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Product Details of [ 107-91-5 ]

CAS No. :107-91-5 MDL No. :MFCD00008024
Formula : C3H4N2O Boiling Point : -
Linear Structure Formula :- InChI Key :DGJMPUGMZIKDRO-UHFFFAOYSA-N
M.W : 84.08 Pubchem ID :7898
Synonyms :

Calculated chemistry of [ 107-91-5 ]

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.33
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 19.19
TPSA : 66.88 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.5 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.34
Log Po/w (XLOGP3) : -0.97
Log Po/w (WLOGP) : -0.61
Log Po/w (MLOGP) : -1.36
Log Po/w (SILICOS-IT) : -0.74
Consensus Log Po/w : -0.67

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 0.32
Solubility : 174.0 mg/ml ; 2.07 mol/l
Class : Highly soluble
Log S (Ali) : 0.05
Solubility : 94.5 mg/ml ; 1.12 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : 0.15
Solubility : 119.0 mg/ml ; 1.41 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.22

Safety of [ 107-91-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 107-91-5 ]

* 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 [ 107-91-5 ]
  • Downstream synthetic route of [ 107-91-5 ]

[ 107-91-5 ] Synthesis Path-Upstream   1~54

  • 1
  • [ 102-52-3 ]
  • [ 107-91-5 ]
  • [ 20577-27-9 ]
Reference: [1] Patent: US6335345, 2002, B1, . Location in patent: Page column 59
  • 2
  • [ 110-89-4 ]
  • [ 5444-80-4 ]
  • [ 107-91-5 ]
  • [ 20577-27-9 ]
Reference: [1] Chemische Berichte, 1940, vol. 73, p. 156
[2] DRP/DRBP Org.Chem.,
  • 3
  • [ 590-86-3 ]
  • [ 107-91-5 ]
  • [ 185815-59-2 ]
Reference: [1] Tetrahedron Asymmetry, 2007, vol. 18, # 12, p. 1481 - 1485
  • 4
  • [ 95-54-5 ]
  • [ 107-91-5 ]
  • [ 4414-88-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 12, p. 1746 - 1753
[2] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 500 - 513
[3] Molecular Diversity, 2017, vol. 21, # 1, p. 201 - 210
  • 5
  • [ 95-54-5 ]
  • [ 107-91-5 ]
  • [ 13570-08-6 ]
Reference: [1] Patent: US3933847, 1976, A,
  • 6
  • [ 67-64-1 ]
  • [ 107-91-5 ]
  • [ 109-94-4 ]
  • [ 4241-27-4 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With sodium methylate In tetrahydrofuran at 0 - 20℃; for 2 h;
Stage #2: With piperidine; acetic acid In tetrahydrofuran; water for 2 h; Reflux
46.5 g of sodium methoxide in 950 ml of tetrahydrofuran (THF) was added in the reaction vessel, the ice bath was cooled to an internal temperature of 0 ~ 5 °C, and a solution of 46.5 g of acetone and 59.6 g of ethyl formate was added dropwise within 1 h, after the addition, the ice bath was withdrawn and slowly raised to room temperature within 1 h and concentrated under reduced pressure (not exceeding 50° C.). The concentrate was transferred to a reaction vessel, 67 g of cyanoacetamide in 400 ml of water and piperidine acetic acid (condensation catalyst) were added, refluxed for 2h, cooled to room temperature, adjusted ρΗ=about 5 with acetic acid, the reaction mixture was allowed to stand at room temperature overnight, cooled in an ice bath for 45 minutes, suction-filtered, washed with ice water three times, dried in vacuo overnight at 80 ° C, to obtain compound 2 as a yellow solid 65.5g (yield 61.0percent).
58%
Stage #1: With sodium In diethyl ether at 20℃; Cooling with ice
Stage #2: at 20℃; for 0.1 h;
Stage #3: With piperidine; water; acetic acid In diethyl ether for 2 h; Reflux
General procedure: A substituted alkyl methyl ketone or cyclic ketone (1 equiv) and ethyl formate or ethyl acetic(1 equiv) was added dropwise to absolute ether solution of sodium metal (1 equiv) for 1 h whilemaintained below 20 C. After the addition, the reaction was allowed to stir in an ice bath untilthe sodium metal had disappeared. The precipitate was filtered, washed with absolute ether anddried to give the corresponding compound which was directly used for the next step without further purification. To a solution of previous product (1 equiv), and cyanoacetamide (1.05 equiv) in water was stirred6 min at room temperature. The mixture was added dropwise piperidine acetate solution (0.3 equiv),which was prepared from piperidine (1 equiv), acetic acid (1 equiv) and water (5 equiv). The solutionwas heated to reflux for 2 h. Then, the reactor was cooled to room temperature, and adjusted to pH 4 by 4 N hydrochloric acid. The resulting solid was filtered, respectively washed with water and ether,and dried to give the corresponding compound which was purified by recrystallizing using menthol as solvent.
49%
Stage #1: With sodium methylate In diethyl ether at 0 - 20℃; for 2 h;
Stage #2: With piperdinium acetate In water for 2 h; Heating / reflux

To stirred a mixture of sodium methoxide (46.5 g, 860 mmole) in diethyl ether (950 ML), cooled in an ice bath, was added a mixture of acetone (46.5 g, 800 mmole) and ethyl formate (59.6 g, 800 mmole) dropwise over 1 hour..
When addition was complete, the cooling bath was removed and the mixture was warmed to room temperature over a 1 hour period..
The volatile materials were distilled, keeping the oil bath at no more than 60° C.
To the solid residue was added cyanoacetamide (67 g, 800 mmole) in water (400 ML) and piperidine acetate
The flask was fitted with a reflux condenser, and the mixture was heated for 2 hours under reflux..
The mixture was cooled to room temperature and acidified to PH 5 with acetic acid..
After standing overnight at room temperature, the mixture was cooled in an ice bath for 45 minutes..
The yellow solid product was filtered, washed with ice water four times and dried under vacuum at 80° C. overnight..
Crystallization from 50percent (v/v) ethanol afforded the title compound as a yellow solid (52.6 g, 49percent yield). Rf=0.29 (silica gel, 95:5 chloroform:methanol)..
Fast atom bombardment mass spectrometry confirmed the theoretical molecular weight of 134.
