Reflux
Example 12: Synthesis of 4-[dimethylamino)diazenyl]thiophene-2-carboxamide (compound 12); Step a:4-Nitrothiophene-2-carboxylic acid: Sulfuric acid (3.0 mL, 5.505 g, 56.17 mmol) was added to nitric acid (2.0 mL, 2.98 g, 49.6 mmol) slowly at 0-10 0C. After completion of the addition, thiophene-2-carboxylic acid (2.8 g, 21.87 mmol) was added to the above nitration mixture slowly for 15 min at the same temperature and stirred the mixture for 1 h. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitated solid was filtered, washed with cold water and dried. The filtrate was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The combined product was stirred with hexane (2 x 50 mL) and filtered the solid and dried to give the product as an off-white solid (2.8 g, 75percent), mp 110-118 0C. The product was a mixture of two compounds by HPLC and 1H NMR and was proceeded to the next step. Step b:Methyl 4-nitrothiophene-2-carboxylate: To a solution of nitrothiophene-2-carboxylic acids (6.8 g, 39.3 mmol) in methanol (50 mL) was added thionyl chloride (6 mL, 78.6 mmol) drop wise under stirring at rt. The reaction mixture was refluxed for 2 h and attained to rt. The mixture was poured into ice cooled water and stirred for 15 min. The precipitated solid was filtered, washed with cold water and dried to give the product as an off-white solid (6.2 g, 85percent). 1H NMR showed that, it is a mixture of two compounds and the crude product was proceded to the next step.; Step c:Methyl 4-aminothiophene-2-carboxylate: To a solution of methyl nitrothiophene-2- carboxylates (7 g, 37.43 mmol) in a mixture of water (150 mL) and methanol (50 mL) was added Cone, hydrochloric acid (4.5 mL). To the above solution was added iron powder (10.5 g, 188 mmol) followed by ammonium chloride (1O g, 187 mmol) at rt. The reaction mixture was stirred and warmed to 70 0C for 1 h and was then allowed to cool to rt. The solution was filtered and basified with saturated sodium bicarbonate solution. The solution was extracted with chloroform (4 x 100 mL). The combined organic layer was dried over sodium sulfate and filtered. Solvent was evaporated and the residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10 and small amount of triethyl amine) as eluent to give methyl 4-aminothiophene-2-carboxylate (1.8 g, 31percent), mp 76-780C. 1H NMR (400 MHz, CDCl3): δ 7.31 (IH, d, JH .6 Hz), 6.40 (IH, d, J=I.6 Hz), 3.85 (3H, s), 3.63 (2H, br s).Further elution of the column with the same solvent system provided methyl 5- aminothiophene-2-carboxylate (0.5 g, 8.5percent), mp 70-720C. 1H NMR (400 MHz, CDCl3): δ 7.45 (IH, d, J=4.0 Hz), 6.09 (IH, d, J=4.0 Hz), 4.29 (2H, br s), 3.81 (3H, s).
Reference: [1] Patent: WO2010/29577, 2010, A2, . Location in patent: Page/Page column 38-39
  • 39
  • [ 527-72-0 ]
  • [ 1292766-17-6 ]
YieldReaction ConditionsOperation in experiment
42% Dean-Stark; Reflux In a flask equipped with a Dean-Stark system was added Cu2O (1 eq., 1.4 g, 9.78 mmol) withtoluene (15 mL). Then the 2-thiophenecarboxylic acid (3.99 eq., 5 g, 39 mmol) was added. Themixture was heated to reflux overnight.The resulting suspension was filtered and washed with diethyl ether to give ((thiophene-2-carbonyl)oxy)copper (3.10 g, 16.3 mmol, 42percent) as a tan powder.
Reference: [1] Chemistry - A European Journal, 2013, vol. 19, # 31, p. 10353 - 10359
[2] Tetrahedron Letters, 2018, vol. 59, # 36, p. 3349 - 3352
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