Reference: [1] Patent: CN105037261, 2017, B, . Location in patent: Paragraph 0048-0049
[2] Molecules, 2018, vol. 23, # 7,
[3] Patent: US6342504, 2002, B1, . Location in patent: Page column 50
[4] Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3303 - 3312
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 6, p. 2212 - 2215
  • 7
  • [ 110-89-4 ]
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  • [ 109-94-4 ]
  • [ 4241-27-4 ]
YieldReaction ConditionsOperation in experiment
49% With sodium methylate; piperdinium acetate; acetic acid In diethyl ether; water; acetone EXAMPLE 11
Preparation of 6-methylpyrid-2-one-3-carbonitrile STR35
To stirred a mixture of sodium methoxide (46.5 g, 860 mmole) in diethyl ether (950 mL), cooled in an ice bath, was added a mixture of acetone (46.5 g, 800 mmole) and ethyl formate (59.6 g, 800 mmole) dropwise over 1 hour.
When addition was complete, the cooling bath was removed and the mixture was warmed to room temperature over a 1 hour period.
The volatile materials were distilled, keeping the oil bath at no more than 60° C.
To the solid residue was added cyanoacetamide (67 g, 800 mmole) in water (400 mL) and piperidine acetate (140 mmole, prepared by adding piperidine to a solution of 8.0 mL of acetic acid in 20 mL water until the solution was greater than pH 7).
The flask was fitted with a reflux condenser, and the mixture was heated for 2 hours under reflux.
The mixture was cooled to room temperature and acidified to pH 5 with acetic acid.
After standing overnight at room temperature, the mixture was cooled in an ice bath for 45 minutes.
The yellow solid product was filtered, washed with ice water four times and dried under vacuum at 80° C. overnight.
Crystallization from 50percent (v/v) ethanol afforded the title compound as a yellow solid (52.6 g, 49percent yield). Rf =0.29 (silica gel, 95:5 chloroform:methanol).
Fast atom bombardment mass spectrometry confirmed the theoretical molecular weight of 134.
49% With sodium methylate; piperdinium acetate; acetic acid In diethyl ether; water; acetone Example 11
Preparation of 6-methylpyrid-2-one-3-carbonitrile STR37
To stirred a mixture of sodium methoxide (46.5 g, 860 mmole) in diethyl ether (950 mL), cooled in an ice bath, was added a mixture of acetone (46.5 g, 800 mmole) and ethyl formate (59.6 g, 800 mmole) dropwise over 1 hour.
When addition was complete, the cooling bath was removed and the mixture was warmed to room temperature over a 1 hour period.
The volatile materials were distilled, keeping the oil bath at no more than 60° C.
To the solid residue was added cyanoacetamide (67 g, 800 mmole) in water (400 mL) and piperidine acetate (140 mmole, prepared by adding piperidine to a solution of 8.0 mL of acetic acid in 20 mL water until the solution was greater than pH 7).
The flask was fitted with a reflux condenser, and the mixture was heated for 2 hours under reflux.
The mixture was cooled to room temperature and acidified to pH 5 with acetic acid.
After standing overnight at room temperature, the mixture was cooled in an ice bath for 45 minutes.
The yellow solid product was filtered, washed with ice water four times and dried under vacuum at 80° C. overnight.
Crystallization from 50percent (v/v) ethanol afforded the title compound as a yellow solid (52.6 g, 49percent yield). Rf =0.29 (silica gel, 95:5 chloroform:methanol).
Fast atom bombardment mass spectrometry confirmed the theoretical molecular weight of 134.
49% With sodium methylate; piperdinium acetate; acetic acid In diethyl ether; water; acetone Example 11
6-methylpyrid-2-one-3-carbonitrile STR32
To stirred a mixture of sodium methoxide (46.5 g, 860 mmole) in diethyl ether (950 mL), cooled in an ice bath, was added a mixture of acetone (46.5 g, 800 mmole) and ethyl formate (59.6 g, 800 mmole) dropwise over 1 hour.
When addition was complete, the cooling bath was removed and the mixture was warmed to room temperature over a 1 hour period.
The volatile materials were distilled, keeping the oil bath at no more than 60° C.
To the solid residue was added cyanoacetamide (67 g, 800 mmole) in water (400 mL) and piperidine acetate (140 mmole, prepared by adding piperidine to a solution of 8.0 mL of acetic acid in 20 mL water until the solution was greater than pH 7).
The flask was fitted with a reflux condenser, and the mixture was heated for 2 hours under reflux.
The mixture was cooled to room temperature and acidified to pH 5 with acetic acid.
After standing overnight at room temperature, the mixture was cooled in an ice bath for 45 minutes.
The yellow solid product was filtered, washed with ice water four times and dried under vacuum at 80° C. overnight.
Crystallization from 50percent (v/v) ethanol afforded the title compound as a yellow solid (52.6 g, 49percent yield). Rf =0.29 (silica gel, 95:5 chloroform:methanol).
Fast atom bombardment mass spectrometry confirmed the theoretical molecular weight of 134.
49% With sodium methylate; piperdinium acetate; acetic acid In diethyl ether; water; acetone Example 11
6-Methylpyrid-2-one-3-carbonitrile STR30
To stirred a mixture of sodium methoxide (46.5 g, 860 mmole) in diethyl ether (950 mL), cooled in an ice bath, was added a mixture of acetone (46.5 g, 800 mmole) and ethyl formate (59.6 g, 800 mmole) dropwise over 1 hour.
When addition was complete, the cooling bath was removed and the mixture was warmed to room temperature over a 1 hour period.
The volatile materials were distilled, keeping the oil bath at no more than 60° C.
To the solid residue was added cyanoacetamide (67 g, 800 mmole) in water (400 mL) and piperidine acetate (140 mmole, prepared by adding piperidine to a solution of 8.0 mL of acetic acid in 20 mL water until the solution was greater than pH 7).
The flask was fitted with a reflux condenser, and the mixture was heated for 2 hours under reflux.
The mixture was cooled to room temperature and acidified to pH 5 with acetic acid.
After standing overnight at room temperature, the mixture was cooled in an ice bath for 45 minutes.
The yellow solid product was filtered, washed with ice water four times and dried under vacuum at 80° C. overnight.
Crystallization from 50percent (v/v) ethanol afforded the title compound as a yellow solid (52.6 g, 49percent yield). Rf =0.29 (silica gel, 95:5 chloroform:methanol).
Fast atom bombardment mass spectrometry confirmed the theoretical molecular weight of 134.

Reference: [1] Patent: US6008351, 1999, A,
[2] Patent: US6011158, 2000, A,
[3] Patent: US5656645, 1997, A,
[4] Patent: US5658930, 1997, A,
  • 8
  • [ 5436-21-5 ]
  • [ 107-91-5 ]
  • [ 4241-27-4 ]
YieldReaction ConditionsOperation in experiment
87.4% With piperdinium acetate In water for 24 h; Reflux 40.0 g of compound v (0.303 mol), 28.0 g of cyanoacetamide (0.333 mol) and 17.5 g of piperidinium acetate were added to 160 ml of purified water, the solution was clarified, heated and stirred to reflux. The mixture was stirred for 24 hours and cooled to 10 ° C. The crystals were collected by stirring and filtered to give a pale red solid which was weighed to give 35.5 g of a yield of 87.4percent.
Reference: [1] Patent: CN106349246, 2017, A, . Location in patent: Paragraph 0023; 0024
  • 9
  • [ 110-89-4 ]
  • [ 584-08-7 ]
  • [ 107-91-5 ]
  • [ 109-94-4 ]
  • [ 4241-27-4 ]
Reference: [1] Patent: US5521179, 1996, A,
  • 10
  • [ 51731-17-0 ]
  • [ 107-91-5 ]
  • [ 4241-27-4 ]
Reference: [1] Patent: US3965107, 1976, A,
  • 11
  • [ 42731-40-8 ]
  • [ 107-91-5 ]
  • [ 4241-27-4 ]
Reference: [1] Nucleosides and Nucleotides, 1999, vol. 18, # 10, p. 2335 - 2343
  • 12
  • [ 107-91-5 ]
  • [ 4241-27-4 ]
Reference: [1] Liebigs Annales, 1996, # 10, p. 1501 - 1509
  • 13
  • [ 75-15-0 ]
  • [ 77-78-1 ]
  • [ 107-91-5 ]
  • [ 17823-69-7 ]
YieldReaction ConditionsOperation in experiment
42%
Stage #1: With potassium hydroxide In acetonitrile at 20℃; for 1 h;
Stage #2: at 20℃; for 3 h;
Stage #3: at 20℃;
Preparation of 2-cyano-3,3-bis(methylthio)acrylamide 1-2
A mixture of 2-cyanoacetamide (10 g, 118.9 mmol) and potassium hydroxide (6.661 g, 118.9) in ACN (100 mL) was stirred at room temperature for 1 hr followed by slow addition of carbon disulfide (9.054 g, 118.9 mmol) at room temperature.
After the solution was stirred for 3 hrs at room temperature, dimethylsulfate (19.5 g, 154.6 mmol) was added and the reaction mixture was stirred overnight at room temperature.
The volatiles were then removed under vacuum, and the residual was redissolved in EtOAc and washed sequentially with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo.
The resulting solid was triturated with EtOAc/hexanes, filtered, and dried to give compound I-2 (9.4 g, 42percent yield, 99.0percent purity) as a yellow solid.
Reference: [1] Patent: US2016/176857, 2016, A1, . Location in patent: Paragraph 0275
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 24, p. 5453 - 5458
[3] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 13, p. 5242 - 5246
[4] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 4, p. 901 - 906
  • 14
  • [ 75-15-0 ]
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  • [ 74-88-4 ]
  • [ 17823-69-7 ]
Reference: [1] Chemische Berichte, 1962, vol. 95, p. 2861 - 2870
  • 15
  • [ 107-91-5 ]
  • [ 623-47-2 ]
  • [ 35441-10-2 ]
Reference: [1] Angewandte Chemie, 1980, vol. 92, # 5, p. 390 - 391
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 6, p. 2215 - 2226
  • 16
  • [ 874-14-6 ]
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  • [ 35441-10-2 ]
Reference: [1] Journal of Organic Chemistry, 1981, vol. 46, # 5, p. 846 - 851
[2] Journal of Organic Chemistry, 1981, vol. 46, # 5, p. 846 - 851
[3] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 9, p. 1498 - 1506
  • 17
  • [ 110-89-4 ]
  • [ 99-91-2 ]
  • [ 107-91-5 ]
  • [ 109-94-4 ]
  • [ 23148-51-8 ]
Reference: [1] Patent: US4405552, 1983, A,
  • 18
  • [ 40160-35-8 ]
  • [ 107-91-5 ]
  • [ 23148-51-8 ]
Reference: [1] Nucleosides and Nucleotides, 1999, vol. 18, # 10, p. 2335 - 2343
  • 19
  • [ 99-91-2 ]
  • [ 4637-24-5 ]
  • [ 107-91-5 ]
  • [ 23148-51-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3303 - 3312
  • 20
  • [ 372-31-6 ]
  • [ 107-91-5 ]
  • [ 3335-46-4 ]
YieldReaction ConditionsOperation in experiment
80.1%
Stage #1: With potassium hydroxide In methanolReflux
Stage #2: for 24 h; Reflux
Take potassium hydroxide 29.8g (0.53mol) input with mechanical stirring with reflux condenser 250mL four-necked flask was slowly added 100mL of methanol, stirring for stand-by 43.4 g (0.52 mol) of cyanoacetamide were charged into a flask equipped with a mechanical stirrer, constant pressure dropping funnel, drying tube and reflux condenser 500mL four-necked flask, add 150mL of methanol, mechanical stirring heating reflux, the reaction solution was changed from cloudy to light yellow transparent and added 100 g (0.54 mol) of ethyl trifluoroacetoacetate, keep the reflux state, slowly dropping the configured potassium hydroxide methanol solution, Heated to reflux reaction 24h, central control raw materials cyanoacetamide reaction is complete, Change the reflux device for the distillation device, Methanol recovery 3/4, The residue was added to cold water, cooled, adjusted with dilute hydrochloric acid PH = 3-4, stirred 0.5h, the reaction mixture was filtered, the filter cake washed with water to give the white target 2,6-dihydroxy-3-cyano-4 - (trifluoromethyl) pyridine, dried at 80 to constant weight to give 84.5 g, yield 80.1percent, hplc 98percent.
Reference: [1] Patent: CN107382848, 2017, A, . Location in patent: Paragraph 0034-0045
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  • [ 3335-46-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 475 - 477
  • 22
  • [ 122-51-0 ]
  • [ 292638-85-8 ]
  • [ 107-91-5 ]
  • [ 615-79-2 ]
Reference: [1] Patent: US6172230, 2001, B2,
  • 23
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  • [ 107-91-5 ]
  • [ 105-34-0 ]
Reference: [1] Journal of Organic Chemistry, 1981, vol. 46, p. 5351 - 5353
  • 24
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  • [ 932021-64-2 ]
  • [ 590-17-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 1, p. 63 - 67
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  • [ 4815-28-5 ]
YieldReaction ConditionsOperation in experiment
90% With morpholine; sulfur In ethanol at 20℃; for 6 h; To the stirred solution of Compound 1 (3.0 g, 30.56 mmol), 2-cyanoacetamide (2.56 g, 30.56 mmol), sulfur powder (0.97 g,30.56 mmol) in ethanol (40 mL) was added morpholine (5.31 mL,61.11 mmol) and stirred the reaction mixture at room temperature for 6 h. The reaction mixture was concentrated, diluted with EtOAc and washed the organic layer with H2O (2x30 mL). The separated organic layer was dried over anhydrous Na2SO4, evaporated and purified by column chromatography to get Compound 2 (5.40 g,90percent) as an light yellow solid. ESI-MS found 197 [M+H]+.
79% With morpholine; sulfur In ethanol at 50℃; for 5 h; Compound 2: 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide Cyclohexanone (Compound 1,10 mL),morpholine (2 mL), elemental sulfur (3.2 g), and cyanoacetamide(8.4 g) were added to absolute ethanol (80 mL).The reaction mixture was refluxed at 50 °C for 5 h. After cooling, a yellow solid was filtered, washed with absolute ethanol, and dried at 40 °C under an infrared lamp to give Compound 2 in a yield of 79percent.
78% at 20 - 58℃; To a stirred mixture of cyanoacetamide (1a; 10 g) and cyclohexanone(2a; 12.3 g), at room temperature, Sulfur was added (3a;4.139 g). Upon addition of diethylamine (11.8 ml) an exothermic reaction started and the temperature rose to 55-58 °C for 1 h. The reaction mixture was stirred at 45-50 °C for 1 h and left overnightat room temperature. The solid obtained was filtered, washed withchilled ethanol and dried. 4.1.1.1. 3-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (4a). 78percent yield; M.P.178 °C; IR (KBr) ν(cm-1): 3390,3155, 2941,1660, 1560; 1H NMR (400 MHz, DMSO-d6):δ (ppm) 6.90(br s, 2H, NH2), 6.32 (br s, 2H, NH2), 2.59e2.62 (m, 2H, CyclohexylCH2), 2.46e2.48 (m, 2H, Cyclohexyl CH2), 1.70e1.77 (m, 4H, CyclohexylCH2); LC-MS/MS (M+H)+: 197.0 (calculated 196.07); Elemental analysis (percent): Calculated (Found) for C9H12N2OS: C 55.08(55.01), H 6.16 (6.19), N 14.27 (14.31), S 16.34 (16.40).
68% With morpholine; sulfur In ethanol for 4 h; Reflux General procedure: Cyclohexanone (for 18a), 1-benzoylpiperidin-3-one (for 18b) or 1-benzoylpiperidin-4-one (for 18c) (0.42mmol), cyanoacetamide (34mg, 0.40mmol) and sulfur (16mg, 0.50mmol) were suspended in EtOH (1mL). To this was added morpholine (70mg, 0.80mmol). The resulting mixture was refluxed gently with stirring for 4h, and was allowed to cool to room temperature. Solvent was removed and the residue was purified by flash chromatography on silica gel using hexanes:EtOAc (1:2) to give compounds 18a-c as off white powder.
49.6% With sulfur; diethylamine In ethanol at 40 - 50℃; for 5 h; In a 250 mL three-necked flask, 10.1 g (120 mmol) of cyanoacetamide, 3.8 g (120 mmol) of elemental sulfur,11.8 g (120 mmol) of cyclohexanone and 38 mL of absolute ethanol,8.8 g (5.0 mmol) of diethylamine was slowly added dropwise to the above mixture at a temperature of 40 to 50 ° C and stirred for 5 h. The crystals were cooled and filtered to give a brownish solid which was washed twice with a small amount of anhydrous ethanol. To give 11.7 g of a yellow solid powder in a yield of 49.6percent.
4.8% With morpholine; sulfur In ethanol at 20 - 55℃; for 22 h; General procedure: A mixture of the ketone (1 eq.), cyanoacetate (1 eq.), and elemental sulphur (1eq.) in ethanol were combined and heated at 40-70 °C. Morpholine or diethylamne (1 eq.) was added dropwise. The reaction was stirred at 40-70 °C for 1-4 hours, and then stirred at room temperature overnight. The resulting precipitate was typically collected by filtration and recrystallised from ethanol or toluene.

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[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 11, p. 2367 - 2371
[4] Medicinal Chemistry, 2017, vol. 13, # 8, p. 753 - 760
[5] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 1053 - 1065
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[11] Patent: CN105061462, 2017, B, . Location in patent: Paragraph 0017-0018; 0021-0023
[12] Tetrahedron, 2006, vol. 62, # 29, p. 7121 - 7131
[13] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7089 - 7093
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[24] Main Group Metal Chemistry, 2018, vol. 41, # 1-2, p. 21 - 26
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  • [ 4815-28-5 ]
YieldReaction ConditionsOperation in experiment
50% With sulfur In methanol at 20℃; Reflux General procedure: Tert-butyl cyanoacetate (10 mmol), prepared according to known procedure [6] was heated to reflux with TEA (30 mmol), sulphur (10 mmol) and freshly distilled cyclohexane (10 mmol) in 15 ml of methanol for 5 h and stirred in RT overnight. The solvent was rotatory evaporated and the residue was dissolved in chloroform and filtrated. The organic layer was washed with 0.1 M solution of hydrochloric acid and distilled water. The organic layer was dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography (n-hexane: chloroform). Yield 72 percent as dark yellow oil that solidifies under vacuum.The reaction was carried out as for tert-butyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate. Purification by column chromatography (chloroform: ethyl acetate) Yield 50percent as yellow crystals. mp 185-188 °C. IR (ATR): 3398, 3299, 3183, 2928, 2832, 1626, 1558, 1480, 1418 cm-1. 1H NMR (300 MHz, CDCl3) δ 5.56 (s, 2H), 5.42-4.81 (wm, 2H), 2.69-2.59 (m, 2H), 2.59-2.48 (m, 2H) 1.85-1.77 (m,4H).13C NMR (75 MHz, CDCl3) δ 168.6, 160.8, 129.2, 118.8, 107.7, 77.4, 27.2, 24.7, 23.1.
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 261 - 267
  • 27
  • [ 14371-10-9 ]
  • [ 107-91-5 ]
  • [ 19006-81-6 ]
Reference: [1] Journal of Organic Chemistry, 2002, vol. 67, # 12, p. 4304 - 4308
  • 28
  • [ 123-38-6 ]
  • [ 107-91-5 ]
  • [ 51486-03-4 ]
YieldReaction ConditionsOperation in experiment
67% With octasulfur; triethylamine In DMF (N,N-dimethyl-formamide); ethanol at 20 - 70℃; for 1.5 h; To a DMF (100 mL) solution of cyanoacetamide (42.0 g, 0.5 mol), sulfur (16.0 g, 0.5 mol), and triethylamine (50.5 g, 0.5 mol) was slowly added dropwise an ethanol (15 mL) solution of propionaldehyde (31.9 g, 0.55 mol) at room temperature (inner temperature rose to 70°C), followed by heating under stirring at 60°C for 1.5 hours.
After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate.
The resulting extract solution was washed with water and brine and then the solvent was removed by evaporation.
The residue was washed with methylene chloride to obtain an objective product (42.4 g).
The filtrate was purified on a silica gel column (Kiesel gel 60 manufactured by MERCK, 20percent AcOEt-Hex) to obtain 2-amino-5-methylthiophene-3-carboxamide (52.6 g, 67percent).
1H-NMR (400MHz, CDCl3): 2.27(d, 3H, J=1.2Hz), 5.32(br s, 2H), 6.01(br.s, 2H), 6.33(q, 1H, J=1.2Hz).
mp: 140-141°C
Reference: [1] Patent: EP1544202, 2005, A1, . Location in patent: Page/Page column 51
  • 29
  • [ 123-72-8 ]
  • [ 107-91-5 ]
  • [ 51486-03-4 ]
YieldReaction ConditionsOperation in experiment
53% With sulfur In ethanol at 60℃; for 1.5 h; Step A: To a stirred solution of 2-cyanoacetamide (4.2 g, 50 mmol), elemental sulfur (1.6 g, 50 mmol) and TEA (5.1 g, 50 mmol) in DMF at rt was added slowly a solution of propionaldehyde (3.2 g, 55 mmol) in EtOH. The reaction mixture was heated at 60 °C for 1.5 h, and then partitioned between water and EtOAc. The organic layer was separated, washed sequentially with water then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a mixture of DCM in MeOH to afford 2-amino-5-methylthiophene-3-carboxamide (4.1 g, 53percent). 1H NMR (400 MHz, DMSO-t/e) δ ppm 2.18 (s, 3H), 6.69 (s, 1H), 7.05 (s, 2H); LC-MS (ESI) m/z 157 (M + H)+.
Reference: [1] Patent: WO2012/30894, 2012, A1, . Location in patent: Page/Page column 99
  • 30
  • [ 40018-26-6 ]
  • [ 107-91-5 ]
  • [ 14080-51-4 ]
YieldReaction ConditionsOperation in experiment
88% With triethylamine In ethanol at 20℃; for 2.08333 h; Heating / reflux Triethylamine (36 mL, 256 mmol) was added to the solution of 2- cyanoacetamide (10.8 g, 128 mmol) and [1, 4] -dithiane-2,5-diol (19.5 g, 128 mmol) in ethanol (400 mL). The resulting reaction mixture was stirred at room temperature for 5 min, then heated at reflux for 2 h. After the reaction mixture is cooled to room temperature, it was filtered and concentrated under vacuum. The residue was then taken up into ethyl acetate (400 mL) and washed with aqueous sodium hydroxide (1 M, 1X200 mL), water (2X200 mL) and brine (1X200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the above titled compound as a light yellow solid (16 g, 113 mmol, 88percent yield). LC-MS [M+H]+ m/z 143.
82% With triethylamine In ethanol for 5 h; Reflux Step A: A stirred mixture of 2-cyanoacetamide (2 g, 23.8 mmol), 1,4- dithiane-2,5-diol (3.6 g, 23.8 mmol) and TEA (4.8 g, 47.6 mmol) in EtOH was heated at reflux for 5 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and 1 M aq sodium hydroxide (300 mL). The organic layer was separated and washed with water and brine., dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-aminothiophene-3-carboxamide (2.78 g, 82percent). 1H NMR (400 MHz, DMSO- d6) δ ppm 6.23 (d, J = 6 Hz, 1H), 6.76 (brs, 2H), 7.05 (d, J = 6 Hz, 1H), 7.23 (brs, 2H); LC-MS (ESI) m/z 143 (M + H)+.
69% With triethylamine In ethanol at 70℃; for 4 h; Step 1
A solution of 2,5-dihydroxy-1,4-dithiane (11.8 g, 155 mmol), cyanoacetamide (17.0 g, 202 mmol) and triethylamine (20 mL) in ethanol (100 mL) was stirred under heating at 70°C for 4 hr.
The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to an about half volume.
Water was added to the residue, the precipitated insoluble material was collected by filtration, and the solid was washed with water to give 2-amino-3-thiophenecarboxamide as a brown powder (15.3 g, 69percent).
1H-NMR (200MHz, DMSO-d6) δ: 6.22 (1H, d, J = 6.0 Hz), 7.04 (1H, d, J = 6.0 Hz), 7.21 (2H, brs).
69% With triethylamine In ethanol at 70℃; for 4 h; Step 1
A solution (100 mL) of 2,5-dihydroxy-1,4-dithiane (11.8 g, 155 mmol), cyanoacetamide (17.0 g, 202 mmol) and triethylamine (20 mL) in EtOH was heated at 70° C. for 4 hrs.
The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to about a half amount of the solution.
Water was added to the concentrated residue and the precipitated insoluble material was collected by filtration.
The solid was washed with water to give 2-amino-3-thiophenecarboxylic amide as a brown powder (15.3 g, 69percent).
1H-NMR (200 MHz, DMSO-d6)
δ: 6.22 (1H, d, J=6.0 Hz), 7.04 (1H, d, J=6.0 Hz), 7.21 (2H, bs).
64% With triethylamine In ethanol at 70℃; for 1 h; l,4-dithian-2,5-diol (4.56g, 30mmole) and 2-cyanoacetamide (2.52 g, 30 mmole) were combined in ethanol (50 ml). Triethylamine (6 ml) was added and heated to 70°C for 1 hour. The volume of solvent was reduced under vacuum, and the product was isolated by filtration. Product was recrystallized from ethanol to give 2.7 Ig of product (yield 64percent)
63% With triethylamine In 2,2,2-trifluoroethanol at 60℃; for 6.5 h; Microwave irradiation General procedure: In a 2–5 mL microwave vial was added the nitrile (0.22 mmol, 1 equiv) and trifluoroethanol (2 mL) which was stirring for 2 min to dissolve. Next, 1,4-dithian-2,5-diol (0.11 mmol, 0.5 equiv) was then added and stirred for 5 min before triethylamine(0.242 mmol; 1.1 equiv) was added and the mixture further stirred for 2 min. The vial was then sealed and heated in the microwave for 390 min at 60 °C. The solvent was evaporated under vacuo and the crude residue was then purified using flash chromatography on silica (EtOAc/hexanes).
53% With triethylamine In ethanol at 20℃; for 3.08333 h; Reflux Example 15: Synthesis of 3-methylthiopheno[2,3-d]l,2,3-triazin-4-one (compound 15); Step a:2-An.inothiophene-3-carboxan.ide: To a solution of 2,5-dihydroxy-l,4-dithiane (10 g, 65.78 mmol) in ethanol (200 mL) and triethylamine (2 mL) was added cyanoacetamide (5.52 g, 65.78 mmol) at rt for 5 min. The reaction mixture was refluxed for 3 h and attained to rt. Ethanol (appr. 150 mL) was removed under reduced pressure and poured the contents into ice cold water and stirred for 15 min. The solution was extracted with ethyl acetate (3 x 100 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a pale yellow color solid (4.9 g, 53percent), mp 150-152 0C.
53% With triethylamine In ethanol at 20℃; for 3.08333 h; Reflux Step a:; 2-Aminothiophene-3-carboxamide:; To a solution of 2,5-dihydroxy-1,4-dithiane (10 g, 65.78 mmol) in ethanol (200 mL) and triethylamine (2 mL) was added cyanoacetamide (5.52 g, 65.78 mmol) at rt for 5 min. The reaction mixture was refluxed for 3 h and attained to rt. Ethanol (appr. 150 mL) was removed under reduced pressure and poured the contents into ice cold water and stirred for 15 min. The solution was extracted with ethyl acetate (3.x.100 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a pale yellow color solid (4.9 g, 53percent), mp 150-152° C.

Reference: [1] Patent: WO2003/104218, 2003, A1, . Location in patent: Page 13
[2] Synthesis (Germany), 2013, vol. 45, # 1, p. 45 - 52
[3] Patent: WO2012/30894, 2012, A1, . Location in patent: Page/Page column 87
[4] Tetrahedron Letters, 2007, vol. 48, # 30, p. 5261 - 5264
[5] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6734 - 6750
[6] Patent: EP1953148, 2008, A1, . Location in patent: Page/Page column 133
[7] Patent: US2015/329556, 2015, A1, . Location in patent: Paragraph 1622-1624
[8] Patent: WO2006/35061, 2006, A1, . Location in patent: Page/Page column 44
[9] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 875 - 883
[10] Patent: WO2010/29577, 2010, A2, . Location in patent: Page/Page column 43
[11] Patent: US2010/68178, 2010, A1, . Location in patent: Page/Page column 18
[12] Patent: US2002/107252, 2002, A1,
[13] Patent: US2008/32988, 2008, A1, . Location in patent: Page/Page column 21
[14] Patent: US2003/207900, 2003, A1, . Location in patent: Page/Page column 18
  • 31
  • [ 107-91-5 ]
  • [ 14080-51-4 ]
YieldReaction ConditionsOperation in experiment
51% With triethylamine In ethanol at 70℃; for 2 h; Example 442-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahvdro--//-/-indazole-1-yl)acetamido)thiophene-3- carboxamidea) 2-aminothiophene-3-carboxamideA solution of 2,5-dihydroxy-1 ,4-dithiane (5.83 g, 38.3 mmol), 2-cyanoacetamide (8.4 g, 99.1 mmol) and triethylamine (10 mL, 71.9 mmol) in EtOH (30 mL) was heated at 70 0C for 2 h then allowed to stand overnight. The reaction mixture was reduced by half in vacuo and the solution cooled with ice to produce a precipitate. The solid was filtered off, washing with heptane (200 mL) to give product as a brown solid (7.12 g, 50.1 mmol, 51 percent). 1 H NMR (400MHz, CD3OD): δ 6.21 (d, 1 H), 6.93 (d, 1 H).
Reference: [1] Patent: WO2008/3452, 2008, A1, . Location in patent: Page/Page column 42
  • 32
  • [ 6851-93-0 ]
  • [ 107-91-5 ]
  • [ 14080-51-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1996, vol. 39, # 8, p. 1635 - 1644
[2] Patent: US2004/24047, 2004, A1,
  • 33
  • [ 75-07-0 ]
  • [ 107-91-5 ]
  • [ 14080-51-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 19, p. 5753 - 5756
  • 34
  • [ 107-91-5 ]
  • [ 144-48-9 ]
Reference: [1] Tetrahedron, 2015, vol. 71, # 38, p. 6824 - 6831
  • 35
  • [ 67-63-0 ]
  • [ 107-91-5 ]
  • [ 13195-64-7 ]
Reference: [1] Journal of the Chinese Chemical Society, 2004, vol. 51, # 2, p. 359 - 362
[2] Journal of the Chinese Chemical Society, 2014, vol. 51, # 2, p. 359 - 362
  • 36
  • [ 453-72-5 ]
  • [ 107-91-5 ]
  • [ 110964-79-9 ]
YieldReaction ConditionsOperation in experiment
111 g
Stage #1: With sodium hydroxide In dimethyl sulfoxide at 310℃; for 3 h;
Stage #2: With dihydrogen peroxide In dimethyl sulfoxide for 3 h;
In 1000mL three-necked flask, 500mLDMSO, 40g NaOH, 41g cyano acetamide and 105g2- nitro-4-methanesulfonyl-fluorophenyl group, controlling the temperature of the reaction at 10 , the reaction was stirred for 3 hours. Added 122g40percent H2O2, 3 hours, quenched with hydrogen peroxide recovered by distillation of DMSO, water, salt acidified, precipitate a solid, the filter cake was dried to give 111g2- nitro-4-methanesulfonyl-benzoic acid.
Reference: [1] Patent: CN105712912, 2016, A, . Location in patent: Paragraph 0004; 0053; 0054
  • 37
  • [ 107-91-5 ]
  • [ 4540-33-4 ]
Reference: [1] Patent: US3948903, 1976, A,
  • 38
  • [ 1122-98-1 ]
  • [ 107-91-5 ]
  • [ 109-94-4 ]
  • [ 4540-33-4 ]
Reference: [1] Patent: US3948903, 1976, A,
  • 39
  • [ 107-91-5 ]
  • [ 109-94-4 ]
  • [ 5586-88-9 ]
  • [ 4540-33-4 ]
Reference: [1] Patent: US3948903, 1976, A,
  • 40
  • [ 41894-93-3 ]
  • [ 107-91-5 ]
  • [ 109-94-4 ]
  • [ 4540-33-4 ]
Reference: [1] Patent: US3948903, 1976, A,
  • 41
  • [ 6975-60-6 ]
  • [ 107-91-5 ]
  • [ 109-94-4 ]
  • [ 4540-33-4 ]
Reference: [1] Patent: US3948903, 1976, A,
  • 42
  • [ 5436-21-5 ]
  • [ 107-91-5 ]
  • [ 93271-59-1 ]
YieldReaction ConditionsOperation in experiment
45%
Stage #1: With ammonium acetate; acetic acid In toluene for 8 h; Reflux; Dean-Stark
Stage #2: With sulfuric acid In ethanol; water at 25 - 50℃; for 3 h;
A mixture of 4,4-dimethoxyl-2-butanone (2.0 g, 15.13 mmol), cyanoacetamide (1.6 g, 18.92 mmol), ammonium acetate (79.3 mg, 1.03 mmol), acetic acid (0.6 mL) in anhydrous toluene (12.4 mL) was refluxed under stirring for 8 h, removing the produced water by Dean-Stark apparatus. When this step was finished, the reaction mixture was evaporated under reduced pressure, the residual oil was cooled to room temperature and EtOH (7.0 mL) was added under stirring at 25 °C. After that, H2SO4 50percent (2.6 mL) was added slowly and the mixture was heated at 50 °C under stirring for 3 h. The reaction mixture was then cooled to 5 °C, and water (1.3 mL) was added slowly. The obtained brown solid was purified by crystallization in EtOH to obtain 2-hydroxy-3-cyano-4-methylpyridine 1 (0.900 g, yield: 45percent); mp: 233-236 °C. 1H NMR (400 MHz, DMSO): δ 12.58 (bs, 1H, NH), 8.04 (d, J = 7.4 Hz, 1H, H6 Py), 6.24 (d, J = 7.4 Hz, 1H, H5 Py), 2.31 (s, 3H, CH3).
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 154, p. 155 - 171
  • 43
  • [ 143193-92-4 ]
  • [ 107-91-5 ]
  • [ 72716-80-4 ]
YieldReaction ConditionsOperation in experiment
70% With piperidine; pyridine; acetic acid In water at 20℃; for 20 h; Reflux To a solution of 480mL of water (E / Z) -2- methyl-3-oxo-1-ene-1-ol Sodium (77.6g, 0.64mol) was added cyanoacetamide (49.0g, 0.70mol). To this mixture was added a solution of piperidine-acetic acid(From acetic acid (9.16g, 8.75mL, 0.15mol),21.2mL of water and pyridine (13.0g, 15.1mL, 0.15mol) was obtained), and the mixture was heated at reflux through 4h, then stirred at room temperature for 16h. Acetic acid (75.5g, 72mL, 1.26mol) was added to the reaction mixture, the precipitated pale yellow solid. The latter was filtered off with suction, washed with water and dried under reduced pressure at 2h at 55 . To give 66.4 g of (70percent of theory) of a pale yellow solid.
Reference: [1] Patent: CN105530814, 2016, A, . Location in patent: Paragraph 0328; 0329; 0330
[2] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 351 - 355
  • 44
  • [ 78-93-3 ]
  • [ 107-91-5 ]
  • [ 109-94-4 ]
  • [ 72716-80-4 ]
YieldReaction ConditionsOperation in experiment
54%
Stage #1: With sodium In diethyl ether at 20℃; Cooling with ice
Stage #2: at 20℃; for 0.1 h;
Stage #3: With piperidine; water; acetic acid In diethyl ether for 2 h; Reflux
General procedure: A substituted alkyl methyl ketone or cyclic ketone (1 equiv) and ethyl formate or ethyl acetic(1 equiv) was added dropwise to absolute ether solution of sodium metal (1 equiv) for 1 h whilemaintained below 20 C. After the addition, the reaction was allowed to stir in an ice bath untilthe sodium metal had disappeared. The precipitate was filtered, washed with absolute ether anddried to give the corresponding compound which was directly used for the next step without further purification. To a solution of previous product (1 equiv), and cyanoacetamide (1.05 equiv) in water was stirred6 min at room temperature. The mixture was added dropwise piperidine acetate solution (0.3 equiv),which was prepared from piperidine (1 equiv), acetic acid (1 equiv) and water (5 equiv). The solutionwas heated to reflux for 2 h. Then, the reactor was cooled to room temperature, and adjusted to pH 4 by 4 N hydrochloric acid. The resulting solid was filtered, respectively washed with water and ether,and dried to give the corresponding compound which was purified by recrystallizing using menthol as solvent.
Reference: [1] Molecules, 2018, vol. 23, # 7,
[2] Patent: EP2128163, 2009, A1, . Location in patent: Page/Page column 63-64
  • 45
  • [ 132247-74-6 ]
  • [ 107-91-5 ]
  • [ 72716-80-4 ]
YieldReaction ConditionsOperation in experiment
65.9%
Stage #1: With piperdinium acetate In water at 127℃; for 21 h; Heating / reflux
Stage #2: With acetic acid In water at 24 - 65℃;
Water (546 mL) was added to 2-methyl-3-oxobutanal sodium salt (1-013-01) (34.73 g), and to the reaction mixture was added 2-cyanoacetamide (23.91 g) and 1.76 mol/L piperidinium acetate (119.4 mL), and the reaction mixture was stirred under reflux in an oil bath at 127 °C. After 21 h, to the reaction mixture was added gradually dropwise acetic acid (42.7 mL) at 65 °C as internal temperature for 15 min. After the stirring was continued until internal temperature became to 24 °C, the resulting crystal was filtered, and washed with water to give 3-cyano-5,6-dimethyl-2-pyridone (1-013-02) (27.76 g, 65.9percent, m.p. 258-263 °C).1H NMR (300 MHz, DMSO): δ 1.98 (s, 3H), 2.23 (s, 3H), 7.95 (s, 1H), 12.45 (br s, 1H).
65.9%
Stage #1: at 127℃; for 21 h; Heating / reflux
Stage #2: With acetic acid In water at 65℃; for 0.25 h;
Water was added to 2-methyl-3-oxobutanal sodium salt (1-013-01) (34.73 g), and to the reaction mixture was added 2-cyanoacetamide (23.91 g) and 1.76 mol/L piperidinium acetate (119.4 mL), and the reaction mixture was stirred under reflux in an oil bath at 127 DEG C. After 21 h, to the reaction mixture was added gradually dropwise acetic acid (42.7 mL) at 65 DEG C as internal temperature for 15 min. After the stirring was continued until internal temperature became to 24 DEG C, the resulting crystal was filtered, and washed with water to give 3-cyano-5,6-dimethyl-2-pyridone (1-013-02) (27.76 g, 65.9percent, m.p. 258-263 DEG C).<1>H NMR (300 MHz, DMSO): delta 1.98 (s, 3H), 2.23 (s, 3H), 7.95 (s, 1H), 12.45 (br s, 1H).
33%
Stage #1: at 20℃; for 1 h;
Stage #2: With piperdinium acetate In water for 24 h; Heating / reflux
Step (ii): Synthesis of 2-oxo-l,2, dihydro-5,6-dimethyl pyridine-3-carbonitrile; Cyano acetamide (3.78 g, 0.237 mol) was added to a solution of the sodium salt of 3-formyl-2-butanone (5.00 g, 40.9 mmol) in water (100 niL), and this reaction was allowed to stir at room temperature for 1 h. Afterwards, a 2 M solution of piperidine acetate in water (10 mL) was added, and the reaction mixture was allowed to reflux for 24 h. This mixture was allowed to cool and was acidified with acetic acid. The suspension was filtered and the precipitate was washed with toluene. The filtrate was collected and was concentrated to afford a sticky residue, which was washed with diethyl ether followed by ethyl acetate, to afford the title compound (2.00 g), yield: 33 percent, as a light brown solid. Mp: 103 0C1H NMR (DMSO-rfft 200 MHz): d 12.44 (s, IH), 7.94 (s, IH), 2.23 (s, 3H), 1.98 (s, 3H) m/z (CI-MS): 148 (M+, 100percent)
Reference: [1] Patent: EP1477186, 2004, A1, . Location in patent: Page/Page column 28; 29
[2] Patent: EP1357111, 2003, A1, . Location in patent: Page/Page column 46
[3] Patent: WO2006/73973, 2006, A2, . Location in patent: Page/Page column 254-255
[4] Patent: WO2006/35967, 2006, A1, . Location in patent: Page/Page column 88-89
[5] Patent: WO2006/35967, 2006, A1, . Location in patent: Page/Page column 88-89
  • 46
  • [ 132247-74-6 ]
  • [ 107-91-5 ]
  • [ 72716-80-4 ]
Reference: [1] Nucleosides and Nucleotides, 1999, vol. 18, # 10, p. 2335 - 2343
  • 47
  • [ 106730-70-5 ]
  • [ 107-91-5 ]
  • [ 106730-54-5 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1556 - 1567
  • 48
  • [ 589-92-4 ]
  • [ 107-91-5 ]
  • [ 95211-68-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 14, p. 5336 - 5341
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4731 - 4735
  • 49
  • [ 120-92-3 ]
  • [ 107-91-5 ]
  • [ 77651-38-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 13, p. 5436 - 5445
[2] Mendeleev Communications, 2012, vol. 22, # 1, p. 15 - 17
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4337 - 4350
[4] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 16, p. 3763 - 3766
[5] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 568 - 576
  • 50
  • [ 120407-73-0 ]
  • [ 107-91-5 ]
  • [ 116548-04-0 ]
YieldReaction ConditionsOperation in experiment
70.4%
Stage #1: With sodium ethanolate In ethanol at 60℃; for 0.5 h;
Stage #2: for 5 h; Reflux
Cyanoacetamide (2.35 g, 0.028 mol) was taken in ethanol (50 mL) containing sodium ethoxide (shining sodium metal was dissolved in anhydrous ethanol at 0°C, 0.87 g, 0.038 mol) and raised the temperatureup to 60°C for 30 min, cooled to RT and 4-butoxy-1,1,1-trifluoro-but-3-en-2-one (5.0 g, 0.025 mol) was added drop-wise for 20 min. Reaction was allowed to reflux for 5 h and the overall reaction was monitored by TLC. After completion of the reaction, it was neutralized with 15percent HCl solution, residue was extracted with ethyl acetate, dried over anhydrous sodium sulphate and distilled under vacuum, the obtained residue was purified using 60-120 mesh silica gel column chromatography. Compound was eluted with 25percent ethyl acetate in n-hexane (1:3). Yield 70.4percent (Pale yellow solid). m.p. 210-11°C. FTIR (KBr): 2230 (CN), 1672 cm−1 (C=O); 1H NMR: (DMSO-d6, 300 MHz) δ ppm: 7.26 (d, J = 7.74, 1H, =CH-), δ 8.18 (d, J = 7.55, 1H, =CH-); 13C NMR (DMSO-d6, 75 MHz): δ 99.20(C-CN), 110.06 (Ar-C), 113.70 (CN), 119.52 (q, J = 275.09 Hz) (CF3), 144.58 (Ar-C), 146.81 (q, J = 35.21 Hz) (C-CF3), 163.58 (C=O); ESI-MS: m/z 189 (M+1), 211 (M + Na).
Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 11, p. 1361 - 1375
[2] Journal of Heterocyclic Chemistry, 2015, vol. 51, # 5, p. 1531 - 1535
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 18, p. 4427 - 4432
  • 51
  • [ 59938-06-6 ]
  • [ 107-91-5 ]
  • [ 116548-04-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8392 - 8408,17
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8392 - 8408
  • 52
  • [ 109317-78-4 ]
  • [ 107-91-5 ]
  • [ 116548-04-0 ]
Reference: [1] Helvetica Chimica Acta, 1988, vol. 71, # 3, p. 596 - 601
  • 53
  • [ 59938-06-6 ]
  • [ 107-91-5 ]
  • [ 116548-04-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 4, p. 803 - 806
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 13, p. 2905 - 2908
  • 54
  • [ 5067-24-3 ]
  • [ 107-91-5 ]
  • [ 491871-58-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 6, p. 1679 - 1683
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